MX2008008282A - Preparation of gamma-amino acids having affinity for the alpha-2-delta protein - Google Patents

Abstract

Disclosed are materials and methods for preparing optically activeγ-amino acids of Formula (I), which bind to the alpha-2-delta (α2δ) subunit of a calcium channel.

Description

PREPARATION OF GAMMA-AMINO ACIDS THAT HAVE AFFINITY FOR THE PROTEIN ALFA-2-DELTA DESCRIPTIVE MEMORY This invention relates to materials and methods for preparing optically active α-amino acids which bind to the alpha-2-delta (a2d) subunit of a calcium channel. These compounds, including their pharmaceutically acceptable salts, solvates and hydrates, are useful for treating vasomotor symptoms (hot flushes and night sweats), restless legs syndrome, fibromyalgia, epilepsy, pain and a variety of neurodegenerative, psychiatric and sleep disorders. WO-A-2000/076958 and U.S. Pat. No. 6,642,398 describe? -amino acids of the formula: or a pharmaceutically acceptable salt thereof in which: R1 is hydrogen, linear or branched alkyl of 1 to 6 carbon atoms or phenyl; R2 is linear or branched alkyl of 1 to 8 carbon atoms, linear or branched alkenyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylcycloalkyl, alkylalkoxy, alkyl-OH, alkylphenyl, alkylphenoxy, phenyl or substituted phenyl; and R1 is linear or branched alkyl of 1 to 6 carbon atoms or phenyl when R2 is methyl. These compounds, together with their pharmaceutically acceptable salts, solvates and hydrates, bind to the a2d subunit of a calcium channel and can be used to treat a variety of disorders, medical conditions and diseases including, among others, epilepsy, pain (e.g. , acute and chronic pain, neuropathic pain and psychogenic pain), neurodegenerative disorders (for example, acute brain injury as a consequence of stroke, head trauma and asphyxia), psychiatric disorders (for example, anxiety and depression) and sleep disorders (for example , insomnia, insomnia associated with drugs, hypersomnia, narcolepsy, sleep apnea and parasomnias). WO-A-2004/054566 describes the use of these compounds in a method of treating a disorder selected from obsessive-compulsive disorder (OCD), phobias, post-traumatic stress disorder (PTSD), restless leg syndromes, disorder premenstrual dysphoric, hot flushes and fibromyalgia. Many of the α-amino acids described in WO-A-2000/076958 are optically active. Some of the following compounds possess two or more stereogenic (chiral) centers, which makes their preparation a challenge. Although WO-A-2000/076958 describes methods useful for preparing optically active α-amino acids, Some of the procedures can be problematic for pilot scale or large scale production due to efficiency or cost issues. Thus, improved methods for preparing optically active α-amino acids will be desirable. The present invention provides improved methods for preparing compounds of formula 1 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R1 and R2 are each independently selected from hydrogen and C1-3alkyl, with the proviso that when R1 is hydrogen, R2 is not hydrogen; R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, aryl and arylalkyl C? -3, wherein each aryl moiety is optionally substituted with to three substituents independently selected from C-? -3 alkyl, C -3 alkoxy, amino, C? .3-amino alkyl and halogen, and wherein each of the alkyl, alkenyl, cycloalkyl and alkoxy moieties previously menti are optionally substituted with to three fluorine atoms.

The methods provided by the present invention can be more profitable or efficient than the known procedures and require smaller volumes of solvents. aspect of the invention provides, as modality A, a process for preparing a compound of formula 10 or a salt of the same, and a compound of formula 11 or a salt thereof: 1 1 10 which comprises: (a) contacting a compound of formula 7 with an enzyme, in which the enzyme hydrolyzes diastereoselectively the compound of formula 7 to the compound of formula or a salt thereof, or to the compound of formula 11 or a salt thereof; (b) isolating the compound of formula 10, a diastereomer thereof or a salt thereof; Y (c) optionally hydrolyzing the compound of formula 10 or 11, providing the free carboxylic acid, wherein R1 and R2 are each independently selected from hydrogen and C-? -3 alkyl, with the proviso that R1 and R2 are not both hydrogen; R 3 is selected from C 2-6 alkenyl C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-d 6 alkyl, d 6 alkoxy, aryl and C 1-3 arylalkyl, wherein each aryl moiety is optionally substituted with one to three substituents independently selected from C 1 alkyl, C 1 - 3 alkoxy, amino, C 1 - 3 - amino alkyl and halogen; and wherein each of the aforementioned alkyl, alkenyl, cycloalkyl and alkoxy moieties is optionally substituted with one to three fluorine atoms; R6 in formula 7 is selected from alkyl C? -6 > C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3- cycloalkenyl, C6-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, arylalkyl C-uß, arylalkenylC2_6 and arylalkynylC2-6; and R8 and R9 in formula 10 and 11 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- cycloalkyl, C3-7 cycloalkenyl, C6-6 haloalkyl, C2 haloalkenyl -6, C2-6 haloalkynyl, C1.6 arylalkyl, C2-6 arylalkenyl and C2-6 arylalkynyl, with the proviso that R8 and R9 are not both hydrogen; and wherein each of the aforementioned aryl moieties can be optionally substituted with one to three substituents independently selected from C? -3 alkyl, C? -3 alkoxy, amino, C? -3-amino alkyl and halogen. As a mode A1, the invention provides a process for preparing a compound of formula 10 or a salt thereof: wherein R1 and R2 are each independently selected from hydrogen and C1.3alkyl, with the proviso that when R1 is hydrogen, R2 is not hydrogen; R 3 is selected from d-β alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy aryl, and C 1-3 arylalkyl, wherein each aryl moiety is optionally substituted with one to three substituents independently selected from d-3 alkyl, C? -3 amino alkoxy, C? -3-amino alkyl and halogen, and wherein each of the aforementioned alkyl, alkenyl, cycloalkyl and alkoxy moieties it is optionally substituted with one to three fluorine atoms; and R8 is selected from C6-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3- cycloalkenyl, C6-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, arylalkyl d-6 , C2-6 arylalkenyl and C2-6 arylalkynyl, and wherein each of the aforementioned aryl moieties can be optionally substituted with one to three substituents independently selected from alkyl d-3, alkoxy d-3, amino, alkyl and halogen; and wherein said method comprises: (a) contacting a compound of formula 7 with an enzyme, wherein the enzyme hydrolyzes diastereoselectively the compound of formula 7 to the compound of formula 11a: 7Ha where R1, R2 and R3 are as defined for a compound of formula 10; and R6 in formula 7 is selected from d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C3-7 cycloalkenyl, d-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, arylalkyl d.6, C2-6 arylalkenyl and C2-6 arylalkynyl, and wherein each of the aforementioned aryl moieties may be optionally substituted with one to three substituents independently selected from C1-3alkyl, d -3alkoxy, amino, alkyl d-3-amino and halogen; and (b) isolating the compound of formula 10. As mode A2, the invention provides a process as defined in mode A, wherein R9 is hydrogen. As an A3 mode, the invention provides a method as defined in embodiment A, A1 or A2, wherein R6 and R8 are independently selected from C6-6alkyl preferably methyl, ethyl, n-propyl and isopropyl; most preferably methyl and ethyl. As an A4 mode, the invention provides a method as defined in the mode A, A1, A2 or A3, wherein R1 and R2 are each independently hydrogen or methyl, with the proviso that R1 and R2 are not both hydrogen, and R3 is C1-6 alkyl, preferably R1 is hydrogen, R2 is methyl and R3 is methyl, ethyl, n-propyl or isopropyl; most preferably, R1 is hydrogen, R2 is methyl and R3 is ethyl. As the A5 modality, the invention provides a method as defined in the A, A1, A2, A3 or A4 modality, in which the enzyme in step (a) is a lipase, preferably the enzyme is a lipase of the microorganism Burkholderia cepacia or of the microorganism Thermomyces lan? ginosus. As the A6 modality, the invention provides a method as defined in the embodiment A1, A2, A3, A4 or A5, wherein the method further comprises the step of: (c) optionally converting the compound of formula 10 to a salt of the same, preferably in an alkali metal salt thereof; most preferably in the sodium salt thereof. A further aspect of the invention provides, as a modality A7, a process for preparing a compound of formula 10a, or a salt thereof: 10a in which R1, R2 and R3 are as defined in embodiments A or A3. The method comprises the steps of (a) contacting a compound of formula 7 7 with an enzyme, providing a compound of formula 10 or a salt thereof, and a compound of formula 11 or a salt thereof, p wherein the enzyme diastereoselectively hydrolyzes the compound of formula 7 to the compound of formula 10 or a salt thereof, or to the compound of formula 11 or a salt thereof; (b) isolating the compound of formula 10 or a salt thereof; and (c) optionally hydrolyzing the compound of formula 10, to provide the compound of formula 10a, wherein R1, R2 and R3, in formula 7, formula 10 and formula 11 are as defined for formula 1 above; R6 in formula 7 is selected from alkyl d-6, alkenyl C2-6, alkynyl C2-6, cycloalkyl C3-7, cycloalkenyl C3-7, haloalkyl d-6, haloalkenyl C2_6, haloalkynyl C2-6, arylalkyl C1-6 , C2-6 arylalkenyl and C2-6 arylalkynyl; and R8 and R9 in formula 10 and 11 are each independently selected from hydrogen, d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3- cycloalkenyl, d6 haloalkyl, C2- haloalkenyl 6, C2-6 haloalkynyl, arylalkyl d-6, arylalkenyl C2.6 and arylalkynyl C2-6; wherein each of the aforementioned aryl moieties is optionally substituted with one to three substituents independently selected from C 1-3 alkyl, C 1-3 alkoxy, amino, C 1 .3-amino alkyl and halogen. The invention additionally provides, as a B-modality, a compound of formula 7 as defined above in the A, A1 or A4 modality, preferably R6 is C1-6 alkyl, more preferably R6 is methyl, ethyl, n-propyl or isopropyl. In the B1 embodiment, the invention provides a compound of formula 7 selected from: (2'R) -2-cyano-2- (2'-methylbutyl) succinic acid diethyl ester; (2'f?) - 2-cyano-2- (2'-methylpentyl) succinic acid diethyl ester; (2'R) -2-cyano-2- (2'-methylhexyl) succinic acid diethyl ester; (2 '?) - 2-cyano-2- (2', 4'-dimethylpentyl) succinic acid diethyl ester; ethyl ester of (5f?) - 3-cyano-5-methylheptanoic acid; ethyl ester of (5f?) - 3-cyano-5-methyloctanoic acid; ethyl ester of (5f?) - 3-cyano-5-methylnonanoic acid; (5R) -3-cyano-5,7-dimethyloctanoic acid ethyl ester; (5f?) - 3-cyano-5-methylheptanoic acid; (5f?) - 3-cyano-5-methyloctanoic acid; (5f?) - 3-cyano-5-methylnonanoic acid; (5R) -3-cyano-5,7-dimethyloctanoic acid; (3S, 5f?) - 3-cyano-5-methylheptanoic acid; (3S, 5R) -3-cyano-5-methyloctanoic acid; (3S, 5R) -3-cyano-5-methylnonanoic acid; (3S, 5f?) - 3-cyano-5J-dimethyloctanoic acid; ethyl ester of (3S, 5R) -3-cyano-5-methylheptanoic acid; ethyl ester of the acid (SS.S / ^ - S-cyano-d-methyloctanoic acid) (3S, 5f?) - 3-cyano-5-methyloctanoic acid methyl ester; (3S, 5R) -3- ethyl ester cyano-5-methylnonanoic acid (3S, 5f?) - 3-cyano-5,7-dimethyloctanoic acid ethyl ester (3R, 5f?) - 3-cyano-5-methylheptanoic acid; (3f?, 5f?) - 3-cyano-5-methyloctanoic acid; (3R, 5f?) - 3-cyano-5-methylnonanoic acid; (3R, 5R) -3-cyano-5,7-dimethyloctanoic acid; ethyl ester of (3f?, 5f?) - 3-cyano-5-methylheptanoic acid; ethyl ester of (3?, 5f?) - 3-cyano-5-methyloctanoic acid; ethyl ester of (3f?, 5f?) - 3-cyano-5-methylnonanoic acid; ethyl ester of (3f?, 5f?) - 3-cyano-5,7-dimethyloctanoic acid; and diastereomers and opposite enantiomers of the aforementioned compounds, and salts of the aforementioned compounds, their diastereomers and opposite enantiomers. As mode B2, the invention provides a compound of formula 10 selected from: (3S, 5R) -3-cyano-5-methylheptanoic acid; (3S, 5R) -3-cyano-5-methyloctanoic acid; (3S, 5f?) - 3-cyano-5-methylnonanoic acid; acid (SS.d / ^ - S-cyano-SJ-dimethyloctanoic acid ethyl ester of (3S, 5 /?) - 3-cyano-5-methylheptanoic acid, ethyl ester of (3S, 5R) -3-cyano- 5-methyloctanoic acid (3S, 5R) -3-cyano-5-methyloctanoic acid methyl ester (3S, 5f?) - 3-cyano-5-methylnonanoic acid ethyl ester (3S, 5f? ) -3-cyano-5,7-dimethyloctanoic acid, and the salts and esters thereof As a B3 modality, the invention provides the compound (3S, 5f?) - 3-cyano-5-methyloctanoic acid or a salt or ester thereof (compounds of formula 10b): 10b wherein R8 is selected from hydrogen, d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-C7 cycloalkenyl, d-6 haloalkyl, C2-6 haloalkenyl, C2.6 haloalkynyl, C 1-6 arylalkyl, C 2-6 arylalkenyl and C 2-6 arylalkynyl, and wherein each of the aforementioned aryl moieties may be optionally substituted with one to three substituents independently selected from d 3 alkyl, C 1-3 alkoxy, amino , C C. 3-amino alkyl and halogen, and salts thereof. Preferably, the ester thereof is a compound of formula 10b wherein R8b is alkyl d.6, more preferably R8b is methyl or ethyl. Preferably, the salt thereof is an alkali metal salt of (3S, 5R) -3-cyano-5-methyloctanoic acid, more preferably the sodium salt thereof. The invention further provides, as mode C, a process for preparing a compound of formula 7 or a salt thereof: wherein R1, R2, R3 are as defined in mode B, and R6 is alkyl Ci-e; and wherein said method comprises (a) reacting a compound of formula 19 with an orthoester compound of formula 20 in the presence of a base 19 wherein R1, R2, R3 and R6 are as defined above for a compound of formula 7; and X2 is halogen; and (b) hydrolyzing the resulting orthoester intermediate yielding the carboxylic ester of formula 7. The invention further provides, as a D-mode, a process for the preparation of a compound of formula 1, as defined above, a diastereomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate complex thereof, comprising the steps (a) to (c) of the process as defined in mode A, A6 or A7, and further comprises the steps of: (d) reducing the cyano residue of a compound of formula 10, or a salt thereof: Wherein R1, R2 and R3 in formula 10 are as defined for a compound of formula 1 and R8 is as defined in mode A; and (e) further optionally converting the compound of formula 1 or a salt thereof into a pharmaceutically acceptable salt, solvate or hydrate thereof. As a D1 modality, the invention provides a process for the preparation of a compound of formula 1, as defined above, or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising steps (a) to (c) of the process as they are defined in the A6 modality, and further comprises the steps of: (d) reducing the cyano residue of the salt of the compound of formula 10, providing a salt of the compound of formula 1; and (e) additionally optionally converting the resulting salt of the compound of formula 1 or into a pharmaceutically acceptable salt, solvate or hydrate. acceptable of it. As a D2 embodiment, the invention provides a method as defined in the D1 mode, wherein in step (c), the compound of formula 10 is converted to an alkali metal salt, most preferably the sodium salt. As mode D3, the invention provides a method as defined in claim D, wherein in step (e) the resulting salt is converted to the free acid of formula 1. The invention further relates to a process for preparing a compound of formula 1, as defined above, including a diastereomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising steps (a) to (c) of the process as defined in mode A, and further comprises the steps of: (d) reducing a cyano residue of a compound of formula 8 Or a salt thereof, providing a compound of formula 9 or a salt thereof, wherein R 1, R 2 and R 3 in formula 8 and formula 9 are as defined for formula 1; (b) optionally, treating a salt of the compound of formula 9 with an acid; (c) solving the compound of formula 9 or a salt thereof; and (d) optionally converting the compound of formula 1 or a salt thereof into a pharmaceutically acceptable complex, salt, solvate or hydrate thereof. A further aspect of the invention provides a compound of formula 19, 19 including salts thereof, wherein R1, R2 and R3 are as defined for formula 1 above. R8 is selected from hydrogen, C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C3_7 cycloalkenyl, haloalkyl d-6, C 2-6 haloalkenyl, C 2-6 haloalkynyl, arylalkyl d-6, arylalkenyl C 2-6 and arylalkynyl C 2-6; R12 is hydrogen or -C (O) OR7; and R7 is selected from alkyl d-6, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, arylalkyl d-6, arylalkenyl C2 -6 and C2-6 arylalkynyl, wherein each of the aforementioned aryl moieties is optionally substituted with one to three substituents independently selected from d-3 alkyl, d-3 alkoxy, amino, C C-3-amino alkyl and halogen; and wherein each of the aforementioned alkyl, alkenyl, cycloalkyl and alkoxy moieties is optionally substituted with one to three fluorine atoms. A further aspect of the invention provides compounds of formula 7, formula 8, formula 10, formula 11 and formula 10a above, selected from: (2'f?) - 2-cyano-2- (2'-methylbutyl) diethyl ester ) succinic; (2'f?) - 2-cyano-2- (2'-methylpentyl) succinic acid diethyl ester; (2'f?) - 2-cyano-2- (2'-methylhexyl) succinic acid diethyl ester; (2'R) -2-cyano-2- (2 ', 4'-dimethylpentyl) succinic acid diethyl ester; ethyl ester of (5f?) - 3-cyano-5-methylheptanoic acid; ethyl ester of (5f?) - 3-cyano-5-methyloctanoic acid; ethyl ester of (5f?) - 3-cyano-5-methylnonanoic acid; (5R) -3-cyano-5,7-dimethyloctanoic acid ethyl ester; (5f?) - 3-cyano-5-methylheptanoic acid; (5f?) - 3-cyano-5-methyloctanoic acid; (5f?) - 3-cyano-5-methylnonanoic acid; (5f?) - 3-cyano-5,7-dimethyloctanoic acid; (3S, 5R) -3-cyano-5-methylheptanoic acid; acid (SS.S ^ -S-cyano-d-methyloctanoic; (3S, 5R) -3-cyano-5-methylnonanoic acid; (3S, 5f?) - 3-cyano-5J-dimethyloctanoic acid; ethyl ester of acid (3S, 5R) -3-cyano-5-methylheptanoic acid (3S, 5ft) -3-cyano-5-methyloctanoic acid ethyl ester (3S, 5?) - 3-cyano-5-methylnonanoic acid ethyl ester (3S, 5f?) - 3-cyano-5,7-dimethyloctanoic acid ethyl ester, (3f?, 5f?) - 3-cyano-5-methylheptanoic acid, (3 5f?) - 3-cyano- 5-methyloctanoic acid (SR.S / ^ - S-cyano-d-methylnonanoic acid (3R, 5) -3-cyano-5,7-dimethyloctane, ethyl ester of (3f?, 5f?) Acid -3-cyano-5-methylheptanoic acid (3R, 5f?) - 3-cyano-5-methyloctanoic acid ethyl ester (3f?, 5f?) - 3-cyano-5-methylnonanoic acid ethyl ester; of (3R, 5f?) - 3-cyano-5,7-dimethyloctanoic acid, and the salts thereof The invention further provides, as mode E, (3S, 5f?) - 3-aminomethyl-5-acid -methyl methanoic acid essentially pure in Form A, which is characterized by a powder X-ray diffraction pattern (PXRD) obtained by irradiation with CuKa radiation that includes peaks at 7.7, 15.8, 20.8 and 23.1 ° angle 2 teta ± 0.2 °. As E1 modality, the invention provides crystalline (3S, 5) -3-aminomethyl-5-methyloctanoic acid essentially pure in A form, which is characterized by a differential scanning calorimetry (DSC) thermogram showing a single maximum endothermic peak narrow at 194 ° C ± 2 ° C. As E2 mode, the invention provides crystalline (3S, 5R) -3-aminomethyl-5-methyloctanoic acid essentially pure in A form, which is characterized by a Fourier transform infrared (FT-IR) spectrum including absorption bands at 1006 and 894 cm "1. As E3 mode, the invention provides crystalline (3S, 5f?) - 3-aminomethyl-5-methyloctanoic acid essentially pure in form A, which is characterized by a Fourier transform Raman spectrum ( FT-Raman) that includes absorption bands at 1550, 595 and 386 cm "1. The term "essentially pure" when used herein means at least 95% by weight of purity. More preferably, "essentially pure" means at least 98% by weight of purity, and most preferably means at least 99% by weight of purity. As E4 mode, the invention provides (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A for use as a medicament. As E5 modality, the invention provides (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A for use in the treatment of a disease or disorder for which an alpha-2-delta receptor ligand is indicated, particularly for the treatment of a disease or disorder selected from epilepsy, pain (eg, acute and chronic pain, neuropathic pain and psychogenic pain), neurodegenerative disorders (eg, acute brain injury as a result of stroke, brain trauma and asphyxia), psychiatric disorders (eg, anxiety and depression), sleep disorders (eg, insomnia, drug-induced insomnia, hypersomnia, narcolepsy, sleep apnea) and parasomnias), obsessive-compulsive disorder (OCD), phobias, post-traumatic stress disorder (PTSD), restless legs syndrome, premenstrual dysphoric disorder, vasomotor symptoms (hot flushes and night sweats) and fibromyalgia. As the E6 modality, the invention provides the use of (3S, 5f?) - 3-aminomethyl-5-methyloctanoic acid in form A in the manufacture of a medicament for the treatment of a disease or disorder for which a ligand is indicated. alpha-2-delta receptor, particularly for the treatment of a disease or disorder selected from epilepsy, pain (e.g., acute and chronic pain, neuropathic pain and psychogenic pain), neurodegenerative disorders (e.g., acute brain injury as a consequence of stroke) , brain trauma and asphyxia), psychiatric disorders (eg, anxiety and depression), sleep disorders (eg, insomnia, drug-induced insomnia, hypersomnia, narcolepsy, sleep apnea and parasomnias), obsessive-compulsive disorder (OCD) , phobias, post-traumatic stress disorder (PTSD), leg syndrome restlessness, premenstrual dysphoric disorder, vasomotor symptoms (hot flushes and night sweats) and fibromyalgia. As E7 modality, the invention provides a method of treating a disease or disorder for which an alpha-2-delta receptor ligand is indicated in a mammal, particularly for the treatment of a disease or disorder selected from epilepsy, pain (eg, example, acute and chronic pain, neuropathic pain and psychogenic pain), neurodegenerative disorders (eg, acute brain injury as a result of stroke, brain trauma and asphyxia), psychiatric disorders (eg, anxiety and depression), sleep disorders (eg, example, insomnia, insomnia associated with drugs, hypersomnia, narcolepsy, sleep apnea and parasomnias), obsessive-compulsive disorder (OCD), phobias, post-traumatic stress disorder (PTSD), restless legs syndrome, premenstrual dysphoric disorder, vasomotor symptoms (hot flushes and night sweats) and fibromyalgia, it comprises administering to a mammal in need of said treatment (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A. The treatment of vasomotor symptoms (hot flushes and night sweats) is a preferred use. As E8 modality, the invention provides a pharmaceutical composition that includes (3S, 5f?) - 3-aminomethyl-5-methyloctanoic acid in A form and one or more pharmaceutically acceptable excipients. As E9 mode, the invention provides a method to prepare acid (SS.S ^ -S-aminomethyl-d-methyloctanoic acid in form A by recrystallization from a solution of crude (3S, 5f?) - 3-aminomethyl-5-methyloctanoic acid in a mixture of ethanol and water or isopropyl alcohol (IPA) and water, more preferably from a solution of crude (3S, 5f?) - 3-aminomethyl-5-methyloctanoic acid in a 1: 1 by volume mixture of ethanol: water or a 1: 1 volume of IPA: water, most preferably from a solution of crude (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in a 1: 1 by volume mixture of ethanol: water The present invention includes all the complexes and salts, whether pharmaceutically acceptable or not, solvates, hydrates and polymorphic forms of the disclosed compounds Certain compounds may contain an alkenyl or cyclic group, so that cis / trans (or Z / E) stereoisomers are possible or they may contain a keto or oxime group, so that tautomerism may occur. The invention generally includes all Z / E isomers and tautomeric forms, whether or not they are pure, substantially pure or mixtures. Unless otherwise indicated, this description uses definitions provided below. Some of the definitions and formulas may include a dash ("-") to indicate a link between atoms or a point of attachment to a named or unnamed atom or group of atoms. Other definitions and formulas may include an equal sign ("=") or an identity symbol ("=") to indicate a double bond or triple bond, respectively. Certain formulas may also include one or more asterisks ("*") to indicate stereogenic centers (asymmetric or chiral), although the absence of an asterisk does not indicate that the compound lacks a stereocenter. Said formulas can designate the racemate or individual enantiomers or individual diastereomers, which may be pure, substantially pure or not. Other formulas may include one or more wavy links ("-"). When attached to a stereogenic center, the undulated links designate both stereoisomers, both individually and in mixtures. Likewise, when they are attached to a double bond, the wavy bonds indicate a Z-isomer, an E-isomer or a mixture of Z- and E-isomers. Some formulas may include a hyphen U = IZ "link to indicate a single or double bond. "Substituted" groups are those in which one or more hydrogen atoms have been replaced by one or more other atoms or groups of hydrogen, with the proviso that the valence requirements are met and that the substitution results in a compound chemically stable "Approximately", when used in relation to a measurable numerical variable, designates the indicated value of the variable and all the values of the variable that are within the experimental error of the indicated value (for example, within the confidence interval) 95% for the mean) or within ± 10 percent of the indicated value, whichever is greater. "Alkyl" designates straight and branched chain saturated hydrocarbon groups that have gene a specified number of carbon atoms (namely, alkyl d_3 designates an alkyl group having 1, 2 or 3 carbon atoms and alkyl d-6 designates an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, / ere-butyl, pent-1-yl, pent-2-yl, pent-3-yl, -methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethylethyl-1-yl, n-hexyl and the like. "Alkenyl" designates straight and branched chain hydrocarbon groups having one or more unsaturated carbon-carbon bonds, and generally having a specified number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3- buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl and the like. "Alkynyl" designates straight or branched chain hydrocarbon groups having one or more triple carbon-carbon bonds, and generally having a specified number of carbon atoms. Examples of the alkynyl group include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2- butin-1-yl and the like. "Alkoxy" designates alkyl-O-, alkenyl-O- and alkynyl-O-, wherein alkyl, alkenyl and alkynyl are defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy and the like. "Halo" and "halogen" can be used interchangeably and designate fluoro, chloro, bromo and iodo.

"Haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" designate, respectively, alkyl, alkenyl, alkynyl and alkoxy groups substituted with one or more halogen atoms, wherein alkyl, alkenyl, alkynyl and alkoxy are as defined previously. Examples of haloalkyl groups include trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, and the like. "Cycloalkyl" designates saturated monocyclic and bicyclic hydrocarbon rings having generally a specified number of carbon atoms comprising the ring (namely, C3-7 cycloalkyl designates a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members). The cycloalkyl may be attached to an original group or to a substrate at any ring atom, unless said binding violates the valence requirements. Likewise, the cycloalkyl groups may include one or more non-hydrogen substituents unless said substitution violates the valence requirements. Useful substituents include alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of bicyclic cycloalkyl groups include bicyclo [1.1.0] butyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.0] pentyl, bicyclo [2.1.1] hexyl, bicyclo [3, .1.0] hexyl, bicyclo [ 2.2.1] heptyl, bicyclo [3.2.0] heptyl, bicyclo [3.1.1] heptyl, bicyclo [4.1.0] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [4.1.1] octyl, bicyclo [3.3.0] octyl, bicyclo [4.2.0] octyl, bicyclo [ 3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.0] nonyl, bicyclo [3.3.2] decyl, bicyclo [4.2.2] decyl, bicyclo [4.3.1] decyl, bicyclo [ 4.4.0] decyl, bicyclo [3.3.3] undecyl, bicyclo [4.3.2] undecyl, bicyclo [4.3.3] dodecyl, and the like. "Cycloalkenyl" denotes monocyclic and bicyclic hydrocarbon rings having one or more unsaturated carbon-carbon bonds, and having generally a specified number of carbon atoms comprising the ring (specifically, C3.7 cycloalkenyl designates a cycloalkenyl group having 3, 4, 5, 6 or 7 carbon atoms as ring members). The cycloalkenyl may be attached to an original group or to a substrate at any ring atom, unless such binding violates the valence requirements. Likewise, the cycloalkenyl groups may include one or more non-hydrogen substituents unless said substitution violates the valence requirements. Useful substituents include alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkoxycarbonyl, alkanoyl, and halo, as defined above, and hydroxy, mercapto, nitro, and amino. "Aryl" and "arylene" designate monovalent and divalent aromatic groups, respectively, including 5 and 6 membered monocyclic aromatic groups containing 0 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of monocyclic aryl groups include phenyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and the like. The aryl and arylene groups also include bicyclic groups, tricyclic groups, etc., including the 5 and 6 membered fused rings described above. Examples of multicyclic aryl groups include naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, indolizinyl, and the like. The aryl and arylene groups may be attached to an original group or to a substrate at any ring atom, unless said binding violates the valence requirements. Likewise, the aryl and arylene groups may include one or more substituents other than hydrogen unless said substitution violates the valence requirements. Useful substituents include alkylalkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl and halo, as defined above, and hydroxy, mercapto, nitro, amino and alkylamino. "Arylalkyl" designates arylalkyl wherein aryl and alkyl are defined above. Examples include benzyl, fluorenylmethyl and the like. "Exiting group" refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions and addition-elimination reactions. The leaving groups can be nucleofugues, in which the group leaves with a pair of electrons that previously served as a link between the group protruding and the molecule, or they can be electrofugal, in which the group leaves without the pair of electrons. The ability of a nucleophilic outgoing group to exit depends on its basic strength, with the strongest bases being the worst outgoing groups. Common nucleophilic leaving groups include nitrogen (for example, diazonium salts), sulfonates, including alkylsulfonates (e.g., mesylate), fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate) and arylsulfonates (e.g., tosylate, brosylate) , closilato and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions and alkoxides. Some strong bases such as NH2 'and OH "can be made better leaving groups by treatment with an acid.The common electrofugal leaving groups include proton, CO2 and metals." Enantiomeric excess "or" ee "is a measure, for a given sample, of the excess of an enantiomer against a racemic sample of a chiral compound, and is expressed as a percentage.The enantiomeric excess is defined as 100 x (re -1) / (re +1), in which "re" is the ratio of the most abundant enantiomer to the least abundant enantiomer. "Diastereomeric excess" or "ed" is a measure, for a given sample, of the excess of a diastereomer against a sample having equal amounts of diastereomers, and is expressed as a percentage. The diastereomeric excess is defined as 100 x (rd-1) / (rd + 1), in which "rd" is the ratio of the most abundant diastereomer to the least abundant diastereomer. "Stereoselective", "enantioselective", "diastereoselective" and variants thereof designate a given process (e.g., hydrogenation) that provides more than one stereoisomer, enantiomer or diastereomer than the other, respectively. "High level of stereoselectivity", "high level of enantioselectivity", "high level of diastereoselectivity" and variants thereof designate a given process that provides products having an excess of a stereoisomer, enantiomer or diastereomer, comprising at least about one 90% of the products. For a pair of enantiomers or diastereomers, a high level of enantioselectivity or diastereoselectivity would correspond to an ee or ed of at least about 80%. "Stereoisomerically enriched", "enantiomerically enriched", "diastereomerically enriched" and variants thereof designate, respectively, a sample of a compound having more than one stereoisomer, enantiomer or diastereomer than the other. The degree of enrichment can be measured by the% of total product, or by a pair of enantiomers or diastereomers, by ee or ed. "Stereoisomers" of a specified compound designates the opposite enantiomer of the compound and any diastereomer or geometric isomer (Z / E) of the compound. For example, if the specified compound has stereochemical configuration S, R, Z, its stereoisomers will include its opposite enantiomer having R, S, Z configuration, its diastereomers having S, S, Z configuration and R, R, Z configuration and its geometric isomers having configuration S, R, E, configuration R, S, E, configuration S, S, E and configuration R, R, E. "Substantially pure stereoisomer", "substantially pure enantiomer", "substantially pure diastereomer" and variants thereof designate, respectively, a sample containing a stereoisomer, enantiomer or diastereomer, comprising at least about 95% of the sample. For pairs of enantiomers and diastereomers, a substantially pure enantiomer or diastereomer would correspond to samples having an ee or ed of about 90% or more. A "pure stereoisomer", "pure enantiomer", "pure diastereomer" and variants thereof designate, respectively, a sample containing a stereoisomer, enantiomer or diastereomer comprising at least about 99.5% of the sample. For pairs of enantiomers and diastereomers, a pure enantiomer or pure diastereomer would correspond to samples having an ee or ed of about 99% or more. "Opponent enantiomer" means a molecule that is a non-superimposable mirror image of a reference molecule, which can be obtained by inverting all the stereogenic centers of the reference molecule. For example, if the reference molecule has the absolute stereochemical configuration S, then the opposite enantiomer has absolute stereochemical configuration R. Similarly, if the reference molecule has an absolute stereochemical configuration S, S, then the opposite enantiomer has a stereochemistry configuration R, R, and so successively. "Enantioselectivity value" or "E" designates the ratio of specificity constants for each enantiomer (or for each stereoisomer of a pair of diastereomers) of a compound undergoing reaction or chemical conversion, and can be calculated (for the S-enantiomer) by from the expression:? s' SM ln 1 -? Q + ee.) \ n [\ -? (\ - ees)] KR! KRM ln 1 -? (I - eep) \ n [\ -? (\ + Ees)] wherein Ks and KR are the first order rate constants for the conversion of the S and R enantiomers, respectively; KS and KRM are the Michaelis constants for the S and R enantiomers, respectively; x is the conversion fraction of the substrate; eep and ees are the enantiomeric excess of product and substrate (reactive), respectively. "Lipase unit" or "UL" designates the amount of enzyme (in g) that releases 1 μmol of titratable butyric acid / min when contacted with tributyrin and an emulsifier (gum arabic) at 30 ° C and pH 7. " Solvate "designates a molecular complex comprising a compound disclosed or claimed and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (eg, ethanol). "Hydrate" means a solvate comprising a compound disclosed or claimed and a stoichiometric or non-stoichiometric amount of water. "Pharmaceutically complexed, salts, solvates or hydrates "acceptable" designates complexes, acid or base addition salts, solvates or hydrates of claimed and disclosed compounds that are within the scope of formal medical criteria, suitable for use in contact with the tissues of patients without toxicity, irritation, allergic response undue and similar, corresponding to a reasonable and efficient benefit / risk ratio for its intended use. "Precatalyst" or "catalyst precursor" means a compound or set of compounds that are converted into a catalyst before use. , alleviating, inhibiting the progression of, or preventing a disorder or condition to which the term applies, or preventing one or more symptoms of said disorder or condition. "Treatment" means the act of "treating", as defined immediately above. Table 1 lists the abbreviations used throughout the specification.

TABLE 1 List of abbreviations Abbreviation Description Ac Acetyl ACN acetonitplo Ac20 acetic anhydride ac aqueous (R, R) -BDPP (2R, 4R) - (+) - 2,4-b? S (d? Phen? Lfosf? No) pentane BES acid ? /,? / - b? s- (2-H? drox? et? l) -2-am? noetanesulfon? co (R) -BICHEP (R) - (-) - 2,2'-b? s (d? c? clohex? lfosfino) -6,6'-d? met? l-1, 1 '-b? phenol BICINE? /,? / - b? s- (2-h? drox? et ? l) gl? c? na (SS) -BICP (2S, 2'S) -b? s (d? phen? lfosf? no) - (1 S, 1 'S) -b? c? clopentane BIFUP 2.2 '-b? s (d? phen? lfosf? no) -4,4', 6,6'-tetraqu? s (tr? fluoromet? l) -1,1 '-b? phenol (R) - Tol-BINAP (R) - (+) - 2,2'-b? S (d? -p-tol? Lfosf? No) -1, 1'-b? Naphthol (S) -Tol-BINAP ( S) - (+) - 2,2'-b? S (d? -p-tol? Lfosf? No) -1, 1'-b? Naphthol (R) -BINAP (R) -2.2 '-b? s (d? phen? lphosfino) -1', 1-b? naphthl (S) -BINAP (S) -2,2'-b? s (d? phen? phosph? no) -1 ', 1-b? naft? lo BIPHEP 2,2'-b? s (d? phen? lfosf? no) -1, 1'-b? phenol (R) -MeO-BIPHEP ( R) - (6,6'-d? Methox? B? Phen? L-2,2'-d?) B? S (d? Phen? L phosphine) (R) -CI-MeO- ( R) - (+) - 5,5'-d? Chlor-6,6'-d? Methox? -2,2'-b? S (d? Phen? Lfosf? No) -1,1 '-b ? BIPHEP (S) -CI-MeO- (S) - (+) - 5,5'-d? chlor-6,6'-d phenol? methox? -2.2'-b? s (d? phen? lfosf? no) -1, 1'-b? phenol BIPHEP BisP * (S, S) -1, 2-b? s (ter- but? lmet? lfosf? no) ethane (+) - tetraMeBITIANP (S) - (+) - 2,2'-b? s (d? phen? lphosfino) -4,4 ', 6,6'-tetramet? l-3,3'-benzo [b] t? ofeno Bn benalo BnBr BnCI benzyl bromide, benzyl chloride Boc tert-butoxycarbonyl BOP benzotrol azol-1-? lox? tr? s hexafluorophosphate (d? met ? lam?) phosphono? (R) - (S) -BPPFA (-) - (R) -N, Nd? met? l-1 - ((S) -1 ', 2-b? s (d ? fen? lfosf? no) ferrocen? l) -et? lam? na (RR) -Et-BPE (+) - 1, 2, -b? s ((2R, 5R) -2,5-d? et ? lphospholane) ethane (R, R) - e-BPE (+) - 1, 2-b? s ((2R, 5R) -2,5-d? met? lfosfolano) ethane (SS) -BPPM (-) - (2S, 4S) -2-d? Phen? Lfosf? Nomet? L-4-d? Phen? Lfosf? No-1-tert-butox? Carbon? Lp? Rrol? D? Na Bs brosyl or p-bromobenzenesulfonyl Bu butyl n-BuLi n-butyl thio tere-Bu tere-butyl Bu4N + B- tetrabutylammon bromide tert-BuOK tert-butoxide potassium tert-BuLi tert-butoxide lithium terc-BuOMe tert- butylmethylether tert-BuONa sodium tert-butyloxide (+) - CAMP (R) - (+) - c? Clohex? l- (2-an? s? l) met? lfosf? na, a monophosphine CARBOPHOS aD-glucop? methyl-2,6-d-benzoate-3,4-d? (b? s (3,5-d? met? lfen? l) phosph? n? to) methyl Cbz benzyloxycarbonyl CDI N, N-carbon? Ld? M? Dazo X conversion fraction CnTunaPHOS 2,2'-b? Sd? Phen? Lfosfan? Lb? Phen? Which has a group -0- (CH2) n- 0- linking the carbon atoms 6,6 'of the biphenyl (for example (R) -1, 14-b? Sd? Phen? Lfosfan? L- 6,7,8,9-tetrah? Dro-5,10- d? oxad? benzo [a, c] c? clodecene for n = 4) COD 1, 5-c? clooctad? ene (R) -CYCPHOS (R) -1, 2-b? s (d? phen? lfosfino ) -1-c? Clohex? DABCO 1,4-d? Azab? C? Clo [2 2 2] octane DBAD azodicarboxylic acid di-tert-butyl ester DBN 1, 5-d? Azab? C? Clo [4? 3.0] non-5-ene DBU 1, 8-d? Azab? C? Clo [5 4,0] undec-7-ene DCC dicyclohexylcarbodnmide ed excess diastereomepco DEAD diethyl azodicarboxylate (R, R) -DEGUPHOS? -benzyl- (3R, 4R) -3,4-b? s (d? phen? lfosf? no) p? rrol? d? na DIAD dnsopropyl azodicarboxylate (R, R) -DIOP (4R, 5R) - (-) - 0-? Soprop? L? Den-2,3-d? H? Drox? -1, 4-b? S (d? Phen? Lphosfino) butane (RR) -DIPAMP (R, R) - (-) - 1, 2-b? S - [(0-methox? Phen?) (Phen? L) phosph?) Ethane DIPEA dnsopropylethylamine (Hunig's base) DMAP 4- (d? Met? Lam? No) ?? r? D? Na DMF dimethylformamide DMSO dimethylsulfoxide DMT-MM chloride 4- (4,6-d? Methox? -1, 3,5-tr? Az? n-2-? l) -4-methylmorphine (R, R) -Et-DUPHOS (-) - 1, 2-b? s - ((2R, 5R) -2,5-d ? et? lfosfolano) benzene (SS) -Et-DUPHOS (-) - 1, 2-b? s - ((2S, 5S) -2,5-d? et? lphospholane) benzene (RR) -? Pr- DUPHOS (+) - 1, 2-b? S - ((2R, 5R) -2,5-d? Soprop? Lphospholane) -benzene (RR) -Me-DUPHOS (-) - 1, 2-b? s - ((2R, 5R) -2,5-d? met? lfosfolano) benzene (SS) -Me-DUPHOS (-) - 1, 2-b? s - ((2S, 5S) -2,5- d? met? lfosfolano) benzene E Enantioselectivity value or ratio of specificity constants for each enantiomer of a compound undergoing chemical conversion reaction EDCI 1 - (3-d? met? lam? noprop? l) -3-et? lcarbod ??? ee (eep or ees) excess enantiomepco (of product or reagent) eq equivalents re ratio enantiomepca Et ethyl Et3N tpetilamina AcOEt ethyl acetate Et20 diethylether EtOH alcohol ethyl alcohol FDPP pentafluorophenyl diphenylphosphonate (R, R) -Et-FerroTANE 1, 1 '-b? s ((2R, 4R) -2,4-d? et? lphosphotano) ferrocene Fmoc 9-fluoroen? lmetox? carbon? GC gas chromatography h, min, s hour (s), m? nuto (s), second (s) HEPES acid 4- (2-h? drox? et? l) p? peraz? n-1-ethanesulfon Acetic Acid AcOH AtOH 1-hydroxy? -7-azabenzotr? azole BtOH? / - hydrox? benzotr? azol HODhbt 3-hydrox? -3,4-d? h? dro-4-oxo -1, 2,3-benzotpaz? Na HPLC high performance liquid chromatography lAcOEt ethyl iodoacetate IPA isopropanol i-PrOAc isopropyl acetate (R) - (R) -JOSIPHOS (R) - (-) - 1 - [(R ) -2- (d? Phen? Lfosf? No) ferrocen? L] et? Ld? C? Clo-hex? Lfosfina (S) - (S) -JOSIPHOS (S) - (-) - 1 - [(S ) -2- (d? Phen? Lphosfino) ferrocen? L] et? Ld? C? Clo-hexylphosphine (R) - (S) -JOSIPHOS (R) - (-) - 1 - [(S) - 2- (d? Phen? Lfosfino) ferrocen? L] et? Ld? C? Clo-hex? Lfosfina KHMDS potassium hexamethyldisilazane KF Karl Fischer s, KR constant speed of 1 order for the S or R KSM enantiomer, KRM constant of Michaehs for the enantiomer S or R LAH lithium aluminum hydride CL / EM liquid chromatography-mass spectrometry LDA lithium dnsopropylamide LHMDS lithium hexamethyldisilazane LICA lithium isopropylcyclohexylamide LTMP 2,2,6,6-tetramet? lp? per? d? na MeOH methyl alcohol UL unit lipase Me methyl MeCI2 methylene chloride Mel methyl iodide MEK methyl ethyl ketone or 2-butanone MeONa sodium methylated acid MES acid 2-morpholiethanesulfon? Co (R, R) -terc-but? Lm? N? PHOS ( R, R) -1, 2-b? S (d? -terc-but? Lmet? Lphosphino) methane (SS) -MandyPhos (S, S) - (-) - 2,2'-b? S [( R) - (N, Nd? Met? Lam? No) (fen? L) met? L] -1, 1'- b? S (d? Phen? Lfosf? No) ferrocene (R) -MonoPhos (R) - (-) - [4-N, Nd? Met? Lam? No] d? Naphtho [2,1-d 1 ', 2'- f] [1 3 2] d? Oxaphosfep? Na (R) -MOP (R) - (+) - 2- (d? Phen? Lfosf? No) -2'-methox? -1, 1'-b? Naphthole MOPS 3- (N-morpholone) propanesulfon? MPa megapascals Pf melting point Ms mesyl or methanesulfonyl MTBE methyl-tert-butylether NMP N-methylpyrrolidone Ns nosyl or nitrobenzenesulfonyl (RR) -NORPHOS (2R, 3R) - (-) - 2,3-b? S (d? Phen ? lfosf? no) b? c? [2 2 1] -5-heptene OTf-tpflato (tpfluoromethanesulfonic acid anion) PdCI2 (dppf) 2 d? chloro adduct [1, 1'-b? s (d? phenolphosphino) ferrocene) -palladium (II) and dichloromethane (R, S, R, S) -Me-PENNPHOS (1 R, 2S, 4R, 5S) -2,5-d? Met? L-7-phosphat? Cyclo [2 2 1] -heptane Ph phenyl Ph3P tpfenilina Ph3As tpfenilarsina (R) -PHANEPHOS (R) - (-) - 4,12-b? S (d? Phen? L? No) - [2 2] parac? Clofan (S) -PHANEPHOS (S) - (-) - 4,12-b? S (d? Phen? L? No) - [2 2] parac? Clofan (R) -PNNP N, N'-b? S - [(R) - (+) - a-met ? lbenc? l] -N, N'-bís (d? phen? l-ino) et? lend? am? na PPh2-PhOX-Ph (R) - (-) - 2- [2- (d? phen ? llno) fen? l] -4-phenH-2-oxazole? na PIPES p? peraz? n-1, 4-b? s- (2-ethanesulfonic) Pr propyl iPr Isopropyl (R) -PROPHOS (R) - (+) - 1, 2-b? S (d? Phen? L? No) propane PyBOP benzotr? Azole-1? -loxilr? Sp? Rrol? D? Noon hexafluorophosphate? (R) -QUINAP (R) - (+) - 1- (2-d? Phen? Lfosfino-1-naft? L)? Soqu? Nolma RaNi nickel Raney IR refractive index TA room temperature (approximately 20 ° C a 25 ° C) s / c molar ratio of substrate to catalyst sp Species (R) -Sp? ROP ester of acid (1 R, 5R, 6R) -sp? Ro [4 4] nonan-1, 6-diildyphenylphosphiny, a Spirocyte ligand of phosphinite (R, R, S, S) -TangPhos (R, R, S, S) -1, 1'-d? -terc-but? l- [2 2 '] b? phospholanum TAPS N- [tr? S (h? Drox? Met? L) met? L] -3-aminopropane-sulfon acid? TATU tetrafluoroborate of 0- (7-azabenzotrolol-1-? L) -1, 1, 3,3-tetramethyluronium (R) -eTCFP (R) -2-. { [(d? -terc-but? lfosfan? l) et? l] met? lfosfan? l} -2-met? Lpropane (S) -eTCFP (S) -2-. { [(d? -terc-but? lfosfan? l) et? l] met? lfosfan? l} -2-met? Lpropane (R) -mTCFP (R) -2-. { [(d? -terc-but? lfosfan? l) met? l] met? lfosfan? l} -2-met? Lpropane (S) -mTCFP (S) -2-. { [(d? -terc-but? lfosfan? l) met?] methylphosphan? l} -2-met? Lpropane TEA tpetanolamma TES acid N- [tps (h? Drox? Met? L) met? L] -2-aminoethane-sulfon? Co Tf triflil or tpfluoromethylsulfonyl TFA trifluoroacetic acid F tetrahydrofuran "LC thin layer chromatography" MEDA? /,? /,? / ', W-tetramet? L-1, 2-et? Lend? Am? Na "MS tpmetilsililo" r tptilo or tpfenilmetilo "RICINE / - [tps (h? drox? met? l) met?] gl? amp? amp Tris tampon tps (hydrox? met? l) amomethane "RITON B benzyltrimethylammonium hydroxide" RIZMA® 2-am? no -2- (h? Drox? Met? L) -1, 3-propanod? Ol s tosyl or p-toluenesulfonyl) -TSA para-toluenesulfonic acid '/ v percentage by volume) / p weight percentage Some of the following schemes and examples may omit details of common reactions, including oxidations, reductions and so forth, separation techniques and analytical procedures that are known to those skilled in the art of organic chemistry. Details of such reactions and techniques may be found in a series of treatises, including Richard Larock, "Comprehensive Organic Transformations" (1999) and the multi-volume series edited by Michael B Smith et al., "Compendium of Organic Synthetic Methods" (1974-2005) In many cases, the materials and reagents starting materials may be obtained from commercial sources or may be prepared using literature procedures. Some of the reaction schemes may omit minor products resulting from chemical transformations (eg, an alcohol from the hydrolysis of an ester, C02 from decarboxylation of a diacid, etc.) Also, in some cases, the int Reaction media can be used in later stages without isolation or purification (specifically, in situ) In some of the following reaction schemes and examples, Certain compounds can be prepared using protecting groups, which prevent an undesirable chemical reaction at sites that would otherwise be reactive. The protecting groups may also be used to enhance the solubility or otherwise modify the physical properties of a compound. For a discussion of protective group strategies, a description of the materials and methods for introducing and removing protecting groups and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes and the like, see TW Greene and P.G. Wuts, "Protecting Groups in Organic Chemistry" (1999) and P. Kocienski, "Protective Groups" (2000), which are incorporated herein by reference in their entirety for all purposes. Generally, the chemical transformations described throughout the specification can be carried out using substantially stoichiometric amounts of reagents, although certain reactions may benefit from using an excess of one or more of the reagents. Additionally, many of the reactions disclosed throughout the specification can be carried out at about room temperature and ambient pressure, but depending on the kinetics of the reaction, yields and the like, some reactions can be performed at high pressures or employ higher temperatures (for example, reflux conditions) or lower (for example, -70 ° C to 0 ° C). Many of the chemical transformations can also use one or more solvents compatible, which can influence the speed and performance of the reaction. Depending on the nature of the reagents, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents or some combination. Any reference in the description to a stoichiometric interval, a temperature range, a pH range, etc., expressly or not use the word "range", also includes the indicated ends. Generally, and unless otherwise indicated, when defining a particular substituent identifier (R1, R2, R3, etc.) for the first time in relation to a formula, the same substituent identifier, when used in a later formula , will have the same definition as in the previous formula. Thus, for example, if R30 in a first formula 1 is hydrogen, halogen or alkyl d. 6, then, unless otherwise stated or otherwise clear from the context of the text, R30 in a second formula 1 is also hydrogen, halogen or C? -6 alkyl- This description refers to materials and processes for preparing optically active α-amino acids of formula 1 above, as well as their stereoisomers (for example, diastereomers and opposite enantiomers) and their pharmaceutically acceptable complexes, salts, solvates and hydrates. The claimed and disclosed processes provide compounds of formula 1 (or their stereoisomers) which are stereoisomerically enriched and which, in many cases, are pure or substantially pure stereoisomers. For clarity, the specification describes procedures and materials for preparing intermediates and final products that have specific stereochemical configurations. However, by using starting materials, resolving agents, chiral catalysts, enzymes and the like having different stereochemical configurations, the methods for preparing the corresponding diastereomers and opposite enantiomers of the products and intermediates disclosed can be used. The compounds of formula 1 have at least two stereogenic centers, as designated by wedge bonds, and include the substituents R1, R2 and R3, which are defined above. The compounds of formula 1 include those in which R1 and R2 are each independently hydrogen or methyl, with the proviso that R1 and R2 are not both hydrogen, and those in which R3 is C1-6 alkyl, including methyl, ethyl, n-propyl or isopropyl. Representative compounds of formula 1 also include those in which R1 is hydrogen, R2 is methyl and R3 is methyl, ethyl, n-propyl or isopropyl, namely (3S, 5f?) - 3-aminomethyl-5-methylheptanoic acid, acid (3S, 5R) -3-aminomethyl-5-methyloctanoic, (3S, 5f?) -3-aminomethyl-5-methylnonanoic acid or (3S, 5f?) -3-aminomethyl-5,7-dimethyloctanoic acid. Representative diastereomers of the latter compounds are (3R, 5R) - or (3S, 5S) -3-aminomethyl-5-methylheptanoic acid, (3R, 5R) - or (3S, 5S) -3-aminomethyl-5-acid methyloctanoic acid (3R, 5R) - or (3S, 5S) -3-aminomethyl-5-methylnonanoic acid and (3R, 5R) - or (3S, 5S) -3-aminomethyl-5J-dimethyloctanoic acid; the representative opposing enantiomers are (3R, 5S) -3-aminomethyl-5-methylheptanoic acid, (3R, 5S) -3- aminomethyl-5-methyloctanoic acid (3f?, 5S) -3-aminomethyl-5-methylnonanoic acid and (3f?, 5S) -3-aminomethyl-5,7-dimethyloctanoic acid. Scheme I shows two processes for preparing compounds of formula 1. The methods include reacting a chiral alcohol (formula 2) with an activating agent (formula 3). The resulting activated alcohol (formula 4) is reacted with a diester of 2-cyanuccinic acid (formula 5) to provide a diester of 2-alkyl-2-cyanuccinic acid (formula 6) having a second stereogenic center, which is represented by wavy links. The ester moiety that is directly attached to the second asymmetric carbon atom (see formula 6) is subsequently cleaved, by providing a 3-cyanocarboxylic acid ester (formula 7), which is converted to the desired final product (formula 1) by contact with a resolving agent or an enzyme. In the first procedure, the ester (formula 7) is hydrolyzed, yielding a 3-cyanocarboxylic acid (formula 8) or salt. The reduction of cyano residue (see formula 8) provides, upon acidification (if necessary), an α-amino acid (formula 9) which is resolved by contact with a resolving agent (eg, a chiral acid), followed by separation of the salt or desired diastereomeric free amino acid (formula 1). Alternatively, a diastereomer of the monoester (formula 7) is hydrolyzed diastereoselectively by contact with an enzyme, which results in a mixture enriched in 3-cyanocarboxylic acid or ester having the necessary stereochemical configuration at C-3 (formula 10). The ester or acid (formula 10) is separates from the undesirable diastereomer (formula 11) and hydrolyzes (if necessary), providing a pure diastereomer, or substantially pure, of 3-cyanocarboxylic acid (formula 10a), or alternatively converted to a salt The reduction of the cyano moiety provides, after acid treatment (if the compound of formula 1 is necessary. excuse esler C °? idro zar .CfhR * 'i reduce CN esler R. 2 acidify "CN CN (if necessary) '3 enzyme 1 resolving agent 2 separating diastereomers H, 0 i 12 10 1 reduce the rest CN 2 convert in the free acid 12 Scheme 1 The substituents R1, R2 and R3 in formula 2, 4 and 6-12 are as defined for formula 1 above; the substituent R4 in the formula 3 is selected from tosyl, mesyl, brosyl, closyl (p-chlorobenzenesulfonyl), nosyl and triflyl; the substituent R5 in the formula 4 is a leaving group (for example, R4O-); and the substituent X1 in formula 3 is halogen (e.g., Cl) or R4O-. The substituents R6 and R7 in the formula 5-7 are each independently selected from C?-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C3-7 cycloalkenyl, C6-6 haloalkyl, haloalkenyl C2-6, C2-6 haloalkynyl, C6-6 arylalkyl, C2-6 arylalkenyl and C2-6 arylalkynyl. The substituents R8 and R9 in formula 10 and 11 are each independently selected from hydrogen, C-? 6 alkyl, C2-6 alkenyl, C2.6 alkynyl, C3-7 cycloalkyl, C3_7 cycloalkenyl, C1-6 haloalkyl, haloalkenyl C2-6, C2-6al haloalkynyl arylalkyl C6-6) arylalkenyl C2- and arylalkynyl C2.6. Each of the aforementioned aryl moieties can be optionally substituted with one to three substituents independently selected from C 1-3 alkyl, C 1 -C 3 alkoxy, amino, C 1 -C 3 alkylamino and halogen. X is a suitable counterion, preferably an alkali metal, more preferably sodium. The chiral alcohol (formula 2) shown in scheme 1 has a stereogenic center at C-2, as designated by the wedge bonds, and includes the substituents R1, R2 and R3, which are as defined above. The compounds of formula 2 include those in which R1 and R2 are independently each hydrogen or methyl, with the proviso that R1 and R2 are not both hydrogen, and those in which R3 is C6-C6 alkyl, including methyl, ethyl, n-propyl or isopropyl. Representative compounds of formula 2 also include those in which R1 is hydrogen, R2 is methyl and R3 is methyl, ethyl, n-propyl or isopropyl, namely, (f?) - 2-methyl-1-butanol, (R) - 2-methyl-1-pentanol, (R) -2-methyl-1-hexanol, or (f?) -2,4-dimethyl-1-pentanol. Representative opposing enantiomers of the latter compounds are (S) -2-methyl-1-butanol, (S) -2-methyl-1-pentanol, (S) -2-methyl-1-hexanol and (S) -2 , 4-dimethyl-1-pentanol. As shown in scheme 1, the hydroxy moiety of the chiral alcohol (formula 2) is activated by reaction with a compound of formula 3. The reaction is typically carried out in excess (eg, about 1.05 eq to about 1.1 eq) of activating agent (formula 3) at a temperature from about -25 ° C to about room temperature. Useful activating agents include sulfonylating agents such as TsCI, MsCI, BsCI, NsCI, TfCI and the like, and their corresponding anhydrides (e.g., p-toluenesulfonic acid anhydride). Thus, for example, the compounds of formula 2 can be reacted with TsCl in the presence of pyridine and an aprotic solvent such as AcOEt, MeCl2, ACN, THF and the like, yielding 2- (methyl) butyl methyl ester of (3-toluene-4-toluene) sulphonic, 2-methylpentyl ester of (R) -toluene-4-sulfonic acid, 2-methylhexyl ester of (f?) -toluene-4-sulfonic acid and 2,4-dimethylpentyl ester of (f?) -toluene- 4-sulfonic. Similarly, compounds of formula 2 can be reacted with MsCl in the presence of an aprotic solvent such as MTBE, toluene or MeCl 2 and a weak base such as Et 3 N, providing 2-methylbutyl ester of (R) -methanesulfonic acid, 2-methylpentyl ester of (R) -methanesulfonic acid, 2-methylhexyl ester of (R) -methanesulfonic acid and 2,4-dimethylpentyl ester of (R) - methanesulfonic After activation of the hydroxy moiety, the resulting intermediate (formula 4) is reacted with a diester of 2-cyano-succinic acid (formula 5) in the presence of a base and one or more solvents, yielding a diester of 2-alkyl-2-acid. -cyanosuccinic (formula 6). Representative compounds of formula 5 include diethyl ester of 2-cyanuccinic acid. Likewise, representative compounds of formula 6 include (2'f?) - 2-cyano-2- (2'-methylbutyl) succinic acid diethyl ester, (2'R) -2-cyano-2-diethyl ester (2'-methylpentyl) succinic, diethyl ester of (2'f?) - 2-cyano-2- (2'-methylhexyl) succinic acid and diethyl ester of (2'R) -2-cyano-2- ( 2 ', 4'-dimethylpentyl) succinic. The alkylation can be carried out at temperatures that are in the range of from about room temperature to reflux, from about 70 ° C to 110 ° C, or from about 90 ° C to about 100 ° C, using stoichiometric or excess amounts (per example, about 1 eq to about 1.5 eq) of base and diester (formula 5). Representative bases include metal carbonates of group 1 (for example, Cs2C03 and K2C03), metal phosphates of group 1 (by example, K3PO) and metal alkoxides of group 1 (for example, 21% NaOEt in EtOH), as well as sterically non-nucleophilic hindered bases such as Et3N, ferc-BuOK, DBN, DBU and the like. The reaction mixture may comprise a single organic phase or may comprise an aqueous phase, an organic phase and a phase transfer catalyst (for example, a tetraalkylammonium salt such as Bu4N + Br "). Representative organic solvents include protic solvents such as MeOH, EtOH, PrOH and other alcohols, polar aprotic solvents such as AcOEt, AcOiPr, THF, MeCl2 and ACN, and non-polar aromatic and aliphatic solvents such as toluene, heptane and the like. the ester residue which is directly attached to the second asymmetric carbon atom (see formula 6), yielding a 3-cyanocarboxylic acid ester (formula 7) such as (5R) -3-cyano-5-methylheptanoic acid ethyl ester, (5f?) - 3-cyano-5-methyloctanoic acid ethyl ester, (5f?) - 3-cyano-5-methylnonanoic acid ethyl ester and (5f?) - 3-cyano-5,7-ethyl ester -dimetiloctanoic ester it can be removed by reacting the diester (formula 6) with a chloride salt (eg, LiCI, NaCl, etc.) in a polar aprotic solvent such as aqueous DMSO, NMP and the like, at a temperature of about 135 ° C or higher ( conditions of Krapcho). Higher temperatures (eg, 150 ° C, 160 ° C or higher) or the use of a phase transfer catalyst (eg, Bu4N + Br ") can be used to reduce reaction times to 24 hours or less. , the reaction uses chloride salt in excess (eg, from about 1.1 eq to about 4 eq or from about 1.5 eq to about 3.5 eq). As shown in scheme 1 and observed above, the 3-cyanocarboxylic acid ester (formula 7) can be converted to the desired product (formula 1) by contact with a resolving agent. In this process, the ester (formula 7) is hydrolysed by contact with an aqueous acid or base, yielding a 3-cyanocarboxylic acid (formula 8) or salt. For example, the compound of formula 7 can be treated with HCl, H2SO and the like, and with excess of H20, providing the carboxylic acid of formula 8. Alternatively, the compound of formula 7 can be treated with an aqueous inorganic base such as LiOH, KOH, NaOH, CsOH, Na2CO3, K2CO3, Cs2C03 and the like, in an optional polar solvent (for example, THF, MeOH, EtOH, acetone, ACN, etc.), providing a base addition salt that can be treated with an acid , generating 3-cyanocarboxylic acid (formula 8). Representative compounds of formula 8 include (5R) -3-cyano-5-methylheptanoic acid, (5R) -3-cyano-5-methyloctanoic acid, (5R) -3-cyano-5-methylnonanoic acid and (5R) acid -3-cyano-5,7-dimethyloctanoic, and its salts. The cyano residue of the carboxylic acid (formula 8), or its corresponding salt, is subsequently reduced, providing, upon acid treatment if necessary, an α-amino acid (formula 9). The penultimate free acid can be obtained by treating a salt of the α-amino acid with a weak acid such as AcOH aq. Representative compounds of formula 9 include (5í) - 3-aminomethyl-5-methylheptanoic acid, (5f?) - 3-aminomethyl- -methyloctanoic, (5R) -3-aminomethyl-5-methylo-nanoic acid and (5f?) -3-aminomethyl-5,7-dimethyloctanoic acid and its salts. The cyano moiety can be reduced by reaction with H2 in the presence of a catalyst or by reaction with a reducing agent such as LiAIH4, BH3-Me2S and the like. In addition to Raney nickel and other sponge-type metal catalysts, potentially useful catalysts include heterogeneous catalysts containing from about 0.1% to about 20%, or from about 1% to about 5% by weight, transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combinations thereof, which are typically supported on various materials, including Al203, C, CaCO3, SrCO3, BaSO4, MgO, SiO2, TiO2, ZrO2 and the like. Many of these metals, including Pd, can be doped with an amine, sulfide or a second metal such as Pb, Cu or Zn. Exemplary catalysts thus include palladium catalysts such as Pd / C, Pd / SrC03, Pd / AI2O3, Pd / MgO, Pd / CaC03, Pd / BaSO4, PdO, Pd black, PdCI2 and the like, containing about 1% to about 5% Pd, based on weight. Other catalysts include Rh / C, Ru / C, Re / C, PtO2, Rh / C, Ru0 and the like. The catalytic reduction of the cyano moiety is typically carried out in the presence of one or more polar solvents, including but not limited to water, alcohols, ethers, esters and acids such as MeOH, EtOH, IPA, THF, AcOEt and AcOH. The reaction can be carried out at temperatures in the range of about 5 ° C to about 100 ° C, although reactions at room temperature are common. Generally, the ratio of substrate to catalyst may be in the range of about 1: 1 to about 1,000: 1, based on weight, and the pressure of H 2 may be in the range of about atmospheric pressure, 0 kPa, a approximately 10,342 MPa (1500 psig). More typically, the substrate to catalyst ratios are in the range of about 4: 1 to about 20: 1, and the H2 pressures are in the range of about 0.1724 MPa (25 psig) to about 1.0342 MPa (150 psig). As shown in scheme 1, the penultimate y-amino acid (formula 9) is resolved, providing the desired stereoisomer (formula 1). The amino acid (formula 9) can be resolved by contact with a resolving agent such as an enantiomerically pure or substantially pure acid or base (e.g., S-mandelic acid, S-tartaric acid and the like), providing a pair of diastereomers (by example, salts having different solubilities), which are separated, for example, by recrystallization or chromatography. The α-amino acid having the desired stereochemical configuration (formula 1) is subsequently regenerated from the appropriate diastereomer, for example, by contact with a base or acid or by solvent removal (for example, contact with EtOH, THF and the like) . The desired stereoisomer can be further enriched by multiple recrystallizations in a suitable solvent.

In addition, by using a resolving agent as described above, the 3-cyanocarboxylic acid ester (formula 7) can be converted to the desired product (formula 1) by contacting an enzyme. As shown in scheme 1 and discussed above, a diastereomer of the monoester (formula 7) is diastereoselectively hydrolyzed by contact with an enzyme, which results in a mixture containing a 3-cyanocarboxylic acid (or ester) having the necessary stereochemical configuration in C-3 (formula 10) and a 3-cyanocarboxylic ester (or acid) having the opposite (undesired) stereochemical configuration in C-3 (formula 11). Representative compounds of formula 10 include (3S, 5R) -3-cyano-5-methylheptanoic acid, (3S, 5R) -3-cyano-5-methyloctanoic acid, (3S, 5f?) - 3-cyano-5 acid -methylnonanoic acid and (3S, 5f?) - 3-cyano-5,7-dimethyloctanoic acid and salts thereof, as well as C-? -6 alkyl esters of the aforementioned compounds, including ethyl ester of (3S, 5R) -3-cyano-5-methylheptanoic acid, (3S, 5f?) - 3-cyano-5-methyloctanoic acid ethyl ester, (3S, 5R) -3-cyano-5-methylnonanoic acid ethyl ester and ethyl ester of (3S, 5f?) - 3-cyano-5,7-dimethyloctanoic acid. Exemplary compounds of formula 11 include (3f?, 5 /?) - 3-cyano-5-methylheptanoic acid, (3f?, 5f?) - 3-cyano-5-methyloctanoic acid, (3f?, 5f?) Acid -3-cyano-5-methiinonanoic acid and (3f?, 5f?) - 3-cyano-5,7-dimethyloctanoic acid and salts thereof, as well as C? .6 alkyl esters of the aforementioned compounds, including ester Ethyl (3R, 5R) -3-cyano-5-methylheptanoic acid, (3R, 5f?) - 3-cyano-5-methyloctanoic acid ethyl ester, ethyl ester of acid (3R, 5R) -3-cyano-5-methylnonanoic acid and (3R, 5) -3-cyano-5,7-dimethyloctanoic acid ethyl ester. The choice of the enzyme (biocatalyst) used to resolve the desired diastereomer (formula 10) depends on the structures of the substrate (formula 7) and the bioconversion product (formula 10 or formula 11). The substrate (formula 7) comprises two diastereomers (formula 13 and formula 14) having opposite stereochemical configuration at C-3.

In formula 13 and formula 14, the substituents R1, R2 and R6 are as defined for formula 1 and formula 5 above. The enzyme hydrolyzes one of the two diastereomers stereoselectively (formula 13 or formula 14). Therefore, the enzyme can be any protein that, having little or no effect on the compound of formula 13, catalyzes the hydrolysis of the compound of formula 14, providing a 3-cyanocarboxylic acid (or salt) of formula 11. Alternatively, the enzyme can be any protein which, having little or no no effect on the compound of formula 14, catalyze the hydrolysis of the compound of formula 13, providing a 3-cyanocarboxylic acid (or salt) of formula 10. Enzymes useful for diastereoselectively hydrolyzing the compounds of formula 13 or formula 14 to compounds of formula 10 or formula 11, respectively, may include both hydrolases, including lipases, certain proteases and other stereoselective esterases. Said enzymes can be obtained from a variety of natural sources, including animal organs and microorganisms. See, for example, table 2 for a non-limiting list of commercially available hydrolases TABLE 2 Commercially available hydrolases Enzyme Trade name Pancreatic porcine lipase Altus 03 CAL-A ofi zada Altus 11 Altus 12 Candida polyiica lipase 12 CAL-B Altoflowed 13 Altus Geotnchum candidus Altus 28 Pseudomonas arogmosa lipase Altus 50 Pseudomonas esterase Pseudomonas esterase Amano 2 Lipase from Aspergillus niger Lipasa Amano AS Lipase from Burkholdena cepacia Lipase Amano AH Lipase from Pseudomonas fluorescens Lipase Amano AK 20 Lipase from Candida rugosa Lipase Amano AYS Lipase from Rhizopus delemar Lipase Amano D Lipase from Rhizopus oryzae Lipase Amano F-AP 15 Lipase from Penicillium camembertn Lipasa Amano G 50 Lipase from Mucor javanicus Lipase Amano M 10 Lipase from Burkholdepa cepacia Lipase Amano PS Lipase from Burkholdepa cepacia Lipase Amano PS-SD Lipase from Burkholdepa cepacia Lipase Amano PS-C I Lipase from Burkholdepa cepacia Lipase Amano PS-C ll Lipase from Burkholdepa cepacia Lipasa Amano PS-D I Lipase from Penicillium roquefortí Lipase Amano R Lipase from Burkholdepa cepacia Lipa sa Amano S Protease from Aspergillus sp BioCatalytics 101 Lipase from Pseudomonas sp B? oCatalyt? cs 103 Lipase fungic BioCatalytics 105 Lyophilized microbial lipase BioCatalytics 108 CAL-B lyophilized B? oCatalyt? cs 110 Candida sp lyophilized BioCatalytics 111 CAL-A ofi zada BioCatalytics 112 Lipase from Thermomyces sp BioCatalytics 115 Lipase from Alcahgenes sp lyophilized BioCatalytics 117 Lipasa from Chromobactepum viscosum Altus 26 CAL-B, L2 sun Chpazyme L2 Sol Lipase from Candida c ndracea Fluka 62302 Lipase from Candida utilis Fluka 6 Rhizopus niveus Lipase Sigma L8 Swine pancreatic lipase Sigma L12 Lipoprotein lipase from Pseudomonassp. Sigma L13 Lipase from Thermomyces lanuginosus Lipolase Sigma L9 Lipase from Thermomyces lan? Ginosus Sigma L10 Novo 871 Lipase from Rhizomucor miehei Palatasa Sigma L6 Lipase from Pseudomonas sp. Sigma L14 type XIII Wheat germ lipase Sigma L11 Rhizopus arrhizus lipase Sigma L7 type XI Pancreatic lipase 250 Valley Research V1 Altus protease trypsin 33 Altus chymopapain protease Altus 38 Bromelain protease Altus 40 Aspergillus niger Altus protease 41 Aspergillus oryzae Altus protease 42 Protease from Penicillium sp. Altus 43 Protease from Aspergillus sp. Altus 45 Calcium Renal Protease Sigma P24 Carlsberg Altus Protein Altus 10 Bacillus lentus Altus Proteus 53 Fungal Protease Genencor Protease 500,000 Fungal Protease Fungal Protease Concentrate Genencor Protectant Genencor Protex 6L Protease Protein Genencor 899 Bacterial Protease Genencor Multifect P3000 Bacterial Protease Genencor Primatan Bacterial Protease Genencor Purafect (4000L) Bacterial Protease Genencor Multifect Neutral Aspergillus niger Protease Amano Protease Amano A Rhizopus niveus Protease Amano Protease Amano II Rhizopus niveus Protease Newlase Amano F Rhizopus oryzae Peptidase Amano Protein Bacillus Protease subtilis Amano Proleather FGF Protease from Aspergillus oryzae Protease Amano A Protease from Aspergillus oryzae Protease Amano M Protease from Bacillus subtilis Protease Amano N Protease from Aspergillus melleus Protease Amano P 10 Protease from Bacillus stearothermophilus Protease Amano SG Est freeze-dried porcine liver erasa BioCat Chirazyme E1 Freeze-dried porcine liver esterase BioCat Chirazyme E2 Proteases from Streptomyces sp. BioCatalytice 1 18 Tritirachium protease album Proteinase K Fluka P6 Bovine pancreatic protease Alpha-chymotrypsin I Sigma P18 Streptomyces griseus protease Sigma P16 bacterial Bovine pancreatic protease Beta-chymotrypsin Sigma P21 Clostridium protease Histolyticum Clostripain Sigma P13 Bovine intestinal protease Enteropeptidase Sigma P17 Porcine intestinal protein Enteropeptidase Sigma P25 Bacillus sp. Esperasa Sigma P8 Protease from Aspergillus oryzae Flavourzyme Sigma P1 Bacillus amyloliquefaciens Protesse Neutrase Sigma P5 Protease from Carica papaya Papain Sigma P12 Bacillus thermoproteolyticus rokko Protease Sigma P10 Protease from Pyrococcus furiosis Protease S Sigma P14 Protease from Bacillus sp. Savinase Sigma P9 Bovine pancreatic protease Sigma P19 type 1 (crude) Bacillus polymyxa protease Sigma P7 type IX Bacillus licheniformis protease Sigma P6 type VIII Aspergillus saitoi protease Sigma P3 type XIII Protein of Aspergillus sojae Sigma P4 of type XIX Protease of Aspergillus oryzae Sigma P2 of type XXIII Bacterial protease Sigma P11 of type XXIV Newlase of Rhizopus sp Newlase Sigma 15 Protease of Aspergillus oryzae Concentrate of validasa FP Pina (Ananas comosus and Ananas bracteatus (L) ] Bromelain Concentrate Aspergillus sp Acrya Amano Am1 Swine renal acylase Aalasa I Sigma A-S2 Penicillin G acylase Altus 06 Mucor meihei esterase Fluka E5 Candida rugose esterase Altus 31 Swine pancreatic elastase Altus 35 Acetyl nesterase Sigma ES8 Cholesterolesterase BioCatalytics E3 PLE- Ammonium sulfate BioCatalytics 123 Liver hepatic rabbit Sigma ES2 Cholesterolesterase from Pseudomonas sp Sigma ES4 As shown in the examples section, the enzymes useful for the diastereoselective conversion of the substituted ester with cyano (formula 13 or formula 14) into the carboxylic acid ( or salt) of formula 10 or formula 11 include lipases. The lipases part Particularly useful for conversion of the cyano substituted ester of formula 14 into a carboxylic acid (or salt) of formula 11 include enzymes derived from the microorganism Burkholderia cepacia (formerly Pseudomonas cepacia) such as those available from Amano Enzyme Inc. under the trade names PS, PS-SD, PS-C I, PS-C II, PS-D I and S These enzymes are available in the form of fluid powder (PS) or of off-site powder (S) or can be immobilized on ceramic particles (PS- C I and PS-C II) or diatomaceous earth (PS-D I). They have lipolytic activity which may be in the range of about 30 kUL / g (PS) to about 2,200 kUL / g (S). The PS-SD lipase from Amano Enzyme Inc. is a preferred enzyme for use in the method of the invention. Lipases particularly useful for the conversion of the substituted ester with cyano of formula 13 into a carboxylic acid (or salt) of formula include enzymes derived from the microorganism Thermomyces lanuginosus such as those available from Novo-Nordisk A / S under the trade name LIPOLASE®. LIPOLASE® enzymes are obtained by submerged fermentation of a genetically modified Aspergillus oryzae microorganism with Thermomyces lanuginosus DSM 4109 DNA encoding the amino acid sequence of the lipase. LIPOLASE® 100 L and LIPOLASE® 100T are available in the form of liquid solution and granular solid, respectively, each having a nominal activity of 100 kUL / g. Other forms of LIPOLASE® include LIPOLASE® 50L, which has half the activity of LIPOLASE® 100L, and LIPOZYME® 100L, which has the same activity as LIPOLASE® 100L, but is of food purity. Various selection techniques can be used to identify suitable enzymes. For example, large numbers of commercially available enzymes can be selected using high throughput screening techniques described in the examples section below. Other enzymes (or microbial sources of enzymes) can be selected using enrichment isolation techniques. Such techniques typically involve the use of limited carbon or limited nitrogen media supplemented with an enrichment substrate, which may be the substrate (formula 7) or a structurally similar compound. Potentially useful microorganisms are selected for further investigation based on their ability to grow in media containing the enrichment substrate. In these microorganisms, their ability to stereoselectively catalyze ester hydrolysis by contacting suspensions of microbial cells with the unresolved substrate, and assaying for the presence of the desired diastereomer (formula 10) using analytical methods such as chiral HPLC, gas-liquid chromatography, LC / MS and the like . Once a microorganism having the necessary hydrolytic activity has been isolated, enzymatic engineering can be employed to improve the properties of the enzyme it produces. For example, and without limitation, enzymatic engineering can be used to increase the yield and diastereoselectivity of the ester hydrolysis, to extend the operating temperature and pH ranges of the enzyme, and to improve the tolerance of the enzyme to organic solvents. Useful enzymatic engineering techniques include rational design methods such as site-directed mutagenesis, and in vitro directed evolution techniques that utilize successive rounds of random mutagenesis, gene expression, and high-throughput screening to optimize the desired properties. See, for example, K.M. Koeller and C.-H. Wong, "Enzymes for chemical synthesis", Nature 409: 232-240 (January 11, 2001) and references cited therein, the complete disclosure of which is incorporated herein by reference. The enzyme may be in the form of whole microbial cells, permeabilized microbial cells, microbial cell extracts, partially purified enzymes, purified enzymes and the like. The enzyme may comprise a dispersion of particles having a size of medium particle, based on volume, of less than about 0.1 mm (fine dispersion) or approximately 0.1 mm or greater (coarse dispersion). Thick enzyme dispersions offer potential processing advantages over fine dispersions. For example, coarse enzymatic particles can be used repeatedly in batch processes, or in semi-continuous or continuous processes, and can be separated more easily (eg by filtration) from other components of the bioconversion more easily than fine dispersions of enzyme. Useful thick enzyme dispersions include crosslinked enzyme crystals (CLEC) and crosslinked enzyme aggregates (CLEA), which comprise primarily enzyme. Other coarse dispersions may include enzymes immobilized on or within an insoluble support. Useful solid supports include polymeric matrices comprising calcium alginate, polyacrylamide, EUPERGIT® and other polymeric materials, as well as inorganic matrices such as CELITE®. For a general description of CLECs and other enzymatic immobilization techniques, see U.S. Pat. No. 5,618,710 of M.A. Navia and N.L. St. Clair. For a general discussion of the CLEAs, including their preparation and use, see U.S. Patent Application Ser. No. 2003/0149172 of L. Cao and J. Elzinga et al. See also A.M. Anderson, Biocat. Biotransform. 16: 181 (1998) and P. López-Serrano et al., Biotechnol. Lett. 24: 1379-1383 (2002) for a discussion of the application of CLEC and CLEA technology to a lipase. The Full descriptions of the aforementioned references are incorporated herein by reference for all purposes. The reaction mixture may comprise a single phase or may comprise multiple phases (eg, a two- or three-phase system). Thus, for example, the diastereoselective hydrolysis shown in scheme 1 can take place in a single aqueous phase containing the enzyme, the substrate (formula 7), the desired diastereomer (formula 10) and the undesired diastereomer (formula 11). Alternatively, the reaction mixture may comprise a multiphase system that includes an aqueous phase in contact with a solid phase (e.g., enzyme or product), an aqueous phase in contact with an organic phase, or an aqueous phase in contact with a organic phase and a solid phase. For example, diastereoselective hydrolysis can be carried out in a biphasic system comprising a solid phase containing the enzyme and an aqueous phase containing the substrate (formula 7), the desired diastereomer (formula 10) and the undesired diastereomer (formula 11). ). Alternatively, the diastereoselective hydrolysis can be carried out in a three-phase system comprising a solid phase containing the enzyme, an organic phase containing the substrate (formula 7) and an aqueous phase initially containing a small fraction of the substrate. In some cases, the desired diastereomer (formula 10) is a carboxylic acid having a pKa lower than the unreacted ester (formula 14). Because the carboxylic acid exhibits a higher aqueous solubility, the organic phase it is enriched in the unreacted ester (formula 14), while the aqueous phase is enriched in the desired carboxylic acid (or salt). In other cases, the undesired diastereomer (formula 11) is a carboxylic acid, so that the organic phase is enriched in the desired unreacted ester (formula 13), while the aqueous phase is enriched in the undesired carboxylic acid (or salt ). Preferably, the undesired diastereomer (formula 11) is selectively hydrolyzed to the carboxylic acid, which is soluble in the aqueous phase, while the desired diastereomer (ester of formula 10) does not react and remains in the organic phase. The amounts of substrate (formula 7) and biocatalyst used in stereoselective hydrolysis will depend, among other things, of the properties of the ester substituted with particular cyano and enzyme. However, generally, the reaction may employ a substrate having an initial concentration of about 0.1 M to about 5.0 M and, in many cases, having an initial concentration of about 0.1 M to about 1.0 M. Additionally, the reaction may employ generally an enzymatic load of about 1% to about 20% and, in many cases, can employ an enzyme load of about 5% to about 15% (w / w). The stereoselective hydrolysis can be carried out in a range of temperature and pH. For example, the reaction can be carried out at temperatures of about 10 ° C to about 60 ° C, but it is typically carried out at temperatures of about TA to about 45 ° C. Such temperatures generally allow a substantially complete conversion (eg, about 42% to about 50%) of the substrate (formula 7) with an ed (3S, 5R diastereomer) of about 80% or more (eg 98%) in an amount reasonable time (eg, about 1 h to about 48 h or about 1 h to about 24 h) without deactivating the enzyme. Additionally, stereoselective hydrolysis can be carried out at a pH of about 5 to a pH of about 11, more typically at a pH of about 6 to about 9, and often at a pH of about 6.5 to about 7.5. In the absence of pH control, the pH of the reaction mixture will be reduced as hydrolysis of the substrate proceeds (formula 7) due to the formation of a carboxylic acid (formula 10 or formula 11). To compensate for this change, the hydrolysis reaction can be carried out with internal pH control (specifically, in the presence of a suitable buffer) or can be carried out with external pH control by the addition of a base. Suitable buffers include sodium hydrogen carbonate, potassium phosphate, sodium phosphate, sodium acetate, ammonium acetate, calcium acetate, BES, BICINE, HEPES, MES, MOPS, PIPES, TAPS, TES, TRICINE, Tris, TRIZMA® or other buffers having a pKa of about 6 to a pKa of about 9. The buffer concentration is generally in the range of about 5 mM to about 1 mM, and is typically in the range of about 50 mM to approximately 200 mM. Suitable bases include aqueous solutions comprising KOH, NaOH, NH 4 OH, etc., having concentrations in the range of about 0.5 M to about 15 M, or more typically, in the range of about 5 M to about 10 M. also other inorganic additives such as calcium acetate. After or during the enzymatic conversion of the substrate (formula 7), the desired diastereomer (formula 10) is isolated from the product mixture using standard techniques. For example, in the case of a batch reaction in a single (aqueous) phase, the product mixture can be extracted one or more times with an organic solvent such as hexane, heptane, MeCl2, toluene, MTBE, THF, etc., which separates the acid (ester) having the necessary stereochemical configuration in C-3 (formula 10) from the unwanted ester (acid) (formula 11) in the aqueous (organic) and organic (aqueous) phases, respectively. Alternatively, in the case of a multiphase reaction employing aqueous and organic phases enriched in acid or ester, the two diastereomers (formula 10 and formula 11) can be separated in batches after the reaction, or they can be separated semicontinuously or continuously during Stereoselective hydrolysis. As shown in scheme 1, once the desired diastereomer (formula 10) is isolated from the product mixture, it is optionally hydrolyzed using conditions and reagents associated with the ester hydrolysis of the compound of formula 7 above. The cyano residue of the carboxylic acid The resulting salt (formula 10a), or its corresponding salt, is subsequently reduced by providing, upon acid treatment if necessary, the desired α-amino acid (formula 1). The reduction can employ the same conditions and reagents described above for the reduction of the cyano residue of the compound of formula 8, and can be undertaken without isolating the cyanoacid of formula 10a. Representative compounds of formula 10a include (3S, 5R) -3-cyano-5-methylheptanoic acid, (3S, 5f?) -3-cyano-5-methyloctanoic acid, (3S, 5R) -3-cyano-5 acid -methylnonanoic acid and (3S, 5R) -3-cyano-5,7-dimethyloctanoic acid, and their salts. As shown in scheme 1, the desired diastereomer (formula 10) can be converted into a suitable salt, preferably an alkali metal salt. The cyano residue of the resulting salt is subsequently reduced, providing the salt of the desired α-amino acid (formula 1). The reduction can employ the same conditions and reagents described above for the reduction of the cyano moiety of the compound of formula 8. The resulting salt of the compound of formula 1 can then be further converted into the free acid, or into a pharmaceutically acceptable salt, solvate or hydrate. of the same. A preferred salt of a compound of formula 10a is the sodium salt of (3S, 5R) -3-cyano-5-methyloctanoic acid. The chiral alcohol (formula 2) shown in scheme 1 can be prepared using various methods. For example, chiral alcohol can be prepared by stereoselective hydrolysis mediated by enzyme a racemic ester using conditions and reagents described above with respect to the enzymatic resolution of the compound of formula 7. For example, n-decanoic acid 2-methylpentyl ester can be hydrolyzed in the presence of a hydrolase (eg, lipase) and water, providing a pure (or substantially pure) chiral alcohol, (R) -2-methyl-1-pentanol, which can be separated from the non-chiral acid and the unreacted chiral ester (n-decanoic acid and 2-methylpentyl ester of the acid (S) -pentanoic acid) by fractional distillation. The ester substrate can be prepared from the corresponding racemic alcohol (e.g., 2-methyl-1-pentanol) and acid chloride (e.g., n-decanoic acid chloride) or acid anhydride using procedures known in the art. Alternatively, the chiral alcohol (formula 2) can be prepared by asymmetric synthesis of an appropriately substituted 2-alkenoic acid. For example, 2-methyl-2-pentenoic acid (or its salt) can be hydrogenated in the presence of a chelate catalyst, yielding (R) -2-methylpentanoic acid or a salt thereof that can be directly reduced with LAH, providing (f) ?) - 2-methyl-1-pentanol or converted to the mixed anhydride or acid chloride and then reduced with NaBH 4, providing the chiral alcohol. Potentially useful chiral catalysts include cyclic or acyclic chiral phosphine ligands (e.g., monophosphines, bisphosphines, bisphospholanes, etc.). or phosphinite ligands bound to transition metals such as ruthenium, rhodium, iridium or palladium. The complexes of Ru-, Rh-, Ir- or Pd-phosphine, -phosphinite or -phosphinooxazoline are optically active because that they possess a chiral phosphorus atom or a chiral group connected to a phosphorus atom, or due, in the case of BINAP and similar atropoisomeric ligands, that they possess axial chirality. Exemplary chiral ligands include BisP *, (R) -BINAPINE, (S) -Me-ferrocene-Ketalphos, (R, R) -D?, (R, R) -D? PAMP, (R) - (S) ) -BPPFA, (S, S) -BPPM, (+) - CAMP, (S, S) -CHIRAPHOS, (R) -PROPHOS, (R, R) -NORPHOS, (fi) -BINAP, (f?) -CYCPHOS, (R, R) -BDPP, (R, R) -DEGUPHOS, (f?, R) -Me-DUPHOS, (f?, K) -Et-DUPHOS, (?, F?) - Pr -DUPHOS, (R, f?) - Me-BPE, (R, R) -E \ -BPE, (R) -PNNP, (tf) -BICHEP, (f?, S, R, S) -Me- PENNPHOS, (S, S) -BICP, (f?, R) -Et-FerroTANE, (R, R) -tert-butyl-PHOS, (R) -Tol-BINAP, (R) -MOP , (tf) -QUINAP, CARBOPHOS, (R) - (S) -JOSIPHOS, (f?) - PHANEPHOS, BIPHEP, (R) -CI-MeO-BIPHEP, (R) -MeO-BIPHEP, (R) - MonoPhos, BIFUP, (R) -SpirOP, (+) - TMBTP, (+) - tetraMeBITIANP, (R, f?, S, S) -TANGPhos, (R) -PPh2-PhOx-Ph, (S, S) -MandyPhos, (tf) -eTCFP, (R) -mTCFP and (f?) - CnTunaPHOS, where n is an integer from 1 to 6. Other chiral ligands include (f?) - (-) - 1- [ (S) -2- (di- (3,5-bistrifluoromethylphenyl) phosphino) ferrocenyl] ethyldicyclohexylphosphine; (R) - (-) - 1 - [(S) -2- (di- (3,5-bistrifluoromethylphenyl) phosphino) ferrocenyl] ethyldi (3,5-dimethylphenyl) phosphine; (R) - (-) - 1 - [(S) -2- (di-re-C-butylphosphino) ferrocenyl] ethyldi (3,5-dimethylphenyl) phosphine; (ft) - (-) - 1 - [(S) -2- (dicyclohexylphosphino) ferrocenyl] ethyldi-tert-butylphosphine; (f?) - (-) - 1 - [(S) -2- (dicyclohexylphosphino) ferrocenyl] ethyldicyclohexylphosphine; (f?) - (-) - 1 - [(S) -2- (dicyclohexylphosphino) ferrocenyl] ethyldiphenylphosphine; (R) - (-) - 1 - [(S) -2- (di- (3,5-dimethyl-4-methoxyphenyl) phosphino) ferrocenyl] ethyldicyclohexylphosphine; (R) - (-) - 1 - [(S) -2- (diphenylfosphine) ferrocenyl] ethyldi-rerc-butylphosphine; (f?) -? / - [2 - (? /,? / - dimethylamino) ethyl] -? / - methyl-1 - [(S) -1 ', 2-bis (diphenylphosphino) ferrocenyl] ethylamine; (R) - (+) - 2- [2- (diphenylphosphino) phenyl] -4- (1-methylethyl) -4,5-dihydrooxazole; . { 1 - [((?, F?) -2-benzylphospholanyl) -fen-2-yl] - (R *, R *) - phospholan-2-yl} phenylmethane; Y . { 1 - [((R, R) -2-benzylphospholanyl) ethyl] - (f? *, R *) - phospholan-2-yl} phenylmethane. Useful ligands may also include stereoisomers (enantiomers and diastereomers) of the chiral ligands described in the preceding paragraphs, which may be obtained by inverting all or some of the stereogenic centers of a given ligand or reversing the stereogenic axis of an atropoisomeric ligand. So, for example, useful chiral ligands may also include (S) -CI-MeO-BIPHEP, (S) -PHANEPHOS, (SS) -Me-DUPHOS, (S, S) -Et-DUPHOS, (S) -BINAP , (S) -Tol-BINAP, (tf) - (R) -JOSIPHOS, (S) - (S) -JOSIPHOS, (S) -eTCFP, (S) -m-TCFP and so on. Many of the chiral catalysts, catalyst precursors or chiral ligands can be obtained from commercial sources or can be prepared using known methods. A catalyst precursor or precatalyst is a compound or set of compounds that is converted to the chiral catalyst before use. Catalyst precursors typically comprise Ru, Rh, Ir or Pd complexed with the phosphine ligand and a diene (eg, norbornadiene, COD, (2-methylallyl) 2, etc.) or a halide (Cl or Br) or a diene and a halide, in the presence of a counter-ion, X 'such as OTf, PF6. "BF4", SbF6", CIO4", etc. By both, for example, a catalyst precursor comprising the complex [(bisphosphine ligand) Rh (COD)] + X "can be converted to a chiral catalyst by hydrogenating the diene (COD) in MeOH, providing [(bisphosphine ligand) Rh (MeOH ) 2] + X ". The MeOH is subsequently displaced by the enamide (formula 2) or enamine (formula 4), which undergoes enantioselective hydrogenation to the desired chiral compound (formula 3). Examples of chiral catalysts or catalyst precursors include complex of (+) - TMBTP-ruthenium chloride (ll) -acetone, complex of (S) -CI-MeO-BIPHEP-ruthenium chloride (II) -Et3N, complex of (S) -BINAP- ruthenium (II) Br2, complex of (S) -tol-BINAP ruthenium (II) Br2, complex of [((3R, 4R) -3,4-bis (diphenylphosphino) -1-methylpyrrolidine) Rhodium- (1, 5-cyclooctadiene)] - tetrafluoroborate, complex of [((R, R, S, S) -TANGPhos) rhodium (l) -bis (1,5-cyclooctadiene)] - trifluoromethanesulfonate, complex of [( R) -BINAPINE-rhodium- (1, 5-cyclooctadiene)] - tetrafluoroborate, complex of [(S) -eTCFP- (1, 5-cyclooctadiene) rhodium (l)] - tetrafluoroborate and complex of [(S) -mTCFP - (1, 5-cyclooctadiene) rhodium (1)] - tetrafluoroborate. For a given chiral catalyst and hydrogenation substrate, the molar ratio of substrate and catalyst (s / c) may depend, among other things, on the H2 pressure, the reaction temperature and the solvent (if any). Usually, the ratio of substrate to catalyst exceeds approximately 100: 1 or 200: 1, and the substrate to catalyst ratios of approximately 1,000: 1 or 2,000: 1 are common. Although the chiral catalyst can be recycled, higher substrate ratios are more useful. catalyst. For example, substrate to catalyst ratios of about 1,000: 1, 10,000: 1 and 20,000: 1, or greater would be useful. The asymmetric hydrogenation is typically carried out at about room temperature or above, and under about 10 kPa or more of H2. The temperature of the reaction mixture may be in the range of about 20 ° C to about 80 ° C, and the pressure of H 2 may be in the range of about 10 kPa to about 5,000 kPa or greater, but more typically is in the range of range from about 10 kPa to about 100 kPa. The combination of temperature, H2 pressure and substrate to catalyst ratio is generally selected to provide a substantially complete conversion (ie, approximately 95% by weight) of the substrate (formula 2 or 4) in about 24 hours. With many of the chiral catalysts, reducing the H2 pressure increases the enantioselectivity. A variety of solvents can be used in the asymmetric hydrogenation, including protic solvents such as water, MeOH, EtOH and iPrOH. Other useful solvents include polar aprotic solvents such as THF, ethyl acetate and acetone. The stereoselective hydrogenation may employ a single solvent or may employ a mixture of solvents such as THF and MeOH, THF and water, EtOH and water, MeOH and water and the like. The compound of formula 1, or its diastereomers, can be further enriched, for example, by recrystallization fractionated or chromatography, or by recrystallization in a suitable solvent. Alternatively, a compound of formula 10 or 11 can be prepared as illustrated by scheme 2.

Item Scheme 2 wherein R1, R2, R3, R8 and R9 are as defined above; R 4 is selected from tosyl, mesyl, brosyl, closyl (p-chlorobenzenesulfonyl), nosyl and triflyl, preferably mesyl; R5 is a suitable leaving group such as R40-, preferably mesyl-O-; R6 is C1-6 alkyl, preferably methyl; X1 is halogen, preferably chlorine or bromine; R * -X2 is an alkali metal halide, preferably bromide sodium; and X2 is halogen, preferably bromine. A compound of formula 4 can be prepared from a compound of formula 3 by the procedure described above for scheme 1. A compound of formula 19 can be prepared from a compound of formula 4 and a compound of formula 18 by reacting an amount stoichiometric or in excess of a compound of formula 18 with a compound of formula 4 for 2 to 6 hours at a temperature range of 45 ° C to 90 ° C. The reaction mixture may comprise an aqueous phase, an organic phase and a phase transfer catalyst (e.g., a tetraalkylammonium salt such as Bu4N + Br ~). Representative organic solvents include polar aprotic solvents such as TMBE, THF, AcOEt, AcOiPr and non-polar aromatic solvents such as toluene. A compound of formula 7 can be prepared from a compound of formula 19 and an orthoester compound of formula 20. The alkylation can be carried out at temperatures that are in the range of -5 ° C to 5 ° C using a stoichiometric amount or in excess (eg, 1 to 1.5 equivalents) of the compound of formula 20 for 2 to 12 hours. Representative bases include KO-ferc-Bu, LDA, nBuLi and LiHMDS using an excess of base (e.g., 1.2-3 equivalents). The reaction mixture comprises a single organic solvent (for example, THF, TBME or toluene).

The intermediate orthoester product is hydrolysed during the treatment under acidic conditions, for example, HCl, H2SO and the like, with excess water to provide the carboxylic ester of formula 7. A compound of formula 10 or 11 can be prepared from a compound of formula 7 by diastereoselective hydrolyzation with a suitable enzyme, as described above for scheme 1. Preferably, the enzyme is a lipase from the microorganism Burkholderia cepacia or from the microorganism Thermomyces lanuginosus. Most preferably, the enzyme is a Burkholderia cepacia lipase commercially available from Amano Enzyme Inc .; most preferably lipase PS-SD. As described throughout the specification, many of the compounds disclosed have stereoisomers. Some of these compounds may exist in the form of single enantiomers (enantiomerically pure compounds) or mixtures of enantiomers (enriched and racemic samples), which depending on the relative excess of one enantiomer against the other in a sample may exhibit optical activity. Said stereoisomers, which are non-superimposable mirror images, possess a stereogenic axis or one or more stereogenic centers (specifically, chirality). Other compounds disclosed may be stereoisomers that are not mirror images. Said stereoisomers, which are known as diastereomers, can be chiral or achiral (they do not contain stereogenic centers). They include molecules that contain alkenyl or cyclic group, so that cis / trans (or Z / E) stereoisomers are possible, or molecules that contain two or more stereogenic centers, in which the inversion of a single stereogenic center generates a corresponding diastereomer. Unless indicated or otherwise clarified (e.g., by the use of stereo links, stereocenter descriptors, etc.), the scope of the present invention generally includes the reference compound and its stereoisomers, whether or not they are pure ( for example, enantiomerically pure) as mixtures (for example, enantiomerically enriched or racemic). Some of the compounds may also contain a keto or oxime group, so that tautomerism may occur. In such cases, the present invention generally includes tautomeric forms, whether they are each pure or mixtures. The pharmaceutically acceptable salts of the compounds of formula 1 include the acid addition salts and the base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide, iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisal acids and bases can also be formed, for example, hemisulfate and hemicalcium salts. For a review of suitable salts, see Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, 2002). The pharmaceutically acceptable salts of compounds of formula 1 can be prepared by one or more of three methods: (i) by reacting the compound of formula 1 with the desired acid or base; (ii) removing an acid or base labile protecting group from a suitable precursor of the compound of formula 1 or by ring opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) converting one salt of the compound of formula 1 to another by reaction with an appropriate acid or base or by a suitable ion exchange column. The three reactions are typically carried out in solution. The The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized. The compounds of the invention can exist in a continuum of solid states in the range from fully amorphous to fully crystalline. The term "amorphous" designates a state in which the material lacks long-range order at the molecular level and, depending on the temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not provide distinctive X-ray diffraction patterns and, although they exhibit the properties of a solid, they are more formally described as a liquid. After heating, a change of properties from solid to liquid occurs which is characterized by a change of state, typically of second order ("vitreous transition"). The term "crystalline" designates a solid phase in which the material has a regular ordered internal structure at the molecular level and provides a distinctive X-ray diffraction pattern with defined peaks. Such materials, when heated sufficiently, will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically of first order ("melting point"). The compounds of the invention can also exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more solvent molecules pharmaceutically acceptable, for example, ethanol. The term "hydrate" is used when said solvent is water. A currently accepted classification system for organic hydrates is one that defines isolated site hydrates, channel hydrates or hydrates coordinated with metal ion, see Polymorphism in Pharmaceutical Solids by K.R. Morris (Ed. H.G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are those in which the water molecules are isolated from direct contact with each other by intermediate organic molecules. In channel hydrates, water molecules are found in grid channels where they are close to other water molecules. In hydrates coordinated with metal ion, the water molecules are attached to the metal ion. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of moisture. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on the humidity and the drying conditions. In such cases, non-stoichiometry will be the norm. Also included in the scope of the invention are multicomponent complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents that are linked together by non-covalent interactions, but could also be a complex of a neutral molecule with a salt. The co-crystals can be prepared by crystallization in the molten state, by recrystallization from solvents or by physical joint trituration of the components, see Chem. Commun. 17, 1889-1896, by O. Almarsson and M.J. Zaworotko (2004). For a general review of multicomponent complexes, see J. Pharm. Sci. 64 (8), 1269-1288 of Haleblian (August 1975). The compounds of the invention can also exist in the mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (in the molten state or solution). The mesomorphism that arises as a result of a change in temperature is described as "thermotropic" and that resulting from the addition of a second component, such as water or other solvent, is described as "lyotropic". Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic" and consist of molecules that have an ionic polar head group (such as -COO "Na +, -COO" K + or -SO3"Na +) or non-ionic (such as -N "N + (CH3) 3). For more information, see Crvstals and the Polarizinq Microscope by N.H. Hartshorne and A. Stuart, 4th edition (Edward Arnold, 1970). Hereinafter, all references to compounds of formula 1 include references to salts, solvates, multicomponent complexes and liquid crystals thereof, and to solvates, multicomponent complexes and liquid crystals of the salts thereof, and include all polymorphs and crystalline forms thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereafter, and isotopically-labeled compounds of formula 1. In the compounds of formula 1 their biopharmaceutical properties such as solubility and stability in solution can be evaluated (with pH), permeability, etc., to select the most appropriate dosage form and route of administration for treatment of the proposed indication. The compounds of formula 1 intended for pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example, in the form of solid plugs, powders or films by processes such as precipitation, crystallization, lyophilization, spray drying or evaporative drying. Microwave or radiofrequency drying can be used for this purpose. They can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or in any combination thereof). Generally, they will be administered in the form of a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of formula 1, and methods for their preparation, will be readily apparent to those skilled in the art. Said compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th edition, (Mack Publishing Company, 1995).

Oral Administration The compounds of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and / or buccal, lingual or sublingual administration, whereby the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nanoparticles, liquids or powders; chewable pills (including liquid-filled); chewing gum; gels; rapid dispersion dosage forms; films; ovules sprays and mouth / mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Said formulations can be used as fillers in soft or hard capsules (made, for example, with gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more emulsifying agents. and / or suspension agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a sachet. The compounds of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, can also be used in rapidly dissolving and rapid disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents 11 (6), 981-986, by Liang and Chen (2001). For dosage forms in tablets, depending on the dose, the drug can constitute from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, the tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1% to 25% by weight, preferably from 5% by weight to 20% by weight of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, tol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally comprise surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactants may comprise from 0.2 wt% to 5 wt% of the tablet, and the glidants may comprise from 0.2 wt% to 1 wt% of the tablet. The tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricants generally comprise from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the compressed. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents. Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight of binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about 10% by weight. % by weight of disintegrant, and from about 0.25% by weight to about 10% by weight of lubricant. The tablet mixtures can be compressed directly or by rollers into tablets. The tablet mixtures or portions of mixtures may be granulated as an alternative wet, dry or melt, freeze in the molten state, or extruded before the tablet is formed. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. Tablet formulation is addressed in Pharmaceutical Dosaqe Forms: Tablets, vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980). Oral consumption films for human or veterinary use are typically water soluble or water swellable flexible thin film dosage forms which can be fast dissolving or mucoadhesive and typically comprise a compound of formula 1, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifying agent and a solvent. Some components of the formulation can perform more than one function. The compound of formula 1 can be soluble or insoluble in water. A water-soluble compound typically comprises from 1% by weight to 80% by weight, more typically from 20% by weight to 50% by weight, of solutes. Less soluble compounds can comprise a greater proportion of the composition, typically up to 88% by weight of solutes. Alternatively, the compound of formula 1 may be in the form of multiparticulate beads. The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids, and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight. Other possible ingredients include antioxidants, dyes, flavorings and aroma enhancers, preservatives, saliva stimulating agents, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants and taste masking agents. Films according to the invention are typically prepared by evaporative drying of thin aqueous films coated on a base backing or release paper. This can be done in a drying oven or tunnel, typically a combined drying dryer, or by lyophilization or vacuum. Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Modified release formulations suitable for the purposes of the invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic particles and coated in Pharmaceutical Technology On-line, 25 (2), 1-14, by Verma et al. (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Parenteral Administration The compounds of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, can also be administered directly to the bloodstream, to the muscle or to an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Devices suitable for parenteral administration include needle injectors (including microneedle), needleless injectors and infusion techniques.

Topical Administration The compounds of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, can also be administered topically, (intra) dermally or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powders, dressings, foams, films, dermal patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated, see, for example, J. Pharm. Sci. 88 (10), 955-958, by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection (e.g., Powderject ™, Bioject ™, etc.).

Inhaled / lntranasal Administration The compounds of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, in the form of a mixture, for example, in a dry mixture with lactose, or in the form of a particle of mixed components, for example, mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler, in the form of a spray in aerosol from a container to pressure, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1, 1, 1 , 2,3,3,3-heptafluoropropane, or in the form of nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

Rectal / intravaginal administration Compounds of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema . Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Eye / Ear Management The compounds of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, can also be administered directly to the eye or ear, typically in the form of droplets of a suspension or micronized solution in sterile isotonic saline with adjusted pH. Other formulations suitable for ocular and atrial administration include ointments, gels, biodegradable implants (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone), wafers, lenses and particulate or vesicular systems such as niosomes or liposomes Other Technologies Compounds of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, can be combined with soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol to improve its solubility, rate of dissolution, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, specifically as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha-, beta- and gamma-cyclodexthines, examples of which can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148.

Kit of Parts Whereas it may be desirable to administer a combination of active compounds, for example, in order to treat a Particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of formula 1, can be conveniently combined in the form of a kit suitable for co-administration of the compositions. Thus, the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula 1, in particular (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A, and means for separately retaining said compositions such as a container, divided bottle or divided sheet container. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the compositions separated from each other. To aid compliance, the kit typically comprises instructions for administration and may be provided with a so-called reminder.

Dosage For administration to human patients, the total daily dose of the compounds of formula 1 is typically in the range of 0.1 mg to 1,000 mg depending, of course, on the mode of administration. The dose The total daily dose may be administered in single or divided doses and, at the discretion of the physician, may fall outside the typical range given herein. The preferred daily dose range for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A is in the range of 1 mg to 250 mg, more preferably the daily dose range is in the range of 1 mg to 125 mg. These dosages are based on an average human subject weighing approximately 60 kg to 70 kg. The doctor will be able to easily determine doses for subjects whose weights fall outside this range, such as children and the elderly. To avoid doubts, references in this report to "treatment" includes references to curative, palliative and prophylactic treatment. EXAMPLES The following examples are intended to be illustrative and not limiting, and to represent specific embodiments of the present invention. Enzymatic selection was carried out using a 96-well plate, which is described in D. Yazbeck et al., Synth. Catal. 345: 524-532 (2003), whose full description is incorporated herein by reference for all purposes. All enzymes used in the selection plate (see Table 2) were obtained from commercial enzyme suppliers, including Amano Enzyme Inc. (Nagoya, Japan), Roche (Basel, Switzerland), Novo Nordisk (Bagsvasrd, Denmark), Altus Biologics Inc. (Cambridge, MA), Biocatalytics (Pasadena, CA), Toyobo (Osaka, Japan), Sigma-Aldrich (St. Louis, MO), Fluka (Buchs, Switzerland), Genencor International Inc. (Rochester, NY) and Valley Research (South Bend, IN). The selection reactions were performed in an Eppendorf Thermomixer-R (VWR). Larger scale enzymatic resolutions used LIPOLASE® 100L EX, which is available from Novo-Nordisk A / S (CAS No. 9001-62-1), as well as PS lipase, PS-C I, PS-C II and PS -D I, which are available at Amano Enzyme Inc.

EXAMPLE 1. Preparation of 2-methylpentyl ester of (ff) -methanesulfonic acid A 4,000 I reactor was charged with (R) -2-methyl-1-pentanol (260 kg, 2,500 moles), methyl tert-butyl ether (2,000 I) and cooled to -10 ° C to 0 ° C. Methanesulfonyl chloride (310 kg, 2,600 moles) was charged and then Et 3 N (310 kg, 3,100 moles) was added keeping the internal temperature at 0 ° C to 10 ° C. After the addition was complete, the reaction mixture was heated at 15 ° C to 25 ° C and stirred at this temperature for at least 1 hour until completion according to the gas chromatography analysis. A solution of aqueous HCl (88 kg of HCl in 700 l of water) was then added to the reaction mixture. The resulting mixture was stirred for at least 15 minutes, settled for at least 15 minutes and then the lower aqueous phase was removed. The phase was washed organic top with water (790 I) and aqueous sodium bicarbonate (67 kg of sodium bicarbonate in 840 I of water). The solution was then concentrated in vacuo, removing the methyl-re-tert-butyl ether, affording the title compound as an oil (472 kg, 95% yield). 1 H-NMR (400 MHz, CDCl 3) 4.07-3.93 ppm (m, 2H), 2.97 (s, 3H), 1. 91-1.80 (m, 1 H), 1.42-1.09 (m, 4H), 0.94 (d, J = 6.57 Hz, 3H), 0.87 (t, J = 6.56 Hz, 3H); 13 C-NMR (CDCl 3) 74.73, 37.01, 34.81, 32.65, 19.71, 16.29, 14.04.

EXAMPLE 2 Preparation of (2 ') -2-cyano-2- (2'-methylpenti-succinic acid) diethyl ester A 4,000 I reactor was charged with (R) -methanesulfonic acid 2-methylpentyl ester (245 kg, 1.359 moles), 2-cyanuccinic acid diethyl ester (298 kg, 1, 495 moles) and anhydrous ethanol (1 , 300 kg). Sodium ethoxide (506 kg, 21% by weight in ethanol) was added. The resulting solution was heated at 70 ° C to 75 ° C, and the mixture was stirred at this temperature for at least 18 hours until completion according to the gas chromatography analysis. After completion of the reaction, a solution of aqueous HCl (32 kg of HCl in 280 I of water) was added to the reaction mixture until the pH was < 2. Additional water (400 I) was added and the reaction mixture was then concentrated in vacuo to remove the ethanol. Methyl-re-t-butylether (1,000 kg) was added and the mixture was stirred for at least 15 minutes, settled for minus 15 minutes, and then the lower aqueous phase was back-extracted with methyl-re-tert-butyl ether (900 kg). The combined organic phases were concentrated in vacuo to give the title compound as a dark oil (294 kg, 79% yield corrected for purity). 1 H-NMR (400 MHz, CDCl 3): 4.29 ppm (c, J = 7.07 Hz, 2H), 4.18 (c, J = 7.07 Hz, 2H), 3.03 (dd, J = 6.6, 7.1 Hz, 2H), 1.93 -1.61 (m, 3H), 1.40-1.20 (m, 10H), 0.95-0.82 (m, 6H); 13 C-NMR (CDCl 3) 168.91, 168.67, 168.59, 168.57, 119.08, 118.82, 62.95, 62.90, 44.32, 44.19, 42.21, 42.02, 3977, 39.64, 30.05, 29.91, 20.37, 19.91, 19.66, 13.99.

EXAMPLE 3 Preparation of (5R) -3-cyano-5-methyloctanoic acid ethyl ester (method A) A 4,000 I reactor was charged with NaCl (175 kg, 3,003 moles), tetrabutylammonium bromide (33.1 kg, 103 moles), water (87 I) and dimethylsulfoxide (1,000 kg). Diethyl ester of (2'R) -2-cyano-2- (2'-methylpentyl) succinic acid (243 kg, 858 mol) was charged and the mixture was heated at 135 ° C to 138 ° C, and stirred at this temperature for at least 48 hours, until completion according to the gas chromatography analysis. After cooling the reaction at 25 ° C to 35 ° C, heptane (590 kg) was added, and the mixture was stirred for at least 15 minutes, settled for at least 15 minutes, and then the lower aqueous phase was removed. The upper organic phase was washed with water (800 I). The heptane solution containing the product was decolorized with carbon and concentrated in vacuo to give the title compound as an orange oil (133.9 kg, 74% yield corrected for purity). 1 H-NMR (400 MHz, CDCl 3) 4.20 ppm (c, J = 7.07 Hz, 2H), 3.13-3.01 (m, 1 H), 2.75-2.49 (m, 2H), 1.80-1.06 (m, 10H), 0.88-0.86 (m, 6H); 3C-NMR (CDCl3) 169.69, 169.65, 121.28, 120.99, 61.14, 39.38, 39.15, 38.98, 37.67, 37.23, 36.95, 30.54, 30.47, 25.67, 25.45, 19.78, 19.61, 19.53, 18.56, 14.13, 14.05.

EXAMPLE 4 Preparation of (5R) -3-cyano-5-methyloctanoic acid ethyl ester (method B) A 250 ml flask was charged with LiCI (3.89 g, 0.0918 mol), water (7 ml) and dimethylsulfoxide (72 ml). Diethyl ester of (2'R) -2-cyano-2- (2'-methylpentyl) succinic acid (25.4 g, 0.0706 moles, 78.74% by gas chromatography) was charged, the mixture was heated at 135 ° C to 138 ° C. ° C and stirred at this temperature for at least 24 hours, until completion according to the gas chromatography analysis. After cooling the reaction at 25 ° C to 35 ° C, heptane (72 ml), saturated NaCl (72 ml) and water (72 ml) were added, and the mixture was stirred for at least 15 minutes, settled for minus 15 minutes, and then the lower aqueous phase was washed with heptane (100 ml).

The combined organic phases were concentrated in vacuo to provide the title compound as an orange oil (13.0 g, 84% corrected yield for purity).

EXAMPLE 5 Preparation of (5R) -3-cyano-5-methyloctanoic acid sodium salt A 4,000 I reactor was charged with (5R) -3-cyano-5-methyloctanoic acid ethyl ester (250 kg, 1.183 moles) and tetrahydrofuran (450 kg). An aqueous solution of NaOH (190 kg of 50% NaOH in 350 I of water) was prepared and then added to the tetrahydrofuran solution. The resulting solution was stirred at 20 ° C at 30 ° C for at least 2 hours, until the reaction was completed according to gas chromatography analysis. After this time, tetrahydrofuran was removed by vacuum distillation to provide an aqueous solution of the title compound, which was used immediately in the next step.

EXAMPLE 6 Preparation of sodium salt of (5R) -3-aminomethyl-5-methyloctanoic acid A 120 I autoclave was charged with nickel sponge catalyst (3.2 kg, Johnson &Mathey A7000), followed by an aqueous solution of sodium salt of (5R) -3-cyano-5-methyloctanoic acid (15 kg in 60 I of water), and the resulting mixture was hydrogenated at 344J kPa of hydrogen at 30 ° C to 35 ° C for at least 18 hours, or until the uptake of hydrogen ceased. The reaction was then cooled to 20 ° C to 30 ° C, and the spent catalyst was removed by filtration through a 0.2 μm filter. The filter cake was washed with water (2 x 22 I) and the resulting aqueous solution of the title compound was directly used in the next step.

EXAMPLE 7 Preparation of (5R) -3-aminomethyl-5-methyloctanoic acid A 4,000 I reactor was charged with an aqueous solution of (5R) -3-aminomethyl-5-mef-loctanoic acid (~ 150 kg in -1,000 I of water) and cooled to 0 ° C to 5 ° C. . Glacial acetic acid was added until the pH was 6.3 to 6.8. Anhydrous ethanol (40 kg) was added to the mixture. The resulting dense suspension was heated at 65 ° C to 70 ° C for less than 20 minutes and cooled to 0 ° C to 5 ° C for 3 hours. The product was collected by filtration, affording the title compound as a wet cake of water (76 kg, 97% yield corrected for purity, 10% water according to the Karl Fischer analysis), which was used in the following stage. 1 H-NMR (400 MHz, D 3 COD) 4.97 ppm (s a, 3 H), 3.00-2.74 (m, 2H), 2.48-2.02 (m, 3H), 1.61-1.03 (m, 7H), 0.94-0.86 (m, 6H); 13C-NMR (D3COD) 181.10, 181.07, 46.65, 45.86, 44.25, 43.15, 42.16, 41.64, 41.35, 33.45, 31.25, 31.20, 21.45, 21.41, 20.52, 20.12, 15.15, 15.12.

EXAMPLE 8 Preparation of (3S, 5R) -3-aminomethyl-5-methyloctanoic acid by contact with a resolving agent A 4,000 I reactor was charged with (5R) -3-aminomethyl-5-methyloctanoic acid (76 kg, 365 moles) wet with water (10%), (S) -mandelic acid (34.8 kg, 229 moles), anhydrous ethanol (1, 780 kg) and water (115 I). The resulting mixture was heated at 65 ° C to 70 ° C and stirred until the solids dissolved. The solution was then cooled to 0 ° C at 5 ° C for 2 hours, and stirred at this temperature for an additional 1 hour. The product was collected by filtration and the cake was washed with ethanol (3 x 60 kg) at -20 ° C. The crude product (18 kg with 48% yield) and ethanol (167 kg) were loaded into a reactor. The mixture was cooled to 0 ° C to 5 ° C and stirred at this temperature for 1.5 hours. The product was then collected by filtration, and the cake was washed with ethanol (3 x 183 kg) at -20 ° C to provide the title compound (17 kg, 94% yield). The quasimolecular ion (MH +) of the title compound was observed at 188.1653 urn, and is in accordance with the theoretical value of 188.1650; the measured value establishes the molecular formula as C? 0H2? NO2 since there can not be any reasonable alternative chemical entity containing only C, H, N and O with a molecular ion within the experimental error of 5 ppm (0.9 mDa) of the value measured IR (KBr) 2955.8 cm "1, 22.12.1, 1643.8, 1551.7, 1389.9, 1 H-NMR (400 MHz, D3COD) 4.91 ppm (sa, 2H), 3.01-2.73 (m, H), 2.45-2.22 (m, 2H), 1.60-1.48 (m, 1 H), 1.45-1.04 (m, 6H), 0.98-0.86 (m, H); 13 C-NMR (D3COD) 181.04, 45.91, 44.30, 42.13, 40.65, 33.42, 31.24, 1.39, 20.49, 15.11.

EXAMPLE 9 Enzymatic selection by enzymatic hydrolysis of (5R) -3-cyano-5-methyloctanoic acid ethyl ester (formula 15), yielding (3S, 5R) -3-cyano-5-methyloctanoic acid sodium salt (formula 16, R10 = Na +) and (3R, 5R) -3-cyano-5-methyloctanoic acid ethyl ester (formula 17, R11 = Et) or (3S, 5R) -3-cyano-5-methyloctanoic acid ethyl ester (formula 16) , R10 = Et) and sodium salt of (3R, 5R) -3-cyano-5-methyloctanoic acid (formula 17, R11 = Na +). c? it I CN 1 ? 16 Enzymatic selection was carried out using a selection kit comprising individual enzymes deposited in separate wells of a 96-well plate, which was prepared in advance according to a procedure described in D. Yazbeck et al., Synth. Catal. 345: 524-532 (2003). Each of the wells has an empty volume of 0.3 ml (plate of shallow wells). A well of the 96-well plate contains only phosphate buffer (10 μl, 0.1 M, pH 7.2). With few exceptions, each of the remaining wells contains an aliquot of enzyme (10 μl, 83 mg / ml), most of which are listed in table 2 above. Before use, the storage selection kit is removed at -80 ° C and the enzymes are allowed to thaw at room temperature for approximately 5 min. Potassium phosphate buffer (85 μl, 0.1 M, pH 7.2) is dispensed to each of the wells using a multichannel pipette. Concentrated substrate (formula 15.5 μl) is then added to each well by a multichannel pipette and the 96 reaction mixtures are incubated at 30 ° C and 750 rpm. The reactions are inactivated and sampled after 24 h by transferring each of the reaction mixtures to separate wells of a second 96-well plate. Each of the wells has an empty volume of 2 ml (deep well plate) and contains ethyl acetate (1 ml) and HCl (1 N, 100 μl). The components of each well are mixed by aspirating the contents of the well with a pipette. The second plate is centrifuged and 100 μl of the organic supernatant is transferred from each well to separate wells of a third 96-well plate (shallow plate). The wells of the third plate are subsequently sealed using a penetrable grid cover. Once the wells have been sealed, the third plate is transferred to a CG system for the determination of diastereoselectivity (ed). Table 3 lists the enzyme, trade name, value of E,? and selectivity for some of the enzymes that were selected. For one given enzyme, the value of E can be interpreted as the relative reactivity of a pair of diastereomers (substrates). The values of E listed in Table 3 were calculated from CG / derivatization data (conversion fraction, x and ed) using a computer program called Ee2, which is available at the University of Graz. In Table 3, the selectivity corresponds to the diastereomer- (3R, 5R) -3-cyano-5-methyloctanoic acid ethyl ester or (3S, 5R) -3-cyano-5-methaloctanoic acid ethyl ester which experienced the highest hydrolysis for an enzyme Dadaist.

TABLE 3 Results of the selection reactions of example 1 Enzyme Commercial name E x Selectivity Pancreatic porcine lipase Altus 1 5 15 (3R.5R) Lipase from Candida cylindracea Fluka 62302 1 4 3 (3R.5R) Lipase from Burkholdena cepacia Lipase Amano AH 200 15 (3R, 5R) Lipase from Pseudomonas fluorescens Lipase Amano AK 20 200 25 (3R.5R) Lipase from Candida rugosa Lipasa Amano AYS 1 4 2 (3R.5R) Rhizopus lipase delemar Lipase Amano D 6 44 (3S.5R) Lipase from Rhizopus oryzae Lipase Amano F-AP 15 20 1 (3S.5R) Lipase from Penicillium camembertn Lipasa Amano G 50 1 1 6 (3S.5R) Lipase from Mucor javanicus Lipasa Amano M 10 8 3 (3S, 5R) Lipasa from Burkholdena cepaaa Lipasa Amano PS 200 45 (3R.5R) Lipase from Pseudomonas sp BioCatalytics 103 4 7 (3S.5R) Lyophilized microbial lipase BioCatalytics 108 17 45 (3R.5R) CAL-B ofi zada BioCatalytics 110 1.2 96 (3S.5R) Candida sp lyophilized BioCatalytics 111 1.2 8 (3R.5R) CAL-A ofilized BioCatalytics 112 1.6 5 (3R.5R) Lipase from Thermomyces sp BioCatalytics 115 7 50 (3S.5R) Lipasa de Alcaligenes sp ofilizada BioCatalytics 117 15 31 (3R.5R) CAL-B L2 Sun Chnazyme L2 Sun 1 3 31 (3R.5R) Lipase from Thermomyces lanuginosus Lipolase Sigma L9 15 50 (3S.5R) Thermomyces lanuginosus Lipase Sigma L10 Novo 871 10 68 (3S.5R) Lipase from Rhizomucor miehei Palatasa Sigma L6 5.3 90 (3S.5R) Genencor 10 10 (3R.5R) fungal protease concentrate Bovine pancreatic protease a-chymotopsin I Sigma 10 10 (3R.5R) P18 Pineapple [Ananas comosus and Ananas Concentrate 10 10 (3R.5R) bracteatus (L)] bromelma Swine renal acylase Acylase I Sigma A-S2 2 60 (3S .5R) Esterase from Mucor miehei Fluka E5 5 79 (3S.5R) Acetyl nesterase Sigma ES8 1 1 54 (3S.5R) Cholesterolesterase BioCatalytics E3 1 1 54 (3S.5R) PLE-ammonium sulfate BioCatalytics 123 1 3 71 (3S.5R) EXAMPLE 10 Preparation of tert-butylammonium salt of (3S, 5R) -3-cyano-5-methyloctanoic acid by enzymatic resolution (5R) -3-Cyano-5-methyloctanoic acid ethyl ester (8 g, 37.85 mmol) was added to a 50 ml reactor equipped with a pH electrode, a suspended stirrer and a base addition conduit, followed by calcium acetate solution (8 ml), deionized water (3.8 ml) and LIPOLASE® 100L EX (0.2 ml). The resulting suspension was stirred at room temperature for 24 hours. The pH of the solution was maintained at 7.0 by adding 4M NaOH. The course of the reaction was followed by gas chromatography (conversion and% ed of product and starting material), and stopped after a 45-minute period had been consumed. % of the starting material (-4.3 ml of NaOH had been added). After the reaction was complete, toluene (20 ml) was added and the mixture was stirred for 1 minute. The pH was lowered to 3.0 by adding concentrated aqueous HCl, the solution was stirred for 5 minutes, and then transferred to a separatory funnel / extractor. The organic phase was separated and the aqueous phase was extracted once with 10 ml of toluene. The organic phases were combined and the toluene was evaporated to dryness. The crude product (sodium salt of (3S, 5R) -3-cyano-5-methyloctanoic acid, 75% diastereomeric excess according to gas chromatography) was resuspended in methyl-re-tert-butyl ether (40 ml). Tert-butylamine (1.52 g, 1.1 equivalents) was added dropwise to the mixture with stirring over a period of 5 hours. minutes Precipitated crystals shortly after finishing the addition, and were collected in a Buchner funnel. The solid was washed with methyl-rerc-butyl ether (2 x 20 ml). The residue was then dried in vacuo to provide the title compound (2.58 g, 96% diastereomeric excess according to gas chromatography).

EXAMPLE 11 Resolution of (3S, 5ff) -3-cyano-5-methyloctanoic acid ethyl ester by enzymatic hydrolysis of (3ff, 5R) -3-cyano-5-methyloctanoic acid ethyl ester to (3R) sodium salt , 5R) -3-cyano-5-methyloctanoic acid. 50% NaOH aq. (2.0 kg) is added to a vessel containing sodium phosphate (monobasic) monohydrate (4.7 kg) and water (1650 I) at a temperature of 20 ° C to 25 ° C. After stirring for 15 minutes, the pH of the mixture is checked to ensure it is in the range of 6.0 to 8.0. Amano PS lipase (17 kg) is added and the mixture is stirred for 30 to 60 minutes at 20 ° C at 25 ° C. The mixture is filtered to remove solids and the filtrate is combined with sodium bicarbonate (51 kg), (5R) -3-cyano-5-methyloctanoic acid ethyl ester (154 kg) and water (10 I). The mixture is allowed to react at approximately 50 ° C for 24 to 48 hours. The course of enzymatic hydrolysis is controlled by gas chromatography and is considered complete when the ratio of (3S, 5R) -3-cyano-5- (3S, 5-C) ethyl ester Methyloctanoic acid sodium salt of (3R, 5R) -3-cyano-5-methyloctanoic acid is greater than 99: 1, based on gas chromatography analysis. After the reaction is complete, the mixture is added to a vessel loaded with NaCl (510 kg), and the contents of the vessel are stirred at 20 ° C to 25 ° C. The mixture is extracted with methyl-fer-butyl ether (680 I) and the aqueous and organic phases are separated. The aqueous phase is discarded and the organic phase is washed with NaCl (26 kg), sodium bicarbonate (2 kg) and water (85 I). After dissolving the solids, the mixture is extracted again with MTBE (680 I), the aqueous and organic phases are separated and the organic phase is washed again with NaCl (26 kg), sodium bicarbonate (2 kg) and water (85 I). After separation of the aqueous and organic phases, the organic phase is distilled at 70 ° C and at atmospheric pressure, providing (3S, 5R) -3-cyano-5-methyloctanoic acid ethyl ester in the form of an oil (48.9 kg) , 88% yield). 1 H-NMR (400 MHz, CDCl 3) 4.17 ppm (c, J = 7.83 Hz, 2H), 3.13-3.06 (m, 1 H), 2.71-2.58 (m, 2H), 1.75-1.64 (m, 10H), 0.95 (d, J = 6.34, 3H), 0.92 (t, J = 6.83, 3H). 13 C-NMR (CDCl 3) 170.4, 121.8, 61.1, 39.6, 38.6, 37.0, 31.0, 25.9, 20.0, 18.5, 13.9.

EXAMPLE 12 Preparation of (3S, 5R) -3-aminomethyl-5-methyloctanoic acid from (3S, 5R) -3-cyano-5-methyloctanoic acid ethyl ester A solution (700 kg) containing acid ethyl ester is treated (3S, 5R) -3-cyano-5-methyloctanoic acid (30%) in methyl tert-butyl ether with an aqueous solution of sodium hypochlorite (35 kg, 12%) and water (35 I). After stirring for 2 hours at room temperature, the mixture is allowed to settle for 3 hours, and the aqueous and organic phases are separated. The organic phase is washed with water (150 I) at room temperature and the mixture is allowed to separate in the aqueous and organic phases. The organic phase is separated and subsequently reacted with ac NaOH (134 kg, 50%) and water (560 I). The reaction mixture is stirred for 2.5 to 3.5 hours at room temperature and the mixture is allowed to settle for 2 hours. The resulting aqueous phase, which contains sodium salt of (3S, 5R) -3-cyano-5-methyloctanoic acid, is fed to an autoclave which has been charged with nickel sponge A-7063 (43 kg) and is purged with nitrogen. The autoclave is heated at 28 ° C to 32 ° C and is pressurized with hydrogen at 344.7 kPa (50 psig). The pressure is maintained at 344.7 kPa (50 psig) for 18 to 24 hours. The autoclave is subsequently cooled to 20 ° C to 30 ° C and the pressure is reduced to 137.9 to 206.8 kPa (20 to 30 psig) for sampling. The reaction is complete when the conversion fraction of sodium salt of (3S, 5R) -3-cyano-5-methyloctanoic acid is 99% or greater. Filter the reaction mixture and combine the filtrate with an aqueous solution of citric acid (64 kg in 136 kg of water) at a temperature of 20 ° C to 30 ° C. Ethanol (310 I) is added and the mixture is heated at 55 ° C to 60 ° C. The mixture is kept for 1 hour and then cooled at a rate of about -15 ° C / h until the mixture reaches a temperature of about 2 ° C to 8 ° C. The mixture is stirred at that temperature for about 1.5 hours and filtered. The resulting filter cake is rinsed with water (150 I) at 2 ° C to 8 ° C and then dried at room temperature with a nitrogen sweep until the water content is less than 1% according to the Karl Fischer analysis., thus providing crude (3S, 5R) -3-aminomethyl-5-methyloctanoic acid. The crude product (129 kg) is loaded in a container. Water (774 kg) and anhydrous ethanol (774 kg) are added to the vessel and the resulting mixture is heated to reflux (about 80 ° C) until the solution becomes clear. The solution is passed through a polishing filter (1 μm) and heated again to reflux until the solution becomes clear. The solution is allowed to cool at a rate of about -20 ° C / hour until it reaches a temperature of about 5 ° C, at which a precipitate forms. The resulting dense suspension is maintained at 0 ° C to 5 ° C for approximately 90 minutes to complete the crystallization process. The dense suspension is filtered to isolate the title compound, which is rinsed with anhydrous ethanol (305 kg) and dried under a nitrogen sweep at a temperature of 40 ° C to about 45 ° C, until the water content (according to Karl Fischer analysis) and the ethanol content (depending on the gas chromatography analysis) are each less than 0.5% by weight. The representative yield of the title compound from (3S, 5R) -3-cyano-5-methyloctanoic acid ethyl ester is about 76%.

EXAMPLE 13. Preparation of (3S15R) -3-cyano-5-methyloctanoic acid methyl ester 2-methylpentyl methanesulfonic acid ester The reaction vessel was charged with toluene (170 ml, 8.5 ml / g based on the weight of 2-methyl-1-pentanol), 2-methyl-1-pentanol (20.00 g, 0.20 moles , in one portion) and triethylamine (21.78 g, 0.22 moles, in one portion). The reaction mixture was cooled to a temperature of -10 ° C to -5 ° C and methanesulfonyl chloride (22.42 g, 0.2 moles) was added dropwise, keeping the temperature at -10 ° C to -5 ° C. The reaction was stirred for 1 hour at a temperature of -10 ° C to -5 ° C. The reaction was quenched with 1.0 M aqueous HCl (60 mL, 3 mL / g based on the weight of 2-methyl-1-pentanol) and stirred for 30 minutes. The reaction mixture was allowed to warm to 25 ° C and the phases were separated. The organic phase was washed with 1 M aqueous NaHCO3 (60 ml, 3 ml / g based on the weight of 2-methyl-1-pentanol) and the phases were separated. The resulting solution of 2- methylpentyl ester of methanesulfonic acid in toluene was used directly in the next step. 1 - . 1-Bromo-2-methylpentane The reaction vessel was charged with methanesulfonic acid 2-methylpentyl ester (35.29 g, 0.2 moles, toluene solution), H20 (14 ml, 0.4 ml / g based on the weight of ester 2- methylpentyl of methanesulfonic acid), NaBr (20.14 g, 0.2 moles) and tetrabutylammonium bromide (12.61 g, 0.04 moles). The reaction mixture was heated to 90 ° C and stirred at this temperature for 3 hours. H 2 O (600 ml, 3 ml / g based on the weight of 2-methylpentyl ester of methanesulfonic acid) was charged and the phases were separated. The resulting solution of 1-bromo-2-methylpentane in toluene was used directly in the next step.

Methyl ester of (5R) -3-cyano-5-methyloctanoic acid The reaction vessel was charged with toluene (152 ml, 4.1 ml / g based on the weight of 1-bromo-2-methylpentane), followed by urea-butoxide of potassium (76.87 g, 0.69 moles) in one portion with stirring. The reaction mixture was cooled to a temperature of -10 ° C to -5 ° C. 4,4,4-Trimethoxybutyronitrile (37.39 g, 0.23 mol) was charged to the solution of 1-bromo-2-methylpentane in toluene from the previous step and the resulting solution was added dropwise to the reaction, maintaining the temperature at -5 ° C. The reaction mixture was stirred for 18 hours at a temperature of -10 ° C to -5 ° C. The reaction was quenched with H2O (323 ml, 10 ml / g based on the weight of 1-bromo-2-methylpentane), concentrated HCl (48.5 ml) was added dropwise to a pH range of 1-2, and the reaction mixture was stirred at 25 ° C for 1 hour. The phases were separated, the organic phase was washed with H20 (323 ml, 10 ml / g based on the weight of 1-bromo-2-methylpentane) and the phases were separated. The toluene was distilled from the organic phase, leaving a volume of 65 ml. The solution of (5R) -3-cyano-5-methyloctanoic acid methyl ester in resulting toluene was used directly in the next step.

Methyl ester of (3S, 5R) -3-cyano-5-methyloctanoic acid NaHCO3 (47.4 g, 0.75 equivalents), KH2P04 (4.4 g, 0.042 equivalents) and NaOH (0.84 g, 0.031 equivalents) were charged in H20 (1,500 ml) ) and stirred at room temperature until a solution formed. The PS-SD lipase enzyme (30 g, commercially available from Amano Enzyme Inc.) was loaded in the reaction and the suspension was stirred at room temperature until a solution formed. The reaction mixture was heated to 45 ° C while adding a solution of (5R) -3-cyano-5-methyloctanoic acid methyl ester (150 g, 0.76 mol, 1 equivalent) in toluene in one portion over a period of 5 minutes. The resulting oil-in-water suspension was stirred vigorously for 48 hours at 45 ° C. After completion of the reaction, the product was extracted with fer-butyl methyl ether (600 ml), the organic phases were combined and washed with brine (300 ml). The title compound was maintained in the form of a solution in fer-butyl methyl ether for further use in the preparation of (3S, 5R) -3-aminomethyl-5-methyloctanoic acid.

EXAMPLE 14 (3S, 5R) -3-aminomethyl-5-methyloctanoic acid, form A Procedure A Ethanol (25 ml) and water (25 ml) were charged into a vessel and stirred vigorously to ensure mixing. Crude (3S, 5R) -3-aminomethyl-5-methyloctanoic acid (2.5 g) was charged and the suspension was heated at reflux temperature (80 ° C) until a solution formed. The reaction was stirred at 80 ° C for 1 h to ensure complete dissolution. The solution was filtered through an in-line filter and transferred to a container without particles. The solution was allowed to cool at a rate of 0.5 ° C / minute until it reached 67 ° C, and it was seeded with 0.5% micronized seed (2.5-10 μm) in a dense suspension at 67 ° C. The suspension was cooled to 0 ° C at a rate of 0.5 ° C / minute and stirred at 0 ° C for 12 hours. The product was collected by filtration and the cake was washed with water without particles (2.5 ml), followed by ethanol without particles (2.5 ml). The product was dried in a vacuum tray and at 40 ° C for 24 hours, or until the water content was < 0.5% by weight.

Method B Charge crude (3S, 5R) -3-aminomethyl-5-methyloctanoic acid (25 mg / ml) in ethanol and water (50:50 by volume) in the reactor and stir at a moderately fast rate at throughout the process. HE heat the reactor to a temperature of 55 ° C at a heating rate of 0.5 ° C / minute, and maintain the temperature at 55 ° C for 1 hour to ensure complete dissolution. The solution is cooled to 51 ° C at a rate of 0.5 ° C / minute and maintained at this temperature for 15 minutes. Seed the solution with 5% micronized seed (2-25 μm) in a dense suspension (75 mg / ml in ethanol). The dense suspension of seed in ethanol is stirred before sowing to break up the agglomeration. The temperature is maintained at 51 ° C for an additional 20 minutes after sowing. The resulting dense suspension is cooled to 0 ° C at a rate of 0.5 ° C / minute and maintained at this temperature for 2 hours. The solids are filtered under vacuum and washed with cold ethanol. The filtered solids are dried in a vacuum oven at 50 ° C.

Procedure C Charge crude (3S, 5R) -3-aminomethyl-5-methyloctanoic acid (50 mg / ml) in ethanol and water (50:50 by volume) in the reactor and stir at a moderately fast rate at throughout the process. The reactor is heated to 80 ° C (reflux temperature) at a heating rate of 0.5 ° C / minute. The temperature is maintained at 80 ° C for 1 hour to ensure complete dissolution. The solution is cooled to 0 ° C at a rate of 0.5 ° C / minute and maintained at 0 ° C for 2 hours. The solids are filtered off in vacuo and washed with cold ethanol. The filtered solids are dried in a vacuum oven at 50 ° C.

Characterization of (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A The (3S, 5R) -3-aminomethyl-5-methyloctanoic acid was characterized in form A using the following techniques: 1. X-ray diffraction powder (PXRD) 2. Differential scanning calorimetry (DSC) 3. Fourier transform infrared spectroscopy (FT-IR) 4. Fourier transform Raman spectroscopy (FT-Raman) The following experimental conditions were used.

X-ray powder diffraction (PXRD) The powder X-ray diffraction pattern was determined using a D4 X-ray powder diffractometer from Bruker-AXS Ltd. equipped with an automatic sample changer, a teta-theta goniometer, a Automatic beam divergence slot and Vantec-1 PSD detector. The sample was prepared for analysis by arranging it on a low background silicon wafer sample assembly. The sample was rotated while it was irradiated with K-alfal copper X-rays (wavelength = 1.5406 Angstrom) with the X-ray tube operated at 40 kV / 30 mA. The analyzes were performed with the goniometer operating in continuous mode set at a count of 0.2 s per stage of 0.018 ° during a two-interval interval from 2 ° to 55 °.

As one skilled in the art will appreciate, the relative intensities of the various peaks in Tables 1 and 2 given below may vary due to a number of factors such as, for example, effects of orientation of the crystals in the X-ray beam, or the purity of the material that is being analyzed, or the degree of crystallinity of the sample. The peak positions can also be displaced by variations in the height of the sample, but the peak positions will remain substantially as defined in the given tables. The person skilled in the art will also appreciate that measurements that use a different wavelength will result in different shifts according to the Bragg equation -n? = 2d sin?. Such additional PXRD patterns generated by the use of alternative wavelengths are considered alternative representations of the PXRD patterns of the crystalline material of the present invention, and as such are within the scope of the present invention. The crystal structure in form A was determined by monocrystal X-ray diffraction analysis. In addition, the 2-theta angles, d-spacings and relative intensities were calculated from the monocrystalline structure using the "Reflex Powder Diffraction" module of Accelrys Materials Studio ™ (version 2.2). The relevant simulation parameters were, in each case: Wavelength: 1.540562 A (Cu Ka) Polarization factor: 0.5 Pseudo-Voigt profile: (U = 0.01, V = -0.001, W = 0.002).

Differential Scanning Calorimetry (DSC) The DSC was performed using a Perkin Elmer Pyris 1 DSC in 50 μl vented aluminum cuvettes with aluminum caps. Approximately 3 mg of the sample was heated at 10 ° C per minute in a range of 10 to 215 ° C with a nitrogen gas purge.

FT-IR The IR spectrum was acquired using a FT-IR spectrometer Avatar ThermoNicolet equipped with a unique reflective "Golden Gate ™" ATR accessory (diamond top plate and zinc selenide lenses) and a DTGS KBr detector. The spectrum was collected at a resolution of 2 cm "1 and with coadition of 256 scans Happ-Genzel apodization was used Because the FT-IR spectrum was recorded using single reflection ATR, no sample preparation was required. FT-IR ATR will cause the relative intensities of the infrared bands to differ from those observed in an FT-IR transmission spectrum using sample preparations in KBr disk or mull suspension in nujol Due to the nature of the FT-IR ATR, The bands at the lower wave number are more intense than those at the larger wave number.The experimental error, unless otherwise indicated, was ± 2 cm'1.

FT-Raman The Raman spectrum was collected using a FT-Raman ThermoNicolet 960 spectrometer equipped with a 1064 nm NdYAG laser and germanium detector. The spectrum was collected using a laser power of 320 mW in the sample and 5,140 co-added scans at a resolution of 2 cm "1. Happ-Genzel apodization was used, each sample (approximately 5 mg) was placed in a glass vial and was exposed to laser radiation.The data are presented as Raman intensity as a function of Raman displacement.The experimental error, unless otherwise indicated, was ± 2 cm "1.

Data The measured PXRD pattern is shown in Figure 1. The main characteristic peaks, with a relative intensity greater than 5%, are listed in Table 1. The pattern of calculated PXRD is shown in Figure 2. The main characteristic peaks, with a relative intensity greater than 5%, are listed in Table 2. The main characteristic peaks for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A are at 7.7, 15.8, 20.8 and 23.1 ° of angle two-teta ± 0.2 °. The DSC thermogram for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A is shown in Figure 3, and this shows a single peak of acute endothermic peak at 194 ° C ± 2 ° C. This event represents the fusion of (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A. The spectrum of FT-IR for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A is shown in Fig. 4 and 5. The main characteristic peaks for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in the form A are listed in Table 3. The FT-Raman spectrum for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A is shown in Figures 6 and 7. The main characteristic peaks for acid (3S, 5R ) -3-aminomethyl-5-methyloctanoic in form A are listed in table 4.

TABLE 1 PXRD peaks characteristic of the measured pattern for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in Form A TABLE 2 PXRD peaks characteristic of the calculated pattern for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in Form A TABLE 3 List of peaks for FT-IR data of (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in Form A The main absorption band frequencies (d: weak, m: medium, f: strong) are listed in the following table. The intensity assignments are relative to the main spectrum band, and are not based on the absolute values measured from the baseline.

TABLE 4 List of peaks for the FT-Raman data of (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in Form A Table of relatively sharp well-defined FT-Raman bands. Intensity assignments are relative to the band of the spectrum, and are not based on the absolute values measured from the baseline (d: weak, m: medium, f: strong, mf: very strong).

Figure 1 shows the measured PXRD pattern for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A. Figure 2 shows the PXRD standard calculated for (3S, 5R) -3-aminomethyl-5 -methonooctanoic in form A. Figure 3 shows the DSC thermogram for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A. Figure 4 shows the spectrum of FT-IR for (3S, 5R) acid -3-aminomethyl-5-methyloctanoic in form A. Figure 5 shows the region of identification of the spectrum of FT-IR for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A. Figure 6 shows the FT-Raman spectrum for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A .

Figure 7 shows the region of identification of the FT-Raman spectrum for (3S, 5R) -3-aminomethyl-5-methyloctanoic acid in form A. It should be noted that, as used in this specification and the appended claims, singular items such as "a", "an" and "he / she" can designate a single object or a plurality of objects unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing "a compound" can include a single compound or two or more compounds. It is to be understood that the foregoing description is intended to be illustrative and not restrictive. Many modalities will be apparent to those skilled in the art upon reading the above description. Therefore, the scope of the invention should be determined with reference to the appended claims, and includes the full scope of equivalents to which those claims relate. Descriptions of all articles and references, including patents, applications and patent publications, are incorporated herein by reference in their entirety for all purposes. Having described the invention as above, the contents of the following are declared as property

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing a compound of formula 10 or a salt thereof:

Wherein R1 and R2 are each independently selected from hydrogen and C1.3alkyl, with the proviso that R1 and R2 are not both hydrogen; R3 is selected from C6-6alkyl, C2-6alkenyl, C3.6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C6-6alkoxy, aryl, and arylalkylC3 -3, wherein each Aryl moiety is optionally substituted with one to three substituents independently selected from C 1 -C 3 alkyl, C 1-3 alkoxy, amino, C 1 -3-amino alkyl and halogen, and wherein each of the alkyl, alkenyl, cycloalkyl moieties and alkoxy mentioned above is optionally substituted with one to three fluorine atoms; and R8 is selected from C? -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C3.7 cycloalkenyl, haloalkyl

C2-6 haloalkenyl, C2-6 haloalkynyl, C6-6 arylalkyl, C2-6 arylalkenyl and C2-6 arylalkynyl, and in which each of the aforementioned aryl radicals can be optionally substituted with one to three substituents independently selected from C? -3 alkyl, C? -3 alkoxy, amino, C-? -3-amino alkyl and halogen; and wherein said method comprises: (a) contacting a compound of formula 7 with an enzyme, wherein the enzyme diastereoselectively hydrolyzes the compound of formula 7 to the compound of formula wherein R1, R2 and R3 are as defined for a compound of formula 10; and R6 in the formula 7 is selected from C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C6-6 haloalkyl, C2.6 haloalkenyl, C2-6 haloalkynyl , C6-6 arylalkyl, C2-6 arylalkenyl and C2-6 arylalkynyl, and in which each of the aforementioned aryl moieties may be optionally substituted with one to three substituents independently selected from C?-3l alkoxy C? alkyl 3, amino, C1-3alkylamino and halogen; and (b) isolating the compound of formula 10. 2. The process according to claim 1, further characterized in that R6 and R8 are C-? 6 alkyl. 3 - The method according to claim 1 or claim 2, further characterized in that R1 and R2 are independently each hydrogen or methyl, with the proviso that R1 and R2 are not both hydrogen, and R3 is alkyl d-6.

4. - The procedure in accordance with any one of the claims 1 to 3, further characterized in that R1 is hydrogen, R2 is methyl and R3 is ethyl.

5. - The procedure in accordance with any one of the claims 1 to 4, further characterized in that the enzyme in step (a) It is a lipase.

6. - The method according to claim 5, further characterized in that the lipase is from the microorganism Burkholderia cepacia or from the microorganism Thermomyces lanuginosus.

7 '.- The procedure in accordance with any one of the claims 1 to 6, further characterized by additionally comprising the step of: (c) optionally converting the compound of formula 10 in a salt thereof, preferably in an alkali metal salt thereof, most preferably in the sodium salt thereof.

8. - A compound of formula 7 7 wherein R1, R2, R3 and R6 are as defined in claim 1. 9 -. 9 - The compound according to claim 8, further characterized in that R6 is C-? 6 alkyl. 10. The compound according to claim 8 or the claim 9, further characterized in that R6 is methyl, ethyl, n-propyl or Isopropyl. 11. A compound of formula 10 R! Or a salt thereof, wherein R, R2, R3 and R8 are as defined in claim 1. 12. The compound according to claim 10, further characterized in that R8 is selected from hydrogen and C- alkyl. H.H. 13. The compound according to claim 11 or claim 12, further characterized in that R8 is selected from hydrogen, methyl, ethyl, n-propyl and isopropyl. 14. The compound according to any one of the claims 8 to 13, further characterized in that R1 and R2 are each independently hydrogen or methyl, with the proviso that R1 and R2 are not both hydrogen; and R3 is C-? -6 alkyl. 15. The compound according to any one of claims 8 to 14, further characterized in that R1 is hydrogen, R2 is methyl and R3 is selected from methyl, ethyl, n-propyl and isopropyl. 16. The compound according to any one of claims 8 to 15, further characterized in that R1 is hydrogen, R2 is methyl and R3 is ethyl. 17. The compound according to claim 8, further characterized in that it is selected from: (5R) -3-cyano-5-methylheptanoic acid ethyl ester; (5R) -3-cyano-5-methyloctanoic acid ethyl ester; ethyl ester of (5R) -3-cyano-5-methylnonanoic acid; (5R) -3-cyano-5,7-dimethyloctanoic acid ethyl ester; (5R) -3-cyano-5-methylheptanoic acid; (5R) -3-cyano-5-methyloctanoic acid; (5R) -3-cyano-5-methylnonanoic acid; (5R) -3-cyano-5J-dimethyloctanoic acid; (3S, 5R) -3-cyano-5-methylheptanoic acid; (3S, 5R) -3-cyano-5-methyloctanoic acid; (3S, 5R) -3-cyano-5-methylnonanoic acid; (3S, 5R) -3-cyano-5,7-dimethyloctanoic acid; ethyl ester of (3S, 5R) -3-cyano-5-methylheptanoic acid; (3S, 5R) -3-cyano-5-methyloctanoic acid ethyl ester; ethyl ester of (3S, 5R) -3-cyano-5-methylnonanoic acid; ethyl ester of (3S, 5R) -3-cyano-5,7-dimethyloctanoic acid; (3R, 5R) -3-cyano-5-methylheptanoic acid; (3R, 5R) -3-cyano-5-methyloctanoic acid; (3R, 5R) -3-cyano-5-methylnonanoic acid; (3R, 5R) -3- cyano-5J-dimethyloctanoic acid; ethyl ester of (3R, 5R) -3-cyano-5-methylheptanoic acid; (3R, 5R) -3-cyano-5-methyloctanoic acid ethyl ester; ethyl ester of (3R, 5R) -3-cyano-5-methylnonanoic acid; ethyl ester of (3R, 5R) -3-cyano-5,7-dimethyloctanoic acid; and you come out of them. 18. The compound according to claim 17, further characterized in that it is (3S, 5R) -3-cyano-5-methyloctanoic acid or a salt or ester thereof. 1

9. A process for preparing a compound of formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: 1 wherein R1, R2 and R3 are as defined in any one of claims 1, 3 or 4; and wherein said method comprises steps (a) to (c) of the process as defined in any one of claims 1 to 7, and further comprises the steps of: (d) reducing the cyano moiety of a compound of formula 10, or salt thereof, providing a compound of formula 1 or salt thereof; and (e) further optionally converting the resulting compound of formula 1, or salt thereof, into a pharmaceutically acceptable salt, solvate or hydrate thereof. 20. A process for preparing a compound of formula 7, or a salt thereof: wherein R1, R2, R3 are as defined in any one of claims 1, 3 and 4; and, R6 is C6-C6 alkyl; and wherein said method comprises: (a) reacting a compound of formula 19 with an orthoester compound of formula 20 in the presence of a base 19 wherein R1, R2, R3 and R6 are as defined above for a compound of formula 7; and X2 is halogen; and (b) hydrolyzing the resulting orthoester intermediate yielding the carboxylic ester of formula 7.