METHOD FOR PREPARING A DRUG USED FOR PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA * * * FIELD OF THE INVENTION 5 Described herein is a method for preparing methyl 3-[2-[[(4S)-4-cyano-4-(3,4- dimethoxyphenyl)-5-methylhexyl]-methylamino]ethyl]benzoate. STATE OF THE ART Methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]- methylamino]ethyl]benzoate of formula (I) 10
(I), also known as etripamil, is a novel calcium channel blocker belonging to the chemical class of phenylalkylamines. Calcium channel blockers are able to bind to L-type calcium channels, and thereby they regulate the calcium influx ions into cells and the resulting 15 electrical signalling/muscle stimulation. Blocking the entry of calcium ions into the cells of the heart and arteries causes vasodilation of the smooth vascular muscle by reducing the force generated by the myocardium, the heartbeat and the speed of signal conduction. Thanks to these activities, calcium channel blockers have become widely used in the therapeutic field as antihypertensives, antiarrhythmics, in the treatment of angina pectoris 20 and heart attacks, as well as in the treatment of oesophageal spasms. Etripamil has emerged as a new alternative to the classic oral and parenteral calcium channel blockers. Phase III clinical trials have demonstrated its efficacy for the treatment of paroxysmal supraventricular tachycardia (PSVT), an arrhythmia characterized by a sudden acceleration of the heartbeat initiated on the supraventricular side of the heart. 25 Currently, there are parenteral drugs approved for the treatment of PSVT. Oral beta blockers are also prescribed, but they all do not have a rapid onset of effect. In addition, there is a lack of drugs that can be taken independently by patients, and which allow to manage arrhythmias even in an out-of-hospital environment. Etripamil, thanks to its fast action, a half-life of about 20 minutes, and its high solubility, can be formulated as a nasal 30 spray. In this way, the drug can be self-administered by the patient during PSVT. Etripamil is described in US 10,010,523, which claims the racemic compound, a salt or an enantiomer thereof. Example 51 describes the procedure for preparing the etripamil
racemate. WO2016/165014 and US 10,117,848 disclose in Example 1 the preparation of racemic etripamil comprising condensating 5-bromo-2-(3,4-dimethoxyphenyl)-2- isopropylpentanenitrile and methyl 3-(2-(methylamino)ethyl)benzoate. 5 Thus, there remains the need to obtain the (S)-enantiomer of etripamil with a purity suitable to meet regulatory requirements. This has stimulated the search for alternative methods for its preparation, which are efficient, eco-friendly, robust, safe, cost-effective and suitable for a production and purification of etripamil at an industrial scale. A new and safe process for the preparation of etripamil is herein disclosed, which 10 due to its high yields and lower presence of impurities is particularly suitable for an industrial production. This new process, thanks to the specific conditions, provides a pure product, which is suitable to meet the regulatory requirements required for active pharmaceutical ingredients (APIs). SUMMARY OF THE INVENTION 15 In some embodiments, the present invention is directed to a process for preparing a compound of formula (II), or a salt thereof,
(II), wherein R is hydrogen or methyl; 20 comprising: - rearranging the compound of formula (III)
(III), to form 3-(3- (IV)
25 (IV)
- treating 3-(3-isocyanatopropyl)benzonitrile of formula (IV) with R1OH to form a compound of formula (V)
, wherein R1 is hydrogen or C1-C6 alkyl; - and converting the compound of formula (V) into the compound of formula (II), or a salt thereof; and, in the case where R is methyl, comprising methylating the compound of formula (V), wherein R1 is C1-C6 alkyl, forming the compound of formula (VI)
(VI); or methylating the compound of formula (II), wherein R is hydrogen. Further embodiments concern the conversion of the compound of formula (II), or a salt thereof, into the compound of formula (I)
. DETAILED DESCRIPTION OF THE INVENTION In some embodiments, the present invention is directed to a process for preparing a compound of formula (II), or
(II), wherein R is hydrogen or methyl;
comprising: - rearranging the compound of formula (III) to form 3-(3-
(IV)
- treating 3-(3- (IV) with R1OH to form a compound of formula (V)
(V), wherein R1 is hydrogen or C1-C6 alkyl; - and converting the compound of formula (V) into the compound of formula (II), or a salt thereof; and in the case where R is methyl comprising methylating the compound of formula (V), wherein R1 is C1-C6 alkyl, forming the compound of formula (VI)
(VI); or methylating the compound of formula (II), wherein R is hydrogen. The term “salt” or “salts” of a compound of formula (II) refers to, for example, acid addition salts with inorganic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric and phosphoric acids and the like, or organic acids, e.g., acetic, propionic, glycolic, lactic,
oxalic, malonic, malic, tartaric, citric, succinic, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic and salicylic acids, and the like. If the case, the compound of formula (II) can be converted to the salt thereof, or the salt of a compound of formula (II) to its free base according to known methods. 5 The salt of a compound of formula (II) is typically a pharmaceutically acceptable salt. The term "comprising" means that additional reaction steps may be present, but which do not substantially modify the product obtained from the process. The term "comprising" also includes the terms "consisting" and "essentially consisting of". 10 3-Cyano-benzenepropanoic acid, the compound of formula (III), used as a starting material can be in any form. It can be amorphous or crystalline. For instance, it can be an anhydrous, a hydrated or a solvated crystalline form. The compound of formula (III) is known and is commercially available (e.g. Apollo Scientific, catalogue number OR932222). Alternatively, the compound of formula (III) can be prepared, for example, 15 according to the procedures described in GB2184121 or in Example 3 of US 6,323,227. The rearrangement of the compound of formula (III) into the compound of formula (IV) and its subsequent treatment with R1OH, wherein R1OH is as defined above, to the compound of formula (V) can be carried out, for example, according to the Schmidt, Lossen, Hofmann or Curtius reactions. 20 The rearrangement of the compound of formula (III) to provide the compound of formula (V) can be carried out, for example, by treating the compound of formula (III) with hydrazoic acid in presence of sulfuric acid according to the Schmidt reaction, or according to the Curtius reaction, for instance by activating 3-cyano-benzenepropanoic acid of formula (III), e.g. with a halogenating agent or with carbonyldiimidazole (CDI), 25 and its subsequent treatment with sodium azide, or first with hydrazine and then with a nitrite or nitrous acid, or with diphenylphosphorylazide (DPPA) in the presence of an organic base forming 3-(3-cyanophenyl)propanoyl azide, which heated, e.g. to the reflux temperature of the solvent of formula (IV)
30 (IV). 3-(3-Isocyanatopropyl)benzonitrile of formula (IV) can also be prepared according
to the Hofmann reaction by converting the carboxylic acid of formula (III) into the amide according to known methods, and then treating it with an alkaline hypohalogenite, e.g. sodium hypochlorite or sodium hypobromite. Finally, the compound of formula (IV) can be also prepared according to the Lossen reaction by treating the carboxylic acid of formula (III) with a halogenating agent, preferably thionyl chloride or oxalyl chloride. The subsequent reaction with an acyl-hydroxylamine, preferably acetyl-hydroxylamine, leads to the respective acylated hydroxamic acid, which treated with a base, e.g. an alkaline hydroxide, provides 3-(3-isocyanatopropyl)benzonitrile of formula (IV). Examples of halogenating agents are thionyl chloride or oxalyl chloride. Examples of nitrites are lithium nitrite, sodium nitrite, or potassium nitrite. The organic base is typically triethylamine, diisopropylethylamine (DIPEA), tri-n- butylamine, diazabicycloundecene, N-C1-C6 alkyl pyrrolidines, N-C1-C6 alkyl morpholine, N-C1-C6 alkyl piperidine, pyridine, C1-C6 alkyl pyridines, N-C1-C6 alkyl piperazine or N,N’-diC1-C6 alkyl piperazine. In a preferred embodiment, the organic base is triethylamine, DIPEA, or pyridine. The term "C1-C6 alkyl" refers to a linear or branched hydrocarbon chain, consisting only of carbon and hydrogen atoms and having from one to six carbon atoms. In a preferred embodiment, the "C1-C6 alkyl" group is a linear or branched "C1-C4 alkyl" group. Examples of a "C1-C6 alkyl" are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, or tert-butyl. A further embodiment concerns the rearrangement of the compound of formula (III) into the compound of formula (IV). The rearrangement can be carried out as described above. Finally, treating 3-(3-isocyanatopropyl)benzonitrile of formula (IV) with R1OH, wherein R1 is as defined above, yields the compound of formula (V) as defined above. R1OH is a C1-C6 alcohol, such as a C1-C4 alcohol, or water. Examples of a C1-C6 alcohol, which may be linear, cyclic or branched, are methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 1-butanol, 2-butanol, tert- butanol, 1-pentanol, 2-pentanol, 3-pentanol, or cyclohexanol. In a preferred embodiment, R1OH is a C1-C6 alcohol, wherein the C1-C6 alcohol is as defined above. The preparation of the compound of formula (V) comprising rearranging the
compound of formula (III) and reacting the obtained 3-(3-isocyanatopropyl)benzonitrile of formula (IV) with R1OH can be carried out by the one-pot or single-vessel process without isolating the compound of formula (IV). The preparation of the compound of formula (V) comprising rearranging the 5 compound of formula (III) and reacting the obtained 3-(3-isocyanatopropyl)benzonitrile of formula (IV) with R1OH can be carried out in the presence of a solvent, which can be for instance a dipolar aprotic solvent, an acyclic or cyclic ether, a chlorinated solvent, or a non-polar aprotic solvent. For example, the dipolar aprotic solvent may be chosen from the group comprising 10 dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, or dimethyl sulfoxide (DMSO). For example, the acyclic or cyclic ether may be chosen in the group comprising tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (methyl-THF), diethyl ether, methyl tert- butyl ether, or dioxane. 15 In a preferred embodiment, the ether is methyl-THF. For example, the chlorinated solvent can be chosen from the group comprising dichloromethane, dichloroethane, chloroform or chlorobenzene. For example, the non-polar aprotic solvent can be chosen from the group comprising hexane, heptane, cyclohexane, toluene, o-xylene, m-xylene or p-xylene. 20 In a further embodiment, the solvent can be a mixture of two or more solvents, preferably two or three solvents chosen from those listed above. The rearrangement reactions can be carried out according to known methods, e.g. at a temperature ranging approximately from about 0°C to the reflux temperature of the solvent. 25 The reaction time is typically from about 0.5 hours to 48 hours, such as about 1 hour, about 2.5 hours, about 4 hours, about 6 hours, about 9 hours, about 12 hours, about 18 hours, about 24 hours, or about 36 hours. In a further embodiment, the reaction time is from 2 hours to 15 hours, preferably from 5 hours to 10 hours. 30 The reaction of 3-(3-isocyanatopropyl)benzonitrile of formula (IV) with a linear or branched C1-C6 alcohol or with water can be carried out by directly adding alcohol or water to the reaction mixture comprising the isocyanate of formula (IV). The reaction of 3-(3-isocyanatopropyl)benzonitrile of formula (IV) with a linear or
branched C1-C6 alcohol or with water can be carried out according to known methods, e.g. at a temperature varying approximately from about 0°C to the reflux temperature of the solvent. The reaction time is typically from about 0.1 hours to 40 hours, such as about 0.5 5 hours, about 1 hour, about 2.5 hours, about 4 hours, about 6 hours, about 9 hours, about 12 hours, about 18 hours, about 24 hours, or about 36 hours. In one embodiment, the conversion of the compound of formula (V) into methyl 3- (2-aminoethyl)benzoate of formula (II), thus the compound of formula (II), wherein R is hydrogen, may be carried out in the presence of an inorganic acid or an inorganic base 10 forming the carboxylic acid, which can be then treated with methanol in the presence of an inorganic acid. For example, the inorganic acid can be chosen from a group of sulphuric acid, phosphoric acid and a hydrogen halide/hydrohalic acid. Examples of hydrogen halide/hydrohalic acid can be hydrochloric acid (HCl), 15 hydrobromidic acid (HBr) or hydroiodic acid (HI). In one embodiment, the inorganic acid is an aqueous solution of said acid. In a preferred embodiment, the hydrogen halide is hydrochloric acid (HCl). In a more preferred embodiment, the inorganic acid is an aqueous solution of hydrochloric acid, for example at about 2 M, 6 M or 12 M concentration. The use of 20 hydrochloric acid in water furnishes 3-(2-aminoethyl)benzoic acid, which treated with methanol provides methyl 3-(2-aminoethyl)benzoate of formula (II). The inorganic base may be a hydroxide, a carbonate, a hydrogen carbonate, or a phosphate of an alkali metal or of an alkaline earth metal. Examples of inorganic bases are sodium hydroxide, potassium hydroxide, 25 magnesium hydroxide or calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium hydrogen carbonate or calcium hydrogen carbonate, sodium phosphate, potassium phosphate, magnesium phosphate or calcium phosphate. The inorganic base may be 30 an aqueous solution of said base. In a preferred embodiment, the inorganic base is sodium hydroxide or potassium hydroxide. In a preferred embodiment, the compound of formula (V) is first treated with an
aqueous solution of HCl, and then with methanol in presence of an inorganic acid as catalyst, for instance sulphuric acid. In further embodiment, the compound of formula (V) can be treated with an acid, e.g. gaseous HCl, and methanol in the absence of water forming an imine ether, which 5 treated with water provides the compound of formula (II). A compound of formula (V), wherein R1 is hydrogen, spontaneously hydrolyses to 3-(2-aminoethyl)benzonitrile, which can be treated with an inorganic acid or an inorganic base and methanol as described above providing methyl 3-(2-aminoethyl)benzoate of formula (II). The amino group may be optionally protected. 10 Alternatively, 3-[(2-(methylamino)ethyl]benzonitrile can be prepared from 3-(2- oxyethyl)benzonitrile and methylamine according to the Leuckart-Wallach reaction. Examples of amino protecting groups are known to the expert in the field, for example it can be one of the protective groups described in T. W. Greene and P. G. M. Wuts "Protective Groups in Organic Synthesis" Third Edition, Wiley New York 1999. For 15 instance, an amino protecting group can be one of those used for the peptide chemistry, such as benzyl, benzyloxycarbonyl, and tert-butyoxycarbonyl. A further embodiment concerns the conversion of the compound of formula (V) into the compound of formula (II). The conversion can be carried out as described above. The methylation of the compound of formula (V) to form the compound of formula 20 (II), wherein R is methyl, can be done by methylating the compound of formula (V), wherein R1 is C1-C6 alkyl, for instance with an electrophilic methyl source in the presence of a strong base forming the compound of formula (VI)
(VI). 25 The electrophilic methyl source may be for instance iodomethane or methyl iodide, methyl bromide, methyl chloride, methyl fluoride, dimethyl sulfate, methyl triflate (MeOTf), 4-methylsulfonyltoluene, 4-methylsulfonylbenzene, dimethyl carbonate, tetramethylammonium chloride, or mixtures thereof. In a preferred embodiment, the electrophilic methyl source may be iodomethane, 30 dimethyl sulfate, or mixtures thereof. The strong base may be selected from the group comprising an alkali metal
alkoxide, such as sodium methoxide, potassium methoxide, sodium tert-butoxide or potassium tert-butoxide; a hydride of an alkali metal, such as sodium hydride or potassium hydride; a tertiary amine such as diazabicycloundecene (DBU), 2,2,6,6-tetramethyl piperidine or 1,1,3,3-tetramethylguanidine; lithium diisopropylamide (LDA), 5 bis(trimethylsilyl)amide of an alkali metal, such as lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), or potassium bis(trimethylsilyl)amide (KHMDS). Methylation of the compound of formula (V) to form the compound of formula (VI) can be performed in the presence of a solvent, which may be for example a dipolar aprotic 10 solvent, an acyclic or cyclic ether, a chlorinated solvent, or a non-polar aprotic solvent, as defined above. In a preferred embodiment, the solvent is an acyclic or cyclic ether. In a more preferred embodiment, the solvent is methyl-THF. The methylation of the compound of formula (V) to form the compound of formula 15 (VI) can be carried out at a temperature ranging approximately from about 0°C to the reflux temperature of the solvent, for instance at about 10°C, about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C, about 80°C, about 90°C or about 100°C. The reaction time is typically from about 0.5 hours to 96 hours, such as about 1 hour, about 2.5 hours, about 4 hours, about 6 hours, about 9 hours, about 12 hours, about 20 18 hours, about 24 hours, about 36 hours, 48 hours, 60 hours or 72 hours. In a further embodiment, the reaction time is from 2 hours to 48 hours, preferably from 5 hours to 24 hours. The conversion of the compound of formula (VI) into methyl 3-[2- (methylamino)ethyl]benzoate of formula (II), thus the compound of formula (II), wherein 25 R is methyl, may be carried out in the presence of an inorganic acid and methanol, as described above for the conversion of the compound of formula (V) into methyl 3-(2- aminoethyl)benzoate of formula (II). A compound of formula (II), wherein R is methyl, can be obtained by methylating the compound of formula (II), wherein R is hydrogen. 30 In one embodiment, the methylation of the compound of formula (II), wherein R is hydrogen, can be performed under the conditions specified for the reductive amination reaction with formaldehyde as and in the presence of a reducing agent and a solvent. The reducing agent may be, for example, NaCNBH3 or NaB(OAc)3H, optionally
generated in situ from NaBH4 and acetic acid, or a homogenous or heterogeneous palladium (Pd) or platinum (Pt) metal based catalyst and molecular hydrogen, or a homogenous or heterogeneous palladium (Pd) or platinum (Pt) metal based catalyst and a suitable hydrogen donor under hydrogen transfer conditions, as known in the 5 art. The solvent may be an organic solvent selected from the group comprising a dipolar aprotic solvent, a cyclic or acyclic ether, a chlorinated solvent, non-polar aprotic solvent, a C1-C6 alcohol, as defined above, or an ester; or the solvent may be water. For example, the ester may be chosen from the group comprising ethyl acetate 10 (EtOAc), isopropyl acetate or butyl acetate. In a further embodiment, the solvent may be a mixture of two or more solvents, preferably two or three solvents chosen from those listed above. Formaldehyde may be used, for example, in the form of an oligomer, for instance as 1,3,5-trioxane or as paraformaldehyde - or as the hydrate, hemiacetal, acetal, N,O-acetal, 15 aminal or hemiaminal. In a further embodiment, the methylation of the compound of formula (II), wherein R is hydrogen, can be performed with an electrophilic methyl source as defined above. The methylation reaction with electrophilic methyl source may be performed at a wide temperature range, e.g. between -100° C and +50° C. 20 In a preferred embodiment, the reaction is carried out in a range from -80° C to +20° C. In a more preferred embodiment, the reaction is carried out in a range from -10° C and +10° C, for example at 0° C. The methylation reaction with electrophilic methyl source can be carried out in a 25 solvent, which may be for example an acyclic or cyclic ether or a non-polar aprotic solvent, as defined above. In a preferred embodiment, the methylation reaction with electrophilic methyl source can carried out in the presence of a base. The base may be an organic base or an inorganic base. 30 The organic base may be an organic base as defined above. The inorganic base may be an inorganic base as defined above. In a preferred embodiment, the methylation reaction with electrophilic methyl source is carried out with potassium carbonate.
A further embodiment concerns the methylation of the compound of formula (V) into the compound of formula (VI). The methylation can be carried out as described above. A compound of formula (V), wherein R1 is hydrogen, spontaneously hydrolyses to 3-(2-aminoethyl)benzonitrile, which can be methylated and treated with an inorganic acid 5 and methanol as described above providing methyl 3-[2-(methylamino)ethyl]benzoate of formula (II). The amino group may be optionally protected as described above. A further embodiment concerns the conversion of the compound of formula (II), or a salt thereof, into the compound of formula (I)
10 (I). The compound of formula (II), or a salt thereof, may be prepared according to the procedures described above. The compound of formula (II), or a salt thereof, may be converted into the compound of formula (I) by treating it with the compound of formula ((S)-VII) 15
, to obtain the amide of formula (VIII)
, 20 wherein R is hydrogen or methyl; which, when treated with a reducing agent, forms the compound of formula (I). In some embodiments, the present invention is directed to a process for preparing the compound of formula (I)
comprising
- reducing the compound of formula (VIII) 5
wherein R is or - and in the case where R is hydrogen, methylating the so obtained reduced 10
In some embodiments, the compound of formula (VIII)
, 15 wherein R is hydrogen or methyl; may be prepared by a of formula (II), or a salt thereof,
, wherein R is hydrogen or methyl; 20 with a compound of formula ((S)-VII)
- . In some embodiments, the compound of formula (II), or a salt thereof, can be prepared as described above. 5 The compound of formula ((S)-VII) is a known compound, and its synthesis is described for example by Bannister et al. in ORPD 2000, 4, 467-472. For example, the compound of formula ((S)-VII) may be prepared by treating 3,4- dimethoxybenzeneacetonitrile with 2-bromopropane, in the presence of a strong base as defined above, e.g. an alkali metal alkoxide, an alkali metal hydride, or an alkali metal10 bis(trimethylsilyl)amide, such as sodium bis(trimethylsilyl)amide (NaHMDS), to obtain 2- (3,4-dimethoxyphenyl)-3-methyl-butanenitrile of formula (X)
(X). 3,4-Dimethoxybenzeneacetonitrile is commercially available (e.g. Sigma Aldrich, 15 catalogue number: 126349). 2-Bromopropane is commercially available (e.g. Sigma Aldrich, catalogue number: B78114). The reaction of dimethoxybenzeneacetonitrile with 2-bromopropane can be carried out in the presence of a solvent, which may be for example a dipolar aprotic solvent, an acyclic or cyclic ether, a chlorinated solvent, or a non-polar aprotic solvent, as defined 20 above. In a preferred embodiment, the solvent is an acyclic or cyclic ether. In a more preferred embodiment, the solvent is tetrahydrofuran (THF). 2-(3,4-Dimethoxyphenyl)-3-methyl-butanenitrile of formula (X) can be converted to (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid of formula ((rac)-VII) 25 with a C1-C6 alkyl acrylate, e.g. methylacrylate, in the presence of a strong base, as defined above, e.g. an alkali metal alkoxide, for example tert-BuOK, in a protic polar solvent and by subsequent hydrolysis with an inorganic base. For example, the protic polar solvent may be chosen from a group comprising water
or a C1-C6 alcohol, wherein the C1-C6 alcohol is as defined above. In one embodiment, the protic polar solvent may be a mixture of two or more protic polar solvents, preferably two or three of the protic polar solvents chosen from those listed above. 5 The inorganic base may be an inorganic base as defined above. In a preferred embodiment, the inorganic base is sodium hydroxide. ((S)-4-Cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid of formula ((S)- VII) can be prepared by isolating the (R)-phenylethylamine salt of (S)-4-cyano-4-(3,4- dimethoxyphenyl)-5-methylhexanoic acid of formula ((S)-VII) according to the 10 procedures described by Bannister et al. in ORPD 2000, 4, 467-472. After isolating the (S)-phenylethylamine salt of (R)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylexanoic acid ((R)-VII) in ethyl acetate (EtOAc), the organic phase is acidified and concentrated. The (R)-phenylethylamine salt of (S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid of formula ((S)-VII) is isolated from toluene after addition of (R)-phenylethylamine. 15 The (R)-phenylethylamine salt of (S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexanoic acid of formula ((S)-VII) is then treated with an acid, e.g. hydrochloric acid, in a non-polar solvent as defined above, for example in o-xylene, m-xylene or p- xylene to obtain (S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic of formula ((S)- VII). 20 The amidation reaction of the compound of formula (II), or a salt thereof, with the compound of formula ((S)-VII) providing the compound of formula (VIII) can be carried out according to conventional amidation techniques. In one embodiment, the amidation reaction can be performed under the reaction conditions under which an amine and a carboxylic acid couple to form an amide, using a 25 coupling reagent and, optionally, a coupling additive, in the presence of an organic base as defined above. For example, the coupling reagents may be chosen from the group comprising oxalyl chloride, thionyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), carbonyl diimidazole (CDI), 30 isobutyl chloroformate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, 2-chloro-4,6-dimethoxy[1,3,5]triazine (CDMT) and N-
methylmorpholine (NMM), and the like. In a preferred embodimòlent, the coupling reagent is oxalyl chloride, thionyl chloride, CDI or CDMT and NMM. For example, the coupling additives may be chosen from the group comprising 4- 5 (dimethylamino)pyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and the like. The amidation reaction may be carried out in a solvent. For example, the solvent may be chosen from the group comprising a dipolar aprotic solvent, an acyclic or cyclic ether, a chlorinated solvent, a non-polar aprotic solvent, 10 or an ester, as defined above. In some embodiments, the solvent is acetonitrile or THF. In some embodiments, the amidation reaction can be carried out at a temperature of from about 120°C or less. In some embodiments, the amidation reaction may be carried out at a temperature 15 in a range of from about -20°C to about 120°C, for example from about 0°C to about 40°C or from about 10°C to about 30°C. In some embodiments, the amidation reaction can be carried out at about -20°C, at about -10°C, at about 0°C, at about 10°C, at about 20°C, at about 25°C, at about 30°C, at about 40°C, at about 50°C, at about 60°C, at about 70°C, at about 80°C, at about 90°C, at 20 about 100°C or at about 110°C. A compound of formula (VIII), wherein R is methyl, may be obtained by reacting the compound of formula (VIII), wherein R is hydrogen, with an electrophilic methyl source in the presence of a strong base according to the procedures disclosed above for the preparation of a compound of formula (VI) by methylating the compound of formula (V). 25 In some embodiments, the reduction of the amide moiety of the compound of formula (VIII) is performed without reducing the methyl benzoate group. In some embodiments, the reduction of the amide moiety of the compound of formula (VIII) may be performed with a borane reagent. In some embodiments, the borane reagent may be selected from the group 30 comprising diborane or a borane complex, wherein the borane complex may comprise a borane-tetrahydrofuran complex, borane dimethylsulfide complex, or a borane-amine complex, for example borane-triethylamine, borane-diethylaniline and the like. The borane reagent may also be prepared in situ from sodium borohydride with the
addition of a reducing agent, such as iodine, or an acid. In a preferred embodiment, the borane reagent is a borane-tetrahydrofuran complex, a borane dimethylsulfide complex or sodium borohydride and iodine. In a more preferred embodiment, the borane reagent is a borane-tetrahydrofuran 5 complex. In some embodiments, the borane reagent used in the reduction is about 1 to 10 mols per mole of the compound of formula (VIII). In a preferred embodiment, the borane reagent used in the reduction is about 1.5 to 8 mols per mole of the compound of formula (VIII), more preferably from 2 to 6 mols, for 10 instance about 1.5 mol, about 2 mol, about 3 mol, about 4 mol, about 5 mol, about 6 mol or about 7 mol per mole of the compound of formula (VIII). In some embodiments, the reduction of the amide moiety of the compound of formula (VIII) may also be achieved by using silane reagents. In some embodiments, the silane reagents may be selected from the group 15 comprising PMHS (polymeric hydrosiloxanes), 1,1,3,3-tetramethyldisiloxane (TMDS), Et2OMeSiH, (OEt)3SiH, Ph3SiH, Ph2SiH2, PhSiH3, Et3SiH, Me(OEt)2SiH, alone or combined with a metal catalyst, such as rhodium catalysts, platinum catalysts, iron catalysts, zink catalysts, manganese catalysts, molybdenum catalysts. Alternatively, triflic anhydride may be used in combination with Hantzsch ester or 20 a silane reagent. The reduction of a compound of formula (VIII) can be carried out in a solvent. The solvent can be an organic solvent selected from the group comprising a cyclic or acyclic ether, a non-polar aprotic solvent, or an ester, as defined above. In a preferred embodiment, the solvent is THF. 25 The reduction of a compound of formula (VIII) can be carried out at a temperature ranging from about -10°C to the reflux temperature. In a preferred embodiment, the reduction of a compound of formula (VIII) can be carried out at a temperature ranging from about 0°C to 40°C, for instance at about 5°C, at about 10°C, at about 15°C, at about 20°C, at about 25°C or at about 30°C. 30 The reaction time is typically from about 0.5 hours to 96 hours, such as about 1 hour, about 2.5 hours, about 4 hours, about 6 hours, about 9 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, 48 hours, 60 hours or 72 hours. The compound of formula (I) may be obtained by methylating the compound of
formula (IX) according to the procedures disclosed above, for instance as for the preparation of a compound of formula (II), wherein R is methyl, by methylating the compound of formula (II), wherein R is hydrogen. In a further embodiment, the present disclosure relates to the compounds selected 5 from the following list: methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoyl]- methylamino]ethyl]benzoate of formula (VIII); methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexanoyl]amino]ethyl]benzoate of formula (VIII); or 10 methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexyl]amino]ethyl]benzoate of formula (IX). In a further embodiment, the present disclosure relates to the use of a compound selected from the following list: methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoyl]- 15 methylamino]ethyl]benzoate of formula (VIII); methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexanoyl]amino]ethyl]benzoate of formula (VIII); or methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexyl]amino]ethyl]benzoate of formula (IX); 20 in a process for preparing the compound of formula (I). In some embodiments, the present invention is directed to a process for preparing the compound of formula (I)
25 comprising methylating methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexyl]amino]ethyl]
(IX). Methylating the compound of formula (IX) to provide the compound of formula (I) can be performed as described above. Methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- 5 methylhexyl]amino]ethyl]benzoate of formula (IX) may be obtained by reducing the compound of formula (VIII)
wherein R is 10 In some embodiments, the compound of formula (I)
may be prepared by a process comprising reducing methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- 15 methylhexanoyl]-methylamino]ethyl]benzoate, thus the compound of formula (VIII)
, wherein R is methyl. The reduction of the compound of formula (VIII), wherein R is methyl, to the 20 compound of formula (I) or of the compound of formula (VIII), wherein R is hydrogen, to the compound of formula (IX) can be carried out as described above. The compound of formula (VIII), wherein R is hydrogen or methyl, can be prepared as described above. The following non-limiting examples are provided to further illustrate certain 25 teachings provided by the present application. EXAMPLE
Experimental part The 1H-NMR spectra were acquired with a Varian 500 MHz instrument. The chemical shifts are expressed in parts per million (ppm). The coupling constants are expressed in Hertz (Hz) and the splitting patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), hept (heptet), m (multiplet). Example 1: Synthesis of 2-(3,4-Dimethoxyphenyl)-3-Methyl-Butanenitrile of Formula (X) 15.1 g (85.1 mmol) of 3,4-dimethoxybenzeneacetonitrile are dissolved in 212 mL THF in a 400 mL reactor under nitrogen atmosphere and the solution is brought to a temperature of 20°C. 44.8 mL of a 1.9 M (85.1 mmol) solution of sodium bis(trimethylsilyl)amide (NaHMDS) in THF is added over 5 hours. Then 20.93 g (170.2 mmol) of 2-bromopropane are added. The solution is heated to reflux for 2 hours and then allowed to cool down to room temperature.40 mL of a saturated ammonium chloride solution is added, and the mixture is stirred for 10 minutes. Subsequently, the phases are separated, and the aqueous phase is extracted twice with 25 mL of ethyl acetate (EtOAc). The combined organic phases are washed with 100 mL of brine and dried over Na2SO4. After evaporation of the solvent, the product is dissolved in a methanol/water mixture (4:2, v:v) heated to 40°C, and a seed is added while the solution is cooling down to 20°C. Once crystals are formed, the solution is cooled in an ice bath at 0-5°C for 1 hour. The so obtained solid is dried at 40°C providing 17.0 g of 2 2-(3,4-dimethoxyphenyl)-3-methyl- butanenitrile of formula (X) as a white yellowish crystalline solid (yield: 91.3%). 1H NMR (CDCl3) δ: 6.87-6.77 (m, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.59 (d, J=6.4 Hz, 1H), 2.15-2.04 (m, 1H), 1.04 (d, J=6.7 Hz, 6H). Example 2: Synthesis of (4RS)-4-Cyano-4-(3,4-Dimethoxyphenyl)-5- Methylhexanoic Acid of Formula ((RAC)-VII) 12.2 g (55.5 mmol) of 2-(3,4-dimethoxyphenyl)-3-methyl-butanenitrile of formula (X), obtained as described in Example 1, 60 mL of tert-butanol, and 3.12 g (27.8 mmol) of tert-BuOK are placed in a 250 mL four-neck flask. The solution is stirred under nitrogen atmosphere at room temperature until complete dissolution of the solid.6.2 g (72 mmol) of methyl acrylate are added within 90 minutes. Once the reaction is complete, 25 mL of water is added, the mixture is cooled down in an ice bath, and the tert-butanol is evaporated. 12 mL of toluene and 7.4 g of NaOH 30% (weight:weight, w:w) are added to the resulting aqueous mixture, and the resulting biphasic mixture is stirred under nitrogen atmosphere
and at room temperature for 15 hours. The two phases are separated, and water is added to the aqueous phase up to a volume of 50 mL. The solution is heated to 50-60°C and a 6 M solution of HCl is added until reaching a pH of 5.4. Once the formation of crystals has been observed, further 6 M HCl is added until reaching a pH < 1. The mixture is allowed to cool down to T=20°C, the white solid is filtered off, washed 4 times with 10 mL of water and dried at 50-60° to provide 11.54 g (yield 71.4%) of (4RS)-4-cyano-4-(3,4- dimethoxyphenyl)-5-methylhexanoic acid of formula ((rac)-VII). 1H NMR (CDCl3) δ: 6.92 (dd, J=8.4, 2.3 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 2.52-2.41 (m, 2H), 2.17-2.01 (m, 3H), 1.22 (d, J=6.6 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H).13C NMR (126 MHz, CDCl3) δ: 178.45, 149.22, 148.62, 129.35, 120.56, 118.73, 111.27, 109.30, 55.98, 55.89, 52.71, 37.90, 32.61, 30.44, 18.97, 18.52. Example 3: Synthesis of the S-(-)-Phenylethylamine Salt of (4R)-4-Cyano-4- (3,4-Dimethoxyphenyl)-5-Methylhexanoic Acid of Formula ((R)-VII) 3.98 g (13.7 mmol) of (4RS)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid of formula ((rac)-VII), prepared as described in Example 2, is dissolved in 20 mL EtOAc in a 50 mL three-neck flask. The stirred solution is heated to 40°C under nitrogen atmosphere and 1.80 mL (13.7 mmol) of S-(-)-phenylethylamine are added within 10 minutes. Then, the solution is slowly cooled down to 0-10°C. Once the formation of a solid is observed, the mixture is heated up to 50°C and then slowly cooled down to room temperature overnight. The mixture is kept in an ice bath for 1 hour and the formed crystals are filtered off. The obtained white solid is washed twice with 7 mL of cold EtOAc and dried at 35-45°C to provide 1.59 g (yield: 28.3%) of the S-(-)-phenylethylamine salt of the (4R)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid of formula ((R)-VII). 1H NMR (D2O) δ: 7.39-7.29 (m, 5H), 6.95-6.82 (m, 3H), 4.40 (td, J=7.2, 6.6 Hz, 1H), 3.76-3.71 (m, 6H), 2.34-2.25 (m, 1H), 2.17-1.92 (m, 3H), 1.74-1.65 (m, 1H), 1.51 (dt, J=6.9, 0.7 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), 0.62 (dd, J=6.7, 0.8 Hz, 3H). Example 4: Synthesis of the R-(-)-Phenylethylamine Salt of (4S)-4-Cyano-4- (3,4-Dimethoxyphenyl)-5-Methylhexanoic Acid of Formula ((S)-VII) The organic phase in EtOAc, obtained as described in Example 3, is treated with 1 M HCl until reaching a pH ≤ 2 and washed with 10 mL of water. The solution is concentrated, the solid is re-dissolved with 8 mL of toluene and the mixture is heated to 50-55°C.1.0 mL (8.1 mmol) of R-(-)-phenylethylamine is added within 5 minutes, and the
solution is then allowed to cool down overnight. The resulting suspension is heated to 60- 65°C and cooled again down to 5-10°C. The obtained white solid is filtered off, washed twice with 8 mL of cold toluene and dried at 35-45°C to provide 1.45 g (yield: 25.8%) of the R-(-)-phenylethylamine salt of (4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexanoic acid of formula ((S)-VII). (m, 5H), 6.95-6.82 (m, 3H), 4.40 (td, J=7.2, 6.6 Hz, 1H),
, (m, 1H), 2.17-1.92 (m, 3H), 1.74-1.65 (m, 1H), 1.51 (dt, J=6.9, 0.7 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), 0.62 (dd, J=6.7, 0.8 Hz, 3H). HPLC: 98.4%, 99.03%ee. Example 5: Synthesis of tert-Butyl N-[2-(3-Cyanophenyl)ethyl]carbamate of Formula (V) A mixture of 1.0 g (5.7 mmol) of 3-cyano-benzenepropanoic acid of formula (III), 4.22 g (57 mmol) of tert-butanol, 1.48 g (11.4 mmol) of DIPEA and 6 mL of toluene is heated to reflux under nitrogen atmosphere in a 100 mL 4-neck flask.1.73 g (6.27 mmol) of DPPA are added in 4 hours to the mixture and the solution is stirred under reflux for one further hour.20 mL of a 1 M NaOH solution is added, the two phases are separated, and the organic phase is washed twice with 10 mL of water and concentrated. The so obtained crude product is purified by column chromatography (solid phase: SiO2; eluent: toluene/EtOAc from 99:1 to 80:20 in 30 minutes) providing 0.70 g (yield: 50%) of tert- butyl N-[2-(3-cyanophenyl)ethyl]carbamate of formula (V). 1H NMR (500 MHz, DMSO) δ: 7.66-7.60 (m, 2H), 7.52 (d, J=7.8 Hz, 1H), 7.49- 7.44 (m, 1H), 6.87-6.85 (t, J=5.6 Hz, 1H), 3.17-3.13 (q, J=7.0 Hz, 2H), 2.75-2.70 (t, J=7.0 Hz, 2H), 1.32 (s, 9H). Example 6: Synthesis of Ethyl N-[2-(3-Cyanopheny)lethyl]carbamate of Formula (V) Step A 1.39 g (8.56 mmol) of carbonyldiimidazole (CDI) and 10 mL of methyl-THF are placed under nitrogen atmosphere in a 50 mL three-neck flask and the mixture is cooled down to 0°C.1.0 g (5.7 mmol) 3-cyano-benzenepropanoic acid of formula (III) dissolved in 10 mL of methyl-THF are added, and the reaction mixture is stirred under nitrogen
1H NMR (500 MHz, DMSO) δ: 8.44 (s, 1H), 7.80 (s, 1H), 7.71-7.70 (t, J=1.5 Hz, 1H), 7.69-7.63 (m, 2H), 7.48-7.51 (t, J=1.7 Hz, 1H), 7.05-7.04 (t, J=1.7 Hz, 1H), 3.43-
3.40 (t, J=8.1 Hz, 2H), 3.04-3.02 (t, J=7.6 Hz, 2H). Step B The obtained reaction mixture of Step A is added to a mixture of 0.23 g (5.98 mmol) of NaOH, 10 mL of water and 0.83 g (17 mmol) of monohydrated N2H4 over about 2 hours and at 0°C. After about 40 minutes, no more starting material can be detected, and the obtained product is used in the next step without further purification. 1H NMR (500 MHz, DMSO) δ: 7.68-7.59 (m, 2H), 7.57-7.51 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 6.99 (d, J=1.0 Hz, 1H), 4.15 (s, 1H), 2.85 (t, J=8.7 Hz, 2H), 2.34 (dd, J=8.1 Hz, 2H). Step C 6.76 g (68.8 mmol) of 37% HCl is added to the reaction mixture of Step B and the stirred mixture kept under nitrogen atmosphere is cooled down to 0°C.3.8 g (23 mmol) of an aqueous 30% (w:w) NaNO2 solution are added in about 90 minutes and the mixture is allowed to reach room temperature within 40 minutes. Once no starting material can be detected, the organic phase is separated, and the aqueous phase is extracted with 20 mL of methyl-THF. The combined organic phases are used in the next step without further purification. 1H NMR (500 MHz, DMSO) δ: 7.72 (s, 1H), 7.66-7.74 (d, J=7.6 Hz, 1H), 7.60- 7.57 (m, 1H), 7.49-7.46 (t, J=7.7 Hz, 1H), 2.91-2.88 (t, J=7.4 Hz, 2H), 2.79-2.78 (t, J=7.4, Hz, 2H). Step D The solution comprising 3-cyanobenzenepropanoic azide in methyl-THF of Step C is then added to 20 mL of ethanol heated to reflux within 90 minutes. The stirred reaction mixture is maintained under nitrogen atmosphere at the reflux temperature for 40 minutes and then the solvent is evaporated to provide 0.37 g (yield: 30%) of ethyl N-[2-(3- cyanophenyl)ethyl]carbamate of formula (V). 1H NMR (500 MHz, DMSO) δ: 7.67-7.61 (m, 2H), 7.53-7.52 (d, J=7.8 Hz, 1H), 7.51-7.44 (m, 1H), 7.15-7.09 (t J=6.0 Hz, 1H), 3.92 (q, J=7.1 Hz, 2H), 3.21 (t, J=7.0 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 1.10 (t, J=7.1 Hz, 3H). Alternatively to Step A, 3-cyano-benzenepropanoic acid of formula (III) can be activated with an halogenating agent, for example with oxalyl chloride. 3.0 g (17 mmol) of 3-cyano-benzenepropanoic acid of formula (III), 10 µL of DMF and 60 mL of dichloromethane are placed in a 100 mL four-neck flask and the
stirred mixture is cooled down to 0°C under a nitrogen atmosphere.2.8 g (22 mmol) of oxalyl chloride are added and the reaction mixture is maintained at room temperature for about 16 hours. Then, the solvent is evaporated providing 2.6 g (yield: 79%) of 3-cyanobenzenepropanoyl chloride as a thick orange oil. 1H NMR (500 MHz, CDCl3) δ: 7.54-7.52 (d, J=7.1 Hz, 1H), 7.49 (s, 1H), 7.46- 7.38 (m, 2H), 3.23-3.20 (t, J=7.3, 0.6 Hz, 2H), 3.06-3.00 (t, 2H). 3-Cyanobenzenepropanoyl chloride can be converted according to Steps B-D into ethyl N-[2-(3-cyanophenyl)ethyl]carbamate of formula (V). Example 7: Synthesis of Isopropyl N-[2-(3-Cyano)phenylethyl]carbamate of Formula (V) Isopropyl N-[2-(3-cyano)phenylethyl]carbamate of formula (V) is prepared according to the procedure disclosed in Example 6, but using isopropanol instead of ethanol.
7.62 (m, 2H), 7.54-7.51 (m, 1H), 7.49-7.45 (m, 1H), 7.06-7.04 (t, J=5.8 Hz, 1H), 4.69-4.63 (hept, J=6.3 Hz, 1H), 3.21-3.18 (q, J=7.0 Hz, 2H), 2.78-2.69 (t, J=6.7 Hz, 2H), 1.13-1.07 (d, 6H). Example 8: Synthesis of Methyl 3-(2-Aminoethyl)benzoate Hydrochloride salt of Formula (II) 2.0 g (8.1 mmol) of tert-butyl N-[2-(3-cyanophenyl)ethyl]carbamate of formula (V), prepared as described in Example 5, and 2 mL of MeOH are placed under nitrogen atmosphere in a 100 mL three-neck flask and the mixture is cooled down to 10°C.10 mL of hydrochloric acid 37% (w:w) in water are added dropwise to the mixture within 10 minutes and the reaction mixture is then heated to reflux. After 24 hours the solvent is evaporated under reduced pressure and the intermediate is suspended in 10 mL of MeOH. The mixture is cooled down to 0-5°C and H2SO4 (96% w:w) is added dropwise maintaining the temperature at no more than 10°C. After the addition, the mixture is allowed to reach room temperature. After 20 hours the mixture is cooled down to 10°C and diluted with 26 mL of methyl-THF. The pH is corrected to 10 with a 30% (w:w) aqueous solution of NaOH, then H2O is added. The phases are separated, and the aqueous phase is extracted three times with 15 mL of methyl-THF. The organic layers are combined and brought to pH 1 with hydrochloric acid 37% (w:w) in water. The solution is concentrated, EtOAc is added to the mixture leading to the precipitation of the product. The solid is filtered off and dried under vacuum providing the hydrochloride salt of methyl 3-(2-aminoethyl)benzoate
of formula (II). 1H NMR (500 MHz, DMSO) δ: 8.21 (bs, 3H), 7.80-7.85 (m, 2H), 7.44-7.49 (dt, J1=7.6 Hz, J2=1.5 Hz, 1H), 7.47 (m, 1H), 3.83 (s, 3H), 2.99-3.05 (m, 2H), 2.94-2,99 (m, 2H). Example 9: Synthesis of tert-Butyl N-[2-(3-Cyanophenyl)ethyl]-N-Methyl- Carbamate of Formula (VI) 5.00 g (20.3 mmol) of tert-butyl N-[2-(3-cyanophenyl)ethyl]carbamate of formula (V), obtained as described in Example 5, and 50 mL of THF are placed under nitrogen atmosphere in a 100 mL pressure-reactor.1.05 g of sodium hydride (60% suspension in paraffin oil) and 4.03 g (28.4 mmol) of iodomethane are added to the mixture and the vessel is sealed under nitrogen pressure (1 bar) and heated to 70°C. The reaction typically reaches completion in 16 hours. The reaction mixture is quenched with water and extracted three times with EtOAc. The combined organic phases are dried over anhydrous Na2SO4 and concentrated to residue providing 4.75 g (yield: 90%) of tert-butyl N-[2-(3- cyanophenyl)ethyl]-N-methyl-carbamate of formula (VI). 1H NMR (500 MHz, DMSO) δ: 7.64 (m, 2H), 7.49 (m, 2H), 3.40 (s, 2H), 2.78-2.80 (t, J=6.9 Hz, 2H), 2.74 (s, 3H), 1.20 (s, 9H). Example 10: Synthesis of Methyl 3-[2-(Methylamino)ethyl]benzoate of Formula (II) 4.7 g (18 mmol) of tert-butyl N-[2-(3-cyanophenyl)ethyl]-N-methyl-carbamate of formula (VI), obtained as described in Example 9, and 4.7 mL of MeOH are placed under nitrogen atmosphere in a 100 mL three-neck flask and the mixture is cooled down to 10°C. 23 mL of a 37% (w:w) aqueous solution of HCl is added dropwise to the mixture within 10 minutes. After the addition, the reaction is heated to reflux for 24 hours. The solid is then filtered off and washed with 9.4 mL of MeOH to obtain 2.6 g (yield: 68 %) of 3-[2- (methylamino)ethyl]benzoic acid hydrochloride. 1H NMR (500 MHz, DMSO) δ: 8.90 (bs, 2H), 7.71-7.76 (m, 2H), 7.46 (dt, J1=5.8 Hz, J2=1.3 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 3.01-3.08 (m, 2H), 2.96 (t, J=10.3 Hz, 2H), 2.49 (t, J=5.4 Hz, 3H). 2.6 g (12 mmol) of 3-[2-(methylamino)ethyl]benzoic acid hydrochloride and 10 mL of MeOH are placed under nitrogen atmosphere in a 100 mL three-neck flask and the mixture is cooled down to 0-5°C. H2SO4 (96% w:w) is added dropwise maintaining the temperature below 10°C. After the addition, the mixture is allowed to reach room
temperature. After 20 hours, the mixture is cooled down to 10°C and diluted with 26 mL of methyl-THF. The solution is then brought to pH value of 10 with a 30% (w:w) aqueous solution of NaOH.26 mL of H2O are added, the phases are separated, and the aqueous phase is extracted three times with methyl-THF (3x15 mL). The organic layers are 5 combined and concentrated providing 2.16 g (yield: 93%) of methyl 3-[2- (methylamino)ethyl]benzoate of formula (II). 1H NMR (500 MHz, DMSO) δ: 7.82-7.87 (m, 2H), 7.54 (d, J=7.5 Hz, 1H), 7.49 (t, J=7.5 Hz, 2H), 3.84 (s, 3H), 3.13 (t, J=6.5 Hz, 2H), 2.95 (t, J=6.5 Hz, 2H), 2.56 (s, 3H). Example 11: Synthesis of Methyl 3-[2-[[(4S)-4-Cyano-4-(3,4- 10 Dimethoxyphenyl)-5-Methylhexanoyl]-Methylamino]ethyl]benzoate of Formula (VIII) 1.30 g (4.40 mmol) of (4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid of formula ((S)-VII) (prepared as described in Example 4 or according to the procedure disclosed by Bannister et al. in ORPD 2000, 4, 467-472), 0.75 g (4.6 mmol) of 15 CDI and 5 mL of THF are placed under nitrogen atmosphere in a 50 mL three-neck flask. A solution of 0.85 g (4.4 mmol) of methyl 3-[2-(methylamino)ethyl]benzoate of formula (II), obtained as described in Example 10, in 6 mL of THF are added dropwise at room temperature within 30 minutes. The mixture is stirred at room temperature until complete conversion. The reaction is quenched with 6.5 mL of a saturated aqueous NaHCO3 20 solution, then 13 mL of EtOAc are added. The phases are separated, the aqueous layer is extracted with 13 mL of EtOAc, and the combined organic phases are to obtain 1.7 g (yield: 83%) of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoyl]- methylamino]ethyl]benzoate of formula (VIII) as oil. HPLC-MS (ESI+) [M+H]+=467. Example 12: Synthesis of Methyl 3-[2-[[(4S)-4-Cyano-4-(3,4- 25 Dimethoxyphenyl)-5-Methylhexyl]-Methylamino]ethyl]benzoate of Formula (I) 1.30 g (2.79 mmol) of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexanoyl]-methylamino]ethyl]benzoate of formula (VIII), obtained as described in Example 11, and 5 mL of THF are placed under nitrogen atmosphere in a 50 mL three- neck flask and the mixture is cooled down to 0°C.12.4 mL (11.2 mmol) of a solution of a 30 borane tetrahydrofuran complex (0.9 M) is added dropwise maintaining the temperature below 5°C. The mixture is allowed to reach room temperature, stirred for 6 hours and then quenched at 0-5°C with 7.8 g of a 6.5% (w:w) methanolic solution of HCl. The mixture is allowed to reach room temperature, stirred for 1 hour and then concentrated and diluted
with EtOAc and H2O. The acidic aqueous layer is discarded, and the organic phase is washed with 1 M aqueous solution of NaOH. The organic layer is concentrated providing 0.63 g (yield: 50%) of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexyl]-methylamino]ethyl]benzoate of formula (I) as an oil. 1H NMR (500 MHz, DMSO) δ: 7.82-7.71 (m, 2H), 7.43 (dt, J1=7.6 Hz, J2=1.4 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.81-6.88 (m, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H), 2.71 (t, J=7.4 Hz, 2H), 2.43 (t, J=7.4 Hz, 2H), 2.21-2.30 (m, 2H), 2.09-2.13 (m, 1H), 2.05 (s, 3H), 1.89-1.96 (m, 1H), 1.80-1.88 (m, 1H), 1.23-1.30 (m, 1H), 1.02 (d, J=6.7 Hz, 3H), 0.88-0.98 (m, 1H), 0.64 (d, J=6.7 Hz, 3H). Example 13: Synthesis of Methyl 3-[2-[[(4S)-4-Cyano-4-(3,4- Dimethoxyphenyl)-5-Methylhexanoyl]amino]ethyl]benzoate of Formula (VIII) 1.35 g (4.64 mmol) of (4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexanoic acid of formula ((S)-VII), and 0.79 g (4.87 mmol) of CDI are dissolved in 5 mL of THF under nitrogen atmosphere in a 50 mL three-neck flask. A suspension of 1 g (4.64 mmol) of methyl 3-(2-aminoethyl)benzoate hydrochloride salt of formula (II), prepared as described in Example 8, and 0.7 g (7 mmol) of triethylamine in 5 mL of THF is added dropwise to the solution at room temperature. The mixture is stirred at room temperature until no more starting material is detected. The reaction mixture is quenched with 10 mL of water, then 10 mL of EtOAc is added. The phases are separated, and the aqueous layer is extracted with 10 mL of EtOAc. The combined organic phases are washed with 10 mL of a 1 M HCl aqueous solution and with 10 mL of water. The organic phase is then concentrated under vacuum to obtain 2 g (yield: 95%) of methyl 3-[2-[[(4S)-4-cyano-4- (3,4-dimethoxyphenyl)-5-methylhexanoyl]amino]ethyl]benzoate of formula (VIII) as an oil. 1H NMR (500 MHz, DMSO) δ: 7.87 (t, J=5.6 Hz, 1H), 7.77 (dt, J1=7.4 Hz, J2=1.7 Hz, 1H), 7.72-7.75 (m, 1H), 7.37-7.46 (m, 2H), 6.95 (d, J=8.3 Hz, 1H), 6.86-6.92 (m, 2H), 3.82 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.13-3.26 (m, 2H), 2.70 (t, J=7.2 Hz, 2H), 2.17-2.27 (m, 2H), 2.08-2.16 (m, 1H), 1.89-2.00 (m, 1H), 1.55-1.66 (m, 1H), 1.08 (d, J=6.6 Hz, 3H), 0.66 (d, J=6.7 Hz, 3H). HPLC-MS confirmed m/z ratio of the product, [M+H]+ = 453. Example 14: Synthesis of Methyl 3-[2-[[(4S)-4-Cyano-4-(3,4- Dimethoxyphenyl)-5-Methylhexyl]amino]ethyl]benzoate of Formula (IX) 1.0 g (2.2 mmol) of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexanoyl]amino]ethyl]benzoate of formula (VIII), prepared as described in
Example 13, are dissolved in 5 mL of THF under nitrogen atmosphere in a 100 mL three- neck flask. The mixture is cooled down to 0°C and 9.8 mL (8.84 mmol) of a solution of a borane tetrahydrofuran complex (0.9 M) is added dropwise maintaining the temperature at no more than 5°C. The mixture is allowed to reach room temperature and is stirred for 6 hours. The reaction is then quenched at 0-5°C with 6.2 g of a 6.5% (w:w) methanolic solution of HCl, and the mixture is allowed to reach room temperature and stirred for 1 hour. The resulting solution is concentrated under reduced pressure and diluted with EtOAc and H2O. The acidic aqueous layer is discarded, the organic phase is washed with 1 M aqueous solution of NaOH and concentrated under vacuum to obtain 0.63 g (yield: 77 %) of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexyl]amino]ethyl]benzoate of formula (IX) an oil. 1H NMR (500 MHz, DMSO) δ: 7.70-7.88 (m, 2H), 7.40-7.48 (m, 1H), 7.30-7.40 (m, 1H), 6.77-6.97 (m, 3H), 3.81 (s, 3H), 3.68-3.77 (m, 6H), 2.68 (t, J=6.8 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H), 2.37-2.46 (m, 2H), 2.09-2.19 (m, 1H), 1.97-2.05 (m, 1H), 1.87-1.97 (m, 1H), 1.23-1.34 (m, 1H), 1.06 (d, J=6.6 Hz, 3H), 0.90-1.01 (m, 1H), 0.65 (d, J=6.7 Hz, 3H). HPLC-MS confirmed m/z ratio of the product, [M+H]+ = 439. Example 15: Synthesis of Methyl 3-[2-[[(4S)-4-Cyano-4-(3,4- Dimethoxyphenyl)-5-Methylhexyl]-Methylamino]ethyl]benzoate of Formula (I) 200 mg (0.456 mmol) of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5- methylhexyl]amino]ethyl]benzoate of formula (IX), prepared as described in Example 14, and 2 mL of MeOH are placed under nitrogen atmosphere in a 50 mL three-neck flask. The mixture is cooled down to 0°C and 94 mg (0.88 mmol) of sodium triacetoxyborohydride suspended in 1 mL of MeOH is added dropwise at no more than 5°C. Then, 70 µL (0.88 mmol) of formaldehyde (37% (w:w) aqueous solution) are added at no more than 5°C and the mixture is allowed to reach room temperature. After 1 hour the reaction is quenched with 5 mL of water and diluted with 10 mL EtOAc. The phases are separated, the organic layer is washed with 5 mL of water and concentrated under vacuum providing 180 mg (yield: 90%) of methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]- methylamino]ethyl]benzoate of formula (I) as an oil. 1H NMR (500 MHz, DMSO) δ: 7.82-7.71 (m, 2H), 7.43 (dt, J1=7.6 Hz, J2=1.4 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.81-6.88 (m, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H), 2.71 (t, J=7.4 Hz, 2H), 2.43 (t, J=7.4 Hz, 2H), 2.21-2.30 (m, 2H), 2.09-2.13 (m, 1H), 2.05 (s, 3H), 1.89-1.96 (m, 1H), 1.80-1.88 (m, 1H), 1.23-1.30 (m, 2H),
1.02 (d, J=6.7 Hz, 3H), 0.88-0.98 (m, 1H), 0.64 (d, J=6.7 Hz, 3H). HPLC-MS confirmed m/z ratio of the product, [M+H]+ = 453.