WO2025141495A1 - Novel method of preparing ervogastat - Google Patents
Novel method of preparing ervogastat Download PDFInfo
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- WO2025141495A1 WO2025141495A1 PCT/IB2024/063184 IB2024063184W WO2025141495A1 WO 2025141495 A1 WO2025141495 A1 WO 2025141495A1 IB 2024063184 W IB2024063184 W IB 2024063184W WO 2025141495 A1 WO2025141495 A1 WO 2025141495A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention relates to a novel method of preparing ervogastat with a metal catalyst free process.
- the invention also relates to novel compounds, intermediates, salts, polymorphs used and prepared by this novel method.
- Ervogastat (PF-06865571) is a systemically acting diacylglycerol acyltransferase 2 (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis.
- DGAT2 diacylglycerol acyltransferase 2
- NASH non-alcoholic steatohepatitis
- Ervogastat and the corresponding method of preparation have been disclosed in the United States Patent No. 10,071 ,992. The synthetic method was further disclosed and discussed by Futatsugi et al., Discovery of Ervogastat (PF- 06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis. J. Med. Chem.
- the present invention provides a crystalline form of 2-(5-((3- ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 7.1, 9.4, and 14.3 °2-Theta ⁇ 0.2 °2-Theta.
- PXRD powder X-ray diffraction
- Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
- the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
- the compounds of the invention, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms.
- solvate is used herein to describe a molecular complex comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
- solvent molecules for example, ethanol.
- hydrate is employed when said solvent is water.
- Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
- channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
- metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
- the complex When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
- multi-component complexes other than salts and solvates
- complexes of this type include clathrates (drughost inclusion complexes) and co-crystals.
- clathrates drughost inclusion complexes
- co-crystals The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, for example, hydrogen bonded complex (cocrystal) may be formed with either a neutral molecule or with a salt.
- Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17;1889-1896, by O. Almarsson and M. J. Zaworotko (2004).
- Chem Commun 17;1889-1896
- O. Almarsson and M. J. Zaworotko (2004).
- the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
- amorphous refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
- a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’).
- the compounds of the invention may also exist in a 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 (either melt or solution) and consists of two dimensional order on the molecular level.
- Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’.
- Stereoisomers of the compounds may include c/s and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers.
- compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers.
- the pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl- arginine).
- a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl- arginine).
- Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
- racemate or the racemate of a salt or derivative
- HPLC high pressure liquid chromatography
- the racemate or a racemic precursor
- a suitable optically active compound for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
- racemic compound true racemate
- the second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).
- tautomeric isomerism (‘tautomerism’) may occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino/amino, keto/enol, or oxime/nitroso group, lactam/lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
- the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
- isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
- hydrogen such as 2 H and 3 H
- carbon such as 11 C, 13 C and 14 C
- chlorine such as 36 CI
- fluorine such as 18 F
- iodine such as 123 l and 125 l
- nitrogen such as 13 N and 15 N
- oxygen such as 15 O, 17 O and 18 O
- phosphorus such as 32 P
- sulfur such as 35 S.
- isotopically-labelled compounds of the invention for example those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissue distribution studies.
- Substitution with deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability.
- positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N
- PET Positron Emission Topography
- the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein.
- “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%).
- the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D.
- the concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the invention may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions.
- the deuterium compound is selected from any one of the compounds set forth in Table 7.
- the deuterium compounds shown in Table 7 may be prepared with method disclosed in this disclosure, when combined with deuteration methods known to a person with ordinary skill in the art.
- one or more hydrogen atoms on certain metabolic sites on the compounds of the invention are deuterated.
- Isotopically-labeled compounds of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.
- a compound may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step.
- PG protecting group
- the temperature was adjusted to 3 °C and water (1000 mL) was added while maintaining the temperature below 10 °C. The mixture was stirred for 10-15 min and transferred to a separatory funnel. The layers were separated, and the organic layer was washed with water (500 mL). The combined aqueous layer was cooled to 3 °C and the pH was adjusted to 6.5 using 50 %w/w aqueous NaOH. terf-Butanol (2000 mL) was charged, and the temperature was adjusted to 3 °C.
- the resulting filtrate was concentrated to 1-2 L at the inner temperature of no more than 45°C.
- Heptane (10 L) was charged, and the resulting solution was concentrated to 1-2 L at the inner temperature of no more than 45°C.
- Heptane (10 L) was charged into the concentrated solution and concentrated to 1-2 V at the inner temperature of NMT 45 °C.
- the concentrated solution was purified by column chromatography on silica eluting with 100:1-50:1 heptane and EtOAc. 1.29 kg of 5-bromo-2-(tert-butylthio)pyrimidine was obtained as a white solid with 99.9% HPLC purity, 96.8%, assay in 91.4% assay-corrected yield.
- Characteristic PXRD peaks for P-02 Form 1 are 6.1, 12.2, and 13.9 °2-Theta ⁇ 0.2 °2- Theta. Characteristic PXRD peaks for P-02 Form 1 can also include 21.2 and 31.0 °2-Theta ⁇ 0.2 °2-Theta, providing 6.1, 12.2, 13.9, 21.2, and 31.0 °2-Theta ⁇ 0.2 °2-Theta.
- An embodiment of the present invention includes an anhydrous crystalline form of tert-butyl 2-(tert- butylsulfonyl)pyrimidine-5-carboxylate, having a powder X-ray diffraction (PXRD) pattern comprising peaks values of 6.1, 12.2, and 13.9 °2-Theta ⁇ 0.2 °2-Theta.
- Another embodiment of the present invention includes the anhydrous crystalline form having a PXRD pattern comprising peaks values of 6.1, 12.2, and 13.9, 21.2 and 31.0 °2-Theta ⁇ 0.2 °2-Theta.
- the resulting Grignard reagent was added to a solution of fert-butyl 2-(tert- butylsulfonyl)pyrimidine-5-carboxylate (P-02, 39.0 g, 0.132 mol, 1.00 eq) at 20-26 °C.
- the reaction mixture was agitated at ambient temperature for 18 h.
- Methanol (39 mL) and a solution of sodium hydroxide (264 mL, 4 equiv, 2 M in water) were added.
- Reaction mixture was heated to 35 to 40 °C, stirred for 6 h, and then cooled to 20 to 25 °C.
- HCI 290 mL, 4.4 equiv, 2 M in water
- Compound (d) Form 2 monohydrate was prepared by adding a mixture of dimethylacetamide and water (75:25 v/v DMAc:water) to a vial containing Compound (d) Form 1 anhydrous to prepare a slurry. The slurry was stirred with a magnetic stir bar for approximately 5 hours. Solids were isolated by vacuum filtration and rinsed with water. The solids were allowed to dry at ambient conditions to provide Compound (d) Form 2 monohydrate.
- Characteristic PXRD peaks for Compound (d) Form 1 are 7.1 , 9.4, and 14.3 °2-Theta ⁇ 0.2 °2-Theta. Characteristic PXRD peaks for Compound (d) Form 1 can also include 12.5 and 19.0 °2-Theta ⁇ 0.2 °2-Theta, providing 7.1, 9.4, 12.5, 14.3 and 19.0 °2-Theta ⁇ 0.2 °2-Theta.
- Characteristic PXRD peaks for Compound (d) Form 2 monohydrate are 8.7, 10.2, and 13.0 °2-Theta ⁇ 0.2 °2-Theta. Characteristic PXRD peaks for Compound (d) Form 2 monohydrate can also include 17.3 and 27.8 °2-Theta ⁇ 0.2 °2-Theta, providing 8.7, 10.2, 13.0, 17.3 and 27.8 °2-Theta ⁇ 0.2 °2-Theta.
- Procedure: P-03 may be isolated.
- terf-butyl 2-(tert- butylsulfonyl)pyrimidine-5-carboxylate P-02, 20 g, 68 mmol, 1.0 equiv
- the reaction mixture was agitated at ambient temperature for 18 h, cooled to 0- 6 °C and quenched by the addition of 10 %w/w aqueous ammonium chloride (100 mL).
- the mixture was extracted twice with isopropyl acetate (100 mL) and concentrated to ⁇ 50 mL.
- 3-Pyridyl Grignard reagent was utilized to optimize the synthesis of 2-substituted pyrimidines via a S «Ar strategy to ensure generality and compatibility with heterocyclic nucleophiles (Table 6).
- 2-chloro pyrimidine D-1 was employed, exclusive addition at position 6 was observed to generate F-1 (entry 1).
- ND Not detected by LIPLC. Reaction conditions: D (0.34 mmol, 1 equiv), THF (5 vol), 3- pyridylmagnesium chloride (1 equiv), RT, 3 h. a Percentage determined by area of LIPLC trace of crude reaction mixture b Yield determined by NMR assay using an internal standard.
- 2-sulfonylpyrimidine analogs may provide unexpected advantage for scale-up synthesis when compared to 2-chloropyrimidine analogs.
- the coupling reaction between a Grignard reagent and a 2- sulfonylpyrimidine analog without using a metal catalyst is even more unexpected.
- the compounds provided in Table 7 are prophetic deuterated analogs (PDA) of Ervogastat.
- the Formula (A) is the generic formula of deuterated Ervogastat, wherein Y 1a , Y 1 b , Y 2a , Y 2b , Y 3 , Y 4a , Y 4b , Y 5 , Y 6 , Y 7 , Y 8a , Y 8b , Y 9 , Y 10a , Y 10b , and Y 10c are each independently H or D.
- the deuterated analogs of Ervogastat in Table 7 are predicted based on the metabolic profile of Ervogastat, with MetaSite (moldiscovery.com/software/metasite/).
- Predicted deuterated analogs A-1 to A-21 of Ervogastat in Table 7 may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability.
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Abstract
The present invention relates to a novel method of preparing ervogastat with a metal catalyst free process. The invention also relates to novel compounds, intermediates, salts, polymorphs used and prepared by this novel method. Formula (I).
Description
Novel Method of Preparing Ervogastat
Background of the Invention
The present invention relates to a novel method of preparing ervogastat with a metal catalyst free process. The invention also relates to novel compounds, intermediates, salts, polymorphs used and prepared by this novel method.
Ervogastat (PF-06865571) is a systemically acting diacylglycerol acyltransferase 2 (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis. Ervogastat and the corresponding method of preparation have been disclosed in the United States Patent No. 10,071 ,992. The synthetic method was further disclosed and discussed by Futatsugi et al., Discovery of Ervogastat (PF- 06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis. J. Med. Chem. 2022, 65, 15000-15013. However, it has been found that the scale-up synthesis of ervogastat with the method disclosed in United States Patent No. 10,071 ,992 and Futatsugi et al. could not provide optimized results as disclosed in this invention.
Accordingly, there remains a need for an improved method of preparing ervogastat in larger/commercial scale.
Summary of the Invention
According to an embodiment of the invention there is provided a method of preparing ervogastat, or a pharmaceutically acceptable salt thereof, wherein the method comprises: a) providing a compound of formula (a), wherein X is Cl, Br, or I; providing a compound of formula (b), wherein R1 is Ci-Ce alkyl, C3-C10 cycloalkyl, 3-methoxy-3-oxopropyl, 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, Ce-Cio aryl optionally substituted with one or two groups selected from halogen, C1-C3 alkoxy, C1-C3 fluoroalkyl, and -NO2, or 4-12 membered heteroaryl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; R2 is Ci-Ce alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; and allowing the compound of formula (a) and the compound of formula (b) to contact in a solvent to provide a reaction product of compound of formula (c):
b) hydrolyzing the compound of formula (c) to provide a compound of formula (d):
c) allowing the compound of formula (d) to contact with a compound of formula (e) to provide a reaction product of ervogastat, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (e) is either a free base or a salt.
Described below are embodiments of the invention, where for convenience Embodiment 1 (E1) is identical to the embodiment provided above.
In another embodiment, the present invention provides a compound of formula (b),
wherein R1 is Ci-Ce alkyl, C3-C10 cycloalkyl, 3-methoxy-3-oxopropyl, 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, Ce-C aryl optionally substituted with one or two groups selected from halogen, C1-C3 alkoxy, C1-C3 fluoroalkyl, and -NO2, or 4-12 membered heteroaryl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; R2 is Ci-Ce alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S.
In another embodiment, the present invention provides a crystalline form of tert-butyl 2- (tert-butylsulfonyl)pyrimidine-5-carboxylate, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 6.1, 12.2, and 13.9 °2-Theta ± 0.2 °2-Theta.
In another embodiment, the present invention provides a crystalline form of tert-butyl 2- (5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 9.7, 12.5, and 21.7 °2-Theta ± 0.2 °2-Theta.
In another embodiment, the present invention provides a crystalline form of 2-(5-((3- ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 7.1, 9.4, and 14.3 °2-Theta ± 0.2 °2-Theta.
In another embodiment, the present invention provides a crystalline form of 2-(5-((3- ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid monohydrate, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 8.7, 10.2, and 13.0 °2-Theta ± 0.2 °2- Theta.
In another embodiment, the present invention provides a crystalline form of 2-((5- bromopyridin-3-yl)oxy)-3-ethoxypyridine, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 9.8, 24.8, and 29.2 °2-Theta ± 0.2 °2-Theta.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
Brief Description of the Drawing
FIG. 1 shows an illustrative PXRD pattern of P-01 Form 1 anhydrous.
FIG. 2 shows an illustrative PXRD pattern of P-02 Form 1 anhydrous.
FIG. 3 shows an illustrative PXRD pattern of P-03 Form 1 anhydrous.
FIG. 4 shows an illustrative PXRD pattern of Compound (d) Form 1 anhydrous.
FIG. 5 shows an illustrative PXRD pattern of Compound (d) Form 2 monohydrate.
Detailed Description of the Invention
The present invention provides, in part, novel method of preparing ervogastat with metal catalyst free process. In particular, the present invention provides a metal catalyst free process to form pyridyl-pyrimidine bond of ervogastat in a scaled-up effort. The invention also relates to novel compounds, intermediates, salts, polymorphs used and prepared by this novel
method. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.
The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.
E1 A method of preparing ervogastat, or a pharmaceutically acceptable salt thereof, as defined above.
E2 A method of embodiment E1 , wherein R1 and R2 are each t-butyl.
E3 A method of embodiment E1 or E2, wherein step a) is free of using a metal catalyst.
E4 A method of any one of embodiments E1 to E3, wherein the reaction of step a) is carried out at room temperature.
E5 A method of any one of embodiments E1 to E4, wherein the compound of formula (c) is hydrolyzed to the compound of formula (d) under a basic condition.
E6 A method of any one of embodiments E1 to E5, wherein the compound of formula (e) is a salt form.
E7 A method of embodiment E6, wherein the compound of formula (e) is in HCI or tosylate salt form.
E8 A method of preparing a compound of formula (c), wherein the method comprises: providing a compound of formula (a), wherein X is Cl, Br, or I; providing a compound of formula (b), wherein R1 is Ci-Ce alkyl, C3-C10 cycloalkyl, 3- methoxy-3-oxopropyl, 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, Ce-C™ aryl optionally substituted with one or two groups selected from halogen, C1-C3 alkoxy, C1-C3 fluoroalkyl, and -NO2, or 4-12 membered heteroaryl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; R2 is Ci-Ce alkyl, C3-C10
cycloalkyl, or 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; and allowing the compound of formula (a) and the compound of formula (b) to contact in a solvent to provide a reaction product of compound of formula (c):
E9 A method of embodiment E8, wherein R1 and R2 are each t-butyl.
E10 A method of embodiment E8 or E9, wherein the method is free of using a metal catalyst.
E11 A method of any one of embodiments E8 to E10, wherein the reaction is carried out at room temperature.
E12 A compound of formula (b),
wherein R1 is Ci-Ce alkyl, C3-C10 cycloalkyl, 3-methoxy-3-oxopropyl, 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, Ce-Cio aryl optionally substituted with one or two groups selected from halogen, C1-C3 alkoxy, C1-C3 fluoroalkyl, and -NO2, or 4-12 membered heteroaryl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; R2 is Ci-Ce alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S.
E13 A compound of embodiment E12, wherein R1 is Ci-Ce alkyl, C3-C10 cycloalkyl, Ce-C aryl optionally substituted with one or two groups selected from halogen, C1-C3 alkoxy, C1-C3 fluoroalkyl, and -NO2; R2 is Ci-Ce alkyl or C3-C10 cycloalkyl.
E14 A compound of embodiment E12 or E13, wherein the compound is:
E15 A crystalline form of tert-butyl 2-(tert-butylsulfonyl)pyrimidine-5-carboxylate, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 6.1 , 12.2, and 13.9 °2- Theta ± 0.2 °2-Theta.
E16 A crystalline form of embodiment E15, having a PXRD pattern further comprising peaks of 21.2, and 31.0 °2-Theta ± 0.2 °2-Theta.
E17 A crystalline form of tert-butyl 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5- carboxylate, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 9.7, 12.5, and 21.7 °2-Theta ± 0.2 °2-Theta.
E18 A crystalline form of embodiment E17, having a PXRD pattern further comprising peaks of 19.5 and 24.1 °2-Theta ± 0.2 °2-Theta.
E19 A crystalline form of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 7.1 , 9.4, and 14.3 °2-Theta ± 0.2 °2-Theta.
E20 A crystalline form of embodiment E19, having a PXRD pattern further comprising peaks of 12.5 and 19.0 °2-Theta ± 0.2 °2-Theta.
E21 A crystalline form of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid monohydrate, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 8.7, 10.2, and 13.0 °2-Theta ± 0.2 °2-Theta.
E22 A crystalline form of embodiment E21, having a PXRD pattern further comprising peaks of 17.3 and 27.8 °2-Theta ± 0.2 °2-Theta.
E23 A crystalline form of 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine, having a powder X- ray diffraction (PXRD) pattern comprising peaks of 9.8, 24.8, and 29.2 °2-Theta ± 0.2 °2- Theta.
E24 A crystalline form of embodiment E23, having a PXRD pattern further comprising peaks of 19.6 and 31.5 °2-Theta ± 0.2 °2-Theta.
E25 A compound having structure
or a pharmaceutically acceptable salt thereof.
Each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds, stereoisomers of the compounds, deuterated analogs of the compounds, hydrates of the compounds, and pharmaceutically acceptable salts of the stereoisomers described herein.
Definitions
Unless otherwise defined herein, scientific, and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.
The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.
As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of 5 mg) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e. , it may vary between 4.5 mg and 5.5 mg.
“Optional" or "optionally" means that the subsequently described event or circumstance may, but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.
The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=0) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups
may be the same or different. Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to one of ordinary skill in the art.
The term “room temperature” or “ambient temperature” means a temperature between about 15 °C to about 25 °C, or up to about 30 C°.
“Halogen” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).
"Hydroxy" refers to an -OH group.
"Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 6 carbon atoms (“Ci-Ce alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t-butyl and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.
“Fluoroalkyl” refers to an alkyl group, as defined herein, wherein from one to all of the hydrogen atoms of the alkyl group are replaced by fluoro atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).
“Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 3 carbon atoms (“C1-C3 alkoxy”), or 1 to 2 carbon atoms (“C1-C2 alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and the like.
“Cycloalkyl” refers to a fully saturated hydrocarbon ring system that has the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. Cycloalkyl groups may contain, but are not limited to, 3 to 10 carbon atoms (“C3-C10 cycloalkyl”), 3 to 5 carbon atoms (“C3-C5 cycloalkyl”) or 3 to 4 carbon atoms (“C3-C4 cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.
“Heterocycloalkyl” refers to a fully saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O and S as a ring member, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(O)q, where q is 0, 1 or 2) and where the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N. Heterocycloalkyl rings include monocyclic or polycyclic such as bicyclic rings. Heterocycloalkyl rings also include rings which are spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, where such spirocyclic,
bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system.
Heterocycloalkyl rings may contain 1 to 4 heteroatoms selected from N, O, and S(O)q as ring members, or 1 to 3 ring heteroatoms, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms.
Heterocycloalkyl rings may be optionally substituted, unsubstituted or substituted, as further defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a monocyclic, bicyclic, tricyclic, spirocyclic, bridged or fused ring attached thereto.
Heterocycloalkyl rings may include, but are not limited to, 4-12 membered heterocyclyl groups, for example 5-8 or 4-6 membered heterocycloalkyl groups, in accordance with the definition herein. Examples of heterocycloalkyl ring group of the present invention may include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxaazepanyl, thieazepanyl, a radical of hexahydro- 1H-pyrrolizine ring, a radical of 8-oxa-3-azabicyclo[3.2.1]octane ring, a radical of 3-azabicyclo[3.2.1]octane ring, a radical of 6-azabicyclo[3.2.1]octane ring, or a radical of 3-azabicyclo[3.2.0]heptane ring.
"Aryl" or “aromatic” refers to monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms, in which all carbon atoms in the ring are of sp2 hybridization and in which the pi electrons are in conjugation. Aryl groups may contain, but are not limited to, 6 to 10 carbon atoms ("Ce-Cioaryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.
Similarly, "heteroaryl" or “heteroaromatic” refer to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in a ring in which all carbon atoms in the ring are of sp2 hybridization and in which the pi electrons are in conjugation. Heteroaryl groups may contain, but are not limited to, 5 to 14 ring atoms (“5-14 membered heteroaryl”), 5 to 12 ring atoms (“5-12 membered heteroaryl”), 5 to 10 ring atoms (“5-10 membered heteroaryl”), 5 to 9 ring atoms (“5-9 membered heteroaryl”), or 5 to 6 ring atoms (“5- 6 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring. Thus, either 5- or 6-membered heteroaryl rings, alone or in a fused structure, may be attached to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,
pyrrolo[3,2-b]pyridinyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, carbazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyidinyl, pyrazolo[4,3-c]pyidinyl, pyrazolo[3,4-c]pyidinyl, pyrazolo[3,4-b]pyidinyl, isoindolyl, purinyl, indolininyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5-a]pyridinyl, pyrazolo[1,5- a]pyridinyl, pyrrolo[1 ,2-b]pyridazinyl, imidazo[1 ,2-c]pyrimidinyl, azaquinazolinyl, phthalazinyl, , (pyrido[3,2-d]pyrimidinyl, (pyrido[4,3-d]pyrimidinyl, (pyrido[3,4-d]pyrimidinyl, (pyrido[2,3- d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.
The term “metal catalyst” means a reaction catalyst having metal element. In particular, “metal catalyst” means a reaction catalyst having metal element such as but is not limited to zinc or palladium. The metal element may exist as elemental form or ion form.
The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient.
“Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
Salts
Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this invention which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the invention that is suitable for administration to a subject or patient.
In addition, other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds as disclosed herein; 2) purifying compounds as disclosed herein; 3)
separating enantiomers of compounds as disclosed herein; or 4) separating diastereomers of compounds as disclosed herein.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/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, 1 ,5-naphathalenedisulfonic acid and xinofoate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
For a review on suitable salts, see Paulekun, G. S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007; 50(26), 6665-6672.
Pharmaceutically acceptable salts of compounds of the invention may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures
(i) by reacting a compound of the invention with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of a compound of the invention to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure.
These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
Solvates
The compounds of the invention, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention, or a pharmaceutically acceptable
salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.
A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.
When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
Complexes
Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drughost inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, for example, hydrogen bonded complex (cocrystal) may be formed with either a neutral molecule or with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17;1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64(8), 1269-1288, by Haleblian (August 1975).
Solid form
The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives 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 first order (‘melting point’).
The compounds of the invention may also exist in a 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 (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO'Na+, -COO'K+, or -SOs'Na+) or non-ionic (such as -N'N+(CH3)S) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970).
Stereoisomers
Compounds of the invention may exist as two or more stereoisomers. Stereoisomers of the compounds may include c/s and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers.
The pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl- arginine).
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M.,
Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein).
When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).
Tautomerism
Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) may occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino/amino, keto/enol, or oxime/nitroso group, lactam/lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
It must be emphasized that while, for conciseness, the compounds of the invention have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention.
Isotopes
The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S.
Certain isotopically-labelled compounds of the invention, for example those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. , 3H, and carbon-14, i.e. , 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability.
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the invention may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions.
In some embodiments, the deuterium compound is selected from any one of the compounds set forth in Table 7. The deuterium compounds shown in Table 7 may be prepared with method disclosed in this disclosure, when combined with deuteration methods known to a person with ordinary skill in the art.
In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds of the invention are deuterated.
Isotopically-labeled compounds of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, de-acetone, de- DMSO.
Synthetic Methods
Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature.
For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are discussed below, other starting materials and reagents may be substituted to provide one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of the invention. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.
In the preparation of compounds of the invention it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of the invention). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition.
For example, if a compound contains an amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as /V-terf-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9- fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.
General Experimental Details
1H and 19F Nuclear Magnetic Resonance (NMR) spectra were recorded on Bruker XWIN-NMR (400 or 700 MHz) spectrometer. 1H and 19F resonances are reported in parts per million (ppm) downfield from tetramethylsilane. 1H NMR data are reported as multiplicity (e.g. s, singlet; d, doublet; t, triplet; q, quartet; quint, quintuplet; dd, doublet of doublets; dt, doublet of triplets; br s, broad singlet). For spectra obtained in CDC , DMSO-cfe, and CD3OD, the residual protons (7.27, 2.50, and 3.31 ppm, respectively) were used as the internal reference. All observed coupling constants, J, are reported in Hertz (Hz). Exchangeable protons are not always observed.
Optical rotations were determined on a Jasco P-2000 or a Rudolph Autopol IV polarimeter. All final compounds were purified to > 95% purity, unless otherwise specified. When absolute stereochemistry is known, (R,S) labels are used. When absolute stereochemistry is not known, the software-generated names are modified to include (+)- and (-)-prefixes according to the optical rotations, and (R*/S*) labels are used to show relative configuration.
Mass spectra, MS (m/z), were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Where relevant and unless otherwise stated, the m/z data provided are for isotopes 19F, 35CI, 79Br and 127l.
The nomenclature is written as described by IIIPAC (International Union of Pure and Applied Chemistry generated within Perkin Elmers Chemdraw 18.0.0.231. The naming convention provided with Perkin Elmers Chemdraw 18.0.0.231 is well known by those skilled in the art and it is believed that the naming convention provided with Perkin Elmers Chemdraw 18.0.0.231 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules.
Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source (K-a average). The divergence slit was set at 15 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 4.10 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.01 degrees and a step time of 1.0 second. The antiscatter screen was set to a fixed distance of 3.0 mm. Samples were rotated at 15/min during collection. Samples were prepared by placing them in a silicon low background sample holder.
Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software. Data analysis was performed by EVA diffract plus software. The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the EVA software, peaks selected with a threshold value of 8 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was visually checked, and peak positions were adjusted to the peak
maximum. Peaks with relative intensity of > 3.0% were generally chosen. Typically, the peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position from PXRD stated in USP up to +/- 0.2° 2-Theta (USP-941).
Abbreviations
ACN is acetonitrile; aq is aqueous;
Boc is terf-butoxycarbonyl;
BOC2O is di-terf-butyl dicarbonate; br is broad; tBu is terf-butyl;
°C is degrees celcius;
CDC is deutero-chloroform;
5 is chemical shift; d is doublet; dd is doublet of doublets; ddd is doublet of doublet of doublets; dt is doublet of triplets;
DCM is dichloromethane; methylene chloride;
DMAP is 4-dimethylaminopyridine;
DMF is N,N-dimethylformamide;
DMSO is dimethyl sulfoxide;
DMSO-de is deuterodimethylsulfoxide; ee is enantiomeric excess;
ESI is electrospray ionization;
EtOAc is ethyl acetate; g is gram;
GCHS is gas chromatography headspace;
HPLC is high performance liquid chromatography; hr(s) is hour(s);
HRMS is high-resolution mass spectrometry;
I PA is iso-propyl alcohol;
L is liter;
LCMS is liquid chromatography mass spectrometry; m is multiplet;
M is molar;
MeCN is acetonitrile;
MeOH is methanol;
mg is milligram;
MHz is mega Hertz; min(s) is minute(s); mL is milliliter; mmol is millimole; mol is mole;
MS (m/z) is mass spectrum peak;
MTBE is methyl tert-butyl ether;
NMR is nuclear magnetic resonance; pH is power of hydrogen; ppm is parts per million; psi is pounds per square inch;
PXRD is powder X-ray diffraction; q is quartet; rpm is revolutions per minute; rt is room temperature;
RT is retention time; s is singlet; t is triplet;
THF is tetrahydrofuran;
TLC is thin layer chromatography; pL is microliter; and pmol is micromole.
The schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present invention. Some of the compounds of the present invention contain a single chiral center. In the following schemes, the general methods for the preparation of the compounds are shown either in racemic or enantioenriched form. It will be apparent to one skilled in the art that all of the synthetic transformations may be conducted in a precisely similar manner whether the materials are enantioenriched or racemic. Moreover, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and in the chemistry literature.
Synthetic Methods for Ervogastat
Synthesis of 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (P-01)
Condition A:
To a reactor was added sulfolane (10 vol) and Compound A (1.0 equiv) at 20-30 °C. Compound B (0.90 equiv), K2CO3 (3.0 equiv) and CuBr (0.1 equiv) were added, and the resulting mixture was stirred at 20-30 °C for 10 min and then warmed to 105-115 °C. After stirring at that temperature for 16 h, the reaction mixture was cooled to 20-30 °C and treated with 5% solution of ammonia in water (18 vol) at 0- 10 °C. The resulting slurry was stirred at 0-10 °C for 1 h and filtered. The filter cake was washed with water (5 vol X 2). The solid was dissolved in MTBE (15 V) at 20-30 °C, and the resulting solution was washed with 5% solution of ammonia in water (18 V). Organic layer was separated and treated with 5% w/w activated charcoal for 1 h. Mixture was filtered, and the filtrate was concentrated to 3V at 30- 40 °C. IPA (5 V) was charged, and the resulting solution was concentrated to 5 V. IPA (5 V) was charged, and the resulting solution was concentrated to 6 V. The reaction mixture was heated to 45-55 °C until the mixture becomes homogeneous. Water (15 V) was charged dropwise at 45-55 °C, and the resulting mixture was stirred for 1 h at that temperature, cooled to 20- 30 °C and then stir for one more hour. The slurry was filtered, and the filter cake was washed with IPA/Water (1/2) (2 V). The material was dried under vacuum to give 690 g of an off-white solid (Form 1 anhydrous, 96.8%
assay, 62% assay-corrected yield). Characterization data were consistent with previously reported values.
Condition B:
CuBr, N,N-dimethylglycine
K2CO3, sulfolane
A B
To a reactor was charged Compound A (7.54 g, 37.35 mmol, 1.3 eq), Compound B (5 g, 28.73 mmol, 1.0 eq), K2CO3 (7.94 g, 57.46 mmol, 2.0 eq) and sulfolane (25 mL, 5 vol). Solution was heated to heated to 35 °C and sparged with N2 for 10-15 min. After CuBr (0.206 g, 0.05 eq) and /V,/V-dimethylglycine (0.148 g, 0.05 eq) were added, the reaction mixture was heated to 110 °C and stirred for 20 h. Reaction mixture was cooled to 25 °C and treated with MTBE (50 mL, 10 vol), water (25 mL, 5 vol), and aq. KH2PO4 (25 mL, 5 vol, 5% w/w). Aqueous layer was extracted with MTBE (25 mL, 5 vol). Organic layers were combined and washed with water (50 mL, 10 vol) twice. Organic layer was distilled under vacuum to ca. 10 mL (2 vol), treated with IPA (25 mL, 5 vol), distilled under vacuum to ca. 10 mL (2 vol), treated with IPA (25 mL, 5 vol), distilled under vacuum to ca. 10 mL (2 vol), charged IPA (25 mL, 5 vol), and distilled under vacuum to ca. 10 mL (2 vol). Water (25 mL, 5 vol) was added dropwise at 25 °C. Resulting mixture was agitated 1 h at 25 °C and filtered. Solid was rinsed with IPA/Water (10 mL, 1 :2) and MTBE (5 mL, 1 vol). Resulting solid was dried under vacuum to give 2-((5-bromopyridin-3- yl)oxy)-3-ethoxypyridine (2, P-01) as 6.3 g of an off-white solid (99.4% assay, 74% assay- corrected yield). Characterization data were consistent with previously reported values.
The PXRD result for P-01 Form 1 anhydrous is shown in Table 1 below.
Table 1 : Form 1 anhydrous peak table:
Characteristic PXRD peaks for P-01 Form 1 are 9.8, 24.8, and 29.2 °2-Theta ± 0.2 °2- Theta. Characteristic PXRD peaks for P-01 Form 1 can also include 19.6 and 31.5 °2-Theta ± 0.2 °2-Theta, providing 9.8, 19.6, 24.8, 29.2, and 31.5 °2-Theta ± 0.2 °2-Theta. An embodiment of the present invention includes an anhydrous crystalline form of 2-((5-bromopyridin-3-yl)oxy)-3- ethoxypyridine, having a powder X-ray diffraction (PXRD) pattern comprising peaks values of 9.8, 24.8, and 29.2 °2-Theta ± 0.2 °2-Theta. Another embodiment of the present invention includes the anhydrous crystalline form having a PXRD pattern comprising peaks values of 9.8, 19.6, 24.8, 29.2, and 31.5 °2-Theta ± 0.2 °2-Theta.
Synthesis of tert-butyl 2-(tert-butylsulfonyl)pyrimidine-5-carboxylate (P-02)
Route A
i. BU4NHSO4
To a 5 L 3-neck flask equipped with an overhead stirrer were added ethyl 2-chloropyrimidine-5- carboxylate (150 g, 0.80 mol, 1.0 equiv), BU4NHSO4 (27 g, 0.080 mol, 1.0 equiv) and dichloromethane (600 mL). The mixture was agitated vigorously, and a gentle flow of nitrogen was used purge the headspace of the flask into a trap containing a 1 :1 bleach/isopropyl alcohol solution (The thiol employed has very low odour threshold and efficient trapping in the bleach/isopropanol solution is essential to prevent exposure). 2-methyl-2-propanethiol (100 mL, 0.88 mol, 1.1 eq) and 50 %w/w NaOH (300 mL) were added, in sequence, slowly to the flask via an addition funnel maintaining the internal temperature below 15 °C using an ice-bath. The mixture was stirred for 30 min at 15 °C. Water (750 mL) was added slowly, maintaining the temperature below 35 °C. The mixture was stirred at ambient temperature for 16 h. The reaction mixture was transferred to a separatory funnel, and the organic layer was separated and concentrated to dryness under reduced pressure at 30 °C. Water (750 mL) was added and the solids were dissolved, and additional water (250 mL) was used to dissolve and transfer the remaining solids. The mixture was cooled to 3 °C, and the pH was adjusted to ca. 1.0 with 11.6 M HCI at 3 °C. The resulting thick white precipitate was filtered through a Buchner funnel and washed with water (600 mL). After two additional washed with water (1.5 L), the solids were dried under vacuum under a flow of nitrogen over 24 h to afford 153 g (90% yield) of 2-(tert- butylthio)pyrimidine-5-carboxylic acid as a white solid. 1H NMR (300 MHz, DMSO) 5 13.54 (s, 1 H), 8.97 (s, 2H), 1.57 (s, 9H). 13C NMR (75 MHz, DMSO) 5 176.60, 165.37, 158.24, 120.32, 47.99, 29.89. IR (neat) vmax: 3103, 2991 , 1728, 1571 , 1553, 1403, 1377, 1343, 1321 , 1292, 1255, 1209, 1169, 1144, 1111 , 1059, 850, 711 , 626, 592, 566, 512, 427. HRMS (ESI) m/z [M+H]+ calculated for C9H13N2O2S, 213.0692; found 213.0690.
To a 5 L 3-neck round bottom flask equipped with an overhead stirrer was added 2-(tert- butylthio)pyrimidine-5-carboxylic acid (100 g, 0.472 mol, 1.00 equiv), DMAP (5.8 g, 0.047 mol, 0.10 equiv) and THF (500 mL). The mixture was stirred until a homogeneous solution was obtained. The mixture was heated to 60 °C, and a solution of BOC2O (271 mL, 1.18 mol, 2.5 equiv) in THF (500 mL) was added over 1.5 h at reflux (Efficient venting of the condenser is essential to
prevent build-up of gasses generated from the reaction). The reaction mixture was stirred at reflux for 2 h. The reaction mixture was cooled to 22 °C and isopropyl acetate (1 L) was added. 1M aqueous HCI (500 mL) was added and the mixture was stirred for 15 min and transferred mixture to a separatory funnel. The layers were separated, and the organic layer was washed with 2M aqueous NaOH (500 mL). The organic layer was concentrated to dryness under reduced pressure. 5 %w/w aqueous NaHCCh (200 mL) was added to the flask and the mixture was agitated for 20 min. The resulting solids were filtered and washed twice with 5 %w/w aqueous NaHCOs (50 mL) and water (400 mL, 4 vol). The solids were dried under vacuum and a flow of nitrogen for 24 h to afford 120 g (95% yield) of tert-butyl 2-(tert-butylthio)pyrimidine-5-carboxylate as a light brown solid. 1H NMR (300 MHz, CDCI3) 5 8.93 (s, 2H), 1.60 (s, 9H), 1.57 (s, 9H). 13C NMR (75 MHz, CDCh) 6 177.49, 163.30, 157.73, 120.46, 82.51 , 48.11 , 29.89, 28.27. IR (neat) vmax: 2983, 2970, 2919, 1714, 1583, 136, 1407, 1368, 1299, 1221 , 11225, 1025, 848, 782, 644, 557. HRMS (ESI) m/z [M+H]+ calculated for C13H21N2O2S, 269.1318; found 269.1318.
Method 1 :
To a 2 L 3-neck round bottom flask was charged tert-butyl 2-(tert-butylthio)pyrimidine-5- carboxylate (30 g, 1.0 equiv), MeCN (300 mL, 10 vol) and stirred for 15 min. A solution of oxone (103 g, 3.0 equiv) in water (360 mL, 12 vol) was added to the sulfide solution at room temperature over 60 min, keeping the internal temperature below 25 °C using a water bath. The tri-phasic reaction mixture was agitated overnight at room temperature. 10 %w/w aq. sodium bisulfite (10 vol) was added to the reaction mixture over 15 min and a Kl-starch paper test indicated the absence of residual oxone. The reaction mixture was distilled to remove ca. 300 mL of the solvent at 35 °C and the resulting solids were filtered and washed twice with water (10 vol) and dried overnight to afford 31.8 g of P-02 as a white solid (94% yield). 1H NMR (300 MHz, CDCh) 6 9.35 (s, 2H), 1.58 (s, 9H), 1.42 (s, 9H). 13C NMR (75 MHz, CDCh) 5 166.31 , 161.12, 159.23, 127.23, 84.47, 61.08, 27.98, 23.75. IR (neat) vmax: 2998, 2981 , 2931 , 1725, 1575, 1558, 1472, 1463, 1405, 1392, 1368, 1299, 1286, 1253, 1168, 1136, 1110, 1031 , 958, 849, 800, 788, 778, 744, 669, 635, 589, 507, 406. HRMS (ESI) m/z [M+H]+ calculated for C13H21N2O4S, 301.1217; found 301.1214.
Method 2:
To the flask was charged MeOH (5.7 L) and tert-butyl 2-(tert-butylthio)pyrimidine-5-carboxylate (226 g, 1 .0 equiv) at at 20-25 °C. The suspension of oxone (2.0 equiv) in water (3 L) was slowly charged while maintaining the temperature at 25-30 °C. Reaction mixture was agitated for at least
16 hours. To the reaction stream was charged 10% w/w aqueous NaHSCh (2.3 L) at 20-25 °C. After stirring for at least 20 mins at 20-25 °C, the mixture was filtered. The filter cake was rinsed with MeOH (450 mL). The filtrate was concentrated until no droplets at the temperature no more than 35 °C. Resulting mixture was filtered and rinsed with water (230 mL). Filter cake was suspended in heptane (340 mL) for at least 1 hour at 15-20 °C, filtered and rinsed with heptane (110 mL). The filter cake was dried. To the flask was charged the resulting solid and MTBE (2.2 L) at 0-5 °C. Saturated aqueous solution NaHCOs was charged dropwise to adjust the pH to 7.5- 8.0. Organic phase was concentrated to -620 mL while maintaining the temperature no more than 40 °C. Heptane (1.5 L) was charged into the concentrated solution and concentrated to -620 mL while maintaining the temperature no more than 40 °C. Heptane (1.5 L) was charged into the concentrated solution and concentrated to -620 mL while maintaining the temperature no more than 40 °C. The resulting suspension was stirred at 15-20 °C for 1 hour. Slurry was filtered. The filter cake was rinsed with heptane (310 mL) and dried at room temperature to afford 225 g of P- 02 as a light pink solid (Form 1 anhydrous).
Method 3: terf-Butyl 2-(tert-butylthio)pyrimidine-5-carboxylate (147 g, 1 equiv) was dissolved in DCM (1.6 L). Resulting mixture was cooled to 0-5 °C, treated with mCPBA (2.5 equiv, added in portions) and agitated at 0-5 °C for 5 h. The mixture was filtered to remove 3-chlorobenzoic acid, and the filter cake washed with DCM (300 mL). The combined filtrates were washed with 2 M NaOH (300 mL, twice) at 0-5 °C followed by 5 %w/w NaCI (150 mL). The organic layer was concentrated (vacuum distillation) to -730 mL, and heptane (1.5 L) was charged. The pot was vacuum-distilled to -730 mL and heptane (1.5 L) was charged, resulting in the formation of a thick slurry. The pot was vacuum distilled to -730 mL, and then the slurry was agitated at ambient temperature ca. 30 min. The product was collected by filtration, washed with heptane (300 mL) and dried under vacuum. 106.8 g of off-white solid with 97.23 %w/w assay, 95.66 %a/a UPLC purity was isolated. 80 g of the crude cake was dissolved in MTBE (160 mL). Heptane (400 mL) was added over ca. 30 min resulting in formation of a slurry. The mixture was heated to 45 °C, held for 30 min, cooled gradually to 0-5 °C and aged at 0-5 °C for 1 h. The product P-02 was collected by filtration and washed with cold heptane (320 mL) and dried under vacuum. 70.8 g was isolated as a white solid (89% recovery; 97.75 %w/w qNMR assay, 99.22 %a/a UPLC purity, Form 1 anhydrous).
Route B:
To a 5 L 3-neck flask was charged DCM (1500 mL). The solution was cooled to -6 °C and DMF (162 mL, 2.10 moles, 1.50 equiv) was charged, followed by dropwise addition of oxalyl chloride (180 mL, 2.10 mol, 1.50 equiv) while maintaining the internal temperature below 10 °C. CO2 and CO gases are generated during the addition and the reaction was carried out in a well-ventilated fume hood to prevent exposure to the gases. The mixture was agitated for 45 min keeping the temperature below 10 °C. To the resulting thick white slurry was charged a solution of ethyl (E)- 3-(dimethylamino)acrylate (200 g, 1.40 mol, 1.00 equiv) in DCM (1000 mL, 5 vol) over 1 h, keeping the internal temperature below 3 °C using an ice-salt bath. The reaction mixture was allowed to warm to room temperature and allowed to stir for 16-18 h to afford a clear pale-yellow solution. TLC analysis (Eluent: 6:4 heptane/ethyl acetate) indicated complete consumption of ethyl (E)-3-(dimethylamino)acrylate (analysis with phosphomolybdic acid solution TLC stain). The temperature was adjusted to 3 °C and water (1000 mL) was added while maintaining the temperature below 10 °C. The mixture was stirred for 10-15 min and transferred to a separatory funnel. The layers were separated, and the organic layer was washed with water (500 mL). The combined aqueous layer was cooled to 3 °C and the pH was adjusted to 6.5 using 50 %w/w aqueous NaOH. terf-Butanol (2000 mL) was charged, and the temperature was adjusted to 3 °C. 2-(terf-Butyl)isothiouronium bromide (249 g, 1.17 moles, 0.84 eq) and Na2HPC>4 (139 g, 1.16 moles, 0.83 eq) were added in sequence and the temperature was adjusted to 19-25 °C over 1- 2 h. The mixture was agitated for 16-18 h at room temperature. The solids were filtered, and the layers were separated. The combined organic layers were concentrated under reduced pressure. MeOH (2000 mL, 10 vol) was added, and the mixture was cooled to 3 °C. 5M aqueous NaOH (330 mL, 1.2 eq) was charged while maintaining temperature below 10 °C. The mixture was agitated for 2.5 h below 10 °C, and the reaction mixture was concentrated at 45 °C to obtain a syrup. Water (1000 mL) was added, and the mixture was agitated for 10 min. Isopropyl acetate (1000 mL) was added and the mixture was stirred for 15 min. The mixture was transferred to a separatory funnel and the aqueous layer was separated and cooled to -3 °C. The pH of the aqueous layer was adjusted to 1 with 11.36 M HCI keeping the temperature below 10 °C, and the mixture was agitated for 20-30 min at 0-6 °C to obtain a well-stirred slurry. The solids were filtered, and the filter cake was washed four times with water (1000 mL) and dried under vacuum for 16 h
to afford 163.5 g of 2-(ferf-butylthio)pyrimidine-5-carboxylic acid as a white solid (63% yield based on the 2-(tert-butyl)isothiouronium input). The characterization data matched that of 2-(tert- butylthio)pyrimidine-5-carboxylic acid presented above. See route A for the conversion of 2-(tert- butylthio)pyrimidine-5-carboxylic acid to P-02.
Route C:
To a 100 mL 3-neck round bottom flask equipped with magnetic stirrer, thermometer, addition funnel and nitrogen inlet were added DCM (20.3 mL) and DMF (1.47 mL, 0.0189 mol, 1.2 eq). The mixture was agitated for 10 min and cooled to -10 °C. Oxalyl chloride (1.4 mL, 0.0189 mol, 1.05 eq) was added drop wise over 15 min and the mixture was warmed to 0 °C and agitated for 45 min. The oxalyl chloride addition was accompanied by generation of CO2 and CO gases. To the resulting thick slurry was added a solution of tert-butyl (E)-3-(dimethylamino)acrylate (2.7 g, 0.0158 mol) in DCM (9 mL). The mixture was warmed to ambient temperature and stirred for 2 h. TLC analysis (4:6 EtOAc/Heptane) indicated complete consumption of tert-butyl (E)-3- (dimethylamino)acrylate. The mixture was cooled to 0 °C, and water (19 mL) was charged at 3 °C and the mixture was stirred for 10-15 min. The organic and aqueous layers were separated, and the organic layer was washed with water (10 mL). The combined aqueous layers were cooled to 0 °C and the pH was adjusted to ca. 1.0 using 50 %w/w NaOH. MeOH (5.4 mL) and 2-(tert- butyl)isothiouronium bromide (3.26 g) were added and the pH was adjusted to ca. 7.4 with 1 N NaOH. The reaction mixture was agitated at 19-25 °C for 15 h. The solids were filtered and washed twice with water (10 mL, 4 vol). The solids were dried under vacuum to afford 2.35 g of yellow solid (82% yield). The characterization data matched that of fert-butyl 2-(tert- butylthio)pyrimidine-5-carboxylate presented above. See route A for the conversion of terf-butyl 2-(terf-butylthio)pyrimidine-5-carboxylate to P-02.
Route D:
To a reactor was charged ACN (5 L) and 5-bromo-2-chloropyrimidine (1.07 kg, 1.00 equiv). The resulting mixture was stirred at 15-25 °C for at least 10 mins until the solids dissolve completely. 2-Methyl-2-propanethiol (1.1 equiv) at 15-25 °C was charged next. CS2CO3 (1.2 equiv) was then added in portions. It is recommended to charge in at least 6 portions at interval of at least 10 mins to avoid drastic exotherm. The mixture was heated to 50-55 °C and held at that temperature for at least 5 hours. The mixture was cooled to 15-25°C. The reaction mixture was filtered through celite. The resulting filtrate was concentrated to 1-2 L at the inner temperature of no more than 45°C. Heptane (10 L) was charged, and the resulting solution was concentrated to 1-2 L at the inner temperature of no more than 45°C. Heptane (10 L) was charged into the concentrated solution and concentrated to 1-2 V at the inner temperature of NMT 45 °C. The concentrated solution was purified by column chromatography on silica eluting with 100:1-50:1 heptane and EtOAc. 1.29 kg of 5-bromo-2-(tert-butylthio)pyrimidine was obtained as a white solid with 99.9% HPLC purity, 96.8%, assay in 91.4% assay-corrected yield.
To a reactor were charged THF (500 mL) and E436 (100 g) at 15-25 °C. After the mixture was cooled to -5 to 5 °C. Cyclohexylmagnesim chloride solution (1 M in THF, 1.2 equiv) was charged dropwise. After at least 1 hour, a solution of BOC2O (1.5 equiv) in THF (100 mL) was added. After stirring for at least 1 hour, aqueous NH4CI (10% w/w, 1 L) was added. Mixture was extracted with isopropyl acetate (1.5 L) twice. Organic layers were combined and concentrated to give an oil. Oil was suspended with heptane (100-200 mL) and stirred at -20 C for at least 2 hours. Slurry was filtered, and the filter cake was washed with pre-cooled heptane (50 mL). The resulting soild was dried at room temperature under nitrogen overnight give to give 253 g of a light yield solid with 90.1% assay (51% assay-corrected yield). See route A for the conversion of terf-butyl 2-(tert- butylthio)pyrimidine-5-carboxylate to P-02.
The PXRD result for P-02 Form 1 anhydrous is shown in Table 2 below.
Table 2: P-02 Form 1 anhydrous peak table:
Characteristic PXRD peaks for P-02 Form 1 are 6.1, 12.2, and 13.9 °2-Theta ± 0.2 °2- Theta. Characteristic PXRD peaks for P-02 Form 1 can also include 21.2 and 31.0 °2-Theta ± 0.2 °2-Theta, providing 6.1, 12.2, 13.9, 21.2, and 31.0 °2-Theta ± 0.2 °2-Theta. An embodiment of the present invention includes an anhydrous crystalline form of tert-butyl 2-(tert- butylsulfonyl)pyrimidine-5-carboxylate, having a powder X-ray diffraction (PXRD) pattern comprising peaks values of 6.1, 12.2, and 13.9 °2-Theta ± 0.2 °2-Theta. Another embodiment of the present invention includes the anhydrous crystalline form having a PXRD pattern comprising peaks values of 6.1, 12.2, and 13.9, 21.2 and 31.0 °2-Theta ± 0.2 °2-Theta.
Synthesis of compound of formula (d)
Steps 1 and 2: Formation of compound of formula (d)
Procedure:
To a stirred solution of 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (P-01 , 39.7 g, 0.132 mol, 1 equiv) in THF (200 mL) was added cyclohexyl magnesium chloride (79 mL, 1.0 equiv, 1.67 M in THF) at 20 °C dropwise over 20 min. The resulting homogenous solution was agitated for 3 h at 20-25 °C. The resulting Grignard reagent was added to a solution of fert-butyl 2-(tert- butylsulfonyl)pyrimidine-5-carboxylate (P-02, 39.0 g, 0.132 mol, 1.00 eq) at 20-26 °C. The reaction mixture was agitated at ambient temperature for 18 h. Methanol (39 mL) and a solution of sodium hydroxide (264 mL, 4 equiv, 2 M in water) were added. Reaction mixture was heated to 35 to 40 °C, stirred for 6 h, and then cooled to 20 to 25 °C. HCI (290 mL, 4.4 equiv, 2 M in water) was charged over 40 min. The mixture was heated to 45 to 50 °C over 30 min and agitated for 1 h. Reaction mixture was cooled to 20 to 25 °C over 40 min and agitated for 1 h. The mixture was filtered, washed with 1 :1 mixture of THF and water (80 mL), then with water (120 mL), and dried under vacuum to afford 35.8 g (73%) of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3- yl)pyrimidine-5-carboxylic acid (Compound (d)) as a powder. Compound (d) Form 1 anhydrous, Form 2 monohydrate, or a mixture thereof were isolated from this process. 1H NMR (400 MHz, DMSO-cfe, 298K): 5 13.87 (s, 1 H), 9.40 (d, J = 1.7 Hz, 1 H), 9.32 (s, 2H), 8.66 (d, J = 2.7 Hz, 1 H), 8.36 (t, J = 2.2 Hz, 1 H), 7.69 (dd, J = 4.8, 1.5 Hz, 1 H), 7.58 (dd, J = 8.1 , 1.5 Hz, 1 H), 7.19 (dd, J = 8.0, 4.9 Hz, 1 H), 4.18 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).
Two forms for Compound (d) have been isolated using this process.
Compound (d) Form 2 monohydrate was prepared by adding a mixture of dimethylacetamide and water (75:25 v/v DMAc:water) to a vial containing Compound (d) Form 1 anhydrous to prepare a slurry. The slurry was stirred with a magnetic stir bar for approximately 5 hours. Solids were isolated by vacuum filtration and rinsed with water. The solids were allowed to dry at ambient conditions to provide Compound (d) Form 2 monohydrate.
The PXRD result for Compound (d) Form 1 anhydrous is shown in Table 3 below.
Table 3: Compound (d) Form 1 anhydrous peak table
Characteristic PXRD peaks for Compound (d) Form 1 are 7.1 , 9.4, and 14.3 °2-Theta ± 0.2 °2-Theta. Characteristic PXRD peaks for Compound (d) Form 1 can also include 12.5 and 19.0 °2-Theta ± 0.2 °2-Theta, providing 7.1, 9.4, 12.5, 14.3 and 19.0 °2-Theta ± 0.2 °2-Theta. An embodiment of the present invention includes an anhydrous crystalline form of 2-(5-((3- ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid, having a powder X-ray diffraction (PXRD) pattern comprising peaks values of 7.1 , 9.4, and 14.3 °2-Theta ± 0.2 °2- Theta. Another embodiment of the present invention includes the anhydrous crystalline form having a PXRD pattern comprising peaks values of 7.1, 9.4, 12.5, 14.3 and 19.0 °2-Theta ± 0.2 °2-Theta.
The PXRD result for Compound (d) Form 2 monohydrate is shown in Table 4 below:
Table 4: Compound (d) Form 2 monohydrate peak table
Characteristic PXRD peaks for Compound (d) Form 2 monohydrate are 8.7, 10.2, and 13.0 °2-Theta ± 0.2 °2-Theta. Characteristic PXRD peaks for Compound (d) Form 2 monohydrate can also include 17.3 and 27.8 °2-Theta ± 0.2 °2-Theta, providing 8.7, 10.2, 13.0, 17.3 and 27.8 °2-Theta ± 0.2 °2-Theta. An embodiment of the present invention includes an crystalline form of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid monohydrate, having a powder X-ray diffraction (PXRD) pattern comprising peaks values of 8.7, 10.2, and 13.0 °2-Theta ± 0.2 °2-Theta. Another embodiment of the present invention includes the anhydrous crystalline form having a PXRD pattern comprising peaks values of 8.7, 10.2, 13.0, 17.3 and 27.8 °2-Theta ± 0.2 °2-Theta.
Alternate synthesis of compound P-03
Step 1 : Alternate Preparation of P-03
Step 1
Procedure: P-03 may be isolated.
To a stirred solution of 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (P-01 , 20 g, 68 mmol, 1.0 equiv) in THF (100 mL) was added cyclohexylmagnesium chloride (85 mL, 1.0 equiv, 1.67 M in THF) at 22 °C dropwise over 10 min. The resulting solution was agitated for 3.5 h at ambient temperature. To the resulting solution was added a solution of terf-butyl 2-(tert- butylsulfonyl)pyrimidine-5-carboxylate (P-02, 20 g, 68 mmol, 1.0 equiv) in 100 mL of THF at 22 °C over 30 min. The reaction mixture was agitated at ambient temperature for 18 h, cooled to 0- 6 °C and quenched by the addition of 10 %w/w aqueous ammonium chloride (100 mL). The mixture was extracted twice with isopropyl acetate (100 mL) and concentrated to ~50 mL. 100 mL of isopropanol was added, and the resulting mixture was concentrated to ~50 mL. 100 mL of isopropanol was added, and the resulting mixture was concentrated to ~50 mL. A mixture of I PA and water (3:1 , 40 mL) was added. This mixture was heated to 40-45 °C, held for 15 min, cooled to 20-25 °C, and stirred for 18 h. This slurry was filtered. The solids were washed with
IPA and water mixture (3:1 , 80 mL and 20 mL) and dried to afford 17 g (64%) of P-03 as Form 1 (anhydrous).1 H NMR (300 MHz, CDCI3) 5 9.54 (s, 1 H), 9.26 (s, 2H), 8.75 - 8.47 (m, 2H), 7.70 (d, J = 5.0 Hz, 1 H), 7.25 (d, J = 7.4 Hz, 1H), 7.02 (dd, J = 7.7, 4.7 Hz, 1 H), 4.17 (q, J = 6.9 Hz, 2H), 1.63 (s, 9H), 1.50 (d, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCI3) 5 164.75, 162.76, 158.40, 152.90, 151.07, 145.96, 145.91 , 144.07, 137.42, 133.21, 128.47, 123.73, 120.76,
119.91, 83.01, 64.65, 28.14, 14.65. IR (neat) vmax: 3034, 2977, 1708, 1586, 1570, 1543, 1445, 1417, 1389, 1244, 1213, 1140, 1121, 1070, 932, 814, 751 , 707, 645. HRMS (ESI) m/z [M+H]+ calculated for C21H22N4O4, 395.1714; found 395.1714. The PXRD result for P-03 Form 1 anhydrous is shown in Table 5 below.
Table 5: P-03 Form 1 anhydrous peak table
Characteristic PXRD peaks for P-03 Form 1 anhydrous are 9.7, 12.5, and 21.7 °2-Theta ± 0.2 °2-Theta. Characteristic PXRD peaks for P-03 Form 1 anhydrous can also include 19.5 and 24.1 °2-Theta ± 0.2 °2-Theta, providing 9.7, 12.5, 21.7, 19.5 and 24.1 °2-Theta ± 0.2 °2- Theta. An embodiment of the present invention includes an anhydrous crystalline form of tertbutyl 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate, having a powder X- ray diffraction (PXRD) pattern comprising peaks values of 9.7, 12.5, and 21.7 °2-Theta ± 0.2 °2-
Theta. Another embodiment of the present invention includes the anhydrous crystalline form having a PXRD pattern comprising peaks values of 9.7, 12.5, 21.7, 19.5 and 24.1 °2-Theta ± 0.2 °2-Theta.
Synthesis of Ervogastat
Step 3
Procedure:
To a reactor were charged acetonitrile (35 mL), 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3- yl)pyrimidine-5-carboxylic acid ((d), 5.0 g), (S)-tetrahydrofuran-3-amine hydrochloride ((e), 2.2 g), and /V,/V-diisopropylethylamine (18 mL). Propylphosphonic anhydride (50% solution in acetonitrile, 12.6 mL) was charged while reaction temperature was maintained at 20 °C. The mixture was stirred for at least 1 hour, and then heated to 40 °C. A solution of sodium hydroxide (2.2 M, 16 mL) was charged. The reaction mixture was stirred for at least 2 hours, heated to 50- 60 °C to generate a homogeneous solution, and then filtered. Reactor was rinsed with 3:1 acetonitrile:water (10 mL), which was pushed through the filter. Solution was cooled to 40-45 °C at 1 °C /min. Ervogastat Form 1 seed (12.5 mg) was charged. The mixture was stirred for at least 2 hours, cooled to 20 °C at 0.2 °C /min. Solution was distilled under vacuum at no more than 40 C, followed by addition of water (25 mL) over 1 hour to generate a solution containing 20-25% acetonitrile by KF and GCHS analysis. Reaction mixture was cooled to 20 C at 0.2 K/min, held for at least 1 hour, heated to 38 °C at 1 K/min, held for at least 1 hour, cooled to 20 °C at 0.2 K/min, held for at least 1 hour, heated to 38 °C at 1 K/min, held for at least 1 hour, cooled to 20 °C at 0.2 K/min, and then held for at least 2 hour. Slurry was filtered. Filter cake was washed with 4 ml acetonitrile and 15 ml water twice. Solids were dried under vacuum at 45 C to yield 5.6 g (93%) of Ervogastat.
Recrystallization of Ervogastat
Procedure:
To a reactor was charged water (170 mL), acetonitrile (255 mL), and Ervogastat prepared according to Step 3 (85 g). The mixture was heated to 72 °C and held for at least 30 minutes to form a homogeneous solution. The solution was cooled to 67 °C and seeded with 2.55 g of
Ervogastat Form 1. The slurry was held at 67 °C for at least 60 min and then cooled to 15 °C over 10 hours. Water (425 mL) was added over 2 hours at that same temperature. High shear wet milling was then performed using either an I KA or Silverson mill to reduce particle size to meet project targets. After this milling operation the material was filtered. The cake was washed first with 170 mL of 50/50 acetonitrile/water. Two additional acetonitrile cake washes were performed with 170 mL of each wash. The final acetonitrile washes are required to help displace water and prevent significant agglomeration during drying.
The PXRD was consistent with Ervogastat Form 1 , the thermodynamically stable form at ambient conditions.
Comparison Example
The following scheme provided scaled up synthesis according to the method disclosed in the United States Patent No. 10,071 ,992. However, it has been found that the scale-up of making ervogastat with the method disclosed in United States Patent No. 10,071,992 does not provide similar results. The method disclosed in United States Patent No. 10,071,992 provides 70% yield while the larger scale effort as shown in the following scheme only provides about 45% yield in Step 1. The main unexpected challenge seems to be the hydrolysis of the chloride and the ester of the starting material B, especially at larger scale synthesis.
A: 7.77 Kg B: 5.16 Kg
45% yield
3-Pyridyl Grignard reagent was utilized to optimize the synthesis of 2-substituted pyrimidines via a S«Ar strategy to ensure generality and compatibility with heterocyclic nucleophiles (Table 6). When 2-chloro pyrimidine D-1 was employed, exclusive addition at position 6 was observed to generate F-1 (entry 1).
Table 6. Optimization of the Sulfone Substituent
ND=Not detected by LIPLC. Reaction conditions: D (0.34 mmol, 1 equiv), THF (5 vol), 3- pyridylmagnesium chloride (1 equiv), RT, 3 h. a Percentage determined by area of LIPLC trace of crude reaction mixture b Yield determined by NMR assay using an internal standard.
Based on the foregoing disclosures, 2-sulfonylpyrimidine analogs may provide unexpected advantage for scale-up synthesis when compared to 2-chloropyrimidine analogs. In view of the requirement for certain metal catalyst for the coupling reaction as disclosed in previous disclosures, the coupling reaction between a Grignard reagent and a 2- sulfonylpyrimidine analog without using a metal catalyst is even more unexpected.
Prophetic deuterated analogs (PDA) of Ervogastat
The compounds provided in Table 7 are prophetic deuterated analogs (PDA) of Ervogastat. The Formula (A) is the generic formula of deuterated Ervogastat, wherein Y1a, Y1 b, Y2a, Y2b, Y3, Y4a, Y4b, Y5, Y6, Y7, Y8a, Y8b, Y9, Y10a, Y10b, and Y10c are each independently H or D. The deuterated analogs of Ervogastat in Table 7 are predicted based on the metabolic profile of Ervogastat, with MetaSite (moldiscovery.com/software/metasite/). Y1a, Y1 b, Y2a, Y2b, Y3, Y4a, Y4b, Y5, Y6, Y7, Y8a, Y8b, Y9, Y10a, Y10b, and Y10c are most likely to be metabolized position based on MetaSite predictions.
A person with ordinary skill in the art would appreciate that the novel method of preparing Ervogastat disclosed herein can also be used to prepare deuterated analogs of Ervogastat.
(A)
Table 7
General methods I reviews of obtaining metabolite profile and identifying metabolites of a compound are described in: Dalvie, et al., “Assessment of Three Human in Vitro Systems in the Generation of Major Human Excretory and Circulating Metabolites,” Chemical Research in
Toxicology, 2009, 22, 2, 357-368, tx8004357 (acs.org): King, R., “Biotransformations in Drug
Metabolism,” Ch.3, Drug Metabolism Handbook Introduction, https://doi.Org/10.1002/9781119851042. ch3: Wu, Y., et al, “Metabolite Identification in the
Preclinical and Clinical Phase of Drug Development,” Current Drug Metabolish, 2021, 22, 11,
838-857, 10.2174/1389200222666211006104502: Godzien, J., et al, “Chapter Fifteen -
Metabolite Annotation and Identification”.
Numerous publicly available and commercially available software tools are available to aid in the predictions of metabolic pathways and metabolites of compounds. Examples of such
tools include, BioTransofrmer 3.0 (biotransformer, ca/new) which predicts the metabolic biotransformations of small molecules using a database of known metabolic reactions; MetaSite (moldiscovery.com/software/metasite/) which predicts metabolic transformations related to cytochrome P450 and flavin-containing monooxygenase mediated reactions in phase I metabolism; and Lhasa Meteor Nexus (lhasalimited.org/products/meteor-nexus.htm) offers prediction of metabolic pathways and metabolite structures using a range of machine learning models, which covers phase I and phase II biotransformations of small molecules.
Predicted deuterated analogs A-1 to A-21 of Ervogastat in Table 7 may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability.
A person with ordinary skill may make additional deuterated analogs of Ervogastat with different combinations of Y1a, Y1 b, Y2a, Y2b, Y3, Y4a, Y4b, Y5, Y6, Y7, Y8a, Y8b, Y9, Y10a, Y10b, and Y10c. Such additional deuterated analogs may provide similar therapeutic advantages that may be achieved by the deuterated analogs A-1 to A-21 of Ervogastat in Table 7.
It will be apparent to those skilled in the art that various modifications and variations may be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
Claims
We claim:
1 . A method of preparing ervogastat, or a pharmaceutically acceptable salt thereof, wherein the method comprises: a) providing a compound of formula (a), wherein X is Cl, Br, or I; providing a compound of formula (b), wherein R1 is Ci-Ce alkyl, C3-C10 cycloalkyl, 3-methoxy-3-oxopropyl, 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, Ce-C aryl optionally substituted with one or two groups selected from halogen, C1-C3 alkoxy, C1-C3 fluoroalkyl, and -NO2, or 4-12 membered heteroaryl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; R2 is Ci-Ce alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; and allowing the compound of formula (a) and the compound of formula (b) to contact in a solvent to provide a reaction product of compound of formula (c):
b) hydrolyzing the compound of formula (c) to provide a compound of formula (d):
c) allowing the compound of formula (d) to contact with a compound of formula (e) to provide a reaction product of ervogastat, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (e) is either a free base or a salt.
The method of claim 1 , wherein R1 and R2 are each t-butyl.
The method of claim 1 or claim 2, wherein step a) is free of using a metal catalyst.
4. The method of any one of claims 1-3, wherein the reaction of step a) is carried out at room temperature.
5. The method of any one of claims 1-4, wherein the compound of formula (c) is hydrolyzed to the compound of formula (d) under a basic condition.
6. The method of any one of claims 1-5, wherein the compound of formula (e) is a salt form.
7. The method of claim 6, wherein the compound of formula (e) is in HCI or tosylate salt form.
8. A method of preparing a compound of formula (c), wherein the method comprises: providing a compound of formula (a), wherein X is Cl, Br, or I; providing a compound of formula (b), wherein R1 is Ci-Ce alkyl, C3-C10 cycloalkyl, 3- methoxy-3-oxopropyl, 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, Ce-C™ aryl optionally substituted with one or two groups selected from halogen, C1-C3 alkoxy, C1-C3 fluoroalkyl, and -NO2, or 4-12 membered heteroaryl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; R2 is Ci-Ce alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S; and allowing the compound of formula (a) and the compound of formula (b) to contact in a solvent to provide a reaction product of compound of formula (c):
9. The method of claim 8, wherein R1 and R2 are each t-butyl.
10. The method of claim 8 or 9, wherein the method is free of using a metal catalyst.
11 . The method of any one of claims 8-10, wherein the reaction is carried out at room temperature.
12. A crystalline form of tert-butyl 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5- carboxylate, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 9.7, 12.5, and 21.7 °2-Theta ± 0.2 °2-Theta.
13. The crystalline form of claim 12, wherein the PXRD pattern further comprises peaks of 19.5 and 24.1 °2-Theta ± 0.2 °2-Theta.
14. A crystalline form of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 7.1 , 9.4, and 14.3 °2-Theta ± 0.2 °2-Theta.
15. The crystalline form of claim 14, wherein the PXRD pattern further comprises peaks of
12.5 and 19.0 °2-Theta ± 0.2 °2-Theta.
16. A crystalline form of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid monohydrate, having a powder X-ray diffraction (PXRD) pattern comprising peaks of 8.7, 10.2, and 13.0 °2-Theta ± 0.2 °2-Theta.
17. The crystalline form of claim 16, wherein the PXRD pattern further comprises peaks of
17.3 and 27.8 °2-Theta ± 0.2 °2-Theta.
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| US10071992B2 (en) | 2016-08-19 | 2018-09-11 | Pfizer Inc. | Diacylglycerol acyl transferase 2 inhibitors |
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