PROCESSES AND INTERMEDIATES USEFUL FOR PREPARING CYSTEINE PROTEASE INHIBITORS

CROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to U.S. Provisional Patent Application No. 61/827,073, filed May 24, 2013, the entire disclosure of which is herein incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

[0002] The present invention relates to acid addition salts of optically active acids and individual stereoisomers of certain optically active 2-aminoalkanoic acid and acid ester derivatives that are useful in the preparation of cysteine protease inhibitors and processes for making such acid addition salts.

BACKGROUND OF THE INVENTION

[0003] Cysteine protease activity is associated with a number of disease states. For example, the normal protease activity of cathepsin S or its increased expression and activity are associated with a wide range of diseases (e.g., see U.S. Patent Application Publication No. 2008/0214676, and U.S. Patent Application Publication No. 2008/0293819, the complete disclosures of each of which are hereby incorporated by reference in their entirety for all purposes). In particular, cathepsin S is implicated in Alzheimer's disease, and in certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, neuropathic pain, and Hashimoto's thyroiditis. In addition, cathepsin S is implicated in: allergic disorders, including, but not limited to, asthma; and allogenic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts, or immune response to therapeutic agents. Altered expression or activity of cathepsin S has also been implicated in

atherosclerosis and the rupture of atherosclerotic plaque.

[0004] Increased cathepsin B levels and redistribution are found in tumors and play a role in tumor invasion and metastasis. Aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteoarthritis, Pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity are involved in osteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. Cathepsin K expression in the lung plays a role in pulmonary disorders as well. Cathepsin L is implicated in several disease states, including, but not limited to, metastasis of melanomas.

[0005] The acid addition salts of the invention and processes for making such acid addition salts provide efficient and effective means ideal for the preparation of therapeutic cysteine protease inhibitors.

BRIEF SUMMARY OF THE INVENTION

[0006] A first aspect of the invention is an acid addition salt of an optically active acid and a compound of Formula I:

in which R ¹ is hydrogen, (Ci_6)alkyl or fluoro; R ² is (Ci_6)alkyl or (C ₃ _7)cycloalkylmethyl; R ³ is hydrogen, (Ci_6)alkyl or (C ₃ _7)cycloalkyl, wherein (Ci_6)alkyl may be substituted with cycloalkyl, or aryl, wherein aryl may be substituted with 1-3 substituents selected from (Ci-

₅ )alkyl and halo; and R ⁴ is hydrogen or deuterium.

[0007] A second aspect of the invention is a process for preparing an acid addition salt of an optically active acid and a compound of Formula I: in which R ¹ is hydrogen, (Ci_6)alkyl or fluoro; R ² is (Ci_6)alkyl or (C3_7)cycloalkylmethyl; R ³ is hydrogen, (Ci_6)alkyl or (C3_7)cycloalkyl, wherein (Ci_6)alkyl may be substituted with cycloalkyl, or aryl, wherein aryl may be substituted with 1-3 substituents selected from (Ci- ₅ )alkyl and halo; and R ⁴ is hydrogen or deuterium; which process comprises contacting a solution of a mixture of compounds of Formulae I and II:

or of a compound of Formula II alone, with an optically active acid in the presence of a racemization agent and under conditions where the acid forms an insoluble salt with any compound of Formula I present in solution.

[0008] A third aspect of the invention is an acid addition salt of an optically active acid and a compound of Formula II:

in which R ¹ is hydrogen, (Ci_6)alkyl or fluoro; R ² is (Ci_6)alkyl or (C3_7)cycloalkylmethyl; R ³ is hydrogen, (Ci_6)alkyl or (C3_7)cycloalkyl, wherein (Ci_6)alkyl may be substituted with cycloalkyl, or aryl, wherein aryl may be substituted with 1-3 substituents selected from (Ci_ ₅ )alkyl and halo; and R ⁴ is hydrogen or deuterium. [0009] A fourth aspect of the invention is a process for preparing an acid addition salt of an optically active acid and a compound of Formula II:

in which R ¹ is hydrogen, (Ci_6)alkyl or fluoro; R ² is (Ci_6)alkyl or (C3_7)cycloalkylmethyl; R ³ is hydrogen, (Ci_6)alkyl or (C3_7)cycloalkyl, wherein (Ci_6)alkyl may be substituted with cycloalkyl, or aryl, wherein aryl may be substituted with 1-3 substituents selected from (Ci-5)alkyl and halo; and R ⁴ is hydrogen or deuterium; which process comprises contacting a solution of a mixture of compounds of Formulae I and II:

or of a compound of Formula I alone, with an optically active acid in the presence of a racemization agent and under conditions where the acid forms an insoluble salt with any compound of Formula II present in solution.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0010] "Alkyl" means a straight or branched, saturated aliphatic radical containing the number carbon atoms indicated, e.g., (Ci_6)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, and the like.

[0011] "Aryl" means phenyl or napthyl. [0012] "Cycloalkyl" means a cyclic, saturated aliphatic radical containing the number of carbon atoms indicated, i.e., (C3_7)cycloalkyl includes cyclopropyl, cyclobutyl, and cyclohexyl.

[0013] "Halo" means, for example, fluoro, chloro or bromo. [0014] "Optically active acid" means any acid which can selectively form a salt with an enantiomer of the invention and wherein the salt is insoluble in the particular solvent in which the salt is formed. Suitable acids include, but are not limited to, tartaric acid, DBTA, DTTA, CSA, PES, mandelic acid, pyroglutamic acid, malic acid, and the like.

[0015] "Isomers" mean compounds of the invention having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed

"diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers." A carbon atom bonded to four nonidentical substituents is termed a "chiral center." A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture." A compound that has more than one chiral center has 2 ^{n l} enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). It is understood that the names and illustration used in this application to describe compounds of the invention are meant to be encompassed all possible stereoisomers. When referring to compounds of the invention as individual diastereomers in the disclosure or claims it is meant that the individual diastereomer exists in at least 90% purity in a mixture with other diastereomers.

Preferred Embodiments [0016] Certain processes and compounds of the invention within the broadest scope set forth in the Summary of the Invention are preferred.

[0017] Preferred is an acid addition salt of an optically active acid and a compound of Formula I in which R ¹ is fluoro, R ² is cyclopropylmethyl, R ³ is hydrogen, methyl or ethyl and R ⁴ hydro gen; more preferred where the optically active acid is L-(+)-tartaric acid or L-(-)- dibenzoyltartaric acid. In some of these embodiments, R ³ is hydrogen. In other

embodiments, R ³ is methyl. In still other embodiments, R ³ is ethyl.

[0018] Preferred is a process of the Invention for preparing an acid addition salt of an optically active acid and a compound of Formula I, which process comprises contacting a solution of a mixture of compounds of Formulae I and II, or of a compound of Formula II alone, with an optically active acid where the racemization agent is an aromatic aldehyde of Formula III:

III in which X and Y are independently hydrogen, nitro, chloro, bromo or fluoro; more preferred where the aromatic aldehyde is 5-nitrosalicylaldehyde, 3,5-dinitrosalicylaldehyde,

3,5-dichlorosalicylaldehyde or 2,4-dichlorosalicylaldehyde; more preferred where R ¹ is fluoro, R ² is cyclopropylmethyl, R ³ is hydrogen, methyl or ethyl and R ⁴ is hydrogen; and most preferred where the optically active acid is L-(+)-tartaric acid or L-(-)-dibenzoyltartaric acid. [0019] Preferred is an acid addition salt of an optically active acid and a compound of

Formula II where R ¹ is fluoro, R ² is cyclopropylmethyl, R ³ is hydrogen, methyl or ethyl and R ⁴ is hydrogen; and most preferred where the optically active acid is D-(-)-tartaric acid or D-(+)-dibenzoyltartaric acid.

[0020] Preferred is a process of the Invention for preparing an acid addition salt of an optically active acid and a compound of Formula II, which process comprises contacting a solution of a mixture of compounds of Formulae I and II, or of a compound of Formula I alone, with an optically active acid where the racemization agent is an aromatic aldehyde of Formula III: in which X and Y are independently hydrogen, nitro, chloro, bromo or fluoro; more preferred where the aromatic aldehyde is 5-nitrosalicylaldehyde, 3,5-dinitrosalicylaldehyde,

3,5-dichlorosalicylaldehyde or 2,4-dichlorosalicylaldehyde; more preferred where R ¹ is fluoro, R ² is cyclopropylmethyl, R ³ is hydrogen, methyl or ethyl and R ⁴ is hydrogen; and most preferred where the optically active acid is D-(-)-tartaric acid or D-(+)-dibenzoyltartaric acid. In some of these embodiments, R ³ is hydrogen. In other embodiments, R ³ is methyl. In still other embodiments, R ³ is ethyl.

[0021] Preferred is an acid addition salt of an optically active acid and a compound selected from:

methyl (5)-2-amino-5-cyclopropyl-4,4-difluoropentanoate L-(+)-tartaric acid salt in a 1 : 1 or 2: 1 compound to acid ratio;

ethyl (5)-2-amino-5-cyclopropyl-4,4-difluoropentanoate L-(+)-tartaric acid salt in a 1 : 1 or 2: 1 compound to acid ratio;

methyl (5)-2-amino-4-methyl-4-fluoropentanoate L-(+)-tartaric acid salt in a 1 : 1 or 2: 1 compound to acid ratio;

ethyl (5)-2-amino-4-methyl-4-fluoropentanoate L-(+)-tartaric acid salt in a 1 : 1 or 2: 1 compound to acid ratio;

(5 ^* )-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid L-(-)-dibenzoyltartaric acid salt in a 1 : 1 compound to acid ratio; and

(5 ^* )-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid L-(+)-tartaric acid salt in a 1 : 1 compound to acid ratio.

[0022] In some of these embodiments, the compound is methyl (5)-2-amino-5-cyclopropyl- 4,4-difluoropentanoate L-(+)-tartaric acid salt in a 1 : 1 or 2: 1 compound to acid ratio. In other embodiments, the compound is ethyl (5)-2-amino-5-cyclopropyl-4,4-difluoropentanoate L-(+)-tartaric acid salt in a 1 : 1 or 2: 1 compound to acid ratio. In some other embodiments, the compound is methyl (5)-2-amino-4-methyl-4-fluoropentanoate L-(+)-tartaric acid salt in a 1 : 1 or 2: 1 compound to acid ratio. In yet other embodiments, the compound is ethyl (S)-2- amino-4-methyl-4-fluoropentanoate L-(+)-tartaric acid salt in a 1 : 1 or 2: 1 compound to acid ratio. In still other embodiments, the compound is (5)-2-amino-5-cyclopropyl-4,4- difluoropentanoic acid L-(-)-dibenzoyltartaric acid salt in a 1 : 1 compound to acid ratio. In other embodiments, the compound is (5)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid L-(+)-tartaric acid salt in a 1 : 1 compound to acid ratio.

Chemistry [0023] The following scheme illustrates a process for making and isolating an acid addition salt of an optically active acid and a compound of Formula I.

Scheme 1

II I I

in which R ¹ , R ² , R ³ and R ⁴ are as defined in the Summary of the Invention.

[0024] In some other embodiments, R ¹ , R ² , R ³ and R ⁴ , in Scheme I, are as defined above.

[0025] The acid addition salts of optically active acids and compounds of Formula I are prepared by contacting a compound of Formula II or a mixture of the compounds of

Formulae I and II with an optically active acid in the presence of a racemization agent and where an acid addition salt of Formula I is formed that is insoluble in the solvent in which the reaction occurs. Suitable solvents include, but are not limited to, toluene, diethylether, dichloromethane, ethanol, ethylacetate, diisopropylether, isopropylacetate, acetonitrile, and the like. Suitable optically active acids for making the acid addition salts of compounds of Formula I include, but are not limited to, L-(+)-tartaric acid and L-(-)-dibenzoyltartaric acid.

[0026] The acid addition salts of optically active acids and compounds of Formula II can be prepared by proceeding as in Scheme 1 and substituting optically active acids that form insoluble salts with compounds of Formula II. Suitable optically active acids for making the acid addition salts of a compound of Formula II include, but are not limited to, D-(-)-tartaric acid and D-(+)-dibenzoyltartaric acid.

[0027] The racemization agent maintains a mixture of compounds of Formulae I and II where the excess of either of the stereoisomers is converted to the other to maintain a mixture of the two stereoisomers as the salt of the subject stereoisomer falls out of solution. Suitable racemization agents include, but are not limited to, aromatic aldehydes having the Formula III:

in which X and Y are independently hydrogen, nitro, chloro, bromo or fluoro, such as 5-nitrosalicylaldehyde, 3,5-dinitrosalicylaldehyde, 3,5-dichlorosalicylaldehyde,

2,4-dichlorosalicylaldehyde, and the like.

[0028] Additional optically active acids for making acid addition salts of compounds of Formula I or II include, but are not limited to, 2,3-di-o-para-toluoyltartaric acid,

camphorsulfonic acid, 1 -phenylethane sulphonic acid, mandelic acid, pyroglutamic acid, N-Boc -phenylalanine, N-tertbutoxycarbonylphenylalanine, 3-phenyllactic acid, lactic acid, 2,2-dimethyl-5-oxo-l,3-dioxolane-4-acetic acid, malic acid, and the like.

[0029] Compounds of Formula I or II where R ⁴ is deuterium are prepared by proceeding as described above and using ethanol-d (CH ₃ CH ₂ OD) as solvent. The procedure typically is carried out under an inert atmosphere, e.g., under nitrogen, at about 20 to 25°C and requires 15 to 36 hours to complete.

Examples

[0030] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1

Methyl (5)-2-Amino-5-cyclopropyl-4,4-difluoropentanoate

[0031] A 3-neck RB Flask (1 L) fitted with mechanical stirrer and thermometer was charged with methyl (5)-2-amino-5-cyclopropyl-4,4-difluoropentanoate HC1 (30 g, 0.123 mol), MTBE (300 mL) and water (150 mL). The resulting slurry was stirred for 15 minutes at 20-25°C and then cooled to 0-10°C. A solution of 1M K ₂ C0 ₃ (147.8 mL, 0.1477 mol) was added to the slurry keeping the mixture at 0-10°C. The resulting biphasic mixture was stirred for 30 minutes and allowed to settle for 15 minutes. The layers were separated and the aqueous layer was extracted with MTBE (150 mL). The combined organic layer was washed with water (150 L) followed by drying with sodium sulfate. The organic layer was concentrated under vacuum at below 30°C to afford methyl (5)-2-amino-5-cyclopropyl-4,4- difluoropentanoate free base as a light yellow liquid. Yield: 23 g (90.19%). Purity by HPLC: 91.42%. Chiral purity: 100%.

Example 2

Methyl (R)-2-Amino-5-cyclopropyl-4,4-difluoropentanoate D-(-)-Tartaric Acid Salt

[0032] A 3-neck RB flask (500 mL) fitted with the mechanical stirrer, thermometer and 2 U-tube was charged with methyl (5)-2-amino-5-cyclopropyl-4,4-difluoropentanoate free base (10 g, 0.048 mol), prepared as in Example 1, ethanol (100 mL), 5-nitro salicyladehyde (401 mg, 0.0024 mol) and D-(-)-tartaric acid (7.24 g, 0.048 mol) and the mixture was stirred resulting in a thick yellow mixture after ~30 minutes. The mixture was diluted with additional ethanol (5 mL) and stirred for 24 hours at 20-25°C. Solids were filtered, washed with ethanol (20 mL) and dried under vacuum at 50°C for 6 hours to afford methyl (R)-2- amino-5-cyclopropyl-4,4-difluoropentanoate D-(-)-tartaric acid salt as white solid. Yield: 13 g (75.4%). Purity by HPLC: 98.4%. Chiral purity: 98.95%.

Example 3

Methyl (R)-2-Amino-5-cyclopropyl-4,4-difluoropentanoate D-(-)-Tartaric Acid Salt

[0033] A 3-neck RB flask (500 mL) fitted with the mechanical stirrer, thermometer and 2 U-tube was charged with methyl (5)-2-amino-5-cyclopropyl-4,4-difluoropentanoate free base (10 g, 0.048 mol), prepared as in Example 1, (10 g, 0.048 mol, 1 eq), the filtrate from

Example 2, 5-nitro salicyladehyde (401 mg, 0.0024 mol, 0.05 eq) and D-(-)-tartaric acid (7.24 g, 0.048 mol, 1 eq) and the mixture was stirred resulting in a thick yellow mixture after -30 minutes. The mixture was stirred for 24 hours at 20-25°C. Solids were filtered, washed with ethanol (20 mL) and dried under vacuum at 50°C for 6 hours to afford methyl (R)-2- amino-5-cyclopropyl-4,4-difluoropentanoate D-(-)-tartaric acid salt as a white solid. Yield: 15 g (87%). Purity by HPLC: 95.63%. Chiral purity: 99.2%.

Example 4

Methyl (5)-2-Amino-5-cyclopropyl-4,4-difluoropentanoate L-(+)-Tartaric Acid Salt

[0034] A 4-neck RB flask (100 mL) fitted with the magnetic stirring, thermometer and 2 U-tube was charged with methyl (R,5)-2-amino-5-cyclopropyl-4,4-difluoropentanoate free base (0.68 g, 0.0057 mol), ethanol (6.8 mL), 5-nitro salicyladehyde (27 mg, 0.00016 mol) and L-(+)-tartaric acid (0.492 g, 0.0032 mol) and the mixture was stirred resulting in a thick yellow mixture after ~30 minutes. The mixture was diluted with ethanol (50 mL) and stirred for 24 hours at 20-25°C. Solids were filtered, washed with ethanol (1.2 mL) and dried under vacuum at 50°C for 6 hours to afford methyl (5)-2-amino-5-cyclopropyl-4,4- difluoropentanoate L-(+)-tartaric acid salt as a white solid. Yield: 0.75 g (64.1%). Purity by HPLC: 98.65%. Chiral purity: 97.12%.

Example 5

Methyl (5)-2-Amino-5-cyclopropyl-4,4-difluoropentanoate L-(+)-Tartaric Acid Salt

[0035] A 4-neck RB flask (100 mL) fitted with the magnetic stirrer, thermometer and 2 U-tube was charged with methyl (R)-2-amino-5-cyclopropyl-4,4-difluoropentanoate free base (0.5 g, 0.0024 mol), ethanol (5 mL), 5-nitrosalicyladehyde (10 mg, 0.00006 mol) and L-(+)- tartaric acid (0.36 g, 0.0024 mol) and the mixture was stirred resulting in a thick yellow mixture after ~30 minutes. The mixture was diluted with ethanol (50 mL) and stirred for 24 hours at 20-25°C. Solids collected by filtration, washed with ethanol (1 mL) and dried under vacuum at 50°C for 6 hours to afford methyl (5)-2-amino-5-cyclopropyl-4,4- difluoropentanoate L-(+)-tartaric acid salt as a white solid. Yield: 0.58 g (67%). Purity by HPLC: 96.87%. Chiral purity: 99.5%. Example 6

Methyl (R)-2-Amino-5-cyclopropyl-4,4-difluoropentanoate Hydrochloride

[0036] A 4-neck RB flask (250 mL) fitted with the magnetic stirring, thermometer and 2 U-tube was charged with methyl (R)-2-amino-5-cyclopropyl-4,4-difluoropentanoate L-(+)- tartaric acid salt (5 g, 0.0139 mol) and methanol (50 mL) and the mixture was cooled to 0- 5°C. A solution of trimethylsilyl chloride (3.04 mL, 0.0276 mol) was added to the mixture kept at below 5°C. The temperature of the mixture was slowly raised to 20-25°C. The mixture was stirred for 2 hours at 20-25°C and then concentrated under vacuum at 45-50°C. The residue was diluted with MTBE (50 mL) and this mixture was stirred for 2 hours at 20- 25°C. Solids were filtered, washed with MTBE (10 mL) and dried under vacuum at 50°C for 6 hours to afford methyl (R)-2-amino-5-cyclopropyl-4,4-difluoropentanoate hydrochloride as a white solid. Yield: 3.1 g (91.17%). Purity by HPLC: 97.96%.

Example 7

(5)-2-Amino-5-cyclopropyl-4,4-difluoropentanoic Acid (L)-(-)-Dibenzoyltartaric Acid Salt

[0037] A mixture of (R)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid (5 g, .026 mol) and acetic acid (50 mL) was stirred for 10 minutes and treated with 5-nitrosalicyaldehyde (0.216 g, 0.001 mol) and (L)-(-)-dibenzoyltartaric acid (9.3 g, 0.026) for two hours. The mixture was seeded with (5)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid (L)-(-)- dibenzoyltartaric salt (50 mg) from a previous preparation and the mixture was held at room temperature for 3 days. The resulting solids were collected by filtration and washed with acetic acid. The filter cake was dried under vacuum to give (5)-2-amino-5-cyclopropyl-4,4- difluoropentanoic acid (L)-(-)-dibenzoyltartaric salt as a pure white powder. Yield: 9.3 g (65%). [0038] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.