Synthetic intermediates and improved processes for the preparation of ROCK inhibitors

Abstract

Provided herein is a method for synthesizing netarsudil and its intermediates on a large commercial scale with high yield.A key intermediate in this synthesis is the preparation of piperidinium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate, a salt that has been found to be easily purified by recrystallization.The present disclosure relates to a process for preparing compounds useful for treating kinase-related diseases and / or disorders.

Description

[Technical field]

[0001] Related Applications This application claims priority to US63 / 298,751, filed January 12, 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates to processes for preparing compounds useful for treating kinase-associated diseases and / or disorders, including diseases and disorders of the eye such as glaucoma, corneal diseases, retinal diseases, and ocular hypertension, diseases and conditions of the respiratory system, diseases and conditions of the cardiovascular system, and diseases characterized by abnormal growth such as cancer. [Background technology]

[0003] background Rhopressa™ is a once-daily eye drop that, among other attributes, is used to inhibit isoforms of Rho kinase (ROCK) and reduce intraocular pressure (IOP). By inhibiting these and other targets, Rhopressa™ is believed to reduce IOP through three separate mechanisms of action: (i) increasing fluid outflow through the trabecular meshwork, which accounts for approximately 80% of the fluid drainage from the eye, through ROCK inhibition; (ii) reducing episcleral venous pressure, which represents the blood pressure in the episcleral veins of the eye, where ocular fluid drains into the bloodstream; and (iii) potentially reducing ocular fluid production through NET inhibition. Rhopressa™ is FDA and EMA approved and is currently undergoing Phase 3 clinical trials in Japan for the treatment of glaucoma and ocular hypertension. The active pharmaceutical ingredient of Rhopressa™ is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (netarsudil). Methods for its preparation are found in U.S. Pat. No. 8,394,826, which is incorporated herein by reference in its entirety. Due to the clinical success of this compound, there is a continuing need for improved processes to synthesize (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (netarsudil) in an efficient, scalable, reproducible manner that allows for the production of large amounts of material with improved yields. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Pat. No. 8,394,826 Summary of the Invention [Means for solving the problem]

[0005] overview In general, the present disclosure relates to a compound of formula (I): [ka] A method for synthesizing a compound of the formula: (a) Formula (II) [ka] where PG is a nitrogen protecting group. with 6-aminoisoquinoline to give the compound of formula (III) [ka] forming a compound of the formula: (b) removing the nitrogen protecting group to form a compound of formula (I) The present invention covers methods including

[0006] The present disclosure provides a compound of formula (Ia): [ka] wherein each R is independently selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, and cyano; and n is an integer from 0 to 3. A method for synthesizing a compound of the formula: (a) Formula (II-a) [ka] is reacted with 6-aminoisoquinoline to give a compound of formula (III-a) [ka] wherein each R is independently selected from the group consisting of C1-4 alkyl, halogen, C1-4 alkoxy, and cyano; and n is an integer from 0 to 3. forming a compound of the formula: (b) removing the nitrogen protecting group to form a compound of formula (Ia) The present invention further extends to methods, including

[0007] Also provided herein is a compound of formula (XI): [ka] wherein A is cyclohexyl or phenyl substituted with 0-3 substituents selected from the group consisting of alkyl, halogen, alkoxy, and cyano. A method for synthesizing a compound of the formula: (a) Formula (XII) [ka] where PG is a nitrogen protecting group. with 6-aminoisoquinoline to give a compound of formula (XIII) [ka] forming a compound of the formula: (b) removing the nitrogen protecting group to form a compound of formula (XI) The method includes:

[0008] The present disclosure provides a compound of formula (XI-a): [ka] wherein each R is independently selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, and cyano; and n is an integer from 0 to 3. A method for synthesizing a compound of the formula: (a) Formula (XII-a) [ka] with 6-aminoisoquinoline to give a compound of formula (XIII-a) [ka] wherein each R is independently selected from the group consisting of C1-4 alkyl, halogen, C1-4 alkoxy, and cyano; and n is an integer from 0 to 3. forming a compound of the formula: (b) removing the nitrogen protecting group to form a compound of formula (XI-a) The present invention further extends to methods, including

[0009] Also disclosed are pharmaceutical compositions comprising the disclosed compounds and pharma- ceutically acceptable salts thereof, and methods of using the disclosed compounds or pharma- ceutically acceptable salts thereof for the treatment of kinase-related diseases and / or disorders.

[0010] These and other aspects of the present disclosure will be better understood with reference to the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description Disclosed herein is a process for the synthesis of kinase inhibitors. The inhibitors may have formula (I). Compounds of formula (I) can be synthesized in a manner that effectively produces large quantities of compounds of formula (I). Compounds of formula (I) can be used to treat or prevent kinase-related diseases and / or disorders. These include diseases and disorders of the eye, such as glaucoma, corneal damage, retinitis, and ocular hypertension, diseases and disorders of the respiratory system, diseases and disorders of the cardiovascular system, and diseases characterized by abnormal growth, such as cancer.

[0012] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of conflict, this document, including definitions, will control. Preferred methods and materials are described below, but methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods and examples disclosed herein are illustrative only and are not intended to be limiting.

[0013] The terms "comprise(s)", "include(s)", "having", "having", "can", "containing", and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a", "an", and "the" include plural references unless the context clearly indicates otherwise. The present disclosure also contemplates other embodiments that "comprise", "consist of", and "consist essentially of" the embodiments or elements presented herein, whether or not expressly described.

[0014] The modifier "about" used in reference to a quantity is inclusive of the stated value and has the meaning indicated by the context (e.g., including at least the degree of error associated with measurement of the particular quantity). The modifier "about" should also be considered to disclose a range defined as the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4". The term "about" can refer to ±10% of the indicated numerical value. For example, "about 10%" can indicate a range of 9% to 11%, and "about 1" can mean 0.9 to 1.1. Other meanings of "about" can be apparent from the context, such as rounding, so for example, "about 1" can mean 0.5 to 1.4.

[0015] Definitions of specific functional groups and chemical terms are described in more detail below. For the purpose of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. inside cover, and specific functional groups are defined throughout as described therein. In addition, general principles of organic chemistry and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987, the entire contents of each of which are incorporated herein by reference.

[0016] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0017] The term "alkyl" as used herein means a straight or branched saturated hydrocarbon chain containing 1 to 10 carbon atoms. The term "lower alkyl" or "C1-C6 alkyl" means a straight or branched hydrocarbon chain containing 1 to 6 carbon atoms. The term "C3-C7 branched alkyl" means a branched hydrocarbon chain containing 3 to 7 carbon atoms. The term "C1-C4 alkyl" means a straight or branched hydrocarbon chain containing 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. The alkyl group may be substituted or unsubstituted.

[0018] The term "alkylene," as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 10 carbon atoms, e.g., 2 to 5 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-. Alkylene groups can be substituted or unsubstituted.

[0019] The term "alkenyl" as used herein means a straight or branched unsaturated hydrocarbon chain containing at least one carbon-carbon double bond and 1 to 10 carbon atoms. The term "lower alkenyl" or "C2-C6 alkenyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond and 1 to 6 carbon atoms. Alkenyl groups may be substituted or unsubstituted.

[0020] The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[0021] The term "alkynyl" as used herein means a straight or branched unsaturated hydrocarbon chain containing at least one carbon-carbon triple bond and 1 to 10 carbon atoms. The term "lower alkynyl" or "C2-C6 alkynyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond and 1 to 6 carbon atoms. Alkynyl groups can be substituted or unsubstituted.

[0022] The term "aryl" as used herein refers to a phenyl group or a bicyclic fused ring system. The bicyclic fused ring system is exemplified by a phenyl group attached to a parent molecular moiety and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Representative examples of aryl include, but are not limited to, indolyl, naphthyl, phenyl, quinolinyl, and tetrahydroquinolinyl. The aryl group may be substituted or unsubstituted.

[0023] The term "cycloalkyl" as used herein refers to a carbocyclic ring system containing 3 to 10 carbon atoms and containing no heteroatoms and no double bonds. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Cycloalkyl groups may be substituted or unsubstituted.

[0024] The term "cycloalkenyl" as used herein refers to a carbocyclic ring system containing 3 to 10 carbon atoms, no heteroatoms and at least one double bond. Cycloalkenyl groups can be substituted or unsubstituted.

[0025] The term "fluoroalkyl," as used herein, refers to at least one fluorine atom appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of fluoroalkyl include, but are not limited to, trifluoromethyl.

[0026] The term "fluoroalkoxy," as used herein, refers to at least one fluorine atom appended to the parent molecular moiety through an alkoxy group, as defined herein.

[0027] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0028] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0029] The term "haloalkyl," as used herein, refers to at least one halogen atom appended to the parent molecular moiety through an alkyl group, as defined herein.

[0030] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one or more of the carbon atoms are replaced with a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyl include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides. Heteroalkyl groups can be substituted or unsubstituted.

[0031] The term "heteroaryl" as used herein refers to an aromatic monocyclic ring or aromatic bicyclic ring system. An aromatic monocyclic ring is a 5- or 6-membered ring containing at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S). A 5-membered aromatic monocyclic ring has two double bonds, and a 6-membered aromatic monocyclic ring has three double bonds. A bicyclic heteroaryl group is exemplified by a monocyclic heteroaryl ring attached to a parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Representative examples of heteroaryl include, but are not limited to, indolyl, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, thiazolyl, and quinolinyl. The heteroaryl group can be substituted or unsubstituted.

[0032] The term "heterocycle" or "heterocyclic" as used herein means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains no double bonds or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains no double bonds or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains no double bonds or one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain zero, one, two or three double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocyclic group can be substituted or unsubstituted.

[0033] The term "heteroarylalkyl," as used herein, refers to a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[0034] The term "hydroxyalkyl," as used herein, refers to a hydroxy group appended to the parent molecular moiety through an alkyl group, as defined herein.

[0035] The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[0036] In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl or cycloalkyl) is indicated by the prefix “C x ~C y " where x is the minimum number of carbon atoms and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-C3 alkyl" refers to an alkyl substituent containing 1 to 3 carbon atoms.

[0037] The term "substituent" refers to a group that "substitutes" a group at any atom of the group. Any atom can be substituted.

[0038] The term "substituted" refers to a group that can be further substituted with one or more non-hydrogen substituents. Substituents include, but are not limited to, halogen, =O, =S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0039] For the compounds described herein, the groups and substituents may be selected according to the available valences of atoms and substituents such that selection and substitution result in stable compounds that do not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like.

[0040] For purposes of describing numerical ranges herein, each intervening numerical value therebetween is expressly contemplated with the same precision. For example, for the range from 6 to 9, the numerical values ​​7 and 8 are expressly contemplated in addition to 6 and 9, and for the range from 6.0 to 7.0, the numerical values ​​6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated. process Compounds of formula (I)

[0041] In one aspect, disclosed is a compound of formula (I): [ka] wherein A is cyclohexyl or phenyl substituted with 0-3 substituents selected from the group consisting of alkyl, halogen, alkoxy, and cyano. or a pharma- ceutically acceptable salt thereof.

[0042] The process comprises reacting 6-aminoisoquinoline with a compound of formula (II) in which PG is a protecting group for nitrogen to form a compound of formula (III). The compound of formula (III) can be converted to a compound of formula (I) by removing the nitrogen protecting group. The nitrogen protecting group PG can be any suitable nitrogen protecting group known in the art. In certain embodiments, PG is selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), and para-methoxybenzylcarbonyl (Moz). [ka]

[0043] The process further includes the synthesis of a compound of formula (II). Aminoalkylation of a compound of formula (IV), where T is a chiral auxiliary, can provide a compound of formula (V), which can be converted to a compound of formula (II) upon removal of the chiral auxiliary. [ka]

[0044] The compound of formula (VII) can be prepared by reacting methyl 2-(4-(hydroxymethyl)phenyl)acetate with a compound of formula (VI). The compound of formula (VII) can be converted to a compound of formula (VIII), where R 1 is halogen, OR a , O.C.(O)R b , S.R. a or SC(O)R b ;R ais H, alkyl or aryl, and R b is alkyl or aryl. From a compound of formula (VIII), in turn, a compound of formula (IV) can be obtained, where T is a chiral auxiliary. [ka] Compounds of formula (Ia)

[0045] In one embodiment, the process for the synthesis of compounds of formula (I) comprises the compound of formula (Ia): [ka] wherein each R is independently selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, and cyano; and n is an integer from 0 to 3. or a pharma- ceutically acceptable salt thereof. In some embodiments, the C1-C4 alkyl can be C1-C4 fluoroalkyl.

[0046] The process comprises reacting 6-aminoisoquinoline with a compound of formula (II-a) in which PG is a protecting group for nitrogen to form a compound of formula (III-a). The compound of formula (III-a) can be converted to a compound of formula (Ia) by removing the nitrogen protecting group. The nitrogen protecting group PG can be any suitable nitrogen protecting group known in the art. In certain embodiments, PG is selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), and para-methoxybenzylcarbonyl (Moz). [ka]

[0047] The process further includes the synthesis of a compound of formula (II-a). Aminoalkylation of a compound of formula (IV-a), where T is a chiral auxiliary, can provide a compound of formula (Va), which can be converted to a compound of formula (II-a) upon removal of the chiral auxiliary. [ka]

[0048] The compound of formula (VII-a) can be prepared by reacting methyl 2-(4-(hydroxymethyl)phenyl)acetate with a compound of formula (VI-a). The compound of formula (VII-a) can be converted to a compound of formula (VIII-a), where R 1 is halogen, OR a , O.C.(O)R b , S.R. a or SC(O)R b ;R a is H, alkyl or aryl, and R b is alkyl or aryl. From a compound of formula (VIII-a), in turn, a compound of formula (IV-a) can be obtained, where T is a chiral auxiliary. [ka]

[0049] In certain embodiments, T is represented by formula (IX): [ka] (wherein Z is S or O; B is S or O; R c is hydrogen, cycloalkyl, C3-C7 branched alkyl or aryl; R d is C1-C4 alkyl, C3-C7 branched alkyl; arylalkyl or aryl; R c is C1-C4 alkyl or aryl) The compound may be:

[0050] Specifically, T is represented by the formula (IX-a): [ka] (wherein Z is S or O; B is S or O; R c is hydrogen or aryl; R d is C1-C4 alkyl, arylalkyl or aryl; R c is C1-C4 alkyl or aryl) The compound may be:

[0051] More specifically, T is [ka] The compound may be selected from the group consisting of:

[0052] In specific embodiments, T is [ka] It is. Compound (1)

[0053] In one embodiment, the process disclosed for the synthesis of a compound of formula (I) comprises the step of reacting compound (1): [ka] or a process for the synthesis of a pharma- ceutically acceptable salt.

[0054] The process involves reacting 6-aminoisoquinoline with compound (2) to form compound (3), which can be converted to compound (1) by removal of the Boc protecting group. [ka]

[0055] The process further includes the synthesis of compound (2). Aminoalkylation of compound (4) can provide compound (5), which can be converted to compound (2) upon removal of the chiral auxiliary. [ka]

[0056] Compound (4) can be prepared by reacting methyl 2-(4-(hydroxymethyl)phenyl)acetate with compound (6). Compound (7) can be converted to compound (8). From compound (8), compound (4) can in turn be obtained. [ka]

[0057] In a specific embodiment of the process for the synthesis of a compound of formula (I) (e.g., compound (1)), the process comprises coupling of methyl 2-(4-(hydroxymethyl)phenyl)acetate with 2,4-dimethylbenzoic acid (6) in the presence of EDC and DMAP to form compound (7). The methyl ester of compound (7) can be selectively hydrolyzed with a suitable base (e.g., a metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide) in a suitable solvent to give compound (9). Suitably, the hydrolysis conditions comprise lithium hydroxide as the base and a mixture of THF and water as the solvent. These conditions are advantageous as they help limit the amount of hydrolysis of the benzyl ester. [ka]

[0058] Compound (9) can be converted to acid chloride (8) by treatment with a chlorinating agent. The chlorinating agent can be oxalyl chloride or thionyl chloride. The solvent can be a chlorinated solvent, such as methylene chloride, dichloroethane or chloroform, or a non-chlorinated solvent, such as THF, diethyl ether, dioxane or acetonitrile. The chlorinating agent and solvent can be thionyl chloride. Preferably, the chlorinating agent is oxalyl chloride and the solvent is methylene chloride or a solvent mixture of tetrahydrofuran / dimethylformamide. [ka]

[0059] The base can be added to (R)-4-benzyloxazolidin-2-one followed by reaction with compound (8) at a temperature between -90°C and -50°C to provide compound (4). The base used for addition to (R)-4-benzyloxazolidin-2-one can be NaH, LiH, KH, nBuLi, NaHMDS, LDA, triethylamine, ethyldiisopropylamine, methylmagnesium bromide, sodium carbonate, cesium carbonate, sec-BuLi, LiHMDS, potassium t-butoxide, sodium isopropoxide or KHMDS. The solvent can be THF, toluene, diethyl ether, acetonitrile, methyl t-butyl ether or combinations thereof. Preferably, the base used for addition to (R)-4-benzyloxazolidin-2-one is n-BuLi and the solvent is THF. [ka]

[0060] Compound (4) can be treated with a base followed by the addition of N-Boc-1-aminomethylbenzotriazole at a temperature of -50°C to -20°C to provide compound (5) in a diastereoselective manner. The base used to treat compound (4) can be LiHMDS, LDA or NaHMDS. The solvent can be THF, toluene, diethyl ether, acetonitrile, methyl t-butyl ether or a combination thereof. Suitably, the base used to treat compound (4) is LiHMDS and the solvent is THF. In some embodiments, a Lewis acid can be added along with the base to facilitate the deprotonation of compound (4) to form a reaction intermediate. Compound (5) can be obtained in a diastereomeric ratio of greater than 1:1, greater than 2:1, greater than 5:1, greater than 10:1, greater than 20:1, greater than 50:1, or greater than 99:1. The minor amount of diastereomers can be removed by standard purification techniques, such as, but not limited to, recrystallization and silica gel chromatography. [ka]

[0061] Compound (5) can be converted to carboxylic acid (2) by the addition of a suitable nucleophilic base to remove the chiral auxiliary of the oxazolidinone. Preferably, the base is lithium hydroperoxide, which is formed in situ by reaction of lithium hydroxide with hydrogen peroxide. The use of lithium hydroperoxide is advantageous due to its effectiveness in removing the chiral auxiliary but not hydrolyzing the benzyl ester. [ka]

[0062] Compound (2), (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propionic acid, can be purified by converting it to a salt with a suitable base. A preferred base is an organic amine, such as but not limited to piperidine, by crystallization of the salt in a suitable solvent or solvent system, such as but not limited to acetonitrile. The piperidine salt is known as the Pip salt of compound (2), i.e., piperidinium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate. Other amine bases suitable for effecting this transformation are 2-aminoethanol, morpholine, piperidine, dibenzylamine, dicyclohexylamine, diisopropylamine, benzylamine, piperazine, DMAP. Other suitable inorganic bases are NaOH, LiOH·H2O, Ca(OH)2, Ba(OH)2·8H2O. Other suitable solvents and solvent systems include IPA, 1,4-dioxane, IPA+heptane, IPAc, as well as acetonitrile and hepane. After purification, the Pip salt of compound (2) can be converted to the free acid form of compound (2), for example, by dissolving the salt in ethyl acetate, MTBE, or 2-MeTHF, followed by acidification with citric acid, followed by breaking the salt and crystallizing the free acid from heptane / ethyl acetate. Compound (2) can then be converted to compound (3) by activating the carboxylic acid group and reacting with 6-aminoisoquinoline. The carboxylic acid group can be activated by a variety of reagents and conditions, including conversion to a mixed anhydride or acid halide, or the use of standard amide coupling reagents (e.g., EDCI, HOBT, DCC, DIC, HBTU, and HATU). Conveniently, the carboxylic acid group is activated by formation of a mixed anhydride, which can be formed by addition of an alkyl chloroformate, such as trichlorodimethylethyl chloroformate, and a base to form compound (3).In a preferred embodiment, trichlorodimethylethyl chloroformate and collidine are added to compound (2) in the presence of 6-aminoisoquinoline at 0° C. A reactive mixed anhydride intermediate can be formed under reaction conditions such that it can react with 6-aminoisoquinoline to form compound (3). The solvent utilized can be DMF, alone or in combination with methylene chloride, or acetonitrile, preferably the solvent utilized is DMF. Upon isolation, compound (3) can be purified by silica gel column chromatography and / or recrystallization, if necessary. [ka]

[0063] The conversion of compound (3) to compound (1) can be accomplished by adding a suitable reagent to remove the Boc protecting group. Preferably, an acid is used to remove the Boc protecting group. Any acid useful for removing the Boc protecting group can be used. The acid used to remove the Boc protecting group can also promote the formation of a salt of compound (1). The acid can be selected to favor the removal of the protecting group and can also form a suitable pharma-ceutically acceptable salt. Preferably, the acid utilized in the conversion of compound (3) to compound (1) includes at least two equivalents of methanesulfonic acid, resulting in a dimethanesulfonic acid salt of compound (1). Methanesulfonic acid is particularly useful because the desired product is formed in high yield with little decomposition and few by-products. The dimethanesulfonic acid salt offers useful properties such as being easily purified, easy to handle, and can be produced with good reproducibility in large-scale processes. [ka] Compound of formula (XI)

[0064] In another aspect, disclosed is a compound of formula (XI): [ka] wherein A is cyclohexyl or phenyl substituted with 0-3 substituents selected from the group consisting of alkyl, halogen, alkoxy, and cyano. or a pharma- ceutically acceptable salt thereof.

[0065] The process comprises reacting 6-aminoisoquinoline with a compound of formula (XII) in which PG is a protecting group for nitrogen to form a compound of formula (XIII). The compound of formula (XIII) can be converted to a compound of formula (XI) by removing the nitrogen protecting group. The nitrogen protecting group PG can be any suitable nitrogen protecting group known in the art. In certain embodiments, PG is selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (CBZ), and 9-fluorenylmethyl-oxycarbonyl (Fmoc). [ka]

[0066] The process further includes the synthesis of a compound of formula (XII). Aminoalkylation of a compound of formula (IV), where T is a chiral auxiliary, can provide a compound of formula (XV), which can be converted to a compound of formula (XII) upon removal of the chiral auxiliary. [ka]

[0067] In certain embodiments, the compound of formula (XI) can be obtained through the process described above for the synthesis of the compound of formula (I). In particular, the compound of formula (XV) can be formed as a minor product in the conversion of the compound of formula (IV) to the compound of formula (V). Using the reaction steps and scheme described above, the compound of formula (XV) can in turn be converted to the compound of formula (XI). Thus, the intermediate compounds of formula (XII) and (XIII) can also be formed in the process. [ka] Compound of formula (XI-a)

[0068] In one embodiment, the process for the synthesis of a compound of formula (XI) comprises the compound of formula (XI-a): [ka] wherein each R is independently selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, and cyano; and n is an integer from 0 to 3. or a pharma- ceutically acceptable salt thereof. In one embodiment, the C1-C4 alkyl is a C1-C4 fluoroalkyl.

[0069] The process comprises reacting 6-aminoisoquinoline with a compound of formula (XII-a) in which PG is a protecting group for nitrogen to form a compound of formula (XIII-a). The compound of formula (XIII-a) can be converted to a compound of formula (XI-a) by removing the nitrogen protecting group. The nitrogen protecting group PG can be any suitable nitrogen protecting group known in the art. In certain embodiments, PG is selected from the group consisting of tert-butyloxycarbonyl (Boc), carbobenzyloxy (CBZ), and 9-fluorenylmethyl-oxycarbonyl (Fmoc). [ka]

[0070] The process further includes the synthesis of a compound of formula (XII-a). Aminoalkylation of a compound of formula (IV-a), where T is a chiral auxiliary, can provide a compound of formula (XV-a), which can be converted to a compound of formula (XII-a) upon removal of the chiral auxiliary. [ka]

[0071] In certain embodiments, T is represented by formula (IX): [ka] (wherein Z is S or O; B is S or O; R c is hydrogen, cycloalkyl, C3-C7 branched alkyl or aryl; R d is C1-C4 alkyl, C3-C7 branched alkyl; arylalkyl or aryl; R c is C1-C4 alkyl or aryl) The compound may be:

[0072] In certain embodiments, T is represented by formula (IX-b): [ka] (wherein Z is S or O; B is S or O; R c is hydrogen or aryl; R d is C1-C4 alkyl, arylalkyl or aryl; R c is C1-C4 alkyl or aryl) The compound may be:

[0073] In certain embodiments, T is [ka] The compound may be selected from the group consisting of:

[0074] In specific embodiments, T is [ka] It is.

[0075] In certain embodiments, the compound of formula (XI-a) can be obtained through the process described above for the synthesis of the compound of formula (Ia). In particular, the compound of formula (XV-a) can be formed as a minor product in the conversion of the compound of formula (IV-a) to the compound of formula (Va). Using the reaction steps and scheme described above, the compound of formula (XV-a) can in turn be converted to the compound of formula (XI-a). Thus, the intermediate compounds of formula (XII-a) and (XIII-a) can also be formed in the process. [ka] Compound (11)

[0076] In one embodiment, the process disclosed for the synthesis of a compound of formula (XI) comprises the step of producing compound (11): [ka] or a process for the synthesis of a pharma- ceutically acceptable salt.

[0077] The process involves reacting 6-aminoisoquinoline with compound (12) to form compound (13), which can be converted to compound (11) by removal of the Boc protecting group. [ka]

[0078] The process further includes the synthesis of compound (12). Addition of a chiral auxiliary to compound (8) can provide compound (14). Aminoalkylation of compound (14) can provide compound (15), which can be converted to compound (12) by removal of the chiral auxiliary. [ka]

[0079] In certain embodiments, compound (11) can be obtained via the process described above for the synthesis of compound (1). In particular, compound (16) can be formed as a minor product in the conversion of compound (4) to compound (5). Using the reaction steps and scheme described above, compound (15) can in turn be converted to compound (11). Thus, intermediate compounds (12) and (13) can also be formed in the process. [ka]

[0080] In another aspect, the present disclosure provides a method for the formation of an amide or ester bond, comprising: [ka] and reacting an amine or alcohol with a carboxylic acid in the presence of a base. Amines and esters may generally be considered to be non-reactive. In one embodiment, the amine is an aromatic amine. In one embodiment, the alcohol is an aromatic alcohol. 1,1-dimethyl,2,2,2-trichloroethyl chloroformate may allow for stereoselective coupling of carboxylic acids prone to racemization, particularly alpha aromatic acids.

[0081] Abbreviations used in the description of the above structures and schemes include: Bn, benzyl; Ph, phenyl; Me, methyl; EDC, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; Boc, tert-butylcarbonyl; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBT, hydroxybenzotriazole, CDI, carbonyldiimidazole; DCC, N,N'-dicyclohexylcarbodiimide; DIC, N,N'-diisopropylcarbodiimide, HBTU, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DMAP, dimethylaminopyridine; LiHMDS, lithium hexamethyldisilazide; NaHMDS, sodium hexamethyldisilazide; KHMDS, potassium hexamethyldisilazide; LDA, lithium diisopropylamide; DMF, dimethylformamide; and THF, tetrahydrofuran.

[0082] Compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis.Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid support, such as silica gel, alumina, or silica derived from alkylsilane groups, recrystallization at high or low temperatures, optionally with pretreatment with activated carbon, thin layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, and are described, for example, in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0083] The compounds of the present disclosure may have at least one basic nitrogen, which allows them to be treated with acid to form desired salt.For example, the compounds may be reacted with acid at low temperature to above room temperature to provide desired salt, which is collected by settling, cooling, and then filtering.Examples of acids suitable for reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, hydrochloric acid, citric acid, or glutamic acid, etc.

[0084] Optimal reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and the substituents present in the reactants used. Specific procedures are provided in the Examples section. The reactions can be worked up in a conventional manner, for example by removing the solvent from the residue, and further purified by methods commonly known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise stated, starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using conventional laboratory techniques and methods well known in the chemical literature. Routine laboratory techniques, including appropriate manipulation of the reaction conditions, reagents, and synthetic route sequences, protection of any chemical functional groups that are incompatible with the reaction conditions, and deprotection at suitable points in the reaction sequence of the method, are included within the scope of this disclosure. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples thereof can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. It can be understood that the synthetic schemes and specific examples described are illustrative and should not be read to limit the scope of the present disclosure, which is defined in the appended claims. All alternatives, modifications and equivalents of the synthetic methods and specific examples are included within the scope of the claims. compound Compounds of formula (I)

[0085] In another aspect, disclosed herein is a compound of formula (I): [ka] wherein A is cyclohexyl or phenyl substituted with 0-3 substituents selected from the group consisting of alkyl, halogen, alkoxy, and cyano. or a pharma- ceutically acceptable salt thereof.

[0086] In one embodiment, the compound of formula (I) has the formula (Ia): [ka] wherein each R is independently selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, and cyano; and n is an integer from 0 to 3. or a pharma- ceutically acceptable salt thereof.

[0087] In one embodiment, the compound of formula (I) is compound (1): [ka] Or a pharma- ceutically acceptable salt thereof.

[0088] In another aspect, disclosed herein is a compound of formula (XI): [ka] wherein A is cyclohexyl or phenyl substituted with 0-3 substituents selected from the group consisting of alkyl, halogen, alkoxy, and cyano. or a pharma- ceutically acceptable salt thereof.

[0089] In one embodiment, the compound of formula (XI) has the formula (XI-a): [ka] wherein each R is independently selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, and cyano; and n is an integer from 0 to 3. or a pharma- ceutically acceptable salt thereof.

[0090] In one embodiment, the compound of formula (XI) is compound (11): [ka] Or a pharma- ceutically acceptable salt thereof.

[0091] Compound names are assigned using the structure naming algorithm that is part of CHEMDRAW®.

[0092] Compounds may exist as stereoisomers in which asymmetric or chiral centers exist. Stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. As used herein, the terms "R" and "S" are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present disclosure. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of a compound can be prepared by synthesis from commercially available starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the mixture of enantiomers to a chiral auxiliary, recrystallization or chromatographic separation of the resulting diastereomeric mixture, and optional liberation of the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England; or (2) direct separation of the mixture of optical enantiomers on a chiral chromatographic column; or (3) fractional recrystallization techniques.

[0093] It is to be understood that the compounds may have tautomeric forms as well as geometric isomers which also form an aspect of the present disclosure.

[0094] The present disclosure also includes isotopically labeled compounds that are identical to those described in formula (I) except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, each of which is an isotope of, for example, but not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl. Deuterium, i.e. 2 Substitution with heavier isotopes such as H may be preferred in some circumstances, as it may provide certain therapeutic advantages resulting from better metabolic stability, for example, increased half-life in vivo or reduced required dosage. The compounds may incorporate positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that may be incorporated into compounds of formula (I) are: 11 C. 13 N, 15 O, and 18 F. Isotopically labeled compounds of formula (I) 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 using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents.

[0095] The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to water- or oil-soluble or dispersible salts or zwitterions of compounds suitable for treating disorders without undue toxicity, irritation, and allergic reactions, which are effective for their intended use, commensurate with a reasonable benefit / risk ratio. The salts can be prepared during the final isolation and purification of the compounds, or by separately reacting the amino group of the compounds with a suitable acid. For example, the compounds can be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one equivalent of a salt, such as hydrochloric acid. The resulting salts can be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid can be removed under reduced pressure to provide the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, thrichloroacetate, trifluoroacetate, glutamate, paratoluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides, and iodides (alkyl being, for example, methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like).

[0096] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reaction of the carboxyl group with a suitable base, for example, hydroxides, carbonates or bicarbonates of metal cations such as lithium, sodium, potassium, calcium, magnesium or aluminum, or organic primary, secondary or tertiary amines. Quaternary amine salts can be prepared, for example, those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0097] The compounds and processes of the present disclosure will be better understood with reference to the following non-limiting examples, which are merely illustrative and not intended to limit the scope of the disclosure. EXAMPLES

[0098] Unless otherwise stated, temperatures are given in degrees Celsius (°C); synthetic operations are carried out at ambient temperature, "rt", or "RT" (typically in the range of about 18-25°C); evaporation of solvents is carried out using a rotary evaporator under reduced pressure (typically 4.5-30 mm Hg) with a bath temperature of up to 60°C; reaction progress is typically followed using thin layer chromatography (TLC); all melting points, when given, are uncorrected; all intermediates as well as final products are well within the limits of their intended utility. 1 H-NMR, HPLC and / or microanalytical data are presented; the following conventional abbreviations are used: L (liter), mL (milliliter), mmol (millimol), g (gram), mg (milligram), min (minute), and h (hour).

[0099] Proton magnetic resonance ( 1 1 H NMR spectra were obtained using a Varian INOVA 600 MHz (1 H) NMR spectrometer, Varian INOVA 500MHz ( 1 H)NMR spectrometer, Varian Mercury 300MHz( 1 H) NMR spectrometer, or Varian Mercury 200MHz ( 1 H NMR spectrometer. All spectra were determined in the solvent indicated. Chemical shifts are reported in ppm downfield of tetramethylsilane, but they are 1 Reference the residual proton peaks to the respective solvent peaks for H NMR. Interproton coupling constants are reported in Hertz (Hz). Example 1 Preparation of 2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)acetic acid (9) [ka]

[0100] 2-(4-(Bromomethyl)phenyl)acetic acid (B): To a solution of A (4.4 kg, 29.3 mol, 1 equiv.) in acetonitrile (22 L) was added N-bromosuccinimide (NBS) (5740 g, 32.2 mol, 1.1 equiv.) and azobisisobutyronitrile (AIBN) (9.2 g, 0.02 equiv.). The resulting mixture was slowly heated to 80° C. and stirred for 15-30 min. After TLC showed that starting material 1 was consumed, the reaction mixture was slowly cooled to −5° C. and allowed to stand at −5° C. overnight. The resulting solid was collected by filtration. The filter cake was washed with petroleum ether / EtOAc (1:1) (5 L), petroleum ether (5 L×2), saturated NaHSO3(aq.) (5 L), water (5 L), and petroleum ether (5 L) to give the title compound (2.3 kg, yield: 34.2%). HPLC purity: 96.8% (254nm); 1 H NMR (300 MHz, DMSO-d6) δ 12.3 (s, 1H), 7.4 (d, J = 8.0 Hz, 2H), 7.2 (d, J = 8.0 Hz, 2H), 4.7 (s, 2H), 3.57 (s, 2H).

[0101] 2-(4-(hydroxymethyl)phenyl)acetic acid (C): To a solution of NaOH (1.61 kg, 40.2 mol, 4 equiv.) in water (90 L) was added B (2.3 kg, 10.0 mol, 1 equiv.) and the resulting mixture was stirred at RT overnight. TLC analysis indicated consumption of B. The reaction mixture was then carefully acidified to approximately pH 2 with concentrated H2SO4 (1.0 L). Solid NaCl (25 kg) was then added to the mixture followed by extraction with EtOAc (33 L x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated until a significant amount of solid precipitated. The resulting suspension was allowed to stand overnight at approximately 4-6 °C for further crystallization. The solid product was then collected by filtration. The filter cake was washed with petroleum ether (2 L x 2) to give the title compound (1.2 kg, yield: 71.9%). HPLC purity: 97.8% (220 nm); 1 H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H), 7.26-7.12 (m, 4H), 5.14 (s, 1H), 4.47 (s, 2H), 3.53 (s, 2H).

[0102] Methyl 2-(4-(hydroxymethyl)phenyl)acetate (D): To a solution of C (2.5 kg, 15.06 mol, 1 equiv.) in MeOH (15 L) was slowly added concentrated H2SO4 (1.5 L) at 0 °C. The resulting mixture was stirred at RT overnight. After TLC showed that C was consumed, the reaction mixture was poured into water (20 L) and extracted with EtOAc (20 L x 3). The combined organic layers were washed with saturated NaHCO3 solution (aq) (20 L x 3) and then with brine (20 L). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (2.2 kg) as a viscous oil. HPLC purity: 90% (220 nm); 1 H NMR (300 MHz, CDCl3) δ 7.35-7.28 (m, 4H), 4.68 (s, 2H), 3.70 (s, 3H), 3.64 (s, 2H).

[0103] 4-(2-Methoxy-2-oxoethyl)benzyl 2,4-dimethylbenzoate (7): A solution of 2,4-dimethylbenzoic acid (6) (2.01 kg, 13.4 mol, 1.1 eq.) and EDC (4.2 kg, 21.9 mol, 1.8 eq.) in dichloromethane was stirred at RT for 1 h. D (2.2 kg, 12.2 mol, 1 eq.) and 4-dimethylaminopyridine (DMAP) (298 g, 2.44 mol, 0.2 eq.) were added to the reaction mixture and stirred at RT overnight. After complete consumption of D as judged by TLC, the reaction mixture was washed three times with 1N HCl solution (16 L×3) and then once with brine (16 L). The separated organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was recrystallized in MeOH to give the title compound (2.32 kg, 60.9% yield). HPLC purity: 98.6% (210 nm); 1 H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.05 (m, 2H), 5.32 (s, 2H), 3.72 (s, 3H), 3.64 (s, 2H), 2.60 (s, 3H), 2.36 (s, 3H).

[0104] 2-(4-(((2,4-Dimethylbenzoyl)oxy)methyl)phenyl)acetic acid (9): To a solution of 7 (1.2 kg, 3.85 mol, 1 equiv.) in THF (2.4 L) was added a solution of LiOH (176 g, 4.2 mol, 1.1 equiv.) in water (3.6 L) dropwise over 1 h. The resulting mixture was stirred for 1.5 h. TLC analysis indicated consumption of 7. The reaction mixture was washed with MTBE (2.5 L x 4). The aqueous layer was acidified with saturated aqueous citric acid (550 mL) to approximately pH 3-4, forming a precipitate. The resulting mixture was concentrated on a rotary evaporator to remove the organic solvent. The solid product was then collected by filtration. The crude product was slurried in water (3.5 L) for 30 min. After filtration, the collected solid was then slurried with heptane (5 L) to give the title compound (2.05 kg, yield: 89.6%). HPLC purity: 100% (210 nm); LCMS (ESI-): m / z=297 (M-1). 1 H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.05 (m, 2H), 5.32 (s, 2H), 3.69 (s, 2H), 2.59 (s, 3H), 2.36 (s, 3H). If analytical data indicates the presence of citric acid, the compound can be recrystallized from water / acetone. Example 2 Preparation of DBMPA imide. [ka]

[0105] Step 1: Preparation of DBMPA chloride, 4-(2-chloro-2-oxoethyl)benzyl 2,4-dimethylbenzoate (8). The starting material DBMPA acid, (9) (5.0 kg, corrected by assay, 1 eq.) is dissolved in 5.5 volumes of dichloromethane and converted to DBMPA chloride (8) by treatment with oxalyl chloride (1.15 eq.). The reaction is stirred at 20 ± 5 °C for 16-24 h. Additional oxalyl chloride can be added (up to 0.2 eq.) to ensure completion of the reaction (IPC analysis by HPLC or TLC). The dichloromethane is replaced with heptane and the total process volume is adjusted to about 11 volumes with heptane. The resulting suspension of DBMPA chloride (8) is cooled to 0 ± 5 °C. DBMPA chloride (8) is isolated as a crystalline solid, washed with additional heptane (2 × 2.5 volumes) and dried under nitrogen for at least 2 h. The material is dissolved in 2 volumes of tetrahydrofuran (THF) and used directly in the next reaction.

[0106] Step 2: Preparation of DBMPA imide, (7). Subsequent equivalents for step 2 are based on isolated DBMPA chloride. In a separate vessel, the chiral auxiliary, compound A, 0.95 eq., is dissolved in THF (7.5 vol.) and cooled to -80±5°C. Then, n-butyllithium in heptane (1.05 eq.) is added at a rate such that the internal temperature does not exceed -65°C. The mixture is stirred at -70±5°C for not less than 15 min. The DBMPA chloride solution is added to the anion of the chiral auxiliary (rinsing with 0.5 vol. THF) while maintaining an internal temperature of -70±5°C. The reaction mixture is stirred at -70±5°C for not less than 15 min and not more than 60 min until the reaction is complete (IPC by HPLC was TLC). The reaction mixture is then quenched with 2 vol. of 10% aqueous ammonium chloride solution and warmed to 15-30°C for not less than 30 min and not more than 20 h. The bottom aqueous layer is removed and the organic layer is concentrated to about 2 process volumes by distillation under reduced pressure. Residual THF is exchanged with ethyl acetate. After washing with purified water and 14% aqueous sodium chloride, the organic layer is concentrated by distillation and adjusted to about 6 volumes with ethyl acetate. Heptane (10 volumes) is added and the product is crystallized from ethyl acetate / heptane using seeds. The suspension is cooled to 5±5° C. and the product is isolated by filtration, washed with heptane (2×5 volumes) and dried to constant weight at 40±5° C. for not less than 10 hours in a preheated vacuum oven to provide DBMPA imide (bulk weight change of 1% or less) as a white to off-white solid. The solid is sampled for in-process testing (IPC by HPLC) and, based on the results of the in-process testing, can be used for step 3 or recrystallized from ethyl acetate / heptane as described below. After the second crystallization, there is no IPC. This intermediate can also be stored based on supporting retention time data.

[0107] An alternative step 2 procedure utilizes sodium hydride (NaH) instead of n-butyllithium. In this process, the chiral auxiliary is dissolved in THF and added to a suspension of NaH (60% mineral oil, 1.1 equivalents corrected for assay) in THF at 20±5°C. Deprotonation / anion formation proceeds at 20±5°C for 15-30 min, then at 20-25°C for up to 35 h. The resulting mixture is cooled to 3±5°C, after which a solution of DBMPA chloride dissolved in THF is added over 30-60 min. The resulting reaction mixture is stirred at 3±5°C for 2-4 h, then analyzed (IPC or TLC by HPLC) and proceeded to workup as described above.

[0108] Recrystallization: The following volumes are based on the isolated imide but reflect the similar concentrations noted above for the initial isolation from ethyl acetate / heptane. The DBMPA imide is dissolved in 3.6 volumes of ethyl acetate. The solution is then adjusted to 20±5° C. Heptane (7.3 volumes) is added and the product is crystallized from ethyl acetate / heptane using seeds. The suspension is cooled to 5±5° C. and the product is isolated by filtration, washed with heptane (2×3.6 volumes) and dried to constant weight in a preheated vacuum oven for not less than 10 hours at 40±5° C. to provide the DBMPA imide as a white to off-white solid. Example 3 Preparation of N-Boc DBMPP acid [ka]

[0109] Step 3: Preparation of N-Boc DBMPP Imide, Crude. Charge a reactor with DBMPA imide (1 equiv.) followed by anhydrous 2-methyl THF (2-Me THF, 10 volumes, less than 100 ppm water). Cool the solution to -25 ± 5 °C. Add a 1.0 M solution of LiHMDS in THF (1.2 equiv.) to the DBMPA imide solution, maintaining a batch temperature below -15 °C. Stir the reaction mixture at -25 ± 5 °C for 30 to 90 minutes. Separately, charge a separate reactor with N-Boc aminomethylbenzotriazole (NBABT, 1.2 equiv.) and add anhydrous 2-MeTHF (6 volumes). The water content of the NBABT solution with KF should be less than 100 ppm (IPC). If the KF is higher than 100 ppm, distill the solution to dryness using anhydrous 2-Me THF. Transfer the NBABT solution to the reactor, maintaining a temperature below -15 °C. Stir the reaction mixture for 1.5 to 3 h at -25 ± 5 °C. Monitor the progress of the reaction by HPLC.

[0110] After the reaction is complete, quench the mixture with 10% aqueous ammonium chloride (2 volumes) at 25±5°C, followed by 10% aqueous citric acid (2 volumes). Adjust the temperature of the reaction mixture to 10-20°C and age for 1-16 hours. Allow the layers to separate for 15 minutes or more and separate the layers using the organic phase to remove the rag layer. Wash the organic layer with 10% aqueous NaCl (2 volumes) and stir the biphasic mixture for 15 minutes or more. Allow the layers to separate for 15 minutes or more and separate the layers using the organic phase to remove the rag layer. Wash the organic layer with 10% aqueous K2CO3 (3×10 volumes), followed by 10% aqueous KHCO3 (1×10 volumes) and 10% aqueous NaCl (1×10 volumes). Stir the biphasic mixture for 15 minutes or more and separate the layers using the organic phase to remove the rag layer. Concentrate the organic phase to approximately 10 volumes. This is a crude solution of N-Boc DBMPP imide.

[0111] Step 4: Preparation of N-Boc DBMPP acid. Charge the reactor with the crude solution from step 3 and add water (5 volumes). Cool the mixture to 0±5° C. Once cooled, charge hydrogen peroxide (4 equiv.) in one go. Charge the reactor with lithium hydroxide monohydrate solution (1.2 equiv. in 1.3 volumes of water) in one go and stir the reaction for 6 hours or more at 0±5° C. Monitor the progress of the reaction (was IPC, TLC by HPLC).

[0112] Quench the reaction with 10% sodium sulfite solution buffered with citric acid (20 vol.) to target pH 6-7. Adjust temperature to 25±10°C and stir for ≥16 h. Stop stirring, allow layers to separate for ≥15 min, and separate layers using the organic phase to remove rag layer. Wash organic phase with 10% aqueous ammonium chloride solution (3×13 vol.). Concentrate organic phase under vacuum to approximately 5 vol. with vessel jacket temperature ≤40°C. Charge with acetonitrile (2×8 vol.) and concentrate to approximately 5 vol. Charge with additional acetonitrile to approximately 10 vol. total. Cool mixture to 20±5°C and age for ≥30 min. Pass solution through a clarifying filter and collect in a clear vessel.

[0113] Charge piperidine (0.41 equiv.) to the solution over a period of 10 min or more at 20 ± 5 °C. Add 0.20 wt% chirally pure seeds in acetonitrile (0.5x volume) to the solution, stir the solution at 20 ± 5 °C, and age for 2-4 h. Charge the remaining piperidine (0.59 equiv.) for 4-6 h at 20 ± 5 °C, and age the mixture for 12-16 h at 20 ± 5 °C. Filter the contents, wash the cake with acetonitrile (2 volumes), mix for 10 min or more, and filter. Dry the cake at a temperature of 50 °C or less for 6 h to obtain the piperidine salt (IPC - chiral and achiral; recrystallization is performed as necessary based on IPC). In the case of recrystallization, no additional IPC testing is performed.

[0114] Step 4: Decomposition of salt and crystallization of free acid. For calculations in this step, the calculated ratios herein are based on the Pip* salt of compound 2. The piperidine salt is slurried in ethyl acetate (7 vol) and charged to a vessel. The mixture is washed with 10% aqueous citric acid (2×10 vol). Allow the layers to separate for not less than 15 minutes, split the layers and discard the lower aqueous layer. The organic phase is washed with water (2×10 vol). Allow the layers to separate for not less than 15 minutes, split the layers and discard the lower aqueous layer. Cool the organic phase to 0±5° C. and add heptane (7 vol) over 15 minutes. A seed of 1 wt% N-Boc DBMPP acid slurried in 9:1 v / v heptane:ethyl acetate (0.5× vol) is added to the solution. Additional heptane (14 vol) is then added over 6-8 hours. After heptane addition is complete, the solution is aged for not more than 1 hour. Filter the product and wash the cake with 9:1 v / v heptane:ethyl acetate (4 volumes). Dry the product at 50 ± 5 °C under vacuum until dry (IPC chiral and achiral; recrystallization is performed as needed based on IPC). In case of recrystallization, no additional IPC tests are performed. Yield: Cumulative 60-80% (Step 4 65-80%) Example 4 Netarsudil Synthesis - Preparation of N-Boc netarsudil (compound 7). [ka]

[0115] Step 5: Preparation of N-Boc netarsudil compound (7). N-Boc DBMPP acid (approximately 2.0 kg, 1 equiv.) and 6-AIQ (1.3 equiv.) are dissolved in N,N-dimethylformamide (DMF, 13 volumes). 2,4,6-trimethylpyridine (collidine, 1.3 equiv.) is added and the reaction mixture is cooled to 0±5°C. A solution of 2,2,2-trichloro-1,1-dimethylethyl chloroformate (1.3 equiv.) in 3 volumes of DMF is added to the reaction mixture as quickly as possible, followed by rinsing with 1 volume of DMF. The reaction is stirred at 0±5°C for 6-8 hours.

[0116] The reaction is then quenched with 20 volumes of 10% aqueous KHCO3. Ethyl acetate (30 volumes) is charged to the reactor and the temperature is adjusted to 20±5° C. over 10 minutes.

[0117] The aqueous layer is removed and the organic layer is washed with 10 volumes of 10% aqueous citric acid. The aqueous layer is again removed and the organic layer is washed with 10 volumes of 10% aqueous KHCO3. The temperature of the biphasic mixture is adjusted to 40±5°C for 10 minutes or more. The aqueous layer is removed and the remaining organic layer is stirred at 40±5°C for a period of 10 hours or more and 20 hours or less. The reaction mixture is then cooled to 20±5°C and any remaining aqueous layer is removed. The mixture is then concentrated to about 4 volumes through vacuum distillation and further reduced to an oil by rotary evaporation. The residue is dissolved in 2 volumes of dichloromethane for purification by silica gel chromatography, e.g., a Biotage 400L system using a 40 kg column packed with HP Sphere silica with a silica gel to starting material ratio (silica gel:starting material) of 12.5 or more:1.

[0118] The impurities are eluted with 40:60 ethyl acetate:heptane, then the product is eluted with 70:30 ethyl acetate:heptane. The major fractions containing compound 7 as determined by HPLC (TLC) are combined and concentrated under reduced pressure to approximately 10 volumes, then solvent exchanged with acetonitrile to approximately 33 volumes. The internal temperature is adjusted to 70±5°C to dissolve the solids. The solution is then cooled to 55±2°C, seeded with a sample of N-Boc netarsudil (1-5 wt%), and further cooled to 20±2°C. Filtration of the product begins no more than 1 hour after reaching 20±2°C. The cake is washed with acetonitrile (2×2 volumes) and then dried in vacuum at 50±5°C to constant weight to provide compound 7 as a white to pale yellow solid. The product is sampled for in-process achiral and chiral purity. (IPC chiral and achiral; recrystallization based on IPC if necessary).

[0119] If the chiral purity criteria are not met (for isolated compound 7), the product is recrystallized from 30 volumes of acetonitrile.

[0120] If the achiral chromatographic purity criteria are not met (irrelevant to chiral purity), the product is recrystallized from dichloromethane / heptane as described below.

[0121] The product is dissolved in 10 volumes of dichloromethane at 20±5°C. Heptane (4 volumes) is added over a period of not less than 15 minutes while maintaining a temperature of 20±5°C. The solution is seeded with 1-5 wt% of compound 7 and stirred at 20±5°C for not more than 1 hour. Heptane (11 volumes) is then added over 70-120 minutes. After seeding, the resulting mixture is stirred at 20±5°C for not more than 4 hours. The crystallized product is then isolated by filtration. The cake is washed with heptane (2×2 volumes) and then dried in vacuum at 50±5°C to constant weight to provide N-Boc netarsudil as a white to pale yellow solid. This intermediate can be used directly in Step 6 or stored based on supporting retention time data. Yield: 40-80% Average yield at 250 L scale: 68%. Example 5 Netarsudil Synthesis - Preparation of Netarsudil as the dimesylate salt. [ka]

[0122] Step 6: Preparation of netarsudil - reaction and initial isolation. Compound 7 (approximately 1.4 kg, 1 eq., corrected for assay) is dissolved in 15 volumes of dichloromethane and passed through a clarifying filter. The filter is washed with 2 x 2 volumes of dichloromethane and the combined filtrates are adjusted to a temperature of 20 ± 5 ° C. Methanesulfonic acid (2.5 eq.) is dissolved in 2.5 volumes of dichloromethane and added to the reactor through the filter at such a rate as to maintain the reaction temperature at 20 ± 5 ° C. 2.5 volumes of line rinse are added as well. The reaction mixture is then stirred at 20 ± 5 ° C for 48 hours or more. The temperature is adjusted to 40 ± 5 ° C and the mixture is stirred at this temperature for 2-4 hours until the reaction is complete (IPC, HPLC was TLC). The reaction mixture is concentrated to approximately 5 volumes via vacuum distillation. The remaining dichloromethane is exchanged for isopropanol via successive distillations to 25 volumes. The reaction mixture is warmed to 70 ± 5 ° C. The solution is cooled to 50±2°C at a rate of about -0.3°C / min. Netarsudil dimesylate seeds (0.5-5.5 wt%) are suspended in 30 volumes of isopropanol. The suspended seeds are then added to the reactor and the mixture is stirred at 50±2°C for not less than 1 hour. The mixture is cooled to 20±5°C at a rate of about -0.3°C / min and then stirred at this temperature for not less than 1 hour. The resulting slurry is warmed to 50±5°C and stirred at this temperature for not less than 90 minutes. The mixture is recooled to 20±5°C at a rate of about -0.3°C / min and stirred for 1-24 hours. The product is collected by filtration and the crystalline solid is washed with isopropanol (3 volumes).

[0123] Dry the solids on the filter with a stream of nitrogen through the filter cake for 3-16 hours. Transfer the solids to a preheated oven set at 30±5°C for 16-24 hours. Slowly increase the oven temperature to 69±10°C and continue drying at this temperature for 24-48 hours. Break down the solids using a knife mill, sample for purity (IPC achiral by HPLC), then return to the 69±10°C oven for 60-132 hours (or 48 hours or more if in-process testing for HPLC purity fails). The material is then tested for residual isopropanol and moisture content (IPC by GC and KF).

[0124] In this process, an agitated filter drier can be used in place of the knife mill and tray drier. Agitated filter driers typically require up to 72 hours total time.

[0125] The material can be reslurried with isopropanol if necessary, based on in-process testing for purity or isopropanol content.

[0126] Reslurry: Netarsudil is suspended in 25 volumes of filtered isopropanol and the temperature is adjusted to 50±5°C. The mixture is stirred at this temperature for approximately 2 hours and then cooled to 20±5°C at a rate of approximately -0.15°C / min. The cooled suspension is stirred at 20±5°C for 8-24 hours. The product is collected by filtration and washed with filtered isopropanol (3 volumes).

[0127] Dry the solids on the filter with a dry nitrogen flow through the filter cake for 3-16 hours. Transfer the solids to a preheated oven set at 30±5°C for 16-24 hours. Slowly increase the oven temperature to 69±10°C and continue drying at this temperature for 24-48 hours. Break down the solids using a knife mill, sample for purity (by HPLC), then return to the 69±10°C oven for 72±12 hours. The pale yellow to white powder is then dried until the residual isopropanol level is 6000 ppm or less as determined by in-process testing. An agitated filter drier can be used in place of the knife mill and tray drier processing of this product.

[0128] The final API is hygroscopic and should be packaged at a temperature of 25°C or less and a relative humidity of 40% or less. Yield: 80-99%. Average yield at 250L scale: 93%.

[0129] In conclusion, a process has been developed that provides improved chemical yields, and importantly, scale-up, to meet the continuing need for commercial-scale supplies of the glaucoma drug netarsudil.

[0130] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be construed as limitations upon the scope of the present disclosure.

[0131] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those relating to chemical structure, substituents, derivatives, intermediates, synthesis, compositions, formulations, or methods of use of the present disclosure, can be made without departing from the spirit and scope of the present invention.

Claims

1. Formula (I-a): 【Chemistry 64】 (wherein each R is C １ ~C ４ Alkyl, halogen, C １ ~C ４ independently selected from the group consisting of alkoxy and cyano; n is an integer from 0 to 3. A method for synthesizing a compound of the formula: (a) Formula (II-a) 【Chemistry 65】 where PG is a nitrogen protecting group. with 6-aminoisoquinoline to give a compound of formula (III-a) 【Chemistry 66】 (wherein each R is C １～４ Alkyl, halogen, C １～４ independently selected from the group consisting of alkoxy and cyano; n is an integer from 0 to 3. forming a compound of formula (I); and (b) removing the nitrogen protecting group to form the compound of formula (Ia). A method comprising:

2. (a) Formula (IV-a) 【Chemistry 67】 (wherein each R is C １～４ Alkyl, halogen, C １～４ is independently selected from the group consisting of alkoxy and cyano; n is an integer from 0 to 3; and T is a chiral auxiliary. Compound 【Chemistry 68】 where PG is a nitrogen protecting group. to obtain a compound of formula (V-a): 【Chemistry 69】 (wherein each R is C １～４ Alkyl, halogen, C １～４ is independently selected from the group consisting of alkoxy and cyano; n is an integer from 0 to 3; and T is a chiral auxiliary. forming a compound of formula (I); and (b) removing said chiral auxiliary to form said compound of formula (II-a). The method of claim 1 further comprising:

3. Formula (VIII-a): 【Chemistry 70】 (wherein each R is C １ ~C ４ Alkyl, halogen, C １ ~C ４ is independently selected from the group consisting of alkoxy and cyano; n is an integer from 0 to 3; R １ is halogen, OR ａ , O.C.(O)R ｂ , S.R. ａ or SC(O)R ｂ and R ａ is H, alkyl or aryl; R ｂ is alkyl or aryl) With a compound of formula (IV-a) 【Chemistry 71】 (wherein each R is C １ ~C ４ Alkyl, halogen, C １ ~C ４ is independently selected from the group consisting of alkoxy and cyano; n is an integer from 0 to 3; and T is a chiral auxiliary.

3. The method of claim 2, further comprising converting

4. An amine salt of (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propionic acid selected from the list: 2-aminoethanol, morpholine, piperidine, dibenzylamine, dicyclohexylamine, diisopropylamine, benzylamine, piperazine, DMAP.

5. 4. The method of claim 1, wherein n is 2 and each R is methyl.

6. The compound of formula (I-a) 【Chemical Formula 72】 The method according to any one of claims 1 to 3, wherein

7. The compound of formula (VIII-a) 【Chemical Formula 73】 The method according to any one of claims 5 to 6, wherein

8. 4. The method of claim 1, wherein n is 0.

9. T, 【Chemical 74】 (In the formula, Z is S or O; B is S or O; R ｃ is hydrogen, cycloalkyl, C ３ ~C ７ is a branched alkyl or aryl; R ｄ is C １ ~C ４ Alkyl, C ３ ~C ７ branched alkyl; aryl alkyl or aryl The method according to any one of claims 5 to 8, wherein

10. T, 【Chemistry 75】 (In the formula, Z is S or O; B is S or O; R ｃ is hydrogen or aryl; R ｄ is C １ ~C ４ alkyl, arylalkyl or aryl) The method according to claim 9, wherein

11. 1. A method for purifying (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propionic acid, comprising reacting (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propionic acid to form an amine salt, recrystallizing said salt, and then converting the purified salt back to (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propionic acid.

12. 12. The method of claim 11, wherein the amine used to form the amine salt is piperidine.

13. The following formula: 【Chemical Formula 76】 A method for synthesizing a compound of the formula: (a) 【Chemical Formula 77】 with a chlorinating agent to form an acid chloride; (b) crystallizing the acid chloride from n-heptane to form a purified acid chloride; (c) reacting the purified acid chloride in the presence of a base. 【Chemical 78】 React with 【Chemical 79】 forming (d) reacting the product of step (c) in the presence of a base at a temperature between −50° C. and −0° C. 【Chemistry 80】 React with 【Chemistry 81】 forming (e) reacting the product of step (d) with LiOOH to give 【Chemistry 82】 forming (f) forming an amine salt and then recrystallizing the product of step (e) to form a purified product of step (e); (g) activating the carboxylic acid group of the purified product of step (f) and reacting the activated carboxylic acid with 6-aminoisoquinoline; 【Chemistry 83】 forming (h) recrystallizing the product of step (g); (i) The product of step (h) is dissolved in MeSO ３ with at least two equivalents of H, 【Chemistry 84】 forming a

14. 14. The process of claim 13, wherein the solvent used in purifying the amine salt in step (e) is acetonitrile.

15. 14. The method of claim 13, wherein the base in step (c) is NaH, LiH, KH, nBuLi, secBuLi, LiHMDS, NaHMDS, or KHMDS, and step (b) is carried out at a temperature between -90°C and -50°C.

16. 14. The method of claim 13, wherein the base in step (d) is NaH, LiHMDS or NaHMDS.

17. 14. The method of claim 13, wherein the LiOOH is formed in situ from lithium hydroxide and hydrogen peroxide.

18. 14. The method of claim 13, wherein in step (g), the carboxylic acid groups are activated by the addition of trichlorodimethylethyl chloroformate and collidine at a temperature of about 0°C.

19. 20. The method of claim 18, wherein the purified product of step (f), 6-aminoisoquinoline, and collidine are mixed followed by the addition of trichlorodimethylethyl chloroformate.

20. 20. The method of claim 18, wherein the carboxylic acid group is activated by conversion to a mixed anhydride intermediate.

21. 【Chemical 85】 Piperidinium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate; 【Chemistry 86】 Dicyclohexylammonium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate; 【Chemistry 87】 Dibenzylammonium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate; 【Chemistry 88】 Diisopropylammonium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate; 【Chemistry 89】 Benzylammonium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate; or 【Chemistry 90】 Piperazinium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate A compound selected from:

22. 【Chemical 91】 22. The compound of claim 21 which is a solid form of piperidinium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate.

23. 23. The compound of claim 22, wherein the solid form is a crystalline form.

24. 22. The compound of claim 21, which is a solid form of the compound.

25. 26. The compound of claim 25, wherein the solid form is a crystalline form.

26. A compound as described herein, prepared by one or more of the processes described herein.

27. A composition comprising a compound according to one of claims 21 to 26.

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