Process for preparing XPO1 inhibitors and intermediates used in the preparation of XPO1 inhibitors

Abstract

The present invention provides an improved process for the preparation of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (referred to as the compound of structural formula (III)), a key intermediate useful in the synthesis of selinexol ((Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-(pyrazin-2-yl)acrylohydrazide). The process involves reacting a compound of structural formula (I) (as described herein) with a compound of structural formula (II) (as described herein) in the presence of a catalyst, an organic base, and an ether-containing solvent. Subsequent hydrolysis of the formed compound of structural formula (IIIa) (as described herein) is carried out without isolation of the compound of structural formula (IIIa), thereby providing the compound of structural formula (III) in high yield and stereoselectivity.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 841,649, filed May 1, 2019, the entire teachings of which are incorporated herein by reference. [Background technology]

[0002] Selinexor is a selective inhibitor of nuclear export used in the treatment and / or prevention of physiological conditions associated with CRM1 / XPO1 activity. Selinexor has the following structural formula: [ka] It is expressed by:

[0003] The synthesis of selinexol was first disclosed in WO 2013019548A1 by Karyopharm Therapeutics Inc. Although the synthetic method reported therein was successful in providing small amounts of selinexol, they struggled with the need for multiple purification steps (chromatography and crystallization) to provide selinexol with the desired high Z-isomer content. Although the process disclosed in this application was well suited to their intended scale, these purification steps make it inefficient for commercial manufacturing purposes.

[0004] An improved synthesis of selinexor from its penultimate intermediate (represented below by structural formula III) has been disclosed in WO 2016025904 A1, also by Karyopharm Therapeutics Inc. Although the challenge associated with the final synthetic stage of converting intermediate III to selinexor has been resolved, no method for preparing intermediate III is provided. Summary of the Invention [Problem to be solved by the invention]

[0005] A need exists for efficient manufacturing processes suitable for the preparation of selinexor and its intermediates on a commercially relevant scale.

[0006] The present invention aims to provide novel and efficient processes for preparing intermediates useful in the synthesis of selinexor, such as compounds represented by structural formula III, which overcome the challenges associated with the presynthesis of selinexor. [Means for solving the problem]

[0007] The present invention relates to a compound represented by formula III [ka] 1. A process for forming a compound represented by: A compound represented by structural formula (I) and a compound represented by structural formula (II) [ka] and a compound represented by structural formula (IIIa) in the presence of a catalyst, an organic base and an ether-containing solvent. [ka] reacting under conditions suitable for producing reacting, without isolation, the compound represented by structural formula (IIIa) with an inorganic base in the presence of isopropyl alcohol (IPA) under conditions suitable for producing the compound represented by structural formula (III); and isolating the compound represented by structural formula (III), Here, R is C2-C5 alkyl, C6-C 18 Aryl, 5-18 membered heteroaryl, C3-C 12cycloalkyl or 3-12 membered heterocycloalkyl, each of which is optionally and independently substituted with one or more substituents selected from halo, CN, OH, C1-C3 alkyl, C1-C3 haloalkyl, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and C1-C3 alkoxy.

[0008] As described in the Examples herein below, the combination of a catalyst, an organic base, an ether-containing solvent, an inorganic base, and a phase transfer catalyst was employed in a method for the synthesis of a compound represented by structural formula III, which unexpectedly afforded advantageously high yields and excellent stereoselectivities while eliminating the step of isolating intermediates.

[0009] The foregoing will become apparent from the following more particular description of exemplary embodiments of the invention, as illustrated in the accompanying drawings, in which like reference characters refer to the same elements throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the invention. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of selinexor Form A as described in US Pat. No. 10,519,139. [Diagram 2] FIG. 2 is an XRPD pattern of the acetonitrile solvate of selinexor described in U.S. Pat. No. 10,519,139. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The novel features of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of the present invention. However, it should be understood that the detailed description and specific examples presented represent certain embodiments of the present invention, and are provided for illustrative purposes only, since various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from the detailed description and claims below.

[0012] definition The compounds of the present invention broadly include those described above and are further exemplified by the classes, subclasses and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry are identified according to Ed. Also, the general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0013] Unless otherwise specified herein, the nomenclature used herein generally follows the examples and rules set forth in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979 (incorporated herein by reference for exemplary chemical structure names and rules for naming chemical structures). Optionally, names of compounds may be generated using a chemical naming program: ACD / ChemSketch, Version 5.09 / September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

[0014] "Alkyl" refers, for example, to a saturated aliphatic branched or straight-chain monovalent hydrocarbon group having from 1 to 16 carbon atoms. For example, "(C1-C6)alkyl" refers to a group having from 1 to 6 carbon atoms arranged in a straight or branched chain. "(C1-C6)alkyl" includes methyl, ethyl, propyl, butyl, pentyl, and hexyl. In one embodiment, an alkyl group contains from 2 to 5 carbon atoms.

[0015] "Alkane" means a hydrocarbon molecule consisting of an alkyl group, as defined above, bonded to a hydrogen.

[0016] "Cycloalkyl" refers to a saturated aliphatic cyclic hydrocarbon group having, for example, 3 to 12 carbon atoms. It can be monocyclic or polycyclic (e.g., fused, bridged, or spiro). For example, a monocyclic (C3-C8)cycloalkyl refers to a group having 3 to 8 carbon atoms arranged in a monocyclic ring. Examples of monocyclic (C3-C8)cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctane.

[0017] "Cycloalkane" means a hydrocarbon molecule consisting of a cycloalkyl group, as defined above, bonded to a hydrogen.

[0018] "Heterocycloalkyl" means a saturated ring having, for example, 3 to 12 members, containing carbon atoms and 1 to 4 heteroatoms, which may be the same or different, selected from N, O, or S, and optionally containing one or more double bonds. It can be monocyclic or polycyclic (e.g., fused, bridged, or spiro).

[0019] "Haloalkyl" refers to straight or branched alkyl groups as defined above, where the hydrogen atoms may be partially or fully replaced with halogen atoms, and may include mono-, poly- and perhaloalkyl groups, where the halogens are independently selected from fluorine, chlorine and bromine.

[0020] "Heteroaryl" means a monovalent aromatic heterocyclic monocyclic or polycyclic ring radical. The heteroaryl ring can have 5 to 18 members and can contain carbon atoms and 1 to 4 heteroatoms independently selected from N, O, and S. They can be monocyclic or polycyclic and include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole 1,1-dioxide, 1,3,4-thiadiazole ... Examples of suitable quinolidines include pyridine, pyridine-N-oxide, pyrazine, pyrimidine, pyridazine, 1,2,4-triazine, 1,3,5-triazine, tetrazole, indolizine, indole, isoindole, benzo[b]furan, benzo[b]thiophene, indazole, benzimidazole, benzthiazole, purine, 4H-quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.

[0021] "Alkoxy" means an alkyl group as defined above attached through an oxygen linking atom. "(C1-C3)-Alkoxy" includes methoxy, ethoxy, propoxy and isopropoxy.

[0022] "Aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system containing, for example, 6 to 18 carbon members. Aryl systems include, but are not limited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl.

[0023] "Arene" means a hydrocarbon molecule consisting of an aryl group bonded to a hydrogen.

[0024] The definitions of the radicals defined above also include those groups that are optionally substituted at carbon or nitrogen atoms, where valence allows. Suitable substitutions include, but are not limited to, halo, CN, OH, C1-C3 alkyl, C1-C3 haloalkyl, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, and C1-C3 alkoxy.

[0025] As used herein, "halo" refers to fluorine, chlorine, bromine or iodine.

[0026] As used herein, the term "hydrocarbon solvent" means an alkane, cycloalkane, or arene having from 5 to 12 carbon atoms.

[0027] "Catalyst" refers to any compound that can be modified, particularly by increasing the rate of the chemical reaction involved, and that is regenerated at the end of the reaction. Examples of catalysts suitable for the present application include, but are not limited to, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and quinuclidine.

[0028] As used herein, "organic base" refers to an organic compound capable of accepting a proton and forming a hydroxyl ion in aqueous solution or donating an electron pair. Examples of organic bases include, but are not limited to, nitrogen-containing compounds such as Et3N, diisopropylethylamine (DIPEA), piperidine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl-morpholine, dimethylaniline, imidazole, 1-methylpyridine, 2-methylpyridine, 3-methylpyridine, 3,5-dimethylpyridine, 2,4-dimethylpyridine, 2,6-dimethylpyridine, and 2,4,6-trimethylpyridine.

[0029] As used herein, "inorganic base" refers to an inorganic compound capable of accepting a proton and forming a hydroxyl group in an aqueous medium or donating an electron pair. Examples of inorganic bases include, but are not limited to, metal hydroxides such as LiOH, NaOH, KOH, CsOH, Ca(OH)2, Mg(OH)2, and Ba(OH)2.

[0030] As used herein, an "ether-containing solvent" refers to an organic compound that is liquid under ambient conditions and contains an R'-OR" moiety, where R' and R" are each independently selected from straight or branched chain alkyl or cycloalkyl, and R' and R" can form a 5- to 6-membered ring together with their attached oxygen atom. Examples of ether-containing solvents include, but are not limited to, 2-methyltetrahydrofuran (MeTHF), diethyl ether, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), 2,5-dimethyltetrahydrofuran (DiMeTHF), dimethoxyethane (DME), and cyclopentyl methyl ether (CPME).

[0031] It is understood that the substituents and substitution patterns in the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized by techniques known in the art as well as the methods described below. In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens associated with the designated moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted group" can have a suitable substituent at each substitutable position in the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a particular group, the substituents can be the same or different at all positions. Alternatively, an "optionally substituted group" can be unsubstituted.

[0032] The combination of substituents envisioned by the present invention is preferably one that results in the formation of a stable or chemically feasible compound. When a substituent itself is substituted with two or more groups, it is understood that these multiple groups can be on the same carbon atom or on different carbon atoms, so long as a stable and chemically feasible structure results. As used herein, the term "stable" refers to a compound that does not change substantially when subjected to conditions that allow its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0033] Unless otherwise specified, structures depicted herein are also intended to include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms) of the structure; e.g., the R and S configurations for each asymmetric center, Z and E double bond isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0034] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen with deuterium or tritium, or 13 C- or 14 Compounds produced by the replacement of carbon with C-enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention.

[0035] The term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This term includes mirror image isomers (enantiomers), geometric (cis / trans) isomers, and isomers of compounds with two or more chiral centers that are not mirror images of one another (diastereomers).

[0036] When introducing elements disclosed herein, the articles "a," "an," "the," and "said" are intended to mean that there are one or more elements. The terms "comprising," "having," and "including" are intended to be open-ended and mean that there may be additional elements other than the listed elements.

[0037] Abbreviation aq. Water-based CPME Cyclopentyl methyl ether DABCO 1,4-diazabicyclo[2.2.2]octane DD Distilled, deionized DIEA N,N-Diisopropylethylamine DMF Dimethylformamide EA or EtOAc Ethyl acetate Et2O Diethyl ether EtOH Ethanol Et Ethyl eq equivalent h time HCl Hydrochloric acid IPA 2-Propanol KOH Potassium hydroxide LCMS Liquid Chromatography / Mass Spectrometry LiOH Lithium hydroxide MeCN Acetonitrile MeOH Methanol MTBE Methyl t-butyl ether min minutes Me Methyl MeTHF 2-Methyltetrahydrofuran NaOH Sodium hydroxide NaCl Sodium chloride NMT or less NLT or higher ND Not detected NMR nuclear magnetic resonance org.organic RT, rt, rt room temperature THF Tetrahydrofuran Temp Temperature UPLC or UHPLC High Performance Liquid Chromatography wts weight equivalent

[0038] Methods of the Invention In a first embodiment, the present invention provides a compound represented by structural formula III [ka] Regarding the process for forming This process is: A compound represented by structural formula (I) and a compound represented by structural formula (II) [ka] and a compound represented by structural formula (IIIa) in the presence of a catalyst, an organic base and an ether-containing solvent. [ka] reacting under conditions suitable for producing reacting, without isolation, the compound represented by structural formula (IIIa) with an inorganic base in the presence of isopropyl alcohol (IPA) under conditions suitable for producing the compound represented by structural formula (III); and isolating the compound represented by structural formula (III), Here, R is C2-C5 alkyl, C6-C 18 Aryl, 5-18 membered heteroaryl, C3-C 12cycloalkyl or 3-12 membered heterocycloalkyl, each of which is optionally and independently substituted with one or more substituents selected from halo, CN, OH, C1-C3 alkyl, C1-C3 haloalkyl, -NO2, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2 and C1-C3 alkoxy.

[0039] In a first aspect of the first embodiment, R is C2-C5 alkyl or C6-C 18 For example, R is C2-C5 alkyl, for example, R is isopropyl, or R is phenyl.

[0040] In a second aspect of the first embodiment, the catalyst is present in an amount of 0.05 to 0.2 molar equivalents based on the amount of the compound represented by Structural Formula I. For example, the catalyst is present in an amount of 0.1 molar equivalents based on the amount of the compound represented by Structural Formula I. The remainder of the values ​​and example values ​​for the process variables are as described above for the first aspect of the first embodiment.

[0041] In a third aspect of the first embodiment, the catalyst is selected from the group consisting of 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene. For example, the catalyst is DABCO. The remainder of the values ​​and example values ​​for the process variables are as described above for the first and second aspects of the first embodiment.

[0042] In a fourth aspect of the first embodiment, the organic base is present in an amount of 0.5 to 2 molar equivalents based on the amount of the compound represented by Structural Formula I, for example, the organic base is present in an amount of 1.0 molar equivalent based on the amount of the compound represented by Structural Formula I. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through third aspects of the first embodiment.

[0043] In a fifth aspect of the first embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, piperidine, pyridine, and 4-(dimethylamino)pyridine, for example, the organic base is DIPEA. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through fourth aspects of the first embodiment.

[0044] In a sixth aspect of the first embodiment, the ether-containing solvent is selected from the group consisting of MeTHF, CPME, and MTBE. For example, the ether-containing solvent is MeTHF. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through fifth aspects of the first embodiment.

[0045] In a seventh aspect of the first embodiment, the compound of structural formula II is present in an amount of 1.0 to 1.5 molar equivalents based on the amount of the compound of structural formula I. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixth aspects of the first embodiment.

[0046] In an eighth aspect of the first embodiment, the inorganic base is KOH or NaOH. For example, the inorganic base is KOH. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through seventh aspects of the first embodiment.

[0047] In a ninth aspect of the first embodiment, the invention relates to a process in which the conditions suitable for producing a compound represented by structural formula IIIa include reacting a compound represented by structural formula I with a compound represented by structural formula II at a temperature of from about 5° C. to about 55° C., such as from about 10° C. to about 40° C., such as from about 10° C. to about 30° C. (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30). The remainder of the values ​​and example values ​​for the process variables are as described above for the first through eighth aspects of the first embodiment.

[0048] In a tenth aspect of the first embodiment, suitable conditions for producing a compound represented by structural formula IIIa include reacting a compound represented by structural formula I with a compound represented by structural formula II for a period of about 5 hours to about 30 hours, such as about 10 hours to about 30 hours (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30). The remainder of the values ​​and example values ​​for the process variables are as described above for the first through ninth aspects of the first embodiment.

[0049] In an eleventh aspect of the first embodiment, suitable conditions for producing a compound of formula III include reacting a compound of formula IIIa with an inorganic base at a temperature of about 5° C. to about 55° C., such as about 10° C. to about 40° C., such as about 10° C. to about 30° C. (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30). The remainder of the values ​​and example values ​​for the process variables are as described above for the first through tenth aspects of the first embodiment.

[0050] In a twelfth aspect of the first embodiment, suitable conditions for producing a compound represented by structural formula III include reacting a compound represented by structural formula IIIa with an inorganic base for a period of time from about 1 hour to about 20 hours, such as from about 1 hour to about 10 hours (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), such as from about 2 hours to about 4 hours, etc. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through eleventh aspects of the first embodiment.

[0051] In a thirteenth aspect of the first embodiment, the present invention relates to a process further comprising a step of isolating the compound represented by structural formula III from the reaction mixture. For example, the present invention relates to a process further comprising a step of isolating the compound represented by structural formula III from the reaction mixture, the step comprising: (i) adding water and HCl to a reaction mixture containing a compound represented by structural formula III, thereby generating an aqueous phase and an organic phase; (ii) separating and optionally concentrating the organic phase, thereby producing a final organic phase; (iii) C5~C 12 adding a hydrocarbon solvent to the final organic phase, thereby producing a precipitate of the compound represented by structural formula III; and (iv) isolating the precipitate of the compound represented by formula III. For example, the precipitate is isolated by centrifugation or filtration. The remainder of the values ​​and example values ​​for the process variables are as described above for the first to twelfth aspects of the first embodiment.

[0052] In the fourteenth aspect of the first embodiment, 12 The hydrocarbon solvent is heptane. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through thirteenth aspects of the first embodiment.

[0053] In a fifteenth aspect of the first embodiment, C5 to C 12 The hydrocarbon solvent is isooctane. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through thirteenth aspects of the first embodiment.

[0054] In a sixteenth aspect of the first embodiment, the catalyst and organic base are present in a combined total amount less than 1 molar equivalent of the compound represented by structural formula II. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through fifteenth aspects of the first embodiment.

[0055] In a second exemplary embodiment, the present invention relates to a process as described herein above with respect to the first exemplary embodiment and the first to sixteenth aspects thereof, comprising the step of producing a compound represented by structural formula (IV): [ka] and a hydrazine represented by structural formula (V): H2NNH2(V) and a compound represented by structural formula (I): [ka] reacting under conditions suitable for producing Isolating the compound represented by structural formula (I) The process further comprises:

[0056] In a first aspect of the second exemplary embodiment, the step of reacting the compound represented by Structural Formula (IV) with the hydrazine represented by Structural Formula (V) is carried out in the presence of an organic acid, such as formic acid, acetic acid, or propionic acid. In one example, the organic acid is acetic acid. The remainder of the values ​​and example values ​​for the process variables are as described above with respect to the first through sixteenth aspects of the first embodiment.

[0057] In a second aspect of the second exemplary embodiment, the conditions suitable for producing a compound represented by structural formula (I) include reacting a compound represented by structural formula (IV) with a hydrazine represented by structural formula (V) at a temperature between 50° C. and 60° C. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixteenth aspects of the first embodiment and the first aspect of the second exemplary embodiment.

[0058] In a third exemplary embodiment, the present invention relates to a process as described herein above with respect to the first exemplary embodiment and the first to sixteenth aspects thereof, comprising the step of producing a compound represented by structural formula (III): [ka] and a hydrazine represented by structural formula (VI): [ka] and a compound represented by structural formula (VII) in the presence of a polar solvent, a second organic base, and a coupling agent. [ka] reacting under conditions suitable for producing exchanging the polar solvent for acetonitrile (ACN); and Crystallizing the compound of structural formula (VII) from ACN as crystalline form D. The process further comprises:

[0059] In a first aspect of the third exemplary embodiment, the second organic base is selected from the group consisting of DIPEA, Et3N, piperidine, pyridine, and 4-(dimethylamino)pyridine. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixteenth aspects of the first embodiment and the first and second aspects of the second exemplary embodiment.

[0060] In a second aspect of the third exemplary embodiment, the second organic base is DIPEA. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixteenth aspects of the first embodiment, the first and second aspects of the second exemplary embodiment, and the first aspect of the third exemplary embodiment.

[0061] In a third aspect of the third exemplary embodiment, the polar solvent is selected from the group consisting of C1-C6 alcohols, MeTHF, CPME, and MTBE, e.g., MeTHF. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixteenth aspects of the first embodiment, the first and second aspects of the second exemplary embodiment, and the first through second aspects of the third exemplary embodiment.

[0062] In a fourth aspect of the third exemplary embodiment, the coupling agent is selected from the group consisting of propylphosphonic anhydride (T3P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). For example, the coupling agent is T3P. The remainder of the values ​​and example values ​​for the process variables are as described above with respect to the first through sixteenth aspects of the first embodiment, the first and second aspects of the second exemplary embodiment, and the first through third aspects of the third exemplary embodiment.

[0063] In a fifth aspect of the third exemplary embodiment, the conditions suitable for producing a compound represented by structural formula (VII) include reacting a compound represented by structural formula (III) with a hydrazine represented by structural formula (VI) at a temperature between −25° C. and −15° C. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixteenth aspects of the first embodiment, the first and second aspects of the second exemplary embodiment, and the first through fourth aspects of the third exemplary embodiment.

[0064] In a sixth aspect of the third exemplary embodiment, the process further comprises recrystallizing Form D of the compound represented by Structural Formula (VII) in aqueous isopropyl alcohol (IPA) under conditions suitable for producing crystalline Form A of the compound represented by Structural Formula (VII). The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixteenth aspects of the first embodiment, the first and second aspects of the second exemplary embodiment, and the first through fifth aspects of the third exemplary embodiment.

[0065] In a seventh aspect of the third exemplary embodiment, suitable conditions for producing Form A of the compound represented by Structural Formula (VII) include: dissolving Form D in aqueous IPA, thereby producing a slurry; and holding the slurry at a temperature between 38° C. and 42° C. for a time period between 5 hours and 12 hours. The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixteenth aspects of the first embodiment, the first and second aspects of the second exemplary embodiment, and the first through sixth aspects of the third exemplary embodiment.

[0066] In a fourth exemplary embodiment, the present invention relates to a process as described herein above with respect to the first exemplary embodiment and the first to sixteenth aspects thereof, comprising: [ka] and a hydrazine represented by structural formula (V): H2NNH2(V) and a compound represented by structural formula (I): [ka] reacting under conditions suitable for producing isolating the compound represented by structural formula (I); Preparing a compound of formula (III) according to the process described herein (first embodiment and all aspects thereof), and [ka] and a hydrazine represented by structural formula (VI): [ka] and a compound represented by structural formula (VII) in the presence of a polar solvent, a second organic base, and a coupling agent. [ka] reacting under conditions suitable for producing exchanging the polar solvent for acetonitrile (ACN); and further comprising the steps of recrystallizing Form D of the compound of Structural Formula (VII) from ACN under conditions suitable for producing crystalline Form A of the compound of Structural Formula (VII). The remainder of the values ​​and example values ​​for the process variables are as described above for the first through sixteenth aspects of the first embodiment, the first and second aspects of the second exemplary embodiment, and the first through seventh aspects of the third exemplary embodiment. EXAMPLES

[0067] The compounds described in the following examples were identified and analyzed using UHPLC against standard reference compounds. The identity of polymorphic crystalline forms was confirmed and analyzed using XRPD.

[0068] Example 1. Development of a telescoping process for the synthesis of compounds represented by structural formula III. A telescoping process for the synthesis of compounds represented by formula III from compounds of formula I was developed as shown in Scheme 1.

[0069] Scheme 1 [ka] Telescoping stages I and II (Scheme 1) of the synthesis of the compound of formula III by eliminating the need for isolation of the compound of formula IIIa is highly desirable. Telescoping stages I and II allow for a more efficient process due to higher overall yields, shorter process times, and less handling of solvents and reagents. As described below, an unintended and unexpected combination of multiple reaction parameters was found, which allowed the discovery of a novel and highly favorable telescoping process.

[0070] As described below, the combination of catalyst, organic base and ether-containing solvent unexpectedly provided high conversion rate and stereoselectivity for Stage I of Scheme 1 (synthesis of compound represented by formula IIIa). Compound represented by formula IIIa was subjected to hydrolysis without isolation or purification (Stage II, Scheme 1). In Stage II of Scheme 1, inorganic base (e.g., KOH) was employed as hydrolysis reagent and IPA was employed as co-solvent to provide compound represented by formula III in unexpectedly high yield and stereoselectivity.

[0071] The disclosed process eliminates the need to isolate the intermediate compound represented by structural formula IIIa.

[0072] The experiment shown below illustrates the development of the telescoping process shown in Scheme 1. The compound represented by formula II in R=Ph (compound II-Ph) was selected for this experiment. The synthesis scheme is shown in Scheme 2. Scheme 2 illustrates two isomers of the compound represented by formula IIIa (R=Ph). As shown in Scheme 2, the reaction of the compound represented by formula I with the compound represented by formula II-Ph results in the formation of a mixture of the cis- and trans-isomers of the compound represented by formula IIIa, the compound represented by formula Z-IIIa-Ph and the compound represented by formula E-IIIa-Ph, where R is phenyl. Since the desired isomer is the Z-isomer (compound represented by formula Z-IIIa-Ph), efforts were focused on increasing the Z / E isomer ratio while simultaneously increasing the overall conversion rate of the reaction in Stage I.

[0073] Scheme 2. [ka] 1. Effect of DABCO volume on Stage I outcomes It has been demonstrated in the experiments described below that catalytic amounts of DABCO in the presence of an organic base such as DIPEA affords compounds of formula IIIa where R is phenyl in high conversion and stereoselectivity.

[0074] The effect of reducing the DABCO stoichiometry was investigated. Using DMF as the solvent, a 2:1 stoichiometry of the compound represented by formula II-Ph to the compound represented by formula I, and reducing the DABCO stoichiometry from 2, first to 1.1 and then to 0.1 based on the compound represented by formula I, improved the selectivity for stage I (Table 1, entries 1-3). In particular, reducing the DABCO stoichiometry to 0.1 resulted in an approximately 99:1 ratio of Z-IIIa-Ph to E-IIIa-Ph.

[0075] Furthermore, changing the reagent stoichiometry to 1 equivalent of compound represented by formula II-Ph, 1.5 equivalents of compound represented by formula I, and 1.1 equivalents of DABCO and lowering the temperature, first to 0°C-5°C and then to -25°C-20°C, had two notable effects. First, the selectivity for stage I increased with decreasing temperature (at 0-5°C, an 83:17 ratio of compound represented by formula Z-IIIa-Ph to compound represented by formula E-IIIa-Ph was observed, and at -20°C-25°C, a 95:5 ratio of compound represented by formula Z-IIIa-Ph to compound represented by formula E-IIIa-Ph was observed; Table 1, entries 4-5). Second, isomerization was observed to occur over time (Table 1, entries 4-6).

[0076] When the amount of DABCO was reduced to 0.95 equivalents for both the compound represented by formula II-Ph and the compound represented by formula I, good selectivity was observed and no isomerization was observed over time. This suggests that the isomerization of the double bond may be an effect related to the excess of free DABCO, where free DABCO is defined as not protonated and not containing excess iodoacrylate. Further review of the experiments (e.g., entries 4 and 5 compared to entries 3 and 7 in Table 1) showed that the isomerization of the compound represented by formula IIIa where R is phenyl was slower or stopped when the total amount of DABCO equivalents was less than 1 compared to the compound represented by formula II-Ph. This finding suggested that the reaction may be less susceptible when DABCO is inactivated (by binding to the double bond of the iodoacrylate or by being made into a hydroiodide salt) and is not available as a free base.

[0077] It has also been demonstrated that the yield and selectivity of the reaction in Stage I is particularly advantageously high when a catalyst (e.g., DABCO) and an organic base (e.g., DIPEA) are added to the reaction mixture, and when the total amount of equivalents of the catalyst and the organic base is less than 1 equivalent of the compound represented by structural formula II-Ph.

[0078] As an added advantage, under reaction conditions in the presence of catalytic amounts of DABCO, it was not necessary to use 2 equivalents of the compound represented by structural formula II-Ph to drive the reaction to completion: as little as 1.2 equivalents were found to be effective to give a conversion of 94% (Table 1, entry 8).

[0079] [Table 1]

[0080] The above experiments demonstrate that under certain conditions, catalytic amounts of DABCO in the presence of an organic base such as DIPEA affords compounds represented by structural formula IIIa, where R is phenyl, in high conversion and stereoselectivity.

[0081] 2. Effect of solvent on Stage I outcomes. Studies were carried out to determine the rate and stereoselectivity of conversion of stage I, and the effect of solvent on telescoping stages I and II.

[0082] Since DMF is not a desirable solvent for the hydrolysis conditions in Stage II, other solvents were investigated for Stage I. The experiments described below showed that MeTHF was the favored solvent for Stage I, resulting in high conversion and selectivity.

[0083] The effect of solvent polarity in the Stage I reaction was examined. Decreasing the polarity of the solvent (from DMF to toluene or MeTHF) resulted in an improvement in the ratio of the compound represented by the structural formula Z-IIIa-Ph to the compound represented by the structural formula E-IIIa-Ph (from approximately 80:20 in the case of DMF to as high as 95:5 in the case of MeTHF, as shown in Table 1, entry 8 (see Table 2)). As the polarity of the solvent decreased, both the desired reaction rate and the isomerization rate decreased. Compared to toluene, MeTHF resulted in higher selectivity and comparable activity (Table 2, entries 2-4). Due to the high conversion and selectivity of the Stage I process by using MeTHF and carrying out the reaction at room temperature, the possibility of using this solvent as a carrier in a telescoping process to link the process in Stage I with a subsequent hydrolysis step in Stage II was presented.

[0084] [Table 2]

[0085] The use of MeTHF as a solvent in Stage I results in high conversion and selectivity of the compound represented by formula IIIa, thus providing an opportunity for telescoping of Stage I and Stage II, thus avoiding the step of isolating the compound represented by formula IIIa and the associated loss of material.

[0086] 3. Effect of metal hydroxides and co-solvents in stage II. With reference to Scheme 3, Stage II, experiments were carried out to determine different combinations of inorganic bases and solvents. Inorganic bases such as NaOH and KOH, when used as hydrolysis reagents, and IPA, when used as a co-solvent with MeTHF and water, were found to provide compounds of formula III with favorable yields and stereoselectivities.

[0087] Scheme 3. [ka] Lithium hydroxide was initially chosen as the hydrolysis reagent because it provides favorable reaction kinetics and is frequently used in ester hydrolysis processes. The hydrolysis of compounds represented by formula IIIa-iPr with lithium hydroxide (5 equivalents) in MeTHF is relatively slow in the absence of IPA or other phase transfer agents (Table 3, entries 1-4). This process also involved significant isomerization, which resulted in the production of undesired compounds represented by formula E-III.

[0088] Also, LiOH is not a preferred reagent for pharmaceutical applications. Because Li salts are themselves pharma- ceutical active compounds, Li levels must be closely monitored in pharmaceutical intermediates and final products made with LiOH. Thus, NaOH and KOH were tested as alternatives to LiOH (Table 3, entries 5–12, 17–24).

[0089] IPA was tested as a co-solvent due to its ability to promote the reaction between the organic and aqueous phases by imparting partial miscibility. The presence of IPA as a co-solvent significantly improved the success of the hydrolysis process (Table 3, entries 13-24).

[0090] [Table 3]

[0091] In this experiment, the Stage I reaction was carried out under the following conditions: The compound of formula I (12 g) and DABCO (0.1 equivalent, 0.48 g) were dissolved in MeTHF, followed by the addition of the compound of formula II-iPr (1.2 equivalent, 12.3 g) and DIPEA (1.0 equivalent, 7.4 mL). The reaction mixture was stirred for 20 hours and then washed with 5 volume equivalents of water (relative to the volume of the compound represented by structural formula I). An aliquot was taken (1 / 6 of the reaction mixture) and treated with reagents according to the hydrolysis conditions in Table 3.

[0092] The data in Table 3 show that compared to LiOH, both NaOH and KOH improved the hydrolysis rate of compounds represented by formula IIIa-iPr while maintaining low levels of Z / E isomerization, and that IPA improved both the conversion and stereoselectivity for Stage II of Scheme 3.

[0093] Example 2. Synthesis of compounds represented by structural formula III. The following examples disclose the synthesis of the compound represented by formula III on a 1.0 kg scale. The compound represented by formula III is synthesized in 72-75% yield with a purity of >99% (UPLC). Under a nitrogen atmosphere, 1,000 kg of the compound represented by formula I (1 equivalent), 40 g of DABCO (0.1 equivalent), and 2,559 kg of MeTHF were charged into a 50 L glass reactor, and the mixture was stirred to dissolve. To this mixture was added 1,040 kg of a compound represented by formula II, where R is an isopropyl group (1.2 equivalents), and the funnel was rinsed with 0.853 kg of MeTHF. To this mixture was added 460 g of DIPEA (1.0 equiv.) via addition funnel, and the funnel was rinsed with 0.853 kg of MeTHF. The mixture was stirred at 20-25°C for 16 hours and then sampled to check for completion of the reaction. To this vessel, 5.0 kg of DD water was added with gentle stirring and maintaining the temperature at 20-25°C, and the resulting mixture was stirred for 20 minutes. Stop stirring and allow the layers to separate. Remove and discard the lower aqueous layer. To the upper organic layer was added a solution of 30g 37% HCl in 2,975kg water followed by 1.18kg brine with gentle stirring and maintaining the temperature at 20-25°C. The mixture was stirred for 20 minutes at 20-25°C, then stirring was stopped and the layers were allowed to separate. The lower aqueous phase was removed and discarded. · 1.57 kg of IPA was added to the vessel with gentle stirring at 20-25°C. To this reaction mixture was added a solution of 1,174 kg (5 eq.) KOH in 5.0 kg DD water with gentle stirring and maintaining the temperature at 20-25°C. The mixture was stirred at 20-25°C for 3 hours and then sampled to check for completion of the reaction. Once the reaction was complete, 5,935 kg of brine was added to the mixture with gentle stirring. The batch was stirred vigorously for 20 minutes at 20-25°C. The stirring was then stopped and the layers were allowed to separate. The lower aqueous layer was separated and discarded. To the organic layer, 1,998 kg of DD water was added with vigorous stirring, followed by stirring for 20 minutes. Under vigorous stirring, the pH of the mixture (lower phase) was adjusted with 0.934 kg of 5 M HCl solution (aq.) to a target of 0–2. With gentle agitation, the batch temperature was increased to 50-55°C and agitation was maintained for 20 minutes. The lower aqueous layer was separated and discarded while maintaining the temperature at 50-55°C. The retained organic phase was cooled to 0-5°C and then distilled to a target volume of 3 L. Once distillation was complete, the batch temperature was increased to 50-55°C and held at that temperature for 1 hour. · 5,645 kg of isooctane was added to the vessel over a minimum of 30 minutes while maintaining the temperature at 50-55°C and with gentle agitation. Following the addition of isooctane, the temperature was adjusted to 20-25°C over a minimum of 60 minutes and then held at 20-25°C for a minimum of 1 hour. · The batch was cooled to 0-5°C over a minimum of 1 hour and then held at that temperature for at least 1 hour. The batch was filtered and the filter cake was washed with 2,145 kg of isooctane at 0-5°C. The filtered product was dried on the filter under a stream of nitrogen until dry. The compound represented by formula III had a yield of 72-75% and a purity of >99% (UPLC).

[0094] Example 3. Synthesis of compounds represented by structural formula III. The following example discloses the synthesis of the compound represented by formula III on a 100 kg scale. The compound represented by formula III is synthesized in 75±10% yield with a purity of more than 99.7% (UPLC). In contrast to example 2, in which the solid of the compound represented by formula III is precipitated with isooctane, in this example, the solid of the compound represented by formula III is precipitated with heptane. A clean, inert, glass-lined, 4000 L reactor was charged with the compound of formula I (1 eq.), DABCO (0.1 eq.) and MeTHF, and the resulting mixture was stirred at 15 / 20° C. for at least 15 minutes under nitrogen atmosphere to dissolve. The temperature of the mixture was adjusted to 10 / 20° C. and a compound represented by the formula II, where R is an isopropyl group (1.2 equivalents), was added. The mixture was then charged with a MeTHF rinse. DIPEA (1.0 equiv.) was added to this mixture at 10 / 20°C (target temperature of 10°C) followed by a MeTHF rinse at 10 / 20°C. The resulting reaction mixture was stirred at 15° C., adjusting the stirring speed as needed to maintain vigorous stirring of the mixture, until the reaction was determined to be complete (at least 12 hours). The reaction mixture was kept at 15°C with stirring for at least 2 hours. Water was added to the reaction mixture whilst maintaining a mixture temperature of 10 / 25° C. The mixture was stirred at 15 / 20° C. for at least 15 minutes, allowed to separate and the lower first aqueous phase was removed. The remaining organic phase was transferred to a new dry, inert 6000 L glass-lined reactor, followed by a MeTHF rinse. In a clean, inert, glass-lined reactor, prepare a quenching solution by charging water, sodium chloride, and hydrochloric acid and mixing for at least 30 minutes at 15 / 25°C until dissolved. The prepared quench solution was added to the second reactor (6000 L reactor) containing the organic phase and mixed for at least 15 minutes at a mixture temperature of 15 / 20°C (little or no exotherm). The mixture was left to stand for at least a further 15 minutes at 15 / 20°C to allow the aqueous and organic layers to separate. The aqueous phase was removed, leaving the interfacial phase with the organic phase, if present. The reactor was rinsed with water and dried, then water and KOH were charged and mixed for at least 30 minutes at 15 / 25°C. · IPA was added to the organic phase in the 6000 L reactor and the mixture was stirred for 5-10 minutes at 15 / 25°C. At 15° C., the water / KOH solution from the third reactor was added to the organic phase while maintaining the temperature of the second reactor at 15 / 25° C. (the addition was exothermic), thereby forming a reaction mixture. The reaction mixture in the 6000 L glass-lined reactor was then stirred at 20 / 25° C. under nitrogen for at least 2 hours and then sampled. If unsuccessful, the reactor was continued to stir at 20 / 25° C. under nitrogen for at least another 2 hours to form the compound represented by structural formula III. If successful, the reaction was quenched. In a separate reactor, add water and sodium chloride and stir for at least 30 minutes at 15 / 25°C until dissolved. The sodium chloride solution was charged to the reaction mixture and stirred vigorously for at least 15 minutes at 15 / 25°C, then allowed to stand for at least 15 minutes. The aqueous phase was removed, leaving the interfacial phase and the organic phase, if present. The reactor was rinsed with water and dried, then water and HCl were charged and mixed for at least 10 minutes at 20 / 25°C. · To the organic phase in a 6000L reactor, water was added at 15 / 25°C and held without stirring for 5-10 minutes and the total volume was recorded. ·Resume stirring and add the required amount of HCl solution to achieve a target pH of 0.5-2.0 and mix for at least 10 minutes at 15 / 25°C. The mixture was heated at 50 / 55° C. until the compound represented by structural formula III was solubilized, stirred for 10 minutes, and then allowed to stand for at least 15 minutes (bulk temperature 50 / 55° C.). The aqueous phase was removed and the interfacial phase was left with the organic layer and discarded. The organic phase was cooled to 30 / 40°C under reduced pressure and concentrated to approximately 3 volume equivalents. Once the concentration process was complete, the final organic phase was heated to 50 / 55°C. Over 1 hour, 99% heptane was added to the final organic phase in the second reactor at an internal temperature of 50 / 55°C. The mixture was cooled to 0 / 5°C over at least 3 hours and stirred at said temperature for at least 1.5 hours. A cake rinse was prepared by combining MeTHF and 99% heptane. The slurry was centrifuged into a series of equal cakes, and each cake was washed with a MeTHF / heptane mixture. The compound represented by formula III was transferred to a stirred dryer and dried under reduced pressure until the product was dry and homogeneous in appearance. The compound represented by formula III was obtained in 75±10% yield, >99:1 Z / E ratio, and >99.7% purity.

[0095] Example 4: Synthesis of compounds represented by structural formula (I) Synthetic Scheme 3 [ka] Compound (IV) and acetic acid 99% (4.2 wts) were charged into a clean inert glass lined reactor with a headspace of nitrogen atmosphere and kept at or below 25 / 35° C. with stirring until compound (IV) was dissolved.

[0096] The bulk temperature was adjusted to 20 / 25°C then 1.4 molar equivalents of hydrazine monohydrate (compound (V)) stock solution (0.225 wts) was charged (exotherm) to the vessel at NMT for 90 minutes while maintaining the temperature at 20 / 30°C.

[0097] Once the addition was complete, the batch temperature was raised to 55° C. and stirred (80 rpm) for at least 5-16 hours until the reaction was complete (as determined by UHPLC).

[0098] Once the reaction was determined to be complete, crystallization was induced by slowly and uniformly adding demineralized or purified water (referred to as "water" in the following description) (5 wts) to the mixture over a minimum period of 2.5 hours while maintaining the internal temperature at 55°C with stirring.

[0099] An additional 5 wts of water was added to the mixture over a minimum period of 1 hour at a temperature range set point of 55°C.

[0100] The mixture was stirred for at least 30 minutes at 55° C. After nucleation was confirmed, the crystallization was allowed to slowly cool to 20 / 25° C. over a minimum period of 3 hours, where it was stirred at 20 / 25° C. for at least 1 hour.

[0101] The Compound (I) product was isolated by centrifugation, washed with water (12 wts), transferred to a stirred dryer and dried under reduced pressure until dry and homogeneous. Drying was continued until the water and solvent content met specifications.

[0102] The dried product is cooled to < 30°C and packaged.

[0103] Example 5: Synthesis of Compound Form D represented by Structural Formula (VII) Synthetic Scheme 5 [ka] Compound (III), compound (VI) (0.335 wts±2%) and MeTHF (5.8 wts) were charged into a 4000 L dry inert glass-lined reactor and the mixture was stirred for 15 minutes at NLT, 15 / 20° C. under a nitrogen atmosphere.

[0104] The mixture was cooled to −20 / −25° C. DIPEA (0.846 wts±2%) was then added to the mixture with a MeTHF rinse (0.26 wts) while maintaining the temperature between −20 / −25° C. (exothermic).

[0105] Commercially available 50% propylphosphonic anhydride (T3P®) solution (1.22 wts ± 2% based on T3P® stock solution) was slowly added to this mixture over NLT 6 h at a temperature of NMT -20°C, followed by a MeTHF (0.86 wts) rinse. The mixture was stirred for NLT 30 min between -20 / -25°C under nitrogen atmosphere, after which the temperature of the mixture was adjusted to 10 / 15°C with rapid stirring. Once temperature was reached, samples were taken to monitor the reaction (UHPLC with known standards).

[0106] If the reaction was compatible by UHPLC, it was diluted with MeTHF (0.43 wts) and quenched with purified water (5 vol) at 10 / 15° C. with stirring.

[0107] The biphasic mixture was stirred for NLT 15 min at 15 / 25° C. and then the layers were allowed to settle for at least 30 min at 15 / 25° C. after which the aqueous layer (bottom) was removed.

[0108] The interphase and the organic layer, retained if present, were washed with water (4.7 vol) and sodium chloride (0.3 wts) under vigorous stirring at 15 / 25° C. for NLT 25 min.

[0109] The mixture was allowed to stand for NLT 30 min at 15 / 25° C., after which the aqueous layer (bottom) and interfacial phase, if present, were removed. The remaining organic phase was stirred slowly for 5 min at NMT 15 / 25° C., allowed to stand for NLT 15 min and any additional settled aqueous phase was removed.

[0110] The organic layer was put under vacuum and the mixture was heated to 35 / 45° C. with a jacket temperature of 55° C. NMT. ​​The mixture was concentrated at 20 / 45° C. until a residual volume of 5 volumes was reached.

[0111] Once the concentration process was complete, the temperature of the mixture was cooled to 20 / 25°C.

[0112] The organic mixture was filtered and transferred to a concentration vessel with a MeTHF rinse (0.43 wts).

[0113] The MeTHF solution was heated to 35 / 45° C. with a jacket temperature of NMT 55° C. and filtered ACN (7.8 wts) was added. During concentration, the temperature of the mixture was maintained at 20 / 45° C. with a jacket temperature of NMT 55° C. until approximately 10 volumes were reached, while solvent exchange was performed via distillation.

[0114] Filtered ACN (3.9 wts) was added to the organic concentrate and held for NLT 15 min at 20 / 45° C. The mixture was concentrated under reduced pressure at 20 / 45° C. with a jacket temperature of NMT 55° C. until approximately 10 volumes were reached.

[0115] The charge of filtered ACN (3.9 wts) was repeated and the mixture was concentrated to 10 volumes, after which filtered ACN (3.9 wts) was added and stirred for 15 min NLT, 20 / 45°C.

[0116] Once the MeTHF content met specification (determined by GC), the organic mixture was heated to 65±2° C. with a jacket temperature of 75° C. NMT and held for 15 / 30 minutes.

[0117] The organic mixture was transferred to the crystallization vessel along with an ACN (16 kg) rinse. The temperature of the mixture was adjusted if necessary to 65±2° C. and held for 15 / 30 minutes.

[0118] The mixture was cooled to 20 / 25° C. over NLT 3 hours, stirred at 20 / 25° C. for 1-2 hours, then the mixture was further cooled with stirring over NLT 3 hours to 0 / 5° C. The mixture was held at 0 / 5° C. for NLT 1 hour.

[0119] The crystallization mixture was centrifuged into a series of equal cakes (maximum cake size of 30 kg wet cake) and each cake was washed with chilled filtered ACN (141 kg / 180 L). A cake wash of 141 kg / 180 L was equivalent to 10 volumes NLT of ACN (if the cake was 30 kg or less).

[0120] The mother liquor and washes were removed. After 4-6 hours of gentle agitation at atmospheric pressure and ambient temperature, the filter cake was dried under reduced pressure (jacket temperature of 45°C NMT) until the product was dry and homogenous in appearance. The process was completed when the loss on drying criteria were met.

[0121] Example 6: Conversion of Crystalline Isomorph Forms of the Compound Represented by Structural Formula (VII); Preparation of Form A Form D and Form A referred to herein are Form A and Form D described in US Pat. No. 10,519,139, the entire contents of which are incorporated herein by reference.

[0122] Synthetic Scheme 6 [ka] Compound (VII) Form D was charged into a 4000 L dry, inert, glass-lined reactor with filtered IPA (2.4 wts) and stirred. Purified water (3 wts) was added to the mixture.

[0123] The temperature was increased and then held at 40±2° C. for at least 5 hours and not more than 12 hours to effect isomorphic transformation from Form D to Form A.

[0124] The slurry was then cooled to 15 / 20°C over at least 1 hour and purified water (10 wts) was added at 15 / 20°C with stirring.

[0125] The mixture followed by a water rinse (200 L) was transferred to a 6000 L dry, inert, glass-lined reactor and the temperature was maintained at 15 / 20° C. with mixing for at least 1 hour.

[0126] In a separate reactor, filtered IPA (0.79 wts) and water (4 wts) were added and stirred for a minimum of 10 minutes, then the solvent mixture was transferred to a clean dedicated vessel for cake washing.

[0127] A minimum number of centrifuge cakes was calculated to ensure that the size of each individual cake was no more than 40 kg wet cake, and the slurry was centrifuged into approximately equal cakes each no more than 40 kg.

[0128] Each of the centrifuge cakes was washed with a volume of the IPA / water solution (150 L) and then removed from the centrifuge.

[0129] The mother liquor and washes were collected. A portion of the mother liquor could be used to rinse the remainder of the centrifuge if necessary. The filter cakes were pooled and dried under vacuum (maximum jacket temperature of 45° C.) until the product was dry and homogenous in appearance.

[0130] The relevant teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

[0131] Although the present invention has been particularly shown and described with reference to illustrative embodiments thereof, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as encompassed by the appended claims. The aspects of the present invention include the following. Item 1 Compounds represented by structural formula III

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Claims

1. Compounds represented by structural formula III 【Chemistry 1】 1. A process for forming a compound comprising: A compound represented by structural formula I and a compound represented by structural formula II 【Chemistry 2】 and 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst in the presence of an organic base selected from Et 3 N, diisopropylethylamine (DIPEA), piperidine, pyridine, and 4-dimethylaminopyridine (DMAP) and a solvent, 2-methyltetrahydrofuran (MeTHF), to obtain a compound represented by the structural formula IIIa. 【Chemistry 3】 wherein DABCO is present in an amount of 0.05 to 0.2 molar equivalents based on the amount of the compound represented by structural formula I; reacting, without isolation, the compound represented by formula IIIa with an inorganic base in the presence of isopropyl alcohol (IPA) to produce a compound represented by formula III, wherein the inorganic base is LiOH, NaOH or KOH; and isolating the compound represented by formula III; Here, R is C ２ ~C ５ Alkyl or C ６ ~C １８ The process wherein the compound is aryl.

2. 2. The process of claim 1, wherein R is isopropyl or phenyl.

3. 3. The process of claim 1, wherein the catalyst and the organic base are present in a combined amount less than 1 molar equivalent of the compound represented by structural formula II.

4. 4. The process of claim 1, wherein the catalyst is present in an amount of 0.1 molar equivalent based on the amount of the compound represented by structural formula I.

5. 5. The process of claim 1, wherein the organic base is present in an amount of 0.5 to 2 molar equivalents based on the amount of the compound represented by structural formula I.

6. 6. The process of any one of claims 1 to 5, wherein the organic base is present in an amount of 1.0 molar equivalent based on the amount of the compound represented by structural formula I.

7. The process of any one of claims 1 to 6, wherein the organic base is DIPEA.

8. 8. The process of any one of claims 1 to 7, wherein the amount of the compound of formula II is 1.0 to 1.5 molar equivalents based on the amount of the compound of formula I.

9. The process of claim 1, wherein the step of reacting a compound represented by structural formula I with a compound represented by structural formula II to produce a compound represented by structural formula IIIa comprises reacting the compound represented by structural formula I with the compound represented by structural formula II at a temperature between 5°C and 55°C.

10. The process of claim 1, wherein the step of reacting a compound represented by structural formula IIIa with an inorganic base to produce a compound represented by structural formula III comprises reacting the compound represented by structural formula IIIa with an inorganic base at a temperature between 5°C and 55°C.

11. The process of any one of claims 1 to 10, further comprising isolating the compound represented by structural formula III from a reaction mixture.

12. The steps of isolating the compound represented by structural formula III include: (i) adding water and HCl to the reaction mixture containing the compound represented by structural formula III, thereby generating an aqueous phase and an organic phase; (ii) separating and optionally concentrating the organic phase, thereby producing a final organic phase; (iii) C ５ ~C １２ adding a hydrocarbon solvent to the final organic phase, thereby producing a precipitate of the compound represented by structural formula III; and (iv) isolating said precipitate of the compound represented by structural formula III. The process of claim 11 , comprising:

13. Said C ５ ~C １２ 13. The process of claim 12, wherein the hydrocarbon solvent is heptane or isooctane.

14. Compounds represented by structural formula IV 【Chemistry 4】 and a hydrazine represented by structural formula V H ２ NNH ２ V to produce a compound represented by structural formula I 【Chemistry 5】 generating isolating the compound represented by formula I. The process of any one of claims 1 to 13, further comprising:

15. 15. The process of claim 14, wherein the step of reacting the compound represented by structural formula IV with the hydrazine represented by structural formula V is carried out in the presence of an organic acid selected from formic acid, acetic acid, or propionic acid.

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