Process for preparing ivosidenib and its intermediates

Abstract

The present application relates to a substantially and diastereomerically pure crystalline ethanol solvate of compound IIa and its use for synthesizing ivosidenib.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 884,480, filed August 8, 2020, the disclosure of which is incorporated herein by reference. [Background technology]

[0002] Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymes belong to two different subclasses, one of which utilizes NAD(+) and the other NADP(+) as the electron acceptor. Five isocitrate dehydrogenases have been described: three NAD(+)-dependent isocitrate dehydrogenases localized in the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other is mainly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.

[0003] IDH1 (Isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is an NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal localization signal sequence. The presence of this enzyme in peroxisomes suggests a role in the regeneration of NADPH for reduction within peroxisomes (such as the conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA) and in peroxisomal reactions that consume 2-oxoglutarate, namely the α-hydroxylation of phytanic acid. The cytosolic enzyme plays an important role in cytosolic NADPH production.

[0004] The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences of human IDH1 can be found in GenBank entry numbers NM_005896.2 and NP_005887.2, respectively. The nucleotide and amino acid sequences of IDH1 are also described, for example, in Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et al., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res. 11:422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al., Submitted (DEC-2008) to UniProtKB; Kullmann et al., Submitted (JUN-1996) to the EMBL / GenBank / DDBJ databases; and Sjoeblom et al., Science 314:268-274(2006).

[0005] Mutations in IDH1 present in certain cancer cells have been found to confer a novel ability for the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44).

[0006] IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) is also known as IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is an NADP(+)-dependent isocitrate dehydrogenase found in mitochondria. It plays a role in intermediary metabolism and energy production. This protein may be strongly associated with or interact with the pyruvate dehydrogenase complex. The human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences of IDH2 can be found in GenBank entry numbers NM_002168.2 and NP_002159.2, respectively. The nucleotide and amino acid sequences of human IDH2 are also described, for example, in Huh et al., Submitted (NOV 1992) to the EMBL / GenBank / DDBJ databases; and The MGC Project Team, Genome Res. 14:2121-2127(2004).

[0007] Non-mutant, eg, wild-type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG).

[0008] It has been discovered that mutations in IDH2 present in certain cancer cells result in the enzyme's novel ability to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), which is not formed by wild-type IDH2. The production of 2HG is thought to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739-44).

[0009] Mutations in IDH1 or IDH2 occur in more than 70% of diffuse low-grade glioma (LGG) tumors. IDH mutations result in the accumulation of 2-HG, which is thought to promote tumorigenesis through DNA hypermethylation, increased repressive histone methylation, and inhibition of differentiation processes. Studies conducted with a tool compound known as AGI-5198, which has been shown to inhibit mutant IDH1 (mIDH1) but not mutant IDH2 (mIDH2), have demonstrated that inhibition of mIDH1 protein can suppress mIDH1-induced glioma growth in several model systems (D. Rohle et al. Science 340:626-630 (2013)).

[0010] No. 9,474,779 B2 and U.S. Pat. No. 9,968,595 B2, which are incorporated herein by reference in their entireties, disclose a compound having the chemical name (S)-N-((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide, which has been shown to act as an inhibitor of mutant IDH1 protein in biochemical and cellular assays. Depending on the naming convention, this compound may also be called (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide. Furthermore, in 2015, the compound was assigned the following INN: ivosidenib. The structure of ivosidenib is compound I: [ka] As described herein.

[0011] There is a need for an efficient and large-scale manufacturing method for preparing Compound I, which is used to treat patients with hematological malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), myelodysplastic / myeloproliferative neoplasms, chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL) or lymphomas (e.g., T-cell lymphomas), or solid tumors, such as glioma, cholangiocarcinoma, chondrosarcoma, prostate cancer, colon cancer, melanoma, or non-small cell lung cancer (NSCLC), each characterized by the presence of a mutant allele of IDH1. In some embodiments, the hematological malignancies are relapsed or refractory; in other embodiments, the hematological malignancies are newly diagnosed or the patient is refractory to intensive induction chemotherapy. In some embodiments, the hematological malignancies are relapsed or refractory acute myeloid leukemia (AML). In another embodiment, the hematological malignancy is newly diagnosed acute myeloid leukemia (AML). In another embodiment, the solid tumor is cholangiocarcinoma. In yet another embodiment, the cholangiocarcinoma is selected from intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, and distal cholangiocarcinoma. In yet another embodiment, the patient has chondrosarcoma. In another embodiment, the hematological malignancy or solid tumor is advanced.

[0012] Summary of the Invention In one aspect, the present application provides a method for preparing compound I, comprising: Compound IIa: [ka] isolating a crystalline ethanol solvate of The method includes converting the crystalline ethanol solvate of compound IIa to compound I or a solvate thereof. In some embodiments, the crystalline ethanol solvate of compound IIa is substantially chemically and diastereomerically pure. The substantially chemically and diastereomerically pure crystalline ethanol solvate of compound IIa is also called "Form A ethanol solvate of compound IIa". In some embodiments, compound I is obtained as an isopropyl acetate solvate, which can be converted to other solvates, as well as to non-solvated or anhydrous solid forms.

[0013] In another aspect, the present application relates to a method for preparing Form A ethanol solvate of compound IIa, comprising suspending or dissolving a mixture of compounds IIa and IIb in a solution of a base and an ethanol solvent system, adding a non-polar solvent, and isolating said Form A ethanol solvate of compound IIa. As used herein, the term "suspending" means contacting a substance with a solvent or mixture of solvents such that the suspended substance is at least partially dissolved.

[0014] In another aspect, the present application relates to a crystalline Form A ethanol solvate of Compound IIa itself. In some embodiments, Form A ethanol solvate is substantially chemically pure. In other embodiments, Form A ethanol solvate is substantially diastereomerically pure. In other embodiments, Form A ethanol solvate is substantially chemically and diastereomerically pure. [Brief description of the drawings]

[0015] [Figure 1] FIG. 2 is the X-ray powder diffraction diagram (XRPD) of Form A of the ethanol solvate of Compound IIa. [Diagram 2] 1 includes differential scanning calorimetry (DCS) and thermogravimetric analysis (TGA) profiles of Form A of the ethanol solvate of Compound IIa.

[0016] Figures and Detailed Description of Various Embodiments In one aspect, the present application provides a compound of formula II: [ka] The mixture of compounds of formula IIa is stereochemically enriched to give compound IIa: [ka] The present invention relates to a method for providing an ethanol solvate of compound IIa as a substantially chemically and diastereomerically pure crystalline material. As used herein, the term "substantially chemically and diastereomerically pure" compound IIa refers to an ethanol solvate of compound IIa having a diastereomeric excess of at least about 90% and a chemical purity of at least about 80%. In some embodiments, the substantially diastereomerically pure crystalline ethanol solvate of compound IIa has a diastereomeric excess of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least 99.7%, at least 99.8%, at least 99.9% (or any percentage between 90% and 100%). As used herein, in relation to chemical purity, the term "about" means ±0.5%. As used herein, in relation to diastereomeric excess, the term "about" also means ±0.5%. As used herein, diastereomeric excess (or de%) is calculated according to the following formula:

number

[0017] In other embodiments, the crystalline ethanol solvate of Compound IIa has a chemical purity of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least 99.7%, at least 99.8%, at least 99.9% (or any percentage between about 90% and about 100%) based on the weight of Compound IIa (on an unsolvated or anhydrous basis). In relation to chemical purity, it is to be understood that the remaining weight percentage generally includes other substances, such as reaction impurities, starting materials, reagents, by-products, and / or other process impurities (those arising in the preparation and / or isolation and / or purification steps). For example, the crystalline ethanol solvate of Compound IIa may be considered to be substantially chemically pure if it is determined to have a chemical purity of greater than about 80% by weight, as measured by standard and generally accepted methods known in the art. In this case, the remaining weight percentage of less than about 20% constitutes other substances, such as other reaction impurities, starting materials, reagents, by-products, and / or process impurities. Chemical purity may be measured by methods known in the art, such as high performance liquid chromatography (HPLC), LC-MS (liquid chromatography-mass spectrometry), nuclear magnetic resonance (NMR) spectroscopy, or infrared spectroscopy. Those skilled in the art will readily understand these methods and how to use these additional (or alternative) methods to determine or evaluate chemical purity.

[0018] More specifically, the present application relates to a method for stereochemically enriching a mixture of compounds of formula II to provide Form A ethanol solvate of compound IIa as an isolated crystalline material having a diastereomeric excess of at least about 90%, at least about 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0019] As used herein, the terms "mixture comprising a compound of formula II" and "mixture of compounds of formula II" are intended to encompass a mixture of compounds IIa and IIb, where IIa and IIb are present in a ratio between 1:99 and 99:1. In some embodiments, the mixture of compounds of formula II may be a racemic mixture. In other embodiments of the mixture of compounds of formula II, compound IIb may comprise more than 50% of the mixture. In further embodiments of the mixture of compounds of formula II, compound IIa may comprise more than 50% of the mixture, but less than 100% of the mixture.

[0020] It has been found that the ethanol solvate of compound IIa can be selectively crystallized from a mixture of compounds of formula II to provide a substantially chemically and diastereomerically pure ethanol solvate of compound IIa. Selective crystallization allows the ethanol solvate of compound IIa to be isolated with an excess of diastereomers. As used herein, the terms "provide", "isolate", "isolated" and "isolation" refer to obtaining and physically separating compound I, or a solvate thereof, or an ethanol solvate of compound IIa from a reaction mixture. As used herein, the term "about" means ±0.5%. Isolation of any of the compounds described herein, including compound I, or a solvate thereof, or an ethanol solvate of compound IIa, can be achieved using any method known to those skilled in the art for separating solid materials from liquids. An example of a suitable separation technique for isolating compound I, or a solvate of compound I, or an ethanol solvate of compound IIa includes filtration.

[0021] As used herein, a "solvate" refers to a crystalline form of a molecule, atom, and / or ion that further comprises one or more molecules of a solvent incorporated into a crystal lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and / or a non-regular arrangement. The solvate may comprise either a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate or may result directly from a crystallization process. Alternatively, the solvate may occur as a dimer or oligomer containing two or more molecules or may occur within a crystal lattice structure.

[0022] As used herein, the terms "nonsolvate," "nonsolvated," or "anhydrous" refer to a crystalline form that does not have one or more molecules of a solvent incorporated into the crystal lattice structure.

[0023] Compounds IIa and IIb contain a CH group that is susceptible to epimerization and interconversion of stereochemical conformation at the chlorophenyl-substituted carbons of compounds IIa and IIb. When compound IIa is depleted from the solution phase of the crystallization mixture (due to the selective crystallization of compound IIa), an epimerization reaction converts compound IIb to compound IIa (and vice versa). The epimerization reaction is unlikely to be stereoselective due to the distal relationship from the second chiral center (excluding potential minor effects or steric factors from the second chiral center), so that a nearly 50 / 50 mixture of IIa / IIb is likely to be maintained in the solution phase. At the same time, in some cases, compound IIa has been found to be less soluble than compound IIb and therefore preferentially precipitates from solution, so that the solid phase is enriched with compound IIa (a phenomenon referred to herein as stereochemical enrichment). Thus, it has been discovered that by combining the epimerization reaction with selective crystallization, the resulting "dynamic crystallization" process described herein stereochemically enriches the starting mixture of diastereomers (compounds IIa and IIb) with compound IIa (which is then isolated), thus resulting in a higher yield of compound IIa than would be theoretically possible based on the amount of compound IIa in the starting mixture of diastereomers. For example, if a 10 gram mixture of compounds of formula II contains about 5 grams each of compounds IIa and IIb, the dynamic crystallization process described above potentially allows for the isolation of an amount of compound IIa greater than 5 grams.

[0024] In some embodiments, compound IIa is crystallized from an ethanol solvent system in the presence of a base to provide a substantially chemically and diastereomerically pure ethanol solvate of compound IIa. As used herein, the term "ethanol solvent system" refers to any solvent mixture that contains at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, or at least 98% ethanol by volume. In some embodiments, the ethanol solvent system contains 100% ethanol. In some embodiments, the ethanol solvent system does not include toluene, trifluoroethanol (TFE), acetonitrile, N,N-dimethylformamide (DMF), methyl acetate, or MTBE, or any mixtures thereof, unless the ethanol solvent system contains at least 30% (by volume) ethanol.

[0025] In certain embodiments, the base is a primary, secondary or tertiary amine. Suitable bases include 1,5,7-triazabicyclo[4.4.0]dec-5-ene ("TBD"), 1,5-diazabicyclo[4.3.0]non-5-ene ("DBN"), triethylamine, diisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N-methyl-piperazine, pyridine, butylamine, dibutylamine, or 1,5-diazabicyclo(4.3.0)non-5-ene, or combinations thereof.

[0026] The dynamic crystallization process may be carried out at a temperature of -5 to 25°C, -5 to 20°C, 0 to 25°C, 5 to 20°C, 10 to 18°C, 12 to 18°C, 12 to 17°C, 12 to 16°C, or 12 to 15°C.

[0027] In certain embodiments, the dynamic crystallization process is carried out in the presence of at least 0.05 equivalents, at least 0.10 equivalents, at least 0.15 equivalents, at least 0.20 equivalents, or at least 0.25 equivalents of base per equivalent of compounds IIa and IIb. In other embodiments, the dynamic crystallization process is carried out in the presence of about 0.04 equivalents, about 0.07 equivalents, about 0.10 equivalents, about 0.13 equivalents, about 0.16 equivalents, about 0.19 equivalents, about 0.22 equivalents, or about 0.25 equivalents of base per equivalent of compounds IIa and IIb. As used herein, the term "equivalents of compounds IIa and IIb" refers to the total equivalents of the two compounds present in the mixture of compounds of formula II. In other embodiments, the dynamic crystallization is carried out in the presence of about 0.05 to about 0.10 equivalents, about 0.10 to about 0.15 equivalents, or about 0.15 to about 0.20 equivalents of base per equivalent of compounds IIa and IIb. When used in reference to an equivalent of base, the term "about" means ±0.02 equivalents. In some embodiments of the dynamic crystallization process of the present application, the amount of base used is a catalytic amount. As used herein, the terms "catalytic" and "catalytic amount" refer to an amount between about 0.04 equivalents and about 0.25 equivalents per equivalent of compounds IIa and IIb. In some embodiments, the catalytic amount of base is about 0.04 equivalents to about 0.07 equivalents, about 0.04 equivalents to about 0.10 equivalents, about 0.04 equivalents to about 0.13 equivalents, about 0.04 equivalents to about 0.16 equivalents, about 0.04 equivalents to about 0.19 equivalents, or about 0.04 equivalents to about 0.22 equivalents of base per equivalent of compounds IIa and IIb. In other embodiments, the catalytic amount of base is up to about 0.04 equivalents, up to about 0.07 equivalents, up to about 0.10 equivalents, up to about 0.13 equivalents, up to about 0.16 equivalents, up to about 0.19 equivalents, up to about 0.22 equivalents, or up to about 0.25 equivalents of base per equivalent of compounds IIa and IIb.

[0028] The optimal conditions for preparing and isolating the substantially chemically and diastereomerically pure ethanol solvate of compound IIa using the dynamic crystallization process of the present application generally depend on the crystallization temperature, the solvent, the base, and the amount of base. For example, at the upper end of the above-mentioned temperature range, the decomposition process becomes more prevalent than at lower temperatures. A high concentration of base may also increase the decomposition of the product. Furthermore, considering that the compound of formula II contains a peptide bond, the nucleophilicity of the base may also contribute to the decomposition of the compound. However, even with high temperatures, high concentrations of base, and / or nucleophilic base, the dynamic crystallization process may still produce stereochemically enriched compound IIa, although with some decomposition products that may necessitate further purification of the isolated ethanol solvate compound.

[0029] In another aspect, the present application relates to a method for preparing a substantially chemically and diastereomerically pure crystalline ethanol solvate of compound IIa (i.e., Form A ethanol solvate of compound IIa), comprising crystallizing compound IIa from a mixture of a compound of formula II from an ethanol solvent system in the presence of a base. More specifically, the present application relates to a method for preparing Form A ethanol solvate of compound IIa, comprising suspending or dissolving a mixture comprising a compound of formula II in an ethanol solvent system, adding a base, stirring the resulting suspension or solution at a temperature below 25° C. for at least 8 hours, thereafter adding a non-polar aprotic solvent (e.g., hexane, cyclohexane, or methylcyclohexane or heptane), or a mixture of non-polar aprotic solvents, dropwise, and then isolating the ethanol solvate as a solid via filtration. In some embodiments, a solution or suspension of a mixture comprising a base and a compound of formula II in an ethanol solvent system is stirred at a temperature of −5 to 25° C., −5 to 20° C., 0 to 25° C., 5 to 20° C., 10 to 18° C., 12 to 18° C., 12 to 17° C., 12 to 16° C., or 12 to 15° C. for up to 12 hours, up to 14 hours, up to 16 hours, up to 18 hours, or up to 20 hours, and then a non-polar aprotic solvent or a mixture of non-polar aprotic solvents is added to the suspension or solution. In some embodiments, the non-polar aprotic solvent can be selected from carbon tetrachloride, benzene, diethyl ether, chloroform, methyl tert-butyl ether (MTBE), dioxane, or toluene, or a mixture of any two or more thereof. In some embodiments, the non-polar aprotic solvent may be selected from pentane, cyclopentane, n-heptane, n-hexane, cyclohexane, or methylcyclohexane, or a mixture of any two or more thereof. In some embodiments, the non-polar aprotic solvent or mixture of solvents is added dropwise to the suspension or solution over a period of about 1 minute to about 24 hours. In some embodiments, the non-polar aprotic solvent or mixture of solvents is added to the suspension or solution in one or more portions over a period of about 1 minute to about 24 hours.

[0030] Any base capable of epimerizing compound IIa to compound IIb (or vice versa) may be suitable. Although the choice of base may contribute to the decomposition of the compound of formula II, which is undesirable, the dynamic crystallization process does not need to completely avoid decomposition. Instead, the degree of decomposition of the compound should be weighed against the yield of isolated stereochemically enriched compound IIa.

[0031] Suitable bases for the epimerization reaction include 1,5,7-triazabicyclo[4.4.0]dec-5-ene ("TBD"), 1,5-diazabicyclo[4.3.0]non-5-ene ("DBN"), triethylamine, diisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N-methyl-piperazine, pyridine, butylamine, dibutylamine, or 1,5-diazabicyclo(4.3.0)non-5-ene, or combinations thereof.

[0032] In certain embodiments, the dynamic crystallization process is carried out in the presence of at least 0.05 equivalents, at least 0.10 equivalents, at least 0.15 equivalents, at least 0.20 equivalents, or at least 0.25 equivalents of base per equivalent of compounds IIa and IIb. In other embodiments, the dynamic crystallization is carried out in the presence of about 0.04 equivalents, about 0.07 equivalents, about 0.10 equivalents, about 0.13 equivalents, about 0.16 equivalents, about 0.19 equivalents, about 0.22 equivalents, or about 0.25 equivalents of base per equivalent of compounds IIa and IIb. In other embodiments, the dynamic crystallization process is carried out in the presence of about 0.05 to about 0.10 equivalents, about 0.10 to about 0.15 equivalents, or about 0.15 to about 0.20 equivalents of base per equivalent of compounds IIa and IIb. In some embodiments of the dynamic crystallization process of the present application, the amount of base used is catalytic.

[0033] In some embodiments, Form A ethanol solvate of Compound IIa can be prepared by adding a mixture of compound of formula II to an ethanol solvent system, adding a base, and stirring the mixture at −5-25° C., −5-20° C., 0-25° C., 5-20° C., 10-18° C., 12-18° C., 12-17° C., 12-16° C., or 12-15° C. for up to 12 hours, 14 hours, 16 hours, 18 hours, or 20 hours, followed by dropwise addition of a non-polar solvent or a mixture of non-polar solvents such as n-heptane, followed by isolation.

[0034] Form A ethanol solvate of Compound IIa may be identified by one or more of the following characteristics: a diastereomeric excess of at least about 90%, at least about 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, and a powder X-ray diffraction pattern substantially as shown in FIG. 1 (XRPD patterns were measured using a powder diffractometer equipped with a Cu X-ray tube source). The angles 2θ±0.2° and d-spacings of the diffraction peaks identified in the experimental XRPD pattern of FIG. 1 are listed in Table 1. As used herein in reference to diastereomeric excess, the term "about" means ±2.5%.

[0035] [Table 1]

[0036] In some embodiments, Form A of the ethanol solvate of Compound IIa may be characterized by an X-ray powder diffraction (XRPD) pattern including one or more of the peaks at the following 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2°, and 25.2°±0.2°. In some embodiments, Form A of the ethanol solvate of Compound IIa may be characterized by an X-ray powder diffraction (XRPD) pattern that includes one, two, three, four, five, or six of the following peaks at 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2°, and 25.2°±0.2°. In some embodiments, Form A of the ethanol solvate of Compound IIa may be characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more of the peaks at the following 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2°, and 25.2°±0.2°.

[0037] As used herein, the term "substantially representative X-ray powder diffraction (XRPD) pattern" in a defined figure means that, for comparison purposes, at least 50% of the most intense peaks shown in the figure are present. It is further understood that, for comparison purposes, some variation in 2θ peak positions from those shown (e.g., ±0.2°) is permitted and applies to each peak position.

[0038] Crystalline Form A ethanol solvate of Compound IIa may also be characterized by differential scanning calorimetry ("DSC") and thermogravimetric analysis ("TGA"). In one embodiment, crystalline Form A ethanol solvate of Compound IIa exhibits a DSC thermogram containing three endotherms at 120.6°C (peak temperature), 136.4°C (peak temperature), and 203.4°C (onset temperature). Form A ethanol solvate of Compound IIa may also be characterized by a maximum weight loss of 10% by weight at or below 150°C as determined by TGA. In some embodiments, Form A ethanol solvate of Compound IIa is characterized by a weight loss of at least 8.0% by weight.

[0039] FIG. 2 shows the DSC and TGA thermograms of Form A of the ethanol solvate of compound IIa.

[0040] In another aspect, the present application relates to a process for preparing compound I, comprising obtaining a substantially chemically and diastereomerically pure Form A crystalline ethanol solvate of compound IIa and converting it to compound I.

[0041] In some embodiments, obtaining a substantially chemically and diastereomerically pure form A crystalline ethanol solvate of compound IIa comprises stereochemically enriching and selectively crystallizing compound IIa from an ethanol solvent system using the dynamic crystallization process described above.Any mixture of compounds of formula II can be the starting point for obtaining a substantially chemically and diastereomerically pure form A crystalline ethanol solvate of compound IIa.In some embodiments, a substantially chemically and diastereomerically pure compound IIb can be the starting point for obtaining a substantially chemically and diastereomerically pure crystalline ethanol solvate of compound IIa.

[0042] The mixture of compounds of formula II can be prepared according to any method known to one of skill in the art. Starting materials for preparing the mixture of compounds of formula II are known to those skilled in the art or can be prepared by methods such as those described in WO 2013107291, WO 2007076034, WO 2006067445, WO 2006067445, Atkinson, JG et al., J. Amer. Chem. Soc. 90:498 (1968), Berkessel. A. et al., Angew Chemie, Int Ed. 53:11660 (2014);Angew. Chem. Int. Ed. Sun, X. et al., 52:4440 (2013), Topolovcan, N. et al., Eur. J. Org. Chem. 2868 (2015), and Pavlik, JW et al., J Heterocyclic They can be prepared according to methods known to those of skill in the art, as exemplified by the methods described in Chem. 42:73 (2005), both of which are incorporated herein by reference in their entireties.

[0043] For example, a mixture of compounds of formula II may be prepared according to Scheme 1: [ka] It can be prepared according to

[0044] In Scheme 1, a mixture of compounds of formula II can be synthesized by reacting a benzaldehyde S1 with a primary amine S2 in methanol, and then reacting the resulting product with oxopyrrolidine-2-carboxylic acid S3 and isocyanatocyclobutane S4 to give the compound of formula II.

[0045] A mixture of compounds of formula II may be subjected to the dynamic crystallization process of the present application to obtain a substantially chemically and diastereomerically pure Form A crystalline ethanol solvate of compound IIa by the process shown in Scheme 2. [ka]

[0046] By dynamic crystallization, a substantially chemically and diastereomerically pure Form A crystalline ethanol solvate of Compound IIa can be isolated in a diastereomeric excess of at least about 90%, at least about 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0047] The substantially chemically and diastereomerically pure Form A crystalline ethanol solvate of compound IIa can be converted to compound I according to any method known to one skilled in the art. For example, the substantially chemically and diastereomerically pure Form A crystalline ethanol solvate of compound IIa can be converted to compound I according to Scheme 3. In Scheme 3, the Buchwald reaction of compound IIa with bromoisonicotinonitrile gives compound I. [ka]

[0048] Alternatively, the substantially chemically and diastereomerically pure Form A crystalline ethanol solvate of compound IIa can be converted to compound I according to Scheme 4. In Scheme 4, compound I is synthesized by reacting compound IIa with ethyl 2-bromoisonicotinate to give intermediate S9. NH 3 Reduction of intermediate S9 in the presence of provides amide S10. Amide S10 is then reacted with trifluoroacetic anhydride (TFAA) in the presence of pyridine and a suitable solvent to give compound I. Suitable solvents include THF. [ka]

[0049] Experimental section The following examples are provided herein for illustrative purposes and do not constitute limitations to any of the claims. Abbreviation: TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene. DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene. DBN: 1,5-diazabicyclo[4.3.0]non-5-ene. EtOAc: ethyl acetate. IPAc: isopropyl acetate. EtOH: ethanol. I-PrOH: isopropyl alcohol. n-BuOH: n-butanol. t-BuOH: t-butanol. DCM: dichloromethane. THF: tetrahydrofuran. 2-MeTHF: 2-methyltetrahydrofuran. DMF: dimethylformamide. DMSO: dimethyl sulfoxide. RT (or rt): room temperature.

[0050] As used herein, "LCAP," which stands for "liquid chromatography area percent," refers to the percentage of the peak area of ​​a compound of interest relative to the total area of ​​the peak. HPLC experiments were performed using an Agilent 1100 equipped with a Phenomenex Cellulos-4, 250×4.6 mm, 5 μm column and a DAD detector, using hexane / ethanol as the mobile phase. 1 HNMR: 1 H solution NMR was collected on a Bruker 400 MHz NMR spectrometer using DMSO-d6. DSC thermal analysis was performed using a TA Q2000 DSC (TA Instruments). Samples were prepared using crimped aluminum pans and N was used as the purge gas. 2 was used to test from room temperature to the desired temperature at a heating rate of 10° C. / min. TGA thermal analysis was performed using a TA Q5000 TGA (also manufactured by TA Instruments). Samples were prepared using crimped aluminum pans and N was used as the purge gas. 2 was used to test from room temperature to the desired temperature with a 60 second modulation and a heating rate of 10° C. / min. Powder X-ray diffraction samples were irradiated with CuKα1 (1.540598 Å) and CuKα2 (1.544426 Å) radiation with a Kα1 / Kα2 ratio of 0.50, and XRPD data were collected from 2θ between 3 and 40°.

[0051] Dynamic crystallization of mixtures containing compounds IIa and IIb. A 53:47 mixture of compound of formula II (100 g, 89% A by HPLC, 185.0 mmol) in ethanol (300 mL) was combined with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (2.0 g, 14.4 mmol) at 15° C. and then stirred at 14-17° C. for 20 h. n-heptane (300 mL) was added dropwise to the reaction mixture. After further stirring at 14-17° C. for 1 h, the solid was collected by filtration. The filter cake was washed with ethanol / n-heptane (200 mL, 1 v / 1 v) at <25° C. and dried under vacuum at 50° C. to give compound IIa (58.5 g, 99.4% A purity, 65% yield) as a white solid ethanol solvate with a ratio of compound IIa to IIb >99.9:0.1. 1H NMR (400 MHz, DMSO-d6) δ 9.0-8.9 (bm, 2 H), 8.41 (d, J = 2.6 Hz, 1H), 8.02 (bs, 1H), 7.75 (s, 1H), 7.41 (dd, J = 8.1, 1.3 Hz, 1H), 7.21 (td, J = 7.7, 1.7 Hz, 1H), 7.11 (td, J = 7.6, 1.3 Hz, 1H), 6.89 (dd, J = 7.7, 1.6 Hz, 1H), 6.38 (bs, 1H), 4.14 (p, J = 6.5 Hz, 1H), 4.00 (bs, 1H), 3.05 to 2.84 (m, 2H), 2.7 to 2.3 (m, 2H), 2.10 (ddd, J = 16.8, 9.5, 7.6 Hz, 1H), 2.03 to 1.92 (m, 1H), 1.90 to 1.70 (m, 2H) Ethanol δ (4.34, t, J = 5.1 Hz, 1 H), 3.43 (dq, J = 6.9, 4.9 Hz, 2H), 1.04 (t, J = 7.0 Hz, 3H) LC MS of compound IIa: ESI(+) Measured value: [M+H]+481

[0052] Synthesis of compound I by scheme 2 In one embodiment, a substantially chemically and diastereomerically pure crystalline ethanol solvate of Compound IIa is converted to Compound I. Such a conversion can be carried out by mixing Compound IIa (0.20 mmol), 2-bromoisonicotinonitrile (0.30 mmol), Cs 2 CO 3 (129 mg, 0.39 mmol), Pd 2 (dba) 3 (18 mg, 0.02 mmol) and Xant-Phos (9.4 mg, 0.02 mmol) in 1,4-dioxane (10 mL) 2 The reaction mixture is stirred at 80° C. overnight under reduced pressure. After filtration, the filtrate is concentrated in vacuo and the residue is purified by standard methods to give compound I.

[0053] Synthesis of compound I by scheme 3 Alternatively, according to Scheme 3, compound IIa and ethyl 2-bromoisonicotinate (compound S8) are combined in a solvent to undergo a Buchwald reaction to give compound S9. The ethyl ester of compound S9 can be reduced to form amide S10, which can further undergo a condensation reaction to introduce the nitrile functionality of compound I.

[0054] Specifically, the mixture was a substantially chemically and diastereomerically pure crystalline ethanol solvate of compound IIa (0.20 mmol), 2-bromoisonicotinic acid (0.30 mmol), Cs 2 CO 3 (129 mg, 0.39 mmol), Pd 2 (dba) 3 A mixture of 18 mg (0.02 mmol) and Xantphos (9.4 mg, 0.02 mmol) in 1,4-dioxane (10 mL) was 2 The mixture is stirred at 80° C. under reduced pressure overnight. After filtration, the filtrate is concentrated in vacuo and the residue is purified by standard methods to give compound S9. 3 A mixture of S10 (0.4-1 mmol), pyridine, and TFAA is stirred in THF at 0° C. overnight. The reaction mixture is concentrated in vacuo, and the residue is purified by standard methods to give compound I.

[0055] The chemistry of epimerization The optimal conditions for dynamic crystallization generally include rapid epimerization reaction with minimal decomposition of the compound. For compounds susceptible to epimerization, the optimal conditions for achieving rapid epimerization with minimal decomposition generally depend on reaction temperature, base, base concentration and solvent. Numerous experiments have been carried out to show that the dynamic crystallization process of the present application improves the efficiency of large-scale manufacturing methods for preparing compound I.

[0056] When substantially chemically and diastereomerically pure compound IIa was combined with TBD (0.1 equivalent) in 95% ethanol at room temperature, the ratio of compound IIa to IIb was found to be 87.5% / 12.5% ​​after 2 hours (entry 1). Some decomposition was also observed, as indicated by additional peaks in the HPLC spectrogram. After 24 hours, the ratio was still 87.1% / 12.9%, indicating that the epimerization reaction with catalytic amounts of TBD at room temperature was very fast (albeit incomplete).

[0057] The epimerization reaction was found to be slower when carried out with DBN (0.1 equiv.) in ethanol, with only 2.8% compound IIb observed after 2 h at room temperature (entry 2). However, after 24 h, the ratio of IIa to IIb was 86.3% / 13.7%. Decomposition peaks were also observed by HPLC.

[0058] When compound IIa was combined with TBD (0.1 equiv.) in a mixture of EtOAc / n-heptane (1 / 1), only 4.2% IIb was observed after 4 h at room temperature, and the amount of IIb did not increase even after 24 h (entry 3).

[0059] However, when compound IIa was combined with TBD in a mixture of EtOAc / n-heptane (3 / 1), after 4 h at room temperature the ratio of IIa to IIb was 85.1% / 14.9% (entry 4), and the ratio did not change significantly after 24 h. Fewer decomposition products were observed (compared to the ethanol reaction above).

[0060] In another experiment, entry 5, 20 g of compound IIa was combined with TBD (0.1 equiv.) in EtOAc (200 mL, 10 V) at 40° C. for 5 h. The ratio of IIa to IIb was 63.0% / 37.0%, with no decomposition observed. The reaction mixture was then cooled to room temperature and washed with aqueous HCl, followed by brine. The organic layer was washed with anhydrous Na 2 SO 4The mixture was dried at 4° C. and concentrated to dryness to give 20 g of a mixture of IIa / IIb as a white solid, the ratio of which was observed to be 63.6% / 36.4%. This material was used for further epimerization studies.

[0061] [Table 2]

[0062] A mixture containing compounds IIa and IIb in a ratio of 15 / 85, respectively (and with an LCAP of 83.7%) was epimerized in various solvents. In the presence of 0.1 equivalents of TBD, DBU or DBN in EtOAc or IPAc (entries 6-10), the IIa / IIb ratio increased to about 1 / 1, but did not increase further even after 24 h. A significant amount of decomposition was observed, and the chemical purity decreased to 42-68% (from 83.7%). See entries 6-10 in Table 2.

[0063] With TBD in IPAc, the epimerization was faster compared to DBU and DBN, with the IIa / IIb ratio increasing to about 1 / 1 in about 2 h (entry 8), so TBD was selected as the base for further studies.

[0064] In a mixture of EtOAc / ethanol (3 / 1 V / V) containing 0.1 equivalent of TBD, the IIa / IIb ratio increased to about 1 / 1 in a few hours at 10 °C (entry 11). After 20 hours, this ratio did not increase further. However, compared to EtOAc or IPAc as solvent, the decomposition in a mixture of EtOAc / ethanol (3 / 1 V / V) did not increase significantly after overnight at 10 °C (LCAP remained about 74% throughout).

[0065] The epimerization was scaled up to 20 g using the conditions of entry 12. After 3 h at 10 °C, the reaction mixture (IIa / IIb approx. 49 / 51) was filtered to give 4 g of IIa with chiral purity of 99.8% and LCAP purity of 98.2% (entry 12).

[0066] When a mixture of IIa and IIb (IIa / IIb ratio of about 49 / 51) was stirred with 0.1 equivalent of TBD in ethanol at 15 °C for 26 h, the IIa / IIb ratio in the solid was about 75 / 25 and the LCAP was still about 77% (entry 13).

[0067] [Table 3]

[0068] Optimization of temperature for epimerization in ethanol (starting IIa / IIb ratio of 15 / 85) The reaction temperature was further optimized for the epimerization reaction in ethanol. With 0.1 equivalent of TBD, the epimerization was too slow at -5°C and 5°C in ethanol. The ratio of IIa / IIb increased from 15 / 85 to about 50 / 50 after about 24 hours (entries 14-16). Only 5.5 g of solid was obtained from a 20 g experiment.

[0069] At 10°C and 12°C, the ratios of IIa / IIb increased to 70 / 30 and 68 / 32, respectively, after 24 h (entries 17 and 18). At 15°C (entries 19 and 20), the ratio of IIa / IIb was observed in the reaction mixture from 15 / 85 to 82 / 18 after 24 h. After filtration and drying, 9.5 g of solid was obtained from a 20 g experiment. The chiral purity was 99.9% and the LCAP was 98.4%. At 20°C, the ratio of compound IIa / compound IIb increased to 90 / 10 after 24 h, but the reaction mixture showed more severe degradation with an LCAP purity of about 55% (entry 21). These experiments showed that about 15° C. is a suitable temperature for the epimerization reaction in ethanol containing 0.1 equivalent of TBD, and under these conditions, a substantially chemically and diastereomerically pure crystalline ethanol solvate of compound IIa can be obtained in about 32% yield for the second crop.

[0070] [Table 4]

[0071] Screening of different solvents for epimerization reaction: Various solvents were screened for epimerization of the crude IIa / IIb mixture obtained from the mother liquor of the first crop of IIa. The crude mixture (LCAP: 83%, chiral IIa / IIb: 17% / 83%) was stirred in these solvents for 24 h at 15 °C in the presence of TBD (0.1 equiv.). With ethanol, a high IIa / IIb ratio of 90% / 10% was achieved for the reaction mixture (entry 22). However, the decomposition of IIa was intense, and the purity of the reaction mixture measured by HPLC was only about 37%. In EtOAc solvent, only slight decomposition (78% purity by HPLC) was observed, and the IIa / IIb ratio was 53% / 47% (entry 23). Using IPA as the solvent, similar results were obtained, i.e., a purity by HPLC of 78% and a IIa / IIb ratio of 49% / 51% (entry 24).

[0072] [Table 5]

[0073] i-PrOH as a solvent for dynamic crystallization (i.e., crystallization and epimerization) In order to optimize the epimerization reaction while minimizing chemical decomposition, starting with substantially chemically and diastereomerically pure compound IIa and TBD (0.1 equivalents), the epimerization reaction was carried out at 15 °C for 2 h in various solvents (ethanol, EtOAc, i-PrOH, n-PrOH, n-BuOH, t-BuOH, THF, 2-MeTHF, CH 3 The following solvents (CN and acetone) were screened. The data in the following table were collected from various solvents. i-PrOH gave good epimerization with minimal chemical decomposition after 2 hours, resulting in a IIa / IIb ratio of 57% / 42% with a chemical purity of 91.8% (see entry 37). [Table 6]

[0074] Use of TBD in ethanol / n-heptane for epimerization In entries 45 and 46, a mixture of compounds IIa and IIb was dissolved in ethanol in the presence of TBD (0.07 or 0.10 equiv.). The reaction mixture was stirred for the indicated time, n-heptane was added to the solution, and the solid was filtered. The crystalline ethanol solvate of compound IIa was collected as a solid with an LCAP of 99% or higher and a chiral purity of 99% or higher. [Table 7]

[0075] Although many embodiments have been described herein, the scope of the present disclosure should be defined by the appended claims and the specific embodiments included herein as examples.The contents of all references cited throughout this specification (including references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein in their entirety by reference.Unless otherwise defined, all technical and scientific terms used herein are given the meaning commonly known to those skilled in the art.

Claims

1. Compound I: 【Chemistry 10】 A method for preparing Compound IIa: 【Chemistry 11】 isolating a crystal of the ethanol solvate of Converting the ethanol solvate crystals of compound IIa into compound I or a solvate thereof. The method includes:

2. Isolating the crystalline ethanol solvate of compound IIa isotopically isolated from the compound of formula II: 【Chemistry 12】 2. The method of claim 1, comprising crystallizing compound IIa from a mixture of compounds of formula (I).

3. 2. The method of claim 1, wherein converting the crystalline ethanol solvate of compound IIa comprises reacting compound IIa with a 2-halo-4-cyanopyridine to provide compound I.

4. 3. The method of claim 2, wherein crystallizing compound IIa comprises suspending or dissolving a diastereomeric mixture of compound of formula II in an ethanol solvent system, adding a base, stirring the mixture between 0° C. and 25° C., and adding at least one non-polar solvent.

5. 5. The method of claim 4, wherein the base is selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dec-5-ene ("TBD"), 1,5-diazabicyclo[4.3.0]non-5-ene ("DBN"), triethylamine, diisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N-methyl-piperazine, pyridine, butylamine, dibutylamine, and 1,5-diazabicyclo(4.3.0)non-5-ene, or a mixture thereof.

6. 3. The process of claim 2, wherein the mixture of compounds of formula II is prepared by reacting 2-chlorobenzaldehyde with 5-fluoropyridin-3-amine in methanol and then reacting the resulting product with (S)-5-oxopyrrolidine-2-carboxylic acid and 1,1-difluoro-3-isocyanatocyclobutane to provide the mixture of compounds of formula II.

7. 2. The process of claim 1, comprising reacting the crystalline ethanol solvate of compound IIa with 2-bromoisonicotinonitrile to provide compound I.

8. The ethanol solvate crystals of compound IIa were reacted with ethyl 2-bromoisonicotinate to give intermediate S9: 【Chemistry 13】 2. The method of claim 1, comprising providing:

9. N.H. ３ The intermediate S9 is reduced in the presence of 【Chemistry 14】 The method of claim 8, comprising providing:

10. 10. The method of claim 9, comprising combining S10 with trifluoroacetic anhydride (TFAA) in the presence of pyridine to provide compound I.

11. 3. The method of claim 1 or 2, wherein the ethanol solvate crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at the following 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2°, and 25.2°±0.2°.

12. 3. The method of claim 1 or 2, wherein the ethanol solvate crystal is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at the following angles 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2°, and 25.2°±0.2°.

13. 3. The method of claim 1 or 2, wherein the crystalline ethanol solvate of compound IIa has a diastereomeric excess of at least 90% and a chemical purity of at least 80%.

14. 3. The method of claim 1, wherein the crystalline ethanol solvate of compound IIa has a diastereomeric purity of between about 90% and about 99%.

15. 3. The method of claim 1, wherein the crystalline ethanol solvate of compound IIa has a chemical purity of between about 80% and about 99%.

16. Compound IIa: 【Chemistry 15】 A method for preparing a crystal of an ethanol solvate of A method comprising suspending or dissolving a mixture of Compound IIa and Compound IIb and a base in an ethanol solvent system, adding at least one non-polar solvent, and isolating crystals of the ethanol solvate of Compound IIa.

17. 17. The method of claim 16, wherein the base is selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dec-5-ene ("TBD"), 1,5-diazabicyclo[4.3.0]non-5-ene ("DBN"), triethylamine, diisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N-methyl-piperazine, pyridine, butylamine, dibutylamine, and 1,5-diazabicyclo(4.3.0)non-5-ene, or a mixture thereof.

18. 18. The method of claim 16 or 17, wherein the crystalline ethanol solvate of compound IIa has a diastereomeric excess of at least 90% and a chemical purity of at least 80%.

19. The method according to any one of claims 16 to 18, wherein the crystalline ethanol solvate of compound IIa has a diastereomeric purity of between about 90% and about 99%.

20. The method according to any one of claims 16 to 19, wherein the crystalline ethanol solvate of compound IIa is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

21. 20. The method of any one of claims 16 to 19, wherein the crystalline ethanol solvate of Compound IIa is characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at the following angles 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2°, and 25.2°±0.2°.

22. 20. The method of any one of claims 16 to 19, wherein the crystalline ethanol solvate of Compound IIa is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at the following angles 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2°, and 25.2°±0.2°.

23. The method of any one of claims 16 to 22, wherein the crystalline ethanol solvate of Compound IIa has a chemical purity of between about 80% and about 99%.

24. Compound IIa: 【Chemistry 16】 Crystal of ethanol solvate of

25. 25. The crystalline ethanol solvate of compound IIa according to claim 24, characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

26. The ethanol solvate crystal of compound IIa according to claim 24, characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at the following 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2° and 25.2°±0.2°.

27. The ethanol solvate crystal of compound IIa according to claim 24, characterized by an X-ray powder diffraction (XRPD) pattern including three or more peaks at the following 2θ: 7.2°±0.2°, 8.6°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 21.8°±0.2° and 25.2°±0.2°.

28. 25. The crystalline ethanol solvate of claim 24, having a diastereomeric purity of between about 90% and about 99%.

29. 25. The crystalline ethanol solvate of claim 24, having a diastereomeric purity of at least about 99%.

30. A crystal of the ethanol solvate of claim 24 having a diastereomeric excess of at least 90% and a chemical purity of at least 80%.

31. 25. The crystalline ethanol solvate of claim 24, having a chemical purity of between about 80% and about 99%.

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