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KR-102963815-B1 - Method for manufacturing ibosidenib and intermediate thereof

KR102963815B1KR 102963815 B1KR102963815 B1KR 102963815B1KR-102963815-B1

Abstract

The present application relates to a method for preparing a substantially diastereomerically pure crystalline ethanol solvate of compound IIa and its use for the synthesis of ibosidenib.

Inventors

  • 사이즈모어, 제이콥, 폴
  • 장, 시지에
  • 보, 나, 후

Assignees

  • 르 라보레또레 쎄르비에르

Dates

Publication Date
20260511
Application Date
20200807
Priority Date
20190808

Claims (20)

  1. A method for preparing the following compound I comprises separating a crystalline ethanol solvate of the following compound IIa and converting the ethanol solvate of compound IIa into compound I or a solvate thereof. A method in which the crystalline ethanol solvate of compound IIa is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five 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°: .
  2. A method according to claim 1, wherein separating the crystalline ethanol solvate of compound IIa comprises crystallizing compound IIa from a mixture of compounds of the following formula II:
  3. A method according to claim 1, wherein converting the crystalline ethanol solvate of compound IIa comprises reacting compound IIa with 2-halo-4-cyanopyridine to provide compound I.
  4. A method according to claim 2, wherein crystallizing a crystalline ethanol solvate of compound IIa comprises suspending or dissolving a mixture of diastereomers of compounds of formula II in an ethanol solvent system, adding a base, stirring the mixture at 0 to 25°C, and adding at least one nonpolar solvent.
  5. A method according to claim 4, wherein the base is selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dek-5-en("TBD"), 1,5-diazabicyclo[4.3.0]non-5-en("DBN"), triethylamine, diisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N-methyl-piperazine, pyridine, butylamine, dibutylamine, and 1,5-diazabicyclo(4.3.0)non-5-en, or a mixture thereof.
  6. A method according to claim 2, wherein a mixture of compounds of formula II is prepared by reacting 2-chlorobenzaldehyde with 5-fluoropyridine-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 a mixture of compounds of formula II.
  7. A method according to claim 1, comprising reacting a crystalline ethanol solvate of compound IIa with 2-bromoisonicotinonitrile to provide compound I.
  8. A method according to claim 1, comprising reacting a crystalline ethanol solvate of compound IIa with ethyl 2-bromoisonicotinate to provide the following intermediate S9:
  9. A method according to claim 8, comprising reducing intermediate S9 in the presence of NH3 to provide the following amide S10:
  10. A method according to claim 9 comprising mixing S10 with trifluoroacetic anhydride (TFAA) in the presence of pyridine to provide compound I.
  11. A method according to claim 1 or 2, wherein the crystalline ethanol solvate of compound IIa has at least 90% diastereomer excess and at least 80% chemical purity.
  12. A method according to claim 1 or 2, wherein the crystalline ethanol solvate of compound IIa has a diastereomer purity of 90% to 99%.
  13. A method according to claim 1 or 2, wherein the crystalline ethanol solvate of compound IIa has a chemical purity of 80% to 99%.
  14. A method for preparing a crystalline ethanol solvate of compound IIa as follows, comprising suspending or dissolving a mixture of compounds of formula II and a base in an ethanol solvent system, adding at least one nonpolar solvent, and separating the crystalline ethanol solvate of compound IIa. A method in which the crystalline ethanol solvate of compound IIa is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five 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°: .
  15. A method according to claim 14, wherein the base is selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dek-5-en("TBD"), 1,5-diazabicyclo[4.3.0]non-5-en("DBN"), triethylamine, diisopropylamine, N,N-diisopropylethylamine, N-methylmorpholine, morpholine, N-methyl-piperazine, pyridine, butylamine, dibutylamine, and 1,5-diazabicyclo(4.3.0)non-5-en, or a mixture thereof.
  16. A method according to claim 14 or 15, wherein the crystalline ethanol solvate of compound IIa has at least 90% diastereomer excess and at least 80% chemical purity.
  17. A method according to claim 14 or 15, wherein the crystalline ethanol solvate of compound IIa has a diastereomer purity of 90% to 99%.
  18. A method according to claim 14 or 15, wherein the crystalline ethanol solvate of compound IIa is characterized by an X-ray powder diffraction (XRPD) pattern comprising 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°.
  19. A method according to claim 14 or 15, wherein the crystalline ethanol solvate of compound IIa has a chemical purity of 80% to 99%.
  20. Crystalline ethanol solvate of compound IIa, characterized by an X-ray powder diffraction (XRPD) pattern containing at least five 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°:

Description

Method for manufacturing ibosidenib and intermediate thereof Cross-reference regarding related applications [0001] This application claims the benefit of U.S. Provisional Application No. 62/884,480 filed on August 8, 2019, the disclosure of which is incorporated herein by reference. [0002] Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). This enzyme belongs to two distinct subclasses, one of which uses NAD(+) as an electron acceptor and the other uses NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases localized to the mitochondrial matrix and two NADP(+)-dependent isocitrate dehydrogenases (one of which is mitochondria and the other is mainly cytoplasm). Each NADP(+)-dependent isozyme is a homodimer. [0003] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytoplasm) 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 peroxisome targeting signal sequence. The presence of this enzyme in peroxisomes suggests a role in the regeneration of NADPH for intra-peroxisome reductions, such as the conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA, as well as in peroxisome reactions consuming 2-oxoglutarate, namely the alpha-hydroxylation of phytanyl. The cytoplasmic enzyme plays a crucial role in cytoplasmic NADPH production. [0004] The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences for human IDH1 can be found in GenBank entries NM_005896.2 and NP_005887.2, respectively. The nucleotide and amino acid sequences for IDH1 are also described in the literature, for example (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 to UniProtKB (DEC-2008); Kullmann et al., submitted to the EMBL/GenBank/DDBJ database (JUN-1996); and Sjoeblom et al., Science 314:268-274(2006)). [0005] It has been discovered that mutations in IDH1 present in certain cancer cells cause 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+), mitochondria) 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 intermediate metabolism and energy production. This protein may be closely 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 for IDH2 can be found in GenBank entries NM_002168.2 and NP_002159.2, respectively. The nucleotide and amino acid sequences for human IDH2 are also described, for example, in the literature (Huh et al ., submitted to the EMBL/GenBank/DDBJ database (NOV-1992); and The MGC Project Team, Genome Res. 14:2121-2127 (2004)). [0007] Non-mutant, e.g. 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 cause the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH2. The production of 2HG is believed 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 lead to the accumulation of 2-HG, which is believed to promote tumorigenesis through DNA hypermethylation, increased repressive histone methylation, and inhibition of differentiation processes. Studies performed with a tool compound known as AGI-5198, which was found to inhibit mutant IDH1 (mIDH1) but not mutant IDH2 (mIDH2), demonstrated that inhibition of the mIDH1 protein can suppress the growth of mIDH1-induced gliomas in some model systems (D. Rohle et al. Science 340:626-630 (2013)). [0010] U.S. Patent No. 9,474,779 B2 and U.S. Patent No. 9,968,595 B2 (the whole of which is incorporated herein by reference) disclose a compound described by the chemical name (S)-N-((S)-1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide, which has been shown to act as an inhibitor of mutant IDH1 protein in biochemical and cellular assays. According to nomenclature, this compound may also be referred to as (2S)-N-{(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl}-1-(4-c