Process for the preparation of regorafenib

Abstract

A process for preparing regorafenib using N,N'-bis[(2R)-1,1,1-trifluoropropan-2-yl] triamidodicarbonic acid diamide hydrochloride.

Description

[0001] field

[0002] This invention relates to a method for preparing vociniridine, which is an orally available brain-penetrating second-generation double-mutant isocitrate dehydrogenase 1 and 2 (mIDH1 / 2) inhibitor.

[0003] background

[0004] Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-ketoglutarate (i.e., α-ketoglutarate). These enzymes belong to two distinct subclasses, one utilizing NAD(+) as an electron acceptor and the other using NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases located in the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other is primarily cytosol-based. Each NADP(+)-dependent isoenzyme is a homodimer.

[0005] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosol) is also known as IDH; IDP; IDCD; IDPC or PICD. This gene encodes a 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 the peroxisome suggests its role in peroxisome reduction during NADPH regeneration, such as the conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA, and the α-hydroxylation of phytanoic acid in the peroxisome reaction that consumes 2-ketoglutarate. Cytoplasmic enzymes play a crucial role in the production of cytoplasmic NADPH.

[0006] The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences of human IDH1 can be found as GenBank entries NM_005896.2 and NP_005887.2, respectively. The nucleotide and amino acid sequences of IDH1 are also described in the following references: 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 EMBL / GenBank / DDBJ database; and Sjoeblom et al., Science 314:268-274 (2006).

[0007] Non-mutant types, such as wild-type IDH1, catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate.

[0008] It has been discovered that IDH1 mutations in certain cancer cells result in a novel ability of this enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is thought to contribute to cancer formation and progression (Dang, L et al., Nature 2009, 462:739-44).

[0009] IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondria) is also known as IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The gene encodes a protein that is an NADP(+)-dependent isocitrate dehydrogenase found in mitochondria. It plays a role in intermediate metabolism and energy production. This protein may bind tightly to or interact with the pyruvate dehydrogenase complex. The human IDH2 gene encodes a 452-amino acid protein. The nucleotide and amino acid sequences of IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2, respectively. The nucleotide and amino acid sequences of human IDH2 are also described in the following literature, for example, Huh et al., submitted (NOV-1992) to the EMBL / GenBank / DDBJ database; and The MGCProject Team, Genome Res. 14:2121-2127 (2004).

[0010] Non-mutant types, such as wild-type IDH2, catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG).

[0011] It has been discovered that mutations in IDH2 in certain cancer cells result in a novel ability of this enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH2. It is believed that the production of 2HG contributes to cancer formation and progression (Dang, L et al., Nature 2009, 462:739-44).

[0012] Recurrent or progressive IDH-mutant gliomas are oligodendrogliomas and astrocytomas that carry IDH1 or IDH2 gene mutations and relapse or progress after receiving standard care treatments including surgery, radiotherapy, and / or chemotherapy.

[0013] Vocinnib is an orally available, second-generation double-mutant isocitrate dehydrogenase 1 and 2 (mIDH1 / 2) inhibitor that is approved in the United States for the treatment of IDH-mutant gliomas.

[0014]

[0015] Vocinib or (6-(6-chloropyridin-2-yl)-N 2 N 4 -Bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine) is disclosed in PCT Publication No. WO2015 / 003640.

[0016] PCT Publication No. WO2015 / 003640 also discloses a laboratory-scale method for preparing vocinib from methyl 6-chloropyridine-2-carboxylate according to the following reaction scheme:

[0017]

[0018] The 2,4-dichloro-6-(6-chloropyridin-2-yl)-1,3,5-triazine formed as an intermediate in this synthetic route is extremely unstable and should be stored in solution. Furthermore, the industrial-scale application of POCl3 as a reagent is difficult to manage due to its high toxicity (inhalation can be fatal) and the potential for highly exothermic hydrolysis, leading to the formation of phosphoric acid and hydrochloric acid. Its industrial use is strictly regulated in the EU.

[0019] PCT Publication No. WO2015 / 003640 also discloses a method for preparing disubstituted biguanides (e.g., relating to Scheme 19) for use as intermediates in the preparation of voxifenib analogs. The disclosed operating conditions are carried out at 160°C without solvent. These harsh conditions are not suitable for industrial processes due to the high risk of explosion when heating large quantities of powder at such high temperatures.

[0020] Therefore, there is a need to develop a safer method for preparing voxinib, which can be used to produce the molecule on an industrial scale.

[0021] Overview

[0022] This disclosure relates to a method for preparing voxinib of formula (I),

[0023]

[0024] This method involves making (R)-1,1,1-trifluoropropane-2-amine hydrochloride of formula (II):

[0025]

[0026] Reaction with sodium dicyandiamide

[0027] N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triimidodicarbonic diamide hydrochloride of formula (III) was obtained.

[0028]

[0029] The compound of formula (III) was then reacted with methyl 6-chloropyridine-2-carboxylate.

[0030] They obtained Voshineb.

[0031] The free form of voxinib can be prepared by a new method and then converted into a hemicitric acid hemihydrate eutectic.

[0032] The “semi-citric acid hemihydrate eutectic” involved in this patent application refers to the type A semi-citric acid hemihydrate eutectic as described in WO 2019 / 090059.

[0033] This disclosure also relates to the use of N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarboxamide hydrochloride of formula (III) as an intermediate compound in the preparation of vocinib. Brief description of the attached diagram

[0035] Figure 1 The 1H NMR spectrum of N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbamide hydrochloride of formula (III) was depicted.

[0036] Figure 2 The 1H NMR spectrum of the free form of voxinib was depicted.

[0037] Detailed description

[0038] This disclosure relates to a method for preparing voxinib of formula (I).

[0039] Vocinib of formula (I) is 6-(6-chloropyridin-2-yl)-N 2 N 4 The synthesis of bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine is described in PCT Publication No. WO2015 / 003640 (Example 10). Vocinib was prepared according to the following reaction scheme:

[0040]

[0041] Alternative methods for preparing voxinib of formula (I) are disclosed in paragraphs

[00312] -

[00320] of PCT Publication No. WO2019 / 090059 (Example 10), and are carried out according to the following reaction scheme:

[0042]

[0043] This alternative method for preparing vocinib yields the target compound with an overall yield of 30%.

[0044] Two existing methods use 2,4-dichloro-6-(6-chloropyridin-2-yl)-1,3,5-triazine as an intermediate compound. This 2,4-dichloro-6-(6-chloropyridin-2-yl)-1,3,5-triazine is extremely unstable and should be stored in solution. Furthermore, the industrial-scale application of POCl3 as a reagent is difficult to manage due to its high toxicity (inhalation can be fatal) and the formation of phosphoric acid and hydrochloric acid during its hydrolysis. Its industrial use is strictly regulated in the EU.

[0045] This invention discloses a method for preparing vocinib, which can be applied on an industrial scale with limited safety concerns. The method of this invention provides vocinib in good yield and with a minimized number of reaction steps. The key intermediate for this alternative synthesis is N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbamide hydrochloride of formula (III).

[0046] Several existing literatures disclose the preparation of symmetrical or asymmetrical guanidines (e.g., Grytsai, O. et al., Beilstein J. Org. Chem. 2021, 17, 1001–1040; LeBel, O. et al., Can. J. Chem. 2005, 83, 615-625; Nandini R. Pai and Seema S. Sawant. Der Pharma Chemica, 2014, 6, 176-187, WO 2016 / 175357 A1, IMMUNOMET THERAPEUTICS INC. and WO2015 / 003640A1).

[0047] This invention relates to a method for preparing vocinib of formula (I):

[0048]

[0049] This method involves making (R)-1,1,1-trifluoropropane-2-amine hydrochloride of formula (II):

[0050]

[0051] Reaction with sodium dicyandiamide

[0052] The reaction is carried out in an alcoholic solvent selected from methanol, isopropanol, isobutanol, tert-butanol, tert-amyl alcohol (i.e., 2-methylbut-2-ol), cyclopentanol, and cyclohexanol, or in isobutyl acetate, at a temperature of 65°C–140°C.

[0053] The N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbamide hydrochloride of formula (III) is obtained:

[0054]

[0055] The compound of formula (III) was then reacted with methyl 6-chloropyridine-2-carboxylate.

[0056] The reaction is carried out in a solvent selected from alcohols and acetonitrile, at a temperature of 20°C–80°C, in the presence of a base.

[0057] They obtained Voshineb.

[0058] The temperatures mentioned in this application refer to the actual temperatures of the reaction medium.

[0059] In one embodiment, the reaction of compound (II) with sodium dicyandiamide is carried out at a temperature of 85°C-140°C.

[0060] In one embodiment, the solvent used for the reaction of compound (II) with sodium dicyandiamide is an alcohol solvent selected from tert-butanol, tert-amyl alcohol (i.e., 2-methylbut-2-ol), isopropanol, and cyclohexanol.

[0061] In one embodiment, the solvent used for reacting the compound of formula (II) with sodium dicyandiamide is selected from tert-butanol and tert-amyl alcohol (i.e., 2-methylbut-2-ol).

[0062] In one embodiment, the reaction of compound (II) with sodium dicyandiamide is carried out at a concentration of 8 mL / g to 34 mL / g, calculated based on the amount of sodium dicyandiamide.

[0063] In one embodiment, the amount of compound of formula (II) used to react with sodium dicyandiamide is 1.9-3 equivalents calculated based on the molar amount of sodium dicyandiamide.

[0064] In another embodiment, the amount of compound of formula (II) used to react with sodium dicyandiamide is 1.9-2.5 equivalents calculated based on the molar amount of sodium dicyandiamide.

[0065] In one embodiment, the solvent used for reacting the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is an alcohol selected from methanol, ethanol, isopropanol, tert-butanol, and mixtures of methanol and tert-butanol.

[0066] In one embodiment, the solvent used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is acetonitrile.

[0067] In one embodiment, the base used for reacting the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is selected from MeONa, tBuOK (i.e., potassium tert-butoxide), K2CO3, Cs2CO3, NaOH, KOH, LiOH, and K3PO4.

[0068] In a preferred embodiment, the solvent used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is methanol, and the base used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is MeONa.

[0069] In one embodiment, the amount of base used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is 0.8-2 equivalents calculated based on the molar amount of compound (III).

[0070] In a preferred embodiment, the amount of base used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is 1.5-2 equivalents calculated based on the molar amount of compound (III).

[0071] In one embodiment, the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is carried out at a concentration of 5 mL / g to 10 mL / g calculated based on the amount of compound (III).

[0072] In one embodiment, the amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 0.8-3 equivalents calculated based on the molar amount of the compound of formula (III).

[0073] In a preferred embodiment, the amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 1.5-2.5 equivalents calculated based on the molar amount of the compound of formula (III).

[0074] In a further preferred embodiment, the amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 1.5-2.2 equivalents calculated based on the molar amount of the compound of formula (III).

[0075] In one embodiment, the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is carried out at a temperature of 20°C to 50°C, preferably at a temperature of 20°C to 40°C.

[0076] Advantageously, the two steps of this method can be performed sequentially without any separation and purification of the compound of formula (III).

[0077] The present invention also relates to the use of N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacamide hydrochloride as an intermediate compound in the preparation of vocinib.

[0078] Implementation Plan

[0079] E1. A method for preparing voxinib of formula (I),

[0080]

[0081] This method involves making (R)-1,1,1-trifluoropropane-2-amine hydrochloride of formula (II):

[0082]

[0083] Reaction with sodium dicyandiamide

[0084] The reaction is carried out in an alcoholic solvent selected from methanol, isopropanol, isobutanol, tert-butanol, tert-amyl alcohol (i.e., 2-methylbut-2-ol), cyclopentanol, and cyclohexanol, or in isobutyl acetate, at a temperature of 65°C–140°C.

[0085] The N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbamide hydrochloride of formula (III) is obtained:

[0086]

[0087] The compound of formula (III) was then reacted with methyl 6-chloropyridine-2-carboxylate.

[0088] The reaction is carried out in a solvent selected from alcohols and acetonitrile, at a temperature of 20°C–80°C, in the presence of a base.

[0089] They obtained Voshineb.

[0090] E2. The method according to E1 is characterized in that the solvent used for the reaction of compound (II) with sodium dicyandiamide is an alcohol solvent selected from tert-butanol, tert-amyl alcohol (i.e., 2-methylbut-2-ol), isopropanol and cyclohexanol.

[0091] E3. The method according to E2 is characterized in that the solvent used for the reaction of compound (II) with sodium dicyandiamide is tert-butanol or tert-amyl alcohol (i.e., 2-methylbut-2-ol).

[0092] E4. The method according to any one of E1-E3, characterized in that the reaction of compound (II) with sodium dicyandiamide is carried out at a temperature of 85°C-140°C.

[0093] E5. The method according to any one of E1-E4, characterized in that the solvent used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is an alcohol selected from methanol, ethanol, isopropanol, tert-butanol and mixtures of methanol and tert-butanol.

[0094] E6. The method according to any one of E1-E5, characterized in that the base used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is selected from MeONa, tBuOK (i.e., potassium tert-butoxide), K2CO3, Cs2CO3, NaOH, KOH, LiOH and K3PO4.

[0095] E7. The method according to any one of E1-E6, characterized in that the solvent used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is methanol, and the base used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is MeONa or tBuOK (i.e., potassium tert-butoxide).

[0096] E8. The method according to any one of E1-E6, characterized in that the solvent used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is a mixture of methanol and tert-butanol, and the base used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is MeONa.

[0097] E9. The method according to any one of E1-E6, characterized in that the solvent used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is ethanol, and the base used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is K2CO3 or KOH.

[0098] E10. The method according to any one of E1-E9, characterized in that the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is carried out at a temperature of 20°C-50°C, preferably at a temperature of 20°C-40°C.

[0099] E11. The method according to E1 is characterized in that:

[0100] - The solvent used for the reaction of compound (II) with sodium dicyandiamide is tert-butanol or tert-amyl alcohol (i.e., 2-methylbut-2-ol).

[0101] The reaction of compound (II) with sodium dicyandiamide is carried out at temperatures between 85°C and 140°C.

[0102] - The solvent used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is methanol.

[0103] - The base used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is MeONa.

[0104] The reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate was carried out at a temperature of 20°C to 50°C.

[0105] E12. The method according to E11 is characterized by first heating the mixture of compound (II) and sodium dicyandiamide at a temperature of 35°C-45°C, and then heating it at a temperature of 85°C-140°C.

[0106] E13. The method according to any one of E1-E12, characterized in that the solvent used for the reaction of compound (II) with sodium dicyandiamide is tert-amyl alcohol (i.e., 2-methylbut-2-ol).

[0107] E14. The method according to any one of E1-E12, characterized in that the solvent used for the reaction of compound (II) with sodium dicyandiamide is tert-butanol.

[0108] E15. The method according to any one of E1-E14, characterized in that the reaction of the compound of formula (II) with sodium dicyandiamide is carried out at a concentration of 8 mL / g to 34 mL / g calculated based on the amount of sodium dicyandiamide.

[0109] E16. The method according to any one of E1-E15, characterized in that the amount of compound of formula (II) used for the reaction with sodium dicyandiamide is 1.9-3 equivalents calculated based on the molar amount of sodium dicyandiamide.

[0110] E17. The method according to E16 is characterized in that the amount of compound of formula (II) used for the reaction with sodium dicyandiamide is 1.9-2.5 equivalents calculated based on the molar amount of sodium dicyandiamide.

[0111] E18. The method according to any one of E1-E17, characterized in that the amount of base used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is 0.8-2 equivalents calculated according to the molar amount of the compound of formula (III).

[0112] E19. The method according to E18 is characterized in that the amount of base used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is 1.5-2 equivalents calculated according to the molar amount of the compound of formula (III).

[0113] E20. The method according to any one of E1-E19, characterized in that the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is carried out at a concentration of 5 mL / g to 10 mL / g calculated according to the amount of the compound of formula (III).

[0114] E21. The method according to any one of E1-E20, characterized in that the amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 0.8-3 equivalents calculated according to the molar amount of the compound of formula (III).

[0115] E22. The method according to E21, characterized in that the amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 1.5-2.5 equivalents calculated according to the molar amount of the compound of formula (III).

[0116] E23. The method according to E22 is characterized in that the amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 1.5-2.2 equivalents calculated according to the molar amount of the compound of formula (III).

[0117] E24. Use of N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacetamide hydrochloride of formula (III) in the preparation of vocinib.

[0118] E25. According to the method of E1, the compound of formula (III) obtained by reacting (R)-1,1,1-trifluoropropane-2-amine hydrochloride of formula (II) with sodium dicyandiamide is not subjected to any purification or separation before reacting with methyl 6-chloropyridine-2-carboxylate.

[0119] E26. The method according to E25 is characterized in that the solvent used for the reaction of compound (II) with sodium dicyandiamide is tert-butanol, and the solvent used for the reaction of compound (II) with methyl 6-chloropyridine-2-carboxylate is a mixture of methanol and tert-butanol.

[0120] E27. The method according to E25 or E26, characterized in that the reaction of compound (II) with sodium dicyandiamide:

[0121] - Performed at a temperature of 85℃-140℃

[0122] - The concentration is calculated based on the amount of sodium dicyandiamide, ranging from 8 mL / g to 34 mL / g.

[0123] E28. The method according to any one of E25-E27, characterized in that the amount of compound of formula (II) used to react with sodium dicyandiamide is 1.9-3 equivalents calculated based on the molar amount of sodium dicyandiamide, preferably 1.9-2.5 equivalents calculated based on the molar amount of sodium dicyandiamide.

[0124] E29. The method according to any one of E25-E28, characterized in that the base used for the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is MeONa, and the amount used is 0.8-2 equivalents calculated based on the molar amount of sodium dicyandiamide, preferably 1.5-2 equivalents calculated based on the molar amount of sodium dicyandiamide.

[0125] E30. The method according to any one of E25-E29, characterized in that the amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 0.8-3 equivalents based on the molar amount of sodium dicyandiamide, preferably 1.5-2.5 equivalents based on the molar amount of sodium dicyandiamide, and more preferably 1.5-2.2 equivalents based on the molar amount of sodium dicyandiamide.

[0126] E31. The method according to any one of E25-E30, characterized in that the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is carried out at a concentration of 5 mL / g to 10 mL / g, calculated from the theoretical amount of compound (III) obtained when the reaction of compound (II) with sodium dicyandiamide is completed.

[0127] E32. The method according to any one of E25-E31, characterized in that the reaction of the compound of formula (III) with methyl 6-chloropyridine-2-carboxylate is carried out at a temperature of 20°C-50°C, preferably at a temperature of 20°C-40°C.

[0128] E33. The method according to any one of E1-E32, characterized in that the vocinib of formula (I) is further converted into a hemicitric acid hemihydrate eutectic.

[0129] Example

[0130] abbreviation

[0131]

[0132] Data were collected using a Bruker 400MHz NMR spectrometer. 1 1H liquid-phase NMR spectra. Chemical shifts relative to tetramethylsilane (TMS) are given in ppm using partially deuterated dimethyl sulfoxide (DMSO) as an internal standard. In partially deuterated DMSO solution, the resonance at 2.5 ppm on the 1D 1H NMR spectrum is attributed to the partially deuterated DMSO, and the resonance at 3.30 ppm is attributed to the presence of water.

[0133] In this experimental section, the following terms are used:

[0134] The (R)-1,1,1-trifluoropropane-2-amine hydrochloride of formula (II) is called Cpd2.

[0135] • The N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacetamide hydrochloride of formula (III) is called Cpd 3.

[0136] Methyl 6-chloropyridine-2-carboxylate is called Cpd 4.

[0137] LC conditions

[0138] Column: Acquity UPLC BEH C18 (50 mm × 2.1 mm) - Injection volume: 0.5 µL - Analysis time: 5.6 min - Temperature: 40℃ - Wavelength: 210 nm - Eluent: Phase A H2O / MeCN / MSA (1000:25:1), Phase BH2O / MeCN / MSA (25:1000:1) - Elution: t(0-1 min) A 95%, B 5%; t(1-4.5 min) A 95%, B 5% → A 5%, B 95%; t(4.5-5.5 min) A 5%, B 95% - Flow rate: 0.8 mL / min.

[0139] Retention time

[0140] Cpd2: 1.50 minutes

[0141] Cpd 3: 2.03 minutes

[0142] Vocinnib free form: 2.85 minutes

[0143] Example 1: Preparation of N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacetamide hydrochloride Filtering based on conditions

[0144]

[0145] Sodium dicyandiamide (1.8 g, 20.1 mmol, 1.0 equivalent), Cpd₂ (2.1-3 equivalents, see Table 1), and solvent (8-34 mL / g based on the amount of sodium dicyandiamide) were added to a reactor equipped with a mechanical stirrer at 35 °C under a nitrogen atmosphere. The reaction mixture was heated to 65-115 °C (see Table 1) and stirred at this temperature for the times indicated in Table 1. After cooling to 35 °C, the reaction progress was monitored by LC.

[0146] Table 1

[0147]

[0148] *This trial was conducted at a 60 mg scale.

[0149] Example 2: Preparation of N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbonate in tert-butanol Screening of conditions for amide hydrochloride (Cpd 3)

[0150] The same general procedure as used in Example 1 was employed. The dilution of the reaction medium was set at 17 mL / g, calculated based on the amount of sodium dicyandiamide.

[0151] Table 2

[0152]

[0153] Example 3: Preparation from N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacetamide hydrochloride Screening of conditions for the free form of voxifenib

[0154]

[0155] In a nitrogen atmosphere at 20°C, Cpd 3 (4 g, 12.1 mmol, 1.0 equivalent), Cpd 4 (0.8-2 equivalent, see Table 3), and solvent (5-10 mL / g calculated based on the amount of Cpd 3) were added to a reactor equipped with a mechanical stirrer. The reaction mixture was heated to 20-80°C (see Table 3), and base (1 equivalent-equivalent, see Table 3) was added dropwise (or in batches for solid bases) to the reaction mixture. After stirring the reaction mixture at the temperatures specified in Table 3 for the times indicated, the reaction progress was monitored by LC.

[0156] Sometimes the reaction mixture is cooled to 20°C and diluted with water (5 mL / g), and the mixture is stirred for 3 hours. The suspension is filtered, and the cake is washed with a 1:1 mixture of methanol (1 mL / g) and water (1 mL / g). The solid is then dried in a ventilated oven at 40°C for 24 hours to give the free form of voxincone.

[0157] Table 3

[0158]

[0159] Example 4: Synthesis of vocinib hemicitric acid hemihydrate eutectic

[0160] Step 1: N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbamide salt of formula (III) Preparation of acid salts

[0161] Sodium dicyandiamide (0.35 kg, 3.9 mol, 1.0 equivalent), Cpd₂ (1.25 kg, 8.3 mol, 2.1 equivalent), and tert-butanol (5.9 L, 16.7 volume) were added to an 8 L reactor equipped with a mechanical stirrer at 35 °C under a nitrogen atmosphere. The reaction mixture was heated to 130 °C and stirred at 130 °C for 4 hours. After cooling to 35 °C, the reaction progress was monitored by LC.

[0162] The reaction mixture was diluted with isopropanol (2.4 L, 7 volumes) at 35 °C, and the mixture was stirred for 30 minutes. The suspension was filtered, and the cake was washed with isopropanol (0.7 L, 2 volumes). The solid was then dried in a ventilated oven at 40 °C for 72 hours to give Cpd 3 (1.03 kg, 3.1 mol, yield 80%, LC purity 83%).

[0163] 1H NMR analysis of Cpd 3

[0164] 1 H NMR (400 MHz; DMSO-d6) δ: 8.48 (br s, 2H), 7.47 (br s, 4H), 4.57 (m, 2H), 1.27 (d, J = 8.0 Hz, 6H).

[0165] Step 2: Preparation of voxinib

[0166] In a nitrogen atmosphere at 20°C, Cpd 3 (1 kg, 3.0 mol, 1.0 equivalent), Cpd 4 (0.78 kg, 4.5 mol, 1.5 equivalent), and methanol (5 L, 5 volumes) were added to a 22 L reactor equipped with a mechanical stirrer. The reaction mixture was heated to 50°C, and sodium methoxide (30%, in methanol, 1.1 kg, 6.0 mol, 2.0 equivalent) was added dropwise. After stirring at 50°C for 3 hours, the reaction progress was monitored by LC.

[0167] The reaction mixture was cooled to 20°C and diluted with water (5 L, 5 volumes), and the mixture was stirred for 3 hours. The suspension was filtered, and the cake was washed with a 1:1 mixture of methanol (1.5 L, 1.5 V) and water (5 L, 5 volumes). The solid was then dried in a ventilated oven at 40°C for 24 hours to give voxifenib in its free form (0.79 kg, 1.9 mol, yield 69%, LC purity 99%).

[0168] Voshineb 1 H NMR analysis

[0169] 1 H NMR (400 MHz; DMSO-d6) δ: 8.59, 8.48 and 8.20 (m, 2H), 8.35 and 8.25 (m, 1H), 8.03 (t, J = 8 Hz, 1H), 7.67 (d, J = 4 Hz, 1H), 5.11–4.89 (m, 2H), 1.34 (d, J = 8.0 Hz, 6H).

[0170] Step 3: Preparation of eutectic of vocinib and citric acid

[0171] In a nitrogen atmosphere, a solution of acetone / n-heptane 9:1 v / v (0.26 kg) and the free form of vocinib obtained according to the methods disclosed in steps 1 and 2 (57.6 g, 0.14 mol, 1.0 equivalent) were added to a 500 mL reactor equipped with a mechanical stirrer. Once dissolved, citric acid monohydrate (15 g, 0.07 mol, 0.51 equivalent) was added to the reaction mixture at 30 °C and stirred until completely dissolved. The reaction mixture was finely filtered and transferred to another reactor. It was washed with a solution of acetone / n-heptane 9:1 v / v (32 g). N-heptane (51.6 g) was added to the purified solution over 1 hour. Then, vocinib hemicitric acid hemihydrate eutectic seed crystals (1.26 g, 1.21 mmol, 0.8% equivalent) were added at approximately 30 °C, and the mixture was stirred at 30 °C for 45 minutes. Then, n-heptane (0.62 kg) was added over 4.5 hours to control eutectic formation. The suspension was maintained at 32°C for 1 hour, cooled to 10°C for 2.5 hours, and stirred at 10°C for 12 hours. The suspension was then wet-milled to PSD specifications. Finally, the slurry was filtered, and the cake was washed twice with a mixture of acetone / n-heptane (1:3.2 v / v) (98 g). The wet solid was vacuum-dried at approximately 30°C for 4 days to obtain a eutectic of vocinib hemicitric acid hemihydrate (64.7 g, 111 mol, yield 90%, LC purity 99%).

[0172] Example 5: One-pot preparation of vocinib in free form

[0173] A. Reaction conditions for step 1 of Example 1

[0174] Sodium dicyandiamide (1.8 g, 20.1 mmol, 1.0 equivalent), Cpd₂ (7.5 g, 50.2 mmol, 2.1 equivalent), and tert-butanol (30 mL, 16.7 volume) were added to a 100 mL reactor equipped with a mechanical stirrer at 25 °C under a nitrogen atmosphere. The reaction mixture was heated to 115 °C and stirred at 115 °C for 3 hours. After cooling to 30 °C, the reaction progress was monitored by LC until the amount of Cpd₂ was ≤5%. The reaction mixture was then partially concentrated and proceeded to the second step without any separation or purification.

[0175] B. Reaction conditions in step 2 of Example 1

[0176] In a nitrogen atmosphere at 20°C, a solution of Cpd3 in tert-butanol (total volume 20 mL), Cpd4 (5.2 g, 30.1 mmol, 1.5 equivalents), and methanol (30 mL, 16.7 volume) were added to a 250 mL reactor equipped with a mechanical stirrer. The reaction mixture was heated to 40°C, and sodium methoxide (25%, in methanol, 8.6 mL, 37.6 mmol, 1.9 equivalents) was added to the reaction mixture over 2 hours. After stirring at 40°C for 2 hours, the reaction progress was monitored by LC until the amount of Cpd3 was ≤5%.

[0177] The equivalent in the second step is calculated based on the molar amount of sodium dicyanamide used in step A, taking into account the complete conversion of the sodium dicyanamide in Cpd 3 that occurs during step A.

[0178] The concentration of the reaction medium in step B is 5 mL / g to 10 mL / g, which is calculated based on the theoretical amount of Cpd 3 if step A has a 100% yield (complete reaction).

[0179] C. Post-processing / Separation

[0180] The reaction mixture was cooled to 20°C and diluted with water (59.5 mL, 33.3 vol), and the mixture was stirred for 12 hours. The suspension was filtered, and the cake was washed with a 1:4.2 mixture of methanol (5.4 mL, 3 vol) and water (17.9 L, 10 vol). The solid was then dried in a ventilated oven at 50°C for 24 hours to give voxifenib in its free form (4.29 g, 10.3 mmol, yield 52%, LC purity 99%).

[0181] Example 6: According to Nandini R. Pai et al. (Der Pharma Chemica, 2014, 6, 176-187) The disclosed content prepares N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbamide salt of formula (III). Salt

[0182] Sodium dicyandiamide (0.3 g, 3.3 mmol, 1.0 equivalent) and Cpd 2 (2 equivalent) were mixed together in n-butanol or isobutanol to reproduce the reaction disclosed in Nandini R. Pai et al.

[0183] The results are summarized in the table below.

[0184]

[0185] A few drops of HCl need to be added to the mixture.

[0186] Despite prolonged contact time, the reaction occurred only partially in both cases, making it impossible to separate Cpd 3 in good yield.

[0187] Example 7: N,N'-bis[(2R)-1,1,1-trifluoropropionic acid] was prepared according to the method disclosed in WO 2015 / 003640. 2-yl]triiminodiacetamide hydrochloride

[0188] Sodium dicyandiamide (2 g, 22.5 mmol, 1.0 equivalent) and Cpd 2 (6.7 g, 44.9 mmol, 2 equivalent) were heated at 160 °C for 18 hours. The reaction mixture was then cooled to 25 °C and diluted with water (5 mL / g) and isopropanol (5 mL / g). When analyzed by LC, only 4% of Cpd 3 was observed in the mixture.

[0189] These operating conditions cannot effectively prepare Cpd 3.

[0190] Example 8: Preparation of N,N'-bis[(2R)-1,1,1-trifluoropropionic acid] according to the method disclosed in WO 2015 / 003640 Optimized conditions for 2-yl]triiminodiacarbamide hydrochloride

[0191] To improve the method disclosed in Example 7, optimized conditions were tested, particularly by adjusting the amount of Cpd 2 (2.35 equivalents) and reducing the temperature (approximately 95°C).

[0192] Sodium dicyandiamide (2 g, 22.5 mmol, 1.0 equivalent) and Cpd 2 (7.9 g, 52.8 mmol, 2.35 equivalent) were heated at 40 °C for 12 h and then at 95 °C (reflux) for 10 h. The reaction mixture was then cooled to 25 °C and diluted with water (10 mL / g) and isopropanol (10 mL / g). The suspension was filtered to give only 4% Cpd 3.

[0193] Even with optimized parameters, these operating conditions could not produce Cpd 3 in good yield without solvent.

[0194] Furthermore, these conditions are not suitable for scaling up and application on an industrial scale due to the risks associated with heating powder at high temperatures.

[0195] Example 9: Preparation of voxinib on a pilot-scale basis

[0196] Step 1: N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbamide salt of formula (III) Preparation of acid salts

[0197] Sodium dicyandiamide (2.50 kg, 28 mol, 1.0 equivalent), Cpd₂ (9.87 kg, 66 mol, 2.35 equivalent), and tert-amyl alcohol (25 L, 10 volumes) were added to a 100 L reactor equipped with a mechanical stirrer at 25 °C under a nitrogen atmosphere. The reaction mixture was stirred at 40 °C and then at 95 °C (reflux) until the Cpd₂ concentration passed by LC was ≤2%.

[0198] Post-processing / separation

[0199] The reaction mixture was diluted with water (18.75 L, 7.5 volumes) at 25 °C and stirred for 1 hour. The suspension was filtered and the cake was washed with isopropanol (12.5 L, 5 volumes). The solid was then dried in a ventilated oven at 50 °C for 48 hours to give Cpd 3 (7.07 kg, 21 mol, yield 76.4%, LC purity >99%).

[0200] 1H NMR analysis of Cpd 3

[0201] 1 H NMR (400 MHz; DMSO-d6) δ: 8.48 (2H, NH), 7.47 (4H, NH), 4.57 (m,2H, CH), 1.27 (d, J = 8.0 Hz, 6H, CH3).

[0202] Step 2: Preparation of voxinib

[0203] In a nitrogen atmosphere at 25°C, Cpd 3 (7 kg, 21 mol, 1.0 equivalent), Cpd 4 (8.01 kg, 47 mol, 2.2 equivalent), and methanol (35 L, 5 volumes) were added to a 100 L reactor equipped with a mechanical stirrer. Sodium methoxide (30%, in methanol, 7.64 kg, 42 mol, 2 equivalent) was added dropwise to the reaction mixture over 1 hour. After stirring at 25°C for 12 hours, the reaction progress was monitored by LC until Cpd 3 ≤ 1%.

[0204] Post-processing / separation

[0205] The reaction mixture was diluted with water (35 L, 5 volumes) and stirred for 3 hours. The suspension was filtered, and the cake was washed with a 1:1 mixture of methanol (10.5 L, 1.5 V) and water (10.5 L, 1.5 volumes). The solid was then dried in a filter at 50 °C for 24 hours to give voxifenib in its free form (8.06 kg, 19 mol, yield 92%, LC purity >99%).

[0206] 1H NMR analysis of vocinib

[0207] 1 ¹H NMR (400 MHz; DMSO-d6) δ: 8.59, 8.48 and 8.20 (2H, NH), 8.35 and 8.25 (1H, CH) Ar ), 8.03 (t, J = 8 Hz, 1H, CH Ar), 7.67 (d, J = 4 Hz, 1H, CH Ar ), 5.11-4.89 (m, 2H, CH), 1.34 (d, J = 8.0 Hz, 6H, CH3).

[0208] Step 3: Preparation of eutectic of vocinib and citric acid

[0209] In a nitrogen atmosphere, an acetone / n-heptane solution (9:1 v / v) of 0.26 kg and vocitinib in its free form (57.6 g, 0.14 mol, 1.0 equivalent) were added to a 500 mL reactor equipped with a mechanical stirrer. Once completely dissolved, citric acid monohydrate (15 g, 0.07 mol, 0.51 equivalent) was added to the reaction mixture at 30 °C and stirred until completely dissolved. The reaction mixture was then filtered and transferred to another reactor. The reactor was rinsed with an acetone / n-heptane solution of 32 g (9:1 v / v).

[0210] 51.6 g of n-heptane was added to the purified solution over 1 hour. Then, 1.26 g (1.21 mmol, 0.8% equivalent) of vocinib hemicitric acid hemihydrate seed crystals were added at approximately 30 °C, and the mixture was stirred at 30 °C for 45 minutes. Next, 0.62 kg of n-heptane was added over 4.5 hours to control eutectic formation. The suspension was maintained at 32 °C for 1 hour, cooled to 10 °C for 2.5 hours, and stirred at 10 °C for 12 hours. The suspension was then wet-milled. Finally, the slurry was filtered, and the cake was washed twice with a mixture of acetone / n-heptane (1:3.2 v / v) (98 g). The wet solid was vacuum-dried at approximately 30 °C for 4 days to obtain vocinib hemicitric acid hemihydrate (64.7 g, 111 mol, yield 89%, LC purity 99%).

Claims

1. A method for preparing voxinib of formula (I): This method involves making (R)-1,1,1-trifluoropropane-2-amine hydrochloride of formula (II): Reaction with sodium dicyandiamide The reaction is carried out in an alcoholic solvent selected from methanol, isopropanol, isobutanol, tert-butanol, tert-amyl alcohol (i.e., 2-methylbut-2-ol), cyclopentanol, and cyclohexanol, or in isobutyl acetate, at a temperature of 65°C–140°C. The N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacarbamide hydrochloride of formula (III) is obtained: The compound of formula (III) was then reacted with methyl 6-chloropyridine-2-carboxylate. The reaction is carried out in a solvent selected from alcohols and acetonitrile in the presence of a base at a temperature of 20°C–80°C. They obtained Voshineb.

2. The method according to claim 1, characterized in that... The solvent used for the reaction of compound (II) with sodium dicyandiamide is an alcohol solvent, selected from tert-butanol, tert-amyl alcohol (i.e., 2-methylbut-2-ol), isopropanol and cyclohexanol.

3. The method according to claim 2, characterized in that... The solvent used for the reaction of compound (II) with sodium dicyandiamide is tert-butanol or tert-amyl alcohol (i.e., 2-methylbut-2-ol).

4. The method according to any one of claims 1-3, characterized in that... The reaction of compound (II) with sodium dicyandiamide was carried out at a temperature of 85℃-140℃.

5. The method according to any one of claims 1-4, characterized in that... The solvent used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is an alcohol selected from methanol, ethanol, isopropanol, tert-butanol, and mixtures of methanol and tert-butanol.

6. The method according to any one of claims 1-5, characterized in that... The base used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is selected from MeONa, tBuOK, K2CO3, Cs2CO3, NaOH, KOH, LiOH and K3PO4.

7. The method according to any one of claims 1-6, characterized in that... The solvent used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is methanol, and the base used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is MeONa or tBuOK (i.e., potassium tert-butoxide).

8. The method according to any one of claims 1-7, characterized in that... The reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate was carried out at a temperature of 20°C to 50°C.

9. The method according to claim 8, characterized in that... The reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate was carried out at a temperature of 20°C-40°C.

10. The method according to claim 1, characterized in that: - The solvent used for the reaction of compound (II) with sodium dicyandiamide is tert-butanol or tert-amyl alcohol (i.e., 2-methylbut-2-ol). The reaction of compound (II) with sodium dicyandiamide is carried out at temperatures between 85°C and 140°C. - The solvent used for the reaction of compound (II) with methyl 6-chloropyridine-2-carboxylate is methanol. - The base used for the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is MeONa. The reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate was carried out at a temperature of 20°C to 50°C.

11. The method according to any one of claims 1-10, characterized in that... The solvent used for the reaction of compound (II) with sodium dicyandiamide is tert-amyl alcohol (i.e., 2-methylbut-2-ol).

12. The method according to any one of claims 1-11, characterized in that... The reaction of compound (II) with sodium dicyandiamide was carried out at a concentration of 8 mL / g to 34 mL / g, calculated based on the amount of sodium dicyandiamide.

13. The method according to any one of claims 1-12, characterized in that... The amount of compound (II) used to react with sodium dicyandiamide is 1.9–3 equivalents calculated based on the molar amount of sodium dicyandiamide.

14. The method according to claim 13, characterized in that... The amount of compound of formula (II) used to react with sodium dicyandiamide is 1.9-2.5 equivalents calculated based on the molar amount of sodium dicyandiamide.

15. The method according to any one of claims 1-14, characterized in that... The amount of base used to carry out the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is 0.8-2 equivalents calculated based on the molar amount of compound (III).

16. The method according to claim 15, characterized in that... The amount of base used to carry out the reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate is 1.5-2 equivalents calculated based on the molar amount of compound (III).

17. The method according to any one of claims 1-16, characterized in that... The reaction of compound (III) with methyl 6-chloropyridine-2-carboxylate was carried out at a concentration of 5 mL / g to 10 mL / g, calculated based on the amount of compound (III).

18. The method according to any one of claims 1-17, characterized in that... The amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 0.8-3 equivalents calculated based on the amount of the compound of formula (III).

19. The method according to claim 18, characterized in that... The amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 1.5 to 2.5 equivalents calculated based on the molar amount of the compound of formula (III).

20. The method according to claim 19, characterized in that... The amount of methyl 6-chloropyridine-2-carboxylate used to react with the compound of formula (III) is 1.5 to 2.2 equivalents calculated based on the molar amount of the compound of formula (III).

21. Use of N,N'-bis[(2R)-1,1,1-trifluoroprop-2-yl]triiminodiacetamide hydrochloride of formula (III) in the preparation of vocinib.

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