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EP-4741388-A1 - GLP1R AGONIST AND PREPARATION METHOD FOR INTERMEDIATE THEREOF

EP4741388A1EP 4741388 A1EP4741388 A1EP 4741388A1EP-4741388-A1

Abstract

A GLPIR agonist and a preparation method for an intermediate thereof, and particularly, a preparation method for 2-(2-fluoro-4-(oxetane-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine and (S)-2-((4-(6-((2-fluoro-4-(oxetane-3-yl)methyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid. The preparation method has the advantages of low potential safety hazards, controllable cost, stable raw materials, and good yield, and is more suitable for industrial production.

Inventors

  • HAN, Mingliang
  • GUAN, Tihong
  • ZHENG, JUNHAO
  • Wang, Pengfei

Assignees

  • Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240701

Claims (14)

  1. A method for preparing 2-(2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI), comprising the steps of: a-1) dissolving Compound X in an organic solvent, adding Compound 1 to react in the presence of a base to obtain Compound X-1: a-2) removing the amino protecting group R using a suitable solvent and suitable reaction conditions to obtain the Compound XI: wherein said R is independently selected from the group consisting of benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, p-toluenesulfonyl, phthaloyl and allyloxycarbonyl; and said Rx is selected from the group consisting of Cl, Br and I, preferably Cl.
  2. The method according to claim 1, wherein the organic solvent used in Step a-1) is an aprotic solvent selected from the group consisting of dioxane, N,N-dimethyl formamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, toluene, tetrahydrofuran, pyridine and 2-methyl tetrahydrofuran, preferably dioxane, or toluene; and/or, the base used in Step a-1) is selected from the group consisting of sodium hydroxide, sodium bicarbonate, lithium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, n-butyl lithium, lithium diisopropylamide and lithium hexamethyldisilazide, preferably potassium tert-butoxide, or potassium hydroxide.
  3. The method according to claim 1, wherein the molar feed ratio of the base to Compound 1 used in Step a-1) is 1:1 ~ 4:1, preferably 1:1 ~ 3:1; and/or, the molar feed ratio of Compound X to Compound 1 in Step a-1) is 3:1 ~ 1:1; and/or, after adding Compound X and Compound 1, the temperature can be controlled at T1 and then reduced to room temperature in Step a-1); and/or, said T1 in Step a-1) is selected from 30 ~ 130°C, preferably 60 ~ 100°C.
  4. The method according to claim 1, wherein the solvent used in Step a-2) is selected from the group consisting of dichloromethane, methanol, tetrahydrofuran, ethyl acetate, chloroform, acetonitrile and DMF, preferably dichloromethane; and/or, the reaction temperature in Step a-2) is selected from -20 to 50°C.
  5. A method for preparing (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)methyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzoimidazole-6-carboxylic acid (Formula I), comprising the steps of: a-3) dissolving Compound XI in an organic solvent, adding a base and Compound V to react to obtain Compound VI: a-4) dissolving Compound VI in an organic solvent, adding a base to react to obtain Compound I:
  6. The method according to claim 5, wherein the organic solvent used in Step a-3) is selected from the group consisting of acetonitrile, N,N-dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, N,N-dimethyl formamide and n-hexane, preferably N,N-dimethyl formamide; and/or, the molar feed ratio of the compound of Formula XI to the compound of Formula V in Step a-3) is 1:1 ~ 2:1; and/or, the molar ratio of the base to Compound XI used in Step a-3) is 1:1 ~ 3:1.
  7. The method according to claim 5, wherein the organic solvent used in Step a-4) is one or more selected from the group consisting of methanol, ethanol, isopropanol, n-butanol and tert-butanol, preferably methanol; and/or, the molar ratio of the base to Compound VI used in Step a-4) is 1:1 ~ 5:1.
  8. The method according to claim 1 and the method according to claim 5, wherein after the completion of the Step a-1), Step a-2), Step a-3) or Step a-4), post-reaction treatment can be optionally independently performed, wherein the post-treatment includes one or more of extraction, washing, drying, concentration and filtration.
  9. A compound of Formula I prepared by the method according to claim 5.
  10. The compound of Formula I according to claim 9 with a purity of more than 99%.
  11. A compound of Formula XI prepared by the method according to claim 1.
  12. The compound of Formula XI according to claim 11 with a purity of more than 98%.
  13. Use of the method for preparing 2-(2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI) according to claim 1 in the preparation of the compound of Formula I, (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)methyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzoimidazole-6-carboxylic acid.
  14. Use of the compound of Formula I prepared by the method according to claim 5, and the compound of Formula I according to claim 9 or 10, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating GLP-1 receptor mediated diseases or disorders and related diseases or disorders, wherein the GLP-1 receptor mediated diseases and related diseases are preferably selected from the group consisting of diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, etc.; wherein the diabetes includes but is not limited to T1D and/or T2DM, idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, atypical diabetes in adolescents, and gestational diabetes, etc.

Description

Technical Field The present invention belongs to the technical field of drug synthesis, and specifically relates to methods for preparing 2-(2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI), an intermediate of a GLP-1 receptor agonist, and (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)methyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzoimidazole-6-carboxylic acid (Formula I). Background (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)methyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzoimidazole-6-carboxylic acid (the compound of Formula I) is a non-peptide small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist with a molecular weight of 586.26 and a chemical structural formula as follows: Patent of invention WO 2022/268152 A1 discloses for the first time the compound of Formula I, and a feasible preparation method thereof in which 3-(4-(bromomethyl)-3-fluorophenyl)oxetane and tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate are used as raw materials, and subjected to nucleophilic substitution and deprotection of Boc to obtain Intermediate XI of the present invention (the specific steps are as follows) which then gives the compound of Formula I through substitution and hydrolysis reactions. Among others, 3-(4-(bromomethyl)-3-fluorophenyl)oxetane is obtained by bromination of a benzyl alcohol derivative, and tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate is obtained by hydroxylation of a 6-chloropyridine derivative catalyzed by a palladium catalyst. In kilogram order, scale-up synthesis tests on the above route, the raw material 3-(4-(bromomethyl)-3-fluorophenyl)oxetane is unstable and highly sensitized. Even under suitable protection, laboratory personnel still suffer from skin rashes or ulcers, which poses potential safety hazards in industrial production. In addition, the hydroxyl group at 6-position of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate needs to be obtained by conversion of a chloropyridine derivative in the presence of a noble metal palladium catalyst, resulting in high cost. Therefore, there is a great demand for developing a process route with stable raw materials, controllable cost and facile production. Summary of the Invention To overcome the problems of unstable and highly sensitized raw materials or high cost mentioned in the Background, the present invention provides a novel method for preparing 2-(2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI). This method overcomes the instability and potential safety hazards of 3-(4-(bromomethyl)-3-fluorophenyl)oxetane, effectively simplifies the steps and reduces the cost of raw materials, the process of which is as follows: wherein R is an amino protecting group independently selected from one of benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht) and allyloxycarbonyl (Alloc); wherein Rx is selected from the group consisting of Cl, Br and I, for example, Cl. In the method provided in the present invention, Compound 1 and a 6-halopyridine derivative are used as raw materials to generate Compound X-1 through a nucleophilic substitution reaction and give the compound of Formula XI after removing the amino protecting group. Then, the compound of Formula I is obtained from the compound of Formula XI through steps such as substitution and hydrolysis. Detailed Description of the Invention The present invention provides a novel method for preparing 2-(2-fluoro-4-(oxetan-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI), comprising the following steps: a-1) dissolving Compound X in an organic solvent, adding Compound 1 to react in the presence of a base to obtain Compound X-1: a-2) removing the amino protecting group R using a suitable solvent and suitable reaction conditions to obtain Compound XI: wherein said R is independently selected from the group consisting of benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, p-toluenesulfonyl, phthaloyl and allyloxycarbonyl; and said Rx is selected from the group consisting of Cl, Br and I, for example, Cl. In some embodiments, said R is independently selected from the group consisting of benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, p-toluenesulfonyl, phthaloyl and allyloxycarbonyl, preferably tert-butyloxycarbonyl. In some embodiments, the organic solvent used in Step a-1) is an aprotic solvent selected from the group consisting of dioxane, N,N-dimethyl formamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, toluene, tetrahydrofuran, pyridine and 2-methyl tetrahydrofuran, preferably dioxane, or toluene. In some embodiments, the base used in Step a-1) is selected from the group consisting of sodium hydroxide, sodium bicarbonate, lithium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide,