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CN-122010861-A - Buronate clamp Process for the preparation of a medicament

CN122010861ACN 122010861 ACN122010861 ACN 122010861ACN-122010861-A

Abstract

The invention provides a preparation method of a Brillouin cassiterite, which is characterized in that a new intermediate compound 4 is condensed with an intermediate compound 5 by utilizing a condensing agent to obtain an intermediate compound 6, then a dehydration reagent is utilized to complete the reaction of converting an amide group into a cyano group to obtain an intermediate compound 7, and finally the intermediate compound 7 is subjected to Boc removal and free and then crystallized in a hydrate form to obtain a target product of the Brillouin cassiterite hydrate compound 8.

Inventors

  • ZHANG YIPING
  • LIU QIAOLING
  • ZHENG XUCHUN

Assignees

  • 杭州科巢生物科技有限公司

Dates

Publication Date
20260512
Application Date
20260403

Claims (10)

  1. 1. An intermediate hydrochloride compound 4 of brinskabat, characterized by the following structural formula: 。
  2. 2. a process for the preparation of intermediate hydrochloride compound 4 of brinskabat, characterized by comprising the steps of: (1) Coupling the compound 1A with a borate intermediate compound 2 under the action of a palladium catalyst to obtain a compound 3A; Removing Boc from the compound 3A under the action of acid and salifying to obtain an intermediate 4; 。
  3. 3. The preparation method of the intermediate hydrochloride compound 4 of the brinsucatine according to claim 2, wherein in the coupling reaction in the step (1), the palladium catalyst is selected from palladium acetate, palladium chloride, palladium pivalate, pd (dppf) Cl 2 , ditriphenylphosphine palladium dichloride, tetra-triphenylphosphine palladium or Pd 2 (dba) 3 or di-tert-butylphenylphosphine palladium dichloride, no ligand or ligand is selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine or di-tert-butylphenylphosphine, the base is selected from triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaniline, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate or cesium carbonate, and the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, N-butyl acetate, toluene, methanol, ethanol, isopropanol, N-butanol, tert-amyl alcohol, acetonitrile, 1, 4-dioxane, water or a mixture of any two of them.
  4. 4. The method for preparing the intermediate hydrochloride compound 4 of the brinsucatine according to claim 2, wherein the step (2) is a Boc-protecting reaction, wherein the Boc protecting group is removed by acid hydrolysis, wherein the acid is selected from sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and trifluoromethanesulfonic acid, and wherein the reaction solvent is selected from methanol, ethanol, isopropanol, dichloromethane, toluene, acetonitrile, 1, 4-dioxane, tetrahydrofuran, acetic acid, ethyl acetate, isopropyl acetate, water and a mixed solvent formed by any two of the solvents.
  5. 5. A process for the preparation of intermediate hydrochloride compound 4 of brinskabat, characterized by comprising the steps of: (1) Coupling the compound 1B and a borate intermediate compound 2 under the action of a palladium catalyst to obtain a compound 3B; (2) Reacting the compound 3B with an amination reagent under the catalysis of transaminase and coenzyme, and salifying with hydrochloric acid to obtain an intermediate 4; 。
  6. 6. The preparation method of the intermediate hydrochloride compound 4 of the brinsucatine according to claim 5, wherein in the coupling reaction in the step (1), the palladium catalyst is selected from palladium acetate, palladium chloride, palladium pivalate, pd (dppf) Cl 2 , ditriphenylphosphine palladium dichloride, tetra-triphenylphosphine palladium or Pd 2 (dba) 3 , di-tert-butylphenylphosphine palladium dichloride, no ligand or ligand is selected from triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine or di-tert-butylphenylphosphine, the base is selected from triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaniline, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate or cesium carbonate, and the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, N-butyl acetate, toluene, methanol, ethanol, isopropanol, N-butanol, tert-amyl alcohol, acetonitrile, 1, 4-dioxane, water or a mixture of any two of them.
  7. 7. The process for the preparation of an intermediate hydrochloride compound 4 of brinzoate according to claim 5 wherein the aminotransferase of step (2) is selected from the group consisting of commercial aminotransferases, preferably KC-ATA-212, KC-ATA-235, KC-ATA-353, or a cured aminotransferase supported on an amino resin; the amino resin is preferably SEPABEADS, EC-HFA/S, LX-1000HFA, LX-HFA001; the coenzyme is pyridoxal 5-phosphate, the amination reagent is selected from isopropylamine, L-alanine, (S) -1-phenylethylamine, (R) -1-phenylethylamine or pharmaceutically acceptable salts thereof, the reaction solvent is selected from dimethyl sulfoxide, methanol, ethanol, isopropanol, methyl tertiary butyl ether, isopropyl ether, ethyl acetate, isopropyl acetate, n-butyl acetate or water and mixed solvents formed by any two of the two, the pH value of the buffer solution used in the reaction is regulated, the buffer solution buffer is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, hydrochloric acid, phosphoric acid, tris (hydroxymethyl) aminomethane hydrochloride and mixed buffer solution systems formed by any two of the two, and the salifying solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, methanol, ethanol, isopropanol, n-butanol, tert-butyl alcohol, tert-amyl alcohol, acetonitrile, acetone, 1, 4-dioxane and water.
  8. 8. The preparation method of the brinskabat is characterized by comprising the following steps of: (1) The compound 4 and the compound 5 are subjected to condensation reaction under the action of alkali and a condensing agent to obtain a compound 6; (2) Dehydrating the amide of the compound 6 under the action of a base and a dehydrating agent to form a cyano group to obtain a compound 7; (3) Removing Boc from the compound 7 under the action of acid to obtain a Brillouin product; 。
  9. 9. The process of claim 7, wherein the condensing agent in step (1) is selected from Carbonyl Diimidazole (CDI), isobutyl Chloroformate (ICBF), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/1-Hydroxybenzotriazole (HOBT) combination, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/2-hydroxypyridine-N-oxide (HOPO) combination, O-benzotriazole-tetramethylurea Hexafluorophosphate (HBTU), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC) or N, N ' -Diisopropylcarbodiimide (DIC), T3P, T, P, BOP or PyBOP, and the base is selected from diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5.4.0] undecene-7-diamine, dimethylmorpholine, dimethylformamide, and mixtures thereof, and the solvent is selected from dimethyl formamide, and mixtures thereof.
  10. 10. The preparation method of the brinsatide according to claim 7, wherein in the dehydration reaction of the step (2), a dehydrating agent is selected from trifluoromethanesulfonic anhydride, phosphorus pentoxide, phosphorus oxychloride, trifluoroacetic anhydride, chlorosulfonyl isocyanate, trichloroisocyanuric acid (TCCA) or Burgess reagent, no alkali is added or an organic alkali is added, the dehydrating agent is selected from triethylamine, diisopropylethylamine, pyridine, 2, 6-lutidine or DBU, the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, DMSO, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, N-butyl acetate, toluene, acetonitrile, dichloromethane, 1, 4-dioxane or a mixed solvent formed by two of any two of them, the step (3) is used for the deprotection reaction of Boc protecting groups, the acid is selected from sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, the reaction solvent is selected from ethanol, isopropanol, 1, 4-dioxane, isopropanol, ethyl acetate or a mixed solvent formed by any two of these solvents.

Description

Buronate clamp Process for the preparation of a medicament Technical Field The invention belongs to the field of pharmaceutical chemical industry, and relates to a preparation method of a drug, namely, a bruxism drug, for treating non-cystic fibrosis bronchiectasis. Background Brillouin Carnot (Brensocatib) is an oral drug for the treatment of non-cystic fibrosis bronchodilator developed by the Cooperation of the American Mild biopharmaceutical company (Insmed incorporated.) and Aspirin (AstraZeneca). The drug is an oral, selective, competitive and reversible dipeptidyl peptidase 1 (DPP 1) inhibitor, inhibits Neutrophil Serine Protease (NSP) activation by inhibiting DPP-1, thereby inhibiting neutrophil mediated inflammatory responses, and is useful in the treatment of bronchodilation, chronic sinusitis (CRSsNP) with nasal polyps and other neutrophil mediated diseases. Bulansopranol was marketed under the FDA approval at month 08 of 2025 under the trade name (BRINSUPRI) for non-cystic fibrosis bronchodilators in adults and children aged 12 years and older, and EMA was marketed under the European approval at month 10 of the same year, with a predicted impact on the sales of billions of dollars over the year. The finished product of the Brillobicatide is prepared into a preparation in the form of a monohydrate, and the chemical name of the preparation is (S) -N- ((S) -1-cyano-2- (4- (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-5-yl) phenyl) ethyl) -1, 4-oxo-nitrogen, and the structural formula is as follows: PCT patent WO2015110826 reports a synthetic route to Brillobicatide, synthesized from 3 major intermediates. The preparation method comprises the steps of taking (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-iodophenyl) propionic acid as a starting material, condensing carboxylic acid and HBTU and ammonolyzing under the action of ammonia to obtain an amide intermediate, dehydrating the amide in chlorosulfonyl carbamic acid methyl ester to form cyano to obtain a main iodobenzene intermediate (S) -tert-butyl (1-cyano-2- (4-iodophenyl) ethyl) carbamate, performing aminomethylation on the starting material of 5-chlorobenzo [ d ] oxazol-2 (3H) -one under the action of iodomethane, coupling the starting material with bipinnamate under the catalysis of palladium to obtain a main borate intermediate 3-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-2 (3H) -one, performing free coupling on the intermediate (S) -tert-butyl (1-cyano-2- (4-iodophenyl) ethyl) carbamate and the borate intermediate 3-methyl-5- (4, 5-tetramethyl-2, 3-dioxaborolan-2-yl) 2-oxo-oxazol-2 (3H) -one under the catalysis of palladium to obtain the main borate intermediate, performing free coupling under the catalysis of 3-methyl-5-dioxazole-2 (3H) -oxazab-c, then condensing with chiral carboxylic acid intermediate (S) -4- (tert-butoxycarbonyl) -1, 4-oxynitride-2-formic acid to obtain N-Boc-Bullebrand intermediate, and finally acidolysis to remove Boc to obtain target product Bullebrand. The route is as follows: The patent also reports another synthesis method of the brinsucatin, wherein (S) -tert-butyl (1-amino-3- (4-iodophenyl) -1-oxypropane-2-yl) carbamate is used for participating in the Suziki coupling with a borate intermediate 3-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazol-2 (3H) -ketone, then the Boc is released by acid, the Boc is condensed with a chiral carboxylic acid intermediate (S) -4- (tert-butoxycarbonyl) -1, 4-oxynitride-2-formic acid under the action of T3P, and amide is dehydrated under the action of excessive T3P under the action of a one-pot method to generate cyano, so that N-Boc protected brinsucatin 1 intermediate is obtained, and finally, a target product of the Bunsucatin is obtained by acidolysis and free ammonia water. In general, the two synthetic methods have a longer route and more steps, wherein the starting raw material of the method I (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-iodophenyl) propionic acid is high in price, chiral aminoacetonitrile fragments are easily racemized in the following reaction process, particularly under the condition of strong acid or weak base, the optical purity of the final product is influenced, the price of the method II (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-iodophenyl) propionic acid is not low, the free amine after the chiral aminoamide intermediate acidolysis is neutralized by ammonia water is not easy to crystallize, the stability is also poor, the separation or the refining is not easy, and in general, the two synthetic routes have a lower total yield, a poor selectivity, a higher price of using reagents and a higher route cost, and are not favorable for the large-scale production. Disclosure of Invention Aiming at the defects of the prior art, the invention aims to provide a preparation method for preparing the brinzoate, and the preparation process route is simple, low in cost, beneficial to synthesizing high-pur