WO2017081590A1 - Procédé de préparation d'omarigliptine - Google Patents

Procédé de préparation d'omarigliptine Download PDF

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Publication number
WO2017081590A1
WO2017081590A1 PCT/IB2016/056656 IB2016056656W WO2017081590A1 WO 2017081590 A1 WO2017081590 A1 WO 2017081590A1 IB 2016056656 W IB2016056656 W IB 2016056656W WO 2017081590 A1 WO2017081590 A1 WO 2017081590A1
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formula
compound
process according
group
omarigliptin
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PCT/IB2016/056656
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English (en)
Inventor
Bhargav Pandya
Mandeep THAKUR
Swapnil SURADKAR
Surender ANGADI
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Sun Pharmaceutical Industries Limited
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Publication of WO2017081590A1 publication Critical patent/WO2017081590A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides a process for preparing omarigliptin.
  • Omarigliptin chemically (2i?,35 * ,5i?)-2-(2,5-difluorophenyl)-5-[2- (methylsulfonyl)-2,6-dihydropyrrolo [3 ,4-c]pyrazol-5 (4H)-yl]tetrahydro-2H-pyran-3 - amine, is represented by Formula I.
  • Omarigliptin is a dipeptidyl peptidase-IV inhibitor being developed for the treatment of diabetes mellitus.
  • U.S. Patent No. 7,902,376 (“the '376 patent”) describes a process for the preparation of omarigliptin comprising the step of reacting ethyl N- (diphenylmethylene)glycinate of Formula A with 3-bromoprop-l-yne in the presence of cesium carbonate to obtain a compound of Formula II.
  • the '376 patent also describes a process for the preparation of omarigliptin comprising the step of cycloisomerizing a compound of Formula VII using a transition metal catalyst in the presence of N-hydroxysuccinimide in DMF to obtain a compound of Formula VIII.
  • the '376 patent also describes a process for the preparation of omarigliptin comprising the step of condensing the compound of Formula IV with ⁇ , ⁇ - dimethylhydroxylamine hydrochloride using CDI ( ⁇ , ⁇ -carbonyldiimidazole) to obtain a compound of Formula V.
  • PCT Publication No. WO 2013/003250 describes a process for the preparation of omarigliptin.
  • PCT Publication No. WO 2015/139859 describes a process for the preparation of tert-butyl-2-(2,5-diflourophenyl)-2-oxoethylcarbamate, an intermediate used for the preparation of omarigliptin.
  • the present invention provides an improved process for the preparation of omarigliptin and its intermediates.
  • the present invention provides an easy, cost-effective, and industrially advantageous process for the preparation of omarigliptin and its intermediates.
  • a first aspect of the present invention provides a process for the preparation of omarigliptin of Formula I,
  • P is an amine protecting group
  • a second aspect of the present invention provides a process for the preparation of gliptin of Formula I,
  • a third aspect of the present invention provides a process for the preparation of omarigliptin of Formula I,
  • a fourth aspect of the present invention provides a process for the preparation of omarigliptin of Formula I,
  • a fifth aspect of the present invention provides a process for the preparation of omarigliptin of Formula I,
  • a sixth aspect of the present invention provides a process for the preparation of omarigliptin of Formula I,
  • a seventh aspect of the present invention provides a process for the preparation of a compound of Formula II,
  • An eighth aspect of the present invention provides a process for the preparation of a compound of Formula V,
  • a ninth aspect of the present invention provides a process for the preparation of a compound of Formula VIII,
  • a tenth aspect of the present invention provides a process for the preparation of a compound of Formula XII,
  • An eleventh aspect of the present invention provides a process for the preparation of a compound of Formula XIII,
  • ambient temperature refers to a temperature in the range of 25 °C to 35°C.
  • amine protecting group refers to Boc, CBz, FMOC, allyloc, methoxycarbonyl, formyl, phthaloyl, benzoyl, phenyl, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.
  • deprotection refers to removing a protecting group under the conditions known in the art.
  • the amine protecting group is Boc
  • it is removable under acidic conditions such as aqueous hydrochloric acid, sulfuric acid, hydrobromic acid, tetrafluoroboric acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, and trifluoroacetic acid in an organic solvent.
  • transition metal catalyst includes rhodium and ruthenium catalysts such as rhodium trichloride hydrate and CpRuCl(Pli3P)2.
  • acid activating agent includes oxalyl chloride, triphenylphosphine/carbon tetrabromide, benzotriazol-l-yloxytris
  • non-nucleophilic base includes sodium hydride, potassium hydride, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium tetramethylpiperidide, triethylamine, N,N- diisopropylethylamine, and diisopropylamine.
  • alkylhaloformate includes methylchloroformate, ethylchloroformate, propylchloroformate, isopropylchloroformate, butylchloroformate, and tert-butylchloroformate.
  • acylhalide includes acetylchloride
  • base includes methylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, N-methylpyridine, morpholine, and N- methy lmo holine .
  • phase transfer catalyst includes chloride, bromide, and iodide salts of benzyltrimethylammonium, benzyltriethylammonium,
  • methyltricaprylammonium methyltributylammonium, methyltrioctylammonium, and tetra-n-butylammonium .
  • phosphine ligand includes triphenylphosphine, tris(3- fluorophenyl)phosphine, tris(3,5-difluorophenyl)phosphine, and tris(4- fluorophenyl)phosphine .
  • cycloisomerizing agent includes NHS, NHP, and NHM.
  • polar aprotic solvent includes dichloromethane, THF, DMF, acetone, ethyl acetate, isopropyl acetate, acetonitrile, DME, 1,4-dioxane, methyl THF, DMA, and DMSO.
  • non polar solvent includes toluene, benzene, cyclohexane, and hexanes.
  • the compound of Formula A is reacted with 3-bromoprop-l-yne in the presence of a pulverized metal hydroxide, and optionally a phase transfer catalyst, to obtain the compound of Formula II .
  • the metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the compound of Formula II is either isolated or used as such for the next reaction.
  • the compound of Formula II is hydrolyzed to obtain the compound of Formula III using an acid.
  • the step of hydrolysis can be performed as described in U.S. Patent No. 7,902,376.
  • the compound of Formula III is either isolated or used as such for the next reaction.
  • the compound of Formula III is protected to obtain the compound of Formula IV by using methods known in the art or as described in U.S. Patent No. 7,902,376.
  • the compound of Formula IV is either isolated or used as such for the next reaction.
  • the compound of Formula IV is condensed with N,0-bismethylhydroxylamine hydrochloride using an acid activating agent in the presence of a base and a polar aprotic solvent to obtain the compound of Formula V.
  • the acid activating agent is selected from the group consisting of alkylhaloformate and acylhalide in the presence of a base.
  • the compound of Formula V is reacted with 2-bromo-l,4-diflourobenzene in the presence of a Grignard reagent to obtain the compound of Formula VI as described in U.S. Patent No. 7,902,376.
  • the compound of Formula VII is cycloisomerized using a transition metal catalyst in the presence of a sodium salt of a cycloisomerizing agent, a phosphine ligand, and tetrabutylammonium hexafluorophosphate in a solvent to obtain the compound of Formula VIII.
  • a sodium salt of a cycloisomerizing agent is sodium salt NHS.
  • the solvent is selected from a group consisting of non polar solvents and polar aprotic solvents.
  • the solvent is toluene or DME.
  • the use of sodium salt NHS is advantageous over the use of NHS in terms of increase in product formation.
  • the use of toluene and DME reduces the reaction time and the amount of catalyst used.
  • the compound of Formula VIII is either isolated or used as such for the next reaction.
  • the compound of Formula X is reductively animated with the compound of Formula XIV or a salt thereof to obtain omarigliptin as described in U.S. Patent Nos. 7,902,376 and 8, 143,289 or PCT Publication Nos. WO 2013/003250 and WO
  • the compound of Formula XIV is obtained by following the process as described in U.S. Patent No. 8, 143,289 or PCT Publication No. WO 2013/003250.
  • the compound of Formula XI is treated with an organic acid to obtain the compound of Formula XII.
  • the organic acid is selected from the group consisting of acetic acid and trifluoroacetic acid.
  • the use of an organic acid ensures the reduction of the compound of Formula XI with retention of the amine protected group.
  • the compound of Formula XI is obtained by following the process as described in U.S. Patent No. 8,143,289 or PCT Publication No. WO 2013/003250.
  • the compound of Formula XII is reacted with methylsulfonyl chloride in the presence of a non-nucleophilic base in THF or DMF or mixtures thereof with non polar solvents and other polar aprotic solvents to obtain the compound of Formula XIII. It has been observed that selection of the solvent plays a pivotal role in determining the regioselectivity of the process, and thus yielding a greater percentage of the desired regioisomer.
  • the compound of Formula XIII is converted to a compound of Formula XIV, and further to omarigliptin, by the process as described in U.S. Patent No. 8,143,289 or PCT Publication No. WO 2013/003250. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • HPLC High Performance Liquid Chromatography
  • Pulverized potassium hydroxide (29.53 g) was added to a solution of ethyl N- (diphenylmethylidene)glycinate (94 g; Formula A), tetrabutylammonium bromide (11.35 g), and 3-bromoprop-l-yne (42.6 inL) in toluene (282 mL) at -5°C to 0°C.
  • the reaction mixture was stirred for 1 hour to 2 hours at the same temperature to obtain ethyl 2- [(diphenylmethylidene)amino]pent-4-ynoate in situ.
  • the reaction mixture was diluted with water (282 mL) at a temperature of -5°C to 0°C. The reaction mixture was used as such for the next reaction.
  • the aqueous layer (Formula II; Example 1) was treated with a solution of hydrochloric acid (50%; 94 mL) at a temperature of 2°C to 8°C.
  • the reaction mixture was allowed to warm to a temperature of 20°C to 25°C, and was then stirred for 6 hours to 10 hours to obtain ethyl 2-aminopent-4-ynoate (Formula III).
  • the layers were separated, and the aqueous layer was cooled to 10°C to 15°C.
  • a solution of sodium hydroxide 50 mL; 18.5 M
  • Di-tert- butyldicarbonate (84.2 g) was added to the reaction mixture.
  • reaction mixture was allowed to warm to 20°C to 30°C.
  • a solution of sodium hydroxide (10 mL to 15 mL; 18.5 M) was again added to the reaction mixture to adjust the pH to 12.5 to 13.
  • toluene (282 mL) was added to the aqueous layer.
  • the reaction mixture was cooled to 0°C to 5°C.
  • An aqueous solution of hydrochloric acid (180 mL) was added to adjust the pH to 2.5 to 3.0.
  • the mixture was stirred for 5 minutes to 10 minutes.
  • the layers were separated.
  • Toluene (282 mL) was added to the aqueous layer, and then the mixture was stirred for 15 minutes. The mixture was allowed to settle for 10 minutes, and the layers were separated.
  • CDI 39.45 g was added to a solution of 2-[(tert-butoxycarbonyl)amino]pent-4- ynoic acid (40 g; Formula IV, Example 2) in dimethylformamide (100 mL), and the mixture was stirred for 2 hours at 20°C to 30°C.
  • N O-Bismethylhydroxylamine hydrochloride (20.1 g) was added to the reaction mixture, and then the mixture was stirred for 1 hour to 3 hours at 20°C to 30°C.
  • water 200 mL was added to the reaction mixture, and then the mixture was stirred for 6 hours to 8 hours at 20°C to 25°C.
  • the reaction mixture was cooled to 0°C to 5°C.
  • Trimethylacetyl chloride 24.50 mL was added to a solution of 2-[(tert- butoxycarbonyl)amino]pent-4-ynoic acid (40 g; Formula IV, Example 2) in
  • the organic layer was washed with an aqueous sodium bicarbonate solution (5%; 25 mL) and then with a saturated sodium chloride solution (25 mL) at 20°C to 25°C.
  • the organic layer was concentrated under reduced pressure at 50°C to 55°C to obtain a residue.
  • IPA (15 mL) was added to the residue, and then the mixture was stirred at 55°C to 60°C for 30 minutes.
  • Water (22.5 mL) was added to the reaction mixture at 50°C to 60°C.
  • the reaction mixture was cooled to 20°C to 25 °C, and then stirred for 15 minutes.
  • the reaction mixture was filtered, and then dried under reduced pressure at 45°C to 50°C to obtain the title compound.
  • the aqueous layer was extracted with toluene (200 mL), and the layers were separated.
  • the organic layers were washed with an aqueous sodium bicarbonate solution (5%; 500 mL), and then stirred for 10 minutes.
  • Tetrabutyl ammonium hexafluorophosphate (13.8 g) and sodium salt of NHS (17.6 g) were added to a solution of tert-butyl [(lR,2S)-l-(2,5-difluorophenyl)-l-hydroxypent-4- yn-2-yl]carbamate (100 g; Formula VII; Example 7) in toluene (600 ml) under nitrogen at ambient temperature, and the mixture was stirred for 10 minutes.
  • Triphenylphosphine (4.2 g) and chloro(cyclopentadienyl) bis (triphenylphosphine) ruthenium(II) ethanol (1.5 g) were added to the reaction mixture, and then the mixture was stirred for 4 hours to 5 hours at 80°C to 85°C. The reaction mixture was allowed to cool to 40°C. Chloro(cyclopentadienyl) bis (triphenylphosphine) ruthenium(II) ethanol (1 g) was again added to the reaction mixture, and then the mixture was stirred for 16 hours to 18 hours at 80°C to 85°C. After completion of the reaction, the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was filtered to obtain a solid.
  • the solid was washed with toluene (50 mL ⁇ 2), and then washed with a sodium bicarbonate solution (5%). The reaction mixture was stirred for 10 minutes, and then allowed to settle for 10 minutes. The layers were separated, and the aqueous layer was extracted with toluene (200 mL). The organic layers were combined, then washed with water (500 mL), and then concentrated under reduced pressure at 55°C to 60°C to obtain the title compound as a viscous liquid.
  • Tetrabutyl ammonium hexafluorophosphate (3.4 g) and sodium salt of NHS (4.4 g) were added to a solution oftert-butyl [(lR,2S)-l-(2,5-difluorophenyl)-l-hydroxypent-4- yn-2-yl]carbamate (20 g, Formula VII; Example 7) in DME (140 mL) under nitrogen at ambient temperature, and the mixture was stirred for 10 minutes.
  • Triphenylphosphine (1.1 g) and chloro(cyclopentadienyl) bis (triphenylphosphine) ruthenium(II) ethanol (0.6 g) were added to the reaction mixture, and then the mixture was stirred for 6 hours at 80°C to 85°C. The reaction mixture was allowed to cool to 40°C. Chloro(cyclopentadienyl) bis (triphenylphosphine) ruthenium(II) ethanol (0.2 g) was again added to the reaction mixture, and then the mixture was stirred for 20 hours at 80°C to 85°C. After completion of the reaction, the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was filtered to obtain a solid.
  • Example 10 Preparation of tert-butyl[(2R.3S)-5-hydroxy-2-(2.5- difluorophenyl)tetrahvdro-2H-pyran-3-vHcarbamate (Formula IX) Borane DMS (24 mL) was added to a solution of tert-butyl [(2R,3S)-2-(2,5- difluorophenyl)-3,4-dihydro-2H-pyran-3-yl]carbamate (50 g; Formula VIII; Example 8 or 9) in MTBE (350 mL) at -10°C to -5°C. The reaction mixture was stirred for 2 hours to 3 hours at the same temperature.
  • reaction mixture was added to an aqueous solution of sodium hydroxide (I N; 400 mL) while maintaining the temperature at 0°C to 10°C.
  • Hydrogen peroxide (18 mL; 50%) was added to the reaction mixture, and then the mixture was stirred for 14 hours at 20°C to 26°C.
  • the reaction mixture was allowed to settle, and the layers were separated.
  • Toluene 150 mL was added to the aqueous layer, and then the mixture was stirred at 20°C to 25°C for 10 minutes.
  • the reaction mixture was allowed to settle, and the layers were separated.
  • the organic layers were combined, then washed with water (300 mL), and then concentrated under reduced pressure at 60°C to 70°C to obtain a residue.
  • Toluene (150 mL) was added to the residue, and then the mixture was heated at 80°C to 85°C for 45 minutes. The reaction mixture was allowed to cool to 20°C to 25 °C. The reaction mixture was filtered, and then dried under reduced pressure at 45°C to 50°C to obtain the title compound.
  • Trifluoroacetic acid 28.2 mL was added to the reaction mixture (Formula XI; Example 12) at 20°C to 25 °C, and the mixture was stirred for 2 hours. After completion of the reaction, water (350 mL) was added to the mixture. The reaction mixture was allowed to settle, and the layers were separated. The organic layer was concentrated under vacuum to obtain a crude mass. N-heptane (210 mL) was added to the crude mass, and then the mixture was stirred for 1 hour to 3 hours at 20°C to 30°C to obtain a solid. The solid was filtered to obtain the title compound.
  • the reaction mixture was allowed to settle, and the layers were separated.
  • the organic layer was washed with a saturated sodium chloride solution (25 mL).
  • the organic layer was concentrated under reduced pressure at 35°C to 45 °C to obtain a crude mass.
  • IPA 7.5 mL
  • n-heptane 25 mL were added to the crude mass, and then the mixture was stirred at 20°C to 30°C for 1 hour to 3 hours to obtain a solid.
  • the solid was filtered, and then dried under reduced pressure at 35°C to 40°C for 30 minutes to obtain the title compound.
  • Triethylamine (1.15 mL) was added to a solution of tert-butyl 4,6- dihydropyrrolo[3,4-c]pyrazole-5(lH)-carboxylate (1 g; Formula XII; Example 13) in tetrahydrofuran (10 mL) at ambient temperature.
  • Mesyl chloride (0.49 mL) was slowly added to the reaction mixture at 0°C to 5°C, and then the mixture was stirred for 30 minutes. The temperature was allowed to rise to ambient temperature, and then the mixture was stirred for 3 hours. After completion of the reaction, water (25 mL) and ethyl acetate (25 mL) were added to the reaction mixture.
  • the reaction mixture was allowed to settle, and the layers were separated.
  • the organic layer was concentrated under reduced pressure at 30°C to 35°C to obtain a crude mass.
  • IPA 7.5 mL
  • n-heptane 25 mL
  • the mixture was stirred at 30°C to 35°C for 30 minutes to obtain a solid.
  • the solid was filtered, and then dried under reduced pressure 30°C to 35°C for 30 minutes to obtain the title compound.
  • Triethylamine (1.15 mL) was added to a solution of tert-butyl 4,6- dihydropyrrolo[3,4-c]pyrazole-5(lH)-carboxylate (1 g; Formula XII; Example 13) in 2- methyltetrahydrofuran (10 mL) at 0°C to 5°C, and the mixture was stirred for 15 minutes.
  • Mesyl chloride (0.49 mL) was slowly added to the reaction mixture at 0°C to 5°C, and then the mixture was stirred for 30 minutes. The reaction mixture was allowed to rise to ambient temperature, and was then stirred at the same temperature for 2 hours.
  • Triethylamine (0.2 mL) was added to the reaction mixture, and then the mixture was stirred for 30 minutes at 30°C to 35°C. After completion of the reaction, water (15 mL) was added. The reaction mixture was allowed to settle, and the layers were separated. The organic layer was washed with a saturated sodium chloride solution (25 mL). The organic layer was concentrated under reduced pressure to obtain a crude mass. IPA (7.5 mL) and n-heptane (25 mL) were added to the crude mass, and then the mixture was stirred at 30°C to 35°C for 30 minutes to obtain a solid. The solid was filtered, and then dried under reduced pressure at 30°C to 35°C for 8 hours to obtain the title compound. Regioselectivity: 90%
  • Triethylamine (1.6 mL) was added to a solution of tert-butyl 4,6-dihydropyrrolo[3,4- c]pyrazole-5(lH)-carboxylate (2 g; Formula XII; Example 13) in N,N-dimethylformamide (20 mL) at ambient temperature, and the mixture was stirred for 2 hours.
  • Mesyl chloride (1.1 mL in 10 mL of N,N-dimethylformamide) was slowly added to the reaction mixture at 0°C to 5°C, and then the mixture was stirred for 2 hours.
  • Triethylamine (3 mL) was added to the reaction mixture, and then the mixture was stirred for 2 hours at 0°C to 5°C.
  • the reaction mixture was allowed to settle, and the layers were separated.
  • the organic layer was washed with a saturated sodium chloride solution (25 mL).
  • the organic layer was concentrated under reduced pressure to obtain a crude mass.
  • IPA 7.5 mL
  • n-heptane 25 mL
  • the mixture was stirred at 30°C to 35°C for 30 minutes to obtain a solid.
  • the solid was filtered, and then dried under reduced pressure at 30°C to 35°C for 8 hours to obtain the title compound.
  • the reaction mixture was extracted in ethyl acetate (20 mL), then dried over sodium sulfate, and then concentrated under reduced pressure to obtain a crude mass.
  • IPA 7.5 mL
  • n-heptane 25 mL
  • the mixture was stirred at 30°C to 35°C for 8 hours to obtain a solid.
  • the solid was filtered, and then dried under reduced pressure at 30°C to 35°C for 30 minutes to obtain the title compound.
  • Trifluoroacetic acid (73.3 g) was added to a solution of tert-butyl ⁇ (2R,3S,5R)-2- (2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)- yl]tetrahydro-2H-pyran-3-yl ⁇ carbamate (8.2 g; Formula XV; Example 23) in
  • dichloromethane ( 123 mL) at 0°C.
  • the reaction mixture was allowed to warm to the ambient temperature, and was then stirred at the same temperature for 30 minutes.
  • water 99 mL at 0°C to 5°C
  • An aqueous ammonia solution (25%) was added to the reaction mixture to adjust the pH to 9.6.
  • the reaction mixture was allowed to settle, and the layers were separated.
  • the organic layer was washed with water (85 mL). The organic layer was separated, and then concentrated under vacuum at 30°C to 35°C to obtain a crude mass.
  • Dichloromethane (95 mL) was added to the crude mass to obtain a solution.

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Abstract

Cette invention concerne un procédé de préparation d'omarigliptine.
PCT/IB2016/056656 2015-11-09 2016-11-04 Procédé de préparation d'omarigliptine WO2017081590A1 (fr)

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CN107473988A (zh) * 2017-08-22 2017-12-15 钟桂发 奥格列汀的中间体的制备方法

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