Teneligliptin synthesis method

A synthetic method, the technology of tiagliptin, applied in the field of drug synthesis, can solve the problems of hydrobromic acid being volatile, many by-products after stirring, difficult to complete the reaction of raw materials, etc., to achieve increased solubility and reducibility, high total yield, The effect that is conducive to industrial production

Active Publication Date: 2016-02-03
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0010] Method 2: In the patent CN101119991B, intermediate III is directly reacted with hydrobromic acid to obtain tiagliptin hydrobromide. Although the steps are shortened, the reaction temperature is relatively high (80°C), and there are many by-products after long-term stirring. Hydrobromic acid is volatile at high temperature, and it is difficult to complete the reaction of raw materials, which brings troubles to post-processing. It needs to be purified by programmed cooling method, beating and recrystallization, and the operation is more complicated.

Method used

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Experimental program
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experiment example 1

[0032] Experimental example 1 toluene and tetrahydrofuran volume ratio screening experiment

[0033] Method 1 Method 1 of the prior art, add 20L toluene to the reactor, and 808g formula (I) (1-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)] piperazine), 1000g formula (II) (3-[(2S)-1-(1,1-dimethylacetylcarbonyl)-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine), 200g acetic acid Add it into the reaction kettle, dissolve it with the treated toluene and tetrahydrofuran mixed solution, add 1413g sodium triacetoxyborohydride, react at 20°C for 2h, concentrate the solvent at 40°C, add 10L ethyl acetate, and use 30L saturated ammonium chloride After washing twice, and drying the organic layer with anhydrous sodium sulfate for 0.5 h, the yield was 87%, and the product purity was 88.17%.

[0034] Method 2 (step A of Example 1): Add 10L of toluene, 10L of tetrahydrofuran and 5g of benzophenone into the reaction kettle, then add 100g of sodium pellets, heat to boiling at 70°C until the solution turns ...

Embodiment 1

[0043]A. Add 10L of toluene, 10L of tetrahydrofuran and 5g of benzophenone into the reaction kettle, then add 100g of sodium pellets, heat to boiling at 70°C until the solution turns blue, and distill off the solvent for later use. With 808g formula (I) (1-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)] piperazine), 1000g formula (II) (3-[(2S)- 1-(1,1-Dimethylacetylcarbonyl)-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine), 200g of acetic acid were added to the reaction kettle, and dissolved in a mixed solution of 10L of toluene and 10L of tetrahydrofuran , add 1413g of sodium triacetoxyborohydride, react at 20°C for 2h, concentrate the solvent at 40°C, add 10L of ethyl acetate, wash twice with 30L of saturated ammonium chloride, dry the organic layer with anhydrous sodium sulfate for 0.5h, reduce Concentrate under reduced pressure to 1710 g of light yellow solid (formula III), the yield is 98%, and the product purity is 98.43%.

[0044] B. Dissolve 1700g of the intermediate (formula III) ...

Embodiment 2

[0047] A. Add 13.5L of toluene, 6.5L of tetrahydrofuran and 3g of benzophenone into the reaction kettle, then add 80g of sodium pellets, heat to boiling at 70°C until the solution turns blue, and distill off the solvent for later use. With 808g formula (I) (1-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)] piperazine), 1000g formula (II) (3-[(2S)- 1-(1,1-Dimethylacetylcarbonyl)-4-oxopyrrolidin-2-ylcarbonyl]thiazolidine), 200g of acetic acid were added to the reaction kettle, dissolved with the treated toluene and tetrahydrofuran mixed solution, and added 1413g of sodium triacetoxyborohydride, reacted at 20°C for 2h, concentrated the solvent at 40°C, added 10L of ethyl acetate, washed twice with 30L of saturated ammonium sulfate, dried the organic layer with anhydrous sodium sulfate for 0.5h, and concentrated under reduced pressure to The light yellow solid (formula III) was 1668g, the yield was 95%, and the product purity was 90.43%.

[0048] B. Dissolve 1660g of the intermediate (fo...

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Abstract

The present invention discloses a Teneligliptin synthesis method. The method comprises the following steps: (1) in the presence of an organic solvent and a catalyst of sodium triacetoxyborohydride, carrying out reduction on 1-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (in formula I) and 3-[(2S)-1-(1,1-dimethyl-acetyl carbonyl)-4-oxo-pyrrolidin-2-ylcarbonyl]thiazolidine (in formula II) into an intermediate (in formula III), wherein the solvent is a mixed solution of tetrahydrofuran and toluene; and (2) using sodium tablets to treat the mixed solution of tetrahydrofuran and toluene. According to the Teneligliptin prepared by the method disclosed by the present invention, the operation is simple, the yield is high, and the product purity is high; and the present method disclosed by the invention can remove basic impurities which require column chromatography to remove in the reaction, so that the process steps are simplified, the production cycle is shortened, and the total yield is relatively high; so that the synthesis method provided by the invention is more conducive to industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing medicines, in particular to a method for synthesizing tiagliptin hydrobromide. Background technique [0002] Teneligliptinhydrobromide (teneligliptinhydrobromide), molecular formula: C 22 h 30 N 6 OS·2.5HBr·xH 2 O, chemical name: 3-[[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2- Pyrrolidinyl]formyl]thiazolidine hydrobromide hydrate. Tiagliptin hydrobromide is a type II diabetes drug jointly developed and marketed by Mitsubishi Tanabe Pharmaceuticals and Daiichi Sankyo Pharmaceuticals. It was launched in Japan in September 2012 and is currently used for patients whose blood sugar cannot be effectively controlled by the following therapies: Diet With exercise, or with diet and exercise therapy with sulfonylureas, or with diet and exercise therapy with thiazolidinediones. Its structural formula is: [0003] [0004] The existing synthetic method of tigeliptin hydrobromide: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14
Inventor 张生烈葛建华王朝阳程志鹏王晶翼王利春胡思玉赵栋
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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