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Synthetic method of sitagliptin and salt thereof

A synthesis method and technology of sitagliptin are applied in the field of synthesis of sitagliptin and its salts, which can solve problems such as platinum-carbon flammability yield, avoid the use of strong bases or Grignard reagents, have high purity, low cost effect

Active Publication Date: 2014-05-28
ZHEJIANG NHU CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The advantage of this method is that it does not need to use expensive chiral ligands, but it needs to be hydrogenated with platinum carbon in the middle, which is extremely flammable and the yield of this step is low

Method used

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  • Synthetic method of sitagliptin and salt thereof
  • Synthetic method of sitagliptin and salt thereof
  • Synthetic method of sitagliptin and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Dissolve 2,4,5-trifluorophenylacetic acid (CAS: 209995-38-0, 1.9 g, 10 mmol) in methanol (20 mL), and add a few drops of concentrated sulfuric acid. After heating to reflux for three hours, it was cooled to room temperature, and the solvent was evaporated by a rotary evaporator. The residue was dissolved in dichloromethane (20 mL), washed with sodium bicarbonate (1M) solution, and washed with water. The organic phase was dried and evaporated to dryness with a rotary evaporator to obtain an oily substance.

[0063] The oil obtained above was dissolved in tetrahydrofuran (40 mL), and DIBAL-H (1M dissolved in toluene, 20 mL, 20 mmol) was added dropwise in an ice-water bath, and reacted overnight at room temperature. The next day, add water (20 mL) to quench the reaction under an ice-water bath, and adjust the pH value to 2-3 with concentrated hydrochloric acid. Extracted three times with dichloromethane (10 mL), combined the organic phases, dried and evaporated to drynes...

Embodiment 2

[0067] 2,4,5-Trifluorophenylacetic acid (CAS: 209995-38-0, 1.9 g, 10 mmol) was dissolved in a solution of tetrahydrofuran (40 mL), and then added dropwise to 1M borane tetrahydrofuran under ice-water bath at 0-5°C solution (12mL, 1.2mmol), the dropwise addition was completed, and the reaction was carried out overnight at room temperature. The next day, the reaction was quenched by adding water (20 mL) under an ice-water bath. Extracted three times with dichloromethane (10 mL), combined the organic phases, dried and evaporated to dryness with a rotary evaporator to obtain a colorless liquid (yield: 89%, purity: 98%) and directly used in the next step.

Embodiment 3

[0069] 2,4,5-Trifluorophenylethanol (1.76g, 10mmol) prepared in Example 1 was dissolved in acetonitrile (40mL), and IBX (Chinese name: o-iodobenzoic acid, CAS: 64297-64-9) was added ( 2.8 g, 10 mmol). After reflux for two hours, the reaction solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was evaporated to dryness with a rotary evaporator, dissolved in diethyl ether, and washed with water. Separate the liquid, dry the organic phase, and evaporate to dryness with a rotary evaporator to obtain a yellow oil (yield: 76%, purity: 92%), which is directly used for the next step. product by 1 Confirmed by H-NMR and TLC. The reaction formula is as follows:

[0070]

[0071] 1 The H-NMR data are as follows: 1 HNMR (CDCl 3 ,400MH Z ): 9.77 (1H, m), 7.69~7.45 (1H, m), 7.38~7.31 (1H, m), 3.74 (2H, s).

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Abstract

The invention discloses a synthetic method of sitagliptin and a salt thereof. The synthetic method comprises the steps: carrying out an esterification reaction, a reduction reaction, an oxidizing reaction and a witting reaction on 2,4,5-trifluorophenylacetic acid as a starting raw material to obtain 4-(2,4,5-trifluorophenyl)-2-ethyl crotonate; then carrying out a hydroamination reaction on 4-(2,4,5-trifluorophenyl)-2-ethyl crotonate and chiral amine in the presence of butyl lithium or hexamethyldisilazane sodium to form a chiral hydroamination product; carrying out an esterolysis reaction, a condensation reaction and a hydrogenation reaction to obtain sitagliptin. The raw materials used in the synthetic method of sitagliptin are low in price and easy to obtain; the synthetic method of sitagliptin is less in step, easy to operate and capable of effectively reducing cost. By the use of the method, high-purity sitagliptin can be obtained, a sitgliptin phosphate obtained through salifying has an HPLC (High Performance Liquid Chromatography) and an ee (enantiomeric excess) value of more than 99% and can be applied to the field of medicine.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of sitagliptin and a salt thereof. Background technique [0002] 7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl base)-1,2,4-triazolo[4,3-a]pyrazine, also known as sitagliptin (structure as shown in formula (I)), is a kind of A new anti-type 2 diabetes drug, approved by the US FDA in October 2006, is the first dipeptidyl peptidase-IV (DPP-IV) inhibitor drug for the treatment of type 2 diabetes, usually in the form of phosphate Used as medicine. Sitagliptin can increase the activity of GLP-1 and GIP in plasma, slightly increase its content and weaken the antagonism of GLP-1 metabolites. At the same time, sitagliptin stimulates insulin secretion with blood sugar dependence, so it can Greatly reduce the incidence of hypoglycemic side effects of traditional oral hypoglycemic drugs. [0003] [0004] There ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 张玉红姚金忠钱洪胜林聪鲁国斌唐家兴沈创
Owner ZHEJIANG NHU CO LTD
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