A kind of preparation method of (r)-3-amino-4-(2,4,5-trifluorophenyl) butyric acid methyl ester

A technology of trifluorophenyl and methyl butyrate, applied in the preparation of organic compounds, organic chemical methods, preparation of cyanide reactions, etc., can solve the problems of long reaction route, poor chiral selectivity of products, etc., and achieve good coordination ability, high chiral stereoselectivity, and the effect of improving catalytic reduction ability

Active Publication Date: 2022-04-19
江苏八巨药业有限公司
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Problems solved by technology

[0005] The present invention aims at the defect existing in the prior art above, provides a kind of preparation method of (R)-3-amino-4-(2,4,5-trifluorophenyl) methyl butyrate, in order to solve the existing The problem of long reaction route and poor chiral selectivity of products

Method used

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  • A kind of preparation method of (r)-3-amino-4-(2,4,5-trifluorophenyl) butyric acid methyl ester
  • A kind of preparation method of (r)-3-amino-4-(2,4,5-trifluorophenyl) butyric acid methyl ester
  • A kind of preparation method of (r)-3-amino-4-(2,4,5-trifluorophenyl) butyric acid methyl ester

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Experimental program
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Effect test

Embodiment 1

[0036] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester(Ⅱ)

[0037] Add 80g of methanol and 20g of 3-oxo-4-(2,4,5-trifluorophenyl) methyl butyrate to a clean reactor, and then stir at room temperature for 10 minutes, then add 25.9g of Ammonium formate, then, slowly heat up to reflux and keep warm for 5 hours, TLC detection confirms that the reaction is complete, after the reaction, cool down to 50°C and control the temperature not to exceed 50°C, carry out vacuum distillation until no liquid flows out to remove the solvent, and obtain the corresponding concentrate , Then, add 60g of toluene and 30g of water to the concentrate, stir for 30 minutes, leave to stand for layering, collect the organic layer toluene layer, the water layer can be extracted once with 30g toluene, then combine the toluene layer, and add to the collected toluene layer Add 10g of anhydrous sodium sulfate, stir and dry at room temperature for 30 minutes, and filter with suction t...

Embodiment 2

[0046] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester(Ⅱ)

[0047] Add 100 g of methanol and 20 g of 3-oxo-4-(2,4,5-trifluorophenyl) methyl butyrate to a clean reactor, then stir at room temperature for 10 minutes, add 23.3 g of formic acid Ammonium, heat up to reflux and keep it warm for 6 hours, TLC detection confirms that the reaction is complete, after the reaction, cool down to 50°C and control the temperature not to exceed 50°C, carry out vacuum distillation until no liquid flows out to remove the solvent, and obtain the corresponding intermediate product concentrate , Then, add 60g of toluene and 30g of water to the concentrate again, stir for 30 minutes, let stand to separate layers, collect the organic layer toluene layer, the water layer can be extracted once with 30g toluene, then merge the collected toluene layer, and pour it into the toluene layer Add 10g of anhydrous sodium sulfate, stir and dry at room temperature for 30 minutes, an...

Embodiment 3

[0056] Preparation of 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester(Ⅱ)

[0057] Add 90g of methanol and 20g of 3-oxo-4-(2,4,5-trifluorophenyl) methyl butyrate (I) into a clean reactor, stir at room temperature for 15 minutes, add 24.5g Ammonium formate, then slowly warming up to reflux for 4 hours, TLC detection confirmed the completion of the reaction, after the reaction, cooled to 50 ℃ and under the condition that the temperature was controlled not to exceed 50 ℃, vacuum distillation was carried out until no liquid flowed out to obtain the corresponding Concentrate, then, add 60g toluene and 30g water again in the concentrate, stir 30 minutes, leave standstill layering, collect the organic layer toluene layer, the aqueous layer can be extracted once with 30g toluene, then merge the toluene layer, to the toluene layer collected Add 10g of anhydrous sodium sulfate, stir and dry at room temperature for 30 minutes, and filter with suction to obtain 3-amino-4-(2,...

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Abstract

The invention relates to a preparation method of (R)-3-amino-4-(2,4,5-trifluorophenyl) methyl butyrate, which belongs to the technical field of synthesis of pharmaceutical intermediates. In order to solve the problem that the existing route is long and selectivity is poor, a kind of preparation method of (R)-3-amino-4-(2,4,5-trifluorophenyl) methyl butyrate is provided, comprising hydroboration Under the action of Lewis acid and crown ether, 3-amino-4-(2,4,5-trifluorophenyl) but-2-enoic acid methyl ester is reacted to obtain 3-amino-4-(2,4 ,5-trifluorophenyl) butyric acid methyl ester; under the action of aminoalcohol ligand, make 3-amino-4-(2,4,5-trifluorophenyl) methyl butyric acid conversion reaction synthesis (R) Methyl ‑3‑amino‑4‑(2,4,5‑trifluorophenyl)butyrate. The invention can improve the reaction reduction ability, has high catalytic conversion rate and reaction rate, and has the effects of high yield and product purity.

Description

technical field [0001] The invention relates to a preparation method of (R)-3-amino-4-(2,4,5-trifluorophenyl)butyric acid methyl ester, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Sitagliptin is a dipeptidyl peptidase-Ⅳ (DDP-Ⅳ) inhibitor and a new type of hypoglycemic drug used for the treatment of type Ⅱ diabetes. The drug has a novel mechanism of action that is different from the hypoglycemic drugs currently on the market. It increases insulin secretion and maintains normal blood sugar levels by improving the ability of diabetic patients to produce insulin from their own pancreatic β cells. After taking sitagliptin, it can reduce the activity of DPP-IV to reduce the degradation of incretin, thereby triggering the clinical effect of increasing insulin production by the pancreas and stopping the liver from producing glucose, and finally reducing the blood sugar concentration. [0003] In the process of synthesizin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/32C07C227/16C07C229/34C07C227/04B01J31/26B01J31/02
CPCC07C227/32C07C227/16C07C227/04B01J31/0271B01J31/0238B01J31/26B01J31/0204B01J27/10B01J27/138B01J27/135B01J35/0006C07B2200/07B01J2231/645B01J2231/52C07C229/34
Inventor 汪东海程加铭陈恬程祖福王建军胡建涛
Owner 江苏八巨药业有限公司
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