Method for synthetizing (R)-N-BOC-3-amino-4-(2,4,5-trifluorophenyl) butyric acid by adopting transaminase method

A technology of trifluorophenyl and transaminase, applied in the direction of fermentation, etc., can solve the problem of low total yield, achieve the effect of improving conversion rate, high yield, and simple and efficient synthetic route

Inactive Publication Date: 2017-11-21
SHANGHAI PUYI CHEM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the route of this method is simple, it requires chemical resolution, not only

Method used

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  • Method for synthetizing (R)-N-BOC-3-amino-4-(2,4,5-trifluorophenyl) butyric acid by adopting transaminase method
  • Method for synthetizing (R)-N-BOC-3-amino-4-(2,4,5-trifluorophenyl) butyric acid by adopting transaminase method
  • Method for synthetizing (R)-N-BOC-3-amino-4-(2,4,5-trifluorophenyl) butyric acid by adopting transaminase method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 ： 4-(3- Oxo -4-(2,4,5- Trifluorophenyl ) Butyryl ) Piperazine -1- tert-butyl formate

[0027]

[0028] Dissolve 15.0 g of 3-oxo-4-(2,4,5-trifluorophenyl) methyl butyrate (1-1) and 14.0 g of N-Boc-piperazine in 100 mL of toluene, heat to reflux, and react After about 2 hours, TLC (PE / EA=3 / 1) monitored the complete reaction of the raw materials. The reaction solution was washed with water and salt water respectively, the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried, and the obtained crude product was purified by column chromatography to obtain the product 4-(3-oxo-4-(2,4,5 -Trifluorophenyl)butyryl)piperazine-1-carboxylic acid tert-butyl ester (1-2) 24.3g, yield 99.7%.

Embodiment 2

[0029] Example 2 ： ( R )-4-(3- Amino -4-(2,4,5- Trifluorophenyl ) Butyryl ) Piperazine -1- tert-butyl formate

[0030]

[0031] 50.0 g of tert-butyl 4-(3-oxo-4-(2,4,5-trifluorophenyl) butyryl) piperazine-1-carboxylate (1-2), 100 g of isopropylamine hydrochloride, Add 0.15 g of PLP to 500 mL of dipotassium hydrogen phosphate buffered saline system, adjust the pH to about 8.5 with a dilute solution of isopropylamine, and add 1.0 g of ω-transaminase freeze-dried powder. The reaction was controlled to pH=8.5 with 20% isopropylamine, converted at 45°C for 24 hours, and the reaction was completed by TLC monitoring. The solid was removed by filtration, the mother liquor was extracted 3 times with ethyl acetate, the combined organic phase was dried and concentrated to obtain a white solid (R)-4-(3-amino-4-(2,4,5-trifluorophenyl) Butyryl)piperazine-1-carboxylic acid tert-butyl ester (2-1) 43.1g, yield 85.7%, ee%=99.3%.

Embodiment 3

[0032] Example 3 ： ( R )- N -BOC-3- Amino -4-(2,4,5- Trifluorophenyl ) butyric acid

[0033]

[0034] Dissolve (R)-4-(3-amino-4-(2,4,5-trifluorophenyl)butyryl)piperazine-1-carboxylic acid tert-butyl ester (2-1) 40.0g in 200mL methanol 50 mL of NaOH aqueous solution containing 10.0 g was added, heated to reflux for 5 hours, and the raw material disappeared on the TLC plate; then cooled to room temperature, 25.0 g of di-tert-butyl dicarbonate was added, and the reaction was continued at room temperature for 2 hours. Add 1 mol / L of potassium bisulfate to adjust the pH to be acidic, extract the product three times with dichloromethane from the reaction solution, dry and concentrate the combined organic phase, and crystallize the obtained crude product with petroleum ether to obtain (R)-N-BOC- 28.3 g of 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (3-1), yield: 85%, ee value: 99.3%.

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Abstract

The present invention provides a method for synthesizing (R)-N-BOC-3-amino-4-(2,4,5-trifluorophenyl) butyric acid (I) by transaminase method, in which 3-oxo-4- (2,4,5-trifluorophenyl) methyl butyrate (IV) is a starting material, reacted with nitrogen-protected piperazine to obtain 3-oxo-4-(2,4,5-trifluorophenyl) butane Amide intermediate (III); (III) reacts in the presence of amino donor and transaminase, and is converted into 3-amino-4-(2,4,5-trifluorophenyl) butyramide intermediate (II); with ( The amide of II) is hydrolyzed into an acid, and the amino group is protected by BOC to obtain the target intermediate (I); wherein the protecting group of piperazine in formula (III) and formula (II) is C1-4 alkoxycarbonyl, benzyloxycarbonyl or methyl. The invention has the advantages of ingenious design, simple and efficient synthesis route, simple and easy process flow, and environmental protection, and provides a new method for industrial scale production of formula (III).

Description

[0001] technical field [0002] The present invention relates to the synthetic technical field of sitagliptin, more specifically, relate to transaminase synthesis ( R )- N -BOC-3-amino-4-(2,4,5-trifluorophenyl) butyric acid enzymatic synthesis technical field, especially refers to a transaminase method synthesis transaminase method synthesis ( R )- N -BOC-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid method. Background technique [0003] Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that controls blood sugar levels by protecting endogenous incretins and enhancing their action. Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), are incretins released in response to dietary intake. Sitagliptin inhibits the degradation of incretins by DPP-4, so it can enhance the function of GLP-1 and GIP, increase insulin release and reduce circulating glucagon levels. [0004] (R)- N -BOC-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid (I)...

Claims

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Application Information

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IPC IPC(8): C12P13/04
CPCC12P13/04
Inventor 李涛
Owner SHANGHAI PUYI CHEM CO LTD
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