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Preparation method of saxagliptin intermediate

An intermediate, azabicyclic technology, applied in the field of medicinal chemistry, can solve the problems of high cost and low yield, and achieve the effect of simple operation, high selectivity and large-scale production

Inactive Publication Date: 2015-05-20
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Aiming at the above technical problems in the prior art, the invention provides a saxagliptin intermediate (1S, 3S, 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane- The preparation method of 2-tert-butyl formate, the described preparation method solves the problem of preparing (1S, 3S, 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane in the prior art The technical problem that the method cost of alkane-2-carboxylic acid tert-butyl ester is high and the yield is low

Method used

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  • Preparation method of saxagliptin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Preparation of ethyl L-pyroglutamate (hereinafter referred to as compound 2)

[0037] In a dry 500ml four-necked reaction flask, N 2 Under protection, add L-pyroglutamic acid (25.9g, 0.20mol) and dissolve it in 250ml of absolute ethanol, keep the temperature of the system at -5°C, and start adding thionyl chloride (SOCl 2 ) (26.2g, 0.22mol), added dropwise for 2h, stirred for 0.5h after the dropwise addition, then raised the temperature to 22°C, stirred for 2 hours, concentrated the solvent under reduced pressure at a water bath temperature of 45°C, and obtained a colorless oil. Then add 100ml of toluene and stir evenly, then concentrate the solvent under reduced pressure at a water bath temperature of 45°C to obtain a colorless oily substance, then add 200ml of toluene to maintain the temperature at 10°C, then add 200ml of triethylamine (TEA) to adjust the pH of the system to 8, then Stir for 0.5h, filter, and wash the filter cake with toluene. The filtrate was conce...

Embodiment 2

[0041] Preparation of Boc-L-ethyl pyroglutamate (hereinafter referred to as compound 3)

[0042] In a dry 500ml four-necked reaction flask, add compound 2 (28.3g, 0.18mol) and dissolve it in 250ml of toluene, add dimethylaminopyridine (DMAP) (11.2g, 0.09mol) and stir, maintain at 14°C and add di Di-tert-butyl carbonate ((Boc) 2 O) (58.9g, 0.27mol) toluene solution system, add dropwise for 1h, keep warm at 25°C after dropwise addition, stir for 3h, then wash once with 10ml4.5% sodium bicarbonate solution, and wash twice with water, Carefully separate the water layer, concentrate the organic layer at 50°C under reduced pressure to obtain a yellow oil, then add 100ml of toluene and stir evenly, and keep the temperature at 50°C, start adding 100ml of n-heptane dropwise, and keep the temperature at 25°C after the dropwise addition After stirring for 2 hours, the system was cooled to 5°C, stirred for 30 minutes, filtered, the filter cake was slurried with n-heptane, sucked dry, and...

Embodiment 3

[0046] Preparation of (S)-1-N-tert-butoxycarbonyl-2-hydroxyl-2-pyrrolecarboxylic acid ethyl ester (hereinafter referred to as compound 4)

[0047] In a dry 250ml three-neck reaction flask, N 2 Add compound 3 (30.9g, 0.12mol) under protection and dissolve it in 180ml tetrahydrofuran (THF), and add a toluene solution of diisobutylaluminum hydride (DIBAL-H) ​​dropwise at a temperature of -65°C. After the dropwise addition is completed, Stir for 1.5h, concentrate under reduced pressure to remove the solvent to obtain a colorless oily substance, then add 100ml of toluene, adjust the pH to 8 with 200ml of triethylamine (TEA), concentrate under reduced pressure, and recrystallize with n-heptane to obtain a white solid, namely compound 4 (23.8 g, 91.8%).

[0048] (S)-1-N-tert-butoxycarbonyl-2-hydroxyl-2-pyrrolecarboxylate ethyl NMR spectrum data are as follows:

[0049] 1 H NMR (400MHz, CDCl 3 ): δ=6.75-6.40(m,1H), 4.98(d,J=19.1Hz,1H), 4.35-4.08(m,2H), 3.19-2.94(m,2H), 2.77-2.54(m...

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Abstract

The invention provides a preparation method of a saxagliptin intermediate (1S, 3S, 5S)-3-(amino carbonyl)-2-azabicyalo[3.1.0]hexane-2-tert-butyl formate. According to the preparation method, L-pyroglutamic acid is taken as a raw material, and an esterification reaction, Boc protection, reduction, elimination, cyclopropylation, resolution, hydrolyzation, ammonolysis, Boc deprotection and ammonolysis are performed on L-pyroglutamic acid, and finally, the compound (1S, 3S, 5S)-3-(amino carbonyl)-2-azabicyalo[3.1.0]hexane-2-tert-Butyl formate is obtained. The preparation method of the saxagliptin intermediate is cheap and easily available in raw materials, reasonable in process, simple and convenient to operate, high in enantiomer selectivity and high in yield.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a saxagliptin intermediate, specifically a saxagliptin intermediate (1S, 3S, 5S)-3-(aminocarbonyl)-2-azabicyclo [3.1.0] Preparation method of tert-butyl hexane-2-carboxylate. Background technique [0002] Saxagliptin is the first hypoglycemic drug based on the mechanism of incretin jointly developed by two global pharmaceutical companies, Bristol-Myers Squibb and AstraZeneca. It was approved by the US Food and Drug Administration in July 2009. Approved for initial listing. [0003] Saxagliptin is a high-efficiency dipeptidyl peptidase-4 (DPP-4) inhibitor with good tolerance and safety. It can be used as an adjuvant therapy with diet and exercise to improve the health status of adults with type 2 diabetes. Blood sugar control status. The drug has a unique mechanism of action. It selectively inhibits the DPP-4 enzyme, thereby promoting the secretion of insulin and reducing the...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 余焓于娜高静郭国才韩生
Owner SHANGHAI INST OF TECH
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