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Preparation method of key intermediate of saxagliptin

The technology of tert-butoxycarbonyl and dihydrogen, which is applied in the field of preparation of compound intermediates, can solve the problems of environmental pollution, low cyclopropanation conversion rate and high cost, avoid environmental pollution problems, have high reaction selectivity and reduce production. cost effect

Inactive Publication Date: 2017-04-05
HYBIO PHARMA
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Problems solved by technology

[0007] In the above synthetic route, compound 4 is subjected to the classic Simmons-Smith reaction, that is, the cyclization reaction is carried out through the action of diethylzinc and diiodomethane to obtain compound 3 and compound 4. According to the literature Bioorg.Med.Chem.22( 2014) reported that the conversion rate of cyclopropanization is low (45%), causing the target product yield to be low (10%-20%), and the cost is high; at the same time, a large amount of waste water and waste residues will be produced during industrial production, which will cause environmental damage. extreme pollution [1，2]

Method used

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  • Preparation method of key intermediate of saxagliptin
  • Preparation method of key intermediate of saxagliptin
  • Preparation method of key intermediate of saxagliptin

Examples

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Embodiment 1

[0032] Example 1: Preparation of (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid methyl ester

[0033] In a 500 mL three-neck flask, under nitrogen protection, Boc-methyl pyroglutamate (21.8 g) and toluene (144 mL) were added. Stir to dissolve, and cool the system temperature to -60°C ~ -70°C. Keeping the temperature at -60°C to -70°C, a solution of lithium triethylborohydride in tetrahydrofuran (1 mol / L, 91.6 mL) was slowly added dropwise, and stirring was continued for 3 hours after the dropwise addition. Add DIPEA, DMAP, and TFAA to the reaction liquid in sequence, and control the temperature not to exceed -60°C. Naturally warmed to room temperature, stirring was continued for 3 hours. Cool to 0-5°C, add water (200 mL), and stir for 20 minutes. After standing still for liquid separation, the organic phase was washed successively with 3 mol / L dilute hydrochloric acid (200 mL), saturated sodium bicarbonate solution (200 mL), and saturated saline solution. ...

Embodiment 2

[0034] Example 2: Preparation of (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid N,N-diisopropylethylamine salt

[0035] In a 500 mL three-necked flask, (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid methyl ester (20.3 g) and methanol (100 mL) were added. The temperature of the reaction solution was cooled to 0-5°C, and aqueous lithium hydroxide solution (0.1 g / mL, 70.7 mL) was slowly added dropwise. After the dropwise addition was completed, the mixture was raised to room temperature and stirred for 2 hours. After the reaction solution was concentrated to half volume at 40°C, water (100 mL) and methyl tert-butyl ether (100 mL) were added, and stirring was continued for 10 minutes. After standing still for liquid separation, the aqueous phase was collected, and methyl tert-butyl ether (100 mL) was added. Cool the mixture to 5-10°C, and adjust the pH to 2.3 with a mixed solution (1:4) of 85% phosphoric acid-water (1:4). Keep the temperature...

Embodiment 3

[0036]Example 3: Preparation of (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrole carboxamide

[0037] In a 500mL three-necked flask, add (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid N,N-diisopropylethylamine salt (26.5g), tetrahydrofuran (150mL ), stir to dissolve. The temperature of the system was lowered to -20°C, methanesulfonyl chloride (13.2g) was slowly added dropwise, and the temperature was controlled not to exceed 0°C, after the dropwise addition, DIPEA (36mL) was added. After stirring for 3 hours, the temperature was controlled not to exceed 0°C. Ammonium carbonate (13.0 g) was added and stirring was continued overnight at room temperature. The reaction was filtered, and the filter cake was washed with an appropriate amount of tetrahydrofuran, and the filtrate was collected and concentrated to dryness at 40°C. The concentrate was dissolved with dichloromethane (150mL), washed with water (150mL), allowed to stand for liquid separation, and the ...

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Abstract

The invention relates to a preparation method of (1S, 3S, 5S)-3-(amidogen carbonyl)-2- azabicyalo [3.1.0] hexane-2-tert-butyl formate. The preparation method comprises the following steps that (1), Boc-L-pyroglutamic acid methyl ester is restored through lithium triethylborohydride and then dewatered through trifluoroacetic anhydride to obtain (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole ethyl formate; (2), DIPEA is added in the hydrolysis reaction of (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole ethyl formate under a alkaline condition, then salifying is conducted, and (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole formic acid N, N-diisopropyl ethylamine salt is obtained; (3), (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole formic acid N and N-diisopropyl ethylamine salt obtained in the step (2) are subjected to amidating, and (S)-1-N- tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole formamide is obtained; and (4), (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole formamide is catalyzed through a chirality nickel catalyst and subjected to a ciprofloxacin reaction, and a target material with single configuration, namely (1S, 3S, 5S)-3-(amidogen carbonyl)-2-azabicyalo [3.1.0] hexane-2-tert-butyl formate (SM1), is obtained.

Description

technical field [0001] The invention relates to a preparation method of a compound intermediate, in particular to a preparation method of a key intermediate of saxagliptin. Background technique [0002] Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) competitive inhibitor developed by Bristol-Myers Squibb, which can reduce the inactivation rate of incretin hormone and increase its blood concentration, thereby Reduces fasting and postprandial blood glucose concentrations in type 2 diabetic patients in a glucose-dependent manner. It was launched in the United States on July 31, 2009. [0003] The chemical name of saxagliptin is (1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo [3.1.0] Hexane-3-carbonitrile monohydrate. At present, it is mainly composed of (1S,3S,5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (SM1), 3-hydroxyadamantane-Boc The two key intermediates of -S-glycine (SM2) are obtained as starting mate...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 陶志强刘飞孟宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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