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Synthetic method of avibactam intermediate (2S,5S)-N-protective group-5-hydroxy-2-piperidine formate

A technology of piperidine formate and a synthetic method, which is applied in the field of drug synthesis, can solve the problems of unsuitability for industrial production, insufficient total yield, high cost, etc., and achieve the effects of easy control of impurities, low price, and simple operation

Active Publication Date: 2019-12-17
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the total yield is less than 7%, the cost is high, and it is not suitable for industrialized production
[0007] In summary, the method for the synthesis of avibactam intermediate (2S, 5S)-N-protecting group-5-hydroxyl-2-formic acid piperidine analogs reported in the above literature has obvious deficiencies, and the difficulty lies in the six-membered piperidine acid build

Method used

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  • Synthetic method of avibactam intermediate (2S,5S)-N-protective group-5-hydroxy-2-piperidine formate
  • Synthetic method of avibactam intermediate (2S,5S)-N-protective group-5-hydroxy-2-piperidine formate
  • Synthetic method of avibactam intermediate (2S,5S)-N-protective group-5-hydroxy-2-piperidine formate

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Experimental program
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Effect test

Embodiment 1

[0046] 1. Synthesis of (S)-ethyl-2-[(tert-butoxycarbonyl)amino]-6-(dimethylsulfinyl)-5-oxohexanoate (compound II)

[0047]

[0048] Add tetrahydrofuran (540mL) and dimethyl sulfoxide (650mL) to the reaction flask in turn, stir trimethylsulfoxide iodide (154g) to completely dissolve, and slowly add potassium tert-butoxide (78.6g) at 0-10°C , and stirred for 1 hour. A solution of tetrahydrofuran (180mL) containing ethyl tert-butoxycarbonyl-L-pyroglutamate (150g) was added dropwise at -15~-10°C, and reacted for 2h. After the reaction, add saturated ammonium chloride solution (700mL) and ethyl acetate (1000mL), separate the ethyl acetate, extract the aqueous phase with ethyl acetate (1000mL×3), combine the ethyl acetate phase, and add saturated ammonium chloride After washing (200 mL×1), drying over anhydrous sodium sulfate, the organic layer was concentrated to obtain compound II as a white solid (182 g, HPLC>99%, yield 89.3%).

[0049] [ 1 H NMR (CDCl 3 ),400MHz]δ: 1.29(3...

Embodiment 2

[0066] 1. Same as step 1 in Example 1.

[0067] 2. Synthesis of (S)-ethyl-2-[(tert-butoxycarbonyl)amino]-6-chloro-5-oxohexanoate (compound III')

[0068]

[0069]Add tetrahydrofuran (120 mL) solution, compound II (20 g), and lithium chloride (2.92 g) to the reaction flask in sequence. A solution of tetrahydrofuran (20 mL) containing methanesulfonic acid (6.57 g) was added dropwise at -10 to 0° C., and the mixture was incubated and stirred for 2 hours. React at a temperature of 20-35° C. for 16-20 hours. After the reaction was over, most of the solvent was removed under reduced pressure, ethyl acetate (40mL×3) and water (40mL) were added, the aqueous layer was removed, the organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and filtered, the filtrate Concentration under reduced pressure gave an off-white solid (15 g, HPLC>94%, yield 84.8%) compound III', which was sealed and stored at low temperature. [ 1 HNMR (CDCl 3 ),400MHz]δ:...

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Abstract

The invention discloses a synthetic method of an avibactam intermediate (2S,5S)-N-protective group-5-hydroxy-2-piperidine formate. N-protective group-L-pyroglutamate (SM) is taken as an initial raw material, and the (2S,5S)-N-protective group-5-hydroxy-2-piperidine formate is obtained through six steps of reactions including trimethyl sulfoxide iodide recarburization ring opening, halogenation under the action of acid, high-selectivity reduction, lactone ring formation under the catalysis of acid, piperidine ring closing under the action of alkali and hydrolysis. The synthetic method is mild in reaction conditions, simple and convenient to operate, easy in impurity control and stable in yield. The used reagents are low in price, the cost is effectively reduced, and the method is environment-friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing an avibactam intermediate (2S, 5S)-N-protecting group-5-hydroxyl-2-formic acid piperidine. Background technique [0002] Avibactam (Avibactam, NXL-104) belongs to the diazabicyclooctone compound and is a new type of β-lactamase inhibitor currently on the market. (2S,5S)-N-protecting group-5-hydroxypiperidine-2-carboxylate and its derivatives (such as (2S,5S)-N-protecting group-5-hydroxypiperidine-2-carboxylic acid ethyl ester) are Its important intermediate, the six-membered ring piperidine structure of this kind of compound has two chiral centers, the synthesis is very difficult, and generally needs to go through tedious synthesis steps to obtain. Due to the high price in the market, the cost of medicines using it as a raw material increases, so it is necessary to develop a new method to prepare the compound. [0003] Document 1: Tetrahedron letters, vol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60Y02P20/55
Inventor 王文宽师军寿颜连忠郑长胜杨庆坤李卓华
Owner 山东安信制药有限公司
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