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Preparation of carbapenem antibiotic side chain

A carbapenem and antibiotic technology, applied in the field of medicine, can solve the problems of high cost and complicated preparation process, and achieve the effects of simplified operation, easy purification and reduced production cost

Active Publication Date: 2009-07-15
ZHEJIANG HISOAR CHUANNAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In the above technology, the thiolactone intermediate usually needs to be purified by silica gel column chromatography before it can be used to prepare the meropenem side chain, and the prepared ramipenem side chain also needs to be purified by silica gel column chromatography, so the preparation process is complex, high cost

Method used

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  • Preparation of carbapenem antibiotic side chain
  • Preparation of carbapenem antibiotic side chain
  • Preparation of carbapenem antibiotic side chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1, preparation of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxyl-L-proline compound (iii)

[0037] Add 100g (0.763mol) of L-hydroxyproline and 500ml of water, stir to dissolve, cool to 0°C, add a solution of p-nitrobenzyl chloroformate (181g, 0.84mol) in dichloromethane (268.6ml), dropwise Potassium carbonate (133.9 g, 0.968 mol) in water (268.6 ml) was dripped in 1.5 hours, kept for 2 hours, and then reacted at room temperature for 2 hours. Separate the dichloromethane phase, wash the water phase with dichloromethane (200ml×1), add concentrated hydrochloric acid to adjust the pH to 1-2, stir overnight, filter with suction after the solid precipitates, wash with water, and dry at 50°C to obtain trans- 1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (iii) crude product m=235.6g. The yield is 99.61%.

Embodiment 2

[0038] Embodiment 2, preparation of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxyl-L-proline compound (iii)

[0039] Add 100g (0.763mol) of L-hydroxyproline and 500ml of water, stir to dissolve, cool to 0°C, add a solution of p-nitrobenzyl chloroformate (181g, 0.84mol) in dichloromethane (268.6ml), dropwise A solution of sodium hydroxide (67.2g, 1.68mol) in water (268.6ml) was dropped in 1.5 hours, kept for 2 hours, and then reacted at room temperature for 2 hours. Separate the dichloromethane phase, wash the water phase with dichloromethane (200ml×1), add concentrated hydrochloric acid to adjust the pH to 1-2, stir overnight, filter with suction after the solid precipitates, wash with water, and dry at 50°C to obtain trans- 1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (iii) crude product m=236g. The yield is 99.78%.

Embodiment 3

[0040] Example 3, purification of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxyl-L-proline compound (iii)

[0041] After dissolving 235.6 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (iii) crude product under reflux with 668 ml of ethyl acetate, the temperature was lowered to 75°C, and 0.5 g of activated carbon was added. Suction filtration, the filtrate was crystallized by cooling at 0°C, suction filtration, the solids were washed with ethyl acetate, the ethyl acetate phases were combined, and rotary evaporated at 40°C, the solids were precipitated, suction filtration, washed with ethyl acetate, the solids were combined, and dried at 40°C , to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (iii) refined product 213.1 g, yield 90.1%.

[0042] The physical properties of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline (iii) refined product are as follows

[0043] Molecular formula: C 13 h 14 N 2 o 7 ;

[0044] Molecular weight: 310;

[00...

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Abstract

The invention discloses a method for preparing side chains of carbapenems antibiotics, comprising the following steps: A) L-hydroxyproline (ii) reacts with 4-nitrobenzyl chloroformate and then is separated and crystallized to obtain a compound (iii); B) the compound (iii) reacts with diphenylphosphinyl chloride to obtain a compound (iv); the compound (iv) reacts with methanesulfonyl chloride to obtain a compound (v); the compound (v) reacts with sodium sulfide nonahydrate and is heated to 15-35 DEG C to react for 0.5-6h to obtain a compound (vii); C) the compound (vii) reacts with dimethyl amine hydrochloride and then is separated and crystallized to obtain a compound (i). The method simplifies the operation, ensures easy industrial production, reduces the production cost and leads the products to be easily purified; therefore, the obtained products have high purity and yield.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of a carbapenem side chain. Background technique [0002] Penem (carbapenem) drugs such as imipenem, meropenem and biapenem have good antibacterial effects on many drug-resistant bacteria, especially have a fairly strong inhibitory effect on B-type enzymes. A unique inhibitor of β-lactamase. (2S,4S)-substituted carbamoyl-4-mercapto-1-(N-substituted)pyrrolidine (i) is an important side chain intermediate of penem drugs such as meropenem. [0003] [0004] US4943569 reports two synthetic routes of compound (i). The first method is to use trans-4-hydroxy-L-proline as raw material, protect the amino group on the pyrrole ring, protect the carboxyl group at the 2-position to form an ester, replace the hydroxyl group at the 4-position to obtain a sulfhydryl compound, and then hydrolyze the 2-position to obtain Carboxylic acid, amidation, and 4-position hydrolysis have ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
Inventor 刘小辉赵大同
Owner ZHEJIANG HISOAR CHUANNAN PHARMA
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