Dual-protection ertapenem crystal and preparation method thereof

Abstract

The invention discloses a dual-protection ertapenem crystal and a preparation method thereof. The dual-protection ertapenem crystal has a powder X-ray diffraction spectrogram shown as a Figure 1 and is prepared according to the following steps of: firstly, performing condensation reaction of carbapenems mother nucleus MAP and an ertapenem side chain, pouring a reaction liquid into a mixed solvent which is prepared from a buffer solution with a pH value of 4 to 6 and an ester solvent after reaction, extracting and layering; and secondly, adding the buffer solution into an organic layer for washing; and finally, drying the organic layer by using anhydrous sodium sulfate, filtering, stirring and crystallizing at the temperature of 0 to 30 DEG C, filtering, washing a filter cake, and performing vacuum drying. The dual-protection ertapenem crystal provided by the invention is high in stability and purity, and establishes a foundation and provides a guarantee for subsequent preparation of high-purity and stable-quality ertapenem. Moreover, the preparation method is simple, is easy for realizing mass production, meets industrial production requirement and has practical and promotional values, and raw materials are cheap and readily available.

Description

technical field [0001] The invention relates to a double-protected ertapenem crystal and a preparation method thereof, in particular to a (4R, 5R, 6S)-3-[(3S, 5S)-5-[(3-carboxyphenyl )carbamoyl]-N-p-nitrobenzyloxycarbonyl-pyrrolidin-3-yl]sulfur-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1- The invention relates to azabicyclo[3.2.0]hept-2-ene-2-carboxylate p-nitrobenzyl ester crystal and a preparation method thereof, belonging to the technical field of organic chemistry. Background technique [0002] Ertapenem sodium (ertapenem sodium) was invented by AstraZeneca in the UK and later transferred to Merck for further research and development. It is a new broad-spectrum long-acting carbapenem for injection with a 4-position (R) methyl group Antibiotics, listed in the U.S. for the first time in 2002, its structural formula is as shown in formula I: [0003] [0004] (4R, 5R, 6S)-3-[(3S, 5S)-5-[(3-carboxyphenyl)carbamoyl]-N-p-nitrobenzyloxycarbonyl-pyrrolidin-3-yl]thio- 6-[(1R)-...

AI Technical Summary

Problems solved by technology

[0008] Chinese patent CN1752090 reported that after condensation of MAP and PNZ-protected side chains, ertapenem was prepared by direct hydrogenation reduction without separation of intermediates, and the purification method of double-protected ertapenem was not reported

[0010] WO2008 / 062279 reported three purification methods of double-protected ertapenem. Method 1: Dilute the side chain condensation reaction solution of MAP and PNZ with THF and pour it into a mixed solvent of pH=7 buffer and ethyl acetate , after extraction and stratification, distill ethyl acetate under reduced pressure at 40°C and then add ethyl acetate to crystallize. The disadvantage is that the product is partially decomposed during the rotary distillation of ethyl acetate at 40°C, and the quality of the product cannot be controlled; method 2: put The side chain condensation reaction liquid protected by MAP and PNZ is poured into a mixed solvent of water and ethyl acetate, and the ethyl acetate layer is directly hydrogenated after layering. This method is consistent with most reported methods; The chain condensation reaction solution is poured into water or a buffer solution with pH=7 to directly precipitate solids. The disadvantage of this method is that the alkali used in the reaction cannot be removed, resulting in sticky products and poor purity.

The stability data of the amorphous state of double-protected ertapenem has not been reported. It is well known that the stability of substances in the crystalline state is better than that of the amorphous state, so the storage and transportation of the amorphous state of double-protected ertapenem will be difficult. Faced with many unsolvable difficulties in mass production

[0012] It can be seen from the above that the prior art has not reported any crystal structure of double-protected ertapenem, and the prior art cannot obtain double-protected ertapenem with high stability and high purity.

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