Cephamycin intermediate compound and preparation method thereof

Abstract

The invention relates to a cephamycin intermediate compound and a preparation method thereof. The cephamycin intermediate compound has a structure of formula (I), and is prepared by directly reacting 7beta-chloroacetamide-7alpha-methoxy-3-(1-methyl-1H-tetrazole-5-thiomethyl)-3-cephem-4-carboxylic acid and dicyclohexylamine in a specific solvent to form a salt and crystallizing. The cephamycin intermediate compound has the characteristics of high purity, high stability and the like, is conductive to improving the purity of cephamycin final products such as cefminox sodium, cefmetazole sodium and cefotetan disodium, and is beneficial to large-scale production and application.

Description

technical field

[0001] The invention belongs to the technical field of preparation of cephalosporin compounds in the pharmaceutical synthesis technology, and in particular relates to a cephamycin intermediate compound and a preparation method thereof. Background of the invention

[0002] Cephamycin can be considered as an important branch of cephalosporins. There is a trans-methoxy group at the C7 position on the β-lactam ring, which makes this class of antibiotics have strong resistance to β-lactamase. Common anaerobic bacteria that are prone to producing β-lactamase, such as Bacteroides fragilis (Bf), have strong antibacterial properties, which is precisely the shortcoming of common cephalosporins.

[0003] Common cefamycins currently on the global market include cefminox sodium, cefmetazole sodium, cefotetan disodium and cefoxitin sodium, etc., wherein only cefminox sodium is in crystalline form, and the others are generally non-crystalline; in addition, At present, ceph...

Examples

Embodiment 1

[0031] Embodiment 1, preparation of cephamycin intermediate formula (I) compound

[0032]Dissolve 0.1 mol of the prepared oil containing the compound of formula (II) in 330 ml of acetone, mix thoroughly and cool down to 5°C, slowly add 21.8 g (0.12 mol) of dicyclohexylamine dropwise under stirring, the feed solution It gradually becomes muddy. Keep warm at about 5°C to grow crystals for 2 hours, filter, wash the filter cake with 120ml of acetone, and drain. The obtained solid was vacuum-dried at 40°C until the water content was less than 1%, and 54.2 g of white crystalline powder was obtained, which was the compound of formula (I) of the cephamycin intermediate of the present invention. The yield was 87.9%, and the HPLC purity was 99.53%.

[0033] The structure of the obtained product was confirmed, and the results are as follows:

[0034] IR(KBr):.

[0035] Sample absorption peak / cm -1

vibration type

group

3153

ν N-H

-NH

2939，2858...

Embodiment 2

[0042] Add ethyl acetate to the prepared oil containing 0.1 mol of the compound of formula (II) to prepare an ethyl acetate solution with a concentration of about 100 g / L, cool down to 10°C, and dropwise add 21.8 g of dicyclohexylamine (0.12 mol), add 0.1g of seed crystals, grow the crystals for 3h, cool down to 0°C, continue to grow the crystals for 4h, filter, wash the filter cake with 200ml of ethyl acetate, and drain. The obtained solid was vacuum-dried at 40°C until the water content was less than 1%, and 57.4 g of off-white crystalline powder was obtained, which was the compound of formula (I) of the cephamycin intermediate of the present invention; the yield was 93.1%, and the HPLC purity was 99.27%.

Embodiment 3

[0044] Dissolve 0.1 mol of the oily substance containing the compound of formula (II) in 100 ml of N,N-dimethylformamide, cool down to 5°C, slowly add 21.8 g (0.12 mol) of dicyclohexylamine dropwise, Cultivate the crystal for 2 hours, filter, wash the filter cake with 100ml N,N-dimethylformamide, and drain it. The obtained solid was vacuum-dried at 40°C until the water content was less than 1%, and 53.9 g of white crystalline powder was obtained, which was the compound of formula (I) of the cephamycin intermediate of the present invention. The yield was 87.5%, and the purity of the product was 99.60% by HPLC.

technical field

[0001] The invention belongs to the technical field of preparation of cephalosporin compounds in the pharmaceutical synthesis technology, and in particular relates to a cephamycin intermediate compound and a preparation method thereof. Background of the invention

[0002] Cephamycin can be considered as an important branch of cephalosporins. There is a trans-methoxy group at the C7 position on the β-lactam ring, which makes this class of antibiotics have strong resistance to β-lactamase. Common anaerobic bacteria that are prone to producing β-lactamase, such as Bacteroides fragilis (Bf), have strong antibacterial properties, which is precisely the shortcoming of common cephalosporins.

[0003] Common cefamycins currently on the global market include cefminox sodium, cefmetazole sodium, cefotetan disodium and cefoxitin sodium, etc., wherein only cefminox sodium is in crystalline form, and the others are generally non-crystalline; in addition, At present, ceph...

Examples

Embodiment 1

[0031] Embodiment 1, preparation of cephamycin intermediate formula (I) compound

[0032]Dissolve 0.1 mol of the prepared oil containing the compound of formula (II) in 330 ml of acetone, mix thoroughly and cool down to 5°C, slowly add 21.8 g (0.12 mol) of dicyclohexylamine dropwise under stirring, the feed solution It gradually becomes muddy. Keep warm at about 5°C to grow crystals for 2 hours, filter, wash the filter cake with 120ml of acetone, and drain. The obtained solid was vacuum-dried at 40°C until the water content was less than 1%, and 54.2 g of white crystalline powder was obtained, which was the compound of formula (I) of the cephamycin intermediate of the present invention. The yield was 87.9%, and the HPLC purity was 99.53%.

[0033] The structure of the obtained product was confirmed, and the results are as follows:

[0034] IR(KBr):.

[0035] Sample absorption peak / cm -1

vibration type

group

3153

ν N-H

-NH

2939，2858...

Embodiment 2

[0042] Add ethyl acetate to the prepared oil containing 0.1 mol of the compound of formula (II) to prepare an ethyl acetate solution with a concentration of about 100 g / L, cool down to 10°C, and dropwise add 21.8 g of dicyclohexylamine (0.12 mol), add 0.1g of seed crystals, grow the crystals for 3h, cool down to 0°C, continue to grow the crystals for 4h, filter, wash the filter cake with 200ml of ethyl acetate, and drain. The obtained solid was vacuum-dried at 40°C until the water content was less than 1%, and 57.4 g of off-white crystalline powder was obtained, which was the compound of formula (I) of the cephamycin intermediate of the present invention; the yield was 93.1%, and the HPLC purity was 99.27%.

Embodiment 3

[0044] Dissolve 0.1 mol of the oily substance containing the compound of formula (II) in 100 ml of N,N-dimethylformamide, cool down to 5°C, slowly add 21.8 g (0.12 mol) of dicyclohexylamine dropwise, Cultivate the crystal for 2 hours, filter, wash the filter cake with 100ml N,N-dimethylformamide, and drain it. The obtained solid was vacuum-dried at 40°C until the water content was less than 1%, and 53.9 g of white crystalline powder was obtained, which was the compound of formula (I) of the cephamycin intermediate of the present invention. The yield was 87.5%, and the purity of the product was 99.60% by HPLC.

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