Composite method for cefpiramide midbody D-alpha-(4-Hydroxy-6-methylnicotinamido) hydroxyphenylacetic acid

Abstract

The invention relates to a composite method for cefpiramide midbody D-alpha-(4-Hydroxy-6-methylnicotinamido) hydroxyphenylacetic acid, which includes the steps of using the acyl chloride of 4-hydroxy-6-methylnicotinic acid to directly acylate and esterify D-hydroxyphenylglycine, using water to remove the estersil of an acylation product and directly obtaining an objective product D-alpha-(4-Hydroxy-6-methylnicotinamido) hydroxyphenylacetic acid. Compared with the method of composing D-hydroxyphenylglycine into alkane ester or salt at first, the composite method for cefpiramide midbody D-alpha-(4-Hydroxy-6-methylnicotinamido) hydroxyphenylacetic acid simplifies the operation and is suitable for large-scale production.

Description

technical field

[0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetic acid, an intermediate of cephalosporin antibiotic cefpiramide. Background technique

[0002] Cefpiramide is a third-generation cephalosporin jointly developed by Sumitomo and Yamanouchi, and cefpiramide sodium salt is used clinically. Its chemical name is (6R, 7R,)-7-[(R)-2-(4-hydroxy-6-methyl-3-pyridylcarboxamido)-2-(p-hydroxyphenyl)acetamido ]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0] Oct-2-ene-2-carboxylic acid sodium salt, CAS No: 74849-93-7, the structural formula is:

[0003]

[0004] This product was launched in Japan before 1985, due to its C 3 With a methyl tetrazolyl sulfur group in the position, C 7 There is a hydroxyphenylmethylpyridyl group at the position, thus greatly improving the antibacterial act...

Examples

Embodiment 1

[0038] Embodiment 1: synthetic reaction route is as follows:

[0039]

[0040] (1) Suspend 13.36g of HPG in 120ml of dichloromethane as an organic solvent, cool to 10°C, then add 27g of trimethylchlorosilane (silicon esterification agent) at one time, and then slowly add organic solvent at 15°C to 20°C Base 24.24g of triethylamine, keep stirring at the same temperature for 1.5 hours to obtain HPG silicon esterification solution.

[0041] (2) Take 15g of MHPA and suspend it in 140ml of methylene chloride, and use the MHPA acyl chloride prepared by the conventional acyl chloride preparation method.

[0042] (3) Control the temperature at 15°C to 18°C, slowly add MHPA acid chloride dropwise to the HPG silicon esterification solution in step (1), keep the same temperature for 1.5 hours, then add 260ml deionized water, and use 10% NaOH The pH of the solution was adjusted to 7.1. Still layering.

[0043](4) Decolorize the water layer with activated carbon, remove the activated...

Embodiment 2

[0045] As described in Example 1, the difference is that dichloroethane is used as the organic solvent, and the result is 20.3 grams of D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetic acid, yield 84.02% .

Embodiment 3

[0047] As described in Example 1, the difference is that the silicon esterification agent uses diethylmethylchlorosilane to obtain 19 grams of D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetic acid crystals , yield 78.64%.

technical field

[0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetic acid, an intermediate of cephalosporin antibiotic cefpiramide. Background technique

[0002] Cefpiramide is a third-generation cephalosporin jointly developed by Sumitomo and Yamanouchi, and cefpiramide sodium salt is used clinically. Its chemical name is (6R, 7R,)-7-[(R)-2-(4-hydroxy-6-methyl-3-pyridylcarboxamido)-2-(p-hydroxyphenyl)acetamido ]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,0] Oct-2-ene-2-carboxylic acid sodium salt, CAS No: 74849-93-7, the structural formula is:

[0003]

[0004] This product was launched in Japan before 1985, due to its C 3 With a methyl tetrazolyl sulfur group in the position, C 7 There is a hydroxyphenylmethylpyridyl group at the position, thus greatly improving the antibacterial act...

Examples

Embodiment 1

[0038] Embodiment 1: synthetic reaction route is as follows:

[0039]

[0040] (1) Suspend 13.36g of HPG in 120ml of dichloromethane as an organic solvent, cool to 10°C, then add 27g of trimethylchlorosilane (silicon esterification agent) at one time, and then slowly add organic solvent at 15°C to 20°C Base 24.24g of triethylamine, keep stirring at the same temperature for 1.5 hours to obtain HPG silicon esterification solution.

[0041] (2) Take 15g of MHPA and suspend it in 140ml of methylene chloride, and use the MHPA acyl chloride prepared by the conventional acyl chloride preparation method.

[0042] (3) Control the temperature at 15°C to 18°C, slowly add MHPA acid chloride dropwise to the HPG silicon esterification solution in step (1), keep the same temperature for 1.5 hours, then add 260ml deionized water, and use 10% NaOH The pH of the solution was adjusted to 7.1. Still layering.

[0043](4) Decolorize the water layer with activated carbon, remove the activated...

Embodiment 2

[0045] As described in Example 1, the difference is that dichloroethane is used as the organic solvent, and the result is 20.3 grams of D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetic acid, yield 84.02% .

Embodiment 3

[0047] As described in Example 1, the difference is that the silicon esterification agent uses diethylmethylchlorosilane to obtain 19 grams of D-α-(6-methyl-4-hydroxynicotinamide) p-hydroxyphenylacetic acid crystals , yield 78.64%.

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