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The preparation method of latamoxef sodium intermediate

A technology for latamoxef sodium and intermediates, which is applied in the field of synthesis of latamoxef sodium intermediates, can solve the problems of increased uncontrollable reaction, unsuitability for industrial production, and high production costs, and achieve economic burden reduction and simplification of production equipment , The effect of material cost reduction

Inactive Publication Date: 2011-12-21
河北九派制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because tributylphosphine has a strong reducing property, it may cause the danger of burning when exposed to high heat, open flame or contact with an oxidant; at the same time, due to the addition of a water separator, the uncontrollability of the reaction increases, and the yield is low and the production cost is high.
These disadvantages make the reaction unsuitable for industrial production

Method used

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  • The preparation method of latamoxef sodium intermediate
  • The preparation method of latamoxef sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Latamoxef sodium intermediate of the present invention is [1R-[1a,5a]]-3-methyl-2-(7-oxo-3-phenyl-4-oxa-2,6- The preparation method of diazabicyclo[3.2.0]hept-2-en-6-yl)-3-butenoic acid diphenylmethyl ester comprises the following processing steps:

[0024] a. Add 400mL of toluene, 30g of triphenylphosphine, 45g of 6-β-benzamide-4-oxo-penicillanic acid diphenylmethyl ester and 90mL of 1.2-diphenylmethyl ester in a dry and clean 1L four-necked bottle. For ethyl chloride, after setting up the reflux device, turn on the cooling water, control the internal temperature at 98-105°C, and make the material react under reflux;

[0025] b. When the residue of 6-beta-benzamide-4-oxo-penicillanic acid diphenylmethyl in the above reaction is ≤1.0%, the reaction ends, and then concentrated under reduced pressure at 50-60°C to evaporate to dryness, Then add 300mL of methanol and 280mL of acetonitrile mixed solvent to the evaporated concentrate, fully stir until dissolved a...

Embodiment 2

[0029] Embodiment 2: the difference between this embodiment and embodiment 1 is that

[0030] a. Add 380mL benzene, 32g triphenylphosphine, 45g 6-β-benzamide-4-oxo-penicillanic acid diphenylmethyl ester, 100mL dichloromethane to a dry and clean 1L four-neck bottle, and set aside After the reflux device, turn on the cooling water and control the internal temperature at 98-105°C to make the material react under reflux;

[0031] b. When the residue of 6-beta-benzamide-4-oxo-penicillanic acid diphenylmethyl in the above reaction is ≤1.0%, the reaction ends, and then concentrated under reduced pressure at 50-60°C to evaporate to dryness, Then add 300mL of ethanol and 280mL of acetonitrile mixed solvent to the evaporated concentrate, fully stir until dissolved and clarified, then lower the temperature to below 0°C and keep the crystal for 10 hours;

[0032] c, filter to remove the impurity triphenylthion that generates, then add 30mL ethanol solvent to wash the filter cake, then co...

Embodiment 3

[0035] Embodiment 3: the difference between this embodiment and embodiment 1 is,

[0036] a. Add 400mL benzene, 30g triphenylphosphine, 45g 6-β-benzamide-4-oxo-penicillanic acid diphenylmethyl ester, 100mL dichloromethane to a dry and clean 1L four-neck bottle, set aside Turn on the cooling water after the reflux device, control the internal temperature at 98-105°C, and make the material react under the reflux state;

[0037]b. When the residue of 6-beta-benzamide-4-oxo-penicillanic acid diphenylmethyl in the above reaction is ≤1.0%, the reaction ends, and then concentrated under reduced pressure at 50-60°C to evaporate to dryness, Then add 300mL of methanol and 280mL of acetonitrile mixed solvent to the evaporated concentrate, stir thoroughly until dissolved and clarified, then cool down to below 0°C to grow crystals for 8-10 hours;

[0038] c, filter to remove the impurity triphenylthion that generates, then add 30mL methanol to wash the filter cake, then combine the filtra...

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Abstract

The invention discloses a preparation method of Latamoxef sodium intermediate, which comprises adding 6-beta-benzamide-4-oxo-penicillanic acid diphenylmethyl ester and triphenylphosphine into benzene and alkanes In the solvent, the reaction is carried out under reflux; after concentration under reduced pressure, acetonitrile and alcohol mixed solvent are added to the concentrate, crystal growth, filtration, concentration, cooling and crystallization, and filtration are carried out to obtain the present invention. Since triphenylphosphine was chosen to replace the highly toxic and harmful tributylphosphine desulfurizer, the uncontrollable dehydration device was eliminated, the production equipment was simplified, and the mixed system of the generated by-product triphenylthiophosphine in acetonitrile and alcohol solvents It can be crystallized in solid form, which reduces the subsequent impurity removal process and is beneficial to ensure the improvement of product quality and yield. The product yield can be increased from 40% to 58% of the original process, and the cost of materials can be reduced by about 600 yuan / Kg, which provides technical conditions for the large-scale production of oxycephem parent core, with significant economic benefits and strong market competitiveness .

Description

technical field [0001] The present invention relates to the synthetic method of Latamoxef sodium intermediate, namely [1R-[1a,5a]]-3-methyl-2-(7-oxo-3-phenyl-4-oxa-2,6 - a process for the preparation of diazabicyclo[3.2.0]hept-2-en-6-yl)-3-butenoic acid diphenylmethyl ester. It is used to solve the key reaction steps in the synthesis of oxycephem nuclei, and is specifically applied to the ring-opening desulfurization of 6-β-benzamide-4-oxo-penicillanic acid diphenylmethyl ester to obtain [1R-[1a, 5a]]-3-methyl-2-(7-oxo-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl )-3-butenoic acid diphenylmethyl ester reaction process. [0002] Its reaction process is as follows: [0003] Background technique [0004] Latamoxef sodium is a completely synthetic product with a structure similar to that of cephalosporins, but the S in the mother nucleus is replaced by O. It is an oxacephem (oxacephem) class. Its mechanism of action and antibacterial spectrum are similar to those o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D507/00
Inventor 祁振海殷芳赵翠然程广业张青坡李谦
Owner 河北九派制药股份有限公司
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