Synthetic method of cefcapene pivoxil hydrochloride

A technology of cefcapene pivoxil hydrochloride and cefcapene pivoxil hydrochloride, which is applied in the field of synthesis of cefcapene pivoxil hydrochloride, can solve problems such as unfavorable large-scale production, low total yield, and complexity, and achieve high total yield of finished products and low cost. Inexpensive, easy-to-use effect

Active Publication Date: 2014-06-11
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, it has been found through practice that the above-mentioned route is more complicated to operate, and the total yield is lower, which is not conducive to large-scale production.

Method used

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  • Synthetic method of cefcapene pivoxil hydrochloride
  • Synthetic method of cefcapene pivoxil hydrochloride
  • Synthetic method of cefcapene pivoxil hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: Synthesis of 7-DACA and Boc-7-DACA sodium salt

[0036] Suspend 10.0 g of 7-ACA in 30 mL of methanol / water mixed solvent, cool to -10°C to 0°C, and then add 30 mL of 10% NaOH solution dropwise (by adding in batches). Keep the temperature stable, stir for 2h, follow the reaction by TLC, the raw material point 7-ACA disappears, that is, the reaction is over. Then add cold acetone solution to the reaction system, stir vigorously, gradually a light yellow solid precipitates out. Filter, drain, and recrystallize with absolute ethanol to obtain the product 7-DACA with a yield of 86%.

[0037] 1 H NMR (D 2 O,400MHz):δ3.22-3.27(d,1H),3.43-3.47(d,1H).4.06(s,2H),4.85-4.86(dd,2H).

[0038] If the reaction is complete, add directly without processing (Boc) 2 O, the reaction was followed by TLC. If the reaction is not complete, alkali can be added appropriately. After the reaction was completed, EA was added to extract the organic phase three times, and cold ace...

Embodiment 2

[0040] Embodiment 2: o-chlorobenzoyl chloride protects the amino group

[0041] Suspend 10.0 g of 7-ACA in 30 mL of methanol / water mixed solvent, cool to -10°C to 0°C, and then add 30 mL of 10% NaOH solution dropwise (by adding in batches). Keep the temperature stable, stir for 2h, follow the reaction by TLC, the raw material point 7-ACA disappears, that is, the reaction is over. Then add cold acetone solution to the reaction system, stir vigorously, gradually a light yellow solid precipitates, filter and drain. Dissolve this solid in a mixed solvent of 1,4-dioxane / water (1:1), add a saturated solution of sodium bicarbonate to make the system alkaline, then add o-chlorobenzoyl chloride dropwise, and continue stirring. Saturated sodium bicarbonate solution was added, and the reaction was tracked by TLC. After the reaction was finished, a large amount of solid was precipitated by adding acetone, and washed with cold absolute ethanol to obtain the target product with a yield of...

Embodiment 3

[0042] Example 3: Amidation of Boc-7-DACA 3-Hydroxyl

[0043] in N 2Under protection, suspend Boc-7-DACA (5.0g) in DMF or acetonitrile solvent, lower the temperature -20°C to -10°C, then slowly add DMF solution of chlorosulfonyl isocyanate, keep the temperature, and stir for 1h, Slowly add 5 mL of cold purified water to quench the reaction, continue stirring for 3 h, extract with EA, wash with saturated sodium bicarbonate solution and saturated brine successively, dry, concentrate and recrystallize to obtain the target product with a yield of 68%. Dissolve this product in ethyl acetate, then pass through hydrochloric acid gas, and precipitate a solid while stirring, which is the target product.

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Abstract

The invention discloses a synthetic method of cefcapene pivoxil hydrochloride. The synthetic method comprises following steps: 7-aminocephalosporanic acid (7-ACA) is taken as a raw material, and is subjected to 'one-pot reaction' so as to realize 3-esterolysis, and 7-amino protection is carried out; an obtained product is subjected to 'one-pot reaction' so as to realize 3-amidation, and 7-deprotection is carried so as to obtain an important intermediate of cefcapene pivoxil; the intermediate and a derivative of cefcapene pivoxil with an acid side chain are subjected to condensation, and an obtained cefcapene pivoxil precursor with a 4-acid group is subjected to esterification and acidification so as to obtain cefcapene pivoxil hydrochloride finished products. According to the synthetic method, 'atom economy' principle is fully used so as to shorten reaction route, and increase reaction total yield; and it is beneficial for synthetic technology improvement and optimization of cefcapene pivoxil hydrochloride.

Description

technical field [0001] The invention relates to the technical field of synthesis of cefcapene pivoxil hydrochloride, in particular to a synthesis method of cefcapene pixil hydrochloride. Background technique [0002] Cefcapene Pivoxil Hydrochloride Hydrochloride (Cefcapene Pivoxil Hydrochloride Hydrate) is a third-generation cephalosporin, a broad-spectrum antibiotic drug, developed by Shionogi Pharmaceutical Co., Ltd., Japan. This product is mainly suitable for respiratory infections caused by sensitive bacteria such as pneumonia, bronchitis, pharyngitis, tonsillitis, etc.; otitis media; sinusitis; urinary tract infections such as gonorrhea, pyelonephritis, cystitis; skin and skin tissue infections, etc.; infection etc. [0003] The chemical name of cefcapene pivoxil hydrochloride is: 7-[2-(2-amino-1,3-thiazol-4-yl)pent-3-enamido]-3-(carbamoyloxymethyl)- 8-oxo-5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester hydrochloride, its che...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/04
CPCC07D501/04C07D501/34
Inventor 张万斌吴红伟张振锋刘德龙
Owner SHANGHAI JIAO TONG UNIV
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