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Synthesis method of cefpodoxime proxetil intermediate

A technology of cefpodoxime axetil and a synthesis method is applied in the field of intermediate preparation of cefpodoxime axetil, can solve the problems of low yield, inability to proceed, low yield and purity, etc., and achieves high product yield and purity, high post-processing Uncomplicated and cost-effective

Inactive Publication Date: 2016-06-15
陕西思尔生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Cefpodoxamic acid is the premise intermediate of cefpodoxime axetil. Patent WO2013041999A once reported that it was synthesized with expensive methanesulfonic acid and 7-aminocephalosporin acid, but according to literature reports, the yield and purity were low, and the intermediate After the synthesis of 7-amino-3 methoxymethyl-3 cephem carboxylic acid, it is very difficult to suction filter, the product is sticky, and cannot be quantitatively produced, and it is reported in the literature that it comes out of water and is directly synthesized in the next step without drying. , so the yield is very low, and it cannot be carried out in the pilot test

Method used

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  • Synthesis method of cefpodoxime proxetil intermediate
  • Synthesis method of cefpodoxime proxetil intermediate
  • Synthesis method of cefpodoxime proxetil intermediate

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Embodiment 1

[0034] The intermediate of the present invention (6R,7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyimino)acetamido]-3-methoxymethyl- The synthetic method of 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid specifically comprises the following steps:

[0035] 1) Add 0.99 mol of methanol to the container, cool down to 10°C, add 0.8 mol of chlorosulfonic acid dropwise, and pass nitrogen gas for 4 hours after the drop to remove hydrogen chloride gas generated during the reaction, and concentrate to remove methanol to obtain methoxysulfonic acid.

[0036] 2) Add 50g of methoxysulfonic acid and 2g of dimethylformamide into the container, cool down to 15~20°C, add dropwise 11.4g of trimethyl borate / methanol mixed solution (mass ratio is 7:3), and cool down to 0~5℃; add 20g of 7-ACA, react for 2h; then add 10.8g of trimethyl borate / methanol mixed solution, react for 3h. The reaction solution was added dropwise to 200g of water and 30g of methanol, adjusted to pH=3.5 with co...

Embodiment 2

[0039] The identification of product in the embodiment of the present invention 1

[0040] Identification method: Bruker AvanceIII400MHZ superconducting NMR spectrometer;

[0041] Analytical method: LC (purity by liquid chromatography), Shimadzu LC-10ATVP. Agilent C-18 chromatographic column, mobile phase: methanol: buffer solution (potassium dihydrogen phosphate, disodium hydrogen phosphate, tetrabutylammonium bromide) = 1:3, flow rate 1mL / min, detection wavelength 240nm.

[0042] ESI-MS(m / z):

[0043] 428.0[M+1] + ,450.0[M+Na] + ,854.8[2M+1] + ,876.8[2M+Na] + ;

[0044] 1 HNMR: (400MHz, DMSO-d 6 )

[0045] δ3.20(s,3H),3.46(d,J=18,1H),3.58(d,J=18,1H),3.84(s,3H),

[0046] 4.17(s,2H),5.14(s,1H),5.75(s,1H),6.75(s,1H),9.62(d,J=18,1H)

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Abstract

The invention discloses a synthesis method of a cefpodoxime proxetil intermediate, namely (6R,7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-methanoic acid. The synthesis method includes: enabling chlorosulfonic acid and methanol to react to prepare methoxy sulfonic acid; under the action of the methoxy sulfonic acid and dimethylformamide, etherifying 7-ACA (7-aminocephalosporanic acid) and trimethyl borate prior to aftertreatment, adding into a water and methanol solution reversely to guarantee that the obtained intermediate isn't sticky and is loose, drying and grafting with AE active ester so as to obtain a target product, namely the cefpodoxime proxetil intermediate. The synthesis method of the cefpodoxime proxetil intermediate has the advantages that synthesis steps of 3-position and 7-position protection and desorption of 7-ACA can be omitted, so that low step cost, high yield and high purity are achieved, all materials are cheap and available, and industrial production and little pollution are benefited.

Description

technical field [0001] The invention belongs to the technical field of preparation of cefpodoxime axetil intermediate, in particular to a cefpodoxime axetil intermediate (6R,7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-2 Synthetic method of -(methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid . Background technique [0002] Cefpodoxime axetil is an oral third-generation cephalosporin with a broad antibacterial spectrum. After entering the body, it is hydrolyzed into cefpodoxime by non-specific enzymes to exert antibacterial effects. It has a wide range of antibacterial effects on Gram-positive and Gram-negative bacteria. Spectrum, stable against β-lactamases. [0003] Cefpodoxamic acid is the premise intermediate of cefpodoxime axetil. Patent WO2013041999A once reported that it was synthesized with expensive methanesulfonic acid and 7-aminocephalosporin acid, but according to literature reports, the yield and purity were low, and the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34
CPCY02P20/55C07D501/34
Inventor 王作弟
Owner 陕西思尔生物科技有限公司
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