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Synthesis method of cefotiam hexetil hydrochloride with characteristic of low solvent residue

A technology for the synthesis of cefotiam pivoxil hydrochloride and its synthesis method, which is applied in the field of synthesis of broad-spectrum anti-infective drug cefotiam pivoxil hydrochloride, can solve the problems of incomplete reaction, low product purity, low yield, etc., and achieve the effect of low residue

Inactive Publication Date: 2015-11-18
GUANGZHOU NANXIN PHARMA
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

Obviously, when the reaction temperature was too low, the reaction was not complete, and the utilization rate of 1-iodoethyl cyclohexyl carbonate was low, resulting in low yield
For other disclosed technologies, the yield is all lower than that of the present invention, such as the yield described in patent CN101993449B is 60%
In addition, in other published technologies, the esterification reaction temperature described is mostly at 0~-50C, the reaction temperature is relatively high, and the product->D3 is prone to occur - Conversion of isomers, so at this reaction temperature, the content of related substances, especially D3-by-product (related substance 1) is relatively high, so the purity of the product is low

Method used

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  • Synthesis method of cefotiam hexetil hydrochloride with characteristic of low solvent residue
  • Synthesis method of cefotiam hexetil hydrochloride with characteristic of low solvent residue
  • Synthesis method of cefotiam hexetil hydrochloride with characteristic of low solvent residue

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Experimental program
Comparison scheme
Effect test

Embodiment 11

[0019] The synthesis of embodiment 11-iodoethyl cyclohexyl carbonate:

[0020] Add 2900mL of acetonitrile, 69.5g (464mmol) of anhydrous sodium iodide, and 12.5g of powdered calcium chloride into the reaction tank, and heat to 51 0 c. Add 74.0 g (358 mmol) of 1-chloroethyl cyclohexyl carbonate to the above mixed system, at 40 ~ 45 0 C and stirred for 98min. After the reaction was completed, it was concentrated to dryness under reduced pressure. Concentrated residue cooled to 0 ~ 10 0 C, will precool to 0 ~ 10 0 CH of C 2 Cl 2 315 mL was added to the residue. Continue to add 195 mL of purified water to the residue to dissolve the residue. at 0 ~ 10 0 C stirred for 3 min, allowed to stand for 5-15 min to separate the layers, and collected the organic layer. Na 2 S 2 o 3 . 5H 2 O12.5g was dissolved in 195mL purified water, then cooled to 0 ~ 10 0 c. Add the organic layer to Na 2 S 2 o 3 . 5H 2 O solution, at 0-10 0 C stirred, stood still, separated laye...

Embodiment 2

[0021] Example 2 Cefotiam pivoxil ((6R,7R)-7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-[2-(N,N-dimethyl Amino)ethyl]-1H-tetrazol-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 -Carboxylic acid) synthesis: Potassium bicarbonate 50.0g (499mmol), purified water 15.5mL, acetone 32.0mL were mixed and mixed in 5 ~ 15 0 c Stir. Slowly add cefotiam hydrochloride 63.75g (106.5mmol) to the mixed system, and then ~ 15 0 C Stir to mix to complete the reaction. Acetone 715mL was added to the reaction system, stirred, left to stand, layered, and the supernatant was decanted to obtain the potassium salt of cefotiam. Add 278 mL of DMA to the potassium salt of cefotiam hydrochloride at room temperature, and then stir the mixed system under reduced pressure at room temperature for 60 min to dissolve the potassium salt. Cool the mixture to -10 ~ -15 0 C, then add 107.0 g (358 mmol) of pre-cooled 1-iodoethyl cyclohexyl carbonate to the mixture, and control the temperature a...

Embodiment 3

[0022] Example 3 Cefotiam hydrochloride ((6R,7R)-7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-[2-(N,N-di Methylamino)ethyl]-1H-tetrazol-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- Synthesis of 2-carboxylic acid 1-(cyclohexaneoxycarbonyloxy)ethyl ester dihydrochloride): put 52.0 g (74.7 mmol) of cefotiam in a reaction vessel, add 310 mL of purified water, and stir A suspension mixture is formed. Cool 40g of 15% hydrochloric acid solution to 1 ~ 5 0 C, added to the suspension, at 0 ~ 5 0 C under stirring for 1 hour, completely dissolved. The compound solution was cryogenically dried (freezing temperature -30 0 C, vacuum degree 0.01torr), obtain white powder cefotiam hydrochloride 57.4g, yield 99%, purity 98.7% (HPLC). 1 HNMR (500MHz,D 2 O), NMR (Bruker400MHz, DMSO-d6): chemical shifts 1.3-1.8 (m, 10H), 1.54and1.55 (d, 3H), 2.82 (s, 6H), 3.60 (m, 1H), 3.63 (t , 2H), 3.73&3.90(m, 2H,), 4.30(m, 2H), 4.50(d, 1H), 4.60(m, 1H), 4.81(t, 2H), 5.12(d, 1H), 5.75(...

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Abstract

The present invention relates to a synthesis method of an anti-infection drug cefotiam hexetil hydrochloride ((6R,7R)-7-[2-(2-aminothiazole-4-yl)acetamido]-3-[[[1-[2-(N,N-dimethylamino)ethyl]-1H-tetrazole-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1-(cyclohexane oxy carbonyloxy)ethyl ester dihydrochloride. According to the present invention, (commercially available) cefotiam hydrochloride is adopted as the raw material and the three synthesis steps are performed to prepare the cefotiam hexetil hydrochloride; compared with the cefotiam hexetil hydrochloride prepared through the method reported in the existing literature, the cefotiam hexetil hydrochloride of the present invention has characteristics of low solvent residue, high yield and high purity, and the key quality detection indexes are superior to the limits specified in Japanese Pharmacopoeia; and the the method is effective and practical, and is suitable for industrial scale-production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing a broad-spectrum anti-infective drug cefotiam pivoxil hydrochloride. Background technique [0002] Cefotiam hydrochloride, English name CefotiamHexetilHydrochloride, chemical name (6R,7R)-7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-[2-(N, N-Dimethylamino)ethyl]-1H-tetrazol-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2 -ene-2-carboxylic acid 1-(cyclohexaneoxycarbonyloxy)ethyl ester dihydrochloride, which was first developed by Japan's Takeda Pharmaceutical Co., Ltd. antibiotic. This product itself has no antibacterial effect, and it is rapidly hydrolyzed into cefotiam (CTM) in the intestinal mucosa after oral administration and absorbed. CTM has good antibacterial activity against Gram-positive and negative bacteria, and is stable against β-lactamase. The biggest advantage of cefotiam hydrochloride is its safety, it can be taken orally, it...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/04
CPCC07D501/36C07D501/04
Inventor 林寨伟李建发朱建平
Owner GUANGZHOU NANXIN PHARMA