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Preparation method and synthesis intermediate of cefcapene pivoxil hydrochloride

A technology of cefcapene hydrochloride and cefcapene, which is applied in the preparation method of cefcapene hydrochloride and its synthetic intermediates, can solve the problems of difficult removal of phenol, impact on product quality, cracking, etc., and achieve high product quality, Simple and convenient operation, mild condition effect

Active Publication Date: 2013-05-08
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In US4731361 and WO2008155615, strong acid deamination protecting groups such as boron trifluoride, trifluoroacetic acid and titanium tetrachloride are used in the reaction of formula II compound deamination protecting group Boc, due to boron trifluoride, trifluoroacetic acid and tetrachloride Titanium, etc. are too acidic. When the amino protecting group is removed, the 3- and 4-position groups of the cephalosporin nuclei will be cracked, which will easily produce by-products and impurities, which will affect the quality of the product.
[0010] In CN101717344, in the reaction of formula II compound deamination protecting group Boc, the temperature is raised to 80 DEG C and phenol is used as a cracking agent to remove the amino protecting group Boc. Because the cephalosporin compound is extremely unstable at high temperature, it is prone to side reactions and produces by-products impurities, and phenol itself is difficult to remove as an impurity

Method used

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  • Preparation method and synthesis intermediate of cefcapene pivoxil hydrochloride
  • Preparation method and synthesis intermediate of cefcapene pivoxil hydrochloride
  • Preparation method and synthesis intermediate of cefcapene pivoxil hydrochloride

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preparation example Construction

[0032] (1) Preparation of Cefcapene Proxetil Sulfonate

[0033]

[0034] in:

[0035] R is C 1～12 Alkyl, phenyl, or substituted phenyl, the substituents are selected from C 1～12 Alkyl, C 1～12 Alkoxyl, C 1～12 Unsaturated alkyl halogen, amino; preferably methyl, ethyl, propyl, phenyl, p-methylphenyl; more preferably methyl, ethyl.

[0036] Sulfonic acid derivative is preferably commercially available product, can be pure product, also can be solution form, and sulfonic acid and tert-butoxycarbonyl cefcapene axetil mol ratio are 1~10: 1, are preferably 2~5: 1; Reaction The solvent is selected from one or more of acetone, tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, dichloromethane, acetonitrile, and water. The sulfonic acid used is different, and the reaction solvent is also different. The solid cefcapene axetil sulfonate can be obtained; the weight ratio of the reaction solvent to tert-butoxycarbonyl cefcapene axetil is 5-50:1, preferably 8...

Embodiment 1

[0048] Embodiment 1: the preparation of cefcapene pivoxil mesylate (IVa)

[0049] 100.0 g (0.15 mol) of Boc cefcapene pivoxil (II), 1.5 L of ethyl acetate and 24.7 mL (0.38 mol) of methanesulfonic acid were successively added into a 3 L reaction flask, and stirred at 30° C. for 8 hours. Filter, wash with ethyl acetate, and dry in vacuo to obtain 90.1 g of off-white solid with a molar yield of 90.5%, HPLC purity of 99.2%, and mp 230-232°C.

Embodiment 2

[0050] Embodiment 2: the preparation of cefcapene pivoxil ethanesulfonate (IVb)

[0051]100.0 g (0.15 mol) of Boc cefcapene pivoxil (II), 1 L of methanol and 38.6 mL (0.30 mol) of ethanesulfonic acid were successively added to a 3 L reaction flask, and stirred at 20° C. for 16 hours. Add 1 L of petroleum ether and stir at 20°C for 60 min. Filtration, washing, and vacuum drying yielded 93.8 g of off-white solid with a molar yield of 92.3%, HPLC purity of 99.3%, and mp of 165-167°C. 1H NMR (500MHz, DMSO-d6): δ9.43(d, J=7.5Hz, 1H); 8.80(brs, 1H); 6.65(s, 2H); 6.49(s, 1H); 6.25(t, J =7.5Hz, 1H); 5.89(d, J=6.0Hz, 1H); 5.80-5.83(m, 2H); 5.24(d, J=4.5Hz, 1H); 4.83(d, J=13.0Hz, 1H ); 4.59(d, J=13.0Hz, 1H); 3.65(d, J=18.5Hz, 1H); 3.54(d, J=18.0Hz, 1H); 2.50-2.51(m, 2H); 2.21-2.26 (m, 2H); 1.16(s, 9H); 1.10(t, J=7.5Hz, 3H); 1.02(t, J=7.5Hz, 3H).

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Abstract

The invention relates to a preparation method of cefcapene pivoxil hydrochloride and a synthesis intermediate cefcapene pivoxil sulfonate. According to the invention, a sulfonic acid derivative V is used to perform a de-Boc reaction with cefcapene pivoxil tert-butoxycarbonyl as shown in a formula II to obtain the cefcapene pivoxil sulfonate as shown in a formula IV, and the cefcapene pivoxil sulfonate is then transferred into the cefcapene pivoxil hydrochloride as shown in the formula I. The method provided by the invention is mild in reaction conditions and simple and convenient to operate, meets requirements of environmental protection, and green and safe production; and the prepared cefcapene pivoxil sulfonate is high in purity, can be further transferred into the cefcapene pivoxil hydrochloride, with a purity of more than 99.5 % and high product quality.

Description

technical field [0001] The invention relates to a synthesis method of cephalosporins, in particular to a preparation method of cefcapene pivoxil hydrochloride and a synthesis intermediate thereof. Background technique [0002] Cefcapene pivoxil hydrochloride (cefcapene pivoxil hydrochloride, structural formula as shown in formula I), chemical name is (6R, 7R)-3-((aminocarbonyl)oxy)methyl-7-(((Z)-2-( 2-aminothiazol-4-yl)-2-pentenoyl)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (2,2-Dimethyloxypropoxymethyl) ester hydrochloride monohydrate is a broad-spectrum and β-lactam developed by Shionogi, Japan. An enzyme-stabilized oral antibiotic, which was launched in Japan under the trade name Flomox in July 1997, is used to treat respiratory and urinary system infections, ophthalmic and ENT infections, and skin and soft tissue infections. It has strong clinical application advantages. [0003] [0004] The tert-butoxycarbonyl cefcapene axetil shown in form...

Claims

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Application Information

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IPC IPC(8): C07D501/34C07D501/04
Inventor 龚登凰吕健孙会谦马玉秀赵永杰杨杰郝盼杰杨敏谢华军
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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