A kind of preparation method of cefcapene pivoxil hydrochloride and its synthetic intermediate

A technology of cefcapene pivoxil hydrochloride and cefcapene pivoxil, which is applied in the preparation method of cefcapene pivoxil hydrochloride and its synthetic intermediates, can solve problems such as cracking, difficult removal of phenol, and impact on product quality, and achieve mild conditions and high product quality. The effect of high quality and simple and convenient operation

Active Publication Date: 2016-08-31
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
View PDF8 Cites 0 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of preparation method of cefcapene pivoxil hydrochloride and its synthetic intermediate
  • A kind of preparation method of cefcapene pivoxil hydrochloride and its synthetic intermediate
  • A kind of preparation method of cefcapene pivoxil hydrochloride and its synthetic intermediate

Examples

Experimental program
Comparison scheme
Effect test

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).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
melting pointaaaaaaaaaa
Login to view more

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap