CN104086563A - Method for preparing olefine acid diphenylmethyl ether - Google Patents

Method for preparing olefine acid diphenylmethyl ether Download PDF

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Publication number
CN104086563A
CN104086563A CN201410315428.5A CN201410315428A CN104086563A CN 104086563 A CN104086563 A CN 104086563A CN 201410315428 A CN201410315428 A CN 201410315428A CN 104086563 A CN104086563 A CN 104086563A
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Prior art keywords
reaction
olefin
benzhydryl ester
acid benzhydryl
preparation
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CN201410315428.5A
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CN104086563B (en
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王文斌
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JIANGSU SHAXING CHEMICAL Co Ltd
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JIANGSU SHAXING CHEMICAL Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/02—Preparation
    • C07D505/04—Preparation by forming the ring or condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
    • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
    • C07D505/16—Nitrogen atoms
    • C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
    • C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention relates to a method for synthetizing olefine acid diphenylmethyl ether as a latamoxef sodium intermediate. The method comprises the following step: enabling N-chlorosuccinimide as a reactant to react with (2R)-2-[(1R,5S)-7-oxo-3-p-methyl phenyl-4-oxa-2,6-diaza[3.2.0]heptyl-2-alkene-6-yl]-2-isopropenyl diphenylmethyl acetate. The method disclosed by the invention has the advantages of low total impurity generation rate, high reaction yield, safety in reaction process and reduced production cost.

Description

The preparation method of olefin(e) acid benzhydryl ester
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical field, be specifically related to a kind of preparation method of olefin(e) acid benzhydryl ester.
Background technology
(2R)-3-chloromethyl-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-yl]-Ding-3-olefin(e) acid benzhydryl ester is the important intermediate of Latamoxef Sodium.For (2R)-3-chloromethyl-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2, 6-diaza [3.2.0] hept-2-ene"-6-yl] preparation of-Ding-3-olefin(e) acid benzhydryl ester, the disclosed synthetic method of patent DE2800860 is: with (2R)-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2, 6-diaza [3.2.0] hept-2-ene"-6-yl]-2-pseudoallyl acetic acid benzhydryl ester is raw material, with chlorine, carry out chlorination generation (2R)-3-chloromethyl-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2, 6-diaza [3.2.0] hept-2-ene"-6-yl]-Ding-3-olefin(e) acid benzhydryl ester, its reaction equation is as follows:
With chlorine, carrying out chlorination has certain potential safety hazard, generates impurity more in reaction process, and reaction yield is not high, in 60% left and right, and production cost is high, has restricted its application in suitability for industrialized production.
Summary of the invention
The invention provides a kind of preparation method of olefin(e) acid benzhydryl ester, the method total impurities production rate is low, reaction yield is high, reaction process safety, and production cost reduces.
Preparation method suc as formula the olefin(e) acid benzhydryl ester shown in III, obtains by following operational path:
With (2R)-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-yl]-2-pseudoallyl acetic acid benzhydryl ester (I) is raw material, with N-chlorosuccinimide (II), carry out chlorination generation (2R)-3-chloromethyl-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-yl]-Ding-3-olefin(e) acid benzhydryl ester (III).
In existing technique, adopt chlorine as raw material, chlorine reaction activity is little, therefore need very high temperature of reaction to react, and high reaction temperature can cause a lot of impurity to generate.The application adopts N-chlorosuccinimide (II) to substitute chlorine, and N-chlorosuccinimide reactive behavior is greater than chlorine, therefore can select lower temperature of reaction to avoid the generation of impurity.
As the further improvement of foregoing invention, the temperature of described reaction is 3～6 ℃, and the reaction times is 8～10h, and chemical compounds I and compound ii mol ratio are 1:1.Preferably, when temperature of reaction is at 4～5 ℃, the total growing amount of impurity is less than 0.05%.
Temperature of reaction is during lower than 3 ℃, and reactant reaction is incomplete, and yield is very low; Temperature of reaction is during higher than 6 ℃, and the total growing amount of reaction impurities is greater than 0.10%.Temperature of reaction is at 3～6 ℃, and not only reactant reaction is complete, and the total growing amount of impurity is less than 0.10%, and yield reaches more than 75%.
As the further improvement of foregoing invention, described reaction solvent is methylene dichloride.
Application suc as formula the olefin(e) acid benzhydryl ester shown in III in preparing Latamoxef Sodium.
Compared with prior art, its remarkable advantage is in the present invention: the first, and reactant is solid, reaction process safety; The second, total impurities production rate is low, reaction yield is high, and production cost reduces.
Embodiment
Embodiment 1
In weight part, by 1 part of (2R)-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-yl]-2-pseudoallyl acetic acid benzhydryl ester (formula I) is dissolved in 5 parts of methylene dichloride, then add 0.286 part of N-neoprene imide reaction, temperature of reaction is 3～6 ℃.After reaction 8～10h, reactant is filtered, filter cake is succimide and most of impurity and most of unreacted (2R)-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-yl] mixture of-2-pseudoallyl acetic acid benzhydryl ester, the distillation of gained filtrate, obtain product (2R)-3-chloromethyl-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-yl]-Ding-3-olefin(e) acid benzhydryl ester.Products obtained therefrom HPLC content is greater than 99.9%, and total recovery is 89.7%.1HNMR(CHCl 3-d 1)δ(ppm)：4.15(d，1H)，4.45(d，1H)，4.8-5.0(m，1H)，5.17(s，1H)，5.50(s，1H)，6.17(d，1H)，7.00(s，1H)，7.2-8.00(m，15H)。

Claims (5)

1. the preparation method of olefin(e) acid benzhydryl ester, is characterized in that: operational path is as follows:
2. the preparation method of olefin(e) acid benzhydryl ester according to claim 1, is characterized in that: temperature of reaction is 3～6 ℃, and the reaction times is 8～10h, and chemical compounds I and compound ii mol ratio are 1:1.
3. the preparation method of olefin(e) acid benzhydryl ester according to claim 2, is characterized in that: temperature of reaction is 4～5 ℃.
4. according to the preparation method of the olefin(e) acid benzhydryl ester described in claim 1 to 4 any one, it is characterized in that: reaction solvent is methylene dichloride.
5. olefin(e) acid benzhydryl ester is for the preparation of Latamoxef Sodium.
CN201410315428.5A 2014-07-03 2014-07-03 The preparation method of olefin(e) acid benzhydryl ester Active CN104086563B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4271295A (en) * 1977-01-10 1981-06-02 Shionogi & Co., Ltd. Oxazolines
US4431803A (en) * 1981-12-21 1984-02-14 Eli Lilly And Company 7-Epi 3-exomethylenecephams
CN101538274A (en) * 2009-02-23 2009-09-23 上海医药工业研究院 Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives
CN102285997A (en) * 2011-07-05 2011-12-21 山东睿鹰先锋制药有限公司 Method for preparing chloroallyl beta-lactam antibiotic intermediate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4271295A (en) * 1977-01-10 1981-06-02 Shionogi & Co., Ltd. Oxazolines
US4431803A (en) * 1981-12-21 1984-02-14 Eli Lilly And Company 7-Epi 3-exomethylenecephams
CN101538274A (en) * 2009-02-23 2009-09-23 上海医药工业研究院 Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives
CN102285997A (en) * 2011-07-05 2011-12-21 山东睿鹰先锋制药有限公司 Method for preparing chloroallyl beta-lactam antibiotic intermediate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YI HE ET AL.: "Design,synthesis and antibacterial activity of novel 1-oxacephem analogs", 《CHINESE CHEMICAL LETTERS》 *
王春霞: "芳基偕二氯代化合物的新合成方法的研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 *

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