CN104086563A - Method for preparing olefine acid diphenylmethyl ether - Google Patents
Method for preparing olefine acid diphenylmethyl ether Download PDFInfo
- 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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- CN
- China
- Prior art keywords
- reaction
- olefin
- benzhydryl ester
- acid benzhydryl
- preparation
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002253 acid Substances 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title abstract description 6
- PVQATPQSBYNMGE-UHFFFAOYSA-N [benzhydryloxy(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)OC(C=1C=CC=CC=1)C1=CC=CC=C1 PVQATPQSBYNMGE-UHFFFAOYSA-N 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- GRIXGZQULWMCLU-HUTAOCTPSA-L disodium;(6r,7r)-7-[[2-carboxylato-2-(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C([O-])=O)=O)C(=O)C(C([O-])=O)C1=CC=C(O)C=C1 GRIXGZQULWMCLU-HUTAOCTPSA-L 0.000 claims abstract description 4
- 229960000433 latamoxef Drugs 0.000 claims abstract description 4
- -1 benzhydryl ester Chemical class 0.000 claims description 15
- 150000001336 alkenes Chemical class 0.000 claims description 10
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000000376 reactant Substances 0.000 abstract description 5
- 230000003407 synthetizing effect Effects 0.000 abstract 1
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- QBKMWJRMLACRJD-UHFFFAOYSA-N benzhydryl acetate Chemical compound C=1C=CC=CC=1C(OC(=O)C)C1=CC=CC=C1 QBKMWJRMLACRJD-UHFFFAOYSA-N 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- 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
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.
Priority Applications (1)
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CN201410315428.5A CN104086563B (en) | 2014-07-03 | 2014-07-03 | The preparation method of olefin(e) acid benzhydryl ester |
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CN201410315428.5A CN104086563B (en) | 2014-07-03 | 2014-07-03 | The preparation method of olefin(e) acid benzhydryl ester |
Publications (2)
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CN104086563A true CN104086563A (en) | 2014-10-08 |
CN104086563B CN104086563B (en) | 2016-09-07 |
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CN201410315428.5A Expired - Fee Related CN104086563B (en) | 2014-07-03 | 2014-07-03 | The preparation method of olefin(e) acid benzhydryl ester |
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Citations (4)
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 |
-
2014
- 2014-07-03 CN CN201410315428.5A patent/CN104086563B/en not_active Expired - Fee Related
Patent Citations (4)
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)
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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Granted publication date: 20160907 |