CN104086563B - The preparation method of olefin(e) acid benzhydryl ester - Google Patents
The preparation method of olefin(e) acid benzhydryl ester Download PDFInfo
- Publication number
- CN104086563B CN104086563B CN201410315428.5A CN201410315428A CN104086563B CN 104086563 B CN104086563 B CN 104086563B CN 201410315428 A CN201410315428 A CN 201410315428A CN 104086563 B CN104086563 B CN 104086563B
- Authority
- CN
- China
- Prior art keywords
- acid benzhydryl
- reaction
- benzhydryl ester
- olefin
- preparation
- Prior art date
- 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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- -1 benzhydryl ester Chemical class 0.000 title claims abstract description 14
- 239000002253 acid Substances 0.000 title claims abstract description 13
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 150000001336 alkenes Chemical class 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 abstract description 7
- 239000000376 reactant Substances 0.000 abstract description 5
- 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 abstract description 3
- 229960000433 latamoxef Drugs 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 abstract 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 abstract 1
- MKQAFVYNLATLPE-UHFFFAOYSA-N benzhydryl 3-methylbut-3-enoate Chemical class C1(=CC=CC=C1)C(C1=CC=CC=C1)OC(CC(C)=C)=O MKQAFVYNLATLPE-UHFFFAOYSA-N 0.000 abstract 1
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- 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
- 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
- 239000000543 intermediate Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PWBJWDKDPAPGED-UHFFFAOYSA-N n'-chlorobutanediamide Chemical compound NC(=O)CCC(=O)NCl PWBJWDKDPAPGED-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000009257 reactivity Effects 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
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 And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to the synthetic method of Latamoxef Sodium intermediate olefin(e) acid benzhydryl ester, using N chlorosuccinimide as reactant and (2R) 2 [(1R, 5S) 7 oxo 3 p-methylphenyl 4 oxa-2,6 diazas [3.2.0] heptan 2 alkene 6 base] 2 isopropenyl acetic acid benzhydryl esters reaction, the method total impurities production rate is low, reaction yield is high, course of reaction safety, production cost reduces.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical field, be specifically related to the preparation method of a kind 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-base]-butyl-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-base]-butyl-3-
The preparation of olefin(e) acid benzhydryl ester, synthetic method disclosed in patent DE2800860 is: with (2R)-2-[(1R, 5S)-7-oxygen
Generation-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-base]-2-isopropenyl acetic acid benzhydryl ester is raw material, use
Chlorine carries out chlorination generation (2R)-3-chloromethyl-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-bis-
Azepine [3.2.0] hept-2-ene"-6-base]-butyl-3-olefin(e) acid benzhydryl ester, its reaction equation is as follows:
Carry out chlorination with chlorine and have certain potential safety hazard, course of reaction generates impurity more, reaction yield is the highest,
About 60%, production cost is high, constrains its application in industrialized production.
Summary of the invention
The invention provides the preparation method of a kind of olefin(e) acid benzhydryl ester, the method total impurities production rate is low, reaction yield is high,
Course of reaction safety, production cost reduces.
The preparation method of the olefin(e) acid benzhydryl ester as shown in formula III, is obtained by following process route:
With (2R)-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-base]-2-
Isopropenyl acetic acid benzhydryl ester (I) is raw material, carries out chlorination generation (2R) with N-chlorosuccinimide (II)
-3-chloromethyl-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-base]-butyl-3-
Olefin(e) acid benzhydryl ester (III).
Using chlorine as raw material in existing technique, chlorine reaction activity is little, it is therefore desirable to the highest reaction temperature could be reacted,
And high reaction temperature can cause a lot of impurity to generate.The application uses N-chlorosuccinimide (II) to substitute chlorine, N-chlorine
For succimide reactivity more than chlorine, relatively low reaction temperature therefore can be selected to avoid the generation of impurity.
As the further improvement of foregoing invention, the temperature of described reaction is 3～6 DEG C, and the reaction time is 8～10h, compound
I with compound ii mol ratio be 1:1.Preferably, when reaction temperature is at 4～5 DEG C, the total growing amount of impurity is less than 0.05%.
When reaction temperature is less than 3 DEG C, reactant reaction is incomplete, and yield is the lowest；When reaction temperature is higher than 6 DEG C, reaction impurities
Total growing amount is more than 0.10%.Reaction temperature is at 3～6 DEG C, and not only reactant reaction is complete, and the total growing amount of impurity is less than
0.10%, yield reaches more than 75%.
As the further improvement of foregoing invention, described reaction dissolvent is dichloromethane.
The application in preparing Latamoxef Sodium of the olefin(e) acid benzhydryl ester as shown in formula III.
Compared with prior art, its remarkable advantage is the present invention: first, and reactant is solid, course of reaction safety；The
Two, total impurities production rate is low, reaction yield is high, and production cost reduces.
Detailed description of the invention
Embodiment 1
In parts by weight, 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-base]-2-isopropenyl acetic acid benzhydryl ester (formula I) is dissolved in 5 parts of dichloromethane, is subsequently adding 0.286 part
N-chlorosuccinamide reacts, and reaction temperature is 3～6 DEG C.After reaction 8～10h, being filtered by reactant, filter cake is succinyl
Imines and major part impurity and major part unreacted (2R)-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-
Diaza [3.2.0] hept-2-ene"-6-base] mixture of-2-isopropenyl acetic acid benzhydryl ester, gained filtrate is distilled, is obtained product (2R)
-3-chloromethyl-2-[(1R, 5S)-7-oxo-3-p-methylphenyl-4-oxa--2,6-diaza [3.2.0] hept-2-ene"-6-base]-butyl-3-
Olefin(e) acid benzhydryl ester.Products obtained therefrom HPLC content is more than 99.9%, and total recovery is 89.7%.1HNMR(CHCl3-d1)δ
(ppm): 2.35 (m, 3h), 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 (1)
1. the preparation method of olefin(e) acid benzhydryl ester, it is characterised in that: process route is as follows:
Wherein, reaction temperature is 3～6 DEG C, and the reaction time is 8～10h, and chemical compounds I and compound ii mol ratio are 1:1, instead
Answering solvent is dichloromethane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410315428.5A CN104086563B (en) | 2014-07-03 | 2014-07-03 | The preparation method of olefin(e) acid benzhydryl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410315428.5A CN104086563B (en) | 2014-07-03 | 2014-07-03 | The preparation method of olefin(e) acid benzhydryl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104086563A CN104086563A (en) | 2014-10-08 |
| CN104086563B true CN104086563B (en) | 2016-09-07 |
Family
ID=51634351
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410315428.5A Expired - Fee Related CN104086563B (en) | 2014-07-03 | 2014-07-03 | The preparation method of olefin(e) acid benzhydryl ester |
Country Status (1)
| Country | Link |
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| CN (1) | CN104086563B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1090806A (en) * | 1977-01-10 | 1980-12-02 | Mitsuru Yoshioka | Oxazolines |
| US4431803A (en) * | 1981-12-21 | 1984-02-14 | Eli Lilly And Company | 7-Epi 3-exomethylenecephams |
| CN101538274B (en) * | 2009-02-23 | 2012-06-27 | 上海医药工业研究院 | Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives |
| CN102285997B (en) * | 2011-07-05 | 2013-04-03 | 山东睿鹰先锋制药有限公司 | Method for preparing chloroallyl beta-lactam antibiotic intermediate |
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2014
- 2014-07-03 CN CN201410315428.5A patent/CN104086563B/en not_active Expired - Fee Related
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| CN104086563A (en) | 2014-10-08 |
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Granted publication date: 20160907 |