CN106699683A - Method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate - Google Patents
Method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate Download PDFInfo
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- CN106699683A CN106699683A CN201611253618.4A CN201611253618A CN106699683A CN 106699683 A CN106699683 A CN 106699683A CN 201611253618 A CN201611253618 A CN 201611253618A CN 106699683 A CN106699683 A CN 106699683A
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- bpta
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- chain acid
- dichloromethane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/70—Sulfur atoms
- C07D277/74—Sulfur atoms substituted by carbon atoms
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate and belongs to the technical field of preparation of ceftazidime intermediates. 2-(2-aminothiazole-4-yl)-2-acetic acid and dibenzothiazyl disulfide (DM) are used as raw materials, a dichloromethane and acetonitrile mixed solution serves as a solvent, catalysts pyridine and triethylamine are sequentially added, triethyl phosphite is used as a condensation agent to perform reaction, and suction filtration and drying are performed after reaction is completed to obtain the 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate. The process is simple, mild in condition, low in cost and high in reaction yield, and the prepared target product is high in quality and purity and suitable for mass production.
Description
Technical field
The present invention relates to a kind of synthetic method of BPTA, belong to the preparation of cefotaxime intermediate
Technical field.
Background technology
Cefotaxime is Third generation Cephalosporins antibiotic, and the killing action to Pseudomonas aeruginosa is most strong, is that treatment leather is blue
The choice drug of family name's negative microbial infections, with wide market prospects.
BPTA is the important intermediate of cefotaxime, and its quality has weight with cost to bulk drug
The influence wanted.Therefore, a kind of good quality, low cost, small toxicity, BPTA synthesis simple to operate are explored
Technique, the industrialized production to cefotaxime is significant.
BPTA it is chemical entitled：2- (2- amino -4- thiazolyls) -2- (special butoxy carbonyl isopropyls
Oxyimino group) the thio benzothiazole ester of acetic acid, molecular formula is：C20H22N4O4S3, structural formula is：
At present, the synthetic method of BPTA is with cefotaxime side-chain acid as raw material, from suitable
Organic base as catalyst, obtain BPTA with DM (dibenzothiazyl disulfide) reactions, its reaction
Equation is：
According to pertinent literature, Fu Decai etc. uses dichloromethane and toluene mixture as reaction dissolvent, in alkaline bar
Under part, cefotaxime side-chain acid reacts with DM, triphenylphosphine, and reaction temperature≤30 DEG C, reaction time 8h, yield is reachable
79.6%.The shortcoming of this method is that cefotaxime side chain acid reaction is not thorough, is not easy to the purifying of product herein in reaction dissolvent；
In the basic conditions, with cefotaxime side-chain acid, DM as raw material, acetonitrile is solvent, 5 DEG C of reaction temperature, during reaction to Wang Yuhuan etc.
Between about 5h, yield is 86.8%.The advantage of this method is that triethyl phosphite price is relatively low, and yield increases.Have the disadvantage to use
Acetonitrile is solvent, and the color and luster of product is poor, and the purity of product is relatively low；It is solvent that Harbin Pharmaceutical Group Wang Qing congruences use dichloromethane,
Triethylamine is catalyst, and triphenylphosphine is phosphating, and content is 97~98%.This processing disadvantages be with dichloromethane as solvent,
Portioned product is dissolved in wherein, influences yield, and triphenylphosphine is expensive so that production cost is higher.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of BPTA, its process is simple, bar
Part is gentle, and low cost, reaction yield is high, and the quality and purity of obtained target product are high, is suitable for large-scale production.
The synthetic method of BPTA of the present invention, is with cefotaxime side-chain acid and curing
Bisbenzothiazole (DM) is raw material, and the mixed liquor using dichloromethane and acetonitrile sequentially adds catalyst pyridine and three as solvent
Ethamine, is reacted by condensing agent of triethyl phosphite, and reaction terminates rear suction filtration, drying cefotaxime side chain acid activity
Ester.
In the prior art, dichloromethane and acetonitrile were all used alone as solvent, the present invention using dichloromethane and
Acetonitrile can be avoided because individually again as mixed solvent, the yield reduction caused by can both having avoided because dichloromethane is used alone
The tacky phenomenon of product caused using acetonitrile.
In the prior art, triethylamine was used alone as catalyst, and the present invention is using triethylamine and pyridine as mixed
Close catalyst simultaneously to sequentially add, because there is pyridine high-hydroscopicity can promote the reaction to carry out, triethylamine relatively is used alone can
To improve reaction rate.
The cefotaxime side-chain acid is 1 with the mass ratio of dibenzothiazyl disulfide:1.2~1.4；Charge temperature is 20
~23 DEG C.
The density of the mixed liquor of the dichloromethane and acetonitrile is 0.95~1.05g/cm3。
The biodiversity content of the mixed liquor of the dichloromethane and acetonitrile is 0~0.1%.
The gross mass of the mixed liquor of the dichloromethane and acetonitrile and cefotaxime side-chain acid and dibenzothiazyl disulfide
The ratio between gross mass be 3~4:1.
The cefotaxime side-chain acid is 1 with the mass ratio of pyridine:0.02~0.04.
The cefotaxime side-chain acid is 1 with the mass ratio of triethylamine:0.16~0.18；Be added dropwise triethylamine when temperature be
20~30 DEG C.
The cefotaxime side-chain acid is 1 with the mass ratio of triethyl phosphite:0.7~0.8；Triethyl phosphite is added dropwise
When temperature be 20~22 DEG C, time for adding be 1.5~3h.
The reaction temperature is 20~22 DEG C, and the reaction time is 3~5h.
For raw material dosage defined above when relevant parameter, only within the above range, the present invention can be just reached
The effect.
The present invention compared with prior art, has the advantages that：
(1) process is simple, mild condition, it is easy to mass produce；
(2) high income of target product is obtained up to more than 92%, product color is good, and content is high, high purity more than 99%；
(3) replace the triphenylphosphine of expensive facile hydrolysis using cheap triethyl phosphite, can substantially reduce
Production cost, and the triethyl phosphate of generation is liquefied compound, compared to the solid compounds triphen oxygen that triphenylphosphine is generated
Phosphine subsequent treatment is simple.
Specific embodiment
With reference to embodiment, the present invention is further illustrated, but it is not intended to limit implementation of the invention.
In embodiment it is raw materials used be it is purchased in market.
Embodiment 1
At 20 DEG C, 34g cefotaximes side-chain acid and 44gDM are added to (mixed liquor in the mixed liquor of dichloro and acetonitrile
Quality is 260g, and density is 0.95g/cm3), after stirring 10min, pyridine 0.8mL is added, triethylamine 7.7mL is added dropwise at 20 DEG C,
30 DEG C of insulation reaction 50min are warming up to after completion of dropping, are lowered the temperature, triethyl phosphite 26mL is added dropwise when 20 DEG C, process is added dropwise
1.5h when sharing, is added dropwise to complete after 21 ± 1 DEG C of insulation reaction 4h, is then cooled to 5 DEG C of insulation reaction 30min, suction filtration, and in
60 DEG C dry to obtain BPTA, and yield is 92.3%, and content is 99.1%.
Embodiment 2
At 21 DEG C, 35g cefotaximes side-chain acid and 48gDM are added to (mixed liquor in the mixed liquor of dichloro and acetonitrile
Quality is 250g, and density is 1.0g/cm3), after stirring 10min, pyridine 1.0mL is added, triethylamine 8.0mL, drop are added dropwise at 22 DEG C
Add and be warming up to 30 DEG C of insulation reaction 50min after finishing, lower the temperature, triethyl phosphite 28mL is added dropwise when 21 DEG C, process is added dropwise and is total to
Used time 2.5h, is added dropwise to complete after 21 ± 1 DEG C of insulation reaction 3.0h, is then cooled to 3 DEG C of insulation reaction 30min, suction filtration, and in
60 DEG C dry to obtain BPTA, and yield is 92.6%, and content is 99.3%.
Embodiment 3
At 23 DEG C, 36g cefotaximes side-chain acid and 45gDM are added to (mixed liquor in the mixed liquor of dichloro and acetonitrile
Quality is 298g, and density is 1.05g/cm3), after stirring 10min, pyridine 1.3mL is added, triethylamine 8.4mL is added dropwise at 30 DEG C,
30 DEG C of insulation reaction 50min are warming up to after completion of dropping, are lowered the temperature, triethyl phosphite 30mL is added dropwise when 22 DEG C, process is added dropwise
3.0h when sharing, is added dropwise to complete after 21 ± 1 DEG C of insulation reaction 5.0h, is then cooled to 0 DEG C of insulation reaction 30min, suction filtration, and
BPTA is dried to obtain in 60 DEG C, yield is 92.1%, and content is 99.1%.
Claims (9)
1. a kind of synthetic method of BPTA, it is characterised in that：With cefotaxime side-chain acid and curing
Bisbenzothiazole is raw material, and the mixed liquor using dichloromethane and acetonitrile sequentially adds catalyst pyridine and triethylamine as solvent,
Reacted by condensing agent of triethyl phosphite, BPTA is obtained.
2. the synthetic method of BPTA according to claim 1, it is characterised in that：Cefotaxime side
Chain acid is 1 with the mass ratio of dibenzothiazyl disulfide:1.2~1.4；Charge temperature is 20~23 DEG C.
3. the synthetic method of BPTA according to claim 1, it is characterised in that：Dichloromethane and
The density of the mixed liquor of acetonitrile is 0.95~1.05g/cm3。
4. the synthetic method of BPTA according to claim 1, it is characterised in that：Dichloromethane and
The biodiversity content of the mixed liquor of acetonitrile is 0~0.1%.
5. the synthetic method of BPTA according to claim 1, it is characterised in that：Dichloromethane and
The ratio between the gross mass and cefotaxime side-chain acid of the mixed liquor of acetonitrile and the gross mass of dibenzothiazyl disulfide are 3~4:1.
6. the synthetic method of BPTA according to claim 1, it is characterised in that：Cefotaxime side
Chain acid is 1 with the mass ratio of pyridine:0.02~0.04.
7. the synthetic method of BPTA according to claim 1, it is characterised in that：Cefotaxime side
Chain acid is 1 with the mass ratio of triethylamine:0.16~0.18；Temperature when triethylamine is added dropwise is 20~30 DEG C.
8. the synthetic method of BPTA according to claim 1, it is characterised in that：Cefotaxime side
Chain acid is 1 with the mass ratio of triethyl phosphite:0.7~0.8；Temperature when triethyl phosphite is added dropwise is 20~22 DEG C, drop
It is 1.5~3h between the added-time.
9. the synthetic method of BPTA according to claim 1, it is characterised in that：Reaction temperature is
20~22 DEG C, the reaction time is 3~5h.
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| CN201611253618.4A CN106699683A (en) | 2016-12-30 | 2016-12-30 | Method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate |
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| CN201611253618.4A CN106699683A (en) | 2016-12-30 | 2016-12-30 | Method for synthesizing 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107739351A (en) * | 2017-09-22 | 2018-02-27 | 山东金城医药化工有限公司 | The method of purification of BPTA |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101096364A (en) * | 2006-06-26 | 2008-01-02 | 山东金城医药化工有限公司 | New technique for catalytic synthesis of AE active ester |
| CN101747291A (en) * | 2009-12-22 | 2010-06-23 | 山东鑫泉医药中间体有限公司 | Method for synthesizing AE-active ester |
-
2016
- 2016-12-30 CN CN201611253618.4A patent/CN106699683A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101096364A (en) * | 2006-06-26 | 2008-01-02 | 山东金城医药化工有限公司 | New technique for catalytic synthesis of AE active ester |
| CN101747291A (en) * | 2009-12-22 | 2010-06-23 | 山东鑫泉医药中间体有限公司 | Method for synthesizing AE-active ester |
Non-Patent Citations (1)
| Title |
|---|
| 杨晓辉: "头孢他啶侧链酸及其活性酯的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107739351A (en) * | 2017-09-22 | 2018-02-27 | 山东金城医药化工有限公司 | The method of purification of BPTA |
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