CN108947929A - A kind of synthetic method of cefotetan side chain - Google Patents
A kind of synthetic method of cefotetan side chain Download PDFInfo
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- CN108947929A CN108947929A CN201811058455.3A CN201811058455A CN108947929A CN 108947929 A CN108947929 A CN 108947929A CN 201811058455 A CN201811058455 A CN 201811058455A CN 108947929 A CN108947929 A CN 108947929A
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- methanol
- dithiol
- ethyl alcohol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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 to ring carbon atoms
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- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The present invention relates to a kind of synthetic methods of cefotetan side chain, and using malononitrile and carbon disulfide as raw material, synthetic route is as follows:
Description
Technical field
The invention belongs to technical field of medicine synthesis, in particular to a kind of synthetic method of cefotetan side chain.
Background technique
Cefotetan is half-life period longest drug so far in second generation cephalosporin (cephamycin).Cefotetan with
Penicillin binding protein has very strong affinity and associativity, it blocks the synthesis of bacteria cell wall mucopeptide, to play it
Antibacterial activity.One of its side chain 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt, does not produce at home at present, and external
There is client to seek the product at home.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of cefotetan side chain 3,5- dithiol -4- Isothiazolecarboxyliacid acids three
The synthetic method of sylvite, to meet home and abroad supply requirement.
In order to solve the above technical problems, the technical solution of the present invention is as follows: a kind of synthetic method of cefotetan side chain, described
Cephalo side chain is 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt, and innovative point is: the synthetic method includes following step
It is rapid:
The preparation of (1) 2,2- dicyanoethylene -1,1- bis- (mercaptan sylvite):
S1: sequentially adding methanol and potassium hydroxide in the reaction vessel, then stirs to solid and all dissolves；
S2: being cooled to 10~20 DEG C for above-mentioned solution, malononitrile be then added dropwise, and after dripping, controls at 15~20 DEG C
3~4h is stirred, carbon disulfide is then added dropwise；
S3: after carbon disulfide completion of dropwise addition, being cooled to 10~15 DEG C, and 4~6h is stirred at 10~15 DEG C, then mistake
Filter, filter cake acetone washing, and it is dried under reduced pressure 11~13h at 45~55 DEG C, obtain bis- (the mercaptan potassium of 2,2- dicyanoethylene -1,1-
Salt)；Wherein, the equation of 2,2- dicyanoethylene -1,1- bis- (mercaptan sylvite) preparation is as follows:
The preparation of (2) 3,5- dithiol -4- cyano isothiazole di-potassium:
S1: methanol, water and 2 are sequentially added in the reaction vessel, 2- dicyanoethylene -1,1- is bis- (mercaptan sylvite), then
Stirring is all dissolved to solid；
S2: being cooled to -5~5 DEG C for above-mentioned solution, then controls to hydrogen peroxide is added dropwise at 0~5 DEG C, drips off 4~6h of stirring,
Then -5~2 DEG C are cooled to, and the methanol solution of potassium hydroxide is added dropwise at -5~2 DEG C；
S3: after the methanol solution completion of dropwise addition of potassium hydroxide, reaction solution is concentrated for temperature control≤60 DEG C, is dropped after concentration
To room temperature, ethyl alcohol is then added, stirs 1~2h, then tetrahydrofuran is added dropwise, and stirs 3~4h, filtering, filter cake ethyl alcohol and four
The mixed solution of hydrogen furans washs, and is dried under reduced pressure 11~13h at 45~55 DEG C, obtains 3,5- dithiol -4- cyano isothiazole two
Sylvite；Wherein, the equation of 3,5- dithiol -4- cyano isothiazole di-potassium preparation is as follows:
The preparation of (3) 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt:
S1: sequentially adding water and potassium hydroxide in the reaction vessel, then stirs to solid and all dissolves；
S2: 3,5- dithiol -4- cyano isothiazole di-potassium is added into above-mentioned solution, is warming up to 60~63 DEG C, and stir
2~3h is mixed, is then down to room temperature, then methanol is added dropwise, and stands 3~4h, generates sediment；
S3: the sediment of generation is filtered with diatomaceous earth filter, and filtrate decompression is concentrated for temperature control≤60 DEG C, is then down to
Then room temperature is added methanol and ethyl alcohol, and 4~6h is stirred at room temperature, then filter to obtain filter cake；
S4: filter cake is washed with the mixed solution of methanol and ethyl alcohol, and is dried under reduced pressure 11~13h at 45~55 DEG C, obtains 3,5-
Dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt；Wherein, the equation of 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt preparation is as follows:
Further, the sodium hydroxide used in the preparation process selects mass concentration percentage for 92~98%
Sodium hydroxide.
Further, in the step (2), the volume of ethyl alcohol and tetrahydrofuran in the mixed solution of ethyl alcohol and tetrahydrofuran
Than for 1:1.
Further, in the step (3), the volume ratio of methanol and ethyl alcohol is 1:1 in the mixed solution of methanol and ethyl alcohol.
The present invention has the advantages that cefotetan side chain 3 of the present invention, the conjunction of 5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt
At method, using malononitrile and carbon disulfide as raw material, supplementary material is all more popular, not the industrial chemicals of unexpected winner, and does not have
Special, dangerous chemical reaction, reaction condition is also relatively milder, without reaction conditions such as high temperature, high pressure, deep coolings, because former
Material is more popular, therefore preparation cost is low, and yield is also at higher level, and yield can satisfy home and abroad up to 83%
Supply requirement.
Specific embodiment
The following examples can make professional and technical personnel that the present invention be more fully understood, but therefore not send out this
It is bright to be limited among the embodiment described range.
Embodiment
The synthetic method of the present embodiment cefotetan side chain, cephalo side chain are 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium
Salt, the synthetic method include the following steps:
The preparation of (1) 2,2- dicyanoethylene -1,1- bis- (mercaptan sylvite):
S1: sequentially adding methanol 850ml in the reaction vessel and mass concentration percentage is 95% potassium hydroxide 426g, so
After stir to solid all dissolve；
S2: being cooled to 15 DEG C for above-mentioned solution, and malononitrile 350g is then added dropwise, and after dripping, controls at 15~20 DEG C
3.5h is stirred, carbon disulfide 496g is then added dropwise；
S3: after carbon disulfide completion of dropwise addition, being cooled to 10 DEG C, and stir 5h at 10~15 DEG C, then filter, and filter cake is used
1200ml acetone washing, and it is dried under reduced pressure 12h at 50 DEG C, 636g2 is obtained, 2- dicyanoethylene -1,1- is bis- (mercaptan sylvite)；Its
In, the equation of 2,2- dicyanoethylenes -1,1- bis- (mercaptan sylvite) preparation is as follows:
The preparation of (2) 3,5- dithiol -4- cyano isothiazole di-potassium:
S1: methanol 1260ml, water 1260ml and 2, the bis- (sulphur of 2- dicyanoethylene -1,1- are sequentially added in the reaction vessel
Alcohol sylvite) 636g, then stirs to solid and all dissolves；
S2: being cooled to 0 DEG C for above-mentioned solution, then controls to dropwise addition hydrogen peroxide 424g at 0~5 DEG C, drips off stirring 5h, then
- 5 DEG C are cooled to, and the methanol solution that mass concentration percentage is 95% potassium hydroxide 368g is added dropwise at -5~2 DEG C；
S3: after the methanol solution completion of dropwise addition of potassium hydroxide, reaction solution is concentrated into 950ml, concentration knot by temperature control≤60 DEG C
It is down to room temperature after beam, ethyl alcohol 4500ml is then added, stirs 1h, then tetrahydrofuran is added dropwise, and stir 3h, filters, filter cake is used
The washing of the mixed solution of 500ml ethyl alcohol and 500ml tetrahydrofuran, and it is dried under reduced pressure 12h at 50 DEG C, obtain 518g3,5- dithiol-
4- cyano isothiazole di-potassium；Wherein, the equation of 3,5- dithiol -4- cyano isothiazole di-potassium preparation is as follows:
The preparation of (3) 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt:
S1: sequentially adding water 977ml in the reaction vessel and mass concentration percentage is 95% potassium hydroxide 324g, then
Stirring is all dissolved to solid；
S2: 3,5- dithiol -4- cyano isothiazole di-potassium 518g being added into above-mentioned solution, is warming up to 60~63 DEG C,
And 2.5h is stirred, it is then down to room temperature, then methanol 5900ml is added dropwise, and stand 3h, generates sediment；
S3: the sediment of generation is filtered with diatomaceous earth filter, and temperature control≤60 DEG C concentrate filtrate to 930ml,
Then it is down to room temperature, 835ml methanol and 545ml ethyl alcohol is then added, and 5h is stirred at room temperature, then filters to obtain filter cake；
S4: filter cake is washed with the mixed solution of 300ml methanol and 300ml ethyl alcohol, and is dried under reduced pressure 12h at 50 DEG C, is obtained
292g3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt, yield is up to 83%；Wherein, 3,5- dithiol -4- Isothiazolecarboxyliacid acid three
The equation of sylvite preparation is as follows:
Basic principles and main features and advantages of the present invention of the invention have been shown and described above.The skill of the industry
Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (4)
1. a kind of synthetic method of cefotetan side chain, the cephalo side chain is 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt,
It is characterized by: the synthetic method includes the following steps:
The preparation of (1) 2,2- dicyanoethylene -1,1- bis- (mercaptan sylvite):
S1: sequentially adding methanol and potassium hydroxide in the reaction vessel, then stirs to solid and all dissolves；
S2: being cooled to 10~20 DEG C for above-mentioned solution, malononitrile be then added dropwise, and after dripping, control stirs 3 at 15~20 DEG C
~4h, is then added dropwise carbon disulfide；
S3: after carbon disulfide completion of dropwise addition, being cooled to 10~15 DEG C, and 4~6h is stirred at 10~15 DEG C, then filters, and filters
Cake acetone washing, and it is dried under reduced pressure 11~13h at 45~55 DEG C, it is bis- (mercaptan sylvite) to obtain 2,2- dicyanoethylene -1,1-；Its
In, the equation of 2,2- dicyanoethylenes -1,1- bis- (mercaptan sylvite) preparation is as follows:
The preparation of (2) 3,5- dithiol -4- cyano isothiazole di-potassium:
S1: sequentially adding methanol, water and 2 in the reaction vessel, and 2- dicyanoethylene -1,1- is bis- (mercaptan sylvite), then stirs
It is all dissolved to solid；
S2: being cooled to -5~5 DEG C for above-mentioned solution, then controls to hydrogen peroxide is added dropwise at 0~5 DEG C, drips off 4~6h of stirring, then
- 5~2 DEG C are cooled to, and the methanol solution of potassium hydroxide is added dropwise at -5~2 DEG C；
S3: after the methanol solution completion of dropwise addition of potassium hydroxide, reaction solution is concentrated for temperature control≤60 DEG C, and room is down to after concentration
Then ethyl alcohol is added in temperature, stir 1~2h, then tetrahydrofuran is added dropwise, and stirs 3~4h, filtering, filter cake ethyl alcohol and tetrahydro furan
The mixed solution washing muttered, and it is dried under reduced pressure 11~13h at 45~55 DEG C, obtain 3,5- dithiol -4- cyano isothiazole di-potassium；
Wherein, the equation of 3,5- dithiol -4- cyano isothiazole di-potassium preparation is as follows:
The preparation of (3) 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt:
S1: sequentially adding water and potassium hydroxide in the reaction vessel, then stirs to solid and all dissolves；
S2: 3,5- dithiol -4- cyano isothiazole di-potassium being added into above-mentioned solution, is warming up to 60~63 DEG C, and stir 2~
Then 3h is down to room temperature, then methanol is added dropwise, and stand 3~4h, generates sediment；
S3: the sediment of generation is filtered with diatomaceous earth filter, and filtrate decompression is concentrated for temperature control≤60 DEG C, is then down to room
Then temperature is added methanol and ethyl alcohol, and 4~6h is stirred at room temperature, then filter to obtain filter cake；
S4: filter cake is washed with the mixed solution of methanol and ethyl alcohol, and is dried under reduced pressure 11~13h at 45~55 DEG C, obtains 3,5-, bis- sulphur
Phenol -4- Isothiazolecarboxyliacid acid tripotassium salt；Wherein, the equation of 3,5- dithiol -4- Isothiazolecarboxyliacid acid tripotassium salt preparation is as follows:
2. the synthetic method of cefotetan side chain according to claim 1, it is characterised in that: used in the preparation process
Sodium hydroxide select mass concentration percentage be 92~98% sodium hydroxide.
3. the synthetic method of cefotetan side chain according to claim 1, it is characterised in that: in the step (2), ethyl alcohol
It is 1:1 with the volume ratio of ethyl alcohol and tetrahydrofuran in the mixed solution of tetrahydrofuran.
4. the synthetic method of cefotetan side chain according to claim 1, it is characterised in that: in the step (3), methanol
It is 1:1 with the volume ratio of methanol and ethyl alcohol in the mixed solution of ethyl alcohol.
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| CN201811058455.3A CN108947929A (en) | 2018-09-11 | 2018-09-11 | A kind of synthetic method of cefotetan side chain |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101696194A (en) * | 2009-10-30 | 2010-04-21 | 沧州那瑞化学科技有限公司 | Preparation method of 4-carboxy-3-hydroxy-5-sulfydryl-isoniazthiolane |
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2018
- 2018-09-11 CN CN201811058455.3A patent/CN108947929A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101696194A (en) * | 2009-10-30 | 2010-04-21 | 沧州那瑞化学科技有限公司 | Preparation method of 4-carboxy-3-hydroxy-5-sulfydryl-isoniazthiolane |
Non-Patent Citations (1)
| Title |
|---|
| 李立等: "头孢替坦侧链", 《精细与专用化学品》 * |
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