CN108484526A - A kind of method of ester-interchange method synthesis AE active ester - Google Patents
A kind of method of ester-interchange method synthesis AE active ester Download PDFInfo
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- CN108484526A CN108484526A CN201810330652.XA CN201810330652A CN108484526A CN 108484526 A CN108484526 A CN 108484526A CN 201810330652 A CN201810330652 A CN 201810330652A CN 108484526 A CN108484526 A CN 108484526A
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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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Abstract
The invention discloses a kind of method that ester-interchange method synthesizes AE active ester, using cefotaxime acid esters and 2 mercaptobenzothiazolers as raw material existing for organic solvent under the conditions of, it is obtained by organic base catalytic ester exchange reaction.The ainothiazoly loximate ester type compound used in the reaction is methyl esters, ethyl ester, isopropyl ester and person's tert-butyl ester etc.；Used catalyst is organic amine compound；Reaction dissolvent is the aromatic hydrocarbon solvents such as toluene, ortho-xylene, nitrobenzene.The method and process that the present invention synthesizes AE active ester is simple, yield good 83~88%, avoids and uses organophosphor condensation reagent in traditional handicraft, reaches without phosphorus sewage discharge, sustainable development can be realized by enterprise by greatly reducing environmental protection pressure.In addition solvent can recycle, and production cost is greatly reduced, and have larger implementary value.
Description
Technical field
The present invention relates to a kind of synthetic method of AE active ester, this method utilizes cefotaxime acid esters and 2-mercaptobenzothiazole
Ester exchange reaction prepares AE active ester, and reaction process is simple to operation, and environmental-friendly.
Background technology
AE active ester, Chinese 2- (2- amino -4- thiazolyls) thio benzothiazole of -2- (methoxyimino) acetic acid
Ester, appearance：Light yellow crystals sprills, fusing point：126~132 DEG C, it can be used for manufacturing cefotaxime, ceftriaxone, cephalo bent
Pioneers' class medicine such as pine, Cefetamet Pivoxil.
The traditional synthesis (such as Chinese patent application of Publication No. CN 101747291A) of AE active ester is with ammonia
Thiophene oxime acid and dithio-bis-benzothiazole are raw material, institute and reaction in the organic solvent existing for triethyl phosphite, triethylamine
It is prepared, reaction process is as follows：
It needs to be difficult to recycling using organophosphorus reagents, byproducts of reaction such as triethyl phosphites in traditional handicraft,
Serious environmental pollution can only be necessarily caused with phosphorus discharge of wastewater.Meanwhile Atom economy is bad, and one is will produce in reaction process
The 2- of molecule vulcanizes benzothiazole, it is also difficult to recycle, often directly carry out burning disposal.
The Chinese patent application of Publication No. CN 1709880A discloses a kind of synthetic method of AE active ester, this method
Reaction condition is adjusted, while a degree of processing is carried out to by-product after the completion of reaction and is recycled,
It can solve the above problems.However since post processing mode is excessively complicated, also, reaction condition adjustment after reaction yield under
Drop, practice is got up, and there is also larger problems.
Therefore, it develops one kind and can effectively solve the problem that the above problem, meanwhile, the higher method tool of easy to operate and yield
There is important application value.
Invention content
The present invention provides the methods that a kind of synthetic method ester-interchange method of AE active ester synthesizes AE active ester, and this method is not
It needs, using organophosphorus reagents such as triethyl phosphites, the discharge of a large amount of waste water in industrial production can effectively be avoided to be even up to
Without phosphorus discharge of wastewater, meanwhile, it ensure that reaction has higher efficiency.
A kind of method of ester-interchange method synthesis AE active ester, under the action of organic base, cefotaxime acid esters and 2- sulfydryl benzene
And thiazole carries out ester exchange reaction in organic solvent, passes through post-processing after reaction and obtains the AE active ester；
The cefotaxime acid esters is the Arrcostab of ainothiazoly loximate.
Reaction process such as following formula：
Wherein, R C1~C5Alkyl.
In the present invention, by using cefotaxime acid esters and 2-mercaptobenzothiazole as raw material, directly in the presence of alkali
Carry out ester exchange reaction, the effectively less generation of phosphorus-containing wastewater, meanwhile, the yield of reaction and the purity of product are higher, tool
There is industrial application value.
Preferably, the organic base is triethylamine, pyridine, N-methylmorpholine, DMAP one of which or several mixed
It closes.
Compared with dithio-bis-benzothiazole, 2-mercaptobenzothiazole reactivity is lower, preferably, the ammonia thiophene
Oxime acid esters is ainothiazoly loximate methyl esters, Ethyl Methylaminothiazolyloximate, ainothiazoly loximate isopropyl ester or the ainothiazoly loximate tert-butyl ester.Using these ammonia
Thiophene oxime acid esters, the 2-mercaptobenzothiazole that reactivity can be made not high are preferably converted into target product in the present reaction.
Preferably, the organic solvent is aromatic hydrocarbon solvent.
Preferably, the organic solvent is toluene, ortho-xylene or nitrobenzene.
Preferably, with molar amount, cefotaxime acid esters：2-mercaptobenzothiazole：Organic base=1.0:1.1~1.2:
0.3~0.5.In the present invention, phase is obtained as reaction raw materials by using 2-mercaptobenzothiazole for dithio-bis-benzothiazole
When the product of same amount, Atom economy is more preferable (dithio-bis-benzothiazole can only have a half structure to enter in product).
Preferably, the reaction temperature of the ester exchange reaction is 95~100 DEG C, the reaction time is 12~hour for 24 hours.
Preferably, the post-processing includes：After reaction, it filters, filter cake is washed with acetonitrile, is dried, is obtained institute
The AE active ester sterling stated.
Using cefotaxime acid esters and 2-mercaptobenzothiazole as raw material existing for organic solvent under the conditions of, urged by organic base
Change ester exchange reaction to be made.The ainothiazoly loximate ester type compound used in reaction is methyl esters, ethyl ester, isopropyl ester and person's tert-butyl ester
Deng；Used catalyst is organic amine compound；Reaction dissolvent is the aromatic hydrocarbon solvents such as toluene, ortho-xylene, nitrobenzene.
The specific synthetic method of the present invention is as follows：Cefotaxime acid esters, 2-mercaptobenzothiazole, organic is added in a kettle
After alkali and stirring solvent are uniform, it is warming up to 95~100 DEG C and is stirred to react and detaches the low boiling point solvent generated in reaction process, stir
24~25h of reaction is mixed, adds solvent in batches in the process.Filtering and with the mixed solvent of dichloromethane and acetonitrile after completion of the reaction
Wash filter cake, vacuum drying gained AE active ester.The molar ratio of its material is：Cefotaxime acid esters：2-mercaptobenzothiazole：It is organic
Alkali=1.0:1.1~1.2:0.3~0.5
Advantages of the present invention：Present invention process is simple to operation, and reaction yield is good, avoids in traditional handicraft using having
Machine phosphorus condensation reagent, reaches without phosphorus sewage discharge, and sustainable development can be realized by enterprise by greatly reducing environmental protection pressure.And
To product meet the indices of product in industry, there is larger implementary value.
Specific implementation mode
Illustrate the present invention below by way of specific implementation case, but the scope of the present invention is not limited to that：
Embodiment 1
In four mouthfuls of 1000mL flasks equipped with mechanical agitation, thermometer, water knockout drum and reflux condensing tube, cefotaxime is added
Sour methyl esters (43.0g, 0.2mol), 2-mercaptobenzothiazole (40.1g, 0.24mol), triethylamine (10.1g, 0.1mol), toluene
(400mL) is warming up to 95~100 DEG C or so reaction 12h, adds 100mL toluene and continue to be stirred to react 12h.Subtract after completion of the reaction
Pressure filters, and filter cake is washed with acetonitrile, is dried in vacuo, obtains target product AE active ester 59.2g, yield 84.5%, loss on drying
0.35%, moisture 0.2%, ainothiazoly loximate 0.1%, M0.09%, DM0.08%, content 99.0%, purity 99.6%.
It filters and washs in obtained waste liquid and phosphorus containg substances are not present, be convenient for handling.
Embodiment 2
In four mouthfuls of 1000mL flasks equipped with mechanical agitation, thermometer, water knockout drum and reflux condensing tube, cefotaxime is added
Acetoacetic ester (45.8g, 0.2mol), 2-mercaptobenzothiazole (40.1g, 0.24mol), triethylamine (10.1g, 0.1mol), toluene
(400mL) is warming up to 95~100 DEG C or so reaction 12h, adds 100mL toluene and continue to be stirred to react 12h.Subtract after completion of the reaction
Pressure filters, and filter cake is washed with acetonitrile, is dried in vacuo, obtains target product AE active ester 58.3g, yield 83.2%, loss on drying
0.38%, moisture 0.22%, ainothiazoly loximate 0.09%, M0.08%, DM0.08%, content 98.9%, purity 99.5%.
It filters and washs in obtained waste liquid and phosphorus containg substances are not present, be convenient for handling.
Embodiment 3
In four mouthfuls of 1000mL flasks equipped with mechanical agitation, thermometer, water knockout drum and reflux condensing tube, cefotaxime is added
Isopropyl propionate (48.6g, 0.2mol), 2-mercaptobenzothiazole (40.1g, 0.24mol), triethylamine (10.1g, 0.1mol), first
Benzene (400mL) is warming up to 95~100 DEG C or so reaction 12h, adds 100mL toluene and continue to be stirred to react 12h.After completion of the reaction
Decompression filters, and filter cake is washed with acetonitrile, is dried in vacuo, and obtains target product AE active ester 60.8g, and yield 86.7% is dry to lose
Weigh 0.4%, moisture 0.21%, ainothiazoly loximate 0.05%, M0.08%, DM0.05%, content 99.2%, purity 99.7%.
It filters and washs in obtained waste liquid and phosphorus containg substances are not present, be convenient for handling.
Embodiment 4
In four mouthfuls of 1000mL flasks equipped with mechanical agitation, thermometer, water knockout drum and reflux condensing tube, cefotaxime is added
Tert-butyl acrylate (51.5g, 0.2mol), 2-mercaptobenzothiazole (40.1g, 0.24mol), triethylamine (10.1g, 0.1mol), first
Benzene (400mL) is warming up to 95~100 DEG C or so reaction 12h, adds 100mL toluene and continue to be stirred to react 12h.After completion of the reaction
Decompression filters, and filter cake is washed with acetonitrile, is dried in vacuo, and obtains target product AE active ester 61.8g, and yield 88.1% is dry to lose
Weigh 0.5%, moisture 0.25%, ainothiazoly loximate 0.01%, M0.08%, DM0.09%, content 98.6%, purity 99.6%.
It filters and washs in obtained waste liquid and phosphorus containg substances are not present, be convenient for handling.
Embodiment 5
In four mouthfuls of 1000mL flasks equipped with mechanical agitation, thermometer, water knockout drum and reflux condensing tube, cefotaxime is added
Tert-butyl acrylate (51.5g, 0.2mol), 2-mercaptobenzothiazole (40.1g, 0.24mol), pyridine (7.9g, 0.1mol), toluene
(400mL) is warming up to 95~100 DEG C or so reaction 12h, adds 100mL toluene and continue to be stirred to react 12h.Subtract after completion of the reaction
Pressure filters, and filter cake is washed with acetonitrile, is dried in vacuo, obtains target product AE active ester 61.3g, yield 87.5%, loss on drying
0.5%, moisture 0.19%, ainothiazoly loximate 0.08%, M0.09%, DM0.08%, content 99.1%, purity 99.6%.
It filters and washs in obtained waste liquid and phosphorus containg substances are not present, be convenient for handling.
Embodiment 6
In four mouthfuls of 1000mL flasks equipped with mechanical agitation, thermometer, water knockout drum and reflux condensing tube, cefotaxime is added
Tert-butyl acrylate (51.5g, 0.2mol), 2-mercaptobenzothiazole (40.1g, 0.24mol), DMAP (12.2g, 0.1mol), toluene
(400mL) is warming up to 95~100 DEG C or so reaction 12h, adds 100mL toluene and continue to be stirred to react 12h.Subtract after completion of the reaction
Pressure filters, and filter cake is washed with acetonitrile, is dried in vacuo, obtains target product AE active ester 57.1g, yield 81.4%, loss on drying
0.49%, moisture 0.22%, ainothiazoly loximate 0.18%, M0.16%, DM0.45%, content 97.5%, purity 98.2%.
It filters and washs in obtained waste liquid and phosphorus containg substances are not present, be convenient for handling.
Embodiment 7
In four mouthfuls of 1000mL flasks equipped with mechanical agitation, thermometer, water knockout drum and reflux condensing tube, cefotaxime is added
Tert-butyl acrylate (51.5g, 0.2mol), 2-mercaptobenzothiazole (40.1g, 0.24mol), triethylamine (10.1g, 0.1mol), two
Toluene (400mL) is warming up to 95~100 DEG C or so reactions for 24 hours.Decompression filters after completion of the reaction, and filter cake is washed with acetonitrile, vacuum
It is dry, obtain target product AE active ester 61.6g, yield 87.9%, loss on drying 0.48%, moisture 0.3%, ainothiazoly loximate
0.08%, M0.09%, DM0.09%, content 99.3%, purity 99.5%.
It filters and washs in obtained waste liquid and phosphorus containg substances are not present, be convenient for handling.
Claims (8)
1. a kind of method of ester-interchange method synthesis AE active ester, which is characterized in that under the action of organic base, cefotaxime acid esters with
2-mercaptobenzothiazole carries out ester exchange reaction in organic solvent, passes through post-processing after reaction and obtains the AE activity
Ester；
The cefotaxime acid esters is the Arrcostab of ainothiazoly loximate.
2. the method for ester-interchange method according to claim 1 synthesis AE active ester, which is characterized in that the organic base is
Triethylamine, pyridine, N-methylmorpholine, DMAP one of which or several mixing.
3. the method for ester-interchange method synthesis AE active ester according to claim 1, which is characterized in that the ainothiazoly loximate
Ester is ainothiazoly loximate methyl esters, Ethyl Methylaminothiazolyloximate, ainothiazoly loximate isopropyl ester or the ainothiazoly loximate tert-butyl ester.
4. the method for ester-interchange method synthesis AE active ester according to claim 1, which is characterized in that the organic solvent
For aromatic hydrocarbon solvent.
5. the method for ester-interchange method synthesis AE active ester according to claim 1, which is characterized in that the organic solvent
For toluene, ortho-xylene or nitrobenzene.
6. the method for ester-interchange method synthesis AE active ester according to claim 1, which is characterized in that with molar amount, ammonia
Thiophene oxime acid esters：2-mercaptobenzothiazole：Organic base=1.0:1.1~1.2:0.3~0.5.
7. the method for ester-interchange method synthesis AE active ester according to claim 1, which is characterized in that the transesterification is anti-
The reaction temperature answered is 95~100 DEG C, and the reaction time is 12~hour for 24 hours.
8. the method for ester-interchange method synthesis AE active ester according to claim 1, which is characterized in that the post-processing packet
It includes：After reaction, it filters, filter cake is washed with acetonitrile, is dried, and the AE active ester sterling is obtained.
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| CN201810330652.XA CN108484526B (en) | 2018-04-13 | 2018-04-13 | Method for synthesizing AE active ester by ester exchange method |
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| CN201810330652.XA CN108484526B (en) | 2018-04-13 | 2018-04-13 | Method for synthesizing AE active ester by ester exchange method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111559987A (en) * | 2020-05-29 | 2020-08-21 | 山东金城医药化工有限公司 | Process for synthesizing AE-active ester |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1709880A (en) * | 2005-06-23 | 2005-12-21 | 浙江工业大学 | AE-active ester chemical synthesizing method |
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2018
- 2018-04-13 CN CN201810330652.XA patent/CN108484526B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1709880A (en) * | 2005-06-23 | 2005-12-21 | 浙江工业大学 | AE-active ester chemical synthesizing method |
Non-Patent Citations (3)
| Title |
|---|
| 孙键: "AE活性酯的合成研究", 《中国抗生素杂志》 * |
| 肖海焕: "AE-活性酯合成工艺研究", 《青岛科技大学硕士学位论文》 * |
| 葛洪玉等: "头孢克肟侧链活性酯的合成", 《中国新药杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111559987A (en) * | 2020-05-29 | 2020-08-21 | 山东金城医药化工有限公司 | Process for synthesizing AE-active ester |
| CN111559987B (en) * | 2020-05-29 | 2022-06-10 | 山东金城医药化工有限公司 | Process for synthesizing AE-active ester |
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Effective date of registration: 20200628 Address after: No.399, Jiangnan Road, Hengdian Town, Dongyang City, Jinhua City, Zhejiang Province Applicant after: APELOA PHARMACEUTICAL Co.,Ltd. Applicant after: SHANDONG APELOA PHARMACEUTICAL Co.,Ltd. Address before: 262737 Shandong province Weifang Coastal Economic Development Zone Lingang Road East Industrial Street South of Lingang Industrial Park Applicant before: SHANDONG APELOA PHARMACEUTICAL Co.,Ltd. |
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