CN1321989C - AE-active ester chemical synthesizing method - Google Patents
AE-active ester chemical synthesizing method Download PDFInfo
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- CN1321989C CN1321989C CNB2005100504220A CN200510050422A CN1321989C CN 1321989 C CN1321989 C CN 1321989C CN B2005100504220 A CNB2005100504220 A CN B2005100504220A CN 200510050422 A CN200510050422 A CN 200510050422A CN 1321989 C CN1321989 C CN 1321989C
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Abstract
The present invention provides a chemosynthesis method for AE-activity ester. (2-aminothiazole-4-yl)-2-methoxyimino acetate, dibenzosuberol thioether and triphenylphosphine used as raw materials thoroughly react in an organic solvent under the existence of a catalyst, the reaction liquor is filtered, and the filter cake is washed and dried to obtain the AE-activity ester. Bis(trichloromethyl) carbonate is added in the filter liquor to obtain the dibenzosuberol thioether and the triphenylphosphine by reaction; after being recovered, the benzothiazole thioether and the triphenylphosphine can be circularly used. The chemosynthesis method for AE-activity ester has the advantages of advanced technological lines, reasonable technological conditions, low cost and easy acquirement of raw materials, and simple and safe operation; because by-products are converted into reaction raw materials, the AE-activity ester is converted into the AE-activity ester by putting into operation again, and thus, the present invention greatly improves the reaction yield, reduces the production cost, and has larger implement value and social and economic benefits owning to basically no three waste.
Description
(1) technical field
The present invention relates to a kind of chemical synthesis process of AE-active ester.Adopt two (trichloromethyl) carbonic ethers that by product triphenylphosphinc oxide, 2-sulfuration benzothiazole are converted into raw material, realized recycling of by product.
(2) background technology
The AE-active ester is mainly used in the production cephalosporin analog antibiotic.Before the present invention made, the chemical synthesis process of prior art AE-active ester was to be synthesized into by raw material.Because this method produces a large amount of by product triphenylphosphinc oxides and 2-sulfuration benzothiazole, does not but have suitable recovery method, only burns as waste residue, so production cost is high, and from environmental angle, pollution problem is serious, and environmental problem is outstanding.
(3) summary of the invention
For synthetic with high costs, the contaminate environment that overcomes AE-active ester in the prior art, the deficiency that by product is not utilized effectively, the invention provides the chemical synthesis process of the AE-active ester that a kind of technology is reasonable, production safety is reliable, reaction yield is high, production cost is low.
For reaching goal of the invention the technical solution used in the present invention be:
The chemical synthesis process of a kind of AE-active ester (V), it is characterized in that described method is as follows: with cefotaxime acetate (I), bisbenzothiazole thioether (II), triphenyl phosphorus (III) is that raw material is in the presence of catalyzer, after in organic solvent, fully reacting, reacting liquid filtering, filter cake obtains described AE-active ester through washing drying, filtrate adds two (trichloromethyl) carbonic ethers (IV) again, reaction obtains bisbenzothiazole thioether and triphenyl phosphorus, after described benzothiazole thioether and triphenyl phosphorus reclaim, can synthesize the AE-active ester as raw material once more, thereby reach the effect that recycles;
Described catalyzer is one of following: 1. triethylamine; 2. pyridine; 3. 3-picoline; 4. N-methylpyrrole; 5. N-methyl Pyrrolidine;
Described organic solvent is one of following:
1. tetrahydrofuran (THF); 2. benzene; 3. toluene; 4. dimethylbenzene; 5. chlorobenzene; 6. dichlorobenzene; 7. methylene dichloride; 8. trichloromethane; 9. tetracol phenixin; 10. ethylene dichloride.
The ratio of the amount of described cefotaxime acetate, bisbenzothiazole thioether, triphenyl phosphorus, two (trichloromethyl) carbonic ether, catalyst substance is 1: 1.2～1.5: 1.2～1.5: 0.34～0.8: 0.05～1, and consumption of organic solvent is 3～20 times of cefotaxime quality of acetic acid.
Reaction formula is as follows:
Described temperature of reaction is 0～80 ℃, reaction total time 3～16h.
Described catalyzer is preferably pyridine.
Described catalyzer also can be triethylamine.
Described organic solvent is preferably methylene dichloride.
Concrete, described method is as follows: toward containing cefotaxime acetate, in the organic solvent of bisbenzothiazole thioether and catalyzer, slowly drip the organic solvent that is dissolved with triphenyl phosphorus under the stirring at normal temperature, after dropwising, react 3～8h down at 20～60 ℃, reaction finishes the cooling of afterreaction liquid ice bath, filter, the filter cake methanol wash, vacuum-drying obtains described AE-active ester, filtrate is stirred and is slowly dripped the organic solvent that is dissolved with two (trichloromethyl) carbonic ethers down, after dropwising, reaction 3～8h under 20～60 ℃ is after reaction finishes, filter, the filter cake methanol wash gets the bisbenzothiazole thioether, and filtrate concentrates, recrystallizing methanol gets triphenyl phosphorus.
Preferably, described method is as follows: in the methylene dichloride that contains cefotaxime acetate, bisbenzothiazole thioether and pyridine, slowly drip the dichloromethane solution of triphenyl phosphorus under the stirring at normal temperature, after dropwising, react 3h down at 20～25 ℃, reaction finishes the cooling of afterreaction liquid ice bath, filters, filter cake methanol wash, vacuum-drying obtain described AE-active ester; The stirring of gained filtrate slowly drips the dichloromethane solution of two (trichloromethyl) carbonic ethers down, and after dropwising, reaction 3h under 20～25 ℃ is after reaction finishes, filter, the filter cake methanol wash gets the bisbenzothiazole thioether, filtrate concentrates, and recrystallizing methanol gets triphenyl phosphorus; The ratio of cefotaxime acetate, bisbenzothiazole thioether, triphenyl phosphorus, two (trichloromethyl) carbonic ether, pyridine amount of substance is: 1: 1.2: 1.2: 0.35: 0.5.
Perhaps, described method is as follows: in the methylene dichloride that contains cefotaxime acetate, bisbenzothiazole thioether and pyridine, slowly drip the dichloromethane solution of triphenyl phosphorus under the stirring at normal temperature, after dropwising, react 4h down at 25～30 ℃, reaction finishes the cooling of afterreaction liquid ice bath, filters, filter cake methanol wash, vacuum-drying obtain described AE-active ester; The stirring of gained filtrate slowly drips the dichloromethane solution of two (trichloromethyl) carbonic ethers down, and after dropwising, reaction 4h under 25～30 ℃ is after reaction finishes, filter, the filter cake methanol wash gets the bisbenzothiazole thioether, filtrate concentrates, and recrystallizing methanol gets three stupid basic phosphorus; The ratio of cefotaxime acetate, bisbenzothiazole thioether, triphenyl phosphorus, two (trichloromethyl) carbonic ether, pyridine amount of substance is: 1: 1.2: 1.2: 0.5: 1.0.
The beneficial effect of the chemical synthesis process of AE-active ester of the present invention is mainly reflected in: (1) operational path advanced person, and processing condition are reasonable, and used raw material is cheap and easy to get, safety simple to operate; (2) because by product is converted into reaction raw materials, can come into operation once more is converted into the AE-active ester, has greatly improved reaction yield, has reduced production cost, and has not had the three wastes substantially, has bigger implementary value and economic results in society.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1:
Molar ratio is a cefotaxime acetate: bisbenzothiazole thioether: triphenyl phosphorus: two (trichloromethyl) carbonic ether: pyridine=1: 1.2: 1.2: 0.35: 0.5.
Mechanical stirring is being housed, constant pressure funnel, in the 500ml four-hole boiling flask of reflux condensing tube and thermometer, add 20g (0.0995mol) cefotaxime acetate, add the bisbenzothiazole thioether in proportion, pyridine and 100ml methylene dichloride, open and stir, at normal temperature, slowly drip the 80ml dichloromethane solution of triphenyl phosphorus under the vigorous stirring, finish, stirring reaction 3h (t1) under 20～25 ℃ temperature, the ice bath cooling, filter filter cake methanol wash, vacuum-drying, get AE-active ester 29.1g (0.08314mol, theoretical value is 0.0995mol), yield is 83.6%, content is 98.6% (LC); Slowly drip the 50ml dichloromethane solution of two (trichloromethyl) carbonic ethers under the filtrate vigorous stirring, finish, continue 3 hours (t2) of reaction down at 20～25 ℃, after reaction finishes, filter, the filter cake methanol wash gets bisbenzothiazole thioether 16.6g (0.05mol, theoretical value is for reclaiming gained amount and the amount sum of not participating in reaction, should be 0.0995 * 1.2-0.0995+0.0995/2=0.07mol) herein, yield is 71.43%, and content is 98.1% (LC), filtrate concentrates, recrystallizing methanol gets triphenylphosphine 22.9g (0.0874mol, theoretical value is 0.1194mol), yield is about 73.2%, and content is 98.3% (LC).
Embodiment 2:
Molar ratio is a cefotaxime acetate: bisbenzothiazole thioether: triphenyl phosphorus: two (trichloromethyl) carbonic ether: pyridine=1: 1.2: 1.2: 0.5: 1.0.
Mechanical stirring is being housed, constant pressure funnel, in the 500ml four-hole boiling flask of reflux condensing tube and thermometer, add 20g cefotaxime acetate, it is (partially recycled to add the bisbenzothiazole thioether in proportion, part is newly-increased), pyridine and 80ml methylene dichloride are opened and are stirred, at normal temperature, it is (partially recycled slowly to drip triphenyl phosphorus under the vigorous stirring, part is newly-increased) the 70ml dichloromethane solution, finish, heat up, and under 25-30 ℃ temperature stirring reaction 4h (t1), the filter cake methanol wash is filtered in the ice bath cooling, vacuum-drying, get AE-active ester 29.8g (0.085mol), yield is 85.4%, and content is 98.7% (LC); Slowly drip the 60ml dichloromethane solution of two (trichloromethyl) carbonic ethers under the filtrate vigorous stirring, finish, continue 4 hours (t2) of reaction down at 25～30 ℃, after reaction finishes, filter, use the methanol wash filter cake, get bisbenzothiazole thioether 17.1g (0.0515mol), yield is 73.6%, and content is 98.0% (LC), and the filtrate rotation concentrates, recrystallizing methanol, triphenylphosphine 23.6g (0.09mol), yield is about 75.4%, content is 98.2% (LC).
Embodiment 3:
Molar ratio is a cefotaxime acetate: bisbenzothiazole thioether: triphenyl phosphorus: two (trichloromethyl) carbonic ether: pyridine=1: 1.2: 1.2: 1.5: 1.0.
Mechanical stirring is being housed, constant pressure funnel, in the 500ml four-hole boiling flask of reflux condensing tube and thermometer, add 20g cefotaxime acetate, it is (partially recycled to add the bisbenzothiazole thioether in proportion, part is newly-increased), pyridine and 100ml methylene dichloride are opened and are stirred, at normal temperature, it is (partially recycled slowly to drip triphenyl phosphorus under the vigorous stirring, part is newly-increased) the 80ml dichloromethane solution, finish, heat up, and under 40～45 ℃ temperature stirring reaction 4h (t1), the filter cake methanol wash is filtered in the ice bath cooling, vacuum-drying, get AE-active ester 28.7g (0.082mol), yield is 82.4%, and content is 98.1% (LC); Slowly drip the 100ml dichloromethane solution of two (trichloromethyl) carbonic ethers under the filtrate vigorous stirring, finish, continue 4 hours (t2) of reaction down at 40～45 ℃, after reaction finishes, filter, use the methanol wash filter cake, get bisbenzothiazole thioether 16.3g (0.049mol), yield is 70.14%, and content is 98.0% (LC), and the filtrate rotation concentrates, recrystallizing methanol, triphenylphosphine 21.9g (0.083mol), yield is about 70.1%, content is 98.2% (LC).
Embodiment 4:
Catalyzer changes triethylamine into, and other is operated with embodiment 2, gets AE-active ester 27.3g (0.078mol), and yield is 78.4%, and content is 98.2% (LC); Get bisbenzothiazole thioether 15.6g (0.047mol), yield is 67.1%, and content is 98.1% (LC); Triphenylphosphine 22.0g (0.084mol), yield is about 70.4%, content is 98.0% (LC).
Embodiment 5:
Catalyzer changes N-methyl Pyrrolidine into, and other is operated with embodiment 2, gets AE-active ester 27.4g (0.0783mol), and yield is 78.7%, and content is 98.3% (LC); Get bisbenzothiazole thioether 15.7g (0.0473mol), yield is 67.6%, and content is 98.2% (LC); Triphenylphosphine 22.5g (0.0859mol), yield is about 71.9%, content is 98.0% (LC).
Embodiment 6:
Catalyzer changes the N-methylpyrrole into, and molar ratio is a cefotaxime acetate: bisbenzothiazole thioether: triphenyl phosphorus: two (trichloromethyl) carbonic ether: N-methylpyrrole=1: 1.2: 1.2: 0.5: 0.2., other is operated with embodiment 2, gets AE-active ester 23.8g (0.068mol), and yield is 68.3%, and content is 98.1% (LC); Get bisbenzothiazole thioether 13.7g (0.0413mol), yield is 59.0%, and content is 98.2% (LC); Triphenylphosphine 20.3g (0.0775mol), yield is about 64.9%, content is 98.2% (LC).
Embodiment 7:
Catalyzer changes the 3-picoline into, and other is operated with embodiment 2, gets AE-active ester 27.9g (0.0797mol), and yield is 80.1%, and content is 98.2% (LC); Get bisbenzothiazole thioether 16.5g (0.0497mol), yield is 80.0%, and content is 98.3% (LC); Triphenylphosphine 23.6g (0.09mol), yield is about 75.4%, content is 98.1% (LC).
Embodiment 8:
Reaction times t1 changes 5h into, reaction times t2 changes 5h into, and other gets AE-active ester 29.2g (0.0834mol) with embodiment 1, and yield is 83.8%, and content is 98.6% (LC); Get bisbenzothiazole thioether 16.8g (0.0506mol), yield is 72.3%, and content is 98.2% (LC); Triphenylphosphine 23.1g (0.088mol), yield is about 73.8%, and content is 98.3% (LC).
Embodiment 9:
Reaction times t1 changes 8h into, reaction times t2 changes 8h into, and other gets AE-active ester 30.1g (0.086mol) with embodiment 1, and yield is 86.4%, and content is 98.7% (LC); Get bisbenzothiazole thioether 17.3g (0.052mol), yield is 74.4%, and content is 98.3% (LC); Triphenylphosphine 24.1g (0.092mol), yield is about 77.0%, and content is 98.3% (LC).
Embodiment 10:
Reaction solvent changes trichloromethane into, and temperature of reaction changes 50～55 ℃ into, and all the other with embodiment 2, get AE-active ester 27.6g (0.0789mol) with other, and yield is 79.3%, and content is 98.0% (LC); Get bisbenzothiazole thioether 15.2g (0.0458mol), yield is 65.4%, and content is 98.1% (LC); Triphenylphosphine 22.1g (0.0844mol), yield is about 70.6%, and content is 98.1% (LC).
Embodiment 11:
Reaction solvent changes toluene into, and temperature of reaction changes 55～60 ℃ into, and all the other with embodiment 2, get AE-active ester 25.3g (0.723mol) with other, and yield is 72.7%, and content is 98.0% (LC); Get bisbenzothiazole thioether 14.8g (0.0446mol), yield is 63.7%, and content is 98.2% (LC); Triphenylphosphine 21.8g (0.0832mol), yield is about 69.6%, and content is 98.1% (LC).
Embodiment 12:
Reaction solvent changes benzene into, and temperature of reaction changes 75～80 ℃ into, and all the other with embodiment 2, get AE-active ester 19.2g (0.055mol) with other, and yield is 55.1%, and content is 98.0% (LC); Get bisbenzothiazole thioether 11.8g (0.0355mol), yield is 50.8%, and content is 98.1% (LC); Triphenylphosphine 18.3g (0.070mol), yield is about 58.5%, and content is 98.1% (LC).
Embodiment 13:
Reaction solvent changes tetrahydrofuran (THF) into, and temperature of reaction changes 0～5 ℃ into, and all the other with embodiment 2, get AE-active ester 17.8g (0.0509mol) with other, and yield is 51.2%, and content is 97.8% (LC); Get bisbenzothiazole thioether 10.2g (0.0307mol), yield is 43.9%, and content is 98.0% (LC); Triphenylphosphine 16.7g (0.0637mol), yield is about 53.4%, and content is 98.1% (LC).
Embodiment 14:
It is stupid that reaction solvent changes diformazan into, and temperature of reaction changes 65～70 ℃ into, and all the other with embodiment 2, get AE-active ester 19.7g (0.0563mol) with other, and yield is 56.6%, and content is 98.1% (LC); Get bisbenzothiazole thioether 15.5g (0.0469mol), yield is 66.7%, and content is 98.0% (LC); Triphenylphosphine 19.6g (0.0748mol), yield is about 62.6%, and content is 98.2% (LC).
Embodiment 15:
Reaction solvent changes chlorobenzene into, and all the other with embodiment 2, get AE-active ester 25.7g (0.0734mol) with other, and yield is 73.8%, and content is 98.2% (LC); Get bisbenzothiazole thioether 14.9g (0.0449mol), yield is 64.1%, and content is 98.0% (LC); Triphenylphosphine 23.6g (0.090mol), yield is about 75.4%, and content is 98.1% (LC).
Embodiment 16:
Reaction solvent changes dichlorobenzene into, and all the other with embodiment 2, get AE-active ester 25.9g (0.074mol) with other, and yield is 74.4%, and content is 98.2% (LC); Get bisbenzothiazole thioether 14.7g (0.443mol), yield is 63.3%, and content is 98.1% (LC); Triphenylphosphine 23.5g (0.0897mol), yield is about 75.1%, and content is 98.1% (LC).
Embodiment 17:
Reaction solvent changes tetracol phenixin into, and temperature of reaction changes 5～10 ℃ into, and all the other with embodiment 2, get AE-active ester 21.8g (0.623mol) with other, and yield is 62.6%, and content is 98.2% (LC); Get bisbenzothiazole thioether 12.7g (0.0383mol), yield is 54.7%, and content is 98.3% (LC); Triphenylphosphine 21.3g (0.0813mol), yield is about 68.1%, and content is 98.1% (LC).
Embodiment 18:
Reaction solvent changes ethylene dichloride into, and temperature of reaction changes 15～20 ℃ into, and all the other with embodiment 2, get AE-active ester 25.7g (0.0734mol) with other, and yield is 73.8%, and content is 98.3% (LC); Get bisbenzothiazole thioether 14.1g (0.0425mol), yield is 60.7%, and content is 98.1% (LC); Triphenylphosphine 23.4g (0.089mol), yield is about 74.8%, and content is 98.2% (LC).
The present invention and existing chemical synthesis process relatively, it is cheap and easy to get to have a raw material, safety simple to operate, reaction time is short, the reaction yield height, good product quality, advantages such as non-environmental-pollution are methods that is suitable for suitability for industrialized production.
Claims (8)
1. the chemical synthesis process of an AE-active ester, it is characterized in that described method is as follows: with cefotaxime acetate, bisbenzothiazole thioether, triphenyl phosphorus is that raw material is in the presence of catalyzer, in the organic solvent fully after the reaction, reacting liquid filtering, filter cake obtains described AE-active ester through washing drying, filtrate adds two (trichloromethyl) carbonic ethers again, reaction obtains bisbenzothiazole thioether and triphenyl phosphorus, and described benzothiazole thioether and triphenyl phosphorus recycle after reclaiming;
Described catalyzer is one of following: 1. triethylamine; 2. pyridine; 3. 3-picoline; 4. N-methylpyrrole; 5. N-methyl Pyrrolidine;
Described organic solvent is one of following:
1. tetrahydrofuran (THF); 2. benzene; 3. toluene; 4. dimethylbenzene; 5. chlorobenzene; 6. dichlorobenzene; 7. methylene dichloride; 8. trichloromethane; 9. tetracol phenixin; 10. ethylene dichloride.
The ratio of the amount of described cefotaxime acetate, bisbenzothiazole thioether, triphenyl phosphorus, two (trichloromethyl) carbonic ether, catalyst substance is 1: 1.2～1.5: 1.2～1.5: 0.34～0.8: 0.05～1, and consumption of organic solvent is 3～20 times of cefotaxime quality of acetic acid.
2. the chemical synthesis process of AE-active ester as claimed in claim 1 is characterized in that temperature of reaction is 0～80 ℃, reaction total time 3～16h.
3. the chemical synthesis process of AE-active ester as claimed in claim 1 or 2 is characterized in that described catalyzer is a pyridine.
4. the chemical synthesis process of AE-active ester as claimed in claim 1 or 2 is characterized in that described catalyzer is a triethylamine.
5. the chemical synthesis process of AE-active ester as claimed in claim 1 or 2 is characterized in that described organic solvent is a methylene dichloride.
6. the chemical synthesis process of AE-active ester as claimed in claim 1 or 2 is characterized in that described method is as follows:
Toward containing cefotaxime acetate, in the organic solvent of bisbenzothiazole thioether and catalyzer, slowly drip the organic solvent that is dissolved with triphenyl phosphorus under the stirring at normal temperature, after dropwising, react 3～8h down at 20～60 ℃, reaction finishes the cooling of afterreaction liquid ice bath, filters, the filter cake methanol wash, vacuum-drying obtains described AE-active ester, and filtrate is stirred and slowly dripped the organic solvent that is dissolved with two (trichloromethyl) carbonic ethers down, after dropwising, react 3～8h down in 20～60 ℃, after reaction finishes, filter the filter cake methanol wash, get the bisbenzothiazole thioether, filtrate concentrates, and recrystallizing methanol gets triphenyl phosphorus.
7. the chemical synthesis process of AE-active ester as claimed in claim 3 is characterized in that described method is as follows:
In the methylene dichloride that contains cefotaxime acetate, bisbenzothiazole thioether and pyridine, slowly drip the dichloromethane solution of triphenyl phosphorus under the stirring at normal temperature, after dropwising, react 3h down at 20～25 ℃, reaction finishes the cooling of afterreaction liquid ice bath, filter, the filter cake methanol wash, vacuum-drying obtains described AE-active ester; The stirring of gained filtrate slowly drips the dichloromethane solution of two (trichloromethyl) carbonic ethers down, and after dropwising, reaction 3h under 20～25 ℃ is after reaction finishes, filter, the filter cake methanol wash gets the bisbenzothiazole thioether, filtrate concentrates, and recrystallizing methanol gets triphenyl phosphorus;
The ratio of cefotaxime acetate, bisbenzothiazole thioether, triphenyl phosphorus, two (trichloromethyl) carbonic ether, pyridine amount of substance is: 1: 1.2: 1.2: 0.3 5: 0.5.
8. the chemical synthesis process of AE-active ester as claimed in claim 3 is characterized in that described method is as follows:
In the methylene dichloride that contains cefotaxime acetate, bisbenzothiazole thioether and pyridine, slowly drip the dichloromethane solution of triphenyl phosphorus under the stirring at normal temperature, after dropwising, react 4h down at 25～30 ℃, reaction finishes the cooling of afterreaction liquid ice bath, filter, the filter cake methanol wash, vacuum-drying obtains described AE-active ester; The stirring of gained filtrate slowly drips the dichloromethane solution of two (trichloromethyl) carbonic ethers down, and after dropwising, reaction 4h under 25～30 ℃ is after reaction finishes, filter, the filter cake methanol wash gets the bisbenzothiazole thioether, filtrate concentrates, and recrystallizing methanol gets triphenyl phosphorus;
The ratio of cefotaxime acetate, bisbenzothiazole thioether, triphenyl phosphorus, two (trichloromethyl) carbonic ether, pyridine amount of substance is: 1: 1.2: 1.2: 0.5: 1.0.
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| CN101357908B (en) * | 2008-09-04 | 2012-05-23 | 浙江工业大学 | Bisbenzothiazole disulfide and triphenylphosphine preparation by means of one pot |
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| CN100448856C (en) * | 2006-06-26 | 2009-01-07 | 山东金城医药化工股份有限公司 | New technique for catalytic synthesis of AE active ester |
| CN1958591B (en) * | 2006-09-06 | 2010-08-11 | 珠海联邦制药股份有限公司 | Method for preparing intermediate in cephalosporins, and method for preparing ceftizoxime alapivoxil |
| CN103641793B (en) * | 2013-11-28 | 2015-06-03 | 山东鑫泉医药有限公司 | Treatment method of AE (Active Ester) residual liquid |
| CN104387337A (en) * | 2014-12-15 | 2015-03-04 | 山东鑫泉医药有限公司 | Method for synthesizing 3-ethyl-2-sulfur ethyl benzothiazole perchlorate by AE (Active Ester) residues |
| CN108484526B (en) * | 2018-04-13 | 2021-10-22 | 普洛药业股份有限公司 | Method for synthesizing AE active ester by ester exchange method |
| 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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| CN101357908B (en) * | 2008-09-04 | 2012-05-23 | 浙江工业大学 | Bisbenzothiazole disulfide and triphenylphosphine preparation by means of one pot |
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