CN107129472A - A kind of technique for preparing acetazolamide intermediate - Google Patents
A kind of technique for preparing acetazolamide intermediate Download PDFInfo
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- CN107129472A CN107129472A CN201710351723.XA CN201710351723A CN107129472A CN 107129472 A CN107129472 A CN 107129472A CN 201710351723 A CN201710351723 A CN 201710351723A CN 107129472 A CN107129472 A CN 107129472A
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- acetazolamide
- technique
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- thiadiazoles
- piperidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
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Abstract
The invention belongs to medical synthesis field, more particularly to a kind of technique for preparing acetazolamide intermediate：Using thiosemicarbazides and carbon disulfide as reactant, using the mixture of pyridine and piperidines as solvent, purify, dry after reaction, obtain the thiadiazoles of 2 amino, 5 sulfydryl 1,3,4, the i.e. intermediate of acetazolamide.
Description
Technical field
The invention belongs to medical synthesis field, more particularly to a kind of technique for preparing acetazolamide intermediate.
Background technology
Acetazolamide is a kind of new non-mercurial diuretic, and its mechanism of action is to play profit by suppressing carbonate dehydratase
Urine is acted on, and rear to have clinical report again, the medicine also has to illnesss such as the oedema caused by Cardiac Insufficiency, glaucoma, epilepsys
Good therapeutic effect.
Acetazolamide is synthesized first in nineteen fifty by Miller et al., and its synthetic method is：
2- amino -5- sulfydryls -1,3,4- thiadiazoles is the key intermediate of synthesis of acetyl azoles amine, is had been reported that at present almost
The preparation technology of all acetazolamide is obtained by the acetylation of the intermediate, three processes of chlorination and ammonification.
However, in the technology path of existing report, the problem of generally existing product yield is low is even more to reach in actual production
Less than the yield value of document report.The main cause for causing actual recovery not high be cyclised products intermediate 2-amino -5- sulfydryls -
In the presence of 2,5- diaminostilbenes in 1,3,4- thiadiazoles, 3,4- thiadiazoles impurity, and because both cyclised products are in agent structure
It is upper highly similar, there is a situation where similar compatibility to each other, therefore even across multiple working procedure, 2,5- diaminostilbenes, 3,4- thiophenes
Diazole impurity is still not easy to be separated from target product, so that follow-up acetazolamide product qualification rate reduction.
The content of the invention
To overcome shortcomings and deficiencies present in above-mentioned prior art, it is intended to ensure key intermediate 2- amino -5- sulfydryls -
The good yield of 1,3,4- thiadiazoles and purity, and then the product qualification rate of acetazolamide is improved, the invention provides one kind system
The technique of standby acetazolamide intermediate：
Using thiosemicarbazides and carbon disulfide as reactant, using the mixture of pyridine and piperidines as solvent, purify, dry after reaction
It is dry, obtain 2- amino -5- sulfydryls -1,3, the intermediate of 4- thiadiazoles, i.e. acetazolamide,
Wherein, the weight ratio of thiosemicarbazides and carbon disulfide is 1：1.67~2.09,
The volume ratio of pyridine and piperidines is 5~20：1,
The temperature of reaction is 80~130 DEG C, and the reaction time is 5 hours,
Reacted purification operations are the carbon disulfide that solvent and excess is distilled off, and gained solid is dissolved with diluted alkaline, plus
Enter activated carbon decolorizing and filter, acid adding separates out solid in filtrate, filtering, filter cake is washed three times,
Wherein, diluted alkaline is the sodium hydrate aqueous solution that Solute mass fraction is 20%, and acid is concentrated hydrochloric acid.
The beneficial effects of the present invention are：By changing type of solvent and controlling related process parameters, effectively inhibit with
2,5- diaminostilbenes, the appearance of the accessory substance based on 3,4- thiadiazoles, but without prejudice to target product 2- amino -5- sulfydryls -
The generation of 1,3,4- thiadiazoles, so that 2- amino -5- sulfydryls -1,3 are significantly improved, the yield and purity of 4- thiadiazoles, then according to
Secondary to obtain acetazolamide through acetylation, chlorination and aminating reaction, this method is workable, technical maturity, can effectively solve
Certainly acetazolamide product qualification rate is low, the problem of quality is unstable.
By 2- amino -5- sulfydryls -1,3 prepared by the present invention, 4- thiadiazoles is anti-through acetylation, chlorination and ammonification three
Answer and finished product acetazolamide is obtained after step：
Glacial acetic acid is added in 2- amino -5- sulfydryls -1,3,4- thiadiazoles and acetic anhydride is reacted, and reaction adds after terminating
Frozen water, is passed through in system with chlorine, is led to and is finished filtering, and filter cake obtains 2- acetylaminohydroxyphenylarsonic acids 5- sulphonyl chloro- 1,3,4- thiadiazoles through washing；
By 2- acetylaminohydroxyphenylarsonic acids 5- sulphonyl chloro- 1,3,4- thiadiazoles are added in ammoniacal liquor, insulation reaction, and reaction is finished plus frozen water,
So that in sulfuric acid and system, filtering, filter cake twice, obtains finished product acetazolamide through washing and with water recrystallization.
Embodiment
Embodiment 1
1.5L pyridines, 300mL piperidines, 100g thiosemicarbazides and 132.6mL curing are sequentially added in 3L there-necked flask
Carbon, stirring is heated in bottle 80 DEG C of temperature and reacted 5 hours, after reaction terminates, and solvent and excessive carbon disulfide is distilled off,
Gained solid adds addition 2.9g activated carbons at 350mL sodium hydroxide solutions (Solute mass fraction is 20%) dissolving, 60 DEG C and taken off
Color 0.5 hour, decolourizes to finish, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fractions are added in gained filtrate
Solid is separated out, and stirring is filtered after 0.5 hour, and filter cake, in decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercaptos through washing three times
Base -1,3,4- thiadiazoles 110g, purity 99.7%.
After testing：231-231.5 DEG C of product fusing point；Elementary analysis：Theoretical value (C 18.03%, H 2.27%, N
31.55%th, S 48.15%), measured value (C 18.07%, H 2.21%, N 31.59%, S 48.12%).
Comparative example 1
Solvent " 1.5L pyridines, 300mL piperidines " is replaced with into " 1.8L pyridines ", remaining operates equal be the same as Example 1.
2- amino -5- sulfydryls -1,3 obtained by preparation, the purity only 84.2% of 4- thiadiazoles.
Embodiment 2
1.5L pyridines, 300mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in 3L there-necked flask
Carbon, stirring is heated in bottle 80 DEG C of temperature and reacted 5 hours, after reaction terminates, and solvent and excessive carbon disulfide is distilled off,
Gained solid adds addition 2.9g activated carbons at 350mL sodium hydroxide solutions (Solute mass fraction is 20%) dissolving, 60 DEG C and taken off
Color 0.5 hour, decolourizes to finish, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fractions are added in gained filtrate
Solid is separated out, and stirring is filtered after 0.5 hour, and filter cake, in decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercaptos through washing three times
Base -1,3,4- thiadiazoles 118.2g, purity 99.6%.
After testing：230-231 DEG C of product fusing point；Elementary analysis：Theoretical value (C 18.03%, H 2.27%, N
31.55%th, S 48.15%), measured value (C 18.03%, H 2.29%, N 31.55%, S 48.10%).
Comparative example 2
Solvent " 1.5L pyridines, 300mL piperidines " is replaced with into " 0.9L pyridines, 0.9L piperidines ", remaining operation is with implementation
Example 2.
2- amino -5- sulfydryls -1,3 obtained by preparation, the purity only 85.3% of 4- thiadiazoles.
Embodiment 3
1.5L pyridines, 300mL piperidines, 100g thiosemicarbazides and 165.8mL curing are sequentially added in 3L there-necked flask
Carbon, stirring is heated in bottle 80 DEG C of temperature and reacted 5 hours, after reaction terminates, and solvent and excessive carbon disulfide is distilled off,
Gained solid adds addition 2.9g activated carbons at 350mL sodium hydroxide solutions (Solute mass fraction is 20%) dissolving, 60 DEG C and taken off
Color 0.5 hour, decolourizes to finish, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fractions are added in gained filtrate
Solid is separated out, and stirring is filtered after 0.5 hour, and filter cake, in decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercaptos through washing three times
Base -1,3,4- thiadiazoles 117.1g, purity 99.7%.
After testing：231-231.5 DEG C of product fusing point；Elementary analysis：Theoretical value (C 18.03%, H 2.27%, N
31.55%th, S 48.15%), measured value (C 18.01%, H 2.23%, N 31.55%, S 48.18%).
Comparative example 3
Solvent " 1.5L pyridines, 300mL piperidines " is replaced with into " 1.8L piperidines ", remaining operates equal be the same as Example 2.
2- amino -5- sulfydryls -1,3 obtained by preparation, the purity only 83.6% of 4- thiadiazoles.
Embodiment 4
1.5L pyridines, 300mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in 3L there-necked flask
Carbon, stirring is heated in bottle 115 DEG C of temperature and reacted 5 hours, after reaction terminates, and solvent and excessive carbon disulfide is distilled off,
Gained solid adds addition 2.9g activated carbons at 350mL sodium hydroxide solutions (Solute mass fraction is 20%) dissolving, 60 DEG C and taken off
Color 0.5 hour, decolourizes to finish, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fractions are added in gained filtrate
Solid is separated out, and stirring is filtered after 0.5 hour, and filter cake, in decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercaptos through washing three times
Base -1,3,4- thiadiazoles 126.1g, purity 99.7%.
After testing：231.5-232 DEG C of product fusing point；Elementary analysis：Theoretical value (C 18.03%, H 2.27%, N
31.55%th, S 48.15%), measured value (C 18.09%, H 2.23%, N 31.56%, S 48.12%).
Comparative example 4
Solvent " 1.5L pyridines, 300mL piperidines " is replaced with into " 1.8L dimethylformamides ", remaining operates equal be the same as Example
2。
2- amino -5- sulfydryls -1,3 obtained by preparation, the purity only 84.5% of 4- thiadiazoles.
Embodiment 5
1.5L pyridines, 300mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in 3L there-necked flask
Carbon, stirring is heated in bottle 130 DEG C of temperature and reacted 5 hours, after reaction terminates, and solvent and excessive carbon disulfide is distilled off,
Gained solid adds addition 2.9g activated carbons at 350mL sodium hydroxide solutions (Solute mass fraction is 20%) dissolving, 60 DEG C and taken off
Color 0.5 hour, decolourizes to finish, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fractions are added in gained filtrate
Solid is separated out, and stirring is filtered after 0.5 hour, and filter cake, in decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercaptos through washing three times
Base -1,3,4- thiadiazoles 125.7g, purity 99.5%.
After testing：231-232 DEG C of product fusing point；Elementary analysis：Theoretical value (C 18.03%, H 2.27%, N
31.55%th, S 48.15%), measured value (C 18.01%, H 2.25%, N 31.58%, S 48.17%).
Embodiment 6
1.64L pyridines, 164mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in 3L there-necked flask
Carbon, stirring is heated in bottle 115 DEG C of temperature and reacted 5 hours, after reaction terminates, and solvent and excessive carbon disulfide is distilled off,
Gained solid adds addition 2.9g activated carbons at 350mL sodium hydroxide solutions (Solute mass fraction is 20%) dissolving, 60 DEG C and taken off
Color 0.5 hour, decolourizes to finish, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fractions are added in gained filtrate
Solid is separated out, and stirring is filtered after 0.5 hour, and filter cake, in decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercaptos through washing three times
Base -1,3,4- thiadiazoles 130.7g, purity 99.6%.
After testing：232-232.5 DEG C of product fusing point；Elementary analysis：Theoretical value (C 18.03%, H 2.27%, N
31.55%th, S 48.15%), measured value (C 18.03%, H 2.26%, N 31.57%, S 48.18%).
Embodiment 7
1.71L pyridines, 90mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in 3L there-necked flask
Carbon, stirring is heated in bottle 115 DEG C of temperature and reacted 5 hours, after reaction terminates, and solvent and excessive carbon disulfide is distilled off,
Gained solid adds addition 2.9g activated carbons at 350mL sodium hydroxide solutions (Solute mass fraction is 20%) dissolving, 60 DEG C and taken off
Color 0.5 hour, decolourizes to finish, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fractions are added in gained filtrate
Solid is separated out, and stirring is filtered after 0.5 hour, and filter cake, in decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercaptos through washing three times
Base -1,3,4- thiadiazoles 123.5g, purity 99.7%.
After testing：231-232 DEG C of product fusing point；Elementary analysis：Theoretical value (C 18.03%, H 2.27%, N
31.55%th, S 48.15%), measured value (C 18.02%, H 2.26%, N 31.53%, S 48.17%).
2- amino -5- the sulfydryls -1,3 obtained in 500mL glacial acetic acid, 80g the present embodiment are sequentially added in 3L there-necked flasks,
4- thiadiazoles and 76.4mL acetic anhydride, stirring, are heated to back flow reaction 2 hours, are cooled to temperature in bottle<30 DEG C, add 1L ice
Temperature continues after stirring 2 hours, chlorine is slowly passed through in system, to system gas saturation (about at 0-5 DEG C in water, control bottle
2.5 hours), terminate ventilation, filtering, filter cake obtains the thiadiazoles wet product of 2- acetylaminohydroxyphenylarsonic acids 5- sulphonyl chloro- 1,3,4- through washing three times
154.7g, next step reaction is directly carried out without purifying；
It is in 3L there-necked flasks, the above-mentioned thiadiazoles wet products of 2- acetylaminohydroxyphenylarsonic acids 5- sulphonyl chloro- 1,3,4- of 154.7g is in batches slow
Add in 600mL ammoniacal liquor, control temperature is reacted 1.5 hours at 0-10 DEG C, and reaction is finished, add 1L frozen water, stirring is lower to be added dropwise sulphur
Acid is neutralized to pH=6-7, filtering, and filter cake respectively with 240mL water recrystallization twice, obtains finished product acetazolamide through washing three times.
After testing：253-256 DEG C of finished product fusing point；Elementary analysis：Theoretical value (C 21.62%, H 2.72%, N
25.21%th, O 21.60%, S 28.86%), measured value (C 21.60%, H 2.77%, N 25.29%, O 21.64%, S
28.88%).
Claims (7)
1. a kind of technique for preparing acetazolamide intermediate, it is characterised in that：Described technique is, with thiosemicarbazides and curing
Carbon is reactant, using the mixture of pyridine and piperidines as solvent, purifies, dries after reaction, obtains 2- amino -5- sulfydryls -1,3,
The intermediate of 4- thiadiazoles, i.e. acetazolamide.
2. the technique as claimed in claim 1 for preparing acetazolamide intermediate, it is characterised in that：Thiosemicarbazides and carbon disulfide
Weight ratio be 1：1.67~2.09.
3. the technique as claimed in claim 1 for preparing acetazolamide intermediate, it is characterised in that：The volume ratio of pyridine and piperidines
For 5~20：1.
4. the technique as claimed in claim 1 for preparing acetazolamide intermediate, it is characterised in that：The temperature of reaction be 80~
130 DEG C, the reaction time is 5 hours.
5. the technique as claimed in claim 1 for preparing acetazolamide intermediate, it is characterised in that：Reacted purification operations
The carbon disulfide of solvent and excess to be distilled off, gained solid is dissolved with diluted alkaline, adding activated carbon decolorizing and filter, filtrate
Middle acid adding separates out solid, and filtering, filter cake is washed three times.
6. the technique as claimed in claim 5 for preparing acetazolamide intermediate, it is characterised in that：Described diluted alkaline is solute matter
Measure the sodium hydrate aqueous solution that fraction is 20%.
7. the technique as claimed in claim 5 for preparing acetazolamide intermediate, it is characterised in that：Described acid is concentrated hydrochloric acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111646954A (en) * | 2020-07-22 | 2020-09-11 | 双鹤药业（商丘）有限责任公司 | Novel acetazolamide crystal form and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85101435A (en) * | 1985-04-01 | 1986-07-09 | 四川省化学工业研究所 | Novel cpd N, N '-methylene-two (2 amino-5 sulfydryl-1,3,4 thiadiazoles) preparation method and contain the control vegetative bacteria of this compound, the disease sterilant |
| CN1040585A (en) * | 1989-09-26 | 1990-03-21 | 四川省化学工业研究所 | 2-amino-5-sulfenyl-1,3, the synthetic method of 4-thiadiazoles |
| CN102702130A (en) * | 2012-03-28 | 2012-10-03 | 南开大学 | Heterocyclic asymmetric aromatic dithioether compound and synthesis method and application thereof |
-
2017
- 2017-05-18 CN CN201710351723.XA patent/CN107129472B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85101435A (en) * | 1985-04-01 | 1986-07-09 | 四川省化学工业研究所 | Novel cpd N, N '-methylene-two (2 amino-5 sulfydryl-1,3,4 thiadiazoles) preparation method and contain the control vegetative bacteria of this compound, the disease sterilant |
| CN1040585A (en) * | 1989-09-26 | 1990-03-21 | 四川省化学工业研究所 | 2-amino-5-sulfenyl-1,3, the synthetic method of 4-thiadiazoles |
| CN102702130A (en) * | 2012-03-28 | 2012-10-03 | 南开大学 | Heterocyclic asymmetric aromatic dithioether compound and synthesis method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111646954A (en) * | 2020-07-22 | 2020-09-11 | 双鹤药业（商丘）有限责任公司 | Novel acetazolamide crystal form and preparation method thereof |
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