CN107129472B - A kind of technique preparing acetazolamide intermediate - Google Patents
A kind of technique preparing acetazolamide intermediate Download PDFInfo
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- CN107129472B CN107129472B CN201710351723.XA CN201710351723A CN107129472B CN 107129472 B CN107129472 B CN 107129472B CN 201710351723 A CN201710351723 A CN 201710351723A CN 107129472 B CN107129472 B CN 107129472B
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- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960000571 acetazolamide Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 36
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 150000003053 piperidines Chemical class 0.000 claims abstract description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 150000003583 thiosemicarbazides Chemical class 0.000 claims abstract description 12
- GDGIVSREGUOIJZ-UHFFFAOYSA-N 5-amino-3h-1,3,4-thiadiazole-2-thione Chemical class NC1=NN=C(S)S1 GDGIVSREGUOIJZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 3
- 239000000376 reactant Substances 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 239000012065 filter cake Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 5
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 2
- 238000011403 purification operation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 21
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 229910052717 sulfur Inorganic materials 0.000 description 16
- 239000000243 solution Substances 0.000 description 14
- 238000000921 elemental analysis Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 230000006837 decompression Effects 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 150000004869 1,3,4-thiadiazoles Chemical class 0.000 description 3
- HRFBRMUMYWGLEQ-UHFFFAOYSA-N 2-(2-phenylethenyl)benzene-1,4-diamine Chemical compound NC1=CC=C(N)C(C=CC=2C=CC=CC=2)=C1 HRFBRMUMYWGLEQ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000012797 qualification Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LXJOYRVJPWDJBZ-UHFFFAOYSA-N (2-acetamido-3-hydroxyphenyl)arsonic acid Chemical compound OC=1C(=C(C=CC1)[As](O)(O)=O)NC(C)=O LXJOYRVJPWDJBZ-UHFFFAOYSA-N 0.000 description 2
- -1 2- acetylaminohydroxyphenylarsonic acid 5- sulphonyl chloro- 1,3,4- thiadiazoles Chemical class 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000004176 ammonification Methods 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- UHOKROAAKKMQQX-UHFFFAOYSA-N 2-chloro-1,3,4-thiadiazole Chemical class ClC1=NN=CS1 UHOKROAAKKMQQX-UHFFFAOYSA-N 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention belongs to medical synthesis fields, in particular 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, it purifies, dry after reaction, obtain 2- amino -5- sulfydryl -1,3,4- thiadiazoles, the i.e. intermediate of acetazolamide.
Description
Technical field
The invention belongs to medical synthesis field, in particular to a kind of technique for preparing acetazolamide intermediate.
Background technique
Acetazolamide is a kind of novel non-mercurial diuretic, and mechanism of action is by inhibiting carbonate dehydratase to play benefit
Urine effect, rear to have clinical report again, which also has the illnesss such as oedema caused by Cardiac Insufficiency, glaucoma, epilepsy
Good therapeutic effect.
Acetazolamide is synthesized in nineteen fifty by Miller et al. for the first time, synthetic method are as follows:
2- amino -5- sulfydryl -1,3,4- thiadiazoles are the key intermediates for synthesizing acetazolamide, are had been reported that at present almost
The preparation process of all acetazolamide is obtained by three acetylation of the intermediate, chlorination and ammonification processes.
However, in the technology path of existing report, generally existing product yield low problem is even more to reach in actual production
Less than yield value reported in the literature.The main reason for causing actual recovery not high is cyclised products intermediate 2-amino -5- sulfydryl -
There are 2,5- diaminostilbene in 1,3,4- thiadiazoles, 3,4- thiadiazoles impurity, and since both cyclised products are in main structure
Upper height is similar, there is the case 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 subsequent acetazolamide product qualification rate be made to reduce.
Summary of the invention
To overcome above-mentioned shortcomings and deficiencies existing in the prior art, it is intended to guarantee key intermediate 2- amino -5- sulfydryl -
The good yield of 1,3,4- thiadiazoles and purity, and then the product qualification rate of acetazolamide is improved, the present invention provides a kind of systems
The technique of standby acetazolamide intermediate:
Using thiosemicarbazides and carbon disulfide as reactant, using the mixture of pyridine and piperidines as solvent, purifies, dries after reaction
It is dry, obtain 2- amino -5- sulfydryl -1,3,4- thiadiazoles, the i.e. intermediate of 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,
Purification operations after reaction are solvent to be distilled off and excessive carbon disulfide, obtained solid are dissolved with diluted alkaline, are added
Entering active carbon decoloring and filters, solid, filtering is precipitated in acid adding in filtrate, and 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: type of solvent and control related process parameters by changing, effectively inhibit with
2,5- diaminostilbenes, the appearance of the by-product based on 3,4- thiadiazoles, but target product 2- amino -5- sulfydryl-is not interfered
The generation of 1,3,4- thiadiazoles, so that 2- amino -5- sulfydryl -1,3 is significantly improved, the yield and purity of 4- thiadiazoles, then according to
Secondary to obtain acetazolamide, this method strong operability through acetylation, chlorination and aminating reaction, technical maturity can be solved effectively
The problem of certainly acetazolamide product qualification rate is low, unstable quality.
By 2- amino -5- sulfydryl -1,3 prepared by the present invention, 4- thiadiazoles is anti-through acetylation, chlorination and ammonification three
Finished product acetazolamide is obtained after answering step:
Glacial acetic acid and acetic anhydride are added in 2- amino -5- sulfydryl -1,3,4- thiadiazoles to be reacted, after reaction plus
Ice water is passed through in system with chlorine, is led to and is finished filtering, and filter cake is washed, and obtains 2- acetylaminohydroxyphenylarsonic acid 5- sulphonyl chloro- 1,3,4- thiadiazoles；
By 2- acetylaminohydroxyphenylarsonic acid 5- sulphonyl chloro- 1,3,4- thiadiazoles are added in ammonium hydroxide, insulation reaction, and reaction is finished plus ice water,
To recrystallize twice with system, filtering, filter cake through washing and with water in sulfuric acid, finished product acetazolamide is obtained.
Specific embodiment
Embodiment 1
1.5L pyridine, 300mL piperidines, 100g thiosemicarbazides and 132.6mL curing are sequentially added in the there-necked flask of 3L
Carbon, stirring are heated to 80 DEG C of temperature in bottle and react 5 hours, after reaction, solvent and excessive carbon disulfide be distilled off,
350mL sodium hydroxide solution (Solute mass fraction 20%) dissolution is added in obtained solid, and it is de- that 2.9g active carbon is added at 60 DEG C
Color 0.5 hour, decoloration was finished, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fraction is added in gained filtrate
Solid is precipitated, and stirring is filtered after 0.5 hour, and filter cake is washed three times, decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercapto
Base -1,3,4- thiadiazoles 110g, purity 99.7%.
Through detecting: 231-231.5 DEG C of product fusing point；Elemental analysis: theoretical value (C 18.03%, H 2.27%, N
31.55%, S 48.15%), measured value (C 18.07%, H 2.21%, N 31.59%, S 48.12%).
Comparative example 1
Solvent " 1.5L pyridine, 300mL piperidines " is replaced with into " 1.8L pyridine ", remaining operation is the same as embodiment 1.
Prepare resulting 2- amino -5- sulfydryl -1,3, the purity of 4- thiadiazoles only 84.2%.
Embodiment 2
1.5L pyridine, 300mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in the there-necked flask of 3L
Carbon, stirring are heated to 80 DEG C of temperature in bottle and react 5 hours, after reaction, solvent and excessive carbon disulfide be distilled off,
350mL sodium hydroxide solution (Solute mass fraction 20%) dissolution is added in obtained solid, and it is de- that 2.9g active carbon is added at 60 DEG C
Color 0.5 hour, decoloration was finished, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fraction is added in gained filtrate
Solid is precipitated, and stirring is filtered after 0.5 hour, and filter cake is washed three times, decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercapto
Base -1,3,4- thiadiazoles 118.2g, purity 99.6%.
Through detecting: 230-231 DEG C of product fusing point；Elemental analysis: theoretical value (C 18.03%, H 2.27%, N
31.55%, S 48.15%), measured value (C 18.03%, H 2.29%, N 31.55%, S 48.10%).
Comparative example 2
Solvent " 1.5L pyridine, 300mL piperidines " is replaced with into " 0.9L pyridine, 0.9L piperidines ", remaining operation is the same as implementation
Example 2.
Prepare resulting 2- amino -5- sulfydryl -1,3, the purity of 4- thiadiazoles only 85.3%.
Embodiment 3
1.5L pyridine, 300mL piperidines, 100g thiosemicarbazides and 165.8mL curing are sequentially added in the there-necked flask of 3L
Carbon, stirring are heated to 80 DEG C of temperature in bottle and react 5 hours, after reaction, solvent and excessive carbon disulfide be distilled off,
350mL sodium hydroxide solution (Solute mass fraction 20%) dissolution is added in obtained solid, and it is de- that 2.9g active carbon is added at 60 DEG C
Color 0.5 hour, decoloration was finished, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fraction is added in gained filtrate
Solid is precipitated, and stirring is filtered after 0.5 hour, and filter cake is washed three times, decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercapto
Base -1,3,4- thiadiazoles 117.1g, purity 99.7%.
Through detecting: 231-231.5 DEG C of product fusing point；Elemental analysis: theoretical value (C 18.03%, H 2.27%, N
31.55%, S 48.15%), measured value (C 18.01%, H 2.23%, N 31.55%, S 48.18%).
Comparative example 3
Solvent " 1.5L pyridine, 300mL piperidines " is replaced with into " 1.8L piperidines ", remaining operation is the same as embodiment 2.
Prepare resulting 2- amino -5- sulfydryl -1,3, the purity of 4- thiadiazoles only 83.6%.
Embodiment 4
1.5L pyridine, 300mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in the there-necked flask of 3L
Carbon, stirring are heated to 115 DEG C of temperature in bottle and react 5 hours, after reaction, solvent and excessive carbon disulfide be distilled off,
350mL sodium hydroxide solution (Solute mass fraction 20%) dissolution is added in obtained solid, and it is de- that 2.9g active carbon is added at 60 DEG C
Color 0.5 hour, decoloration was finished, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fraction is added in gained filtrate
Solid is precipitated, and stirring is filtered after 0.5 hour, and filter cake is washed three times, decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercapto
Base -1,3,4- thiadiazoles 126.1g, purity 99.7%.
Through detecting: 231.5-232 DEG C of product fusing point；Elemental analysis: theoretical value (C 18.03%, H 2.27%, N
31.55%, S 48.15%), measured value (C 18.09%, H 2.23%, N 31.56%, S 48.12%).
Comparative example 4
Solvent " 1.5L pyridine, 300mL piperidines " is replaced with into " 1.8L dimethylformamide ", remaining operates same embodiment
2。
Prepare resulting 2- amino -5- sulfydryl -1,3, the purity of 4- thiadiazoles only 84.5%.
Embodiment 5
1.5L pyridine, 300mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in the there-necked flask of 3L
Carbon, stirring are heated to 130 DEG C of temperature in bottle and react 5 hours, after reaction, solvent and excessive carbon disulfide be distilled off,
350mL sodium hydroxide solution (Solute mass fraction 20%) dissolution is added in obtained solid, and it is de- that 2.9g active carbon is added at 60 DEG C
Color 0.5 hour, decoloration was finished, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fraction is added in gained filtrate
Solid is precipitated, and stirring is filtered after 0.5 hour, and filter cake is washed three times, decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercapto
Base -1,3,4- thiadiazoles 125.7g, purity 99.5%.
Through detecting: 231-232 DEG C of product fusing point；Elemental analysis: theoretical value (C 18.03%, H 2.27%, N
31.55%, S 48.15%), measured value (C 18.01%, H 2.25%, N 31.58%, S 48.17%).
Embodiment 6
1.64L pyridine, 164mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in the there-necked flask of 3L
Carbon, stirring are heated to 115 DEG C of temperature in bottle and react 5 hours, after reaction, solvent and excessive carbon disulfide be distilled off,
350mL sodium hydroxide solution (Solute mass fraction 20%) dissolution is added in obtained solid, and it is de- that 2.9g active carbon is added at 60 DEG C
Color 0.5 hour, decoloration was finished, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fraction is added in gained filtrate
Solid is precipitated, and stirring is filtered after 0.5 hour, and filter cake is washed three times, decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercapto
Base -1,3,4- thiadiazoles 130.7g, purity 99.6%.
Through detecting: 232-232.5 DEG C of product fusing point；Elemental analysis: theoretical value (C 18.03%, H 2.27%, N
31.55%, S 48.15%), measured value (C 18.03%, H 2.26%, N 31.57%, S 48.18%).
Embodiment 7
1.71L pyridine, 90mL piperidines, 100g thiosemicarbazides and 149.2mL curing are sequentially added in the there-necked flask of 3L
Carbon, stirring are heated to 115 DEG C of temperature in bottle and react 5 hours, after reaction, solvent and excessive carbon disulfide be distilled off,
350mL sodium hydroxide solution (Solute mass fraction 20%) dissolution is added in obtained solid, and it is de- that 2.9g active carbon is added at 60 DEG C
Color 0.5 hour, decoloration was finished, filtering, and it is a large amount of to have after 37% hydrochloric acid solution that 135mL Solute mass fraction is added in gained filtrate
Solid is precipitated, and stirring is filtered after 0.5 hour, and filter cake is washed three times, decompression drying 4 hours at 60 DEG C, obtains 2- amino -5- mercapto
Base -1,3,4- thiadiazoles 123.5g, purity 99.7%.
Through detecting: 231-232 DEG C of product fusing point；Elemental analysis: theoretical value (C 18.03%, H 2.27%, N
31.55%, S 48.15%), measured value (C 18.02%, H 2.26%, N 31.53%, S 48.17%).
2- amino -5- sulfydryl -1,3 obtained in 500mL glacial acetic acid, 80g the present embodiment is sequentially added in 3L there-necked flask,
4- thiadiazoles and 76.4mL acetic anhydride, stirring, are heated to back flow reaction 2 hours, are cooled to temperature < 30 DEG C in bottle, and 1L ice is added
Water controls temperature in bottle and after continuing stirring 2 hours, chlorine is slowly passed through in system at 0-5 DEG C, until system gas saturation is (about
2.5 hours), terminate ventilation, filtering, filter cake is washed three times, and chloro- 1,3,4- thiadiazoles wet product of 2- acetylaminohydroxyphenylarsonic acid 5- sulphonyl is obtained
154.7g directly carries out next step reaction without purifying；
It is in 3L there-necked flask, above-mentioned chloro- 1,3, the 4- thiadiazoles wet product of 2- acetylaminohydroxyphenylarsonic acid 5- sulphonyl of 154.7g is in batches slow
It is added in 600mL ammonium hydroxide, control temperature is reacted 1.5 hours at 0-10 DEG C, is reacted and is finished, and 1L ice water is added, and stirs lower dropwise addition sulphur
Acid is neutralized to pH=6-7, and filtering, filter cake is washed three times, respectively twice with 240mL water recrystallization, obtains finished product acetazolamide.
Through detecting: 253-256 DEG C of finished product fusing point；Elemental analysis: theoretical value (C 21.62%, H 2.72%, N
25.21%, O 21.60%, S 28.86%), measured value (C 21.60%, H 2.77%, N 25.29%, O 21.64%, S
28.88%).
Claims (5)
1. a kind of technique for preparing acetazolamide intermediate, it is characterised in that: the technique is, with thiosemicarbazides and curing
Carbon is reactant, using the mixture of pyridine and piperidines as solvent, purifies, dries after reaction, obtain 2- amino -5- sulfydryl -1,3,
4- thiadiazoles, the i.e. intermediate of acetazolamide；The volume ratio of the pyridine and piperidines is 5~20:1.
2. the technique for preparing acetazolamide intermediate as described in claim 1, it is characterised in that: thiosemicarbazides and carbon disulfide
Weight ratio be 1:1.67~2.09.
3. as described in claim 1 prepare acetazolamide intermediate technique, it is characterised in that: the temperature of reaction be 80~
130 DEG C, the reaction time is 5 hours.
4. the technique for preparing acetazolamide intermediate as described in claim 1, it is characterised in that: the purification operations after reaction
For solvent is distilled off and excessive carbon disulfide, obtained solid are dissolved with diluted alkaline, active carbon decoloring is added and filters, filtrate
Solid, filtering is precipitated in middle acid adding, and filter cake is washed three times；The diluted alkaline is that the sodium hydroxide that Solute mass fraction is 20% is water-soluble
Liquid.
5. the technique for preparing acetazolamide intermediate as claimed in claim 4, it is characterised in that: the acid is concentrated hydrochloric acid.
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|---|---|---|---|---|
| CN1003589B (en) * | 1985-04-01 | 1989-03-15 | 四川省化学工业研究所 | Composition containing N, N' -methylene-bis (2-amino-5-mercapto-1, 3, 4-thiadiazole) active component, and preparation method and application thereof |
| CN1022242C (en) * | 1989-09-26 | 1993-09-29 | 四川省化学工业研究所 | Method of synthesizing 2-amino-5-sulfo-1,3,4-thiadiazole |
| CN102702130B (en) * | 2012-03-28 | 2014-08-06 | 南开大学 | Heterocyclic asymmetric aromatic dithioether compound and synthesis method and application thereof |
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