CN107759570B - A kind of refining methd of his tosilate of department, Top - Google Patents
A kind of refining methd of his tosilate of department, Top Download PDFInfo
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- CN107759570B CN107759570B CN201610688760.5A CN201610688760A CN107759570B CN 107759570 B CN107759570 B CN 107759570B CN 201610688760 A CN201610688760 A CN 201610688760A CN 107759570 B CN107759570 B CN 107759570B
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- tosilate
- acetonitrile
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
It is the in the mixed solvent that his tosilate crude product of department, Top is added to acetonitrile and water the invention discloses a kind of refining methd of his tosilate of department, Top, heating, stirring and dissolving stands crystallization later, filtering, it is dried under reduced pressure to get his tosilate highly finished product of department, Top；Wherein, the mass volume ratio of his tosilate crude product, acetonitrile and water of department, Top is 1g:1~2mL:5~6mL.The present invention can not only completely remove the lesser impurity of polarity after main peak, and can remove the other impurities in product well, significantly improve the liquid phase purity and active constituent content of product, and highly finished product purity is made to reach 99.8% or more, single miscellaneous respectively less than 0.1%.
Description
Technical field
The present invention relates to a kind of refining methds, and in particular to a kind of refining methd of his tosilate of department, Top.Belong to
In pharmaceutical technology field.
Background technique
Department, Top he, chemical name: 5- (2- cyano -4- pyridyl group) -3- (4- pyridyl group) -1,2,4- triazoles are Japanese strains
A kind of inhibition xanthine oxidase of Fuji, formula commercial firm drug company exploitation, for treating gout, hyperuricemia.
Preparation his key step of department, Top is as follows at present:
Wherein, formula IV is his tosilate of department, Top, is sloughed after tosilate up to V finished product support of formula
Pu Sita.It has been found that the department, Top being prepared he, have more small impurity behind main peak, these impurity derive from formula IV,
Therefore, the quality of his tosilate of department, Top directly influences his quality of department, final product Top, department, Top he to toluene
The purification of sulfonate also just becomes a very important link in entire preparation process.
Patent application CN1826335A discloses the manufacturing method of 1,2,4- triazole compounds and its manufacturer of intermediate
Method, Examples 1 to 3 therein are his preparation process of department, Top shown in formula V.It is disclosed that IV support of formula is prepared
Pu Sita tosilate crude product, is beaten 1 hour under the conditions of 80 DEG C of in the mixed solvent of 2- fourth alcohol and water later, then alkali
Wash under environment and remove tosilate, obtain V department, Top of finished product formula he.The department, Top obtained after purification in the method
It is found after liquid phase detects, small impurity is difficult to remove after main peak, and applicant has attempted to continue to be prepared into tosilate, then weighs
The mode of desalination is gone to be refined again, impurity is without being substantially reduced.
Applicant attempted the purification that various solvent combinations carry out his tosilate of department, Top, in patent application
On the basis of CN1826335A, the volume ratio of 2- butanol and water is directly adjusted, or 2- butanol is changed to methanol, ethyl alcohol or different
The volume ratio of propyl alcohol, alcohol and water is adjusted to 10:1,8:1,6:1,4:1,2:1,1:1,1:2,1:4,1:6,1:8 or 1:10, it
Liquid phase detection is carried out afterwards, cannot remove small impurity after main peak.
Applicant is changed to acetone on this basis, by alcohols solvent, combines it with water, volume ratio 10:1,8:1,6:
1,4:1,2:1,1:1,1:2,1:4,1:6,1:8 or 1:10 carry out liquid phase detection after purification, can not remove small miscellaneous after main peak
Matter.
Summary of the invention
The purpose of the present invention is to overcome above-mentioned the deficiencies in the prior art, provide a kind of his tosilate of department, Top
Refining methd.
To achieve the above object, the present invention adopts the following technical solutions:
A kind of refining methd of his tosilate of department, Top, is that his tosilate crude product is added to by department, Top
The in the mixed solvent of acetonitrile and water, heating, stirring and dissolving stands crystallization later, filters, and is dried under reduced pressure that he is right to get department, Top
Toluene fulfonate highly finished product；Wherein, the mass volume ratio of his tosilate crude product, acetonitrile and water of department, Top be 1g:1~
2mL:5~6mL.
Preferably, heating temperature is 80~85 DEG C.
Preferably, the time for standing crystallization is 4~5 hours.
Preferably, it is dried under reduced pressure and is carried out under the conditions of 45~50 DEG C.
Beneficial effects of the present invention:
The mixed solvent that the present invention is formed using acetonitrile and water, to department, Top, his tosilate crude product is tied again
Crystalline substance can not only completely remove the lesser impurity of polarity after main peak, and can remove the other impurities in product well, significantly mention
The high liquid phase purity and active constituent content of product makes highly finished product purity reach 99.8% or more, single miscellaneous to be respectively less than 0.1%.
Although the present invention has used two class solvent acetonitriles, its residual quantity well below ICH guideline basic standard,
Meet Drug safety requirement.
Refining methd of the invention, without enlarge-effect, remains to the department, Top that higher yields obtain high-purity after amplification production
His tosilate highly finished product are suitable for industrialized production.
Specific embodiment
Below with reference to embodiment, the present invention will be further elaborated, it should explanation, following the description merely to
It explains the present invention, its content is not defined.
This application involves to his tosilate crude product of department, Top according to the side in patent application CN 1826335A
Method is prepared.
Embodiment 1:
By department, 100g Top, his tosilate crude product is added in 100mL acetonitrile and 500mL water, is heated to 80 DEG C of stirrings
After dissolution, crystallization 4 hours are stood, filtering, 45 DEG C are dried under reduced pressure to constant weight, obtain his tosilate highly finished product of department, Top
83g, yield: 83%, purity: 99.8%, single miscellaneous less than 0.1%, acetonitrile vapor detection 0.001% is limited far below two class solvents
Degree requires.
Embodiment 2:
By department, 200g Top, his tosilate crude product is added in 300mL acetonitrile and 1100mL water, is heated to 83 DEG C and is stirred
After mixing dissolution, crystallization 4.5 hours are stood, filtering, 47 DEG C are dried under reduced pressure to constant weight, obtain his p-methyl benzenesulfonic acid salt refining of department, Top
Product 167.4g, yield: 83.7%, purity: 99.8%, single miscellaneous less than 0.1%, acetonitrile vapor detection 0.001% is far below two classes
Solvent bound requirements.
Embodiment 3:
By department, 300g Top, his tosilate crude product is added in 300mL acetonitrile and 1800mL water, is heated to 83 DEG C and is stirred
After mixing dissolution, crystallization 4 hours are stood, filtering, 47 DEG C are dried under reduced pressure to constant weight, obtain his tosilate highly finished product of department, Top
252g, yield: 84.0%, purity: 99.8%, single miscellaneous less than 0.1%, acetonitrile vapor detection 0.001% is far below two class solvents
Bound requirements.
Embodiment 4:
By department, 400g Top, his tosilate crude product is added in 800mL acetonitrile and 2000mL water, is heated to 85 DEG C and is stirred
After mixing dissolution, crystallization 5 hours are stood, filtering, 50 DEG C are dried under reduced pressure to constant weight, obtain his tosilate highly finished product of department, Top
338.4g, yield: 84.6%, purity: 99.8%, single miscellaneous less than 0.1%, acetonitrile vapor detection 0.001% is molten far below two classes
Agent bound requirements.
Embodiment 5:
By department, 500g Top, his tosilate crude product is added in 1000mL acetonitrile and 3000mL water, is heated to 85 DEG C and is stirred
After mixing dissolution, crystallization 5 hours are stood, filtering, 50 DEG C are dried under reduced pressure to constant weight, obtain his tosilate highly finished product of department, Top
425g, yield: 85%, purity: 99.8%, single miscellaneous less than 0.1%, acetonitrile vapor detection 0.001% is limited far below two class solvents
Degree requires.
Embodiment 6:
By department, 2.5kg Top, his tosilate crude product is added in 5L acetonitrile and 15L water, is heated to 85 DEG C of stirring and dissolvings
Afterwards, crystallization 5 hours are stood, filtering, 50 DEG C are dried under reduced pressure to constant weight, obtain his tosilate highly finished product of department, Top
2.15kg, yield: 86%, purity: 99.8%, single miscellaneous less than 0.1%, acetonitrile vapor detection 0.001% is far below two class solvents
Bound requirements.
Embodiment 7:
By department, 10kg Top, his tosilate crude product is added in 20L acetonitrile and 80L water, is heated to 85 DEG C of stirring and dissolvings
Afterwards, crystallization 5 hours are stood, filtering, 50 DEG C are dried under reduced pressure to constant weight, obtain his tosilate highly finished product of department, Top
8.65kg, yield: 86.5%, purity: 99.8%, single miscellaneous less than 0.1%, acetonitrile vapor detection 0.001% is molten far below two classes
Agent bound requirements.
Comparative example 1:
It is suspended in 2- butanol 49ml and water 491ml mixed liquor by his tosilate crude product of department, 90g Top, inside
It heats 1 hour, interior temperature is restored to room temperature, leaching crystallization is washed with 2- butanol-water (volume ratio 1:10) mixed liquor at 80 DEG C of temperature
It washs and is crystallized, is dried under reduced pressure at 60 DEG C 15 hours, obtain his tosilate highly finished product 75.7g of department, Top, yield:
84.1%, purity: 99.4%, latter two list of main peak is miscellaneous still above 0.1%.
Comparative example 2:
By department, 500g Top, his tosilate crude product is added in 1000mL acetonitrile and 1000mL water, is heated to 85 DEG C and is stirred
After mixing dissolution, crystallization 5 hours are stood, filtering, 50 DEG C are dried under reduced pressure to constant weight, obtain his tosilate highly finished product of department, Top
400g, yield: 80%, purity: 99.3%, latter two list of main peak is miscellaneous still above 0.1%.
Comparative example 3:
By department, 500g Top, his tosilate crude product is added in 2L acetonitrile and 2.5L water, is heated to 85 DEG C of stirring and dissolvings
Afterwards, crystallization 5 hours being stood, filtering, 50 DEG C are dried under reduced pressure to constant weight, his tosilate highly finished product 410g of department, Top is obtained,
Yield: 82%, purity: 99.1%, latter two list of main peak is miscellaneous still above 0.1%.
Comparative example 4:
By department, 500g Top, his tosilate crude product is added in 1000mL acetonitrile and 7000mL water, is heated to 85 DEG C and is stirred
After mixing dissolution, crystallization 5 hours are stood, filtering, 50 DEG C are dried under reduced pressure to constant weight, obtain his tosilate highly finished product of department, Top
370g, yield: 74%, purity: 99.1%, latter two list of main peak is miscellaneous still above 0.1%.
Comparative example 5:
By department, 500g Top, his tosilate crude product is added in 1.5L acetonitrile and 1L water, is heated to 85 DEG C of stirring and dissolvings
Afterwards, crystallization 5 hours being stood, filtering, 50 DEG C are dried under reduced pressure to constant weight, his tosilate highly finished product 420g of department, Top is obtained,
Yield: 84%, purity: 99.0%, latter two list of main peak is miscellaneous still above 0.1%.
By comparative example 1~5, it is apparent that the department, Top obtained according to patent application CN 1826335A method he is right
Toluene fulfonate highly finished product, purity is lower, there are two ratio that is singly miscellaneous more than 0.1%, and replacing acetonitrile and water, obtained purification
Product purity and list are miscellaneous also unqualified.And use his p-methyl benzenesulfonic acid salt refining of the department, Top that is refining to obtain of method of Examples 1 to 7
Product purity is high, impurity are few.
Above-mentioned, although specific embodiments of the present invention have been described, not to the limit of the scope of the present invention
System, based on the technical solutions of the present invention, those skilled in the art do not need to make the creative labor can make it is each
Kind modification or deformation are still within protection scope of the present invention.
Claims (3)
1. a kind of refining methd of his tosilate of department, Top, which is characterized in that be by his tosilate of department, Top
Crude product is added to the in the mixed solvent of acetonitrile and water, and heating, stirring and dissolving stands crystallization later, filters, be dried under reduced pressure to get
His tosilate highly finished product of department, Top；Wherein, the mass volume ratio of his tosilate crude product of department, Top, acetonitrile and water
For 1g:1~2mL:5~6mL；Heating temperature is 80~85 DEG C.
2. refining methd according to claim 1, which is characterized in that the time for standing crystallization is 4~5 hours.
3. refining methd according to claim 1, which is characterized in that be dried under reduced pressure and carried out under the conditions of 45~50 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610688760.5A CN107759570B (en) | 2016-08-18 | 2016-08-18 | A kind of refining methd of his tosilate of department, Top |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610688760.5A CN107759570B (en) | 2016-08-18 | 2016-08-18 | A kind of refining methd of his tosilate of department, Top |
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| Publication Number | Publication Date |
|---|---|
| CN107759570A CN107759570A (en) | 2018-03-06 |
| CN107759570B true CN107759570B (en) | 2019-09-03 |
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| CN201610688760.5A Active CN107759570B (en) | 2016-08-18 | 2016-08-18 | A kind of refining methd of his tosilate of department, Top |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1826335A (en) * | 2003-07-24 | 2006-08-30 | 株式会社富士药品 | Process for producing 1,2,4-triazole compound and intermediate therefor |
| CN104411700A (en) * | 2012-07-25 | 2015-03-11 | 株式会社富士药品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
| CN105777655A (en) * | 2014-12-25 | 2016-07-20 | 深圳海王药业有限公司 | Alpha crystal form of butenamide p-toluenesulfonate, preparation method and pharmaceutical composition containing the same |
-
2016
- 2016-08-18 CN CN201610688760.5A patent/CN107759570B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1826335A (en) * | 2003-07-24 | 2006-08-30 | 株式会社富士药品 | Process for producing 1,2,4-triazole compound and intermediate therefor |
| CN104411700A (en) * | 2012-07-25 | 2015-03-11 | 株式会社富士药品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
| CN105777655A (en) * | 2014-12-25 | 2016-07-20 | 深圳海王药业有限公司 | Alpha crystal form of butenamide p-toluenesulfonate, preparation method and pharmaceutical composition containing the same |
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| Publication number | Publication date |
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| CN107759570A (en) | 2018-03-06 |
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Effective date of registration: 20230911 Address after: The first, second, and fourth floors of the quality inspection building at 2350 Kaifeng Road, Jinan City, Shandong Province, 250101 Patentee after: Shandong Chengchuang Blue Sea Pharmaceutical Technology Co.,Ltd. Address before: No. 2350 Kaifeng Road, High tech Zone, Jinan City, Shandong Province, 250101 (Room 101, Chengchuang) Patentee before: SHANDONG CHENGCHUANG PHARMACEUTICAL R&D Co.,Ltd. |