CN102219787B - Method for synthesizing 4-hydroxy pyrazolo[3,4-d]pyrimidine - Google Patents
Method for synthesizing 4-hydroxy pyrazolo[3,4-d]pyrimidine Download PDFInfo
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- CN102219787B CN102219787B CN2011101275313A CN201110127531A CN102219787B CN 102219787 B CN102219787 B CN 102219787B CN 2011101275313 A CN2011101275313 A CN 2011101275313A CN 201110127531 A CN201110127531 A CN 201110127531A CN 102219787 B CN102219787 B CN 102219787B
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Abstract
The invention discloses a method for synthesizing 4-hydroxy pyrazolo[3,4-d]pyrimidine, which comprises the following step of: cyclizing 3-amino pyrazol-4-formamide hemisulphate and formamide which serve as initial raw materials under the protection of inert gas to obtain a product, namely the 4-hydroxy pyrazolo[3,4-d]pyrimidine. The product is separated out of formamide mother liquor gradually with the reduction of a temperature, and is pulped and washed by purified water to remove inorganic salt and the formamide serving as a solvent which are wrapped or adsorbed in the product so as to obtain a white crystal product. In the method, due to the adoption of a new production process, the conventional product purification process is avoided, energy consumption is reduced, the requirement on production equipment is reduced, and the production cost is reduced. The product synthesized by the method is high in quality and yield, the capacity is enlarged, and the economic and social benefits are better.
Description
Technical field
The present invention relates to chemicals and synthesize the field, specially refer to the method with 3-aminopyrazoles-4-formamide hemisulphate and the synthetic Allopurinol of methane amide.
Background technology
The another name of Allopurinol is in allopurinol or other purine, and it is the main medicine for the treatment of gout, and its synthetic route is as follows:
The existing general temperature of reaction of method of producing Allopurinol does not have the protection of rare gas element at 145 ℃～165 ℃ in reaction process, the products obtained therefrom color is generally darker, and foreign matter content is higher, is difficult to product is made with extra care purifying.Because the solubleness of Allopurinol in water is very little at ambient temperature, carries out purifying to it and need to add a large amount of water.Purifying mode to the crude product Allopurinol in current technology has following two kinds.One adds the water of 120 ~ 200 times of crude product quality, and heats up and add decolorization and impurity removal by active carbon after it is dissolved fully, filters, and removes gac, then product crystallization from mother liquor.Its two, crude product with the dissolving of a large amount of low-concentration alkali liquor, then is added decolorization and impurity removal by active carbon, filter, add hydrochloric acid to separate out solid phase prod in filtrate.
Above two kinds of existing techniques all need to add the gac removal of impurities of decolouring, and more difficult the eliminating fully of gac in the operation of filtering and directly enter product affects quality product.On the other hand, gac meeting adsorption production causes yield on the low side, and cost is higher.More outstanding is, these two kinds of techniques all need to add a large amount of water, and method one also needs these water are heated to boiling, and energy consumption is large especially, and to having relatively high expectations of equipment, the production cycle is long, and particularly production capacity is very low, is difficult to the needs of adaptation scale operation.The development energy saving economy of also advocating with country, the theory of environmental protection and economy are inconsistent.
Summary of the invention
For solving above technical problem, the object of the present invention is to provide a kind of operation sequence to simplify, production capacity is large, the production method of the Allopurinol that yield is higher.
The objective of the invention is to realize as follows:
A, 3-aminopyrazoles-4-formamide hemisulphate and methane amide are added in reactor 1:10 ~ 15 in molar ratio, with inert gas replacement 3 times, and make and keep all the time atmosphere of inert gases in reactor.Under protection of inert gas, after intensification, the constant temperature stirring reaction, reaction mixture is first molten then separates out white solid gradually for clear solution, and reaction is cooled to room temperature with reactant after finishing;
B, stop protection of inert gas, products therefrom in a is placed in 5 ~ 10 ℃ of scopes again, allow fully crystallization from formamide soln of product;
C, filtration, filtrate recovery, gained crystal crude product change crystal crude product in mass ratio in the making beating still over to: purified water is that 1:8 ~ 15 add purified water, making beating washing 0.5 ~ 3 hour;
D, filtration again, filtrate discards, and filter cake washs until elutant pH value 〉=6 namely get white Allopurinol product after oven dry with purified water.
Reaction in above-mentioned steps a was reacted under 120 ~ 135 ℃ 8 ~ 12 hours.
In above-mentioned steps a, whole reaction is to carry out under the protection of rare gas element, and rare gas element is one or more the mixed gas in helium, nitrogen, argon gas.
Purifying to crude product in above-mentioned steps c is at ambient temperature, realizes by adding purified water making beating washing, does not need to carry out extra decolouring and processes.
Advantage of the present invention:
1. the present invention can make reaction carry out at relatively low temperature, and energy consumption reduces, and side reaction is controlled, and the products obtained therefrom color is good, purity is high.
2. the purifying mode of product is greatly simplified, and does not need to add activated carbon decolorizing and removal of impurities, has reduced the postprocessing working procedures of complexity together, has improved product yield, has reduced production cost.
3. the purifying of crude product need not add a large amount of water, and is heated to seethe with excitement recrystallization purifying; Alkali lye dissolving and then the acid adding also having avoided strengthening volume low-concentration are separated out the loaded down with trivial details operation of product, have reduced the requirement to equipment, have especially greatly reduced energy consumption, have saved production cost.Have good economic benefit and social benefit.
Embodiment
Embodiment 1
Add 3-aminopyrazoles-4-formamide hemisulphate 15.0g in three mouthfuls of round-bottomed flasks of 100mL, in methane amide 47g, helium replacement reaction flask, air is 3 times, is warming up to 120 ℃, and stirring reaction is 12 hours under the helium atmosphere.Reaction is down to room temperature after finishing gradually, the product crystallization, then placed 8 hours in 5 ~ 10 ℃ of scopes, filter filtrate methane amide recovery.Solid crude product changes in the there-necked flask of 500mL, adds 230g purified water making beating washing.Wash completely, filter, filter cake washs to elutant pH 〉=6 with purified water, namely gets the Allopurinol product after gained filter cake drying, molar yield 90.9%, purity 99.9%(HPLC), state is white crystalline powder.
Embodiment 2
Add 3-aminopyrazoles-4-formamide hemisulphate 75.0g in three mouthfuls of round-bottomed flasks of 500mL, in methane amide 252g, nitrogen replacement reaction flask, air is 3 times, is warming up to 135 ℃, keeps the nitrogen atmosphere stirring reaction 8 hours.Reaction is down to room temperature after finishing gradually, the product crystallization,, then placed 12 hours in 5 ~ 10 ℃ of scopes, filter filtrate methane amide recovery.Solid crude product changes in the there-necked flask of 2000mL, adds 1050g purified water making beating washing.Wash completely, filter, filter cake washs to elutant pH 〉=6 with purified water, namely gets the Allopurinol product after gained filter cake drying, yield 91.8%, purity 99.8%(HPLC), state is white crystalline powder.
Embodiment 3
Add 3-aminopyrazoles-4-formamide hemisulphate 30kg in the reactor of 200L, in methane amide 109kg, helium replacement reaction flask, air is 3 times, is warming up to 130 ℃ ~ 135 ℃, and stirring reaction is 11 hours under the helium atmosphere.Reaction is down to room temperature after finishing gradually, the product crystallization, then placed 10 hours in 5 ~ 10 ℃ of scopes, filter filtrate methane amide recovery.Solid crude product changes in the making beating still of 1000L, adds 385kg purified water making beating washing.Wash completely, filter, filter cake washs to elutant pH 〉=6 with purified water, namely gets the Allopurinol product after gained filter cake drying, molar yield 91.5%, purity 99.9%(HPLC), state is white crystalline powder.
Claims (3)
1. the synthetic method of an Allopurinol is characterized in that carrying out as follows:
A, 3-aminopyrazoles-4-formamide hemisulphate and methane amide are added in reactor 1:10 ~ 15 in molar ratio, under protection of inert gas, be warmed up to 120 ~ 135 ℃, the constant temperature stirring reaction, reaction mixture is first molten then separates out white solid gradually for clear solution, and reaction is cooled to room temperature with reactant after finishing;
B, stop protection of inert gas, products therefrom in a is placed in 5 ~ 10 ℃ of scopes again, allow fully crystallization from formamide soln of product;
C, filtration, filtrate recovery, gained crystal crude product change crystal crude product in mass ratio in the making beating still over to: purified water is that 1:8 ~ 15 add purified water, making beating washing 0.5 ~ 3 hour;
D, filtration again, filtrate discards, and filter cake washs until elutant pH value 〉=6 namely get white Allopurinol product after oven dry with purified water; In described step a, whole reaction is to carry out under the protection of rare gas element, and rare gas element is a kind of in helium, nitrogen, argon gas.
2. a kind of synthetic method of Allopurinol according to claim 1, it is characterized in that: the reaction in described step a was reacted under 120 ~ 135 ℃ 8 ~ 12 hours.
3. a kind of synthetic method of Allopurinol according to claim 1, it is characterized in that: the purifying to crude product in described step c is at ambient temperature, realizes by adding purified water making beating washing.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101275313A CN102219787B (en) | 2011-05-17 | 2011-05-17 | Method for synthesizing 4-hydroxy pyrazolo[3,4-d]pyrimidine |
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| CN2011101275313A CN102219787B (en) | 2011-05-17 | 2011-05-17 | Method for synthesizing 4-hydroxy pyrazolo[3,4-d]pyrimidine |
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| CN102219787A CN102219787A (en) | 2011-10-19 |
| CN102219787B true CN102219787B (en) | 2013-06-05 |
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| CN105272984B (en) * | 2014-06-23 | 2019-06-14 | 湘北威尔曼制药股份有限公司 | Pyrazolo [3,4-d] pyrimidin-4-one-derivatives, preparation method and application |
| CN104447758B (en) * | 2014-11-19 | 2017-04-05 | 上海泰坦科技股份有限公司 | The synthesis technique of pyrazolo [3,4 d] pyrimidines |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1271034A (en) * | 1969-01-25 | 1972-04-19 | Georg Henning Chem Pharm Werk | METHOD OF PRODUCING 4-HYDROXY-PYRAZOLO(3,4-d)PYRIMIDINE |
| SU363704A1 (en) * | 1971-01-20 | 1972-12-25 | METHOD OF OBTAINING 4-OXIPIRZOLO- [3,4 - ^ / 1-P IRIMIDINE | |
| JPS5253894A (en) * | 1975-10-30 | 1977-04-30 | Ss Pharmaceut Co Ltd | Process for preparing 4-hydroxy-1h-pyrazolo 3,4-d pyrmidine |
| CH654009A5 (en) * | 1983-03-21 | 1986-01-31 | Siegfried Ag | METHOD FOR PRODUCING ALLOPURINOL. |
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Address after: 408302, 138, Wu Wu Road, Xinmin Town, Dianjiang County, Chongqing Applicant after: Chongqing Waycome Pharmaceutical Co., Ltd. Applicant after: Chongqing Hallochem Pharma Co.,Ltd. Address before: 408302, 138, Wu Wu Road, Xinmin Town, Dianjiang County, Chongqing Applicant before: Chongqing Waycome Pharmaceutical Co., Ltd. Applicant before: Chongqing Hallochem Pharma Co., Ltd. |
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