CN104447754A - Method for carrying out solvent-out crystallization on allopurinol - Google Patents
Method for carrying out solvent-out crystallization on allopurinol Download PDFInfo
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- CN104447754A CN104447754A CN201410610050.1A CN201410610050A CN104447754A CN 104447754 A CN104447754 A CN 104447754A CN 201410610050 A CN201410610050 A CN 201410610050A CN 104447754 A CN104447754 A CN 104447754A
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- allopurinol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
The invention provides a method for carrying out solvent-out crystallization on allopurinol. The method comprises the following steps: (1) dissolving a crude allopurinol product into a sulfones solvent at the temperature of 98-148 DEG C; (2) adding a solution obtained from the step (1) to an antisolvent for crystallization, and separating to obtain the allopurinol. The finished allopurinol product obtained through the method provided by the invention can achieve the yield as high as 95% or more than 95% and achieve the purity more than 99.88% of the purity achieved through an HPLC normalization method. The method provided by the invention has the advantages of simple process, small occupied equipment size, output increase of equipment with same size, solvent recycling, environmental pollution reduction and suitability for industrialized production.
Description
Technical field
The invention belongs to medicine and chemical technology field, be specifically related to a kind of dilution crystallization method of allopurinol.
Background technology
Allopurinol is also referred to as Zyloric, sieve's Ah purine, Zyloric, Sai Luoli, hydroxyl pyrazolopyrimidine, and English is called Allopurinol, chemistry 1H-pyrazolo [3,4-d] pyrimidine-4-alcohol by name, and chemical structural formula is as follows:
Allopurinol is a kind of xanthine oxidase inhibitor, be applicable to the various diseases that primary or Secondary cases serum uric acid increase, the such as hyperuricemia of gout, acute or chronic leukemia, true polycyth(a)emia, multiple myeloma and other malignant tumour a large amount of caused by necrosis of cell when chemotherapy or radiotherapy, and can prophylactic treatment uric acid salt ephrosis etc., evident in efficacy, side effect is very little, is therefore widely used clinically at present.
The preparation method of allopurinol conventional is at present as follows, not this U.S. etc. the improvement [J] of allopurinol synthetic method. chemical reagent, 2007, the method of 29 (10): 635 ~ 636: add zinc chloride catalyzing and condensing by ethyl cyanoacetate and triethyl orthoformate, generate α-ethoxy methyne ethyl cyanoacetate, add hydrogen chloride gas catalysis with hydrazine hydrate ring, methane amide again and obtain allopurinol crude product, its synthetic route is as follows:
Allopurinol crude product impurity obtained by said synthesis route is more, in actual production technique, therefore also needs to carry out purification further to allopurinol crude product can obtain allopurinol finished product.The purification process of current allopurinol crude product mainly contains three kinds:
1. crystal's method for making
Zhuan Dong. novel water law refines allopurinol Process Exploration [J]. chemical engineering and equipment, the method for 2012,1:35 ~ 38, allopurinol crude product: purified water; Gac is according to weight 1: (80 ~ 120): the proportioning of 0.1, put into tensimeter and can bear 0.1MPa pressure reactor.Under airtight condition, heat, be pressed in 0.01Mpa ~ 0.08Mpa in controlling well, temperature controls under 100 DEG C ~ 108 DEG C conditions, decolour 0.5 hour, then filtered while hot, filtrate cools in a crystallizer, after being cooled to 5 DEG C, leave standstill crystallization 8 hours, then in filtration, drying, obtained allopurinol finished product.The method steam consumption is very large, and pressure operation security risk strengthens, and the equipment of needs is large, and output is little, needs a large amount of water coolants, energy consumption is high, wastewater flow rate is large, is unfavorable for environment protection after decolouring during cooling crystallization.
2. acid-alkali refining method
CN102153560A discloses following methods: alkalized in water by allopurinol and change into sodium salt to increase its solubleness, decolorizing and refining, then acidifying becomes allopurinol again.Although the water consumption of the method is less, operate more loaded down with trivial details, easily form parcel and introduce metal ion, acidifying is incomplete, and sample is easily crossed in acid environment and destroyed crossing alkali, affects product yield, quality.
3. solvent refining process
CN103896944A discloses following methods: by allopurinol crude product thermosol in ethylene glycol, N, in dinethylformamide polar solvent, after adding activated carbon decolorizing, filtered while hot, and with described solvent wash breeze, filtrate cooling crystallization, leach crystallization, washing, drain, drying obtains fine work allopurinol.The method quantity of solvent also reduces, but ethylene glycol, DMF belong to two class organic solvents, ethylene glycol boiling point 197.85 DEG C, " International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use view " (ICHQ3C) residual restriction 620ppm; DMF boiling point 153.0 DEG C, ICHQ3C residual restriction 880ppm.The residual bound requirements of these two kinds of solvents is high, and boiling point is high, and in drying process, organic solvent is not easily dried, and crystallization process causes product organic residue high, affects quality product.
Therefore, in the urgent need to developing the allopurinol crystallization method with practical value made new advances.
Summary of the invention
Technical problem to be solved by this invention is a kind of dilution crystallization method of allopurinol, solve industrial production method ubiquity complex operation, energy consumption be high, production efficiency of equipment is low, wastewater flow rate is large, organic residue is high, product department easily reaches the defects such as medicinal requirements, the allopurinol quality index that present method obtains stably reach 2010 version " Chinese Pharmacopoeia " requirement.
1, the present invention is achieved by the following technical solutions, comprises the following steps:
1) in the temperature of 98 DEG C ~ 148 DEG C by allopurinol dissolving crude product in sulfone kind solvent;
2) by step 1) solution that obtains adds crystallization in solvent resistant, and be separated and obtain allopurinol.
2, method according to claim 1, wherein in step 1) described in sulfone kind solvent be selected from tetramethylene sulfone, dimethyl sulfoxide (DMSO), preferred dimethyl sulfoxide (DMSO).
3, method according to claim 1, wherein in step 2) described in solvent resistant be purified water.
4, method according to claim 1, wherein in step 1) described in the weight of sulfone kind solvent be 4 ~ 10 times of allopurinol crude product weight.
5, method according to claim 3, the weight ratio of allopurinol crude product and purified water is 1: (2 ~ 6).
6, method according to claim 4, wherein when described sulfone kind solvent is tetramethylene sulfone, described allopurinol crude product and the weight ratio of described tetramethylene sulfone are 1: (5 ~ 10).
7, method according to claim 4, wherein when described sulfone kind solvent is dimethyl sulfoxide (DMSO), described allopurinol crude product and the weight 1 of described dimethyl sulfoxide (DMSO): (4 ~ 8).
8, method according to claim 1, wherein in step 2) in, by step 1) solution that obtains adds crystallization in solvent resistant, and solvent resistant feed postition, for add solvent resistant or add solution to solvent resistant in solution, preferably adds solvent resistant in solution.
Advantage of the present invention is as follows:
1, the yield of the allopurinol finished product of purification process gained of the present invention is high, and yield can up to 95%, and purity is good, and purity can higher than more than 99.88%.
2, purification process of the present invention is compared with crystal's method for making, and in purification process of the present invention, same size devices throughput can improve 5 ~ 20 times, substantially increases output, and energy-conservation, consumption reduction, reduce production cost.
3, purification process of the present invention is compared with acid-alkali refining method of the prior art, and purification process technique of the present invention is simple, and simple operation, just can obtain high-quality product.
4, purification process of the present invention is compared with process for purification of the prior art, the crystalline form of product thinner evenly, dissolvent residual seldom, good product quality.
5, the solvent in purification process of the present invention can recycle, and decreases environmental pollution, is suitable for suitability for industrialized production.
Allopurinol crude product is with reference to not this U.S. etc. the improvement [J] of allopurinol synthetic method. and chemical reagent, the method preparation of 2007,29 (10): 635 ~ 636.Requirement can see " Chinese Pharmacopoeia " (2010 editions) second the 351st page for allopurinol finished product indices (as proterties, discriminating, vitriol, related substance, methane amide, weight loss on drying, residue on ignition, heavy metal, content etc.).Sulfone kind solvent is methyl-sulphoxide or tetramethylene sulfone at this patent.Purified water is the water of the hyoscine that tap water obtains through distillation method, ion exchange method, reverse osmosis method or other suitable methods, and not containing any additive, specification of quality can see " Chinese Pharmacopoeia " (2010 editions) second the 411st page.Dilution crystallization refers to solute dissolves in the good solvents such as water or other organic solvents, in xln, then add certain solvent resistant, the solubleness of solute in former solvent is reduced thus rapid crystallization precipitation.Solvent resistant is the solvent low relative to good solubleness to solute.
Further illustrated and explain the dilution crystallization method of allopurinol of the present invention by embodiment, but do not limit the scope of the invention.Wherein temperature is degree Celsius.
Embodiment
Embodiment 1
Tetramethylene sulfone 1000g adds allopurinol crude product 100g, be warming up under stirring 98 DEG C make material dissolution after, obtain solution.In solution, add purified water 200g crystallization, filter cake 30g purified water washing, wash 2 times, drain, 80 DEG C of dryings, obtain white crystalline product 89.2g.
Experimental result: the HPLC normalization method purity of product is 99.92%, and yield is 89.2%; The content that maximum list is mixed is 0.04%, and other quality index all reach 2010 editions " Chinese Pharmacopoeia " requirements.
Embodiment 2
Tetramethylene sulfone 650g adds allopurinol crude product 100g, be warming up under stirring 148 DEG C make material dissolution after, obtain solution.In solution, add purified water 200g crystallization, filter cake 30g purified water washing, wash 2 times, drain, 80 DEG C of dryings, obtain white crystalline product 89.6g.
Experimental result: the HPLC normalization method purity of product is 99.90%, and yield is 89.6%; The content that maximum list is mixed is 0.05%, and other quality index all reach 2010 editions " Chinese Pharmacopoeia " requirements.
Embodiment 3 ~ 6
Based on embodiment 2, by only changing the consumption one of purified water, other conditions constant (with "---", following table represents that this condition is with executing example 2), the result obtained is as following table:
| Sequence | Purified water consumption | Temperature | Yield | Maximum list is mixed | Other quality index |
| 3 | 300g | —— | 91.4％ | 0.052％ | Qualified |
| 4 | 400g | —— | 92.5％ | 0.053％ | Qualified |
| 5 | 500g | —— | 93.8％ | 0.052％ | Qualified |
| 6 | 600g | —— | 92.2％ | 0.051％ | Qualified |
Embodiment 7
Tetramethylene sulfone 650g adds allopurinol crude product 100g, be warming up under stirring 148 DEG C make material dissolution after, obtain solution.In purified water 200g, add crystallization of solution, filter cake 30g purified water washing, wash 2 times, drain, 80 DEG C of dryings, obtain white crystalline product 88.6g.
Experimental result: the HPLC normalization method purity of product is 99.90%, and yield is 88.6%; The content that maximum list is mixed is 0.06%, and other quality index all reach 2010 editions " Chinese Pharmacopoeia " requirements.
Embodiment 8 ~ 11
Based on embodiment 7, by only changing the consumption one of purified water, other conditions constant (with "---", following table represents that this condition is with executing example 7), the result obtained is as following table:
| Sequence | Purified water consumption | Temperature | Yield | Maximum list is mixed | Other quality index |
| 8 | 300g | —— | 88.9％ | 0.074％ | Qualified |
| 9 | 400g | —— | 89.5％ | 0.071％ | Qualified |
| 10 | 500g | —— | 89.8％ | 0.062％ | Qualified |
| 11 | 600g | —— | 88.2％ | 0.058％ | Qualified |
Embodiment 12
Dimethyl sulfoxide (DMSO) 800g adds allopurinol crude product 100g, be warming up under stirring 98 DEG C make material dissolution after, obtain solution.In solution, add purified water 200g crystallization, filter cake 30g purified water washing, wash 2 times, drain, 80 DEG C of dryings, obtain white crystalline product 92.4g.
Experimental result: the HPLC normalization method purity of product is 99.92%, and yield is 92.4%.The content that maximum list is mixed is 0.03%, and other project all meets standards of pharmacopoeia.
Embodiment 13
Dimethyl sulfoxide (DMSO) 600g adds allopurinol crude product 100g, is warming up to 148 DEG C, after making material dissolution, obtains solution under stirring.In solution, add purified water 200g crystallization, filter cake 30g purified water washing, wash 2 times, drain, 80 DEG C of dryings, obtain white crystalline product 92.9g.
Experimental result: the HPLC normalization method purity of product is 99.92%, and yield is 92.9%.The content that maximum list is mixed is 0.03%, and other project all meets standards of pharmacopoeia.
Embodiment 14 ~ 17
Based on embodiment 13, by only changing the consumption one of purified water, other conditions constant (with "---", following table represents that this condition is with executing example 13), the result obtained is as following table:
| Sequence | Purified water consumption | Temperature | Yield | Maximum list is mixed | Other quality index |
| 14 | 300g | —— | 93.4％ | 0.035％ | Qualified |
| 15 | 400g | —— | 94.5％ | 0.038％ | Qualified |
| 16 | 500g | —— | 95.2％ | 0.042％ | Qualified |
| 17 | 600g | —— | 94.6％ | 0.033％ | Qualified |
Embodiment 18
Dimethyl sulfoxide (DMSO) 600g adds allopurinol crude product 100g, is warming up to 148 DEG C under stirring, makes material dissolution obtain solution.In purified water 200g, add crystallization of solution, filter cake 30g purified water washing, wash 2 times, drain, 80 DEG C of dryings, obtain white crystalline product 89.2g.
Experimental result: the HPLC normalization method purity of product is 99.88%, and yield is 89.2%.The content that maximum list is mixed is 0.06%, and other project all meets standards of pharmacopoeia.
Embodiment 19 ~ 22
Based on embodiment 18, by only changing the consumption one of purified water, other conditions constant (with "---", following table represents that this condition is with executing example 18), the result obtained is as following table:
| Sequence | Purified water consumption | Temperature | Yield | Maximum list is mixed | Other quality index |
| 19 | 300g | —— | 90.4％ | 0.042％ | Qualified |
| 20 | 400g | —— | 91.8％ | 0.048％ | Qualified |
| 21 | 500g | —— | 92.2％ | 0.051％ | Qualified |
| 22 | 600g | —— | 91.6％ | 0.043％ | Qualified |
Embodiment 23
Dimethyl sulfoxide (DMSO) 600g adds allopurinol crude product 100g, is warming up to 148 DEG C, after making material dissolution, obtains solution under stirring.In solution, add purified water 200g crystallization, filter cake 30g purified water washing, washs 2 times, drains, 80 DEG C of dryings, obtain off-white color crystallized product 92.8g.
Experimental result: the HPLC normalization method purity of product is 99.89%, and yield is 92.8%.The content that maximum list is mixed is 0.061%, and all other indexs all meet standards of pharmacopoeia.
Detail the present invention above, comprise its preferred embodiment.But it should be understood that and consider content disclosed by the invention, those skilled in the art can change the present invention and/or improve in the scope of described claims, and these improvements and modifications also should be considered as protection scope of the present invention.
Claims (8)
1. a dilution crystallization method for allopurinol, the method comprises the following steps:
1) in the temperature of 98 DEG C ~ 148 DEG C by allopurinol dissolving crude product in sulfone kind solvent;
2) by step 1) solution that obtains adds crystallization in solvent resistant, and be separated and obtain allopurinol.
2. method according to claim 1, wherein in step 1) described in sulfone kind solvent be selected from tetramethylene sulfone, dimethyl sulfoxide (DMSO), preferred dimethyl sulfoxide (DMSO).
3. method according to claim 1, wherein in step 2) described in solvent resistant be purified water.
4. method according to claim 1, wherein in step 1) described in the weight of sulfone kind solvent be 4 ~ 10 times of allopurinol crude product weight.
5. method according to claim 3, the weight ratio of allopurinol crude product and purified water is 1: (2 ~ 6).
6. method according to claim 4, wherein when described sulfone kind solvent is tetramethylene sulfone, described allopurinol crude product and the weight ratio of described tetramethylene sulfone are 1: (5 ~ 10).
7. method according to claim 4, wherein when described sulfone kind solvent is dimethyl sulfoxide (DMSO), described allopurinol crude product and the weight 1 of described dimethyl sulfoxide (DMSO): (4 ~ 8).
8. method according to claim 1, wherein in step 2) in, by step 1) solution that obtains adds crystallization in solvent resistant, and solvent resistant feed postition, for add solvent resistant or add solution to solvent resistant in solution, preferably adds solvent resistant in solution.
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| CN201410610050.1A CN104447754A (en) | 2014-11-04 | 2014-11-04 | Method for carrying out solvent-out crystallization on allopurinol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108195959A (en) * | 2017-12-25 | 2018-06-22 | 南京康舟医药科技有限公司 | Detection method in relation to substance in a kind of Allopurinol content and Allopurinol |
| CN114105994A (en) * | 2021-11-01 | 2022-03-01 | 安徽普利药业有限公司 | Preparation method of allopurinol |
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| HU215597B (en) * | 1994-06-10 | 1999-01-28 | EGIS Gyógyszergyár Rt. | Process for producing 4-hydroxy-1h-pyrazolo[3,4d] pyrimidine of high purity for pharmaceutical use |
| CN102153560A (en) * | 2011-03-07 | 2011-08-17 | 江苏红豆杉药业有限公司 | Rectification method of allopurinol |
| CN102643279A (en) * | 2012-02-09 | 2012-08-22 | 临海市恒源化工有限公司 | Synthesis method of allopurinol |
| CN103896944A (en) * | 2012-12-27 | 2014-07-02 | 北大方正集团有限公司 | Purification method of allopurinol |
-
2014
- 2014-11-04 CN CN201410610050.1A patent/CN104447754A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU215597B (en) * | 1994-06-10 | 1999-01-28 | EGIS Gyógyszergyár Rt. | Process for producing 4-hydroxy-1h-pyrazolo[3,4d] pyrimidine of high purity for pharmaceutical use |
| CN102153560A (en) * | 2011-03-07 | 2011-08-17 | 江苏红豆杉药业有限公司 | Rectification method of allopurinol |
| CN102643279A (en) * | 2012-02-09 | 2012-08-22 | 临海市恒源化工有限公司 | Synthesis method of allopurinol |
| CN103896944A (en) * | 2012-12-27 | 2014-07-02 | 北大方正集团有限公司 | Purification method of allopurinol |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108195959A (en) * | 2017-12-25 | 2018-06-22 | 南京康舟医药科技有限公司 | Detection method in relation to substance in a kind of Allopurinol content and Allopurinol |
| CN114105994A (en) * | 2021-11-01 | 2022-03-01 | 安徽普利药业有限公司 | Preparation method of allopurinol |
| CN114105994B (en) * | 2021-11-01 | 2023-01-03 | 安徽普利药业有限公司 | Preparation method of allopurinol |
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Application publication date: 20150325 |