CN104387394A - Preparation method of allopurinol - Google Patents
Preparation method of allopurinol Download PDFInfo
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- CN104387394A CN104387394A CN201410689405.0A CN201410689405A CN104387394A CN 104387394 A CN104387394 A CN 104387394A CN 201410689405 A CN201410689405 A CN 201410689405A CN 104387394 A CN104387394 A CN 104387394A
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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 discloses a preparation method of allopurinol. The preparation method comprises the following steps of carrying out condensation reaction on cyanoacetamide as a raw material, triethyl orthoformate and morpholine to obtain a condensation product, adding hydrazine hydrate to obtain an intermediate 3-amino-4-pyrazolecarboxamide hemisulfate, and finally preparing allopurinol in formamide. The allopurinol prepared by the preparation method, which is disclosed by the invention, has good quality and yield up to 65%; the preparation method is simple and low in energy consumption and cost.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical raw material, specifically a kind of preparation method of allopurinol.
Background technology
Allopurinol, another name Zyloric
, itsm.P. 350 DEG C; Water-soluble 0.35g/L (25 DEG C); Content:>=99%; Quality index: EP97/BP2001/USP25.Allopurinol and meta-bolites thereof, can suppress XOD, and then make uric acid synthesize minimizing, reduces uric acid concentration in blood, reduces urate at bone, the calmness of joint and kidney.This product can suppress liver drug enzyme active.Oral by gastrointestinal absorption, through hepatic metabolism, about have 70% metabolism to be activated alloxanthine (t1/212 ~ 30 hour), allopurinol t1/2 is 1 ~ 3 hour.Clinical in gout, gouty nephropathy.
The preparation of existing allopurinol is adopted in two ways, one take ethyl cyanoacetate as starting raw material, and triethyl orthoformate condensation in aceticanhydride obtains, and adds hydrazine hydrate cyclization and generate 3-amino-4-pyrazole carboxylic acid ethyl ester, finally obtained allopurinol in methane amide, total recovery 41%; Another kind of is starting raw material with propane dinitrile, and triethyl orthoformate obtains in aceticanhydride condensation, adds hydrazine hydrate and obtains 3-amino-4-itrile group pyrazoles, the Hemisulphate of sulphuric acid hydrolysis synthetic intermediate 3-amino-4-pyrazolecarboxamide, finally obtained allopurinol in methane amide.Method one yield is low, and cost is high, eliminates gradually, and method two raw material propane dinitrile price is high, and total recovery is low.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of allopurinol, and its cost is low, and yield is high.
Technical scheme of the present invention is:
A preparation method for allopurinol, comprises the steps:
(1), triethyl orthoformate, morpholine, acetonitrile, Malonamide nitrile are dropped in reaction vessel in order stir, be steam heated to backflow, back flow reaction 4h, initial reflux temperature can be 117 DEG C, last reflux temperature is 82 DEG C, the mixture obtained after backflow being terminated is cooled to 25-35 DEG C, then carries out successively washing and vacuum-drying, obtains condenses;
(2) condenses, purified water, step (1) obtained, hydrazine hydrate drop in reaction vessel in order and stir, be heated to 90-100 DEG C rapidly, and make temperature remain on more than 90 DEG C 20 minutes, then mixture is cooled to 60 DEG C, then adds dilute sulphuric acid and ice and to be hydrolyzed acidification reaction; Collect crystal water compound after acidification reaction to 5 DEG C, last crystal water compound, through washing and vacuum-drying, obtains the Hemisulphate of 3-amino-4-pyrazolecarboxamide;
(3), by the Hemisulphate of 3-amino-4-pyrazolecarboxamide join in methane amide and be heated with stirring to 140-150 DEG C, insulation reaction 5 hours, after reaction terminates, reactant is cooled to 25-35 DEG C, obtain allopurinol crude product through washing;
(4), allopurinol crude product, gac join in concentrated hydrochloric acid and decolour, and the product after decolouring joins recrystallization in 25 DEG C of sodium hydroxide solutions, finally by washing and vacuum-drying, obtains allopurinol product.
The mass ratio of described formic acid triethyl, morpholine, acetonitrile, Malonamide nitrile is 2.1-2.2: 1.3-1.4: 0.4-0.5: 1.
Described hydrazine hydrate selects volume percent to be the hydrazine hydrate of 85 %, and the mass ratio of described purified water, condenses that step (1) obtains, hydrazine hydrate is 1: 0.2-0.3: 0.08-0.09.
The described Hemisulphate of 3-amino-4-pyrazolecarboxamide and the mass ratio of methane amide are 1:3-3.5.
The pH value of described concentrated hydrochloric acid is 5, and described allopurinol crude product and the mass ratio of gac are 1: 0.1-0.2.
Product after back flow reaction in described step (1) selects ethanol to wash.
The pH value of the dilute sulphuric acid in described step (2) is 1.5, in described step (2), crystal water compound selects water and acetone to wash, in described step (3), reacted reactant washs through water and acetone, and the washing step in described step (4) adopts cold water and acetone to wash.
The mass percent concentration of the sodium hydroxide solution in described step (4) is 1.5-2.5%.
Advantage of the present invention:
Allopurinol quality prepared by the present invention is good, and yield is up to 65%, and preparation method is simple, and less energy consumption, cost is low.
Embodiment
A preparation method for allopurinol, comprises the steps:
(1), 134g triethyl orthoformate, 82.5g morpholine, 37.5ml acetonitrile, 63g Malonamide nitrile are dropped in reaction vessel in order and stir, be steam heated to backflow, back flow reaction 4h, initial reflux temperature can be 117 DEG C, last reflux temperature is 82 DEG C, the mixture obtained after backflow being terminated is cooled to 25-35 DEG C, then carries out washing with alcohol and 30 DEG C of vacuum-dryings successively, obtains condenses;
(2) condenses, 60 of 253ml DEG C of purified water, step (1) obtained, 22.7 g hydrazine hydrates drop in reaction vessel in order and stir, be heated to 90-100 DEG C rapidly, and make temperature remain on more than 90 DEG C 20 minutes, then mixture is cooled to 60 DEG C, then adding pH value is that 1.5 dilute sulphuric acids and ice are hydrolyzed acidification reaction; Collect crystal water compound after acidification reaction to 5 DEG C, last crystal water compound, through water and washing with acetone and 80 DEG C of vacuum-dryings, obtains the Hemisulphate of 3-amino-4-pyrazolecarboxamide;
(3), by the Hemisulphate of 3-amino-4-pyrazolecarboxamide join in methane amide and be heated with stirring to 140-150 DEG C, insulation reaction 5 hours, after reaction terminates, reactant is cooled to 25-35 DEG C, obtain allopurinol crude product through water and washing with acetone;
(4), allopurinol crude product, gac join in concentrated hydrochloric acid and decolour, product after decolouring joins 25 DEG C, mass percent concentration is recrystallization in the sodium hydroxide solution of 1.5-2.5%, finally by cold water and washing with acetone and 60 DEG C of vacuum-dryings, obtain allopurinol product.
Claims (8)
1. a preparation method for allopurinol, is characterized in that, comprises the steps:
(1), triethyl orthoformate, morpholine, acetonitrile, Malonamide nitrile are dropped in reaction vessel in order stir, be steam heated to backflow, back flow reaction 4h, initial reflux temperature can be 117 DEG C, last reflux temperature is 82 DEG C, the mixture obtained after backflow being terminated is cooled to 25-35 DEG C, then carries out successively washing and vacuum-drying, obtains condenses;
(2) condenses, purified water, step (1) obtained, hydrazine hydrate drop in reaction vessel in order and stir, be heated to 90-100 DEG C rapidly, and make temperature remain on more than 90 DEG C 20 minutes, then mixture is cooled to 60 DEG C, then adds dilute sulphuric acid and ice and to be hydrolyzed acidification reaction; Collect crystal water compound after acidification reaction to 5 DEG C, last crystal water compound, through washing and vacuum-drying, obtains the Hemisulphate of 3-amino-4-pyrazolecarboxamide;
(3), by the Hemisulphate of 3-amino-4-pyrazolecarboxamide join in methane amide and be heated with stirring to 140-150 DEG C, insulation reaction 5 hours, after reaction terminates, reactant is cooled to 25-35 DEG C, obtain allopurinol crude product through washing;
(4), allopurinol crude product, gac join in concentrated hydrochloric acid and decolour, and the product after decolouring joins recrystallization in 25 DEG C of sodium hydroxide solutions, finally by washing and vacuum-drying, obtains allopurinol product.
2. the preparation method of a kind of allopurinol according to claim 1, is characterized in that: the mass ratio of described formic acid triethyl, morpholine, acetonitrile, Malonamide nitrile is 2.1-2.2: 1.3-1.4: 0.4-0.5: 1.
3. the preparation method of a kind of allopurinol according to claim 1, it is characterized in that: described hydrazine hydrate selects volume percent to be the hydrazine hydrate of 85 %, the mass ratio of described purified water, condenses that step (1) obtains, hydrazine hydrate is 1: 0.2-0.3: 0.08-0.09.
4. the preparation method of a kind of allopurinol according to claim 1, is characterized in that: the described Hemisulphate of 3-amino-4-pyrazolecarboxamide and the mass ratio of methane amide are 1:3-3.5.
5. the preparation method of a kind of allopurinol according to claim 1, is characterized in that: the pH value of described concentrated hydrochloric acid is 5, and described allopurinol crude product and the mass ratio of gac are 1: 0.1-0.2.
6. the preparation method of a kind of allopurinol according to claim 1, is characterized in that: the product after the back flow reaction in described step (1) selects ethanol to wash.
7. the preparation method of a kind of allopurinol according to claim 1, it is characterized in that: the pH value of the dilute sulphuric acid in described step (2) is 1.5, in described step (2), crystal water compound selects water and acetone to wash, in described step (3), reacted reactant washs through water and acetone, and the washing step in described step (4) adopts cold water and acetone to wash.
8. the preparation method of a kind of allopurinol according to claim 1, is characterized in that: the mass percent concentration of the sodium hydroxide solution in described step (4) is 1.5-2.5%.
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| CN201410689405.0A CN104387394A (en) | 2014-11-26 | 2014-11-26 | Preparation method of allopurinol |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926728A (en) * | 2015-06-03 | 2015-09-23 | 安徽绩溪县徽煌化工有限公司 | Method for preparing 3-amino-4-formamido pyrazole hemisulphate |
| CN108822113A (en) * | 2018-08-20 | 2018-11-16 | 黄石法姆药业股份有限公司 | A kind of synthetic method of 1H- pyrazolo [3,4-d] pyrimidine -4- alcohol |
| CN110526922A (en) * | 2019-09-23 | 2019-12-03 | 江苏红豆杉药业有限公司 | A kind of preparation and its refining methd of Allopurinol crystal |
| CN113979945A (en) * | 2021-11-15 | 2022-01-28 | 湖北理工学院 | Novel method for preparing 3-aminopyrazole-4-formamide hemisulfate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3682957A (en) * | 1968-02-02 | 1972-08-08 | Burroughs Wellcome Co | Method of preparing morpholino cyano-acrylamides |
| CN101774970A (en) * | 2009-01-14 | 2010-07-14 | 常州化学研究所 | Preparation method of 3-aminopyrazoles-4-formamide hemisulphate |
| CN102600166A (en) * | 2011-01-19 | 2012-07-25 | 北京神农润田科技有限公司 | Application of allopurinol compound in preparing information treatment drug, preparation method and prepared novel drug |
| CN102643279A (en) * | 2012-02-09 | 2012-08-22 | 临海市恒源化工有限公司 | Synthesis method of allopurinol |
-
2014
- 2014-11-26 CN CN201410689405.0A patent/CN104387394A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3682957A (en) * | 1968-02-02 | 1972-08-08 | Burroughs Wellcome Co | Method of preparing morpholino cyano-acrylamides |
| CN101774970A (en) * | 2009-01-14 | 2010-07-14 | 常州化学研究所 | Preparation method of 3-aminopyrazoles-4-formamide hemisulphate |
| CN102600166A (en) * | 2011-01-19 | 2012-07-25 | 北京神农润田科技有限公司 | Application of allopurinol compound in preparing information treatment drug, preparation method and prepared novel drug |
| CN102643279A (en) * | 2012-02-09 | 2012-08-22 | 临海市恒源化工有限公司 | Synthesis method of allopurinol |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926728A (en) * | 2015-06-03 | 2015-09-23 | 安徽绩溪县徽煌化工有限公司 | Method for preparing 3-amino-4-formamido pyrazole hemisulphate |
| CN108822113A (en) * | 2018-08-20 | 2018-11-16 | 黄石法姆药业股份有限公司 | A kind of synthetic method of 1H- pyrazolo [3,4-d] pyrimidine -4- alcohol |
| CN110526922A (en) * | 2019-09-23 | 2019-12-03 | 江苏红豆杉药业有限公司 | A kind of preparation and its refining methd of Allopurinol crystal |
| CN113979945A (en) * | 2021-11-15 | 2022-01-28 | 湖北理工学院 | Novel method for preparing 3-aminopyrazole-4-formamide hemisulfate |
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Application publication date: 20150304 |