CN102153560A - Rectification method of allopurinol - Google Patents
Rectification method of allopurinol Download PDFInfo
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- CN102153560A CN102153560A CN 201110053382 CN201110053382A CN102153560A CN 102153560 A CN102153560 A CN 102153560A CN 201110053382 CN201110053382 CN 201110053382 CN 201110053382 A CN201110053382 A CN 201110053382A CN 102153560 A CN102153560 A CN 102153560A
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Abstract
The invention provides a rectification method of allopurinol, in particular relates to a rectification method in which the allopurinol is converted into an allopurinol sodium salt so as to enlarge solubility, decolorizing rectification is carried out on the allopurinol sodium salt, then the allopurinol sodium salt is acidized to form the allopurinol, belonging to the technical field of chemical reaction rectification. The rectification method comprises the following steps: adding crude allopurinol in water, stirring with a dilute alkaline liquid to be clear, and controlling the pH to be neutral; adding activated carbon, and filtering under the hot condition after stirring and decoloring; slowly adding a dilute acid solution in filtrate obtained after decloring and filtering, separating out a white solid, maintaining the pH of the solution to be neutral, and continuously stirring and filtering; and washing the obtained filter cake and drying so as obtain the rectified product allopurinol. In the rectification method, the used raw material is available, reaction and treatment conditions are mild and the yield and purity of the product are high; the yield of rectification can be greatly increased by a proper improvement under the condition of the original equipment conditions, and industrialization is conveniently achieved. By using the method, the dissolving amount can be improved by 5-10 times, and simultaneously, the yield can be improved.
Description
Technical field
A kind of process for purification of allopurinol is meant that specifically allopurinol is converted into the allopurinol sodium salt, increases solubleness, decolorizing and refining under lower temperature, and then acidifying becomes the allopurinol process for purification, belongs to chemical reaction purification techniques field.
Background technology
The allopurinol antigout drug is applicable to the various diseases that primary or Secondary cases serum uric acid increase, as gout, acute or chronic leukemia.
General preparation method: ethyl cyanoacetate, triethyl orthoformate, acetic anhydride are placed on back flow reaction 4h in the retort, and condensation obtains α-ethoxy methyne ethyl cyanoacetate; It is dissolved in the ethanol again, adds hydrazine hydrate, heating reflux reaction 6h gets 3-amino-4-ethoxycarbonyl pyrazoles; Obtain allopurinol with methane amide heating reflux reaction 8h cyclization at last.Use dissolved in distilled water, activated carbon decolorizing gets the purified allopurinol.
During crude product refining, because of the atomic water-soluble and common organic solvents of allopurinol restricts its refined raw output.Highest solubility has only 1% during refining production, and need be under 90～100 ℃ of conditions, and yield is lower than 80%.Steam consumption is very big, needs a large amount of water coolants during cooling again.
Summary of the invention
Order of the present invention is the defective that overcomes existing allopurinol process for purification, a kind of simple, less energy-consumption is provided, meltage can have been improved 5～10 times, the process for purification that yield is improved.
Technical scheme of the present invention: a kind of process for purification of allopurinol, step is as follows:
(1) alkalescence dissolving: by the allopurinol crude product: the purified water mass ratio is that 1: 1.5～2 ratio is dissolved; With the solid alkali configuration concentration is the sig water of 0.1～2.5mol/L, adds under the room temperature in the allopurinol purifying crude aqueous solution of configuration, be stirred to molten clear, control pH 6～8; Solution is in neutrality then can not destroyed because of highly basic.
Described solid alkali is NaOH solid, KOH solid, NaCO
3Solid or NaHCO
3Solid.
Reactional equation is as follows:
(2) decolorization filtering: add the gac of allopurinol crude product weight 5%～10% in step (1) gained solution, 40～60 ℃ are stirred decolouring 1～3 hour, filtered while hot 1～2 time down; Simultaneously because of being its sodium salt solution, there is not obstruction than 98 ℃ low of routine in temperature during decolouring during filtration, can not separate out to be adsorbed on because of product to cause yield to reduce in the gac.
(3) filtrate acidifying: the dilute acid soln of configuration 0.1～2.5mol/L, dilute acid soln is slowly joined in the filtrate behind step (2) decolorization filtering, separate out white solid, control pH value of solution 6～8 stirs filtration in 20～40 minutes; Acid and allopurinol crude product mol ratio in the dilute acid soln that adds are 1: 0.9～1.05; The gained filter cake gets the purified product allopurinol with purified water washing 1～3 time after 80～105 ℃ of following dryings; Solution is in neutrality then can not destroyed because of strong acid.
Described dilute acid soln is HCl solution, H
2SO
4Solution, H
3PO
4Solution, HCOOH solution or CH
3A kind of in the COOH solution.
Reactional equation is as follows:
Control pH is 7 in the described alkalescence dissolving of step (1).
It is described that the Pharmacopoeia of the People's Republic of China 2005 editions is pressed in the quality index detection of allopurinol.
Beneficial effect of the present invention: this process for purification is raw materials used cheap and easy to get, reaction and treatment condition gentleness, and product yield and purity height through the suitable purified output greatly of improving, are convenient to realize industrialization under original appointed condition.The present invention can improve meltage 5～10 times, and yield is improved.
Embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, and be not used in qualification the present invention.
Embodiment 1
(1) alkalescence dissolving: add 10 milliliters of purified water earlier in the 100mL there-necked flask, add 5g (0.036mol) allopurinol crude product again, open and stir, slowly add 0.5mol/LNaOH solution 65mL, control pH6～7 obtain weak yellow liquid until dissolving.
(2) decolouring: add needle-use activated carbon 0.5g, 60 ℃ are stirred decolouring 1h, filtered while hot down.
(3) filtrate acidifying: configuration 0.5mol/L HCl solution 66mL (0.033mol), filtrate is placed the 250mL there-necked flask, stirring state slowly adds down, and the adularescent object is separated out, and keeps PH to be about between 6～7.Add the back and continue to stir filtration in 20 minutes, filter cake cold wash 3 times, 100 ℃ of dryings obtain off-white color solid 4.1g, and yield is 82%.Quality index: differentiate that (colour developing, UV, IR) is up to specification; Heavy metal≤20ppm; Residue on ignition≤0.01%; HPLC product content 99.8%; Related substance: single impurity 0.075%, total impurities 0.20%.
Embodiment 2
(1) alkalescence dissolving: in the 250mL there-necked flask, add 15 milliliters of purified water earlier, add 10g (0.0734mol) allopurinol crude product again, 60 ℃ of water-baths, open and stir, slowly add 1.0mol/L NaOH solution 73mL, control pH6～7 obtain weak yellow liquid until dissolving.
(2) decolouring: add needle-use activated carbon 0.8g, 60 ℃ are stirred 1h, filtered while hot down.
(3) filter: configuration 1mol/L HCl solution 74mL (0.074mol), filtrate is placed the 250mL there-necked flask, stirring state adds down, and the adularescent object is separated out, and keeps PH to be about between 6～7.Add the back and continue to stir filtration in 30 minutes, filter cake cold wash 2 times, 90 ℃ of dryings obtain off-white color 8.0g.Yield 80%.Quality index: differentiate that (colour developing, UV, IR) is up to specification; Heavy metal≤20ppm; Residue on ignition≤0.04%; HPLC product content 99.2%; Related substance: single 0.062% total 0.14%
Embodiment 3.
(1) alkalescence dissolving: in the 250ml there-necked flask, add 20 milliliters of purified water earlier, add 10g (0.0734mol) allopurinol crude product again, 60 ℃ of water-baths, open and stir, slowly splash into 1.5mol/L NaOH solution 41mL, control pH6～7 obtain weak yellow liquid until dissolving.
(2) decolouring: add needle-use activated carbon 0.5g, stir 1h down, filter at 60 ℃.
(3) filter: filtrate is placed the 250ml there-necked flask, open and stir, add 1.5mol/L HCl solution 40mL (0.06mol), the adularescent object is separated out, and keeps PH to be about between 6～7.Add the back and continue to stir filtration in 40 minutes, filter cake washes with water 3 times, and 80 ℃ of dryings obtain off-white color (somewhat faint yellow) object 8.1g.Yield 81%.Quality index: differentiate that (colour developing, UV, IR) is up to specification; Heavy metal :≤20ppm; Residue on ignition :≤0.04%; Content HPLC:98.2%; Related substance: single assorted 0.10%, always assorted 0.35%.
Embodiment 4
(1) alkalescence dissolving: in the 200L stainless steel cauldron, add 20 kilograms of purified water earlier, add 10kg (73.5mol) allopurinol crude product again, 60 ℃ of water-baths, open and stir, slowly add 1.0mol/L NaOH solution 72.5L, control pH6～7 obtain weak yellow liquid until dissolving.
(2) decolouring: add needle-use activated carbon 1kg, 60 ℃ are stirred 1h down, through twice filtration.
(3) filtrate is placed the 300L enamel reaction still, under the stirring state, add 1.0mol/L HCl solution 73L (73mol), the adularescent object is separated out, and keeps PH to be about between 6～7.Add the back and continue to stir 30 minutes, centrifugal, filter cake cold wash 3 times, 100 ℃ of dryings obtain off-white color 8.2Kg.Yield 82%.Quality index: differentiate that (colour developing, UV, IR) is up to specification; Heavy metal :≤20ppm; Residue on ignition :≤0.05%; Content HPLC:98.3%; Related substance: single impurity 0.052%, total impurities 0.14%.
The above only is the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (2)
1. the process for purification of an allopurinol is characterized in that step is as follows:
(1) alkalescence dissolving: by the allopurinol crude product: the purified water mass ratio is that 1: 1.5～2 ratio is dissolved; With the solid alkali configuration concentration is the sig water of 0.1～2.5mol/L, adds under the room temperature in the allopurinol purifying crude aqueous solution of configuration, be stirred to molten clear, control pH 6～8;
Described solid alkali is NaOH solid, KOH solid, NaCO
3Solid or NaHCO
3Solid;
(2) decolorization filtering: add the gac of allopurinol crude product weight 5%～10% in step (1) gained solution, 40～60 ℃ are stirred decolouring 1～3 hour, filtered while hot 1～2 time down;
(3) filtrate acidifying: the dilute acid soln of configuration 0.1～2.5mol/L, dilute acid soln is slowly joined in the filtrate behind step (2) decolorization filtering, separate out white solid, control pH value of solution 6～8 stirs filtration in 20～40 minutes; Acid and allopurinol crude product mol ratio in the dilute acid soln that adds are 1: 0.9～1.05; The gained filter cake gets the purified product allopurinol with purified water washing 1～3 time after 80～105 ℃ of following dryings;
Described dilute acid soln is HCl solution, H
2SO
4Solution, H
3PO
4Solution, HCOOH solution or CH
3COOH solution.
2. according to the process for purification of the described allopurinol of claim 1, it is characterized in that control pH is 7 in the dissolving of step (1) alkalescence.
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|---|---|---|---|
| CN 201110053382 CN102153560A (en) | 2011-03-07 | 2011-03-07 | Rectification method of allopurinol |
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|---|---|---|---|
| CN 201110053382 CN102153560A (en) | 2011-03-07 | 2011-03-07 | Rectification method of allopurinol |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965197A (en) * | 2013-04-15 | 2014-08-06 | 杭州领业医药科技有限公司 | Preparation of allopurinol crystal |
| CN104447754A (en) * | 2014-11-04 | 2015-03-25 | 重庆康乐制药有限公司 | Method for carrying out solvent-out crystallization on allopurinol |
| CN104844604A (en) * | 2014-02-13 | 2015-08-19 | 合肥久诺医药科技有限公司 | Preparation method of high purity allopurinol sodium |
| CN109369450A (en) * | 2018-10-31 | 2019-02-22 | 江苏省农用激素工程技术研究中心有限公司 | The refining methd of tralkoxydim |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3487083A (en) * | 1966-07-14 | 1969-12-30 | Burroughs Wellcome Co | Preparation of 4-hydroxypyrazolo(3,4-d)pyrimidine |
| US3694484A (en) * | 1969-09-09 | 1972-09-26 | Ronald M Cresswell | Process of preparing 3-amino-2-cyano acrylamide |
| US4146713A (en) * | 1968-02-02 | 1979-03-27 | Burroughs Wellcome Co. | Method of preparing 3-morpholino-2-cyanoacrylamide |
-
2011
- 2011-03-07 CN CN 201110053382 patent/CN102153560A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3487083A (en) * | 1966-07-14 | 1969-12-30 | Burroughs Wellcome Co | Preparation of 4-hydroxypyrazolo(3,4-d)pyrimidine |
| US4146713A (en) * | 1968-02-02 | 1979-03-27 | Burroughs Wellcome Co. | Method of preparing 3-morpholino-2-cyanoacrylamide |
| US3694484A (en) * | 1969-09-09 | 1972-09-26 | Ronald M Cresswell | Process of preparing 3-amino-2-cyano acrylamide |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965197A (en) * | 2013-04-15 | 2014-08-06 | 杭州领业医药科技有限公司 | Preparation of allopurinol crystal |
| CN104844604A (en) * | 2014-02-13 | 2015-08-19 | 合肥久诺医药科技有限公司 | Preparation method of high purity allopurinol sodium |
| CN104844604B (en) * | 2014-02-13 | 2017-03-08 | 合肥久诺医药科技有限公司 | A kind of preparation method of allopurinol sodium |
| CN104447754A (en) * | 2014-11-04 | 2015-03-25 | 重庆康乐制药有限公司 | Method for carrying out solvent-out crystallization on allopurinol |
| CN109369450A (en) * | 2018-10-31 | 2019-02-22 | 江苏省农用激素工程技术研究中心有限公司 | The refining methd of tralkoxydim |
| CN109369450B (en) * | 2018-10-31 | 2021-07-27 | 江苏省农用激素工程技术研究中心有限公司 | Refining method of tralkoxydim |
| 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 |
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Application publication date: 20110817 |