CN101463005A - Method for purifying rebamipide crude product - Google Patents
Method for purifying rebamipide crude product Download PDFInfo
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- CN101463005A CN101463005A CNA2009100287941A CN200910028794A CN101463005A CN 101463005 A CN101463005 A CN 101463005A CN A2009100287941 A CNA2009100287941 A CN A2009100287941A CN 200910028794 A CN200910028794 A CN 200910028794A CN 101463005 A CN101463005 A CN 101463005A
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- rebamipide
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Abstract
The invention relates to a purifying method for a Rebamipide crude product. Alkaline is added in alcohol-water mixed solvent to dissolve the Rebamipide crude product. Then, activated carbon is added for decolorizing. Concentrated hydrochloric acid is added dropwise, pH is regulated to 2-3, solids are precipitated, and purified Rebamipide is obtained after filtering and drying. During the process, the mol ratio of the added amount of alkaline to the Rebamipide is controlled to be less than 3 to 1. And the operational temperature during the alkaline adding for dissolution and the acid adding for crystallization is controlled at 150 DEG C; therefore; the ring cleavage reaction of quinolone is inhabited and the generation of two impurities which are similar in structure with Rebamipide is reduced. Rebamipide with the purity of higher than 99.5 percent is obtained. Conditions are provided for improving the application degree of Rebamipide in pharmaceutical aspects of gastric mucosal protective drugs, etc.
Description
Relate to the field
The present invention relates to the production of rebamipide,, belong to the synthetic and separation technology field of organic compound especially to the purification of rebamipide crude product.
Background technology
Rebamipide is a kind of quinolone compounds; its chemical name is: 2-(4-chloro-benzoyl amino)-3-(1; 2-dihydro-2-oxo--4-quinolyl) propionic acid; can be used for preparing gastric mucosa protectant; there is pre-ulcer to take place and the effect of promotion ulcer healing; synthetic and the gastric mucus secretion of gastric mucosal blood flow, prostaglandin E2 be can increase, oxyradical, the healing of promoting digestion ulcer and the improvement of inflammation removed.
Formula (vi) be the structural formula of rebamipide, and its crude product (vi ') adopt following three kinds of methods synthetic usually, institute's rebamipide crude product that obtains is purified through further, and then is used to prepare gastric mucosa protectant etc.
Method one, U.S. Pat 4578381 proposes, and with bromine, N-bromosuccinimide or analogue bromination acetoacetanilide, obtains brooethyl quinolone (i) with the sulfuric acid closed loop then; Then; in the solution of first, sodium ethylate; brooethyl quinolone (i) (ii) reacts with diethyl acetamido and obtains quinolone diethyl malonate compound (iii); quinolone diethyl malonate compound (iii) removes ethanoyl and obtains the quinolone amino-acid compound (iv) in hydrochloric acid soln, and this compound (iv) (v) carries out acylation reaction and obtains rebamipide crude product (vi ') with parachlorobenzoyl chloride under alkaline condition.Its reaction process is shown below:
Method two, the preparation of brooethyl quinolone (i) is identical with method one, then in the solution of first, sodium ethylate, (vii) reaction obtains compound and (viii), obtains rebamipide crude product (vi ') through alkalization, acidifying then for brooethyl quinolone (i) and p-chlorobenzamido oxalic acid diethyl ester.Its reaction process is shown below:
Method three, people such as Morita proposed in 1991, and brooethyl quinolone (i) is at POCl
3Obtain compound (ix) under the condition; compound (ix) obtains (xi) with compound (x) reaction; obtain compound (xii) through open loop then; then under the condition of propylene oxide and hydrochloric acid, remove methyl esters and oxo chlorination; obtain compound (xiii); at last, compound (xiii) (v) carries out acylation reaction and obtains rebamipide crude product (vi ') with parachlorobenzoyl chloride under alkaline condition.Its reaction process is shown below:
Above-mentioned three kinds of preparation methods, its reactions steps is more, relates to multiple reactant and intermediate product, therefore, the rebamipide crude product that reaction makes (vi ') must just can be used for the application of road, back through purifying.In the prior art, adopt the method for decolorizing and refining that rebamipide crude product is purified usually, still, the rebamipide after the purification, its purity is difficult to surpass 99.5%, and this situation has restricted the preparation and the use of rebamipide gastric mucosa protectant.
Summary of the invention
The objective of the invention is to solve the problems referred to above that prior art exists, a kind of method of purification of rebamipide crude product is provided,, satisfy its service requirements at aspects such as pharmacy to obtain purity greater than 99.5% rebamipide.
Technical solution of the present invention is:
The method of purification of rebamipide crude product, in pure water mixed solvent, add alkali, make the rebamipide crude product CL, add activated carbon decolorizing, remove by filter gac, drip concentrated hydrochloric acid then, regulate PH to 2-3, separate out solids, filtering drying, rebamipide after obtaining purifying is characterized in that: the amount of the alkali that is added and the mol ratio of rebamipide are less than 3:1.
Further, the method for purification of above-mentioned rebamipide crude product, wherein, described rebamipide crude product is adding alkali dissolution and is adding acid out to go out in the process, and service temperature is controlled at below 150 ℃.
Further, the method for purification of above-mentioned rebamipide crude product, wherein, described pure water mixed solvent employed " alcohol " is ethanol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) (DMSO) or N, dinethylformamide (DMF); The described alkali that adds in pure water mixed solvent is KOH, NaOH or organic amine; Described concentrated acid is a concentrated hydrochloric acid.
Thus; the amount of the alkali that the present invention is added when dissolving in pure water mixed solvent by the control rebamipide crude product and the mol ratio of rebamipide are less than 3:1; and the service temperature when adding alkali dissolution and add the acid out crystalline substance is controlled at below 150 ℃; suppressed the quinolone ring-opening reaction; closely similar impurity of structure and rebamipide (a) and generation (b) have been reduced; thereby acquisition purity has been created condition for promoting rebamipide at the level of application aspect the pharmacy such as gastric mucosa protectant greater than 99.5% rebamipide.
Embodiment
The present invention is a purpose with the purification rebamipide crude product, and the structure and the origin cause of formation by analyzing obstinate impurity propose terms of settlement pointedly, have played refining effect preferably.
As stated in the Background Art, the present inventor prepares rebamipide crude product by several different methods, and during to its decolorizing and refining, purity all is difficult to surpass 99.5%.Separate through RP-HPLC impurity, and mass spectrum, infrared spectra and the comprehensively analysis and research of hydrogen spectrum, find two kinds of impurity that are difficult to remove be formula (a) and (b) shown in two kinds of materials; And these two kinds of materials come from the decolorizing and refining process to a great extent.That is: in the treating process, the rebamipide after having obtained on the one hand to purify (vi), has also produced the impurity (a) that is difficult to remove and (b) on the other hand.
Because impurity (a) and structure (b) and rebamipide are approaching, adopt the very difficult removals of method such as recrystallization; And repeatedly recrystallization will inevitably lose a certain amount of product, influences yield and cost.So control impurity (a) and generation (b) are the keys that rebamipide crude product is purified.The present inventor finds to take following measure can suppress impurity (a) and generation (b) by exploration and research to crystallization condition:
When measure 1---rebamipide crude product dissolves in pure water mixed solvent, the amount of the alkali that is added and the mol ratio of rebamipide are less than 3:1, dissolving fully behind the salify, because of alkaline intensity control below the quinolone open loop condition, can reduce open loop and produce impurity (a) and (b);
Measure 2---rebamipide crude product is adding alkali dissolution and is adding acid out when brilliant, and service temperature is controlled at below 150 ℃, can reduce impurity (a) and generation (b) equally, obtains purity greater than 99.5% rebamipide.
Aforesaid method is simply effective, and described pure water mixed solvent can adopt ethanol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) DMSO or N, dinethylformamide DMF.
With the water preparation, the alkali that adds during the rebamipide crude product dissolving can be KOH, NaOH or organic amine.
And measure 1 and the measure enforcement of coming in 2 minutes is for reducing impurity (a) and (b) all effective.Certainly, two measures are implemented simultaneously, will further reduce impurity (a) and content (b).
Such as, rebamipide crude product dissolves in ethanol/water mixed solvent, the amount and the rebamipide mol ratio that add KOH are controlled at 2.5:1, slowly heat up dissolving fully behind salify, refluxed 10 minutes, add concentrated hydrochloric acid, PH is transferred to 2-3, separates out large-tonnage product, be cooled to about 10 ℃ the rebamipide product after suction filtration must be purified.Analyze through HPLC, impurity (a) and content (b) are all less than 0.1%, and rebamipide purity is greater than 99.5%.Its process is as follows:
With specific examples technical solution of the present invention is described further below, it is the typically used example only, and protection scope of the present invention is not constituted any limitation.
" embodiment 1 "
38.5 the gram rebamipide crude product, purity 97.5% joins in 30% aqueous ethanolic solution of 300ml, add 14 gram KOH, slowly heat up, up to CL, add gac 2g, slowly be warmed up to backflow again, the after heat in 10 minutes that refluxes removes by filter gac, slowly drip concentrated hydrochloric acid, regulate PH to 2-3, controlled temperature is no more than 90 ℃, stirs cooling 120 minutes, 10 ℃ of left and right sides suction filtration oven dry get the rebamipide elaboration.The HPLC check, rebamipide content 99.53%, impurity (a) content 0.05%, impurity (b) content 0.08%, yield 95.1%.
" embodiment 2 "
76 gram rebamipide crude products, purity 97.8% joins in 30% aqueous ethanolic solution of 600ml, add 27.5 gram KOH, slowly heat up, up to CL, add gac 4g, slowly be warmed up to backflow again, the after heat in 10 minutes that refluxes removes by filter gac, slowly drip concentrated hydrochloric acid, regulate PH to 2-3, controlled temperature is no more than 90 ℃, stirs cooling 100 minutes, 10 ℃ of left and right sides suction filtration oven dry get the rebamipide elaboration.The HPLC check, rebamipide content 99.61%, impurity (a) content 0.03%, impurity (b) content 0.07%, yield 96.5%.
" embodiment 3 "
80 gram rebamipide crude products, purity 97.3% joins in 20% tetrahydrofuran aqueous solution of 600ml, add 28 gram KOH, slowly heat up, up to CL, add gac 4g, slowly be warmed up to backflow again, the after heat in 10 minutes that refluxes removes by filter gac, slowly drip concentrated hydrochloric acid, regulate PH to 2-3, controlled temperature is no more than 80 ℃, stirs cooling 100 minutes, 10 ℃ of left and right sides suction filtration oven dry get the rebamipide elaboration.The HPLC check, rebamipide content 99.60%, impurity (a) content 0.04%, impurity (b) content 0.08%, yield 94.1%.
" embodiment 4 "
76 gram rebamipide crude products, purity 97.8% joins in the 20%DMF aqueous solution of 600ml, add 55 gram triethylamines, slowly heat up, up to CL, add gac 4g, slowly be warmed up to backflow again, the after heat in 10 minutes that refluxes removes by filter gac, slowly drip concentrated hydrochloric acid, regulate PH to 2-3, controlled temperature is no more than 110 ℃, stirs cooling 100 minutes, 10 ℃ of left and right sides suction filtration oven dry get the rebamipide elaboration.The HPLC check, rebamipide content 99.58%, impurity (a) content 0.02%, impurity (b) content 0.06%, yield 93.7%.
" embodiment 5 "
76 gram rebamipide crude products, purity 97.8% joins in the 30%DMF aqueous solution of 600ml, add 27.5 gram KOH, slowly heat up, up to CL, add gac 4g, slowly be warmed up to backflow again, the after heat in 10 minutes that refluxes removes by filter gac, slowly drip concentrated hydrochloric acid, regulate PH to 2-3, controlled temperature is no more than 120 ℃, stirs cooling 100 minutes, 10 ℃ of left and right sides suction filtration oven dry get the rebamipide elaboration.The HPLC check, rebamipide content 99.67%, impurity (a) content 0.02%, impurity (b) content 0.05%, yield 93.2%.
" embodiment 6 "
76 gram rebamipide crude products, purity 97.3% joins in the 30%DMSO aqueous solution of 600ml, drips 93 gram tri-n-butylamine (N (CH
2CH
2CH
2CH
3)
3), slowly heat up, up to CL, add gac 4g, slowly be warmed up to backflow again, the after heat in 10 minutes that refluxes removes by filter gac, slowly drips concentrated hydrochloric acid, regulates PH to 2-3, controlled temperature is no more than 130 ℃, stirs cooling 100 minutes, and 10 ℃ of left and right sides suction filtration oven dry get the rebamipide elaboration.The HPLC check, rebamipide content 99.64%, impurity (a) content 0.02%, impurity (b) content 0.05%, yield 94.6%.
Claims (5)
1, the method for purification of rebamipide crude product, in pure water mixed solvent, add alkali, make the rebamipide crude product CL, add activated carbon decolorizing, remove by filter gac, drip concentrated hydrochloric acid then, regulate PH to 2-3, separate out solids, filtering drying, rebamipide after obtaining purifying is characterized in that: the amount of the alkali that is added and the mol ratio of rebamipide are less than 3:1.
2, the method for purification of rebamipide crude product according to claim 1 is characterized in that: described rebamipide crude product is adding alkali dissolution and is adding acid out to go out in the process, and service temperature is controlled at below 150 ℃.
3, the method for purification of rebamipide crude product according to claim 1 and 2 is characterized in that: the employed alcohol of described pure water mixed solvent is ethanol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or N, dinethylformamide.
4, the method for purification of rebamipide crude product according to claim 1 and 2 is characterized in that: the described alkali that adds in pure water mixed solvent is KOH, NaOH or organic amine.
5, the method for purification of rebamipide crude product according to claim 1 and 2 is characterized in that: described concentrated acid is a concentrated hydrochloric acid.
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| CNA2009100287941A CN101463005A (en) | 2009-01-08 | 2009-01-08 | Method for purifying rebamipide crude product |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102174015A (en) * | 2011-03-07 | 2011-09-07 | 江西同和药业有限责任公司 | Refining method of rebamipide |
| CN103113294A (en) * | 2013-03-11 | 2013-05-22 | 浙江远力健药业有限责任公司 | Synthesizing method of rebamipide |
| CN103476753A (en) * | 2011-02-25 | 2013-12-25 | 诺弗米克斯有限公司 | Novel rebamipide complexes and cocrystals |
| CN104418802A (en) * | 2013-09-07 | 2015-03-18 | 重庆汇智药物研究院有限公司 | Rebamipide monohydrate crystal form and preparation method thereof |
| 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 |
| CN111205231A (en) * | 2020-02-24 | 2020-05-29 | 浙江大学 | Lead compound as ANKRD22 inhibitor and application thereof |
| CN112798728A (en) * | 2020-12-30 | 2021-05-14 | 日照正济药业有限公司 | Chromatographic analysis method for separating rebamipide and m-chloroprebamipide |
| CN112816585A (en) * | 2020-12-30 | 2021-05-18 | 苏州正济药业有限公司 | Method for detecting rebamipide and related substances thereof |
| CN115524417A (en) * | 2022-09-19 | 2022-12-27 | 杭州沐源生物医药科技有限公司 | Analysis method of related substances and isomers of rebamipide tablets |
-
2009
- 2009-01-08 CN CNA2009100287941A patent/CN101463005A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103476753A (en) * | 2011-02-25 | 2013-12-25 | 诺弗米克斯有限公司 | Novel rebamipide complexes and cocrystals |
| CN103476753B (en) * | 2011-02-25 | 2015-12-09 | 诺弗米克斯有限公司 | New rebamipide mixture and eutectic |
| CN102174015A (en) * | 2011-03-07 | 2011-09-07 | 江西同和药业有限责任公司 | Refining method of rebamipide |
| CN103113294B (en) * | 2013-03-11 | 2016-04-27 | 浙江远力健药业有限责任公司 | The synthetic method of rebamipide |
| CN103113294A (en) * | 2013-03-11 | 2013-05-22 | 浙江远力健药业有限责任公司 | Synthesizing method of rebamipide |
| CN104418802B (en) * | 2013-09-07 | 2017-02-22 | 重庆汇智药物研究院有限公司 | rebamipide monohydrate crystal form and preparation method thereof |
| CN104418802A (en) * | 2013-09-07 | 2015-03-18 | 重庆汇智药物研究院有限公司 | Rebamipide monohydrate crystal form and preparation method thereof |
| 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 |
| CN111205231A (en) * | 2020-02-24 | 2020-05-29 | 浙江大学 | Lead compound as ANKRD22 inhibitor and application thereof |
| CN112798728A (en) * | 2020-12-30 | 2021-05-14 | 日照正济药业有限公司 | Chromatographic analysis method for separating rebamipide and m-chloroprebamipide |
| CN112816585A (en) * | 2020-12-30 | 2021-05-18 | 苏州正济药业有限公司 | Method for detecting rebamipide and related substances thereof |
| CN115524417A (en) * | 2022-09-19 | 2022-12-27 | 杭州沐源生物医药科技有限公司 | Analysis method of related substances and isomers of rebamipide tablets |
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