CN102153512B - Preparation method of rebamipide intermediate - Google Patents
Preparation method of rebamipide intermediate Download PDFInfo
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- CN102153512B CN102153512B CN 201110053023 CN201110053023A CN102153512B CN 102153512 B CN102153512 B CN 102153512B CN 201110053023 CN201110053023 CN 201110053023 CN 201110053023 A CN201110053023 A CN 201110053023A CN 102153512 B CN102153512 B CN 102153512B
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Abstract
The invention discloses a preparation method of a compound disclosed as a structural formula 1. The compound is a key intermediate for synthesizing rebamipide. The method comprises the following steps: I. in the presence of alkali, reacting a compound disclosed as a structural formula 2 with a compound disclosed as a structural formula 3 in C1-C4 fatty alcohol; after the reaction finishes, regulating the pH value to higher than or equal to 8 with acid, adding water, and filtering to obtain a compound disclosed as a structural formula 4; and II. in an organic solvent, reacting the compound disclosed as the structural formula 4 in step I with acid at 30-130 DEG C, after the reaction finishes, cooling to crystallize, and filtering to obtain the compound disclosed as the structural formula 1, wherein the acid is composed of organic acid and inorganic acid in any ratio, the organic acid is one or more of formic acid, acetic acid, propanoic acid and oxalic acid, and the inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. The invention solves the problems of high material wash-away tendency and low yield in the prior art.
Description
Technical field
The invention belongs to organic chemistry filed, specifically relate to the rebamipide key intermediate---2-amino-3-(2(1 hydrogen)-quinolone-4-yl) preparation method of propionic salt.
Background technology
Rebamipide can improve gastric motility, the gastric mucosa injury that the acute exacerbation of smelting treatment stomach ulcer, acute gastritis, chronic gastritis causes.Its systematic naming method is: Rebamipide, CAS accession number are 111911-87-6.The synthetic key intermediate of rebamipide is 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) the propionic salt hydrochlorate, outside the desalination hydrochlorate, this 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) vitriol of propionic acid, phosphoric acid salt, hydrobromate etc., also can be as the intermediate of rebamipide, the general structure of above-mentioned various salt is shown in 1.
For 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) preparation method of propionic salt hydrochlorate (compound shown in the structural formula 6), a lot of patents and document have report, common are:
Scheme 1(JP2004131506):
This synthetic route is: at first by the compound (acetamino diethyl malonate) of the compound (4-brooethyl benzene-1 hydrogen-2-quinolinone) of structural formula 2 and structural formula 3 in dehydrated alcohol, and the compound of reaction generating structure formula 4 under sodium ethylate exists [2-acetylaminohydroxyphenylarsonic acid 2-ethyl formate-3-(2-quinolinone-4 base)-ethyl propionate], then the compound of structural formula 4 is obtained the compound [2-acetylaminohydroxyphenylarsonic acid 3-(2(1 hydrogen)-quinolone-4-yl) propionic acid] of structural formula 5 in the alkaline condition hydrolysis, the compound of final texture formula 5 is hydrolyzed the compound that obtains structural formula 6 [2-amino-3-(2(1 hydrogen)-quinolone-4-yl) propionic salt hydrochlorate] under acidic conditions.
The method operation steps is long, through twice hydrolysis, operates loaded down with trivial detailsly, is unfavorable for heavy industrialization.
Scheme 2(US4578381):
Compare scheme 1, the method has reduced single step reaction, and only through an acid hydrolysis, route is simplified.But, still there is reaction not exclusively, easily rush material, the problems such as yield low (only being 70%).
Summary of the invention
The objective of the invention is to overcome the prior art deficiency, a kind of preparation method of rebamipide intermediate of structural formula 1 is provided; The inventive method has overcome aforementioned schemes 2 reactions not exclusively, and easily the problem that yield is low is expected in punching; The product purity that obtains is high, and yield is high, pollutes and lacks, and is easy to industrial production.
In order to solve the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of preparation method of compound of structural formula 1 comprises the steps:
I. the compound of the compound of structural formula 2 and structural formula 3 is in the presence of alkali, at C
1-C
4Fatty Alcohol(C12-C14 and C12-C18) in react; Reaction finishes, and with acid for adjusting pH≤8, adds entry, filters the compound that obtains structural formula 4;
II. in organic solvent, 30-130 ℃, compound and the acid-respons of the structural formula 4 that described step I is obtained, reaction finishes, and crystallisation by cooling filters, and obtains the compound of structural formula 1; Described acid is comprised of organic acid and the mineral acid of arbitrary proportion, and described organic acid is selected from one or more of formic acid, acetic acid, propionic acid, oxalic acid, and described mineral acid is selected from one or more in hydrochloric acid, sulfuric acid, phosphoric acid and the Hydrogen bromide.
In the technique scheme, in the described Step II, described organic acid preferable formic acid or acetic acid; Described mineral acid selects hydrochloric acid or sulfuric acid.For described preferred organic acid and mineral acid, both volume ratios are organic acid: mineral acid=1 ﹕, 0.1 ~ 1 ﹕ 3.The present invention is the mixing acid that forms of formic acid or acetic acid and hydrochloric acid more preferably, and the volume ratio of formic acid or acetic acid and hydrochloric acid is 1 ﹕, 1 ~ 1 ﹕ 2.
In the technique scheme, in the described Step II, the weight/volume of the compound of structural formula 4 and acid is 1 ﹕, 1 ~ 1 ﹕ 50, and preferred weight/volume is 1 ﹕, 1 ~ 1 ﹕ 20.
In the technique scheme, among the described step I, the compound of described structural formula 2 and C
1-C
4The weight/volume of Fatty Alcohol(C12-C14 and C12-C18) be 1 ﹕, 4 ~ 1 ﹕ 20, described C
1-C
4The Fatty Alcohol(C12-C14 and C12-C18) preferred alcohol.
The described step I of the inventive method and II can carry out to the boiling spread of used organic solvent or mixed solvent at 0 ℃.Certainly, those skilled in the art are to be understood that temperature is on the impact of the inventive method.
Organic solvent of the present invention if no special instructions, includes but not limited to C
1-C
4Fatty Alcohol(C12-C14 and C12-C18), ethyl acetate, ethyl formate, acetone, ether, isopropyl ether, tetrahydrofuran (THF), benzene, toluene or methylene dichloride.
The present invention also provides a kind of preferred 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) the propionic salt hydrochlorate the preparation method, concrete operations are:
I. the compound of the compound of structural formula 2, structural formula 3 and sodium ethylate drop in the dehydrated alcohol in molar ratio=1 ﹕, 0.5 ﹕, 1 ~ 1 ﹕, 10 ﹕ 1.2, the compound of described structural formula 2 and the weight/volume of dehydrated alcohol are 1 ﹕, 7 ~ 1 ﹕ 9, be warming up to 75-80 ℃, insulation reaction 10 hours is transferred pH=5 ~ 6 with acetic acid, add the water with ethanol equivalent, be cooled to 0 ℃, crystallization 8 hours is filtered, 60 ℃ of decompression dryings of filter cake 8 hours obtain the compound of structural formula 4; The compound Shou of this step resulting structures formula 4 Shuais＞=and 90%, Chun Du＞=99%;
The compound of the structural formula 4 that II. described step I is obtained drops in the mixing acid that acetic acid that volume ratio is 1 ﹕ 0.5 and hydrochloric acid forms, the compound 4 of described structural formula 4 is 1 ﹕, 5 ~ 1 ﹕ 6 with the weight/volume of described mixing acid, be warming up to 80-90 ℃, it is limpid to be stirred to solution, refluxes 20 hours, is cooled to 0 ℃, crystallization 8 hours, filter, 60 ℃ of decompression dryings of filter cake 8 hours obtain 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) the propionic salt hydrochlorate; This step gained 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) propionic salt hydrochlorate receipts rate＞=95%, pure degree＞=98 %.
Scheme described in the background technology 2 produces the reason of punching material, and the contriver thinks it may is that compound solubleness in hydrochloric acid of structural formula 4 is little, and decarboxylic reaction occurs suddenly to cause during reacting by heating.The present invention is in the decarboxylic reaction of the compound of structural formula 4, the mixing acid that adopts organic acid-mineral acid to form replaces hydrochloric acid, increased the solubleness of the compound of the compound of structural formula 4 and structural formula 1, thereby alleviated the severe degree of reaction, make simultaneously reaction more complete, ultimate yield goes on foot total recovery greater than 80%, far above scheme 2 greater than 90%, two.
Embodiment
The present invention is further elaborated below in conjunction with specific embodiment.Should be appreciated that these embodiment only are used for explanation the present invention and non-limiting scope of the present invention.The experimental technique of unreceipted actual conditions in the following example is usually according to normal condition or the condition that provides or advise according to manufacturer.Except other has definition or explanation, the same meaning that all specialties used herein and scientific words and those skilled in the art are familiar with.In addition, any method similar or impartial to described content and material all can be used in the inventive method, and these equivalent form of values fall within limited range of the present invention equally.
Embodiment 1:2-acetylaminohydroxyphenylarsonic acid 2-ethyl formate-3-(2-quinolinone-4 base)-preparation of ethyl propionate (compound of structural formula 4) is in the 10000ml there-necked flask, drop into first dehydrated alcohol 6000ml, drop into again 4-brooethyl benzene-1 hydrogen-2-quinolinone (compound of structural formula 2) 900 grams, acetamino diethyl malonate (compound of structural formula 3) 900 grams, sodium ethylate 425 grams, be warming up to 75 ℃, insulation reaction 10 hours, transfer PH=6 with acetic acid, add the water with ethanol equivalent, be cooled to 0 ℃ of crystallization 8 hours, filter, 60 ℃ of decompression dryings of filter cake 8 hours obtain 2-acetylaminohydroxyphenylarsonic acid 2-ethyl formate-3-(2-quinolinone-4 base)-ethyl propionate (compound of structural formula 4) 1360 grams, yield 96.2%.Measure the 2-acetylaminohydroxyphenylarsonic acid 2-ethyl formate of preparation-3-(2-quinolinone-4 base through the HPLC method)-purity of ethyl propionate is 98.3%.
Embodiment 2:2-amino-3-(2(1 hydrogen)-quinolone-4-yl) preparation of propionic salt hydrochlorate is in the 1000ml there-necked flask, the 2-acetylaminohydroxyphenylarsonic acid 2-ethyl formate of input formic acid 280g, concentrated hydrochloric acid 280g, embodiment 1 preparation-3-(2-quinolinone-4 base)-ethyl propionate 250g, be warming up to 85 ℃ of insulations 2 hours, be warming up to again backflow, under refluxad insulation reaction
24Hour, be cooled to below 20 ℃, filter.60 ℃ of oven dry of filter cake obtain 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) propionic salt hydrochlorate 163.6g, yield is that 91%, HPLC measures purity more than 99.5%.
1H-NMR(DMSO-
d6，400MHz）:δ11.69(1H,?HCl),?δ8.55(3H,?NH
2,?NH),?δ7.81(1H,?8-Hor11-H),?δ7.52(1H,?9-Hor10-H),?δ7.36(1H,?8-Hor11-H?),?δ7.22(1H,?9-Hor10-H?),?δ6.49(1H,?5-H?),?δ4.14(1H,?2-H?),?δ3.30-3.40(2H,?3-H?)。
13C-NMR(DMSO-
d6，400MHz)：δ170(1C,?1-Cor6-C),?δ161.36(1C,?1-Cor6-C),?δ144.7(1C,?7-C),?δ139.29(1C,?12-C),?δ130.54(1C,?8-Cor9-Cor10-Cor11-C),?δ124.22?(1C,?8-Cor9-Cor10-C?or11-C),?δ123.35(1C,?8-Cor9-Cor10-Cor11-C),?δ122(1C,?8-Cor?9-Cor10-Cor11-C),?δ118.49(1C,?4-C)?,?δ115.99(1C,?5-C),?δ51.64(1C,?2-C),?δ32.54(1C,?3-C)。
ESI-MS：m/z267[M-H]
+，m/z231[M-HCl-H]
+。
Embodiment 3:2-amino-3-(2(1 hydrogen)-quinolone-4-yl) preparation of propionic salt hydrochlorate is in the 1000ml there-necked flask, the 2-acetylaminohydroxyphenylarsonic acid 2-ethyl formate of input acetic acid 280g, concentrated hydrochloric acid 280g, embodiment 1 preparation-3-(2-quinolinone-4 base)-ethyl propionate 250g, be warming up to 87 ℃ of insulations 2 hours, be warming up to again backflow, under refluxad insulation reaction
24Hour, be cooled to below 20 ℃, filter.60 ℃ of oven dry of filter cake obtain 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) propionic salt hydrochlorate 172.6g, yield is that 96%, HPLC measures purity more than 99.5%.
1H-NMR(DMSO-
d6，400MHz）:δ11.72(1H,?HCl),?δ8.69(3H,?NH
2,?NH),?δ7.83(1H,?8-Hor11-H),?δ7.48(1H,?9-Hor10-H),?δ7.30(1H,?8-Hor11-H?),?δ7.19(1H,?9-Hor10-H?),?δ6.52(1H,?5-H?),?δ4.10(1H,?2-H?),?δ3.25-3.34(2H,?3-H?)。
ESI-MS：m/z267[M-H]
+，m/z231[M-HCl-H]
+。
Embodiment 4:2-amino-3-(2(1 hydrogen)-quinolone-4-yl) preparation of propionic acid vitriol is in the 1000ml there-necked flask, the 2-acetylaminohydroxyphenylarsonic acid 2-ethyl formate of input acetic acid 280g, 50% sulfuric acid 180g, embodiment 1 preparation-3-(2-quinolinone-4 base)-ethyl propionate 250g, be warming up to 90 ℃ of insulations 2 hours, be warming up to again backflow, under refluxad insulation reaction
24Hour, be cooled to below 20 ℃, filter.60 ℃ of oven dry of filter cake get 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) propionic acid vitriol 214g, yield is 97%, purity is more than 99.5%.
1H-NMR(DMSO-
d6，400MHz）:δ11.65(2H,?H
2SO
4),?δ8.54(3H,?NH
2,?NH),?δ7.80(1H,?8-Hor11-H),?δ7.55(1H,?9-Hor10-H),?δ7.28(1H,?8-Hor11-H?),?δ7.25(1H,?9-Hor10-H?),?δ6.47(1H,?5-H?),?δ4.12(1H,?2-H?),?δ3.35-3.45(2H,?3-H?)。
ESI-MS：m/z329[M-H]
+，m/z231[M-H
2SO
4-H]
+。
Embodiment 5:2-amino-3-(2(1 hydrogen)-quinolone-4-yl) preparation of propionic acid Hydrogen bromide hydrochlorate is in the 1000ml there-necked flask, the 2-acetylaminohydroxyphenylarsonic acid 2-ethyl formate of input acetic acid 280g, 42% Hydrogen bromide 400g, embodiment 1 preparation-3-(2-quinolinone-4 base)-ethyl propionate 250g, be warming up to 85 ℃ of insulations 2 hours, be warming up to again backflow, under refluxad insulation reaction
24Hour, be cooled to below 20 ℃, filter.60 ℃ of oven dry of filter cake get 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) propionic acid hydrobromate 190g, yield is that 91%, HPLC measures purity more than 99.5%
1H-NMR(DMSO-
d6，400MHz）:δ10.32(1H,?HBr),?δ8.50(3H,?NH
2,?NH),?δ7.83(1H,?8-Hor11-H),?δ7.50(1H,?9-Hor10-H),?δ7.30(1H,?8-Hor11-H?),?δ7.20(1H,?9-Hor10-H?),?δ6.42(1H,?5-H?),?δ4.10(1H,?2-H?),?δ3.26-3.36(2H,?3-H?)。
ESI-MS：m/z311[M-H]
+，m/z231[M-HBr-H]
+。
Claims (8)
1. the preparation method of the compound of a structural formula 1, R=HCl wherein, H
2SO
4, HBr or H
3PO
4, comprise the steps:
I. the compound of the compound of structural formula 2 and structural formula 3 is in the presence of alkali, at C
1-C
4Fatty Alcohol(C12-C14 and C12-C18) in react; Reaction finishes, and with acid for adjusting pH≤8, adds entry, filters the compound that obtains structural formula 4;
II. in organic solvent, 30-130 ℃, compound and the acid-respons of the structural formula 4 that described step I is obtained, reaction finishes, and crystallisation by cooling filters, and obtains the compound of structural formula 1;
It is characterized in that: the acid in the described Step II is comprised of organic acid and mineral acid, and described organic acid is selected from formic acid or acetic acid, and mineral acid is selected from hydrochloric acid or sulfuric acid, and the volume ratio of described organic acid and mineral acid is 1 ﹕, 0.1 ~ 1 ﹕ 3.
2. preparation method according to claim 1, it is characterized in that: described organic acid is selected from formic acid or acetic acid, and mineral acid is selected from hydrochloric acid, and the volume ratio of described organic acid and mineral acid is 1 ﹕, 1 ~ 1 ﹕ 2.
3. preparation method according to claim 1 is characterized in that: in the described Step II, the weight/volume of the compound of structural formula 4 and acid is 1 ﹕ 1g/ml ~ 1 ﹕ 50g/ml.
4. preparation method according to claim 3 is characterized in that: in the described Step II, the weight/volume of the compound of structural formula 4 and acid is 1 ﹕ 1g/ml ~ 1 ﹕ 20g/ml.
5. preparation method according to claim 1 is characterized in that: among the described step I, and the compound of described structural formula 2 and C
1-C
4The weight/volume of Fatty Alcohol(C12-C14 and C12-C18) be 1 ﹕ 4g/ml ~ 1 ﹕ 20g/ml.
6. preparation method according to claim 1 is characterized in that: described C
1-C
4Fatty Alcohol(C12-C14 and C12-C18) be ethanol.
7. preparation method according to claim 1 is characterized in that: the recrystallization that also comprises the compound of the structural formula 1 that described Step II obtains.
8.2-amino-3-(the 2(1 hydrogen)-quinolone-4-yl) preparation method of propionic salt hydrochlorate, concrete operations are:
I. the compound of the compound of structural formula 2, structural formula 3 and sodium ethylate drop in the dehydrated alcohol in molar ratio=1 ﹕, 0.5 ﹕, 1 ~ 1 ﹕, 10 ﹕ 1.2, the compound of described structural formula 2 and the weight/volume of dehydrated alcohol are 1 ﹕ 7g/ml ~ 1 ﹕ 9g/ml, be warming up to 75-80 ℃, insulation reaction 10 hours is transferred pH=5 ~ 6 with acetic acid, add the water with ethanol equivalent, be cooled to 0 ℃, crystallization 8 hours is filtered, 60 ℃ of decompression dryings of filter cake 8 hours obtain the compound of structural formula 4;
The compound of the structural formula 4 that II. described step I is obtained drops in the mixing acid that acetic acid that volume ratio is 1 ﹕ 0.5 and hydrochloric acid forms, the compound of described structural formula 4 and the weight/volume of described mixing acid are 1 ﹕ 5g/ml ~ 1 ﹕ 6g/ml, be warming up to 80-90 ℃, it is limpid to be stirred to solution, refluxes 20 hours, is cooled to 0 ℃, crystallization 8 hours, filter, 60 ℃ of decompression dryings of filter cake 8 hours obtain 2-amino-3-(2(1 hydrogen)-quinolone-4-yl) the propionic salt hydrochlorate.
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|---|---|---|---|---|
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| JPS6019767A (en) * | 1983-07-11 | 1985-01-31 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
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Address after: 330700 Fengxin County Industrial Park, Jiangxi, Yichun Patentee after: Jiangxi with and medicine company limited-liability company Address before: 330700 Fengxin County Industrial Park, Jiangxi, Yichun Patentee before: Jiangxi Synergy Pharmaceuticals Co., Ltd. |