CN1526700A - Synthesis of Important intermediate for mosapride citrate - Google Patents
Synthesis of Important intermediate for mosapride citrate Download PDFInfo
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- CN1526700A CN1526700A CNA031119131A CN03111913A CN1526700A CN 1526700 A CN1526700 A CN 1526700A CN A031119131 A CNA031119131 A CN A031119131A CN 03111913 A CN03111913 A CN 03111913A CN 1526700 A CN1526700 A CN 1526700A
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Abstract
The present invention relates to the preparation process of important intermediates for Mosapride citrate, 2-oxethyl-4-actamino-5-chlorobenzoic acid and 4-(4-fluorobenzyl-2- aminomethyl morpholine. The intermediate 2-oxethyl-4-actamino-5-chlorobenzoic acid is prepared with amino salicylic acid as initial material and through acidification with hydrochloric acid, esterification with methol, acetylation with acetic anhydride, ethylation, NCS chlorination and alkali hydrolysis. The intermediate 4-(4-fluorobenzyl-2- aminomethyl morpholine is prepared with p-fluorobenzaldehyde and phthalimide as initial material and through dropping at 70-90 deg.c, maintaining at 125-145 deg.c, and post-treatment in ice bath in 2-10 deg.c while adding acetic anhydride through stirring for 10-20hr. The present invention can raise the yield of Mosapride citrate and lower its production cost.
Description
Technical field
The invention provides the preparation technology of Mosapride Citrate important intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro-benzoic acid (1) and important intermediate 4-(4-luorobenzyl)-2-aminomethyl morpholine (2), belong to medical technical field.
Background technology
Along with the quickening of social life rhythm, the raising of people's living standard and the factors such as change of dietary structure cause the low morbidity crowd of gastric motility increasing, and people's quality of life is subjected to very big influence.And Mosapride Citrate does not have the medicine for stomach dynamic of Dopamine Receptors antagonistic action as first, and because of its clinical efficacy is good, side effect is low, safety, characteristics such as efficient at home and abroad have been widely used, selection and the help removing slight illness, get well and provide new for the patient.
There is more deficiency in existing Mosapride Citrate raw material synthesis technique, mainly show in the process of preparation intermediate (1), ethylization reagent iodoethane costs an arm and a leg, and yield is not high, and the preparation cost that causes intermediate (1) is near half of the synthetic total cost of Mosapride Citrate raw material; The synthesis yield of intermediate (2) is also lower, has only 40%, and the finished product shade deviation, is Vandyke brown.Find that through intermediate backstepping purifying also the second-rate the finished product that caused of intermediate (2) often are difficult to meet the requirements just when detecting related substance.These many factor affecting the promotion and application of Mosapride Citrate.
Intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro-benzoic acid (1) is:
Intermediate 4-(4-luorobenzyl)-2-aminomethyl morpholine (2) is:
Through long term studies, we have invented a kind of technology, by optimizing intermediate (1) and synthesizing of intermediate (2) reducing production costs, improve final product quality and yield.
Summary of the invention
In the preparation process of intermediate (1), by factors such as control reaction temperature, reaction times, mixing effects, we find to use ethylization reagent monobromethane to replace iodoethane, the former price is about 1/100 of latter's price, so not only can reduce cost, make the preparation cost of intermediate (1) reduce to 500 yuan/kg, yield is slightly improved by 3000 yuan/kg.Intermediate (1) to be being starting raw material to amino salicylic acid, through hcl acidifying, methanol esterification, diacetyl oxide acetylize, monobromethane ethylize, N-chlorosuccinimide (NCS) chloro, 6 steps of basic hydrolysis obtain intermediate (1).The total recovery of intermediate in this process (1) is 55%.
The starting raw material of intermediate (1) is pushed into amino salicylic acid sodium before by 4-acetylaminohydroxyphenylarsonic acid 2 hydroxybenzoic acid methyl esters, makes raw material sources more extensive, provide convenience for producing flexibly, and price problem is alleviated.Be pushed into p-Fluorobenzenecarboxaldehyde before synthesis material 2-(the 4-fluorobenzene methylamine) ethanol with intermediate (2), N-(2, the 3-epoxypropyl) is pushed into phthalic imidine before the phthalic imidine, thereby realized all production domesticization and cheap and easy to get of starting raw material and reaction reagent, whole route reaction is steady and easy to operate.
Mosapride Citrate is starting raw material with the p-Fluorobenzenecarboxaldehyde, through the nucleophilic addition(Adn) of 2-monoethanolamine, obtains imines after the adduct dehydration immediately; Imines is directly used NaBH without separating
4Reduce intermediate 2-(4-fluorobenzene methylamino-) ethanol, with intermediate 2-(4-fluorobenzene methylamino-) ethanol and intermediate N (2, the 3-epoxypropyl) phthalic imidine through the intermediate product of self base catalysis ring-opening reaction gained again through dense H
28O
4Catalytic hydrolysis, high temperature dehydration cyclization get intermediate (2) crude product, and intermediate (2) crude product must be made with extra care intermediate (2) through acetylize, the hydrochloric acid hydrolysis of diacetyl oxide.
The invention reside in, the starting raw material of intermediate (1) is to amino salicylic acid sodium, and ethylization reagent adopts monobromethane; The starting raw material of intermediate (2) is p-Fluorobenzenecarboxaldehyde and phthalic imidine, and in preparation technology, temperature control slowly drips for 70 ℃～90 ℃, and holding temperature is 125 ℃～145 ℃; During aftertreatment, 2 ℃～10 ℃ of ice baths stirred 10 hours～20 hours after adding diacetyl oxide.Intermediate (2) is light yellow, and yield can be up to 75.4%, and makes the difficult qualified problem of the finished product related substance obtain solution in the lump.
The preparation technology of Mosapride Citrate important intermediate provided by the present invention can effectively reduce production costs, and improves the synthesis yield and the final product quality of Mosapride Citrate, and reaction conditions is gentle.
Embodiment
Further specify the present invention by following example, but it has no intention to limit the scope of application.Description in the following example all obtains by method known to those skilled in the art.
Example 1
The preparation of the adjacent hydroxyl para-amino benzoic acid of intermediate: adjacent hydroxyl Sodium p-aminobenzoate two water thing 100g are water-soluble, stir, and drip concentrated hydrochloric acid to 150g, and cooling is filtered, get final product the adjacent hydroxyl para-amino benzoic acid of intermediate, yield is 96.5%.
Example 2
The preparation of the adjacent hydroxyl methyl p-aminobenzoate of intermediate: the adjacent hydroxyl para-amino benzoic acid of intermediate is dissolved in methyl alcohol, stirs, and drips the vitriol oil, refluxes, and removes methyl alcohol, adds saturated K in the residue
2CO
3Solution.Cooling is left standstill, and filters, and gets the off-white color solid, is adjacent hydroxyl methyl p-aminobenzoate, and yield is 79.7%.
Example 3
The preparation of the adjacent hydroxyl paraacetaminobenzoic acid of intermediate methyl esters: the adjacent hydroxyl methyl p-aminobenzoate of intermediate is dissolved in the glacial acetic acid, stir, drip diacetyl oxide, remove then and desolvate, add NaOH solution in the raffinate, separate out the off-white color solid, filter, get the adjacent hydroxyl methyl p-aminobenzoate of intermediate, yield is 80.0%.
Example 4
The preparation of the adjacent oxyethyl group paraacetaminobenzoic acid of intermediate methyl esters: stir in the adjacent hydroxyl paraacetaminobenzoic acid of intermediate methyl esters, monobromethane, Anhydrous potassium carbonate, the DMF adding reactor.Reaction is poured mixture in the frozen water into after finishing, and gets the off-white color throw out, filters, and gets the adjacent oxyethyl group paraacetaminobenzoic acid of off-white color intermediate methyl esters, yield 98.6%.
Example 5
The preparation of intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether: the adjacent oxyethyl group paraacetaminobenzoic acid of intermediate methyl esters, N-chlorosuccinimide, DMF add in the reactor, reacted 2 hours, in the reactant impouring frozen water, the collecting precipitation thing, filter, get the off-white color solid, be intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether, yield is 96.3%.
Example 6
The preparation of intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro-benzoic acid: intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro benzoic ether, sodium hydroxide, water, ethanol add in the reaction flask, reflux, cooling, the reaction solution acidifying, throw out is filtered, get the off-white color solid, be intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro-benzoic acid, yield is 94.1%.
Example 7
The preparation of intermediate 2-(4-fluorobenzene methylamino-) alcoholic acid: the 4-fluorobenzaldehyde, the 2-monoethanolamine refluxes, and adds sodium borohydride, stir, reaction finishes, and filters, and filtrate is concentrated into dried, collect cut, get colorless oil, be intermediate 2-(4-fluorobenzene methylamino-) ethanol, yield is 85%.
Example 8
The preparation of intermediate N (2, the 3-epoxypropyl) phthalic imidine: potassium hydroxide is stand-by in the water-soluble and alcoholic acid mixing solutions.Phthalic imidine, dehydrated alcohol add in the reactor, and the dissolving that refluxes is in the clear liquid impouring stock solution, generate chip solid, suction filtration, small amount of ethanol washing, drain the white plates solid, itself and epoxy chloropropane are added in the reactor, reflux, steam and remove the epoxy chloropropane, add dehydrated alcohol in the resistates, stir, the filtering insolubles, the white granular solid is separated out in cooling, promptly get N-(2, the 3-epoxypropyl) phthalic imidine, yield is 70.2%.
Example 9
The preparation of intermediate (2): with intermediate N (2, the 3-epoxypropyl) phthalic imidine, intermediate 2-(4-fluorobenzene methylamino-) ethanol adds in the reactor, stir, temperature control slowly drips the vitriol oil for 75 ℃, finishes reaction solution in 128 ℃ of reactions 2 hours, be chilled to room temperature, in the impouring frozen water, neutralization, chloroform extraction, ice bath are cooled to 8 ℃, add diacetyl oxide, 20 ℃ were stirred 15 hours, solvent evaporated, and resistates gets white solid with the toluene recrystallization, hydrochloric acid hydrolysis again, yield 75.4%.
Example 10
The preparation of Mosapride Citrate: intermediate (1) is suspended in the chloroform, adds the triethylamine stirring and dissolving, cooling drips isobutyl chlorocarbonate, stir, add the chloroformic solution of intermediate (2), reaction, mixture water and 10% sodium hydroxide solution wash respectively, and drying is concentrated into dried, residue gets white solid with ethyl alcohol recrystallization, and it is added in the aqueous solution of citric acid, refluxes, add gac, reflux half an hour cold analysis, suction filtration gets faint yellow solid, is the Mosapride Citrate crude product.With aqueous solution of citric acid to Mosapride Citrate recrystallization three times, its elaboration, yield 63.0%.The gained elaboration is by proofs such as ultimate analysis, ultraviolet, infrared, nuclear magnetic resonance map, mass spectroscopy, and institute's synthetic Mosapride Citrate and reference substance are in full accord.
Claims (6)
1, the important intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro-benzoic acid (1) of preparation Mosapride Citrate and the preparation technology of important intermediate 4-(4-luorobenzyl)-2-aminomethyl morpholine (2) is characterized in that:
(i) starting raw material of described important intermediate (1) is to amino salicylic acid, through hcl acidifying, methanol esterification, diacetyl oxide acetylize, ethylization, N-chlorosuccinimide chloro, basic hydrolysis 6 go on foot important intermediate (1);
The starting raw material of (ii) described important intermediate (2) is p-Fluorobenzenecarboxaldehyde and phthalic imidine, and in the time of in its building-up process, temperature control slowly drips the vitriol oil for 70 ℃～90 ℃, holding temperature is 125 ℃～145 ℃, during aftertreatment, 2 ℃～10 ℃ of ice baths stirred 10 hours～20 hours after adding diacetyl oxide.
2, the described preparation technology of claim 1, its feature is in the preparation process of important intermediate (1), and employed ethylating agent was a monobromethane when it ethylized.
3, the described preparation technology of claim 1, its feature are in the preparation process of important intermediate (2), and the control temperature when it slowly drips is 75 ℃
4, the described preparation technology of claim 1, its feature are in the preparation process of important intermediate (2), and its holding temperature is 128 ℃.
5, the described preparation technology of claim 1, its feature are in the preparation process of important intermediate (2), and the ice bath temperature during its aftertreatment is 8 ℃.
6, the described preparation technology of claim 1, its feature are in the preparation process of important intermediate (2), and it stirred 15 hours after adding diacetyl oxide.
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| CN 03111913 CN1226295C (en) | 2003-03-03 | 2003-03-03 | Synthesis of Important intermediate for mosapride citrate |
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| CN 03111913 CN1226295C (en) | 2003-03-03 | 2003-03-03 | Synthesis of Important intermediate for mosapride citrate |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102320986A (en) * | 2011-07-25 | 2012-01-18 | 武汉武药科技有限公司 | Preparation method for clopidogrel intermediate |
| CN101565381B (en) * | 2009-06-01 | 2013-07-24 | 重庆英斯凯化工有限公司 | Method for preparing 2-alkoxy-4-amino-5-chlorobenzoic acid |
| CN101538217B (en) * | 2008-03-20 | 2015-04-15 | 成都弘达药业有限公司 | Novel synthesis method and intermediate for 2-ethoxy-4-amino-5-chlorobenzoic acid |
| CN104693137A (en) * | 2013-12-10 | 2015-06-10 | 沈阳药科大学 | Active metabolite of mosapride |
| CN104693064A (en) * | 2013-12-10 | 2015-06-10 | 沈阳药科大学 | Active metabolite of mosapride |
| CN108129414A (en) * | 2018-02-09 | 2018-06-08 | 鲁南制药集团股份有限公司 | A kind of preparation method of mosapride citrate intermediate |
| CN108341788A (en) * | 2018-02-09 | 2018-07-31 | 鲁南制药集团股份有限公司 | A kind of mosapride citrate intermediate and purposes |
| CN111848432A (en) * | 2020-07-15 | 2020-10-30 | 广药白云山化学制药(珠海)有限公司 | Preparation method of p-aminosalicylic acid |
| CN112225708A (en) * | 2020-12-14 | 2021-01-15 | 上海翰森生物医药科技有限公司 | Preparation method of mosapride intermediate |
-
2003
- 2003-03-03 CN CN 03111913 patent/CN1226295C/en not_active Expired - Lifetime
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101538217B (en) * | 2008-03-20 | 2015-04-15 | 成都弘达药业有限公司 | Novel synthesis method and intermediate for 2-ethoxy-4-amino-5-chlorobenzoic acid |
| CN101565381B (en) * | 2009-06-01 | 2013-07-24 | 重庆英斯凯化工有限公司 | Method for preparing 2-alkoxy-4-amino-5-chlorobenzoic acid |
| CN102320986A (en) * | 2011-07-25 | 2012-01-18 | 武汉武药科技有限公司 | Preparation method for clopidogrel intermediate |
| CN102320986B (en) * | 2011-07-25 | 2014-06-25 | 武汉武药科技有限公司 | Preparation method for clopidogrel intermediate |
| CN104693137A (en) * | 2013-12-10 | 2015-06-10 | 沈阳药科大学 | Active metabolite of mosapride |
| CN104693064A (en) * | 2013-12-10 | 2015-06-10 | 沈阳药科大学 | Active metabolite of mosapride |
| CN108129414A (en) * | 2018-02-09 | 2018-06-08 | 鲁南制药集团股份有限公司 | A kind of preparation method of mosapride citrate intermediate |
| CN108341788A (en) * | 2018-02-09 | 2018-07-31 | 鲁南制药集团股份有限公司 | A kind of mosapride citrate intermediate and purposes |
| CN108129414B (en) * | 2018-02-09 | 2020-12-08 | 鲁南制药集团股份有限公司 | Preparation method of mosapride citrate intermediate |
| CN111848432A (en) * | 2020-07-15 | 2020-10-30 | 广药白云山化学制药(珠海)有限公司 | Preparation method of p-aminosalicylic acid |
| CN112225708A (en) * | 2020-12-14 | 2021-01-15 | 上海翰森生物医药科技有限公司 | Preparation method of mosapride intermediate |
| CN112225708B (en) * | 2020-12-14 | 2021-04-09 | 上海翰森生物医药科技有限公司 | Preparation method of mosapride intermediate |
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| CN1226295C (en) | 2005-11-09 |
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Application publication date: 20040908 Assignee: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2013370000261 Denomination of invention: Synthesis of Important intermediate for mosapride citrate Granted publication date: 20051109 License type: Exclusive License Record date: 20131210 |
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Effective date of registration: 20161228 Address after: 276005 Hongqi Road, Shandong, Linyi, No. 209 Patentee after: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Address before: 276005 Hongqi Road, Shandong, Linyi, No. 209 Patentee before: LUNAN PHARMACEUTICAL Group Corp. |
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