CN105439977A - Preparation methods for acotiamide and hydrochloride thereof - Google Patents
Preparation methods for acotiamide and hydrochloride thereof Download PDFInfo
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- CN105439977A CN105439977A CN201410501246.7A CN201410501246A CN105439977A CN 105439977 A CN105439977 A CN 105439977A CN 201410501246 A CN201410501246 A CN 201410501246A CN 105439977 A CN105439977 A CN 105439977A
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Abstract
The invention discloses preparation methods for acotiamide and hydrochloride thereof; 2[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxylic acid methyl ester and N,N-diisoprylamino ethylamine are subjected to a reaction in a molten state to obtain N-[2-(diisopropylamino)ethyl]-2-(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide, and hydrochloric acid is dropwise added to N-[2-(diisopropylamino)ethyl]-2-(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide in methanol to prepare acotiamide hydrochloride trihydrate. The preparation methods reduce the use of toluene, and are economical and convenient, complete in reaction, and safe in process; at the same time, toluene residues in the final products and the amount of an impurity 2[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-4-carboxyl-1,3-thiazole are reduced, and the product quality is improved; and the crude products are easy to refine and purify, and the reaction yield is high.
Description
Technical field
The present invention relates to and a kind ofly prepare the method for Ah examining for amine and hydrochloride thereof.
Background technology
Ah examining is for amine, and chemical name is: N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxylic acid amides, and structure is as follows:
What apply in the market is its hydrochloride, by Japanese ZeriaPharmaceutical company and Astellas joint development, Ah examining is acetylcholinesterase depressant class stomach motility enhancing medicine for amine, namely functional dyspepsia (Functionaldyspepsia is treated, FD) medicine, in June, 2013, commodity were called Acofide in Japanese Initial Public Offering.Along with the raising that people require quality of life and are familiar with functional dyspepsia, the medical number of FD is increasing gradually, becomes the modal disease partner of Digestive System Department and waits one of group.High morbidity, for functional dyspepsia medicine provides huge market.
Formerly grind the preparation method that patent CN200580028537 describes acotiamide hydrochloride hydrate, its reaction process is as follows:
First 2-hydroxyl-4,5-dimethoxybenzoic acid and triphenyl phosphite are placed in toluene, add several vitriol oils as catalyzer back flow reaction, obtain intermediate 2-hydroxyl-4,5-dimethoxybenzoic acid phenyl ester.Afterwards above-mentioned intermediate and thiazolamine-4-methyl-formiate are placed in toluene, add the reaction of triphenyl-boron acid esters, 2-[(2-hydroxyl-4 is obtained through aftertreatment, 5-dimethoxybenzoyl) amino]-1,3-thiazole-4-carboxylic acid methyl esters, with N, N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4 is obtained after N-diisopropyl ethylenediamine reacts in toluene, 5-dimethoxybenzoyl) amino]-1,3-thiazole-4-carboxylic acid amides, then becomes hydrochloride to obtain acotiamide hydrochloride trihydrate with isopropanol water solution recrystallization.
In the method, 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxylate methyl ester and N, N-diisopropyl ethylenediamine react in toluene, avoid reactant painted, make aftertreatment relatively simple.Select toluene to make solvent, after reacting completely, use saturated aqueous common salt heated scrub, be then spin-dried for and be replaced as Virahol and add hydrochloric acid salify, finally use isopropanol water solution recrystallization, then the acquisition target product acotiamide hydrochloride trihydrate of stable yield that can be good.But find that this method exists some defects in practice:
1) acutely seethe with excitement when when toluene makees solvent, temperature is more than 110 DEG C, slower lower than reaction when 110 DEG C, and reaction comparatively easily incomplete (residual 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-1,3-thiazoles-4-carboxylate methyl ester is difficult to removing in aftertreatment and final refining operation);
2) toluene is due to boiling point high (110 DEG C), and toluene replacement cannot cause residual toluene to be easily wrapped difficulty with product molecule generation effect removing by Virahol completely;
3) to main synthesis impurity 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-4-carboxyl-1,3-thiazole { N, the a small amount of water contained in N-diisopropyl ethylenediamine, cause 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-1, the 3-thiazole-4-carboxylic acid methyl esters impurity that hydrolysis produces in the middle of reaction }, removing effect poor (being greater than 0.1% all the time), needs to lose purification process that portion of product yield is cost to obtain qualified end product.
Summary of the invention
For solving the problems of the technologies described above, inventors performed lot of experiments, for the building-up reactions flow process of amine, improvement has been made to Ah examining, by 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-1,3-thiazole-4-carboxylic acid methyl esters [formula (4)] and N, N-diisopropyl ethylenediamine reacts obtained Shi get A Kao in the molten state for amine: N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-1,3-thiazole-4-carboxylic acid amides [formula (5)]
（4）
（5）
Do not need to use toluene as reaction solvent, economical convenient, reaction is carried out comparatively rapid, 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-1,3-thiazole-4-carboxylic acid methyl esters [formula (4)] also can react completely, and overcomes with toluene temperature height when being solvent and then acutely seethes with excitement, there is production safety hidden danger, then react slower when temperature is low, and reaction is comparatively not exclusively easy and in finished product, toluene is difficult to the defect removed completely, reduces Residual Toluene in finished product, Improving The Quality of Products.
2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-1,3-thiazoles-4-carboxylate methyl ester [formula (4)] and N, N-diisopropyl ethylenediamine can fill nitrogen in molten state reaction process, temperature of reaction can select 90 DEG C ~ 120 DEG C, and the reaction times is 2 ~ 6h; Preferably 100 DEG C ~ 110 DEG C, insulation reaction 3 ~ 3.5h, to reaction end, is cooled to less than 90 DEG C, add water insulation 70 ~ 90 DEG C of stirring reactions residual lower than less than 0.15% to raw material, continue to be cooled to less than 40 DEG C, add dichloromethane extraction, collect organic phase, wash with water more once, anhydrous sodium sulfate drying, filter, filtrate 40 DEG C is spin-dried for.Because methylene dichloride is poorly soluble to main synthesis impurity 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-4-carboxyl-1,3-thiazoles, the removing of aforesaid method process to this impurity is effective.
2-used [(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-1,3-thiazole-4-carboxylic acid methyl esters [formula (4)] can by 2-hydroxyl-4,5-dimethoxybenzoic acid phenyl ester [formula (3)] and thiazolamine-4-methyl-formiate, in toluene, add the reaction of triphenyl-boron acid esters and obtain.
（3）
2-hydroxyl-4,5-dimethoxybenzoic acid phenyl ester [formula (3)] used can by 2-hydroxyl-4,5-dimethoxybenzoic acid [formula (2)] and triphenyl phosphite in toluene, obtained using the vitriol oil as catalyzer back flow reaction.
（2）
2-hydroxyl-4,5-dimethoxybenzoic acid used [formula (2)] can by iodo-4, the 5-dimethoxybenzoic acids of 2-[formula (1)] and anhydrous cupric sulfate, and aqueous sodium hydroxide solution and pyridine mixing, drip hydrochloric acid crystallization and obtain after reacting completely.
（1）
This step preferred reaction conditions is: iodo-4, the 5-dimethoxybenzoic acids of 2-[formula (1)] mix with anhydrous cupric sulfate, 10% aqueous sodium hydroxide solution, pyridine, nitrogen protection; stirring is warming up to 95 ~ 100 DEG C, insulation reaction 1.5 ~ 2h, is cooled to 20 ~ 30 DEG C after reacting completely; filter, collect filtrate, under stirring, hydrochloric acid is added dropwise in filtrate; be cooled to 15 ~ 25 DEG C, insulated and stirred crystallization 0.5 ~ 1h, filter; filter cake is washed, and drains, and material 3 ~ 4h is dried in 70 ~ 80 DEG C of air blast; constant weight, rewinding.
The present invention discloses the preparation method of acotiamide hydrochloride trihydrate [formula (6)]: Ah examining obtained for as above method is added hydrochloric acid for amine in methyl alcohol and obtains.
（6）
Preferred reaction conditions adds methyl alcohol for Ah examining for amine, stirs clearly molten, adds hydrochloric acid, to system PH < 1, cooling crystallization, to 15 ~ 25 DEG C of more than stirring and crystallizing 0.5h, filters, filter cake methyl alcohol drip washing, drain, 45 DEG C of air blast dry material to constant weight, rewinding.
Obtained acotiamide hydrochloride trihydrate is by laxative remedy purifying: it mixed with dehydrated alcohol and water, stirring is warming up to 90 ~ 95 DEG C, and system is clearly molten, stops heating, filtered while hot, filtrate naturally cools to 30 DEG C, continues to be cooled to 10 ~ 20 DEG C, insulated and stirred more than crystallization 0.5h, filter, filter cake 25% aqueous ethanolic solution drip washing, drains, and 40 ~ 45 DEG C are dried material to constant weight.The larger impurity of polarity before most of main peak can be removed
In sum, preparation method disclosed in this invention, has technique effect useful as follows:
1) use of toluene is decreased, economical convenient, react completely, process safety;
2) Residual Toluene in finished product is reduced, and the content of impurity 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-4-carboxyl-1,3-thiazoles, Improving The Quality of Products;
3) crude product is easy to polishing purification, and reaction yield is high.
Embodiment
Embodiment 1
Preparation 2-hydroxyl-4,5-dimethoxybenzoic acid [formula (2)]-reaction conditions 1
2-iodo-4 is dropped in 250ml reaction flask, 5-dimethoxybenzoic acid [formula (1)] (20.0g), anhydrous cupric sulfate (1.0g), 10% aqueous sodium hydroxide solution (300ml), pyridine (4.0ml), nitrogen protection, stirring is warming up to 95 ~ 100 DEG C, insulation reaction 1.5 ~ 2h, sampling detects, react completely after (if unreacted continues insulation reaction 0.5h completely), be cooled to 20 ~ 30 DEG C, filter, collect filtrate, under stirring, 6N hydrochloric acid (120ml) is added in filtrate, be cooled to 15 ~ 25 DEG C, insulated and stirred crystallization 0.5 ~ 1h, filter, filter cake 100ml washes, drain, material 3 ~ 4h is dried in 70 ~ 80 DEG C of air blast, constant weight, rewinding, obtain 12.8g2-hydroxyl-4, 5-dimethoxybenzoic acid.
Embodiment 2
Preparation 2-hydroxyl-4,5-dimethoxybenzoic acid [formula (2)]-reaction conditions 2
2-iodo-4 is dropped in 250ml reaction flask, 5-dimethoxybenzoic acid [formula (1)] (45.0g), anhydrous cupric sulfate (2.3g), 10% aqueous sodium hydroxide solution (675ml), pyridine (10.0ml), nitrogen protection, stirring is warming up to 90 DEG C, insulation reaction 2 ~ 2.5h, sampling detects, react completely after (if unreacted continues insulation reaction 0.5h completely), be cooled to 20 ~ 30 DEG C, filter, collect filtrate, under stirring, 6N hydrochloric acid (270ml) is added in filtrate, be cooled to 15 ~ 25 DEG C, insulated and stirred crystallization 0.5 ~ 1h, filter, filter cake 100ml washes, drain, material 2.5 ~ 3h is dried in 75 ~ 85 DEG C of air blast, constant weight, rewinding, obtain 2-hydroxyl-4, 5-dimethoxybenzoic acid 27.4g.
Embodiment 3
Preparation 2-hydroxyl-4,5-dimethoxybenzoic acid phenyl ester [formula (3)]
2-hydroxyl-4 is added in 250ml reaction flask, 5-dimethoxybenzoic acid [formula (2)] (11.8g), triphenyl phosphite (20g, ), toluene (23ml), nitrogen protection, sulfuric acid (0.6ml) is added under stirring, be warming up to 110 ~ 115 DEG C, insulation reaction 3.5 ~ 4.5h, sampling detects, react completely after (if unreacted continues insulation reaction 0.5h completely), be cooled to 20 ~ 30 DEG C, add methyl alcohol (70ml), continue to be cooled to 15 ~ 25 DEG C, insulation crystallization 0.5 ~ 1h, filter, filter cake methyl alcohol 20ml drip washing, drain, 40 DEG C of air blast dry material to constant weight, rewinding, obtain 2-hydroxyl-4, 5-dimethoxybenzoic acid phenyl ester 11.4g.
Embodiment 4
Preparation 2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxylate methyl ester [formula (4)]
2-hydroxyl-4 is added in 250ml reaction flask, 5-dimethoxybenzoic acid phenyl ester [formula (3)] (10.4g), AK01(7.2g, , triphenyl borate (12.5g), toluene (50ml), nitrogen protection, be warming up to 100 ~ 105 DEG C, insulation reaction 3.5 ~ 4h, sampling detects, react completely after (if unreacted continues insulation reaction 0.5h completely), be cooled to 40 ~ 50 DEG C, add methyl alcohol (100ml), continue to be cooled to 15 ~ 25 DEG C, insulation crystallization 0.5 ~ 1h, filter, filter cake methyl alcohol 20ml drip washing, drain, 40 DEG C of air blast dry material to constant weight, rewinding, obtain 2-[(2-hydroxyl-4, 5-dimethoxybenzoyl) amino]-1, 3-thiazole-4-carboxylic acid methyl esters 11.9g.
Embodiment 5
Ah examining is for amine in preparation: N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxylic acid amides [formula (5)]-reaction conditions 1
2-[(2-hydroxyl-4 is added in 250ml reaction flask, 5-dimethoxybenzoyl) amino]-1, 3-thiazole-4-carboxylic acid methyl esters [formula (4)], N, N-diisopropyl ethylenediamine (10.9g), nitrogen protection, be warming up to 100 DEG C ~ 110 DEG C, insulation reaction 3 ~ 3.5h, sampling HPLC detects, react to raw material residual lower than 0.5% time be reaction end, be cooled to less than 90 DEG C, add water 100ml(100ml), be incubated 70 ~ 90 DEG C of more than stirring reaction 15min, residual lower than less than 0.15% to raw material, continue to be cooled to less than 40 DEG C, add methylene dichloride (100ml), extraction, collect organic phase, wash once with 40ml again, appropriate anhydrous sodium sulfate drying, filter, filtrate 40 DEG C is spin-dried for, obtain brown oily matter, do not weigh and directly enter the operation of lower step salify.
Embodiment 6
Ah examining is for amine in preparation: N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxylic acid amides [formula (5)]-reaction conditions 2
2-[(2-hydroxyl-4 is added in 500ml reaction flask, 5-dimethoxybenzoyl) amino]-1, 3-thiazole-4-carboxylic acid methyl esters [formula (4)] (24.7g), N, N-diisopropyl ethylenediamine (25.0g), nitrogen protection, be warming up to 110 DEG C ~ 120 DEG C, insulation reaction 3 ~ 3.5h, sampling HPLC detects, react to raw material residual lower than 0.5% time be reaction end, be cooled to less than 90 DEG C, add water (247ml), be incubated 60 ~ 80 DEG C of more than stirring reaction 20min, residual lower than less than 0.15% to raw material, continue to be cooled to less than 35 DEG C, add methylene dichloride (247ml), extraction, collect organic phase, appropriate anhydrous sodium sulfate drying, filter, filtrate 35 DEG C is spin-dried for, obtain brown oily matter, do not weigh and directly enter the operation of lower step salify.
Embodiment 7
Ah examining is for amine in preparation: N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxylic acid amides [formula (5)]-reaction conditions 3
2-[(2-hydroxyl-4 is added in 10L reactor, 5-dimethoxybenzoyl) amino]-1, 3-thiazole-4-carboxylic acid methyl esters [formula (4)] (1.3120kg), N, N-diisopropyl ethylenediamine (1.3120g), nitrogen protection, be warming up to 90 DEG C ~ 100 DEG C, insulation reaction 4.5h, sampling HPLC detects, react to raw material residual lower than 0.5% time be reaction end, be cooled to less than 90 DEG C, add water (13.1925kg), be incubated 70 ~ 90 DEG C of more than stirring reaction 15min, residual lower than less than 0.15% to raw material, continue to be cooled to less than 40 DEG C, add methylene dichloride (17.4420kg), extraction, collect organic phase, appropriate anhydrous sodium sulfate drying, filter, filtrate 50 DEG C is spin-dried for, obtain brown oily matter, do not weigh and directly enter the operation of lower step salify.
Embodiment 8
Preparation acotiamide hydrochloride trihydrate [formula (6)]-reaction conditions 1
Ah examining obtained for embodiment 5 is added methyl alcohol 50ml in amine oily matter, stir clearly molten, dropping adds hydrochloric acid (15ml), system is strongly-acid (PH < 1), cooling crystallization, to 15 ~ 25 DEG C of more than stirring and crystallizing 0.5h, filter, the drip washing of filter cake 20ml methyl alcohol, drain, 45 DEG C of air blast dry material to constant weight, rewinding, obtain acotiamide hydrochloride trihydrate 12.8g, purity 99.79%{ main technique impurity is all less than 0.05%, hydrolysis impurity: 2-[(2-hydroxyl-4, 5-dimethoxybenzoyl) amino]-4-carboxyl-1, 3-thiazole does not detect }.
H1-NMR(DMSO-
d 6 ,500MHz)δ:1.30(d,J=6.4Hz,6H);1.33(d,J=6.4,6H).
3.17-3.18(m,2H);3.59-3.69(m,4H),3.77(s,3H),3.82(s,3H).
6.76(s,1H),7.50(s,1H),7.89(s,1H);8.64(t,1H,J=5.9Hz).
9.70(s,1H);11.80(s,1H);
MS(FAB)m/e:451(M-H
-)
The measured value of crystal water: 9.99%
Embodiment 9
Preparation acotiamide hydrochloride trihydrate [formula (6)]-reaction conditions 2
Ah examining obtained for embodiment 7 is added methyl alcohol 5.2020kg in amine oily matter, stirs clearly molten, add hydrochloric acid (2.3655kg), system is strongly-acid (PH < 1), and cooling crystallization, to 15 ~ 25 DEG C of more than stirring and crystallizing 1h, filter, the drip washing of filter cake 0.5275kg methyl alcohol, drains, and 50 DEG C of air blast dry material to constant weight, rewinding, obtain acotiamide hydrochloride trihydrate 1.5210kg, purity 99.69%(main technique impurity and be all less than 0.05%, hydrolysis impurity does not detect).
Embodiment 10
Acotiamide hydrochloride trihydrate purification refine
In 100ml reaction flask, add acotiamide hydrochloride trihydrate (6.0g) prepared by embodiment 8, dehydrated alcohol (7.0ml), water (20ml), stir and be warming up to 90 ~ 95 DEG C, system is clearly molten, stop heating, filtered while hot, filtrate naturally cools to 30 DEG C, continue to be cooled to 10 ~ 20 DEG C, insulated and stirred more than crystallization 0.5h, filters, filter cake 25% aqueous ethanolic solution drip washing, drain, 40 ~ 45 DEG C are dried material to constant weight.Must refine acotiamide hydrochloride amine trihydrate 5.7g, purity 99.93%(hydrolysis impurity does not detect).
By 2-iodo-4, initial Ah the examining to refining of 5-dimethoxybenzoic acid (formula 1) is for amine trihydrate (purity more than 99.9%, maximum list is assorted is less than 0.04%, without hydrolysis impurity) system-wide line synthesis weight yield about 80%, technology stability is good, favorable repeatability simple to operate.
Claims (10)
1. formula (5)
（5）
The preparation method of the compound represented, is characterized in that: by formula (4)
（4）
The compound represented and N, N-diisopropyl ethylenediamine react obtained in the molten state.
2. preparation method as claimed in claim 1, is characterized in that described formula (4)
（4）
The formula (3) represented
（3）
The compound represented and thiazolamine-4-methyl-formiate, in toluene, add the reaction of triphenyl-boron acid esters and obtain.
3. preparation method as claimed in claim 2, is characterized in that described formula (3)
（3）
The formula (2) represented
（2）
The compound represented and triphenyl phosphite are in toluene, obtained using the vitriol oil as catalyzer back flow reaction.
4. preparation method as claimed in claim 3, is characterized in that described formula (2)
（2）
The formula (1) represented
（1）
The compound represented and anhydrous cupric sulfate, aqueous sodium hydroxide solution and pyridine mixing, drip hydrochloric acid crystallization and obtain after reacting completely.
5. preparation method as claimed in claim 1, is characterized in that: fill nitrogen in the compound that formula (4) represents and N, N-diisopropyl ethylenediamine reaction process, temperature of reaction is 90 DEG C ~ 120 DEG C, and the reaction times is 2 ~ 6h.
6. preparation method as claimed in claim 5, is characterized in that: the compound that formula (4) represents and N, N-diisopropyl ethylenediamine temperature of reaction are 100 DEG C ~ 110 DEG C, insulation reaction 3 ~ 3.5h, to reaction end, is cooled to less than 90 DEG C, add water insulation 70 ~ 90 DEG C of stirring reactions residual lower than less than 0.15% to raw material, continue to be cooled to less than 40 DEG C, add dichloromethane extraction, collect organic phase, wash with water more once, anhydrous sodium sulfate drying, filter, filtrate 40 DEG C is spin-dried for.
7. preparation method as claimed in claim 4; it is characterized in that: the compound that formula (1) represents mixes with anhydrous cupric sulfate, 10% aqueous sodium hydroxide solution, pyridine; nitrogen protection; stirring is warming up to 95 ~ 100 DEG C; insulation reaction 1.5 ~ 2h, is cooled to 20 ~ 30 DEG C after reacting completely, filter; collect filtrate; under stirring, hydrochloric acid is added dropwise in filtrate, is cooled to 15 ~ 25 DEG C, insulated and stirred crystallization 0.5 ~ 1h; filter; filter cake is washed, and drains, and material 3 ~ 4h is dried in 70 ~ 80 DEG C of air blast; constant weight, rewinding.
8. formula (6)
（6）
The preparation method of compound represented: the formula (5) prepared by preparation method as claimed in claim 1
（5）
The compound represented adds hydrochloric acid and obtains in methyl alcohol.
9. preparation method as claimed in claim 8, it is characterized in that: the compound that formula (5) represents adds methyl alcohol, stirs clearly molten, adds hydrochloric acid, to system PH < 1, cooling crystallization, to 15 ~ 25 DEG C of more than stirring and crystallizing 0.5h, filters, filter cake methyl alcohol drip washing, drain, 45 DEG C of air blast dry material to constant weight, rewinding.
10. the formula (6) as claimed in claim 8 or 9 prepared by preparation method
（6）
The purification process of the compound represented, comprises the steps:
The compound that formula (6) represents is mixed with dehydrated alcohol and water, stirring is warming up to 90 ~ 95 DEG C, and system is clearly molten, stops heating, filtered while hot, filtrate naturally cools to 30 DEG C, continues to be cooled to 10 ~ 20 DEG C, insulated and stirred more than crystallization 0.5h, filter, filter cake 25% aqueous ethanolic solution drip washing, drains, and 40 ~ 45 DEG C are dried material to constant weight.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105753810B (en) * | 2016-04-15 | 2018-09-28 | 浙江新赛科药业有限公司 | The refined and preparation method of acotiamide hydrochloride hydrate trihydrate |
| CN111440128A (en) * | 2020-05-27 | 2020-07-24 | 廊坊市泽康医药科技有限公司 | Preparation method of acotiamide hydrochloride impurity |
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| CN1184471A (en) * | 1995-05-18 | 1998-06-10 | 泽里新药工业株式会社 | Aminothiazole derivatives, drug containing the same and intermediate in the production of the compounds |
| CN101006040A (en) * | 2004-08-23 | 2007-07-25 | 泽里新药工业株式会社 | Method for producing aminothiazole derivative and production intermediate |
| CN103237781A (en) * | 2010-12-07 | 2013-08-07 | 善利亚新药工业股份有限公司 | Method for producing 2-bromo-4,5-dialkoxy benzoic acid |
| CN103387552A (en) * | 2012-05-10 | 2013-11-13 | 上海医药工业研究院 | Method for preparing acotiamide hydrochloride |
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- 2014-09-26 CN CN201410501246.7A patent/CN105439977A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1184471A (en) * | 1995-05-18 | 1998-06-10 | 泽里新药工业株式会社 | Aminothiazole derivatives, drug containing the same and intermediate in the production of the compounds |
| CN101006040A (en) * | 2004-08-23 | 2007-07-25 | 泽里新药工业株式会社 | Method for producing aminothiazole derivative and production intermediate |
| CN103237781A (en) * | 2010-12-07 | 2013-08-07 | 善利亚新药工业股份有限公司 | Method for producing 2-bromo-4,5-dialkoxy benzoic acid |
| CN103387552A (en) * | 2012-05-10 | 2013-11-13 | 上海医药工业研究院 | Method for preparing acotiamide hydrochloride |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105753810B (en) * | 2016-04-15 | 2018-09-28 | 浙江新赛科药业有限公司 | The refined and preparation method of acotiamide hydrochloride hydrate trihydrate |
| CN111440128A (en) * | 2020-05-27 | 2020-07-24 | 廊坊市泽康医药科技有限公司 | Preparation method of acotiamide hydrochloride impurity |
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Application publication date: 20160330 |