CN103709120B - A kind of preparation method of acotiamide hydrochloride trihydrate - Google Patents
A kind of preparation method of acotiamide hydrochloride trihydrate Download PDFInfo
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- CN103709120B CN103709120B CN201410025091.4A CN201410025091A CN103709120B CN 103709120 B CN103709120 B CN 103709120B CN 201410025091 A CN201410025091 A CN 201410025091A CN 103709120 B CN103709120 B CN 103709120B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses a kind of preparation method of acotiamide hydrochloride trihydrate, described method comprises the steps: step 1, and formula (1) compound and DIPEA (2) are being obtained by reacting compound (3); Step 2, compound (3) 2-bit amino deprotection obtains compound (4); Step 3, compound (4) and chloride derivative condensation obtain compound (5); Step 4, compound (5) prepares acotiamide hydrochloride trihydrate (6) further.
Description
Technical field
Patent of the present invention relates to a kind of preparation of medical compounds, particularly the preparation method of a kind for the treatment of or prophylactic function maldigestion medicine acotiamide hydrochloride amine trihydrate.
Background technology
Acotiamide hydrochloride hydrate Acotiamidehydrochloride, chemical name is: N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino]-1,3-thiazole-4-carboxamide hydrochloride, its trihydrate forms of usual use, acotiamide hydrochloride trihydrate structure is as follows:
Acotiamide hydrochloride trihydrate is the acetylcholinesterase depressant class stomach motility enhancing medicine of Japanese ZeriaPharmaceutical company and Astellas joint development, namely functional dyspepsia medicine is treated, it is the medicine that global first of ratifying is specifically designed to treatment FD, in June, 2013, commodity were called Acofide in Japanese Initial Public Offering.Functional dyspepsia (Functionaldyspepsia, FD) refers to that one group of common symptom comprises Abdeminal pain, early full, burning sensation, belch, nausea and vomiting and inenarrable epigastric discomfort sense etc., and without definite organic disease.In default of organic disease basis, functional dyspepsia to the harm that patient brings embody a concentrated expression of digestive symptoms cause discomfort and may on the impact of quality of life.Some patients reduces because functional dyspepsia symptom causes feed, digests and assimilates efficiency reduction, causes malnutrition in various degree (comprising nutritive ingredient not comprehensive).Along with the raising that people require quality of life and are familiar with functional dyspepsia, the medical number of this disease is increasing gradually, becomes the modal disease partner of Digestive System Department and waits one of group.So high morbidity, for functional dyspepsia medicine provides huge market.
The synthetic method reported at present is less, is mainly divided into four kinds of methods, is described below respectively:
Method 1, with reference to CN1084739C, synthetic route is as follows.The weak point of this patent is: (1) use sulfur oxychloride and ethylene dichloride toxicity large, have destructive material to environment; (2) demethylation yield lower (bibliographical information is 64.6%-86%).Report in this patent embodiment that the first step and second step total recovery are 84.6%, after three-step reaction and recrystallization, total recovery is 61%, and total recovery is 51.6%.
Method 2, the preparation method A(reported in patent CN1063442C the 25th page) report (non-reference example 1 and 6 mentions its universal method).Patent CN102030654B(page 3) in mention: second step demethylation reaction can produce a lot of by product, is difficult to optionally only take off the protecting group of 2-hydroxyl, poor selectivity.
Concrete synthesis example is as follows:
The preparation method B(mentioned in method 3 patent CN1063442C does not protect preparation method, the 25th page), wherein the yield of two-step reaction is all very low.Ah examining is for the above example (example 38) of preparation method's reference of amine, and specifically preparation Ah examining is for not mentioned in the yield literary composition of amine, if but adopt the primary amino of above method starting material side reaction can occur.Concrete synthesis example is as follows:
Report method in method 4 patent CN101006040B.The first step demethylation can also use titanium tetrachloride and aluminum chloride; Second step reaction can use phenol/sulfur oxychloride.Yield and purity all higher (total recovery is 73%) in synthetic route.
Though the method reported in synthetic method 3 patent CN1063442C in above method is not suitable for the synthesis of Ah examining for amine, can improve on this basis.
This patent discloses and be a kind ofly different from the preparation method reporting acotiamide hydrochloride trihydrate.This invention is compared with the prior art: although total recovery is lower slightly, and synthetic route is simple, product purity is high, total cost is low, is therefore better than prior art generally, is applicable to suitability for industrialized production
Summary of the invention
The object of the invention is to the preparation method of the acotiamide hydrochloride trihydrate disclosing a kind of novelty.
Another object of the present invention is to disclose midbody compound (3) (N-[2-(diisopropylaminoethyl) the ethyl]-2-amino-1 used in acotiamide hydrochloride trihydrate preparation process, 3-thiazole derivative) and the preparation method of (4) (N-[2-(diisopropylaminoethyl) ethyl]-2-amino-1,3-thiazoles) and the application in preparation-acotiamide hydrochloride trihydrate.
The preparation method of acotiamide hydrochloride trihydrate of the present invention, chemical equation is as follows:
The preparation method of acotiamide hydrochloride trihydrate of the present invention, comprises the following steps,
Step 1, compound (1) and DIPEA (2) are obtained by reacting compound (3),
Wherein, R
1, R
2independently represent amido protecting separately; R
3representation carboxy protecting group;
Step 2, compound (3) amino deprotection under amino deprotecting regent exists obtains compound (4),
Step 3, compound (4) and the condensation of following formula chloride derivative obtain compound (5),
Step 4, compound (5) obtains acotiamide hydrochloride trihydrate by conventional demethylation, acidified and crystallization.
In step 1, described amino protecting group is selected from: trifluoroacetyl group, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), tablet held before the breast by officials methoxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, first (or second) oxygen carbonyl, phthaloyl, p-toluenesulfonyl, neighbour (to) nitrobenzenesulfonyl, pivaloyl group, benzoyl, trityl, 2,4-dimethoxy-benzyls, to methoxy-benzyl or benzyl;
Described carboxyl-protecting group is selected from: C
1-C
4alkyl, benzyl, substituted benzyl, benzhydryl ester class etc.
In step 2, described amino deprotecting regent is selected from: hydrazine hydrate, sodium hydroxide, potassium hydroxide, triethylamine, hydrogen bromide, trifluoroacetic acid, saturated hydrochloric acid methanol or ethanol or chloroform or ethyl acetate solution, Bu
4n
+f
-, piperidines, thanomin, hexahydroaniline, morpholine, pyrrolidone, DBU, Pd (PPh
3)
4, tetrabutyl fluoride amine, tetraethyl-fluoride amine, tetramethyl-fluoride amine, sodium borohydride, H
2/ 1% ~ 30%Pd-C, H
2/ PdCl
2, Pd/HCOOH, 1% ~ 30%Pd-C/HCOOH, 1% ~ 30%Pd-C/HCOONH
4, 1% ~ 30%Pd-C/NH
2nH
2, Na/NH
3.
Preferably,
In step 1, described amino protecting group is selected from: phthaloyl, p-toluenesulfonyl, neighbour (to) nitrobenzenesulfonyl;
Described carboxyl-protecting group is selected from: C
1-C
4alkyl, benzyl, substituted benzyl, benzhydryl ester class etc.
In step 2, described amino deprotecting regent is selected from: hydrazine hydrate, triethylamine, piperidines, thanomin, hexahydroaniline.
In step 1, reaction is carried out in organic solvent, and described organic solvent is selected from: C
1-C
6fatty alcohol, ethers, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), DMF, C
1-C
6aliphatic hydrocarbon and C
1-C
6the ester that fatty alcohol generates, acetonitrile; Temperature of reaction is room temperature ~ 150 DEG C; Reaction times is 0.5 ~ 48 hour;
In step 2, reaction is carried out in organic solvent, and described organic solvent is selected from: C
1-C
6fatty alcohol, ethers, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), DMF, C
1-C
6aliphatic hydrocarbon and C
1-C
6the ester that fatty alcohol generates, acetonitrile; Temperature of reaction is-30 DEG C ~ 150 DEG C; Reaction times is 0.5 ~ 48 hour;
In step 3, described condensation is carried out in organic solvent, and described organic solvent is selected from: C
1-C
6fatty alcohol, ethers, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), DMF, C
1-C
6aliphatic hydrocarbon and C
1-C
6the ester that fatty alcohol generates, acetonitrile; Temperature of reaction controls room temperature-150 DEG C, and the reaction times is 1h-24h.
Preferably
In step 1, described organic solvent is selected from: ethanol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), DMF, ethyl acetate, acetonitrile; Temperature of reaction is 80-120 DEG C; Reaction times is 5-20 hour;
In step 2, reaction is carried out in organic solvent, and described organic solvent is selected from: ethanol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), DMF, ethyl acetate, acetonitrile; Temperature of reaction is 50-100 DEG C; Reaction times is 5-20 hour;
In step 3, described condensation is carried out in organic solvent, and described organic solvent is selected from: ethanol, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), DMF, ethyl acetate, acetonitrile; Temperature of reaction controls at 50-120 DEG C, and the reaction times is 5-10h.
The present invention is to provide a new synthetic route, obtain two kinds of new compounds namely: compound (3) for this reason
Wherein R
1, R
2independently represent amino protecting group separately; these amino protecting groups are selected from: trifluoroacetyl group, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), tablet held before the breast by officials methoxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, first (or second) oxygen carbonyl, phthaloyl, p-toluenesulfonyl, neighbour (to) nitrobenzenesulfonyl, pivaloyl group, benzoyl, trityl, 2,4-dimethoxy-benzyls, to methoxy-benzyl or benzyl.
With compound (4)
The present invention also comprises the application of compound 3 in preparation acotiamide hydrochloride trihydrate.
And the application of compound 4 in preparation acotiamide hydrochloride trihydrate.
The most preferred preparation method of the present invention, step is as follows:
The preparation of N-[2-(diisopropylaminoethyl) ethyl]-2-N-phthalic imidine-1,3-thiazoles
N is added in reaction flask, N-diisopropyl ethylenediamine (28.8g, 0.2mol) with 2-N-phthalic imidine-4-methoxycarbonyl-1,3-thiazoles (54.6g, 0.2mol), be heated to 100 DEG C of reaction 6h, after cool to room temperature, this reaction mixture is poured in Virahol, stirring at room temperature 10h, the crystallization of collected by filtration, 50 DEG C of forced air drying 10h, obtain compound 3.
The preparation of N-[2-(diisopropylaminoethyl) ethyl]-2-amino-1,3-thiazoles
N-[2-(diisopropylaminoethyl) ethyl]-2-N-phthalic imidine-1 is added in reaction flask, 3-thiazole (41.4g, 0.1mol) with ethanol (1L), under room temperature, be added dropwise to hydrazine hydrate (14.6g, 0.3mol), drip rear 70 DEG C of reaction 8h, filter, colloidal solid ethyl acetate is washed, filtrate collection evaporate to dryness, 50 DEG C of vacuum-drying 10h, obtain target compound 4.
The preparation of N-[2-(diisopropylaminoethyl) ethyl]-2-[(2,4,5-trimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxamide hydrochloride
N-[2-(diisopropylaminoethyl) ethyl]-2-amino-1 is added in reaction flask, 3-thiazole (21.6g, 0.08mol), 2,4,5-trimethoxy-1-Benzoyl chloride (18.4g, 0.08mol) with toluene (100mL), be heated to 80 DEG C of reaction 6h, cool this reaction mixture, the crystal of collected by filtration, by toluene wash, 50 DEG C of forced air drying 10h, obtain target compound 5.
The preparation of N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxamide hydrochloride trihydrate
N-[2-(diisopropylaminoethyl) ethyl]-2-[(2 is added in reaction flask, 4, 5-trimethoxybenzoyl) amino]-1, 3-thiazole-4-carboxamide hydrochloride (30g, 0.06mol) and N, dinethylformamide (80ml), be heated to 140 DEG C of reaction 6h, water (400ml) is added after cool to room temperature, stir 30 minutes, suction filtration, solid adds and is dissolved in concentrated hydrochloric acid (10ml), in Virahol (20ml) and water (70ml), argon shield be heated to 50 DEG C complete molten after, cool to room temperature stirs 10h crystallization, suction filtration, solid 40 DEG C of vacuum-drying 10h, obtain acotiamide hydrochloride trihydrate.
Compared with prior art, the method has novelty, reaction conditions gentleness, environmental friendliness, simple to operate, cost is low, product stability is good, quality safety is secure, be applicable to the features such as suitability for industrialized production.
Advantage of the present invention is as follows:
(1) with low cost; (2) purity is high; (3) route is simple; (4) little to environmental disruption.
For further illustrating advantage of the present invention, proved below by way of experimental data:
The present invention contrasts with the prior art CN101006040B having been reported global optimum: although total recovery is lower slightly, route is simple, purity is high, cost is low, is therefore better than prior art generally, is applicable to suitability for industrialized production.
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not confined to following embodiment.
Embodiment 1
The preparation of N-[2-(diisopropylaminoethyl) ethyl]-2-N-phthalic imidine-1,3-thiazoles
N is added in reaction flask, N-diisopropyl ethylenediamine (28.8g, 0.2mol) and 2-N-phthalic imidine-4-methoxycarbonyl-1,3-thiazoles (54.6g, 0.2mol), be heated to 100 DEG C of reaction 6h, after cool to room temperature, this reaction mixture be poured in Virahol, stirring at room temperature 10h, the crystallization of collected by filtration, 50 DEG C of forced air drying 10h, obtain target compound 73.10g, yield: 91.5% thus.
401.23(M+1), 400.23 (23%), 399.23 (4%) LC-MS of product measures ionic current:, ultimate analysis: C content 60.13%, H content 5.99%, O content 11.99%, N content 14.01%.
The preparation of N-[2-(diisopropylaminoethyl) ethyl]-2-amino-1,3-thiazoles
N-[2-(diisopropylaminoethyl) ethyl]-2-N-phthalic imidine-1 prepared by embodiment 1 is added in reaction flask, 3-thiazole (41.4g, 0.1mol) and ethanol (1L), be added dropwise to hydrazine hydrate (14.6g under room temperature, 0.3mol), drip rear 70 DEG C of reaction 8h, filter, colloidal solid ethyl acetate is washed, filtrate collection evaporate to dryness, 50 DEG C of vacuum-drying 10h, obtain target compound 24.87g, yield: 92.1%.
The LC-MS of product measures ionic current: 271.16(M+1), 270.16(15%), 269.16(5%), 289.16(M+18+1), ultimate analysis: C content 53.34%, H content 8.15%, O content 5.93%, N content 20.74%.
The preparation of N-[2-(diisopropylaminoethyl) ethyl]-2-[(2,4,5-trimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxamide hydrochloride
Add in reaction flask embodiment 2 prepare N-[2-(diisopropylaminoethyl) ethyl]-2-amino-1,3-thiazoles (, 21.6g, 0.08mol), 2,4,5-trimethoxy-1-Benzoyl chloride (18.4g, 0.08mol) with toluene (100mL), be heated to 80 DEG C of reaction 6h, cool this reaction mixture, the crystal of collected by filtration, by toluene wash, 50 DEG C of forced air drying 10h, obtain target product 46.55g, yield: 93.0%.
The preparation of N-[2-(diisopropylaminoethyl) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) is amino]-1,3-thiazoles-4-carboxamide hydrochloride trihydrate
N-[2-(diisopropylaminoethyl) ethyl]-2-[(2 prepared by embodiment 3 is added in reaction flask, 4, 5-trimethoxybenzoyl) amino]-1, 3-thiazole-4-carboxamide hydrochloride (30g, 0.06mol) and N, dinethylformamide (80ml), be heated to 140 DEG C of reaction 6h, water (400ml) is added after cool to room temperature, stir 30 minutes, suction filtration, solid adds and is dissolved in concentrated hydrochloric acid (10ml), in Virahol (20ml) and water (70ml), argon shield be heated to 50 DEG C complete molten after, cool to room temperature stirs 10h crystallization, suction filtration, solid 40 DEG C of vacuum-drying 10h, obtain white to light yellow crystalline powder target product 26.28g, productive rate: 81.1%.
Claims (1)
1. a preparation method for acotiamide hydrochloride trihydrate, is characterized in that comprising the following steps:
(1) in reaction flask, 0.2molN is added, N-diisopropyl ethylenediamine and 0.2mol2-N-phthalic imidine-4-methoxycarbonyl-1,3-thiazole, be heated to 100 DEG C of reaction 6h, after cool to room temperature, this reaction mixture is poured in Virahol, stirring at room temperature 10h, the crystallization of collected by filtration, 50 DEG C of forced air drying 10h, obtain compound
(2) in reaction flask, 0.1mol is added
with 1L ethanol, be added dropwise to 0.3mol hydrazine hydrate under room temperature, drip rear 70 DEG C of reaction 8h, filter, colloidal solid ethyl acetate is washed, filtrate collection evaporate to dryness, and 50 DEG C of vacuum-drying 10h, obtain compound
(3) in reaction flask, 0.08mol is added
0.08mol2,4,5-trimethoxy-1-Benzoyl chloride and 100mL toluene, be heated to 80 DEG C of reaction 6h, cool this reaction mixture, the crystal of collected by filtration, by toluene wash, 50 DEG C of forced air drying 10h, obtain compound
hydrochloride;
(4) in reaction flask, 0.06mol is added
hydrochloride and 80mlN; dinethylformamide, is heated to 140 DEG C of reaction 6h, adds 400ml water after cool to room temperature; stir 30 minutes; suction filtration, solid adds and is dissolved in 10ml concentrated hydrochloric acid, 20ml Virahol and 70ml water, argon shield be heated to 50 DEG C complete molten after; cool to room temperature stirs 10h crystallization; suction filtration, solid 40 DEG C of vacuum-drying 10h, obtain acotiamide hydrochloride trihydrate.
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| CN103980226A (en) * | 2014-05-10 | 2014-08-13 | 杭州新博思生物医药有限公司 | Acotiamide hydrochloride hydrate crystal form and preparation method thereof |
| CN104003958A (en) * | 2014-05-30 | 2014-08-27 | 杭州新博思生物医药有限公司 | Novel acotiamide hydrochloride hydrate crystal form and preparation method thereof |
| CN106316979B (en) * | 2016-08-22 | 2018-11-27 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of acotiamide hydrochloride hydrate |
| CN109828043A (en) * | 2019-02-20 | 2019-05-31 | 南京工业大学 | Quantitative analysis method of acotiamide in human plasma |
| CN113121466B (en) * | 2019-12-31 | 2023-12-15 | 成都迪康药业股份有限公司 | Recrystallizing solvent of acotiamide hydrochloride and refining method thereof |
| 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 |
| CN111518052A (en) * | 2020-05-27 | 2020-08-11 | 廊坊市泽康医药科技有限公司 | Preparation method of acotiamide hydrochloride impurity |
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| US6121301A (en) * | 1996-10-24 | 2000-09-19 | Zeria Pharmaceutical Co., Ltd. | Substituted benzoylaminothiazole derivatives and drugs containing the same |
| AU725155B2 (en) * | 1997-06-24 | 2000-10-05 | Zeria Pharmaceutical Co., Ltd. | Process for producing 2-hydroxybenzamide derivatives |
| CN103387552B (en) * | 2012-05-10 | 2016-06-08 | 常州市第四制药厂有限公司 | Prepare the method for acotiamide hydrochloride hydrate |
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