CN104592147A - Preparation method of acotiamide hydrochloride intermediate - Google Patents
Preparation method of acotiamide hydrochloride intermediate Download PDFInfo
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- CN104592147A CN104592147A CN201310526611.5A CN201310526611A CN104592147A CN 104592147 A CN104592147 A CN 104592147A CN 201310526611 A CN201310526611 A CN 201310526611A CN 104592147 A CN104592147 A CN 104592147A
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- preparation
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- hydrochloride hydrate
- acotiamide hydrochloride
- benzotriazole
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- JPQYUDLPVJWPLD-UHFFFAOYSA-N COC(c(cc(c(OC)c1)OC)c1OC)=O Chemical compound COC(c(cc(c(OC)c1)OC)c1OC)=O JPQYUDLPVJWPLD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention relates to a preparation method of an acotiamide hydrochloride intermediate. The preparation method comprises that 2,4,5-trimethoxybenzoic acid and ethyl 2-aminothiazol-4-formate as initial raw materials undergo a condensation reaction under the action of a condensing agent TBTU and an acid binding agent DIEA to produce a desired product. The preparation method is free of a highly corrosive solvent, can be operated simply, is suitable for industrial production and realizes a high yield and good purity.
Description
Technical field
The present invention relates to the field of chemical synthesis, particularly relate to a kind of preparation method of acotiamide hydrochloride hydrate intermediate.
Background technology
Acotiamide hydrochloride hydrate, chemical name: N-2-[(two isopropylamino) ethyl]-2-[(2-hydroxyl-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide hydrochloride trihydrate, CAS:773092-05-0, its structure is as follows:
Acotiamide hydrochloride hydrate belongs to muscarine M1, M2 acceptor and adenosine A 1 receptor antagonists, have and promote gastric motility and anti-acetylcholinesterase activity, have good gastrointestinal motor improvement result, its prophylactic treatment medicine as epigastric discomfort, Nausea and vomiting, uncomfortable in chest, poor appetite, abdominal distension sense, reflux esophagitis etc. known is useful.Developed by Zeria Pharmaceutical CoLtd at first, existing by Zeria and Astellas joint development and listing.
At present, the preparation method of acotiamide hydrochloride hydrate disclosed in document and similar approach comprise following documents report: WO1996/036619A1; WO1998/058918A1; WO2006/022252A1; Following route (scheme 1) can be summarized as:
In this route, usually use sulfur oxychloride to activate 2,4,5-trimethoxybenzoic acid and obtain acyl chlorides active intermediate, then with the condensation of thiazolamine-4-ethyl formate, obtain intermediate (I) (scheme 2) with ethyl alcohol recrystallization after concentration of reaction solution.
The thionyl chloride that this step condensation reaction uses is deep-etching solvent, large to equipment damage, and the method aftertreatment is loaded down with trivial details, not easily amplifies production, and overall yield is low, and cost is high.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, provide one not use deep-etching solvent, purity is high, the preparation method of acotiamide hydrochloride hydrate intermediate that yield is high, the method is simple to operate, be applicable to industrial production.
Preparation method of the present invention comprises the following steps:
2,4,5-trimethoxybenzoic acid and thiazolamine-4-ethyl formate are reacted, in organic solvent environment, add condensing agent and acid binding agent, react 3 to 5 hours in a heated condition, lower the temperature after reacting completely, add ethanol making beating, filter, wash, obtain acotiamide hydrochloride hydrate intermediate (I):
The weight ratio of described thiazolamine-4-ethyl formate and 2,4,5-trimethoxybenzoic acid is 1:1-1:2, preferred 1:1.05.
Preferably, described organic solvent is selected from benzene, toluene and/or dimethylbenzene, chlorobenzene, preferred toluene.
Preferably, described acid binding agent is selected from triethylamine, DIPEA (DIEA), quadrol, pyridine, more preferably DIEA.
Preferably, described condensing agent is selected from I-hydroxybenzotriazole (HOBT), O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid (TBTU), N, N'-carbonyl dimidazoles (CDI), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate (HBTU) or phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl (PyBOP), more preferably TBTU.
Described O-benzotriazole-N, the weight ratio of N, N', N'-tetramethyl-urea Tetrafluoroboric acid and 2,4,5-trimethoxybenzoic acid is 1:1-1:2, preferred 1:1.1.
Preferably, the temperature of reaction of described heating condition is 60 DEG C to 120 DEG C or makes reaction solution to reflux state.
Preferred reaction scheme is reacted at 2,4,5-trimethoxybenzoic acid and thiazolamine-4-ethyl formate, under TBTU and DIEA effect, reflux in toluene reaction 3 to 5 hours, be down to room temperature, add ethanol, pull an oar 2 to 3 hours, filter to obtain intermediate (I).
Preparation method of the present invention does not use deep-etching solvent, and gained intermediate purity is high, yield good, the method industrial production simple to operate, applicable.
Embodiment
Illustrate the present invention below with reference to embodiment, but content of the present invention is not limited to specific embodiment.
The preparation of embodiment 1:2-[N-(2,4,5-trimethoxybenzoy) is amino]-1,3-thiazoles-4-ethyl formate
By 2,4,5-trimethoxybenzoic acid 400g(1.887mol), TBTU664g(2.069mol), DIEA685ml, toluene 4L, thiazolamine-4-ethyl formate 340g(1.977mol) drop into the reaction flask of 10L successively, heated and stirred reaction solution is to reflux state.TLC detects raw material primitive reaction completely (about 8h), and stop heating, stirring reaction liquid also naturally cools to room temperature (25 DEG C).In reaction solution, add 4L ethanol, and the 2h that pulls an oar, filter, filter cake washing with alcohol, 45 DEG C of forced air dryings to be spent the night after (about 12h) to obtain off-white color solid 530g, and molar yield is 76%.
1H NMR(400MHz,CDCl
3):δ=1.29-1.32(t,J=7.2Hz,3H),3.77(s,3H),3.91(s,3H),4.01(s,3H),4.29(q,J=7.6Hz,2H),6.85(s,1H),7.40(s,1H),8.09(s,1H),11.66(s,1H);
13C NMR(100MHz):δ=14.65,56.45,56.52,57.44,61.04,98.29,110.95,113.66,123.57,141.53,143.27,153.82,154.17,158.29,161.43,163.83;
IR(KBr):3304,2982,1725,1662,1550,1519,1466,1437,1273,1223,1209,1099,1020,887,837,809,746,647,583cm
-1;
MS（m/z）：389.2[M+Na]
+
The preparation of embodiment 2:2-[N-(2,4,5-trimethoxybenzoy) is amino]-1,3-thiazoles-4-ethyl formate
By 2,4,5-trimethoxybenzoic acid 5.3g(0.025mol), CDI5.0g(0.03mol), DBU1.9g, toluene 53mL, thiazolamine-4-ethyl formate 4.3g drop into the reaction flask of 250mL, 90 DEG C of stirring reaction liquid successively.TLC detects raw material primitive reaction completely (about 8h), and stop heating, stirring reaction liquid also naturally cools to room temperature (25 DEG C).In reaction solution, add 53mL ethanol, and the 2h that pulls an oar, filter, filter cake washing with alcohol, 45 DEG C of forced air dryings to be spent the night after (about 12h) to obtain off-white color solid, and molar yield is 62%.
Identical with embodiment 1 through collection of illustrative plates structure elucidation determination products therefrom.
The preparation of embodiment 3:2-[N-(2,4,5-trimethoxybenzoy) is amino]-1,3-thiazoles-4-ethyl formate
By 2,4,5-trimethoxybenzoic acid 5.3g(0.025mol), CDI5.0g(0.03mol), DBU1.9g, toluene 53mL, thiazolamine-4-ethyl formate 4.3g drop into the reaction flask of 250mL successively, heated and stirred reaction solution is to reflux state.TLC detects raw material primitive reaction completely (about 8h), and stop heating, stirring reaction liquid also naturally cools to room temperature (25 DEG C).In reaction solution, add 53mL ethanol, and the 2h that pulls an oar, filter, filter cake washing with alcohol, 45 DEG C of forced air dryings to be spent the night after (about 12h) to obtain off-white color solid, and molar yield is 67%.
Identical with embodiment 1 through collection of illustrative plates structure elucidation determination products therefrom.
Claims (7)
1. a preparation method for acotiamide hydrochloride hydrate intermediate, it comprises the following steps:
2,4,5-trimethoxybenzoic acid and thiazolamine-4-ethyl formate are reacted, in organic solvent environment, add condensing agent and acid binding agent, react 3 ~ 5 hours in a heated condition, lower the temperature after reacting completely, add ethanol making beating, filter, wash, obtain acotiamide hydrochloride hydrate intermediate (I)
2. the preparation method of acotiamide hydrochloride hydrate intermediate according to claim 1, is characterized in that, the weight ratio of described thiazolamine-4-ethyl formate and 2,4,5-trimethoxybenzoic acid is 1:1-1:2, preferred 1:1.05.
3. the preparation method of acotiamide hydrochloride hydrate intermediate according to claim 1, is characterized in that, described organic solvent is selected from benzene, toluene and/or dimethylbenzene, chlorobenzene, preferred toluene.
4. the preparation method of acotiamide hydrochloride hydrate intermediate according to claim 1, is characterized in that, described acid binding agent is selected from triethylamine, DIPEA, quadrol, pyridine, preferred DIPEA.
5. the preparation method of acotiamide hydrochloride hydrate intermediate according to claim 1, is characterized in that, described condensing agent is selected from I-hydroxybenzotriazole, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, N, N'-carbonyl dimidazoles, 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate or phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, preferred O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid.
6. the preparation method of acotiamide hydrochloride hydrate intermediate according to claim 5, is characterized in that, described O-benzotriazole-N, and the weight ratio of N, N', N'-tetramethyl-urea Tetrafluoroboric acid and 2,4,5-trimethoxybenzoic acid is 1:1-1:2, preferred 1:1.1.
7. the preparation method of acotiamide hydrochloride hydrate intermediate according to claim 1, is characterized in that, the temperature of reaction of described heating condition is 60 DEG C to 150 DEG C or makes reaction solution to reflux state.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105021740A (en) * | 2015-08-15 | 2015-11-04 | 杭州新博思生物医药有限公司 | High-performance liquid chromatography analytical method for N1,N1-diisopropyl ethylenediamine |
| CN105439978A (en) * | 2015-12-15 | 2016-03-30 | 山东金城医药化工股份有限公司 | Preparation method of acotiamide intermediate |
| CN106800539A (en) * | 2016-12-30 | 2017-06-06 | 江苏吴中医药集团有限公司苏州制药厂 | A kind of acotiamide hydrochloride hydrate intermediate and its synthesis technique and application |
| CN108358867A (en) * | 2018-05-05 | 2018-08-03 | 邳州易萨新型材料有限公司 | A kind of synthetic method of acotiamide hydrochloride hydrate |
| 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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| 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 |
| CN1261357A (en) * | 1997-06-24 | 2000-07-26 | 泽里新药工业株式会社 | Process for producing 2-hydroxybenzamide derivatives |
| EP1489073A1 (en) * | 2002-03-20 | 2004-12-22 | Mitsui Chemicals, Inc. | Process forpreparation of alkoxybenzamides and thiazolyl isocyanates |
| 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 |
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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 |
| CN1261357A (en) * | 1997-06-24 | 2000-07-26 | 泽里新药工业株式会社 | Process for producing 2-hydroxybenzamide derivatives |
| EP1489073A1 (en) * | 2002-03-20 | 2004-12-22 | Mitsui Chemicals, Inc. | Process forpreparation of alkoxybenzamides and thiazolyl isocyanates |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105021740A (en) * | 2015-08-15 | 2015-11-04 | 杭州新博思生物医药有限公司 | High-performance liquid chromatography analytical method for N1,N1-diisopropyl ethylenediamine |
| CN105439978A (en) * | 2015-12-15 | 2016-03-30 | 山东金城医药化工股份有限公司 | Preparation method of acotiamide intermediate |
| CN105439978B (en) * | 2015-12-15 | 2018-02-16 | 山东金城医药化工股份有限公司 | The preparation method of Acotiamide intermediate |
| CN106800539A (en) * | 2016-12-30 | 2017-06-06 | 江苏吴中医药集团有限公司苏州制药厂 | A kind of acotiamide hydrochloride hydrate intermediate and its synthesis technique and application |
| CN106800539B (en) * | 2016-12-30 | 2019-03-22 | 江苏吴中医药集团有限公司苏州制药厂 | A kind of acotiamide hydrochloride hydrate intermediate and its synthesis technology and application |
| CN108358867A (en) * | 2018-05-05 | 2018-08-03 | 邳州易萨新型材料有限公司 | A kind of synthetic method of acotiamide hydrochloride hydrate |
| 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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