CN104045606B - One kettle way prepares the method for Ah examining for amine hydrochlorate - Google Patents
One kettle way prepares the method for Ah examining for amine hydrochlorate Download PDFInfo
- Publication number
- CN104045606B CN104045606B CN201410329900.0A CN201410329900A CN104045606B CN 104045606 B CN104045606 B CN 104045606B CN 201410329900 A CN201410329900 A CN 201410329900A CN 104045606 B CN104045606 B CN 104045606B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- examining
- amine hydrochlorate
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 COC(C1=NC(N)=S*1)=O Chemical compound COC(C1=NC(N)=S*1)=O 0.000 description 1
Classifications
-
- 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
Abstract
The present invention relates to a kind of one kettle way and prepare the method for Ah examining for amine hydrochlorate (compound V), the method is with 2 shown in formula (I), thiazolamine-4-methyl-formiate shown in 4,5-trimethoxybenzoic acid and formula (II) is raw material, obtains compound III through condensation reaction; By selecting suitable solvent and controlling reaction conditions, intermediate III is without separation and purification, directly and the N shown in formula (IV), N-diisopropyl ethylenediamine carries out aminating reaction, and last salify one kettle way prepares Ah examining for amine hydrochlorate (compound V), the present invention's one kettle way prepares Ah examining for amine hydrochlorate, decrease reactions steps, simplify operating process, improve production efficiency, and safety and environmental protection, be applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to the preparation method technical field of Ah examining for amine hydrochlorate.
Background technology
Ah examining is for amine (acotiamide); chemistry N-{2 by name-[two (1-methylethyl) is amino] ethyl }-2-[(2-hydroxyl-4; 5-Dimethoxybenzoyl) amino] thiazole-4-carboxamide hydrochloride trihydrate; developed by AstraZeneca (Astellas) pharmacy and Ze Li new drug K.K. Union; treatment functional dyspepsia (FD) is approved in Japan on June 6th, 2013; first FD medicine in the world; there is good curative effect, have no drug resistance and show high security.
Ah the examining that prepare that current document is reported mainly contains following several for the method for amine hydrochlorate (compound V):
Route one: (1. WO2012077673(CN103237781 A) (2011))
Route one for starting raw material, obtains 2-BROMO-4,5-DIMETHOXYBENZOIC ACID through bromination, hydrolysis with 4,5-dimethoxybenzoic acid.Then react with thiazolamine-4-methyl-formiate again after 2-BROMO-4,5-DIMETHOXYBENZOIC ACID being converted into corresponding phenyl ester and generate 2-(2-hydroxyl-4,5-dimethoxybenzamido) 4-thiazolecarboxylic acid methyl esters.2-(2-hydroxyl-4,5-dimethoxybenzamido) the further ammonification of 4-thiazolecarboxylic acid methyl esters, salify obtain Ah examining for amine hydrochlorate.This overall yield of reaction of bibliographical information reaches 85%, but when the first step carries out bromination, needs to use concentrated hydrochloric acid and the larger bromine of toxicity in a large number, and it is also more to react issuable by product; In addition this route multistep has used toluene, need carry out the repeatedly transfer of steaming except toluene and material, operate more loaded down with trivial details, be unfavorable for suitability for industrialized production.
Route two: (2.CN102040566B(2005))
Route two for starting raw material, obtains 2-hydroxyl-4,5-dimethoxybenzoic acid by the selectivity methyl sloughed on 2 methoxyl groups with 2,4,5-trimethoxybenzoic acid.2-hydroxyl-4,5-dimethoxybenzoic acid phenyl ester is obtained again through over-churning.Further amidation and transesterify can obtain product Ah examining for amine hydrochlorate.The total recovery of this route bibliographical information is 75%, but the method step is more.This route adopts boron trifluoride diethyl etherate simultaneously, and aftertreatment is more loaded down with trivial details.In addition, use triphenylphosphate Atom economy poor, reagent boric acid ester price is more expensive, and these factors make this route economy poor.
Route three: (3.CN1184471A(1996))
This route for starting raw material, prepares Ah examine for amine hydrochlorate through amidation, selectivity demethylation and ammonification three step with 2,4,5-trimethoxybenzoic acid.The method total recovery only has 35%, there is no advantage compared with other method, and needs the pyridine that use toxicity is larger.
Route four: (4.CN1084739C(1998))
Route four is the most succinct and yield is higher, and it for starting raw material, prepares Ah examine for amine hydrochlorate through amidation and ammonification two step with 2,4,5-trimethoxybenzoic acid.But there is following shortcoming in this route: 1. used sulfur oxychloride in preparation process, sulfurous gas and hydrogenchloride can be produced, equipment and workman's protection are had higher requirements, also can produce certain environmental problem; 2. the preparation of acyl chlorides is subject to ambient moisture and sulfur oxychloride quality influence comparatively large, and operational requirement is relatively high; 3. employ kind solvent 1, a 2-ethylene dichloride; 4. need to carry out repeatedly material transfer.And the compound III often first separation and purification in this route, then carry out next step reaction, make industrial operation loaded down with trivial details.The present invention, by selecting suitable solvent and controlling reaction conditions etc., is not separated this intermediate, and directly " one kettle way " prepares Ah examining for amine hydrochlorate, greatly simplify technological operation, improves production efficiency.Meanwhile, the present invention TBTU substitutes sulfur oxychloride, not only avoid the pollution using acyl chlorides to bring, and avoids repeatedly material transfer, thus enhances productivity, and is conducive to carrying out continuous industrial production.
Summary of the invention
The object of the present invention is to provide a kind of simple process, safety and environmental protection, be suitable for the preparation method of Ah examining for amine hydrochlorate of suitability for industrialized production.
In order to realize foregoing invention object, present invention employs a kind of one kettle way and preparing the method for Ah examining for amine hydrochlorate, the following technical scheme of concrete employing:
A kind of one kettle way prepares formula V
Shown Ah examining, for the method for amine hydrochlorate, is characterized in that, by formula (I)
Shown compound and formula (II)
Shown compound is heat condensation in the solvent of condensing agent and alkali, obtains formula (III)
Shown compound, compound (III) without separation, with formula (IV)
Shown compound ammonification, finally uses hydrogenchloride salify, obtains Ah examining for amine hydrochlorate (compound V).
A kind of one kettle way prepares the method for Ah examining for amine hydrochlorate, it is characterized in that, with DMF or DMAc for reaction solvent, under the existence of condensing agent and alkali, with 2 shown in formula (I), after thiazolamine-4-methyl-formiate shown in 4,5-trimethoxybenzoic acid and formula (II) carries out condensation reaction, then shown in adding type (IV)
n, N-diisopropyl ethylenediamine carries out aminating reaction, and last salify one kettle way prepares Ah examining for amine hydrochlorate (compound V).
One kettle way prepares the method for Ah examining for amine hydrochlorate, it is characterized in that, the mol ratio of Compound I and Compound II per is 1:1.0 ~ 2.0, is preferably 1:1.1 ~ 1.5.The mol ratio of Compound I and condensing agent is 1:1.0 ~ 3.0, is preferably 1:1.0 ~ 1.5.The molar ratio of Compound I and compound IV is 1:1.0 ~ 5.0, preferred 1:2.0 ~ 4.0.
Described a kind of one kettle way prepares the method for Ah examining for amine hydrochlorate, and condensing agent can be selected from salt TBTU, HATU, HBTU, TSTU, is preferably TBTU.Setting-up point is 55-105 DEG C, and be preferably 70-90 DEG C, the reaction times is 6-24 hour.
Described a kind of one kettle way prepares the method for Ah examining for amine hydrochlorate, it is characterized in that, described alkali is organic bases, and wherein organic bases can be selected from diisopropylethylamine, triethylamine, pyridine, is preferably diisopropylethylamine.
Described a kind of one kettle way prepares the method for Ah examining for amine hydrochlorate, and aminating reaction temperature is 120-150 DEG C, preferred 130-140 DEG C; Reaction times is 4-10 hour.
Specific operation process of the present invention is as follows: with 2 shown in formula (I), 4, thiazolamine-4-methyl-formiate shown in 5-trimethoxybenzoic acid and formula (II) is raw material, under the effect of condensing agent and alkali, there is condensation reaction, then with DMF or DMAc for reaction solvent, add shown in formula (IV)
n,N-diisopropyl ethylenediamine carries out aminating reaction, finally uses hydrogenchloride salify, obtains Ah examining for amine hydrochlorate (compound V).
Compared with prior art, the present invention has following beneficial effect: 1, overcome industrial operation in prior art loaded down with trivial details, is unsuitable for the shortcoming of suitability for industrialized production.2, adopt one kettle way to prepare Ah examining for amine hydrochlorate, greatly simplifie operating process, improve production efficiency.3, safety and environmental protection, environmental pollution is less.
Embodiment
Come by the following examples to describe the present invention in more detail, but this should not regard limitation of the present invention as.
Example 1: Ah examining is for the preparation of amine hydrochlorate
2,4,5-trimethoxybenzoic acid (20 g, 94.3mmol) is added, 200 ml DMFs in 500ml reaction flask.Add TBTU(30.88 g, 113.2mmol), add
n,N-diisopropylethylamine (14.59g, 113.2mmol), at room temperature stirs 2 hours.Add thiazolamine-4-methyl-formiate (14.92 g, 94.3mmol), DMAP(2.30g, 18.9mmol), be heated to 75 DEG C, stir 24 hours.Add
n,N-diisopropyl ethylenediamine (27.16g, 188.6mmol), is heated to 140 DEG C, stirs 10 hours.After cooling, add 400ml propyl carbinol, stir, stratification.Get upper strata, wash with saturated aqueous common salt 400ml, stratification.Get upper strata, under low temperature, drip hydrogenchloride Virahol 120ml, separate out solid.Filtration under diminished pressure, air dry oven 60 DEG C of dryings 1 hour put into by filter cake.Get A Kao replaces amine hydrochlorate (compound V) 28.5g, HPLC purity 99%, yield 62%.
1H NMR (400 MHz, dmso) δ 12.10 (s, 1H), 11.77 (s, 1H), 9.74 (s, 1H), 8.72 (t,
J= 5.8 Hz, 1H), 7.88 (s, 1H), 7.48 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.62 (d,
J= 6.6 Hz, 4H), 3.16 (d,
J= 6.4 Hz, 2H), 1.32 (dd,
J= 13.4, 6.3 Hz, 12H)。
Example 2: Ah examining is for the preparation of amine hydrochlorate
2,4,5-trimethoxybenzoic acid (20g, 94.3mmol) is added, 200ml in 500ml reaction flask
n,N-N,N-DIMETHYLACETAMIDE.Add TBTU(30.88g, 113.2mmol), add
n,N-diisopropylethylamine (14.59g, 113.2mmol)), at room temperature stir 2 hours.Add thiazolamine-4-methyl-formiate (14.92g, 94.3mmol), DMAP(2.3g, 18.9mmol), be heated to 75 DEG C, stir 24 hours.Add
n,N-diisopropyl ethylenediamine (27.16g, 188.6mmol), is heated to 140 DEG C, stirs 10 hours.After cooling, add 400ml propyl carbinol, stir, stratification.Get upper strata, wash with saturated aqueous common salt 400ml, stratification.Get upper strata, drip hydrogenchloride Virahol 120ml under low temperature, separate out solid, filtration under diminished pressure, air dry oven 60 DEG C of dryings 1 hour put into by filter cake.Get A Kao replaces amine hydrochlorate (compound V) 31.7 g, HPLC purity 99%, yield 69%.
Claims (9)
1. an one kettle way prepares formula V
Shown Ah examining, for the method for amine hydrochlorate, is characterized in that, by formula (I)
Shown compound and formula (II)
Shown compound is under the existence of condensing agent and alkali, and heat condensation in a solvent, obtains formula (III)
Shown compound, compound III without separation, with formula (IV)
Shown compound ammonification, finally uses hydrogenchloride salify, obtains Ah examining for amine hydrochlorate (compound V); Wherein said condensing agent is TBTU, HATU, HBTU or TSTU.
2. preparation method according to claim 1, it is characterized in that, with DMF or DMAc for reaction solvent, under the existence of condensing agent and alkali, with 2 shown in formula (I), after thiazolamine-4-methyl-formiate shown in 4,5-trimethoxybenzoic acid and formula (II) carries out condensation reaction, then shown in adding type (IV)
n,N-diisopropyl ethylenediamine carries out aminating reaction, and last salify one kettle way prepares Ah examining for amine hydrochlorate (compound V).
3. according to preparation method according to claim 1 or claim 2, it is characterized in that, the mol ratio of Compound I and Compound II per is 1:1.1 ~ 1.5; The mol ratio of Compound I and condensing agent is 1:1 ~ 1.5.
4. according to preparation method according to claim 1 or claim 2, it is characterized in that, setting-up point is 55 ~ 105 DEG C, and the reaction times is 6 ~ 24 hours.
5. preparation method according to claim 4, is characterized in that setting-up point is 70 ~ 90 DEG C.
6. according to preparation method according to claim 1 or claim 2, it is characterized in that, described alkali is diisopropylethylamine, triethylamine or pyridine.
7. according to preparation method according to claim 1 or claim 2, it is characterized in that, the molar ratio of Compound I and compound IV is 1:1.0 ~ 5.0.
8. preparation method according to claim 7, is characterized in that, the molar ratio of Compound I and compound IV is 1:2.0 ~ 4.0.
9. according to preparation method according to claim 1 or claim 2, it is characterized in that, aminating reaction temperature is 120 ~ 150 DEG C; Reaction times is 4 ~ 10 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410329900.0A CN104045606B (en) | 2014-07-11 | 2014-07-11 | One kettle way prepares the method for Ah examining for amine hydrochlorate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410329900.0A CN104045606B (en) | 2014-07-11 | 2014-07-11 | One kettle way prepares the method for Ah examining for amine hydrochlorate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104045606A CN104045606A (en) | 2014-09-17 |
| CN104045606B true CN104045606B (en) | 2015-09-30 |
Family
ID=51499051
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410329900.0A Active CN104045606B (en) | 2014-07-11 | 2014-07-11 | One kettle way prepares the method for Ah examining for amine hydrochlorate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104045606B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104698106B (en) * | 2015-03-21 | 2016-06-29 | 石家庄四药有限公司 | A kind of chemicals acotiamide hydrochloride hydrate has the detection method of related substance |
| 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 |
| 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 |
| 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 |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1261357A (en) * | 1997-06-24 | 2000-07-26 | 泽里新药工业株式会社 | Process for producing 2-hydroxybenzamide derivatives |
| EP1493441A1 (en) * | 2002-04-08 | 2005-01-05 | Zeria Pharmaceutical Co., Ltd. | Therapeutic agent for food competence disorder in stomach |
| CN103387552A (en) * | 2012-05-10 | 2013-11-13 | 上海医药工业研究院 | Method for preparing acotiamide hydrochloride |
| CN103709191A (en) * | 2014-01-20 | 2014-04-09 | 华润赛科药业有限责任公司 | Synthetic method of acotiamide hydrochloride hydrate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2819119C (en) * | 2010-12-07 | 2018-02-13 | Zeria Pharmaceutical Co., Ltd. | Method for producing 2-bromo-4,5-dialkoxy benzoic acid |
-
2014
- 2014-07-11 CN CN201410329900.0A patent/CN104045606B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1261357A (en) * | 1997-06-24 | 2000-07-26 | 泽里新药工业株式会社 | Process for producing 2-hydroxybenzamide derivatives |
| EP1493441A1 (en) * | 2002-04-08 | 2005-01-05 | Zeria Pharmaceutical Co., Ltd. | Therapeutic agent for food competence disorder in stomach |
| CN103387552A (en) * | 2012-05-10 | 2013-11-13 | 上海医药工业研究院 | Method for preparing acotiamide hydrochloride |
| CN103709191A (en) * | 2014-01-20 | 2014-04-09 | 华润赛科药业有限责任公司 | Synthetic method of acotiamide hydrochloride hydrate |
Non-Patent Citations (1)
| Title |
|---|
| 首个功能性消化不良治疗药阿考替胺的研究进展;陈琳萍;《上海医药》;20140210;第35卷(第3期);55-57 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104045606A (en) | 2014-09-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104045606B (en) | One kettle way prepares the method for Ah examining for amine hydrochlorate | |
| CN104974060A (en) | Method for preparing sodium, 8-(2-hydroxybenzamido)octanoate | |
| CN104829599B (en) | The preparation method and the midbody compound for preparing Lei Dipawei of Lei Dipawei and its derivative | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN106279104B (en) | A kind of process modification method preparing amber love song Ge Lieting | |
| CN105198821B (en) | Lip river former times replaces the preparation method of Buddhist nun | |
| CN103724259A (en) | Synthesis method for sorafenib | |
| CN102367260A (en) | Synthesis method of 2-aminopyrimidine-5-boric acid | |
| CN101146812B (en) | Optically active ammonium salt compound, production intermediate thereof and method for producing same | |
| CN104447620B (en) | 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate | |
| CN102659605B (en) | Synthesizing method of spermidine | |
| CN105732490A (en) | Preparation method of betrixaban | |
| CN105440012A (en) | Lenalidomide and lenalidomide intermediate preparation method | |
| CN102659629B (en) | Compound and application thereof in preparing erlotinib | |
| CN104311485A (en) | Preparation method of medicine bosutinib for treating leukemia | |
| CN103787924A (en) | New purification method of antitumor drug Belinostat | |
| CN101948479B (en) | Prasugrel intermediate and preparation method thereof | |
| CN105566260A (en) | Furosemide preparation method | |
| CN108727200A (en) | The synthetic method of nonamethylene diamine | |
| CN104876911A (en) | Simple method for synthesizing delafloxacin | |
| CN104311471A (en) | Improved mitiglinide calcium industrialized preparation method | |
| CN105753735B (en) | Preparation method of high-efficiency low-toxicity vasopressin antagonist | |
| CN106946724A (en) | The synthetic method of the benzyl malonic acid mono ethyl ester of 2 acetylamino of monoamine base inhibitor class intermediate 2 | |
| CN105330525A (en) | Preparation method of 7-hydroxy-1-indanone | |
| CN104592222A (en) | Preparation method for antiplatelet medicine AZD6482 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |