CN104926669A - Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride - Google Patents
Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride Download PDFInfo
- Publication number
- CN104926669A CN104926669A CN201410100035.2A CN201410100035A CN104926669A CN 104926669 A CN104926669 A CN 104926669A CN 201410100035 A CN201410100035 A CN 201410100035A CN 104926669 A CN104926669 A CN 104926669A
- Authority
- CN
- China
- Prior art keywords
- trans
- compound
- described step
- dimethyl amido
- preparation formula
- 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.)
- Pending
Links
- CIBYNORTVQSQMW-SNAWJCMRSA-N CN(C)C/C=C/C(OC)=O Chemical compound CN(C)C/C=C/C(OC)=O CIBYNORTVQSQMW-SNAWJCMRSA-N 0.000 description 4
- ITGIYLMMAABTHC-ONEGZZNKSA-N CN(C)C/C=C/C(O)=O Chemical compound CN(C)C/C=C/C(O)=O ITGIYLMMAABTHC-ONEGZZNKSA-N 0.000 description 3
- BGGVJKGMDWLNRC-UHFFFAOYSA-N CC(N(C)C)OC Chemical compound CC(N(C)C)OC BGGVJKGMDWLNRC-UHFFFAOYSA-N 0.000 description 1
- RWIKCBHOVNDESJ-NSCUHMNNSA-N COC(/C=C/CBr)=O Chemical compound COC(/C=C/CBr)=O RWIKCBHOVNDESJ-NSCUHMNNSA-N 0.000 description 1
- MEWNMXOMGLCCMO-ONEGZZNKSA-N COC(/C=C/C[BrH]C)=O Chemical compound COC(/C=C/C[BrH]C)=O MEWNMXOMGLCCMO-ONEGZZNKSA-N 0.000 description 1
Abstract
The invention relates to a preparation method of trans-4-dimethylaminocrotonic acid hydrochloride, wherein the preparation method is a preparation process of the important pharmaceutical intermediate represented by the formula (I), methyl 4-bromocrotonate and a dimethylamine compound are subjected to substitution, salt formation, hydrolysis and salt formation to prepare the compound trans-4-dimethylaminocrotonic acid hydrochloride represented by the formula (I). The preparation method is concise in process, high in yield, and suitable for industrialized amplification requirements.
Description
Technical field
The present invention relates to organic chemical synthesis and medicinal chemistry art, particularly relate to the preparation method of trans-4-dimethyl amido cronate hydrochlorate.
Background technology
The present invention relates to a kind of preparation method of trans-4-dimethyl amido cronate hydrochlorate, trans-4-dimethyl amido cronate hydrochlorate is a kind of very important medicine intermediate, and it is that antitumor drug Ah method is for the important component part in Buddhist nun, HKI-272 structure.Bibliographical information for trans-4-dimethyl amido cronate hydrochlorate synthesis is a lot, such as US2003050222A1, WO2004066919, WO2009033581, WO2010151710A2, WO2011099764 etc.But in the method reported, yield is lower (calculating run-of-the-mill yield for 18% with the throwing gauge of 4-bromo crotonate), cost high (most literature with the tetrahydrofuran solution of dimethylamine for reaction reagent, 2M dimethylamine tetrahydrofuran solution 100ml price is 567 yuan), be unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, and provides a kind of simple, safety, the efficient method preparing trans-4-dimethyl amido cronate hydrochlorate.
Technical scheme of the present invention is realized by following manner:
The method of trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula (I), with compound (II) for starting raw material, is substituted, salify, hydrolysis, obtains target product after salify,
Preferably, described preparation method specifically comprises the steps:
(1) replace: compound (II), dimethyl amine compound, alkali, organic solvent are added in reaction flask and carries out substitution reaction at a proper temperature and obtain compound (III);
(2) salify: compound (III) adjusts pH=1 ~ 2 concentrating under reduced pressure to obtain compound (IV) with 2N hydrochloric acid in organic solvent B;
(3) be hydrolyzed: compound (IV), alkali, water add in reaction flask to be hydrolyzed and reacts to obtain compound (V);
(4) salify: compound (V) 2N hydrochloric acid adjusts pH=1 ~ 2 concentrating under reduced pressure and crystallization obtains formula (I) compound in organic solvent C, and optional, above-mentioned reactions steps is that proceed step by step or one kettle way carry out.
Preferably, in described step (1), dimethyl amine compound is selected from dimethylamine agueous solution, dimethylamine alcoholic solution, dimethylamine tetrahydrofuran solution, dimethylamine hydrochloride or dimethylamine gas, preferred dimethylamine hydrochloride.
Preferably, in described step (1), alkali is selected from triethylamine, diisopropylethylamine or ammoniacal liquor, more preferably triethylamine.
Preferably, in described step (1), temperature of reaction is selected from as-30 ~ 10 DEG C, preferably-10 ~ 0 DEG C.
Preferably, the organic solvent B in described step (2) is methyl alcohol, ethanol, Virahol or propyl carbinol.
Preferably, the hydrolyzation system in described step (3) is selected from sodium hydroxide/water/methyl alcohol, sodium hydroxide/water, potassium hydroxide/water/methyl alcohol, potassium hydroxide/water, lithium hydroxide/water/methyl alcohol or lithium hydroxide, preferred sodium hydroxide/aqueous systems.
Preferably, in described step (3), temperature of reaction is selected from is 10 ~ 100 DEG C, preferably 30 ~ 60 DEG C.
Preferably, the crystallization organic solvent C in described step (4) is selected from Virahol, acetone, ether or Virahol/acetone, more preferably Virahol/acetone.
Preferably, the acid in described step (2) and step (4) is selected from hydrochloric acid, sulfuric acid, nitric acid or acetic acid, preferred hydrochloric acid independently of one another.
Preparation method's route of the present invention is short, and yield is high, cost is low, easy to operate, does not relate to danger or has serious application of poisoning reagent, be applicable to suitability for industrialized production application.
Accompanying drawing explanation
Fig. 1 is embodiment 2 products therefrom hydrogen nuclear magnetic resonance collection of illustrative plates.
Embodiment
Should be appreciated that, those skilled in the art, based on content disclosed herein, can carry out variously not departing from various amendment in spirit and scope of the invention and improvement to the present invention.They should all drop in the scope of patent protection of claim definition of the application.In addition, should be appreciated that, embodiment provided herein only for illustration of object of the present invention, and should not be construed as restriction of the present invention.
Embodiment 1:
Dimethylamine hydrochloride (182.3g) and THF(1000ml) add in reaction flask, be cooled to-10 ~ 0 DEG C, drip triethylamine (310ml) and drip complete-10 ~ 0 DEG C of reaction 0.5h, then 4-bromo crotonate (200g)-THF(500ml is dripped at-10 ~ 0 DEG C) solution, drip and finish,-10 ~ 0 DEG C of reaction 16h, it is complete that TLC detects 4-bromo crotonate primitive reaction, filter, a small amount of THF of filter cake washes, and filtrate decompression contracting is dry, add IPA(Virahol 100ml), and adjust pH=1 ~ 2 with 2N hydrochloric acid, adjust to finish to subtract to compress and do, obtain oily matter 150g;
Embodiment 2:
Above-mentioned oily matter is cooled to-10 ~ 0 DEG C, NaOH(133g is instilled under stirring)-water (1250ml) solution, drip and finish, rise to 50 DEG C of reaction 1h, it is complete that TLC detects trans-4-dimethyl amido methyl crotonate primitive reaction, be chilled to-10 DEG C ~ 0 DEG C, pH=1 ~ 2 are adjusted with 2N HCl, adjust and finish, decompression contracting is dry, add ethanol 800ml and at stirring at room temperature 10min, filter, the a small amount of ethanol of filter cake NaCl is washed, filtrate decompression contracting is dry, adding IPA(Virahol 100ml)-acetone (200ml) stirring and crystallizing spends the night, filter, obtain white solid 92.5g, mass yield 50.7%.
1H-NMR（DMSO-d6）δ:2.70(s,6H),3.88(d,J=6.8Hz,2H),6.18(d,J=15.6Hz,1H),6.84(m,1H),11.39(br,1H),12.71(br,1H).
Embodiment 3:
The first step is identical with reference to embodiment 1(condition), oily matter adds in methyl alcohol (1500ml) by second step, be cooled to-10 ~ 0 DEG C, NaOH(133g is instilled under stirring)-water (1250ml) solution, drip and finish, rise to 50 DEG C of reaction 1h, it is complete that TLC detects trans-4-dimethyl amido methyl crotonate primitive reaction, be chilled to-10 DEG C ~ 0 DEG C, pH=1 ~ 2 are adjusted with 2N HCl, adjust and finish, decompression contracting is dry, add ethanol 800ml and at stirring at room temperature 10min, filter, the a small amount of ethanol of filter cake NaCl is washed, filtrate decompression contracting is dry, adding IPA(100ml)-acetone (200ml) stirring and crystallizing spends the night, filter, obtain white solid 40.6g, mass yield 22.3%.
Through structural identification, gained white solid is identical with embodiment 2 product.
Claims (11)
1. a method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula (I), with compound (II) for starting raw material, is substituted, salify, hydrolysis, salify four-step reaction obtains target product,
2. trans-4-dimethyl amido crotons shown in preparation formula according to claim 1 (I)
The method of acid hydrochloride, comprises following synthesis step:
1) replace: compound (II), dimethyl amine compound solution, alkali, organic solvent A are added in reaction flask and carries out substitution reaction at a proper temperature and obtain compound (III);
2) salify: compound (III) adjusts pH=1 ~ 2 concentrating under reduced pressure to obtain compound (IV) with acid in organic solvent B;
3) be hydrolyzed: compound (IV), alkali, water add in reaction flask to be hydrolyzed and reacts to obtain compound (V);
4) salify: compound (V) adjusts pH=1 ~ 2 concentrating under reduced pressure with acid and crystallization obtains formula (I) compound in organic solvent C, and optional, above-mentioned steps is that proceed step by step or " one kettle way " carry out.
3. the method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula according to claim 2 (I), it is characterized in that, in described step 1), dimethyl amine compound is selected from dimethylamine agueous solution, dimethylamine alcoholic solution, dimethylamine tetrahydrofuran solution, dimethylamine hydrochloride or dimethylamine gas, preferred dimethylamine hydrochloride.
4. the method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula according to claim 2 (I), it is characterized in that, in described step 1), alkali is selected from triethylamine, diisopropylethylamine or ammoniacal liquor, preferred triethylamine.
5. the method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula according to claim 2 (I), it is characterized in that, the organic solvent A in described step 1) is THF.
6. the method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula according to claim 2 (I), it is characterized in that, in described step 1), temperature of reaction is selected from as-30 ~ 10 DEG C, preferably-10 ~ 0 DEG C.
7. the method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula according to claim 2 (I), is characterized in that, described step 2) in organic solvent B be methyl alcohol, ethanol, Virahol or propyl carbinol.
8. the method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula according to claim 2 (I), it is characterized in that, hydrolyzation system in described step 3) is selected from sodium hydroxide/water/methyl alcohol, sodium hydroxide/water, potassium hydroxide/water/methyl alcohol, potassium hydroxide/water, lithium hydroxide/water/methyl alcohol or lithium hydroxide, preferred sodium hydroxide/aqueous systems.
9. the method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula according to claim 2 (I), it is characterized in that, in described step 3), temperature of reaction is selected from is 10 ~ 100 DEG C, preferably 30 ~ 60 DEG C.
10. the method for trans-4-dimethyl amido cronate hydrochlorate shown in preparation formula according to claim 2 (I), it is characterized in that, crystallization organic solvent C in described step 4) is selected from Virahol, acetone, ether or Virahol/acetone, preferred Virahol/acetone.
The method of trans-4-dimethyl amido cronate hydrochlorate shown in 11. preparation formulas according to claim 2 (I), is characterized in that, described step 2) and step 4) in acid be selected from hydrochloric acid, sulfuric acid, nitric acid or acetic acid independently of one another, preferred hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410100035.2A CN104926669A (en) | 2014-03-18 | 2014-03-18 | Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410100035.2A CN104926669A (en) | 2014-03-18 | 2014-03-18 | Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104926669A true CN104926669A (en) | 2015-09-23 |
Family
ID=54114127
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410100035.2A Pending CN104926669A (en) | 2014-03-18 | 2014-03-18 | Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104926669A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669479A (en) * | 2015-12-31 | 2016-06-15 | 重庆威鹏药业有限公司 | Method for preparing highly pure trans-4-dimethylaminocrotonic acid hydrochloride through one-pot technology |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005028443A2 (en) * | 2003-09-15 | 2005-03-31 | Wyeth A Corporation Of The State Of Delaware, Usa | Protein tyrosine kinase enzyme inhibitors |
| CN1761644A (en) * | 2003-01-21 | 2006-04-19 | 惠氏公司 | Synthesis of 4-(amino)-2-butenoyl chlorides and their use in the preparation of 3-cyano quinolines |
| EP1670473A1 (en) * | 2003-09-15 | 2006-06-21 | Wyeth a Corporation of the State of Delaware | Substituted quinolines as protein tyrosine kinase enzyme inhibitors |
-
2014
- 2014-03-18 CN CN201410100035.2A patent/CN104926669A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1761644A (en) * | 2003-01-21 | 2006-04-19 | 惠氏公司 | Synthesis of 4-(amino)-2-butenoyl chlorides and their use in the preparation of 3-cyano quinolines |
| WO2005028443A2 (en) * | 2003-09-15 | 2005-03-31 | Wyeth A Corporation Of The State Of Delaware, Usa | Protein tyrosine kinase enzyme inhibitors |
| EP1670473A1 (en) * | 2003-09-15 | 2006-06-21 | Wyeth a Corporation of the State of Delaware | Substituted quinolines as protein tyrosine kinase enzyme inhibitors |
| US20080319011A1 (en) * | 2003-09-15 | 2008-12-25 | Wyeth | Protein tyrosine kinase enzyme inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669479A (en) * | 2015-12-31 | 2016-06-15 | 重庆威鹏药业有限公司 | Method for preparing highly pure trans-4-dimethylaminocrotonic acid hydrochloride through one-pot technology |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103044329B (en) | Preparation method of high-yield and high-purity celecoxib | |
| CN103601686A (en) | Method for synthesizing fluorine-containing pyrimidine compounds by virtue of one-pot method | |
| CN103936599A (en) | Preparation method of 2-methoxy ethylamine | |
| US9045392B2 (en) | Preparation of 4-amino-2,4-dioxobutanoic acid | |
| CN104926669A (en) | Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride | |
| CN105039450A (en) | Synthetic method of efinaconazole intermediate | |
| US20190202791A1 (en) | Method for synthesizing 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid and intermediates thereof | |
| CN103664675B (en) | The preparation method of a kind of chloro-N-of 2-(4-fluorophenyl)-N-isopropyl acetamide | |
| CN104529815A (en) | Method for synthesizing 2,4-dinitrobenzene oxygen amine | |
| CN103664654A (en) | Industrial production method of high-purity sulfuric acid terbutaline | |
| CN104496900A (en) | Method for preparing 2-methoxy-6-one-5,7,8-trihydro-quinoline | |
| CN105330525A (en) | Preparation method of 7-hydroxy-1-indanone | |
| CN103992241A (en) | Preparation method of N-substituted phenyl glycine | |
| CN105294620A (en) | Synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid | |
| CN102863355B (en) | Purifying method of N-(3-methoxy-2-methyl benzoyl)-N'-tert-butylhydrazine | |
| CN104230883B (en) | A kind of preparation method of the thiophenic acid isopropyl ester of 3 amino 2 | |
| CN109761894A (en) | A kind of preparation method of 5- bromo-2-pyridyl formic acid | |
| CN107935900B (en) | Preparation method of trimethylsulfonium chloride | |
| CN103073498A (en) | Novel preparation method for (R)-Alpha-amino-e-caprolactam | |
| EP3162796B1 (en) | Method for producing 2-amino-6-methylnicotinic acid | |
| CN102731437A (en) | Preparation method of 4-piperazine-3-trifluoromethylaniline hydrochloride | |
| CN106496012B (en) | A kind of preparation method of Alpha-hydroxy tetradecylic acid | |
| CN105085595A (en) | Method for synthesizing 2,6-hologenated purine nucleoside by deacylation protection | |
| CN106365998A (en) | Preparation method of iodomethyl pivalate | |
| CN104995170A (en) | Method for synthesizing 4-piperidin-4-yl-benzene-1,3-diol and the salts of same and novel compound tert-butyl 4-(2,4-dihydroxy-phenyl_-4-hydroxy-piperidine-1-carboxylate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| CB02 | Change of applicant information |
Address after: 222006 Jiangsu province Lianyungang Kaitai Dapu Industrial Zone, economic and Technological Development Zone Road Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222006 Jiangsu province Lianyungang Kaitai Dapu Industrial Zone, economic and Technological Development Zone Road Applicant before: Jiangsu Hansoh Pharmaceutical Group Lianyungang Hongchuang Medical Co., Ltd. |
|
| COR | Change of bibliographic data | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160311 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222006 Jiangsu province Lianyungang Kaitai Dapu Industrial Zone, economic and Technological Development Zone Road Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150923 |