CN104529800A - Preparation method of trans-4-dimethylaminocrotonic acid and its salt - Google Patents
Preparation method of trans-4-dimethylaminocrotonic acid and its salt Download PDFInfo
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- CN104529800A CN104529800A CN201410740561.5A CN201410740561A CN104529800A CN 104529800 A CN104529800 A CN 104529800A CN 201410740561 A CN201410740561 A CN 201410740561A CN 104529800 A CN104529800 A CN 104529800A
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Abstract
The invention relates to a preparation method of trans-4-dimethylaminocrotonic acid and its salt and belongs to the field of organic synthesis. The preparation method comprises the following steps that 1, a compound VI (aniline derivative) and a compound V (diethylphosphonoacetic acid) undergo an aminolysis reaction to produce an intermediate IV, 2, the intermediate IV and a compound III ((dimethylamino)-glyoxyl-diethylacetal) undergo a condensation reaction to produce an intermediate II, and 3, the intermediate II undergoes a hydrolysis reaction to produce a desired compound I. The preparation method are simple and efficient synthesis route, is convenient for operation, is free of use of lower-boiling point dangerous chemical dimethylamine, is economic and environmentally friendly, has a high total yield, realizes good product purity and is suitable for industrial production.
Description
Technical field
The present invention relates to organic synthesis field, particularly the preparation method of a kind of trans-4-Dimethylaminocrotonic acid and salt.
Background technology
Trans-4-Dimethylaminocrotonic acid is the intermediate that antitumour drug HKI-272 (Neratinib) replaces Buddhist nun (Afatinib) important with Ah method.Because trans-4-Dimethylaminocrotonic acid contains α, beta-unsaturated carbonyl structure, as Michael acceptor, with the nucleophilic group generation addition on corresponding protein enzyme, forms covalent linkage and biological effect occurs.Trans-4-Dimethylaminocrotonic acid and salt structural formula as follows:
The synthetic route of existing trans-4-Dimethylaminocrotonic acid is mainly starting material with β-crotonic acid: select different blocking groups (methoxyl group or trimethylchlorosilane) and carboxyl to form ester; introduce dimethylin again, deprotection obtains target compound.
Master thesis as Institutes Of Technology Of Nanjing Liu Shuai: " syntheses and properties of medicine intermediate 4-dimethylamino β-crotonic acid " (Institutes Of Technology Of Nanjing, 2010), the route mentioned is as follows:
Technological line in Chinese patent CN 100537518C (" synthesis of 4-amino-2-butylene acyl chlorides and its application in preparation 3-cyano quinolines ", Wyeth, application number: CN200480007723.9) is as follows:
Above route has all used dimethylamine, and dimethylamine boiling point is low, belongs to hazardous substance, have higher requirement, and products obtained therefrom yield and purity is all on the low side to suitability for industrialized production equipment and manipulation.
Summary of the invention
Technical problem to be solved by this invention is the defect overcoming prior art, devises that raw material is easy to get, the novel method of concise in technology, environmental protection and economy, reaction conditions suitability for industrialized are produced, yield is high trans-4-Dimethylaminocrotonic acid and salt synthesis.
Technical scheme of the present invention is as follows:
A preparation method for trans-4-Dimethylaminocrotonic acid and salt, comprises the steps: 1) there is aminolysis reaction with compound VI (anils) and compound V (diethyl phosphonoacetic acid) and obtain intermediate IV; 2) intermediate IV obtains intermediate II with compound III ((dimethylamino)-acetaldehyde-diethyl acetal) condensation again; 3) intermediate II hydrolysis reaction and target compound I; Reaction formula is as follows:
Described step 1) in compound VI with the aminolysis reaction of compound V be: with tetrahydrofuran (THF) as solvent, compound V is added in tetrahydrofuran (THF), stir, add compound VI, finish in 40 ~ 50 DEG C of stirring reactions, reaction solution is poured in frozen water, stir, suction filtration, gained filter cake, in 40 ~ 50 DEG C of drying under reduced pressure to constant weight, obtains intermediate IV.Described compound VI is 1:1 ~ 2 with the mol ratio of compound V.
Described step 2) intermediate IV with compound III condensation reaction is: hydrochloric acid or sulfuric acid is cooled to 0 DEG C, drips compound III, finish in 40 ~ 50 DEG C of hydrolysis, then be cooled to 0 DEG C (being reserve liquid A) for subsequent use; In dehydrated alcohol, add intermediate IV, lithium chloride successively, be cooled to 0 DEG C, add sodium ethylate, stir, drip reserve liquid A, the reaction of this step is with lithium chloride as catalyzer, and dehydrated alcohol, as solvent, makes reaction carry out under alkaline environment.Add ethyl acetate after completion of the reaction, stir, filter, in filtrate, add water, in organic layer, add anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain intermediate II.The mol ratio of described hydrochloric acid and compound III is 1 ~ 2:1, or the mol ratio of sulfuric acid and compound III is 0.5 ~ 1:1; Described compound III: intermediate IV: the mol ratio of lithium chloride is: 1 ~ 2:1:0.5 ~ 1.
Described step 3) reaction that obtains target compound I of intermediate II hydrolysis reaction is: gets intermediate II under room temperature and joins in methyl alcohol or ethanol or acetone, instillation sodium hydroxide or potassium hydroxide solution, reflux finishes to reaction, reaction solution is poured in frozen water, stir, suction filtration, obtains pale solid, is target compound I.The mol ratio of described intermediate II and sodium hydroxide or potassium hydroxide is: 1:4 ~ 8.
The invention has the beneficial effects as follows: the present invention reacts based on (Wittig-Horner reacts) by phosphorus ylide and aldehyde ketone and designs; the aminolysis reaction of acid is there is with anils and diethyl phosphonoacetic acid; form amido linkage; again with (dimethylamino)-acetaldehyde-diethyl acetal condensation, deprotection and target compound.This synthetic method route is brief, efficient, easy to operate, avoids the use of lower boiling hazardous chemical dimethylamine, environmental protection and economy, overall yield are high, good product purity, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1
React according to following route:
1, the preparation of intermediate IV
Getting 5.00g (0.0255mol) compound V (diethyl phosphonoacetic acid) joins in 50ml tetrahydrofuran (THF) (THF), after stirring 30min, add 3.50g (0.0195mol) compound VI (p-ethyl benzene), finish in 40 DEG C of stirring reactions.Again reaction solution is poured in 1.0L frozen water; stir 30min; suction filtration, gained filter cake, in 45 DEG C of drying under reduced pressure to constant weight, obtains intermediate IV (2-(4-(2-(diethoxy phosphoryl) kharophen) phenyl) ethyl acetate).This step yield is about 73%.
2, the preparation of intermediate II
Under nitrogen protection; get the hydrochloric acid 10.0ml of 6mol/L, be cooled to 0 DEG C, drip compound III ((dimethylamino)-acetaldehyde-diethyl acetal) 9.0ml; finish in 40 DEG C of hydrolysis, then be cooled to 0 DEG C (being reserve liquid A) for subsequent use.
Above-mentioned obtained intermediate IV 10.00g, lithium chloride 0.80g is added successively in 100ml dehydrated alcohol, be cooled to 0 DEG C, add sodium ethylate 4.0g, stir 30min, drip reserve liquid A, the reserve liquid A of aforementioned preparation is all dripped, after dripping Bi Jixu reaction 40min, adds 250ml ethyl acetate, stir 1.0hr, filter, in filtrate, add 125ml water, layering.In organic layer, add anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain intermediate II, this step yield is about 84%.
3, the preparation of target compound I
Under room temperature, getting the above-mentioned obtained intermediate II of 5.00g (0.0172mol) joins in 50.0ml methyl alcohol or ethanol, instillation 30%NaOH solution 15.0ml, reflux finishes to reaction, is poured into by reaction solution in frozen water, stirs 30min, suction filtration, obtain pale solid, be target compound I, this step yield is about 65%.
Embodiment 2
1, the preparation of intermediate IV
Getting 10.00g (0.051mol) compound V (diethyl phosphonoacetic acid) joins in 100ml tetrahydrofuran (THF) (THF), after stirring 30min, add 10.3g (0.049mol) compound VI (p-aminophenyl propyl propionate), finish in 45 DEG C of stirring reactions.Again reaction solution is poured in 2.0L frozen water; stir 30min; suction filtration, gained filter cake, in 45 DEG C of drying under reduced pressure to constant weight, obtains intermediate IV (2-(4-(2-(diethoxy phosphoryl) kharophen) phenyl) ethyl acetate).This step yield is about 70%.
2, the preparation of intermediate II
Under nitrogen protection; get the sulfuric acid 10.0ml of 6mol/L, be cooled to 0 DEG C, drip compound III ((dimethylamino)-acetaldehyde-diethyl acetal) 18.0ml; finish in 45 DEG C of hydrolysis, then be cooled to 0 DEG C (being reserve liquid A) for subsequent use.
Above-mentioned obtained intermediate IV 20.00g, lithium chloride 1.60g is added successively in 200ml dehydrated alcohol, be cooled to 0 DEG C, add sodium ethylate 8.0g, stir 30min, drip reserve liquid A, the reserve liquid A of aforementioned preparation is all dripped, after dripping Bi Jixu reaction 50min, adds 500ml ethyl acetate, stir 1.0hr, filter, in filtrate, add 250ml water, layering.In organic layer, add anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain intermediate II, this step yield is about 81%.
3, the preparation of target compound I
Under room temperature, getting the above-mentioned obtained intermediate II of 10.00g (0.0344mol) joins in 100.0ml acetone, instillation 30%KOH solution 30.0ml, reflux finishes to reaction, is poured into by reaction solution in frozen water, stirs 30min, suction filtration, obtain pale solid, be target compound I, this step yield is about 64%.
Claims (7)
1. the preparation method of a trans-4-Dimethylaminocrotonic acid and salt, it is characterized in that, comprise the steps: 1) there is aminolysis reaction with compound VI (anils) and compound V (diethyl phosphonoacetic acid) and obtain intermediate IV; 2) intermediate IV obtains intermediate II with compound III ((dimethylamino)-acetaldehyde-diethyl acetal) condensation again; 3) intermediate II hydrolysis reaction and target compound I; Reaction formula is as follows:
2. the preparation method of trans-4-Dimethylaminocrotonic acid according to claim 1 and salt, it is characterized in that: described step 1) in compound VI with the aminolysis reaction of compound V be: compound V is added in tetrahydrofuran (THF), stir, add compound VI, finish in 40 ~ 50 DEG C of stirring reactions, reaction solution is poured in frozen water, stir, suction filtration, gained filter cake, in 40 ~ 50 DEG C of drying under reduced pressure to constant weight, obtains intermediate IV.
3. the preparation method of trans-4-Dimethylaminocrotonic acid according to claim 1 and salt, it is characterized in that: described step 2) intermediate IV with compound III condensation reaction is: hydrochloric acid or sulfuric acid are cooled to 0 DEG C, drip compound III, finish in 40 ~ 50 DEG C of hydrolysis, then be cooled to 0 DEG C (being reserve liquid A) for subsequent use; In dehydrated alcohol, add intermediate IV, lithium chloride successively, be cooled to 0 DEG C, add sodium ethylate, stir, drip reserve liquid A, add ethyl acetate after completion of the reaction, stir, filter, in filtrate, add water, in organic layer, add anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain intermediate II.
4. the preparation method of trans-4-Dimethylaminocrotonic acid according to claim 1 and salt, it is characterized in that: described step 3) reaction that obtains target compound I of intermediate II hydrolysis reaction is: gets intermediate II under room temperature and joins in methyl alcohol or ethanol or acetone, instillation sodium hydroxide or potassium hydroxide solution, reflux finishes to reaction, reaction solution is poured in frozen water, stir, suction filtration, obtain pale solid, be target compound I.
5. the preparation method of trans-4-Dimethylaminocrotonic acid according to claim 1 and 2 and salt, is characterized in that: step 1) described in compound VI be 1:1 ~ 2 with the mol ratio of compound V.
6. trans-4-the Dimethylaminocrotonic acid according to claim 1 or 3 and the preparation method of salt, is characterized in that: step 2) described in the mol ratio of hydrochloric acid and compound III be 1 ~ 2:1, or the mol ratio of sulfuric acid and compound III is 0.5 ~ 1:1; Described compound III: intermediate IV: the mol ratio of lithium chloride is 1 ~ 2:1:0.5 ~ 1.
7. trans-4-the Dimethylaminocrotonic acid according to claim 1 or 4 and the preparation method of salt, is characterized in that: step 3) described in the mol ratio of intermediate II and sodium hydroxide or potassium hydroxide be 1:4 ~ 8.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108623490A (en) * | 2018-06-22 | 2018-10-09 | 苏州市贝克生物科技有限公司 | The synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates |
Citations (4)
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| US20070027170A1 (en) * | 2003-10-17 | 2007-02-01 | Rainer Soyka | Process for preparing amino crotonyl compounds |
| WO2009033581A1 (en) * | 2007-09-14 | 2009-03-19 | Bayer Schering Pharma Aktiengesellschaft | Substituted tricyclic compounds and methods of use thereof |
| WO2011099764A2 (en) * | 2010-02-09 | 2011-08-18 | Hanmi Holdings Co., Ltd. | Novel pyrimidine derivative for inhibiting the growth of cancer cells |
| CN102625797A (en) * | 2009-06-25 | 2012-08-01 | 迈德药物研发技术有限公司 | Substituted heterocyclic compounds as kinases inhibitors and method of use thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070027170A1 (en) * | 2003-10-17 | 2007-02-01 | Rainer Soyka | Process for preparing amino crotonyl compounds |
| WO2009033581A1 (en) * | 2007-09-14 | 2009-03-19 | Bayer Schering Pharma Aktiengesellschaft | Substituted tricyclic compounds and methods of use thereof |
| CN102625797A (en) * | 2009-06-25 | 2012-08-01 | 迈德药物研发技术有限公司 | Substituted heterocyclic compounds as kinases inhibitors and method of use thereof |
| WO2011099764A2 (en) * | 2010-02-09 | 2011-08-18 | Hanmi Holdings Co., Ltd. | Novel pyrimidine derivative for inhibiting the growth of cancer cells |
| WO2011099764A3 (en) * | 2010-02-09 | 2012-01-05 | Hanmi Holdings Co., Ltd. | Novel pyrimidine derivative for inhibiting the growth of cancer cells |
Non-Patent Citations (1)
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| 邢其毅等: "《基础有机化学（第三版）》", 31 December 2008 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108623490A (en) * | 2018-06-22 | 2018-10-09 | 苏州市贝克生物科技有限公司 | The synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates |
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