CN104529800B - 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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- CN104529800B CN104529800B CN201410740561.5A CN201410740561A CN104529800B CN 104529800 B CN104529800 B CN 104529800B CN 201410740561 A CN201410740561 A CN 201410740561A CN 104529800 B CN104529800 B CN 104529800B
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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 to the preparation of a kind of trans -4- Dimethylaminocrotonic acid and salt
Method.
Background technology
Trans -4- Dimethylaminocrotonic acid is antineoplastic agent HKI-272 (neratinib) and Afatinib
(afatinib) important intermediate.Because trans -4- Dimethylaminocrotonic acid contains α, beta-unsaturated carbonyl structure, as
There is addition in the nucleophilic group on michael receptor, with corresponding protease, form covalent bond and biological effect occurs.Instead
Formula -4- Dimethylaminocrotonic acid and its salt structural formula are as follows:
The synthetic route of existing trans -4- Dimethylaminocrotonic acid is mainly with .beta.-methylacrylic acid as starting material: from not
Same blocking group (methoxyl group or trim,ethylchlorosilane) forms ester with carboxyl, is re-introduced into dimethylamino, deprotection obtains target
Compound.
Master thesis as Institutes Of Technology Of Nanjing Liu Shuai: " synthesis of medicine intermediate 4- dimethylamino .beta.-methylacrylic acid with
Characterize " (Institutes Of Technology Of Nanjing, 2010), the route mentioned is as follows:
Chinese patent cn 100537518c (" synthesis of 4- amino -2-butylene acyl chlorides and its preparation 3- cyano quinolines
In application ", Wyeth, application number: cn200480007723.9) in technology path as follows:
Above route has all used dimethylamine, dimethylamine low boiling point, belongs to dangerous materials, to industrialized production equipment with operation all
Have higher requirement, and products obtained therefrom yield and purity all low.
Content of the invention
The technical problem to be solved is to overcome the defect of prior art, devise raw material be easy to get, technique letter
Clean, the suitable industrialized production of environmental protection and economy, reaction condition, high income trans -4- Dimethylaminocrotonic acid and salt synthesis
New method.
Technical scheme is as follows:
A kind of trans -4- Dimethylaminocrotonic acid and the preparation method of salt, comprise the steps: 1) with compound
(anil) and compound (diethyl phosphine ethyl acetoacetic acid) occur aminolysis reaction to obtain intermediate；2) intermediate again with
Compound ((dimethylamino)-acetaldehyde-diethyl acetal) is condensed to yield intermediate；3) intermediate hydrolysis and obtain
Target compound；Reaction equation is as follows:
Described step 1) in compound with the aminolysis reaction of compound be: with oxolane as solvent, by chemical combination
Thing adds in oxolane, and stirring adds compound, finishes in 40～50 DEG C of stirring reactions, reactant liquor is poured in frozen water,
Stirring, sucking filtration, gained filter cake obtains intermediate in 40～50 DEG C of drying under reduced pressure to constant weight.Described compound and compound
Mol ratio be 1:1～2.
Described step 2) intermediate reacted with compound condensation and is: hydrochloric acid or sulphuric acid are cooled to 0 DEG C, Deca chemical combination
Thing, finishes in 40～50 DEG C of hydrolysis, then is cooled to 0 DEG C of standby (as reserve liquid a)；Sequentially add intermediate in dehydrated alcohol
, lithium chloride, be cooled to 0 DEG C, add Sodium ethylate, stirring, Deca reserve liquid a, this step is reacted with lithium chloride as catalyst, no
Water-ethanol, as solvent, makes reaction carry out under alkaline environment.Add ethyl acetate, stirring after completion of the reaction, filter, in filtrate
Middle addition water, adds anhydrous sodium sulfate drying in organic layer, filters, is evaporated to dry, obtains intermediate.Described hydrochloric acid with
The mol ratio of compound is 1～2:1, or sulphuric acid is 0.5～1:1 with the mol ratio of compound；Described compound: in
Mesosome: the mol ratio of lithium chloride is: 1～2:1:0.5～1.
Described step 3) reaction that obtains target compound of intermediate hydrolysis is: take intermediate to add under room temperature
To in methanol or ethanol or acetone, instill sodium hydroxide or potassium hydroxide solution, be heated to reflux finishing to reaction, reactant liquor is poured into
In frozen water, stirring, sucking filtration, obtain pale solid, as target compound.Described intermediate and sodium hydroxide or hydroxide
The mol ratio of potassium is: 1:4～8.
The invention has the beneficial effects as follows: the present invention reacts (wittig-horner reacts) as base with phosphorus ylide and aldehyde ketone
Plinth and design, there is the aminolysis reaction of acid with anil and diethyl phosphine ethyl acetoacetic acid, form amido link, then with (dimethyl
Amino) condensation of-acetaldehyde-diethyl acetal, deprotection and target compound.This synthetic method route is brief, efficient, operation side
Just, it is to avoid the use of low boiling hazardous chemical dimethylamine, environmental protection and economy, gross production rate be high, good product purity, is suitable for industry
Metaplasia is produced.
Specific embodiment
Embodiment 1
Reacted according to following route:
1st, the preparation of intermediate
5.00g (0.0255mol) compound (diethyl phosphine ethyl acetoacetic acid) is taken to be added in 50ml oxolane (thf),
After stirring 30min, add 3.50g (0.0195mol) compound (p-ethyl benzene), finish in 40 DEG C of stirring reactions.
Again reactant liquor is poured in 1.0l frozen water, stir 30min, sucking filtration, gained filter cake obtains intermediate in 45 DEG C of drying under reduced pressure to constant weight
(2- (4- (2- (diethoxy phosphoryl) acetylamino) phenyl) ethyl acetate).This step yield is about 73%.
2nd, the preparation of intermediate
Under nitrogen protection, take the hydrochloric acid 10.0ml of 6mol/l, be cooled to 0 DEG C, Deca compound ((dimethylamino
Base)-acetaldehyde-diethyl acetal) 9.0ml, finishes in 40 DEG C of hydrolysis, then is cooled to 0 DEG C of standby (as reserve liquid a).
Sequentially add above-mentioned prepared intermediate 10.00g, lithium chloride 0.80g in 100ml dehydrated alcohol, be cooled to 0
DEG C, add Sodium ethylate 4.0g, stir 30min, Deca reserve liquid a, the reserve liquid a of aforementioned preparation is all dripped, drip Bi Ji
After continuous reaction 40min, add 250ml ethyl acetate, stir 1.0hr, filter, filtrate adds 125ml water, layering.Having
Add anhydrous sodium sulfate drying in machine layer, filter, be evaporated to dry, obtain intermediate, this step yield is about 84%.
3rd, the preparation of target compound
Under room temperature, the above-mentioned prepared intermediate of 5.00g (0.0172mol) is taken to be added in 50.0ml methanol or ethanol,
Instill 30%naoh solution 15.0ml, be heated to reflux finishing to reaction, reactant liquor is poured in frozen water, stir 30min, sucking filtration, obtain
Pale solid, as target compound, this step yield is about 65%.
Embodiment 2
1st, the preparation of intermediate
10.00g (0.051mol) compound (diethyl phosphine ethyl acetoacetic acid) is taken to be added in 100ml oxolane (thf),
After stirring 30min, add 10.3g (0.049mol) compound (p-aminophenyl propyl propionate), finish in 45 DEG C of stirring reactions.Again
Reactant liquor is poured in 2.0l frozen water, stirs 30min, sucking filtration, gained filter cake obtains intermediate in 45 DEG C of drying under reduced pressure to constant weight
(2- (4- (2- (diethoxy phosphoryl) acetylamino) phenyl) ethyl acetate).This step yield is about 70%.
2nd, the preparation of intermediate
Under nitrogen protection, take the sulphuric acid 10.0ml of 6mol/l, be cooled to 0 DEG C, Deca compound ((dimethylamino
Base)-acetaldehyde-diethyl acetal) 18.0ml, finishes in 45 DEG C of hydrolysis, then is cooled to 0 DEG C of standby (as reserve liquid a).
Sequentially add above-mentioned prepared intermediate 20.00g, lithium chloride 1.60g in 200ml dehydrated alcohol, be cooled to 0
DEG C, add Sodium ethylate 8.0g, stir 30min, Deca reserve liquid a, the reserve liquid a of aforementioned preparation is all dripped, drip Bi Ji
After continuous reaction 50min, add 500ml ethyl acetate, stir 1.0hr, filter, filtrate adds 250ml water, layering.Having
Add anhydrous sodium sulfate drying in machine layer, filter, be evaporated to dry, obtain intermediate, this step yield is about 81%.
3rd, the preparation of target compound
Under room temperature, take the above-mentioned prepared intermediate of 10.00g (0.0344mol) to be added in 100.0ml acetone, instill
30%koh solution 30.0ml, is heated to reflux finishing to reaction, reactant liquor is poured in frozen water, stir 30min, sucking filtration, obtain canescence
Solid, as target compound, this step yield is about 64%.
Claims (7)
1. the preparation method of a kind of trans -4- Dimethylaminocrotonic acid and salt is it is characterised in that comprise the steps: 1) with
Anil and compound occur aminolysis reaction to obtain intermediate；2) intermediate is obtained with compound condensation again
Intermediate；3) intermediate hydrolysis and target compound；Reaction equation is as follows:
；
Described anil is p-ethyl benzene or p-aminophenyl propyl propionate.
2. trans -4- Dimethylaminocrotonic acid according to claim 1 and salt preparation method it is characterised in that: institute
Stating compound and the aminolysis reaction of compound in step 1) is: compound is added in oxolane, stirring, and additionization
Compound, finishes in 40～50 DEG C of stirring reactions, reactant liquor is poured in frozen water, stirring, sucking filtration, and gained filter cake subtracts in 40～50 DEG C
Press dry dry to constant weight, obtain intermediate.
3. trans -4- Dimethylaminocrotonic acid according to claim 1 and salt preparation method it is characterised in that: institute
State step 2) intermediate reacted with compound condensation and is: hydrochloric acid or sulphuric acid are cooled to 0 DEG C, Deca compound, in 40
～50 DEG C hydrolysis finish, then be cooled to 0 DEG C standby, obtain reserve liquid a；Intermediate, chlorination is sequentially added in dehydrated alcohol
Lithium, is cooled to 0 DEG C, adds Sodium ethylate, stirring, Deca reserve liquid a, adds ethyl acetate, stirring after completion of the reaction, filter,
Add water in filtrate, in organic layer, add anhydrous sodium sulfate drying, filter, be evaporated to dry, obtain intermediate.
4. trans -4- Dimethylaminocrotonic acid according to claim 1 and salt preparation method it is characterised in that: institute
State step 3) intermediate hydrolysis and obtain the reaction of target compound and be: under room temperature, take intermediate to be added to methanol or second
In alcohol or acetone, instill sodium hydroxide or potassium hydroxide solution, be heated to reflux finishing to reaction, reactant liquor poured in frozen water, stirs
Mix, sucking filtration, obtain pale solid, as target compound.
5. trans -4- Dimethylaminocrotonic acid according to claim 1 and 2 and salt preparation method it is characterised in that:
Compound described in step 1) is 1:1～2 with the mol ratio of compound.
6. trans -4- the Dimethylaminocrotonic acid according to claim 1 or 3 and salt preparation method it is characterised in that:
Step 2) described in the mol ratio of hydrochloric acid and compound be 1～2:1, or the mol ratio of sulphuric acid and compound be 0.5～
1:1；Described compound: intermediate: 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 salt preparation method it is characterised in that:
Intermediate described in step 3) is 1:4～8 with the mol ratio of sodium hydroxide or potassium hydroxide.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009033581A1 (en) * | 2007-09-14 | 2009-03-19 | Bayer Schering Pharma Aktiengesellschaft | Substituted tricyclic compounds and methods of use thereof |
| WO2011099764A3 (en) * | 2010-02-09 | 2012-01-05 | 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| WO2011099764A3 (en) * | 2010-02-09 | 2012-01-05 | Hanmi Holdings Co., Ltd. | Novel pyrimidine derivative for inhibiting the growth of cancer cells |
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