CN105669479B - The method that one kettle way prepares the trans 4 dimethyl amido cronate hydrochlorate of high-purity - Google Patents
The method that one kettle way prepares the trans 4 dimethyl amido cronate hydrochlorate of high-purity Download PDFInfo
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- CN105669479B CN105669479B CN201511027704.9A CN201511027704A CN105669479B CN 105669479 B CN105669479 B CN 105669479B CN 201511027704 A CN201511027704 A CN 201511027704A CN 105669479 B CN105669479 B CN 105669479B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
The invention discloses a kind of method that one kettle way prepares the trans 4 dimethyl amido cronate hydrochlorate of high-purity, it is characterised in that includes the following steps：Trans 4 bromo crotonates is generated with trans crotonates and bromo-succinimide reaction, dimethylamine generation condensation reaction is then added and generates trans 4 dimethyl amido crotonates, alkaline hydrolysis obtains product.Using " one kettle way " prepare, not only operating procedure is simple, and obtain be high-purity product.This method is with material source is wide, cost is low, environmentally friendly, gross production rate is high, good product purity, easy to operate, suitable industrialized production.
Description
Technical field
The present invention relates to organic synthesis field, more particularly to a kind of one kettle way prepares the trans -4- dimethyl amidos of high-purity
The method of cronate hydrochlorate.
Background technology
Trans -4- Dimethylaminocrotonic acids are antineoplastic linatinib (Neratinib) and Afatinib
(Afatinib) important intermediate.Since trans -4- Dimethylaminocrotonic acids contain α, beta-unsaturated carbonyl structure, as
Addition occurs for the nucleophilic group on Michael acceptors, with corresponding protease, forms covalent bond and biological effect occurs.Instead
Formula -4- dimethyl amido cronate hydrochlorate structural formulas are as follows：
The synthetic route of existing trans -4- Dimethylaminocrotonic acids is mainly using crotonic acid as starting material：Select not
Same blocking group (methoxyl group or trim,ethylchlorosilane) forms ester with carboxyl, is re-introduced into dimethylamino, and deprotection obtains target
Compound.
Such as the master thesis of Institutes Of Technology Of Nanjing Liu Shuai：《The synthesis of medicine intermediate 4- dimethylamino crotonic acids with
Characterization》(Institutes Of Technology Of Nanjing, 2010), the route mentioned is as follows：
Chinese patent CN 100537518C (《The synthesis of 4- amino -2- crotonyl chlorides and its prepare 3- cyano quinolines
In application》, Wyeth, application number：CN200480007723.9 the technology path in) is as follows：
Above route has higher requirement to industrialized production equipment and operation, and operating procedure is complex, and gained
Product yield and purity are relatively low.
《Chemical research and application》The 8th phase of volume 27, the synthesising process research of 4- dimethylamino crotonic acids, Chu Chaosen etc. are carried
It is as follows for route：
Column chromatography procedure involved in the route technique, is unfavorable for industrialized production.
The content of the invention
It is an object of the invention to for the problem such as complex process in the prior art, product purity be low, there is provided a kind of material
The one kettle way that source is wide, cost is low, product purity is high prepares the side of the trans -4- dimethyl amidos cronate hydrochlorate of high-purity
Method.
Technical scheme is as follows：
A kind of method that one kettle way prepares the trans -4- dimethyl amidos cronate hydrochlorate of high-purity, includes the following steps：
Trans -4- bromos crotonates is generated with trans crotonates and bromo-succinimide reaction, then adds dimethylamine
Condensation reaction generates trans -4- dimethyl amidos crotonates, and alkaline hydrolysis obtains product；Reaction equation is as follows：
In the above-mentioned technical solutions, the trans crotonates for trans ethyl crotonate or trans ethyl crotonate or
The trans crotons isopropyl propionate of person either trans isobutyl crotonoate or trans crotons tert-butyl acrylate.
In the above-mentioned technical solutions, trans crotonates generates trans -4- bromos crotonates with bromo-succinimide
Reaction be：At room temperature, trans crotonates, bromo-succinimide, benzoyl peroxide, You Jirong are put into reaction vessel
Agent I, reacts to obtain trans -4- bromos crotonates solution.
Preferably, the trans crotonates, bromo-succinimide, the molar ratio of benzoyl peroxide are 1.00:
1.00~1.50:0.02~0.04, the organic solvent I is chloroform either ethyl acetate or carbon tetrachloride, the reaction time 9
~15hr.
Preferably, the condensation reaction of the trans -4- bromos crotonates and dimethylamine is：At room temperature, in container
Middle dropwise addition dimethylamine agueous solution, dropping temperature are -10~25 DEG C, and reaction obtains trans -4- dimethyl amidos crotonates solution.
Preferably, the molar ratio of the dimethylamine and trans crotonates is 1.5~3.0:1.0, the reaction time is
0.5~1.5hr.
In the above-mentioned technical solutions, the trans -4- dimethyl amidos crotonates alkaline hydrolysis obtains the reaction of product
For：At room temperature, aqueous slkali is added dropwise in a reservoir, dropping temperature is -10~25 DEG C, reacts 1.5~3.0hr, separates water layer, adjusts pH
It is worth 1~2, is concentrated under reduced pressure, organic solvent II is added in concentrate, stirs 1.0~1.5hr, filtering, being added in filtrate has
Solvent III, stirring, crystallization, obtains product.
Preferably, the aqueous slkali is sodium hydroxide either potassium hydroxide or calcium hydroxide, the alkali with it is trans
The molar ratio of crotonates is 1.00~2.00:1.00.
Preferably, the organic solvent II is dimethylformamide either tetrahydrofuran or acetonitrile or isopropyl
Alcohol, the organic solvent II I are acetone either ethyl acetate or butyl acetate.
The beneficial effects of the invention are as follows：The present invention provides a kind of new synthetic method, using trans crotonates as starting
Material, occurs condensation reaction after terminal methyl group bromination with dimethylamine, then hydrolyzes, and obtains trans dimethyl amido crotonic acid hydrochloric acid
Salt, altogether three-step reaction, using " one kettle way " prepare, not only operating procedure is simple, and obtain be high-purity product.We
Method is with material source is wide, cost is low, environmentally friendly, gross production rate is high, good product purity, easy to operate, suitable industrialized production.
Embodiment
One kettle way is used in following embodiments, using trans crotonates as starting material, after terminal methyl group bromination with
Condensation reaction occurs for dimethylamine, then hydrolyzes, and obtains trans dimethyl amido cronate hydrochlorate.Carried out according to following route anti-
Should：
Embodiment 1
Trans dimethyl amido cronate hydrochlorate is prepared, is operated in accordance with the following steps：
1st, the preparation of trans -4- bromos crotonates
At room temperature, put into successively in tetra- mouthfuls of reaction bulbs of 1000ml the trans ethyl crotonates of 50.0g (0.4995mol),
89.3g (0.50mol) bromo-succinimide, 3.5g (0.01mol) benzoyl peroxides and 250.0ml chloroforms.Feed intake complete, open
Stirring to back flow reaction 10.0hr, stirring is down to room temperature, obtains trans -4- bromocrotonic acids methyl esters chloroformic solution.
2nd, the preparation of trans -4- dimethyl amidos crotonic acid
At room temperature, 33% dimethylamine agueous solutions of 100.0g are slowly added dropwise in four mouthfuls of reaction bulbs of step 1
(0.7320mol), at -10~25 DEG C, time for adding 0.5h, drop finishes dropping temperature, and stirring reaction 0.5hr, obtains trans -4- two
Methylamino ethyl crotonate chloroformic solution.
3rd, the preparation of trans -4- dimethyl amidos cronate hydrochlorate
At room temperature, 500ml 1mol/L sodium hydrate aqueous solutions are slowly added dropwise in four mouthfuls of reaction bulbs of step 2
(0.5mol), at -10~25 DEG C, time for adding 0.5h, drop finishes dropping temperature, and reaction 3.0hr is stirred at room temperature, and reaction is finished, point
From water layer, with hydrochloric acid tune pH=1~2, decompression concentrated solution adds 180.0ml dimethylformamides (DMF) to the greatest extent in residue
1.0hr, filtering are stirred, filtrate adds 60.0ml acetone, and be stirred overnight at room temperature crystallization, obtains trans -4- dimethyl amidos crotons
Acid hydrochloride 37.2g (0.2246mol), molar yield 45%, HPLC purity are 99.8%.
Embodiment 2
Trans dimethyl amido cronate hydrochlorate is prepared, is operated in accordance with the following steps：
1st, the preparation of trans -4- bromos crotonates
At room temperature, the trans ethyl crotonates of 11.4g (0.1mol), 26.7g are put into successively in tetra- mouthfuls of reaction bulbs of 500ml
(0.15mol) bromo-succinimide, 0.93g (0.004mol) benzoyl peroxides and 114.0ml ethyl acetate.Feed intake complete, open
Stirring to back flow reaction 15.0hr, stirring is opened to be down to room temperature, obtain trans -4- crotonic ethyl bromides chloroformic solution.
2nd, the preparation of trans -4- dimethyl amidos crotonic acid
At room temperature, 33% dimethylamine agueous solutions of 40.8g (0.30mol) are slowly added dropwise in four mouthfuls of reaction bulbs of step 1,
Drop finishes, and stirring reaction 1.0hr, obtains trans -4- dimethyl amidos ethyl crotonate chloroformic solution.
3rd, the preparation of trans -4- dimethyl amidos cronate hydrochlorate
At room temperature, 200ml 1mol/L potassium hydroxide aqueous solutions are slowly added dropwise in four mouthfuls of reaction bulbs of step 2
(0.2mol), drop finish, and reaction 2.0hr is stirred at room temperature, and reaction is finished, and water layer is separated, with hydrochloric acid tune pH=1~2, decompression concentrated solution
To 40.0ml tetrahydrofurans stirring 1.0hr, filtering is added to the greatest extent, in residue, filtrate adds 15.0ml ethyl acetate, stirring
0.5hr, sealing refrigerator cold-storage stand overnight crystallization, obtain trans -4- dimethyl amidos cronate hydrochlorate 6.3g
(0.38mol), molar yield 38%, HPLC purity are 99.7%.
Embodiment 3
Trans dimethyl amido cronate hydrochlorate is prepared, is operated in accordance with the following steps：
1st, the preparation of trans -4- bromos crotonates
At room temperature, put into successively in tetra- mouthfuls of reaction bulbs of 1000ml the trans crotons isopropyl propionates of 20.0g (0.1560mol),
40.0g (0.2248mol) bromo-succinimide, 1.4g (0.0058mol) benzoyl peroxides and 100.0ml carbon tetrachloride.Throw
Material is finished, and opens stirring to back flow reaction 12.0hr, stirring and is down to room temperature, obtains trans -4- bromocrotonic acids methyl esters chloroformic solution.
2nd, the preparation of trans -4- dimethyl amidos crotonic acid
At room temperature, 33% dimethylamine agueous solutions of 40.0g are slowly added dropwise in four mouthfuls of reaction bulbs of step 1
(0.2928mol), drop finish, and stirring reaction 1.5hr, obtains trans -4- dimethyl amidos ethyl crotonate chloroformic solution.
3rd, the preparation of trans -4- dimethyl amidos cronate hydrochlorate
At room temperature, 160ml 1mol/L calcium hydroxide aqueous solutions are slowly added dropwise in four mouthfuls of reaction bulbs of step 2
(0.16mol), drop finish, and reaction 1.5hr is stirred at room temperature, and reaction is finished, and is separated water layer, with hydrochloric acid tune pH=1~2, is concentrated under reduced pressure molten
Liquid adds 24.0ml acetone to 72.0ml acetonitriles stirring 2.0hr, filtering, filtrate is added to the greatest extent, in residue, and be stirred overnight at room temperature analysis
Crystalline substance, obtains trans -4- dimethyl amidos cronate hydrochlorate 14.9g (0.0898mol), molar yield 45%, and HPLC purity is
99.6%.
Embodiment 4
Trans dimethyl amido cronate hydrochlorate is prepared, is operated in accordance with the following steps：
1st, the preparation of trans -4- bromos crotonates
At room temperature, put into successively in tetra- mouthfuls of reaction bulbs of 1000ml the trans crotons tert-butyl acrylates of 40.0g (0.3996mol),
80.0g (0.4495mol) bromo-succinimide, 2.8g (0.0116mol) benzoyl peroxides and 200.0ml chloroforms.Feed intake complete,
Stirring to back flow reaction 13.0hr, stirring is opened to be down to room temperature, obtain trans -4- bromocrotonic acids methyl esters chloroformic solution.
2nd, the preparation of trans -4- dimethyl amidos crotonic acid
At room temperature, it is water-soluble that 100.0g 33% (33%~40%) dimethylamine is slowly added dropwise in four mouthfuls of reaction bulbs of step 1
Liquid (0.73mol), drop finish, and stirring reaction 1.0hr, obtains trans -4- dimethyl amidos ethyl crotonate chloroformic solution.
3rd, the preparation of trans -4- dimethyl amidos cronate hydrochlorate
At room temperature, 450.0ml 1mol/L sodium hydrate aqueous solutions are slowly added dropwise in four mouthfuls of reaction bulbs of step 2
(0.45mol), drop finish, and reaction 3.0hr is stirred at room temperature, and reaction is finished, and is separated water layer, with hydrochloric acid tune pH=1~2, is concentrated under reduced pressure molten
Liquid adds 48.0ml butyl acetates to 144.0ml dimethylformamides stirring 1.5hr, filtering, filtrate is added to the greatest extent, in residue,
1.0hr is stirred, sealing refrigerator cold-storage stands overnight crystallization, obtains trans -4- dimethyl amidos cronate hydrochlorate 27.14g
(0.1638mol), molar yield 41%, HPLC purity are 99.6%.
Claims (1)
1. a kind of method that one kettle way prepares the trans -4- dimethyl amidos cronate hydrochlorate of high-purity, it is characterised in that with instead
Formula crotonates generates trans -4- bromos crotonates with bromo-succinimide reaction, then adds dimethylamine and is condensed
Reaction generates trans -4- dimethyl amidos crotonates, and alkaline hydrolysis obtains product；The trans crotonates is trans crotons
Sour methyl esters either trans ethyl crotonate or trans crotons isopropyl propionate or trans isobutyl crotonoate or trans crotons
Tert-butyl acrylate；Reaction equation is as follows：
Include the following steps：At room temperature, trans crotonates, bromo-succinimide, peroxide benzene first are put into reaction vessel
Acyl, organic solvent I, react to obtain trans -4- bromos crotonates solution；Then it is water-soluble that dimethylamine is added dropwise in a reservoir at room temperature
Liquid, dropping temperature are -10~25 DEG C, and reaction obtains trans -4- dimethyl amidos crotonates solution；Then at room temperature in container
Middle dropwise addition aqueous slkali, dropping temperature are -10~25 DEG C, react 1.5~3.0hr, separate water layer, and adjusting pH value, decompression is dense to 1~2
Contracting, adds organic solvent II in concentrate, stirs 1.0~1.5hr, and filtering, adds organic solvent II I in filtrate, stirs,
Crystallization, obtains the trans -4- dimethyl amidos cronate hydrochlorate of product；
The trans crotonates, bromo-succinimide, the molar ratio of benzoyl peroxide are 1.00:1.00~1.50:0.02
~0.04, for chloroform, either ethyl acetate or carbon tetrachloride, reaction time are 9~15hr to the organic solvent I；The diformazan
The molar ratio of amine and trans crotonates is 1.5~3.0:1.0, the reaction time is 0.5~1.5hr；The aqueous slkali is hydrogen-oxygen
Change sodium either potassium hydroxide or calcium hydroxide, the molar ratio of the alkali and trans crotonates is 1.00~2.00:1.00；Institute
Stating organic solvent II, either tetrahydrofuran or acetonitrile or isopropanol, the organic solvent II I are third for dimethylformamide
Ketone either ethyl acetate or butyl acetate.
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| CL2004000016A1 (en) * | 2003-01-21 | 2005-04-15 | Wyeth Corp | 4-AMINO-2-BUTENOYL CHLORIDE COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME; PROCEDURE TO PREPARE SUCH COMPOUND, USEFUL AS INTERMEDIARY IN THE SYNTHESIS OF INHIBITING COMPOUNDS OF PROTEIN QUINASA TIROSINA. |
| CN104926669A (en) * | 2014-03-18 | 2015-09-23 | 江苏豪森医药集团连云港宏创医药有限公司 | Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride |
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