CN108623490A - The synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates - Google Patents
The synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates Download PDFInfo
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- CN108623490A CN108623490A CN201810649896.4A CN201810649896A CN108623490A CN 108623490 A CN108623490 A CN 108623490A CN 201810649896 A CN201810649896 A CN 201810649896A CN 108623490 A CN108623490 A CN 108623490A
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- Prior art keywords
- dimethylamino
- butenoate
- solution
- hydrochlorates
- synthetic method
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- NKNBYFBSHOGEKE-ARJAWSKDSA-N CN(C)/C=C\C(O)=O Chemical compound CN(C)/C=C\C(O)=O NKNBYFBSHOGEKE-ARJAWSKDSA-N 0.000 description 1
- GPOHHJPOQPILBS-UHFFFAOYSA-N CN(C)CC#CC(O)=O Chemical compound CN(C)CC#CC(O)=O GPOHHJPOQPILBS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
Abstract
The invention discloses a kind of synthetic methods of (2Z) 4 (dimethylamino) 2 butenoate hydrochlorate, include the following steps：Under atmosphere of inert gases, by [bis- (2,2,2 trifluoro ethoxies) phosphinyl] methyl acetate is dissolved in organic solvent, and lithium reagent is added, the solution of alkali is added, controlled at 0 DEG C to 30 DEG C, 2 (dimethylamino) acetaldehyde sulphite are added, are stirred to react, (2Z) 4 (dimethylamino) 2 butenoate hydrochlorate is obtained by acidification, extraction and column purification after the completion of reaction.The method of the present invention is easy to operate, and high income is, it can be achieved that industrialized production.
Description
Technical field
The present invention relates to organic synthesis fields more particularly to organic drug to synthesize field, and in particular to (2Z) -4- (diformazans
Base amino) -2- butenoate hydrochlorates synthetic method.
Background technology
(2Z) -4- (dimethylamino) -2- butenoate hydrochlorates are synthesized in medicine intermediate and important in relation to drug
Mesosome synthesizes the main hydrogenation of method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates at present, such as shown in (one),
This method is step hydrogenation synthesis, and more special to equipment requirement, amplification has certain danger, and reagent cost includes that palladium carbon all compares
Costly, starting material is difficult to synthesize.For the yield of document report about 20% or so, separation is extremely difficult.
Invention content
The technical problem to be solved in the present invention is to provide it is a kind of [(2Z) -4- (dimethylamino) -2- butenoate hydrochlorates
Synthetic method, this method is simple and easy to do, at low cost and efficient.
To achieve the above object, present invention employs following technical schemes：
The present invention provides a kind of synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates, including it is following
Step：Under atmosphere of inert gases, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate is dissolved in organic solvent,
Lithium reagent is added, the solution of alkali is added, controlled at 0 DEG C to 30 DEG C, adds 2- (dimethylamino) acetaldehyde sulphite,
It is stirred to react, (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates is obtained after the completion of reaction.
Further, organic solvent is methanol, ethyl alcohol, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide.
Preferably, organic solvent is tetrahydrofuran, dimethylformamide.
Further, lithium reagent is lithium chloride, lithium bromide, lithium hydroxide, tert-butyl alcohol lithium or bis- (trimethyl silicon substrate) amino
Sodium.
Preferably, lithium reagent is lithium chloride, tert-butyl alcohol lithium or bis- (trimethyl silicon substrate) Sodamides.
Further, the solution of alkali is the dimethyl of the aqueous solution of sodium hydroxide, the aqueous solution of potassium hydroxide, sodium hydroxide
The dimethyl sulfoxide of amide solution, the DMF solution of potassium hydroxide, the solution of dimethyl sulfoxide of sodium hydroxide, potassium hydroxide
Solution, the methanol solution of sodium hydroxide, the methanol solution of potassium hydroxide, the ethyl alcohol alcoholic solution of sodium hydroxide, potassium hydroxide
The tetrahydrofuran of ethanol solution, the tetrahydrofuran solution of bis- (trimethyl silicon substrate) Sodamides or bis- (trimethyl silicon substrate) potassamides is molten
Liquid.
Preferably, the solution of alkali is the dimethyl acyl of the aqueous solution of sodium hydroxide, the aqueous solution of potassium hydroxide, sodium hydroxide
Amine aqueous solution, the DMF solution of potassium hydroxide, the tetrahydrofuran solution of bis- (trimethyl silicon substrate) Sodamides or bis- (trimethyls
Silicon substrate) potassamide tetrahydrofuran solution.
Further, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate and 2- (dimethylamino) acetaldehyde sulfurous
The molar ratio of hydrochlorate is 1:1.2 to 1:2.5.
Preferably, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate and 2- (dimethylamino) acetaldehyde sulfurous acid
The molar ratio of salt is 1:2.
Further, inert gas is argon gas, nitrogen or helium.
Further, the molar ratio of [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate, lithium reagent and alkali is 1:
0.8：3 to 1:1.5:6.
Preferably, the molar ratio of [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate, lithium reagent and alkali is 1:1：5
To 1:1.2:6.
Further, the molar concentration of the solution of alkali is 0.5mol/L to 2.5mol/L.
Preferably, the molar concentration of the solution of alkali is 1mol/L.
Further, the reaction time being stirred to react is 1 to 5 hour.
Preferably, the reaction time being stirred to react is 2 to 3 hours.
Further, after the completion of reaction, (2Z) -4- (dimethylamino) -2- fourths are obtained by acidification, extraction and column purification
Enoic acid hydrochloride.
Compared with prior art, the present invention has the following advantages：
The present invention provides a kind of method of synthesis [bis- (2,2,2- trifluoro ethoxy) phosphinyls] acetic acid, this method is easy
Operation, it is at low cost and efficient, there is industrialization value.
Specific implementation mode
The present invention is further explained in the light of specific embodiments, so that those skilled in the art can be preferably
Understand the present invention and can be practiced, but illustrated embodiment is not as a limitation of the invention.
Embodiment 1
Under nitrogen protection, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate (3.18g, 1eq) is dissolved in second
In alcohol, lithium chloride (0.3g, 0.8eq) is added, ethyl alcohol (1.2g, 3eq, 0.5mol/L) solution of sodium hydroxide, control temperature is added
Degree is 0 DEG C to 30 DEG C, adds 2- (dimethylamino) acetaldehyde sulphite (2.04g, 1.2eq), is stirred to react 1 hour, instead
Should (2Z) -4- (dimethylamino) -2- butenoates hydrochlorate (0.52g) be obtained by acidification, extraction and column purification after the completion.
Embodiment 2
Under nitrogen protection, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate (3.18g, 1eq) is dissolved in four
In hydrogen furans, tert-butyl alcohol lithium (1.2g, 1.5eq) is added, the tetrahydrofuran solution of bis- (trimethyl silicon substrate) potassamides is added
(11.9g, 6eq, 2.5mol/L) solution adds 2- (dimethylamino) acetaldehyde sulphite controlled at 0 DEG C to 30 DEG C
(4.25g, 2.5eq) is stirred to react 5 hours, (2Z) -4- (dimethyl is obtained by acidification, extraction and column purification after the completion of reaction
Amino) -2- butenoates hydrochlorate (0.87g).
Embodiment 3
Under nitrogen protection, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate (3.18g, 1eq) is dissolved in two
In methylformamide, bis- (trimethyl silicon substrate) lithium amides (1.67g, 1eq) are added, the dimethylformamide of potassium hydroxide is added
(2.5g, 5eq, 1mol/L) solution adds 2- (dimethylamino) acetaldehyde sulphite controlled at 0 DEG C to 30 DEG C
(3.4g, 2eq) is stirred to react 2 hours, (2Z) -4- (dimethylaminos is obtained by acidification, extraction and column purification after the completion of reaction
Base) -2- butenoates hydrochlorate (0.72g).
Embodiment 4
Under nitrogen protection, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate (3.18g, 1eq) is dissolved in four
In hydrogen furans, lithium chloride (0.84g, 2eq) is added, water (2.4g, 6eq, 1mol/L) solution of sodium hydroxide is added, controls temperature
It is 0 DEG C to 30 DEG C, adds 2- (dimethylamino) acetaldehyde sulphite (3.4g, 2eq), be stirred to react 3 hours, reaction is completed
(2Z) -4- (dimethylamino) -2- butenoates hydrochlorate (1.02g) is obtained by acidification, extraction and column purification afterwards.
Embodiment 5
Under nitrogen protection, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate (3.18g, 1eq) is dissolved in four
In hydrogen furans, lithium chloride (0.42g, 1eq) is added, water (2.0g, 5eq, 1mol/L) solution of sodium hydroxide is added, controls temperature
It is 0 DEG C to 30 DEG C, adds 2- (dimethylamino) acetaldehyde sulphite (3.4g, 2eq), be stirred to react 3 hours, reaction is completed
(2Z) -4- (dimethylamino) -2- butenoates hydrochlorate (1.09g) is obtained by acidification, extraction and column purification afterwards.
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, protection model of the invention
It encloses without being limited thereto.Those skilled in the art on the basis of the present invention made by equivalent substitute or transformation, in the present invention
Protection domain within.Protection scope of the present invention is subject to claims.
Claims (10)
1. a kind of synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates, which is characterized in that including following step
Suddenly：Under atmosphere of inert gases, [bis- (2,2,2- trifluoro ethoxy) phosphinyls] methyl acetate is dissolved in organic solvent, is added
Enter lithium reagent, the solution of alkali is added, controlled at 0 DEG C to 30 DEG C, adds 2- (dimethylamino) acetaldehyde sulphite, stir
Reaction is mixed, (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates are obtained after the completion of reaction.
2. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1, feature exist
In：The organic solvent is methanol, ethyl alcohol, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide.
3. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1, feature exist
In：The lithium reagent is lithium chloride, lithium bromide, lithium hydroxide, tert-butyl alcohol lithium or bis- (trimethyl silicon substrate) Sodamides.
4. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1, feature exist
In：The solution of the alkali be the aqueous solution of sodium hydroxide, the aqueous solution of potassium hydroxide, sodium hydroxide DMF solution,
The DMF solution of potassium hydroxide, the solution of the dimethyl sulfoxide of sodium hydroxide, potassium hydroxide dimethyl sulfoxide solution, hydrogen
The methanol solution of sodium oxide molybdena, the methanol solution of potassium hydroxide, the ethyl alcohol alcoholic solution of sodium hydroxide, potassium hydroxide ethanol solution,
The tetrahydrofuran solution of the tetrahydrofuran solution of bis- (trimethyl silicon substrate) Sodamides or bis- (trimethyl silicon substrate) potassamides.
5. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1, feature exist
In：Mole of [bis- (2,2,2- trifluoro ethoxies) phosphinyls] methyl acetate and 2- (dimethylamino) acetaldehyde sulphite
Than being 1:1.2 to 1:2.5.
6. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1, feature exist
In：The inert gas is argon gas, nitrogen or helium.
7. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1, feature exist
In：The molar ratio of [bis- (2,2,2- trifluoro ethoxies) phosphinyls] methyl acetate, lithium reagent and alkali is 1:0.8：3 to 1:
1.5:6。
8. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1 or 4, feature
It is：The molar concentration of the solution of the alkali is 0.5mol/L to 2.5mol/L.
9. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1, feature exist
In：The reaction time being stirred to react is 1 to 5 hour.
10. the synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates as described in claim 1, feature exist
In：After the completion of reaction, (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates are obtained by acidification, extraction and column purification.
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| CN201810649896.4A CN108623490A (en) | 2018-06-22 | 2018-06-22 | The synthetic method of (2Z) -4- (dimethylamino) -2- butenoate hydrochlorates |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200908983A (en) * | 2007-06-04 | 2009-03-01 | Avila Therapeutics Inc | Heterocyclic compounds and uses thereof |
| CN101679384A (en) * | 2007-06-05 | 2010-03-24 | 韩美药品株式会社 | Novel amide derivative for inhibiting the growth of cancer cells |
| CN104529800A (en) * | 2014-12-08 | 2015-04-22 | 重庆威鹏药业有限公司 | Preparation method of trans-4-dimethylaminocrotonic acid and its salt |
| CN105061243A (en) * | 2015-08-18 | 2015-11-18 | 褚朝森 | Synthesis method for 4-dimethylamino crotonic acid |
-
2018
- 2018-06-22 CN CN201810649896.4A patent/CN108623490A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200908983A (en) * | 2007-06-04 | 2009-03-01 | Avila Therapeutics Inc | Heterocyclic compounds and uses thereof |
| CN101679384A (en) * | 2007-06-05 | 2010-03-24 | 韩美药品株式会社 | Novel amide derivative for inhibiting the growth of cancer cells |
| CN104529800A (en) * | 2014-12-08 | 2015-04-22 | 重庆威鹏药业有限公司 | Preparation method of trans-4-dimethylaminocrotonic acid and its salt |
| CN105061243A (en) * | 2015-08-18 | 2015-11-18 | 褚朝森 | Synthesis method for 4-dimethylamino crotonic acid |
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Application publication date: 20181009 |