CN105111084A - Synthesis method of 4-substituted-3-methyl-2,4-dioxobutyrate - Google Patents

Synthesis method of 4-substituted-3-methyl-2,4-dioxobutyrate Download PDF

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Publication number
CN105111084A
CN105111084A CN201510559431.6A CN201510559431A CN105111084A CN 105111084 A CN105111084 A CN 105111084A CN 201510559431 A CN201510559431 A CN 201510559431A CN 105111084 A CN105111084 A CN 105111084A
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methyl
replaces
acids ester
reaction
synthetic method
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邱方利
杨健国
任战强
胡华南
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Taizhou University
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Taizhou University
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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
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Abstract

The invention relates to a simple, quick and effective synthesis method of 4-substituted-3-methyl-2,4-dioxobutyrate, which comprises the following step: carrying out methylation reaction on main raw materials 4-substituted-2,4-dioxobutyrate and bromomethane in the presence of a solvent to prepare the 4-substituted-3-methyl-2,4-dioxobutyrate and analogs thereof. The method is simple to operate, and has the advantages of high yield, mild conditions of the reaction system and wide industrial application prospects.

Description

A kind of 4-replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester
Technical field
The present invention relates to a kind of synthetic method that is simple, fast and effectively 4-replacement-3-methyl-2,4-dioxobutyric acids ester.
Technical background
4-replaces-3-methyl-2,4-dioxobutyric acids ester and analogue thereof are important Chemicals and medicine intermediate thereof, purposes is extremely extensive, is mainly used in the important intermediate of synthesizing multiple angiotensin-convertion enzyme inhibitor pril medicine series and selectivity cannabinoid receptor-1 (CB1) antagonist class diet pill and dipeptidyl peptidase (4) inhibitor class antidiabetic medicine.
In the building-up process of this compound, the particularly methyl substituted of 3-position, bibliographical information (United States Patent (USP): US20070287734A1) generally uses methyl iodide, be obtained by reacting under the condition of sodium ethylate, but reaction yield is poor, and the atom utilization of methyl iodide is very poor, cost is quite high, is unfavorable for the application of industrialized production.Therefore, the present invention is the synthetic method that a kind of new 4-replaces-3-methyl-2,4-dioxobutyric acids ester, is obtained by reacting more satisfactory product with 4-replacement-2,4-dioxobutyric acids esters and monobromethane under catalytic condition.
Summary of the invention
The object of the invention is to utilize simple way to solve and methylate the difficult problem that synthesis 4-replaces-3-methyl-2,4-dioxobutyric acids ester.
4-described in invention replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester, and its reaction formula is:
In formula (I) (II), R 1=alkyl, ester group, carbonyl, alkoxyl group, substituted aromatic base etc.;
R 2=methyl, the alkyl such as ethyl.
The preparation process that 4-of the present invention replaces-3-methyl-2,4-dioxobutyric acids ester is:
A certain amount of compound (II) and CH 3br is main raw material, under nitrogen protection, is catalyzer, reacts in organic solvent with alkali.Control certain temperature of reaction and reaction times; Reaction terminates, reaction solution adds appropriate distilled water, be 1.5-2.0 by concentrated hydrochloric acid adjust ph, then use solvent extraction, merge organic layer, use saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration, carries out purifying with rectifying, column chromatography or recrystallization method, the 4-obtaining formula (I) replaces-3-methyl-2,4-dioxobutyric acids ester class product.
Wherein, described formula (II) compound and CH 3the mol ratio of the material that feeds intake of Br is recommended as 1.0:0.8 ~ 3.0, preferred 1.0:1.0 ~ 1.3.
Wherein, the preferred one of the following of described solvent: 1,2-ethylene dichloride, methylene dichloride, trichloromethane, ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, dioxane, DMF, ether, isopropyl ether, acetone, pimelinketone, acetonitrile, propionitrile; More preferably one of following: methylene dichloride, DMF, acetonitrile.
Wherein, described catalyzer comprises organic bases and mineral alkali, comprises CH 3oNa, CH 3cH 2oNa, Na 2cO 3, K 2cO 3, Cs 2cO 3, NaH, KOH, NaOH, DBU, TEA etc.
Wherein, the volumetric usage of described solvent is recommended as 3 ~ 5ml/mmol in the quality of formula (II) compound.
Wherein, described temperature of reaction is-10 DEG C ~ 60 DEG C, reaction times 0.5 ~ 24h.
Wherein, after the completion of reaction described, the separation methods such as rectifying, crystallization, filtration, column chromatography can be adopted to be separated and to obtain formula (I) compound.
Beneficial effect of the present invention is embodied in following several respects: the methylating agent raw material availability that the methylation method that 4-of the present invention replaces-2,4-dioxobutyric acids esters is selected is high, and reaction product purity is high, so far there are no bibliographical information.Product prepared by the inventive method, operating process is simple, and reaction conditions is gentle, and product is important Chemicals and medicine intermediate thereof, and purposes is extremely extensive.
Embodiment
Below with reference to embodiment, the present invention will be further described, and embodiments of the invention are only for illustration of technical scheme of the present invention, and non-limiting the present invention.
Embodiment 1
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join the anhydrous CH of 10mL in molar ratio 3in OH, airtight room temperature stirring reaction 16h, reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 73%.
Embodiment 2
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.2) is mixed to join the anhydrous CH of 10mL in molar ratio 3in OH, airtight room temperature stirring reaction 16h, reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 68%.
Embodiment 3
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.1) is mixed to join the anhydrous CH of 10mL in molar ratio 3in OH, airtight room temperature stirring reaction 16h, reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 60%.
Embodiment 4
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:K 2cO 3(1 ︰ 1.2 ︰ 1.3) is mixed to join the anhydrous CH of 10mL in molar ratio 3in OH, airtight room temperature stirring reaction 16h, reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 51%.
Embodiment 5
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:Cs 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join the anhydrous CH of 10mL in molar ratio 3in OH, airtight room temperature stirring reaction 16h, reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 75%.
Embodiment 6
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:Cs 2cO 3(1 ︰ 1.3 ︰ 1.2) is mixed to join the anhydrous CH of 10mL in molar ratio 3in OH, airtight room temperature stirring reaction 16h, reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain glassy yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 70%.
Embodiment 7
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:Cs 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL in molar ratio, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 81%.
Embodiment 8
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL in molar ratio, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 76%.
Embodiment 9
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous acetonitrile of 10mL in molar ratio, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 67%.
Embodiment 10
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL in molar ratio, airtight room temperature stirring reaction 8h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 68%.
Embodiment 11
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:Na 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL in molar ratio, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 57%.
Embodiment 12
Under nitrogen protection, by raw material acetopyruvic acid methyl esters: CH 3br:CH 3oNa in molar ratio (1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 52%.
Embodiment 13
Under nitrogen protection, by raw material ethyl propionylpyruvate: CH 3br:Cs 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL in molar ratio, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl vinyl Pyruvic Acid Methyl ester, yield is 73%.
Embodiment 14
Under nitrogen protection, by raw material ethyl propionylpyruvate: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL in molar ratio, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain weak yellow liquid 3-methyl propionyl Pyruvic Acid Methyl ester, yield is 69%.
Embodiment 15
Under nitrogen protection, by raw material benzoyl Pyruvic Acid Ethyl ester: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL in molar ratio, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain off-white color solid 3-methyl benzoyl Pyruvic Acid Methyl ester, yield is 71%.
Embodiment 16
Under nitrogen protection, by raw material para hydroxybenzene acyl Pyruvic Acid Ethyl ester: CH 3br:K 2cO 3(1 ︰ 1.3 ︰ 1.3) is mixed to join in the anhydrous propanone of 10mL in molar ratio, airtight room temperature stirring reaction 16h, and reaction terminates, reaction solution concentrated hydrochloric acid adjust ph is 1.5-2.0, filters, and removes solids, filtrate adds 10mL distilled water, then use methylene dichloride 10mL × 3 to extract, merge organic layer, with anhydrous sodium sulfate drying, vacuum concentration, with column chromatography purification, obtain product and obtain off-white color solid 3-methyl toluoyl Pyruvic Acid Methyl ester, yield is 78%.
It should be noted that, foregoing invention content and embodiment are intended to the practical application proving technical scheme provided by the present invention, should not be construed as limiting the scope of the present invention.Those skilled in the art in spirit of the present invention and principle, when doing various amendment, equivalent replace or improve.Protection scope of the present invention is as the criterion with appended claims.

Claims (8)

1. one kind simple, fast and effective 4-replaces-3-methyl-2, the synthetic method of 4-dioxobutyric acids ester, it is characterized in that,-2 are replaced with 4-, 4-dioxobutyric acids ester and monobromethane are main raw material, in the presence of an organic, the method for-3-methyl-2,4-dioxobutyric acids ester and analogue thereof is replaced through methylation reaction synthesis 4-; Reaction formula is:
In formula (I) (II), R 1=alkyl, ester group, carbonyl, alkoxyl group, substituted aromatic base etc.;
R 2=methyl, the alkyl such as ethyl.
2. 4-replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester as claimed in claim 1, it is characterized in that, described formula (II) compound and CH 3the mol ratio of the material that feeds intake of Br pushes away as 1.0:0.8 ~ 3.0.
3. 4-replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester as claimed in claim 2, it is characterized in that, described formula (II) compound and CH 3the mol ratio of the material that feeds intake of Br pushes away as 1.0:1.0 ~ 1.3.
4. 4-replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester as claimed in claim 1, and it is characterized in that, described solvent is selected from one of the following: the compounds such as halogenated alkane, ester compound, ether compound, nitrile; Preferably one of following: methylene dichloride, DMF, acetonitrile.
5. 4-replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester as claimed in claim 1, and it is characterized in that, described catalyzer comprises organic bases and mineral alkali, comprises CH 3oNa, CH 3cH 2oNa, Na 2cO 3, K 2cO 3, Cs 2cO 3, NaH, KOH, NaOH, DBU, TEA etc.
6. as described in claim 1 or 4,4-replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester, and it is characterized in that, the volumetric usage of described solvent is recommended as 3 ~ 5ml/mmol in the quality of formula (II) compound.
7. 4-replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester as claimed in claim 1, and it is characterized in that, described temperature of reaction is-10 DEG C ~ 60 DEG C, reaction times 0.5 ~ 24h.
8. 4-replaces the synthetic method of-3-methyl-2,4-dioxobutyric acids ester as claimed in claim 1, it is characterized in that, after the completion of reaction, the separation methods such as rectifying, crystallization, filtration, column chromatography can be adopted to be separated and obtain formula (I) compound.
CN201510559431.6A 2015-09-07 2015-09-07 Synthesis method of 4-substituted-3-methyl-2,4-dioxobutyrate Pending CN105111084A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111533656A (en) * 2020-05-27 2020-08-14 龙曦宁（上海）医药科技有限公司 Synthesis method of tert-butyl 4-methoxy-3-oxobutyrate

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Publication number Priority date Publication date Assignee Title
US20050192439A1 (en) * 2002-09-09 2005-09-01 Rozzell J. D.Jr. Methods for producing hydroxy amino acids, esters, and derivatives thereof
WO2007146890A2 (en) * 2006-06-09 2007-12-21 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted pyrazole compounds with cannabinoid receptor activity

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050192439A1 (en) * 2002-09-09 2005-09-01 Rozzell J. D.Jr. Methods for producing hydroxy amino acids, esters, and derivatives thereof
WO2007146890A2 (en) * 2006-06-09 2007-12-21 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted pyrazole compounds with cannabinoid receptor activity

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111533656A (en) * 2020-05-27 2020-08-14 龙曦宁（上海）医药科技有限公司 Synthesis method of tert-butyl 4-methoxy-3-oxobutyrate

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