DE1946550A1 - Alpha-acylaminoacrylic acid esters - Google Patents

Abstract

Alpha-Acylaminoacrylic acid esters of formula (I): are prepd. by treating a metallised oxazoline of formula (II): (where R1 and R4 are alkyl, aryl, heteroaryl, aralkyl, R2 and R3 are organic groups or H, but not both H, and M is an alkali metal or an equiv. of Mg, Zn or Cd) with a proton donor. Starting materials (II) may be prepd. by direct metallisn. of the appropriate oxazoline or by condensing a metallised isocyanoacetic acid ester with a carbonyl cpd.

Description

Process for the preparation of B-substituted i-acylaminoacrylic acid esters The invention relates to a process for the preparation of ß-substituted oC-acylaminoacrylic acid esters from metalated A 2-oxazolines.

The previous route follows the scheme of the Erlenmeyer synthesis via the unsaturated azlactones tooC-acylaminoacrylic acids.

This synthesis can only be carried out if by the right under severe condensation reaction conditions, the main reaction is not an aldol condensation the carbonyl compound is triggered.

Are aldehydes with active hydrogen atoms on the oC carbon atom therefore unsuitable. In addition, the yields are not always satisfactory, and after all, amino acids are required as starting compounds, their production is time consuming and costly.

It has now been found that β-substituted oC-acylaminoacrylic acid esters are obtained if metalated oxazolines of the formula I. treated with proton donors, where in the formula I R1 @eine Alkyl, Ary1 or aralkyl groups, R2 and R3 denote identical or different organic radicals or hydrogen, where R2 or R can be hydrogen.

Me means an alkali metal or an equivalent of magnesium, cadmium or zinc.

The procedure can be represented by the following scheme: Rearrangement Me Ring- R C --- 14 oR R1 OOC-C = '/ rv \ R4 5 I II Formula II is the @ -formylaminoacrylic acid ester obtained by the process according to the invention, in which R1, R2, R5 and R4 have the same meaning as in formula I.

The radicals R1 can, for example, be a methyl, ethyl, tert-butyl, Benzyl, phenyl group, but preferably an ethyl or tert-butyl group.

Lithium, sodium and potassium are preferred as the metal radical Me.

According to the invention, the compounds of formula I with proton donors, preferably with water-soluble, with acids such as. Carboxylic acids, including inorganic ones Acids, treated; Acetic acid is preferred. In some cases, an addition is sufficient of water.

The starting compounds of the formula I can be selected directly the corresponding oxazolines by metalation (Examples A) or medium bar Establish condensation of a metalated isocyanate acetate with carbonyl compounds (Examples B).

Metalating agents are strong bases such as metal alkyls, for example Butyllithium, phenyllithium, Grignard reagents, organozinc and cadmium compounds, Metal hydrides and amides, but also alcoholates, in particular sodium alcoholate or Metal hydroxides. Particularly suitable metalated oxazolines of this type are: 4-sodium-4-alkoxycarbony-5-alkyl (or 5,5-dialkyl) - # 2 -oxazoline; 4-sodium-4-alkoxycarbonyl-5-alkyl (or 5,5-dialkyl) -2-phenyl-2 oxazoline; 4-lithium-4-aroxycarbonyl-5-heteroaryl (or 5,5-diheteroaryl) - # 2-oxazoline; 4-Sodium-4-aralkoxycarbonyl-5-vinyl-2-phenyl- # 2 -oxazoline; 4-sodium-4-alkoxycarbonyl-5-polyenyl (or 5,5-dipolyenyl) - # 2 -oxazoline: 4-sodium-4-alkoxycarbonyl-5-alky-5-aryl-2-alkyl- # oxazoline; 4-potassium-4-alkoxycarbonyl-5-heteroaryl-5-alkyl-2-heteroaryl A oxazoline; 4-Sodium-4-aralkoxycarbonyl-5-allyl- (or 5e5-diallyl-a 2-oxazoline.

The invention opens up excellent possibilities, so far right time-consuming, less good yields and also costly multi-stage ones To improve synthetic methods to a considerable extent. The work of Eliot, J.Chem.Soc. 1949, 589 give different results.

# Formylaminoaerylic acid esters can be converted to substituted amino acids, for example.

In addition, treatment of the formylaminoacrylic acid esters obtained according to the invention with strong acids makes it possible to prepare oC-keto acid esters and, ultimately, carboxylic acids substituted by decarbonylation. R ~ R HO + RQ RJi / C'-0C2H5 + R5 25 ha0h0 & 2CH-C / 9 -1 R. / Temy -HCOOH R5 EXAMPLES Production starting from 4-alkoxyearbonyl- # 2 -oxazolines with metalating agents 1. ethyl cis / trans-α-benzoylamino-crotonate; To dissolve 0.05 mol of trans-4-ethoxycarbonyl-2-phenyl- # 2-oxazoline in 100 ml of absol. 0.05 mol of sodium hydride is added to ether and the mixture is stirred for 6 hours at room temperature. It is diluted with 100 ml of ether and shaken with the mixture of 50 ml of glacial acetic acid and 50 ml of water6 The layers are separated, the ether phase is washed three times with water, dried over sodium sulfate and concentrated on a rotary evaporator. 7.6 g of yellow oil are obtained, 2.2 g of which is chromatographed over 32 g of silica gel with ether / petroleum ether (2: 1). In addition to ethyl benzoate, 40% (calculated on the total amount) of ethyl cis / trans-α-benzoylamino-crotonate with melting point 58-59 ° or 65-66 ° are isolated, 2. ethyl cis / trans-α-benzoylamino-crotonate : To the solution of 0.01 mol of cis-4-ethoxycarbonyl-2-phenyl- # 2-oxazoline in 20 ml of ether, 0> 01 mol of sodium hydride is added and the mixture is stirred for 1.5 hours at room temperature. It is diluted with 25 ml of ether and shaken with the mixture of 7.5 ml of glacial acetic acid and 7.5 ml of water. The ethereal phase is separated off, washed three times with water, dried over sodium sulfate and concentrated. The residue is chromatographed over 200 g of silica gel with ether / petroleum ether (2: 1). 39% cis / trans-α-benzoylaminocrotonic acid ethyl ester with melting point 58-59 ° or

65-66 °.

3. cis / trans-α-Benzoylamino-crotonic acid ethyl ester: The solution of O, Ol mol of trans4-ethoxycarbonyl-2-phenyl- # 2-oxazoline is stirred with 50 ml of a 5 percent solution of flat riumethanolate in ethanol at room temperature for 15 minutes, Man mixed with the mixture of 10 ml of glacial acetic acid and 10 ml, are then Add 40 ml of water, äther @@@@ times with 150 ml of ether, washes the ether phase with it 100 ml water @@ dries over sodium sulfate. The residue is chromatographed over 200 g of silica gel with ether / petroleum ether (2: 1), eluted @ 22% ethyl cis / trans-α-benzoylamino-crotonate with schmp. 58-59 ° or 65-66 °.

4. Ethyl α-benzoylamino-acrylic acid ester: 3.2 mmol of 4-ethoxycarbony1-2-phenyl- # 2-oxazoline it is stirred with 9.2 mmol of sodium lo ml of ether at room temperature. 20 are added ml 5o percent

Acetic acid and 30 ml of ether, separates the layers and washes the essential Phase twice with 100 ml of water each time. After drying, however, magnesium sulfate is used on a rotary evaporator i. Vac. constricted. The residue is chromatographed over 100 silica gel with ther. 19% -α-Benzoylamino-acrylic acid ethyl ester koses oil is eluted.

5. Ethyl α-benzoylamine cinnamate: 6.8 mmol of 4-ethoxycarbonyl-2,5-diphenyl- # 2-oxazoline is stirred with 6.8 mmol of sodium hydride in 10 ml of ether for 4 hours at room temperature. 20 ml of 50 percent are added. Acetic acid and 30 ml rther, separates the layers and works on as usual. The residue of the ether phase is chromatographed over silica gel with ether, 69% ethyl α-benzoylamino-cinnamate being eluted; pale yellow, viscous, oil.

Preparation of the 4-metalized oxazolines starting from Isocyanoacetic acid esters, metalating agents and carbonyl compounds α-formylamino-cinnamic acid ethyl ester: To the solution of 0.04 mol of isocyano ethyl acetate in 30 ml of tetrahydrofuran is added dropwise add 0.04 mol of butyllithium (approx. 16 ml of a approx.

2.5 ml solution in pentane), keeping the temperature below -70% and ensuring that the drops fall directly into the reaction mixture. The solution of 0.04 mol of benzaldehyde in 20 ml of tetrahydrofuran is added to the suspension of ethyl isocyanoacetate at -60 °, the mixture is allowed to come to room temperature and the solvent is drawn off, vacuum. away. A mixture of 0.06 mol of glacial acetic acid and 50 ml of water is added, ether is extracted, dried over magnesium sulfate and works on as usual. The residue is chromatographed by men @ be @ silica gel and eluted with ether with 74% cis / trans-α-formylamino-zh @ acid ethyl ester with KP0.1 156-158 °.

-Pormylamino-cinnamic acid ethyl ester: For the suspension of 0.04 mol of sodium hydride in 50 ml of tetrahydrofuran is added dropwise at room temperature with vigorous stirring Mixture of 0.04 mol of ethyl isocyanoacetate, 0.04 mol of benzaldehyde and 30 ml Tetrahydrofuran. jan stirs 3 hours, the solvent draws i. Vac. off and chromatographed the residue over silica gel. 63% cis / trans-α-formylamino-cinnamic acid ethyl ester can be obtained with ether elute with bp 0.1 156-158 °.

@ - @ ormylamino-cyclohexylideneacetic acid ethyl ester: For the solution of 0.04 mol of ethyl isocyanoacetate in 30 ml of tetrahydrofuran is trcpft under vigorous Stir in approx. 30 minutes. 0.04 mol of butyllithium (approx.

16 ml of an approx. 2.5 N solution in pentane), whereby the Tempertur is below -70 ° and ensures that the drops fall directly into the reaction mixture. to the suspension of ethyl lithium isocyanoacetate is added with stirring -70 °, the solution of 0.04 mol of cyclohexanone in 20 ml of tetrahydrofuran, leaves to room temperature Come and pull the solvent i, vac. away. A mixture of 0.06 cl of vinegar is used and add 50 ml of water, ethers out, dries over magnesium sulphate and works as it should usual on. The residue is chromatographed on silica gel and eluted with ether 87% ethyl α-formylamino-cyclohexyl idenacetate; Mp 83 °.

α-Formylamino-ß-isonropyl-crotonic acid ethyl ester: To dissolve c.04 mol of ethyl isocyanoate in 30 ml of tetrahydrofuran, it is added dropwise with vigorous action. Stir for approx. 30 min. 0.04 mol of butyllithium (approx. 16 ml of an approx. 2.5 N solution in pentane), keeping the temperature below -70 ° and ensuring that the drops fall directly into the reaction wipe . The solution of 0.04 mol of isobutyraldehyde in 20 ml of tetrahydrofuran is added at 600 to the suspension of ethyl isocyanoacetate, the solution is allowed to come to room temperature and the solution is drawn off medium i. Vac, off. 0.06 mol of glacial acetic acid and 50 ml of water are extracted from ether, dried over magnesium sulfate and worked on as usual. The residue is chromatographed on silica gel and eluted with ether 58% α-formylamino-β-isopropyl-crotons KpO, 1 approx. 34 ° . α-Formylamino-ß-methyl-cinnamic acid-tert-butyl: To 40 mmol Isoc @.

acetic acid tert.-tutyl ester in 20 ml of tetrahydrofuran is found @ one hour at -60 ° .40 mmol of butyllithium (as a solution in pentane).

The solution of 40 mmol of acetophen® is then added dropwise in one hour in 20 ml of tetrahydrofuran, lets come to room temperature in 12 hours, that pulls Tetrahydrofuran at room temperature i. Vac. and add 100 ml of water to the residue, whereby a brown-red oil parted. One extracts once with 100 ml and twice with 50 ml of ether each and washes the combined ethereal solutions three times with each 100 ml of water. It is dried over sodium sulfate and worked up as usual. Man contains 82% trans / cis-α-formylamino-ß-methyl-cinnamic acid-tert. butyl ester; Kpo, o5 approx. 90

Claims (1)

A process for the preparation of ß-substituted α-acylaminoacrylic acid esters, characterized in that metalated oxazolines of the formula I treated with proton donors, where in the formula R1 and R4 are an alkyl, aryl, heteroaryl or aralkyl group, R2 and R5 are identical or different organic radicals or hydrogen, where R2 or R5 can be hydrogen, and Me is an alkali metal or an equivalent of magnesium , Means zinc or cadmium.