JPH02268144A - Production of beta-amino ester - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] [Industrial Field of Application] The present invention is directed to the use of β-lactams (Japanese Patent Application Laid-Open No.
1-29476), and relates to a method for producing a β-amino ester useful as a precursor for the same.

[Conventional technology and its problems]

β- due to the reaction of ketene silylacecool with imines
For the synthesis of amino esters, TiCl was used as a catalyst.
JP-A-53 using more than the same mole of a strong Lewis acid such as No. 4
-108962 method is the only known method.

However, the fact that a Lewis acid that is difficult to handle, such as TiCl4, must be used in equimolar amounts with the reaction substrate,
It is also disadvantageous in terms of reaction operation, post-reaction metal treatment, and economics. Further, there are problems in that it is difficult to control the reaction, many side reaction products are produced, and the yield of the desired β-amino ester is low.

[Technical means to solve problems]

The present invention provides a method for producing the desired β-amino ester in high yield using a catalytic amount of Lewis acid that is easy to handle.

The present invention consists of 1. -Formula Rx R2Rz P 20 X
2 (wherein R', R'' and R3 are each a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms or a phenyl group or a linear or branched group having 1 to 4 carbon atoms) Indicates a phenyl group having an alkyl substituent, X
represents a trifluoromethanesulfonyl group. ) In the presence of a phosphonium salt catalyst represented by Rh is -3i
(CHs) indicates zRII. R8 is methyl, ethyl,
Represents L-butyl or phenyl group R7 has 1 carbon number
ketenesilylacecur represented by ), which represents a phenyl group having ~10 linear or branched alkyl groups, a phenyl group, or a phenyl group having a linear or branched alkyl substituent having 1 to 10 carbon atoms; IO (wherein R*, R+o and R are hydrogen, carbon number 1-1
5 linear, branched, or cyclic alkyl group, a phenyl group having a linear or branched alkyl substituent having 1 to 4 carbon atoms, and each alkyl group contains a heteroatom. Good too. ) is a method for producing a β-amino ester represented by the general formula (IV), which is characterized by reacting an imine represented by the formula (IV) with an imine represented by the formula (IV).

The phosphonium salt catalyst represented by general formula (I) in the present invention is Tetrahedron Letters
, 1989, vol. 30, p. 495 (
c, Hs) hP to (CF ss 0z)z It can be synthesized from phosphine oxyto and trifluoromethanesulfonic anhydride in the same manner as the synthesis method for hP to (CF ss 0z)z.

Specific examples of phosphine oxide include trimethylphosphine oxide, triethylphosphine oxide, tripropylphosphine oxide, triisopropylphosphine oxide, tributylphosphine oxide, tri-1-methylpropylphosphine oxyto, tri-2-methylpropylphosphine oxyto. Tris-1,1-dimethylethylphosphine oxide, tripentylphosphine oxide, tricyclopentylphosphine oxide, trihexylphosphine oxide, tricyclohexylphosphine oxide, tribenzylphosphine oxide, trihebutylphosphine oxide, trioctyl Mention may be made of phosphine oxyto, triphenylphosphine oxyto and tritolylphosphine oxyto.

Examples of the reaction solvent in the present invention include methylene chloride, chloroform, tetrachloromethane, dichloroethane, benzene, toluene, xylene, chlorobenzene, O-dichlorobenzene, nitrobenzene, nitromethane, carbon disulfide, diethyl ether, diisopropyl ether, dibutyl ether, and tetrahydrofuran. , dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, acetonitrile, and mixed solvents thereof. A particularly preferred solvent is methylene chloride.

In the reaction, the mixing order of the catalyst and the reaction substrate does not particularly affect the reaction.

The amount of ketenesilyl acecool used is 0.5 to 3. It is preferably 0 times the mole, particularly 0.75 to 2.0 times the mole. The amount of phosphonium salt catalyst used is 1. It is preferably 0 to 0.001 times mole, particularly 0.3 to 01005 times mole.

The reaction temperature is usually -100 to 50'' C1, preferably -80
~30°C. When the temperature is higher than 50°C, the yield of the target product decreases, and when it is lower than -100°C, a long reaction time is required. The reaction time is usually 0.11 to 30 hours.

Since ketene silyl acecool, imines and phosphonium salt catalysts are susceptible to hydrolysis, it is preferred that the reaction system be kept anhydrous.

〔Example〕

Examples of the present invention are shown below.

Example 1 15.0 mg (0,021 mmol) of oxobis(tributylphosphonium) trifluoromethanesulfonate was added to 0.75 mj of methylene chloride! Melt at -78°
Cooled to C. Next, benzylidene aniline 54.3m
g (0,30 mmol) and 78.4 mg (0,
A solution of 45 mmol) in 1.5 ml of methylene chloride was added dropwise and stirred, and after 17 hours, a saturated aqueous sodium bicarbonate solution was added and extracted with methylene chloride. The extracted solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified by thin layer chromatography to obtain 2,2-dimethyl-3(phenylamino)benzenepropionic acid methyl ester 85
．． 4 mg (yield 100x) was obtained.

Example 2 The same procedure as in Example 1 was carried out except that 65.4 mg (0,375 mmol) of 0-methyl-trimethylsilyldimethylketene acecool was used, and 2,2-dimethyl-
79.6+ng (yield: 94χ) of 3(phenylamino)benzenepropionic acid methyl ester was obtained.

Example 3 2,2-dimethyl-3(
67.9 mg (yield: 80x) of phenylamino)benzenepropionate methyl ester was obtained.

Example 4 2゜2-dimethyl-3-(phenylamino)benzenepropionic acid was prepared in the same manner as in Example 1 except for using 5.4 mg (0,0075 mmol) of 83.6 mg (yield 98x) of methyl ester was obtained.

Example 5 The same procedure as in Example 1 was carried out, except that 52.3 μ (0,300 mmol) of 0-methyl-〇-trimethylsilyldimethylketene acecool and 81.5 μ (0,450 mmol) of benzylideneaniline were used. ,2,2-dimethyl-
67.8 mg (yield 80x) of 3-(phenylamino)benzenepropionate methyl ester was obtained.

Examples 6 to 12 Reactions were carried out in the same manner as in Example 2, and the results shown in Table 1 were obtained.

Example 13 Oxobis(tributylphosphonium) 1- of Example 8
Using oxobis(triphenylphosphonium)trifluoromethanesulfonate instead of trifluoromethanesulfonate, 85.1 .mu.m (yield: 100.chi.) of 2-methyl-3-(phenylamino)benzenepropionic acid ethyl ester was obtained.

Examples 14-15 Reactions were carried out in the same manner as in Example 3, and the results shown in Table 2 were obtained.

Examples 16 to 18 (In Example 3) 8) Reactions were carried out using various solvents, and the results shown in Table 3 were obtained.

Example 19 Using benzylidene-t-butylamine in place of benzylideneaniline in Example 2, the reaction was carried out at room temperature for 23 hours, and 22.8 mg of 2,2-dimethyl-3-(t-butylamino)benzenepropionic acid ( A yield of 29x) was obtained.

Example 20 21.6 mg (0,030 mmol) of oxobis(tributylphosphonium) trifluoromethanesulfonate was dissolved in 0.75 d of methylene chloride, cooled to -23°C, and stirred. Next, R-(-)-benzylidene-1
-phenylethylamine ([α)”= −72,3,
lit(α]Is・-72,4)62.8mg (0
, 30 mmol) and 78.4 mg (0.45 mmol) of 0-methyl-trimethylsilyldimethylketene acecool in 1.5 mmol of methylene chloride were added dropwise and stirred.
The mixture was kept at 23'C for 7.5 hours, and after stirring at room temperature for 14 hours, a saturated aqueous sodium bicarbonate solution was added and extracted with methylene chloride. The extracted solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified by thin layer chromatography.
2.2 Dimethyl-3-(R-1-phenylethylamino)-R~benzenepropionic acid methyl ester 63.6
mg (yield 68'1), [α) near = 34.4
(C=4.01, CHCl+) and 2,2-dimethyl-
3-(I?-1-phenylethylamino>-S-benzenepropionic acid methyl ester 13.3 mg (yield 1
4χ), [α) 7o'= 115.9 (C=0.8
1, ClIC1ff) was obtained.

(Margin below)

Claims (1)

[Claims] General formula R^1_2R^2_2R^3_2P_2OX_
2(I) (wherein R^1, R^2 and R^3 are each a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms or a phenyl group having 1 to 4 carbon atoms; In the presence of a phosphonium salt catalyst (represents a phenyl group having a linear or branched alkyl substituent, and X represents a trifluoromethanesulfonyl group), there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^4 and R^5 are each hydrogen or a linear, branched, or cyclic alkyl group having 1 to 10 carbon atoms, and may contain a hetero atom. ^6 represents -Si(CH_3)_2R^■, R^■ represents methyl, ethyl, t-butyl, or phenyl group.R^
7 represents a linear or branched alkyl group having 1 to 10 carbon atoms, a phenyl group, or a phenyl group having a linear or branched alkyl substituent having 1 to 10 carbon atoms. )
Ketensilyl acetal shown by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R^9, R^1^0 and R^1^1 are hydrogen,
It refers to a linear, branched, or cyclic alkyl group having 1 to 15 carbon atoms, or a phenyl group having a linear or branched alkyl substituent having 1 to 4 carbon atoms, and each alkyl group has a heteroatom. May contain. ) General formula (IV) characterized by reacting with an imine represented by ) in a solvent
The general formula R^1^1NHC・R^9・R^1^0C・R^4・R
^5CO_2R^7 (IV) Method for producing β-amino ester.