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Process for producing 3-amino-2-oxo-1-halogenopropane derivatives

a technology of halogenopropane and halogenomethyl anion, which is applied in the preparation of carbamic acid derivatives, organic chemistry, chemical production, etc., can solve the problems of unstable halomethyl anion use, and limited industrialization of this method, and achieves the effect of easy conversion into -aminoalcohol derivatives

Inactive Publication Date: 2005-09-13
AJINOMOTO CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]Accordingly, it is one object of the present invention to provide a novel process for preparing compounds which can be easily converted into α-aminoalcohol derivatives.
[0011]It is another object of the present invention to provide a novel process for preparing compounds which can easily be converted into 3-amino-1,2-epoxypropane derivatives.
[0012]It is another object of the present invention to provide a novel process for preparing 3-amino-1,2-epoxypropane derivatives.
[0013]It is another object of the present invention to provide a novel process for preparing 3-amino-2-oxo-1-halogenopropane derivatives.
[0014]It is another object of the present invention to provide an industrial process for producing a 3-amino-2-oxo-1-halogenopropane derivative which can easily be converted to a 3-amino-1,2-epoxypropane derivative.

Problems solved by technology

However, industrialization of this method is limited since it has to use diazomthane having quite a high explosiveness and a strong toxicity as a sub-starting material (see for example, Getman D. P. et al., J. Med. Chem., 1993, vol.
However, quite an unstable halomethyl anion is used, and a halogen to be introduced into the 1-position is presumably limited to chorine or fluorine in view of a common chemical knowledge.
For these reasons, industrialization of this method is limited (Barluenga et al., J. Chem. Soc., Chem. Commun., 1994).
In this method, however, the halogen is limited to a specific element, fluorine.
Consequently, this method involves quite a high cost.
N-substituted aldehyde entail a high cost, but also carbine has to be formed at a low temperature when inserting methylene.
Accordingly, this method is not industrially appropriate.

Method used

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  • Process for producing 3-amino-2-oxo-1-halogenopropane derivatives
  • Process for producing 3-amino-2-oxo-1-halogenopropane derivatives
  • Process for producing 3-amino-2-oxo-1-halogenopropane derivatives

Examples

Experimental program
Comparison scheme
Effect test

production example 1

Production of N,N-dibenzyl-L-phenylalanine benzyl ester (Ia)

[0070]Twenty-five grams (151.3 mmol) of (L)-phenylalanine and 66.67 g (482.4 mmol) of potassium carbonate were dissolved in 100 ml of water, and 57.51 g (454.3 mmol) of benzyl chloride were added thereto. The mixture was heat-stirred at 95° C. for 19 hours. After the reaction mixture was cooled to room temperature, 67 ml of n-heptane and 50 ml of water were added thereto. The organic layer was washed twice with 50 ml of a mixture of methanol and water at a volume ratio of 1:2 and was then dried over anhydrous sodium sulfate. The dried substance was filtered and concentrated to give 61.64 g (90%, 121.8 mmol) of the above-mentioned compound (Ia) in a yield of 84.7%.

[0071]1H-NMR(300 MHz, CDCl3) δ:3.00 (dd,1H), 3.14(dd,1H), 3.53(d,2H),3.71(t,1H),3.92(d,2H),5.12(d,1H),5.23(d,1H), 6.99-7.40(m,20H); Mass spectrum (FAB) 436(MH+)

production example 2

Production of N,N-dibenzyl-L-phenylalanine p-nitrophenyl ester (1b)

[0072]N,N-dibenzyl-L-phenylalanine hydrochloride (7.64 g, 20.0 mmol) was added to 50 ml of chloroform, and 20.0 ml of 10% aqueous ammonia were added dropwise to the suspension for neutralization. The organic layer was separated, washed with 20 ml of water, then dried over magnesium sulfate, and filtered. The filtrate was concentrated, the resulting residue was dissolved in 50 ml of chloroform, and 2.89 g (20.4 mmol) of p-nitrophenol and 4.13 g (20.0 mmol) of N,N′-dicyclohexylcarbodiimide were added to the solution in this order while being cooled with ice. The mixture was reacted overnight. To the reaction solution were added 30 ml of ethyl acetate, and the N,N′-dicyclohexylurea which precipitated was removed by filtration. The filtrate was washed with a 10% potassium carbonate aqueous solution. The organic layer was separated, and concentrated. The resulting residue was redissolved in 30 ml of ethyl acetate, and the...

example 1

Production of (4S)-4-(N,N-dibenzylamino)-4-benzyl-3-oxobutanoic acid tert-butyl ester (IIa)

[0074]A solution (2.0M) (24 ml, 48 mmol) of LDA in heptane, THF and ethyl benzene was dissolved in 64 ml of anhydrous THF, and the mixed solution was cooled to −53° C. in an argon atmosphere. To this solution was added dropwise a solution of 5.8 g (50 mmols) of tert-butyl acetate in 12 ml of THF for approximately 15 minutes, while maintaining the temperature of from −45° C. to −50° C. After the completion of the dropwise addition, the mixture was stirred at −53° C. for 1 hour. Subsequently, a solution of 7.2 g (15 mmols, purity 90%) of N,N-dibenzyl-L-phenylalanine benzyl ester (Ia) in 8 ml of THF was added dropwise thereto for approximately 15 minutes while maintaining the temperature at from −48° C. to −52° C. After the completion of the dropwise addition, the reaction temperature was raised to −5° C. After three hours, a solution of 16.5 g of citric acid in 50 ml of water was added to the re...

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PUM

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Abstract

Compounds formed by reacting a protected amino acid with an alkali metal enolate of an alkyl acetate are reacted with a halogenating agent for halogenation of the 2-position, or a protected amino acid is reacted with an alkali metal enolate of an alkyl halogenoacetate, to form a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative, and hydrolysis and decarboxylation are conducted to produce a 3-amino-2-oxo-1-halogenopropane derivative or its salt. The present method is a useful process for producing a 3-amino-2-oxo-1-halogenopropane derivatives which can easily be converted to a 3-amino-1,2-epoxypropane.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention relates to a process for producing 3-amino-2-oxo-1-halogenopropane derivatives which can easily be converted to optically active 3-substituted-3-amino-1,2-epoxypropane derivatives which are equivalents of α-aminoalcohol derivatives that are important as intermediates for HIV protease inhibitors or certain enzyme inhibitors.[0003]2. Discussion of the Background[0004]α-Aminoalcohol derivatives which can easily be converted from optically active 3-substituted-3-amino-1,2-epoxypropane derivatives are used as intermediates for synthesis of a large number of HIV protease inhibitors such as Ro31-8959 (Parkes K. et al (Roche), J. Org. Chem., 1994, vol. 59, p.3656) SC-52151 (Getman D. P. et al. (Monsanto), J. Med. Chem., 1993, Vol. 36, p. 288) VX478 (Verte, WO9405639), and AG1343 (Lilly, WO9521164].[0005]Known examples of a method of producing 3-amino-1, 2-epoxypropane derivatives include a method in which ...

Claims

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Application Information

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IPC IPC(8): C07C223/00C07C223/02C07C221/00C07C227/16C07C227/32C07C229/22C07C229/34C07C269/06C07C271/22C07C319/20C07C323/43
CPCC07C221/00C07C227/16C07C227/32C07C229/22C07C229/34C07C269/06C07C271/22C07C319/20C07C323/43Y02P20/55
Inventor HONDA, YUTAKAKATAYAMA, SATOSHIIZAWA, KUNISUKENAKAZAWA, MASAKAZUSUZUKI, TAKAYUKIKANNO, NAOKO
Owner AJINOMOTO CO INC
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