Process for producing 3-amino-2-hydroxypropionic acid derivatives

a technology of 3-amino-2-hydroxypropionic acid and derivatives, which is applied in the field of process for preparing 3amino-2-hydroxypropionic acid derivatives, can solve the problems of unsuitable industrial production, process use of phosgene having a very high toxicity as carbonylation agent, and process problems such as unsuitability for industrial production, and achieves stable production, high yield, and reduced yield.

Inactive Publication Date: 2006-06-22
KANEKA CORP
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  • Abstract
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Benefits of technology

[0011] In addition, they found that impurities are apt to be produced secondarily and the yield and quality of 3-amino-2-hydroxypropionic acid derivatives (1) tend to reduce, if intermediate substituted-3-amino-2-hydroxypropionic acid derivatives having an inverted steric configuration at 2-position carbon are supplied to a next step without isolation and / or purification to a pure form. However, they also found that 3-amino-2-hydroxypropionic acid derivatives (1) can be stably produced in a high yield and a high quality, by contacting the intermediate substituted-3-amino-2-hydroxypropionic acid derivatives having an inverted steric configuration at 2-position carbon, without isolation and / or purification to a pure form, with water under acidic to neutral conditions and subjecting the mixture to heat treatment.
[0151] As described above, according to the present invention, it is possible to prepare conveniently and efficiently, and with industrial advantages, 3-amino-2-hydroxypropionic acid derivatives (1) having a particular steric configuration from N-protected-3-amino-2-hydroxypropionic acid derivatives (2) having a reverse steric configuration at 2-position carbon.EXAMPLES

Problems solved by technology

However, the above process must use a cyanogen compound having a very high toxicity, and therefore, is problematic as an industrial production process.
However, all these processes are also problematic as an industrial production process because they need many steps and complicated procedures, for example.
However, these processes are also unsuitable for an industrial production because they use an expensive base (e.g. lithium hexamethyldisilazane and lithium amide), an explosive azide compound, a toxic lead compound, or the like.
However, this process must use phosgene having a very high toxicity as a carbonylation agent, and an expensive base such as an alkali metal or alkaline earth metal alkoxide, an alkali metal amide or an alkyl lithium compound or an alkylmagnesium halide as a strong base.
Accordingly, the process is unsuitable for an industrial production.

Method used

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  • Process for producing 3-amino-2-hydroxypropionic acid derivatives
  • Process for producing 3-amino-2-hydroxypropionic acid derivatives
  • Process for producing 3-amino-2-hydroxypropionic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of (2S,3S)-3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid (erythro-isomer)

[0153] A toluene solution (677.2 g) containing (S)-1,1-dibromo-3-(ethoxycarbonyl)amino-2-oxo-4-phenylbutane (67.65 g) was added dropwise to a 10% aqueous solution of sodium hydroxide (691.3 g) ice-cooled over 10 hours, and stirred at the same temperature for 1 hour. The resultant reaction solution was further reacted at 60° C. for 6 hours. The organic phase was separated from the resultant reaction mixture, ethyl acetate (400 ml) was added to the resultant aqueous phase, and the pH was adjusted to pH 2 with conc. hydrochloric acid (150 g). The organic phase was separated to obtain an aqueous solution (944.7 g) containing erythro-3-amino-2-hydroxy-4-phenylbutyric acid (26.52 g) and threo-3-amino-2-hydroxy-4-phenylbutyric acid (5.44 g). The ratio of erythro-isomer / threo-isomer was 83 / 17, and the diastereomer excess was 66% d.e.

[0154] The aqueous solution (940.4 g) [containing erythro-3-amino-...

example 2

Synthesis of a diastereomer mixture of 3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid

[0156] The ethyl acetate extract (96.5 g) obtained in Example 1 [containing a diastereomer mixture (4.28 g) of 3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid] was concentrated to dry up under reduced pressure. The solid was ground in a porcelain mortar and then further dried in vacuo to obtain a powdery solid (4.43 g). The purity of erythro-3-(ethoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid was 80% by weight. Also, the HPLC area ratio of erythro-isomer / threo-isomer was 83 / 17, and the diastereomer excess was 66% d.e.

example 3

Synthesis of (2S,3S)-3-(t-butoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid (erythro-isomer)

[0157] (S)-1,1-Dibromo-3-(t-butoxycarbonyl)amino-2-oxo-4-phenylbutane (42.12 g) was suspended in toluene (420 ml) and water (280 ml) and the suspension was ice-cooled. To this suspension, a 30% aqueous solution of sodium hydroxide (133 g) was added dropwise over 1 hour, and the mixture was stirred at the same temperature for 20 hours. The organic phase was separated from the resultant reaction mixture, ethyl acetate (600 ml) was added to the resultant aqueous phase, the pH was adjusted to pH 2 with conc. hydrochloric acid (115 g), and the aqueous phase was separated. Then, the resultant organic phase was washed with water (70 ml) to obtain an ethyl acetate extract (591.9 g). Determination by HPLC revealed that the amount of the diastereomer mixture of 3-(t-butoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid in the resultant extract was 27.14 g calculated as an erythro-isomer. Also, the HPL...

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Abstract

The present invention provides a process for preparing 3-amino-2-hydroxypropionic acid derivatives (1) which does not use dangerous reagents, is economically advantageous, and is suitable for an industrial production, which process comprises: treating N-protected-3-amino-2-hydroxypropionic acid derivatives (2) having a steric configuration at 2-position carbon reverse to that of derivatives (1) with a leaving group-introducing agent to convert into N-protected-3-aminopropionic acid derivatives (3), then treating the derivatives with a basic substance to convert into substituted-3-amino-2-hydroxypropionic acid derivatives (4) having an inverted steric configuration at 2-position carbon, and then converting the derivatives into 3-amino-2-hydroxypropionic acid derivatives (1).

Description

TECHNICAL FIELD [0001] The present invention relates to a process for preparing 3-amino-2-hydroxypropionic acid derivatives represented by the following general formula (1): wherein R1, R2 and R3, independently from each other, represent a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms. [0002] 3-Amino-2-hydroxypropionic acid derivatives of the general formula (1) [hereinafter, also referred to as 3-amino-2-hydroxypropionic acid derivatives (1)] are useful compounds as an intermediate of a medicine. Among others, 3-amino-2-hydroxy-4-phenylbutyric acid [a compound of the general formula (1) wherein R1 is a benzyl group, R2 and R3 are hydrogen atoms] is particularly important: (2S,3R)-isomer (i.e. threo-isomer) of the compound can be led, for example, to an immunostimulating anticancer agent, Bestati...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D263/38C07D263/04C07D263/24C07B57/00C07B61/00C07C227/20C07C227/32C07C227/42C07C229/22C07C229/34C07D263/20
CPCC07C227/20C07C227/32C07C227/42C07D263/20C07C229/22C07C229/34Y02P20/55
Inventor MURAO, HIROSHIYAMASHITA, KOKITAKEDA, TOSHIHIROUEDA, YASUYOSHI
Owner KANEKA CORP
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