WO2003020687A1 - Improved method of preparing 2-(s)-amino-4-phenylbutyric acid - Google Patents

Improved method of preparing 2-(s)-amino-4-phenylbutyric acid Download PDF

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WO2003020687A1
WO2003020687A1 PCT/KR2002/001654 KR0201654W WO03020687A1 WO 2003020687 A1 WO2003020687 A1 WO 2003020687A1 KR 0201654 W KR0201654 W KR 0201654W WO 03020687 A1 WO03020687 A1 WO 03020687A1
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acid
formula
mixture
group
amino
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PCT/KR2002/001654
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French (fr)
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Nam Du Kim
Young Ho Moon
Kyung Ik Lee
Ki Eun Kim
Cheol Kyung Kim
Gwan Sun Lee
Young Kil Chang
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Hanmi Pharm. Co., Ltd.
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Publication of WO2003020687A1 publication Critical patent/WO2003020687A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Definitions

  • the present invention relates to an improved method of preparing pure 2-(S)-amino-4-phenylbutyric acid from L-aspartic acid in a high yield.
  • 2-(S)-amino-4-phenylbutyric acid of formula (I) is an important intermediate in the synthesis of angiotensin-converting enzyme (ACE) inhibitors such as analapril of Merck GmbH, quinapril of Pfizer, Inc., benazepril of Novatis Pharma AG, and Ramipril of Aventis GmbH, as well as in the synthesis of other drugs under development such as the antiarthritic drug of formula (II) (see WO98/09957), the somatotropin secretion promoting material of formula (III) (see W095/14666), and the anti-inflammatory and antiarthritic agent of formula (IV) (see WO94/02152):
  • ACE angiotensin-converting enzyme
  • Ri is hydrogen or a C ⁇ -4 alkyl
  • R 2 and R 3 are each independently hydrogen or a C ⁇ -6 alkyl.
  • Japanese Patent Publication No. 97-140391 discloses a method for preparing 2-(S)-amino-4-phenylbutyric acid from a racemate by way of using (R)-mandelic acid, as shown in Scheme 2. However, this method gives a low yield of 21 %:
  • the present inventors have endeavored to develop an improved method for preparing 2-(S)-amino-4-phenylbutyric acid in a high yield starting from L-aspartic acid which is easily obtainable.
  • R is H, CH 3 , CH 3 CH 2 . CH 3 0, CH 3 CH 2 0, t-BuO, CC1 3 CH 2 0, or C 6 H 5 CH 2 O ; and HX is an organic or inorganic acid.
  • an aspartic anhydride of formula (VI) having an amine protection group is prepared by dehydrating an amine- protected derivative of L-aspartic acid of formula (V) at a temperature ranging from 0 to 100 ° C , preferably 40 to 50 ° C for a period ranging 3 to 10 hours.
  • the dehydration reaction may be carried out by reacting L-aspartic acid with an acid selected from the group consisting of formic acid, acetic anhydride, chloroacetic acid and a mixture thereof, preferably a mixture of formic acid and acetic anhydride.
  • the acid may be employed in an amount ranging from 50 to 1000wt% based on the weight of L-aspartic acid.
  • Formic acid and acetic anhydride may be mixed in a weight ratio ranging from 1 : 1 to 1:4.
  • step (b) of the inventive method Friedel-Crafts acylation of benzene with the aspartic anhydride of formula (VI) is performed in the presence of a Lewis acid at a temperature ranging from 0 to 100 °C , preferably 60 to 70 ° C for a period ranging from 30 minutes to 5 hours. Then, the amine protection group is removed by treating the acylation product with a strong acid, to obtain an amine salt of formula (VII).
  • the Lewis acid may be A1C1 3 , BF 3 , BBr 3 , PC1 5 , SnCl 4 , TiCl 4 , poly- phosphoric acid (PPA), phosphoric acid, sulfuric acid or a mixture thereof, preferably AICI 3 .
  • the strong acid used for removing the amine protection group which is represented as HX in the compound of formula (VII), may be hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, sulfurous acid, nitric acid, trifluoroacetic acid, or a mixture thereof, preferably hydrochloric acid.
  • the 2-(S)-amino-4-phenylbutyric acid of formula (I) is prepared by reducing the amine salt of formula (VII) at a temperature ranging from 0 to 100 ° C, preferably 20 to 30 ° C for a period ranging from 20 to 60 hours.
  • the reduction reaction may be carried out by using i) hydrogen gas in the presence of a metal catalyst, ii) a zinc amalgam and a strong acid, or iii) a strong acid in the presence of a reducing agent.
  • the metal catalyst may be Pd/C, Pd, PtO, Ni, Raney nickel, Ru, Rh or a mixture thereof.
  • the strong acid employed in ii) and iii) may be hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, nitric acid, trifluoroacetic acid, or a mixture thereof, preferably hydrochloric acid.
  • the reducing agent may be triethyl silane, sodium borohydride, aluminum borohydride, borane, sodium cyanoborohydride or a mixture thereof, preferably triethyl silane or sodium borohydride.
  • Said 2-(S)-amino-4-phenylbutyric acid of formula (I) can be easily separated from the reaction mixture of the reduction reaction.
  • 2-(S)-amino-4-phenylbutyric acid of formula (I) can be obtained in a high yield of at least 65 % via a simple process under a mild reaction condition.
  • This inventive method can thus be advantageously used in mass production of 2-(S)-amino-4-phenylbutyric acid.
  • step (a) 371 g of aluminum chloride and 133. lg of (S)-N-formylaspartic acid anhydride obtained in step (a) were added to 1.3 L of benzene. The mixture was heated slowly to 45 ° C in a water bath, and vigorously stirred for 2 hours, when the solid turned red. Then the mixture was cooled to 0 ° C in an ice- water bath, 2 L of water was added slowly thereto and stirred for 1 hour to destroy the aluminum chloride. The reaction mixture was filtered, and the filtered cake was dispersed in 2 L of 3N hydrochloric acid, heated at 70 ° C for 3 hours, and water was distilled off under a reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

2-(S)-amino-4-phenylbutyric acid is efficiently prepared in a high yield by (a) dehydrating L-aspartic acid to obtain an aspartic anhydride; (b) reacting the aspartic anhydride with benzene in the presence of a Lewis acid and then with a strong acid to obtain a salt of 2-(S)-amino-4-oxo-4-phenylbutyric acid; and (c) reducing the salt.

Description

IMPROVED METHOD OF PREPARING 2-(S)-AMINO-4- PHENYLBUTYRIC ACID
Field of the Invention
The present invention relates to an improved method of preparing pure 2-(S)-amino-4-phenylbutyric acid from L-aspartic acid in a high yield.
Background of the Invention
2-(S)-amino-4-phenylbutyric acid of formula (I) is an important intermediate in the synthesis of angiotensin-converting enzyme (ACE) inhibitors such as analapril of Merck GmbH, quinapril of Pfizer, Inc., benazepril of Novatis Pharma AG, and Ramipril of Aventis GmbH, as well as in the synthesis of other drugs under development such as the antiarthritic drug of formula (II) (see WO98/09957), the somatotropin secretion promoting material of formula (III) (see W095/14666), and the anti-inflammatory and antiarthritic agent of formula (IV) (see WO94/02152):
Figure imgf000002_0001
Figure imgf000002_0002
Figure imgf000003_0001
Figure imgf000003_0002
wherein Ri is hydrogen or a Cι-4 alkyl; R2 and R3 are each independently hydrogen or a Cι-6 alkyl.
The method disclosed in U.S. Patent. Nos 4,785,089, 5,098,841 and 5,066,801 is illustrated in Scheme 1, wherein 2-(S)-amino-4-phenylbutyric acid is prepared by inverting the chiral center of the (R)-alcohol compound. However, the method has problems in that it requires the use of an expensive and optically pure starting material as well as high pressure reaction conditions, and also that racemization of the chiral center may occur during the reaction.
Scheme 1
Figure imgf000004_0001
Japanese Patent Publication No. 97-140391 discloses a method for preparing 2-(S)-amino-4-phenylbutyric acid from a racemate by way of using (R)-mandelic acid, as shown in Scheme 2. However, this method gives a low yield of 21 %:
Scheme 2
Figure imgf000004_0002
Accordingly the present inventors have endeavored to develop an improved method for preparing 2-(S)-amino-4-phenylbutyric acid in a high yield starting from L-aspartic acid which is easily obtainable.
Summary of the Invention
Accordingly, it is a primary object of the present invention to provide an improved method of preparing 2-(S)-amino-4-phenylbutyric acid.
In accordance with one aspect of the present invention, there is provided a method of preparing 2-(S)-amino-4-phenylbutyric acid of formula (I) which comprises:
(a) dehydrating L-aspartic acid of formula (V) to obtain an aspartic anhydride of formula (VI);
(b) reacting the aspartic anhydride of formula (VI) with benzene in the presence of a Lewis acid and then with a strong acid to obtain an amine salt of formula (VII); and
(c) reducing the amine salt of formula (VII):
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000006_0001
wherein R is H, CH3, CH3CH2. CH30, CH3CH20, t-BuO, CC13CH20, or C6H5CH2O ; and HX is an organic or inorganic acid.
Detailed Description of the Invention
The method of the present invention may be represented by Scheme 3:
Scheme 3
Figure imgf000006_0002
wherein R and HX are as defined above.
The L-aspartic acid of formula (V) which has the same chiral moiety as 2-(S)-amino-4-ρhenylbutyric acid of formula (I) is easily obtainable from a natural source. In step (a) of the inventive method, an aspartic anhydride of formula (VI) having an amine protection group is prepared by dehydrating an amine- protected derivative of L-aspartic acid of formula (V) at a temperature ranging from 0 to 100 °C , preferably 40 to 50 °C for a period ranging 3 to 10 hours.
The dehydration reaction may be carried out by reacting L-aspartic acid with an acid selected from the group consisting of formic acid, acetic anhydride, chloroacetic acid and a mixture thereof, preferably a mixture of formic acid and acetic anhydride. The acid may be employed in an amount ranging from 50 to 1000wt% based on the weight of L-aspartic acid. Formic acid and acetic anhydride may be mixed in a weight ratio ranging from 1 : 1 to 1:4.
In step (b) of the inventive method, Friedel-Crafts acylation of benzene with the aspartic anhydride of formula (VI) is performed in the presence of a Lewis acid at a temperature ranging from 0 to 100 °C , preferably 60 to 70 °C for a period ranging from 30 minutes to 5 hours. Then, the amine protection group is removed by treating the acylation product with a strong acid, to obtain an amine salt of formula (VII).
The Lewis acid may be A1C13, BF3, BBr3, PC15, SnCl4, TiCl4, poly- phosphoric acid (PPA), phosphoric acid, sulfuric acid or a mixture thereof, preferably AICI3. The strong acid used for removing the amine protection group, which is represented as HX in the compound of formula (VII), may be hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, sulfurous acid, nitric acid, trifluoroacetic acid, or a mixture thereof, preferably hydrochloric acid.
In step (c) of the inventive method, the 2-(S)-amino-4-phenylbutyric acid of formula (I) is prepared by reducing the amine salt of formula (VII) at a temperature ranging from 0 to 100 °C, preferably 20 to 30 °C for a period ranging from 20 to 60 hours. The reduction reaction may be carried out by using i) hydrogen gas in the presence of a metal catalyst, ii) a zinc amalgam and a strong acid, or iii) a strong acid in the presence of a reducing agent. The metal catalyst may be Pd/C, Pd, PtO, Ni, Raney nickel, Ru, Rh or a mixture thereof. The strong acid employed in ii) and iii) may be hydrochloric acid, hydrobromic acid, hydriodic acid,sulfuric acid, nitric acid, trifluoroacetic acid, or a mixture thereof, preferably hydrochloric acid. The reducing agent may be triethyl silane, sodium borohydride, aluminum borohydride, borane, sodium cyanoborohydride or a mixture thereof, preferably triethyl silane or sodium borohydride. Said 2-(S)-amino-4-phenylbutyric acid of formula (I) can be easily separated from the reaction mixture of the reduction reaction.
In accordance with the present invention, 2-(S)-amino-4-phenylbutyric acid of formula (I) can be obtained in a high yield of at least 65 % via a simple process under a mild reaction condition. This inventive method can thus be advantageously used in mass production of 2-(S)-amino-4-phenylbutyric acid.
The present invention is further described in the following Examples which are given only for the purpose of illustration, and are not intended to limit the scope of the invention.
Example 1: Preparation of 2-(S -amino-4-phenylbutyric acid
(Step a) Preparation of (S -N-formylaspartic acid anhydride
133.1 g (1 mol) of L-aspartic acid was dissolved in a mixture of 267ml of formic acid and 267 ml of acetic anhydride while stirring at a temperature of 45 to 50 °C for 5 hours. The reaction mixture was cooled and the solvent was distilled off under a reduced pressure. The solid obtained was suspended in 1 L of methylene chloride and filtered, to obtain 133.1 g of the title compound (Yield: 93%).
[αf π26 V-55.7 (c=l, acetone) melting point: 135-136 °C
*H NMR (300MHz, CDC13) δ 2.85(dd,J=6.0Hz,J=18.3Hz,lH), 3.23(d,J=6.0Hz,J=18.3Hz,lH), 4.80(m,lH), 8.10(s,lH,COH), 8.81(broad s,lH,NH)
(Step b Preparation of 2-(S -amino-4-oxo-4-phenylbutyric acid-hydrochloride
371 g of aluminum chloride and 133. lg of (S)-N-formylaspartic acid anhydride obtained in step (a) were added to 1.3 L of benzene. The mixture was heated slowly to 45 °C in a water bath, and vigorously stirred for 2 hours, when the solid turned red. Then the mixture was cooled to 0 °C in an ice- water bath, 2 L of water was added slowly thereto and stirred for 1 hour to destroy the aluminum chloride. The reaction mixture was filtered, and the filtered cake was dispersed in 2 L of 3N hydrochloric acid, heated at 70 °C for 3 hours, and water was distilled off under a reduced pressure. 100 ml of 36 % concentrated hydrochloric acid was added to the residual solid , and the mixture was stirred at 50 °C for 1 hour, cooled to 0 °C and filtered, to obtain 149.5 g of the title compound (Yield: 70 %).
[α]25 D=43.3 (c=l, ethanol) melting point: 213 -215 °C (pyrolysis) H NMR (300MHz, CDC13) δ 3.81(d,J=5.1Hz,2H), 4.42(t,J=5.1Hz,lH), 7.47-7.85(m,5H,aro.) H 122
(Step c) Preparation of 2-(S)-amino-4-phenylbutyric acid
149.5 g of 2-(S)-amino-4-oxo-4-phenylbutyric acid-HCl obtained in step (b) was dissolved in 600 ml of IN HC1, 3.0 g (2 weight/weight %) of Pd/c was added thereto, and stirred at room temperature under hydrogen atmosphere for 48 hours. The reaction mixture was filtered and the filtrate was concentrated under a reduced pressure. 100 ml of water was added to the residue, and 5 % sodium bicarbonate was added thereto to neutralize HC1 in the reaction mixture, and the formed free amino acid was filtered, to obtain 110.8 of the title compound as a white solid (Yield: 95%).
[α]25 D= 45.0 (c=l, 3N HCl) melting point > 300 °C !H NMR (300MHz, CDC13) δ 2.10-2.20(m,2H), 2.64-2.72(m,2H),
3.89(t,J=6.0Hz,lH), 7.20-7.3 l(m,5H,aro.)
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which may also fall within the scope of the invention as defined by the appended claims.

Claims

What is claimed is:
1. A method of preparing 2-(S)-amino-4-phenylbutyric acid of formula (I) which comprises:
(a) dehydrating L-aspartic acid of formula (V) to obtain an aspartic anhydride of formula (VI);
(b) reacting the aspartic anhydride of formula (VI) with benzene in the presence of a Lewis acid and then with a strong acid to obtain an amine salt of formula (VII); and
(c) reducing the amine salt of formula (VII):
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000011_0004
wherein R is H, CH3, CH3CH2, CH30, CH3CH20, t-BuO, CC13CH20 or C6H5CH2θ; and HX is an organic or inorganic acid.
2. The method of claim 1, wherein the dehydration reaction of step (a) is performed by reacting L-aspartic acid with an acid or a derivative thereof selected from the group consisting of formic acid, acetic acid, acetic anhydride, acetylchloride and a mixture thereof.
3. The method of claim 1, wherein the Lewis acid employed in step (b) is selected from the group consisting of A1C13, BF3, BBr3, PCI5, SnCl4, TiCl4, poly-phosphoric acid (PPA), phosphoric acid, sulfuric acid and a mixture thereof.
4. The method of claim 1, wherein the strong acid employed in step (b) is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, sulfurous acid, nitric acid, trifluoroacetic acid, and a mixture thereof.
5. The method of claim 1, wherein the reduction reaction of step (c) is performed by using hydrogen gas in the presence of a metal catalyst; a zinc amalgam with a strong acid; or a strong acid in the presence of a reducing agent.
6. The method of claim 5, wherein the metal catalyst is selected from the group consisting of Pd/C, Pd, PtO, Ni, Raney-nickel, Ru, Rh and a mixture thereof.
7. The method of claim 5, wherein the strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, trifluoroacetic acid, and a mixture thereof.
8. The method of claim 5, wherein the reducing agent is selected from the group consisting of triethyl silane, sodium borohydride, aluminum borohydride, borane, sodium cyanoborohydride and a mixture thereof.
PCT/KR2002/001654 2001-09-04 2002-09-02 Improved method of preparing 2-(s)-amino-4-phenylbutyric acid WO2003020687A1 (en)

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CN114259991A (en) * 2021-12-21 2022-04-01 河南省商业科学研究所有限责任公司 Molecular imprinting material for efficiently adsorbing and removing fluoroquinolone antibiotics and preparation method and application thereof

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