Process for the racemization of α-amino acids

Abstract

According to the present invention, a method is provided wherein a basic aqueous phase containing an optically active -amino acid is brought into contact with an organic phase containing a racemisation catalyst in the form of a copper metal complex of copper ions and an -amino acid and salicylaldehyde, in the presence of a phase transition catalyst, thereby subjecting the optically active -amino acid to racemisation. In the -amino acid racemisation method according to the present invention, the reaction conditions are mild and thus there is little -amino acid breakdown and the yield is high, the racemisation catalyst can be reused, the -amino acid resulting from the racemisation can easily be isolated and purified, and the racemisation method can be implemented in volume such that the invention is economic.

Claims

1. A method for -amino acid racemization, comprising contacting an organic phase comprising a copper metal complex of Formula 1 with a basic aqueous phase comprising an optically active -amino acid in the presence of a phase transfer catalyst ##STR00003## wherein, X represents a hydrogen, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms or a nitro group.

2. The method according claim 1, wherein said phase transfer catalyst is a tetraalkylammonium salt (R.sub.4N.sup.+X.sup.) or tetraalkylphosphonium salt (R.sub.4P.sup.+X.sup.), wherein R independently represents an alkyl group having 1-20 carbon atoms, a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group, and X represents Cl, Br, I or OH.

3. The method according claim 1, wherein said phase transfer catalyst is Aliquat 336.

4. The method according claim 1, wherein said amino acid is phenylalanine, a substituted phenylalanine, leucine, alanine or methionine.

5. The method according claim 1, comprising: (A) preparing an organic phase comprising said copper metal complex and said phase transfer catalyst, (B) preparing a basic aqueous phase comprising an optically active -amino acid and an alkaline compound, and (C) racemizing a two-phase mixture obtained by combining the organic phase and the aqueous phase at a temperature 10 to 80 C.

6. The method according claim 5, further comprising: (D) allowing the two-phase mixture resultant from said step (C) to stand and separate into an organic phase and an aqueous phase, and (F) employing the separated organic phase obtained in step (D) as an organic phase again in step (A).

7. The method according claim 5, wherein said copper metal complex and phase transfer catalyst are obtained by: (a-1) preparing an organic phase comprising salicylaldehyde and a phase transfer catalyst, (a-2) preparing a basic aqueous phase comprising -amino acid, an alkali compound and a copper salt compound, and (a-3) stirring a two-phase mixture of the organic phase and the basic aqueous phase and then allowing it to stand to separate an organic phase and an aqueous phase.

Description

Example 1

Racemization of L-phenylalanine

(1) (1) Preparation of an Organic Layer Containing Copper Metal Complex

(2) In dichloromethane 120 mL, 5-nitrosalicylaldehyde (10.0 g, 59.8 mmol) and Aliquat 336 (33.9 g, 83.9 mmol) were dissolved to give an organic phase. In distilled water 100 ml, racemic phenylalanine (19.8 g, 119.9 mmol), sodium hydroxide (5.75 g, 144 mmol) and copper chloride (CuCl2) (1.6 g, 11.9 mmol) were dissolved to give an aqueous phase. The organic phase and the aqueous phase were mixed, the resultant two-phase mixture was vigorously stirred for 2 hours, followed by a phase separation to give an organic layer containing copper metal complex.

(3) (2) Racemization

(4) In distilled water 500 ml, L-phenylalanine (98.8 g, 598 mmol) and sodium hydroxide (28.7 g, 718 mmol) were dissolved to give an aqueous phase, to which the organic layer obtained in the above step 1) was introduced. The resultant two-phase mixture was stirred at 25 C. for 12 hours, followed by a phase separation to give an aqueous layer. The aqueous layer was analyzed with a chiral column (Chirosil RCA) and it was confirmed that L/D ratio of phenylalanine is 50.2/49.8 and thus a racemization has occurred.

(5) [Conditions for the Chiral HPLC Analysis] Column: Chirosil RCA 5 uM25 Cm Mobile phase: 10 mM HClO4 50% in MeOH Velocity of mobile phase: 0.5 mL/min Column temperature: 40 C.

Examples 25

Racemization of L-phenylalanine

(6) In the same manner as in Example 1 , step 1) and step 2) were performed to proceed a racemization of phenylalanine.

(7) The racemization results of Examples 1-5 are shown in Table 1 below:

(8) TABLE-US-00001 TABLE 1 Examples Reaction time L/D ratio 1 12 h 50.1/49.8 2 12 h 50.1/49.9 3 16 h 50.0/50.0 4 15 h 51.5/45.5 5 16 h 51.0/49.0

Example 6

Racemization of L-phenylalanine

(9) 1) Preparation of an Organic Layer Containing Copper Metal Complex

(10) In dichloromethane 70 mL, 5-nitrosalicylaldehyde (5.0 g) and Aliquat 336 (17 g) were dissolved to give an organic phase. In distilled water 50 ml, L-phenylalanine (10 g), sodium hydroxide (2.9 g) and copper chloride (CuCl2) (0.8 g) were dissolved to give an aqueous phase. The organic phase and the aqueous phase were mixed and the resultant two-phase mixture was vigorously stirred for 2 hours, followed by a phase separation to obtain an organic layer containing copper metal complex.

(11) 2) Racemization

(12) In distilled water 260 ml, L-phenylalanine (50 g) and sodium hydroxide (14.5 g) were dissolved to give an aqueous phase, to which the organic layer obtained in the above step 1) was introduced. The resultant two-phase mixture was stirred at 25 C. for 12 hours, followed by a phase separation to give an aqueous layer. The aqueous layer was analyzed with a chiral column (Chirosil RCA) and it was confirmed that a racemization has occurred.

Example 7

Racemization of L-phenylalanine

(13) 1) Preparation of an Organic Layer Containing Copper Metal Complex

(14) In dichloromethane 115 mL, salicylaldehyde (7.3 g) and Aliquat 336 (33.6 g) were dissolved to give an organic phase. In distilled water 100 ml, racemic phenylalanine (19.8 g), sodium hydroxide (5.75 g) and copper sulfate (CuSO4) (1.9 g) were dissolved to give an aqueous phase. The organic phase and the aqueous phase were mixed and the resultant two-phase mixture was vigorously stirred for 2.5 hours, followed by a phase separation to obtain an organic layer containing copper metal complex.

(15) 2) Racemization

(16) In distilled water 500 ml, L-phenylalanine (98.8 g) and sodium hydroxide (28.7 g) were dissolved to prepare an aqueous phase, to which the organic phase obtained in the above step 1) was added. The resultant two-phase mixture was stirred for 13 hours at 25 C., followed by phase separation to give an aqueous layer. The aqueous layer was analyzed by a chiral column (Chirosil RCA) and it was confirmed that L/D ratio of phenylalanine is 50.8/49.2 and thus a racemization has occurred.

Example 8

Racemization of L-4-chlorophenylalanine

(17) 1) Preparation of an Organic Layer Containing Copper Metal Complex

(18) In dichloromethane 130 mL, 5-nitrosalicylaldehyde (10.0 g) and Aliquat 336 (33.9 g) were dissolved to prepare an organic phase. In distilled water 150 ml, racemic 4-chlorophenylalanine (24.0 g), sodium hydroxide (5.77 g) and copper chloride (CuCl2) (1.4 g) were dissolved to prepare an aqueous phase. The organic phase and the aqueous phase were mixed and the resultant two-phase mixture was vigorously stirred for 2 hours, followed by phase separation to obtain an organic layer containing copper metal complex.

(19) 2) Racemization

(20) In distilled water 700 ml, L-4-chlorophenylalanine (120 g) and sodium hydroxide (28.0 g) were dissolved to prepare an aqueous phase, to which the organic layer obtained in the above step 1) was added. The resultant two-phase mixture was stirred at 30 C. for 13 hours, followed by phase separation to give an aqueous layer. The aqueous layer was analyzed by a chiral column (Chirosil RCA) and it was confirmed that L/D ratio of 4-chlorophenylalanine is 50.1/49.9 and thus a racemization has occurred.

(21) [Conditions for the Chiral HPLC Analysis] Column: Chirosil RCA Mobile phase: 10 mM HClO4 50% in MeOH Velocity of mobile phase: 0.5 mL/min Column temperature: 40 C.

Examples 910

Racemization of L-4-chlorophenylalanine

(22) In the same manner as in Example 8 , step 1) and step 2) were performed to proceed a racemization of L-4-chlorophenylalanine.

(23) The racemization results of Examples 810 are shown in Table 2 below:

(24) TABLE-US-00002 TABLE 2 Examples Reaction time L/D ratio 8 13 h 50.1/49.9 9 15 h 50.0/50.0 10 15 h 51.1/48.9

Example 11

Racemization of L-leucine

(25) 1) Preparation of an Organic Layer Containing Copper Metal Complex

(26) In dichloromethane 40 mL, 5-nitrosalicylaldehyde (3.4 g) and Aliquat 336 (12 g) were dissolved to give an organic phase. In distilled water 40 ml, racemic leucine (5.2 g), sodium hydroxide (1.75 g) and copper chloride (CuCl2) (0.6 g) were dissolved to give an aqueous phase. The organic phase and the aqueous phase were mixed and the resultant two-phase mixture was vigorously stirred for 1 hour, followed by a phase separation to obtain an organic layer containing copper metal complex.

(27) 2) Racemization

(28) In distilled water 100 ml, L-leucine (13.3 g) and sodium hydroxide (4.8 g) were dissolved to prepare an aqueous phase, to which the organic layer obtained in the above step 1) was added. The resultant two-phase mixture was stirred at 35 C. for 15 hours, followed by phase separation to give an aqueous layer. The aqueous layer was analyzed by a chiral column (Sumichiral OA-5000) and it was confirmed that L/D ratio of leucine is 51.0/49.0 and thus a racemization has been carried out.

(29) [Conditions for the Chiral HPLC Analysis] Column: Sumichiral OA-5000 Mobile phase: 10% ACN in 2 mM CuSO4 Velocity of mobile phase: 1.0 mL/min Column temperature: 30 C.

INDUSTRIAL APPLICABILITY

(30) The method of the present invention can be industrially utilized in the production of an optically active -amino acid which can be used as a raw material or intermediate in the field of pharmaceuticals, agriculture and fine chemistry.