DD229685A1 - PROCESS FOR THE PRODUCTION OF OPTICALLY ACTIVE DICARBONE ACIDS - Google Patents

Abstract

The invention relates to a process for the preparation of optically active dicarboxylic acids by resolution of the racemic mixture. According to the invention, the racemate resolution is carried out with L - () - (1S, 2S) -1- (4-nitrophenyl) -2-amino-1,3-propanediol or the N-dimethyl derivative or with the antipode and already leads in 2 separation operations the pure enantiomers of the acids. The optically active dicarboxylic acids are an intermediate for bioactive compounds, complex ligands u. a. usable.

Description

Title of the invention

Process for the preparation of optically active dicarboxylic acids

Field of application of the invention

The invention relates to a process for preparing optically active dicarboxylic acids by resolution of a racemic mixture of a dicarboxylic acid into the individual enantiomers by means of an optically active base. The optically active dicarboxylic acids obtained are intermediates for the production of bioactive compounds and ligands for complex catalysts.

Characteristic of the known technical solutions

It is known to produce optically active dicarboxylic acids by using optically active auxiliaries. Optically active bases or alcohols can be used as optically active auxiliaries which form diastereomeric compounds with the optical antipodes of the racemate, thus permitting separation of the racemic mixture.

Thus, from Houben-Weyl, Methods of Organic Chemistry, Volume 4/2 (1955), page 509 et seq., Especially p. 519 and S, 525, known for the enantiomeric separation of a racemic acid mixture especially plant alkaloids such as brucine, strychnine, quinine , To use quinidine, cinchonine and cinchonidine or else the "i-phenyl-ethylamine"

^ 2 1 / -92O

For example, brucine (H, Wren, L. Miller, Soc., 1935 , 157) and quinidine (F. Bell, FB Smith, Soc., 1949 , 2372) are used to cleave 2,3-diphenylsuccinic acid. For the cleavage of the racemic form, the acidic as well as the neutral salts can be used.

The main disadvantage of the mentioned bases is their relatively low selection in the resolution of the racemate, so that many times up to 10 separation operations are necessary to obtain the pure antipodes. The chemical yields are naturally low. Another disadvantage must be in the alkaloids their z. T, significant toxicity (e.g., brucine and strychnine) should be considered and, finally, the cost of the bases and those to be recovered, as they are not disposable bases.

Furthermore, acids can be separated into the antipodes via their esters of chiral alcohols, for example by esterification with menthol or borneol. However, the use of optically active alcohols is limited to a few compounds and the separating action of the diastereomeric esters also varies within wide limits. For example, the separation of racemic 2,3-diphenylsuccinic acid over the acid menthyl ester is possible only by expensive selective extraction with ether ( N. D, Berova, B, D. Kurtev, Tetrahedron, 2_5, 2301/1969 /).

Object of the invention

The object of the invention is to develop a method for the resolution of the racemic dicarboxylic acids with a cheap optically active auxiliary base to eliminate the indicated defect, which allows the pure preparation of the antipodes in a few separation operations without the need for the recovery of the excipient, but also permits.

Explanation of the essence of the invention

The object of the invention is achieved by resolution of a racemic mixture of a dicarboxylic acid of the general formula I

R ²

R ¹ - C - COOH

<™ 2> "*

R ⁴ - C - COOH

R ³

in the

R and R, which may be the same or different, are alkyl, phenyl, substituted alkyl, substituted phenyl, alkoxy, aryloxy or halogen and

2 3

R and R, which may be the same or different, are hydrogen or alkyl and

η is an integer equal to o, 1, 2, 3 or 4, preferably 0, _#

by means of an optically active base via the diastereomeric salts, according to the invention as the optically active base L - (+) - iS, 2S7-1- (4-nitrophenyl) -2-amino-propanediol-1, 3 or L - (+) 2-isis-2-iso-4-nitrophenyl-2-N, N-dimethylamino-propanediol-1, 3 _# D - (-) - ^ 1R _t 2R 7 -l- (4-nitrophenyl) -2-araino- propanediol-1,3 or D - (-) - lR, 2R7-l- (4-nitro-phenyl) -2-N, N-dimethylamino-propanediol-1,3 is used in an organic solvent.

Alcohols, especially methanol, are used as solvents «

The method according to the invention has the following advantages:

The racemate resolution of the substituted dicarboxylic acids can be carried out with a high separation effect. Thus, the two-fold separation operation of 2,3-diphenylsuccinic acid leads to 100 % pure antipodes, and already at the first cleavage a product with an enantiomeric purity of 93 % is obtained.

The filtrate of the 1, antipodal cleavage is with the other

Antipodes already enriched so much that another

once cleavage with the opposite base leads to the pure enantiomer.

Because of the small number of separation operations, the chemical yields are good and are at 80 to 85%.

The decomposition of the diastereomeric salts proceeds without problem with lye, whereby their recovery can be dispensed with because of the good accessibility and availability of the L (+) base. For the D (-) base, the recovery is easily possible with yields> 90 %.

The pure antipodes of the dicarboxylic acids to be separated according to the invention which can be rapidly and easily prepared in this way can be used as an intermediate in bioactive substances.

embodiments

example 1

(S, S) - (+) - 2,3-Dipheny succinic acid

5 g of racemic diphenylsuccinic acid (18.5 mmol) in 70 ml of methanol are treated with a solution of 7.85 g (37.0 mmol) of L-base [i '1 Jq ¹ = + 22.15 ° (c = 1.0 After stirring for 8 hours, the precipitate is filtered off with suction (filtrate 1) and recrystallised from 175 ml of methanol (5.8 g of (+) (+) - salt). The salt is decomposed with dilute NaOH, filtered, and the filtrate is acidified with dilute HCl. "After precipitation, the precipitated (2S, 3S) -2 _# 3-diphenylated succinic acid weighs 2.6 g of sulfur, ⁵ = + 374.5 ° ( c = 0.4, acetone)! ,

Renewed cleavage of (2S, 3S) -2,3-diphenylsuccinic acid with L-base yields 2.2 g (88 %) of (2S, 3S) -2,3-diphenylsuccinic acid with ^ \ 7q = + 398 ° (c = The filtrate 1 is concentrated to dryness in vacuo, usually resulting in a viscous oil ((+) (-) salt), the residue decomposed with dilute NaOH, filtered and the filtrate acidified with dilute HCl. After drying, 2.3 g of (2R, 3R) -2,3-diphenylated succinic acid are obtained, fr ^ Q ⁵ = -315.7 (C = 0.4, acetone)],

Yield: 2.2 g = 88 %

(Ref: H.Wren, L. Miller, A. Ch. ^ 10 /, 20 ^ 1932 /, 97 and 121; / Wq ⁵ - + 396 ° (c = 0.749; acetone).

Example 2

(R, R) - (-) - 2 _X 3-diphenylated succinic acid

5 g (2R, 3R) -2,3-diphenylsuccinic acid (18.5 raraol)

[- -25 O 1

1 "^ / ₀ - -315.7 (c = 0.4; acetone) J in 70 ml of methanol are treated with a solution of 7.85 g (37.0 mmol) of D-base fö-7 _D -23, 3 ° (c = 1.0, MeOH) in 150 ml of methanol are heated to boiling and then allowed to cool.After 12 hours, the precipitate is filtered off with suction, disassembled with NaOH, filtered and

-i »* i

The filtrate was acidified with dilute HCl. After drying, 3.7 g of (2R, 3R) - (-) - 2,3-diphenylsuccinic acid with a rotational value of ^ 7Q ¹ = -393 ° (c = 0.4, acetone) were obtained.

Yield: 3.7 g (74 %, based on the acid used).

Example 3

(S, S) - (+) - 2,3-Dipheny succinic acid

1 g of racemic diphenylsuccinic acid (3.7 mmol) in 14 mL of methanol is treated with a solution of 1.78 g (7.4 mmol) ^L ( ⁺ ) "(IS, 2S) -1- (4-nitrophenyl) -2 After evaporation of acetone, a precipitate is precipitated, the extracted salt is decomposed with dilute NaOH, filtered and the filtrate is acidified with dilute HCl the (2S _t 3S) -2,3-diphenylsuccinic acid is in the range of + ¹⁷² ° (° ⁼ ° '^2; acetone).

Claims (2)

invention claim 1 «Process for the preparation of optically active dicarboxylic acids by resolution of a racemic mixture of a dicarboxylic acid of general formula I, R ²
R ³ -C- COOH - < ^CH 2> n
R ⁴ - C - COOH in the 1 4 R and R, which may be the same or different, alkyl, Phenyl, substituted alkyl, substituted phenyl, alkoxy, aryloxy or halogen and 2 3 R and R, which may be the same or different. Water· mean or alkyl and η is an integer equal to o, 1, 2, 3 or 4, preferably 0, into the individual enantiomers by means of an optically active base, characterized in that as optically active bases L - (+) - 1S, 2S7-1- (4-nitrophenyl) -2-amino-1,3-propanediol or L- ( +) - ^ is, 2 ~ 7-l- (4-nitrophenyl) -2-N, N-diniethylamino-propanediol-1,3, D - (-) - lR ,, 2R7-l- (4-nitr ° -phenyl-2-amino-1,3-propanediol or D - (-) -> 1R _# 2R7-2-N, N-dimethylamino-1,3-propanediol in an organic solvent, 2. The method according to item 1, characterized in that are used as the solvent alcohols, in particular methanol.