HU207831B - Process for producing enanthiomere mixtures of nitrogen-containing bases dividing raceme composition - Google Patents

Abstract

This method simplifies the usual long and material consuming procedures by sepg. one enatiometer by addn. of a royal cpd., leaving the other enantiometer, which comprises the optical isomer, behind. The royal cpd. is then removal by usual methods

Description

The present invention relates to a process for the preparation of enantiomeric mixtures of nitrogenous bases by resolution of a racemic composition.

In addition to selective synthesis, the most important starting material for the preparation of optical isomers is the racemic compound containing a 1: 1 mixture of enantiomers. In each of these starting processes, the enantiomers can be prepared as a result of very lengthy experimental work. If none of the enantiomers are available because they have not been produced by any method, the so-called "enantiomers" are known. the induced crystallization process cannot be considered for separation. (Such as U.S. Patent No. 2,734,919.)

The same is true if the enantiomers are to be separated by diastereomeric salt formation. [For example, Bull. Chem. Soc., 1962, 35, 694]. We need a seed crystal. Separation of the enantiomers of a previously unresolved racemic compound, even if fortunate with the latter methods, requires a great deal of systematic experimental work, and failure is still rare. Thus, the common mistake of the known methods and procedures is that racemic resolution can only be solved if one or both of the enantiomers, even with very low optical purity, is available. In this case, the enantiomeric excess can be enriched by methods already known [Tetrahedron Lett. 3093 (1981)], and in most cases a very low optical purity enantiomeric mixture may already be a safe starting point. As mentioned above, there is no known method which, under normal laboratory conditions, allows the preparation of enantiomeric mixtures other than 1: 1 in a simple, rapid manner without the use of special equipment, at least in the amount required for preparative work, from the racemic compound.

Unexpectedly, in our work, it has been found that mixing different racemic, nitrogenous bases with less than stoichiometric amounts (0.2-0.9 molar equivalents) of optically active acids and then condensing the base leaving the mixture under heating results in enantiomeric mixtures. The distillate contains an enantiomeric mixture enriched in one enantiomer and the distillation residue in the other. The distillation residue contains not only the enantiomeric mixture but also the optically active acid employed, which can be separated by known methods (e. G., U.S. Patent No. 182,472). In most cases, aqueous alkali is added to the residue and, if the enantiomeric mixture does not precipitate, it is isolated by extraction and the extract is evaporated. Our process is suitable for the decomposition of the racemic composition of any racemic nitrogen-containing base. Examples include alkyl, aryl, and variously substituted amines. Any optically active acid can be used in our process, but especially O-acyl tartaric acids. In the process, the excess molar base is separated from the mixture of base and acid by distillation, preferably under reduced pressure.

The invention is illustrated by the following examples:

1. 2.4 g (0.02 mol) of racemic α-methylbenzylamine and

0.75 g (0.005 mol) of L - (+) - mandelic acid are weighed and mixed and allowed to stand at room temperature for 30 minutes. Subsequently, distillation is started at a pressure of 2x10 ³ Pa using external heating, the vapor temperature is 30 ° C, a sudden decrease of which indicates the end of the distillation. Weight of material collected in collector: 1.1 g [a] ^ = + 1.6 "(c = 1, nHCl).

2. 1.2 g (0.01 mol) of racemic α-methylbenzylamine and

0.75 g (0.005 mol) of L - (+) - mandelic acid were weighed and proceeded as in Example 1. Weight: 0.3 g. [.alpha.] D @ 20 = + 6.6 DEG (c = 1, n HCl).

3. Racemic 2-aminobutanol (17.8 g, 0.20 mol) and L - (+) - tartaric acid (7.5 g, 0.05 mol) were mixed as described in Example 1. The pressure used is 2x10 ³ Pa and the humidity is 32 ° C. Weight: 7.1 g. [α] D = -1.4 ° (c = 1, n HCl).

4. 1.8 g (0.02 mole) of racemic 2-aminobutanol and 1.5 g (0.01 mole) of L - (+) - tartaric acid are weighed according to the procedure of Example 3. mass 0.5 g [α] D = -2.2 ° (c = 1, nHCl).

5. 3.0 g (0.02 mole) of racemic b-phenyl-N-methylisopropylamine and 1.9 g (0.0005 mole) of dibenzoyl-L-tartaric acid monohydrate are weighed, followed by the procedure described in Example 1. we act. The pressure was 20 psi [α] D = + 9.6 ° (c = 1, n HCl).

6. Compound 3.0 g (0.02 mole) of racemic β-phenyl-N-methylisopropylamine and 3.8 g (0.01 mole) of dibenzoyl-L-tartaric acid monohydrate were treated as described in Example 5. . Weight: 0.3 g [α] + = 11.3 ° (c = 1, HCl).

7. Add 13.0 g (0.1 mol) of racemic 2- (N-methyl-O-C-pyrrolidinyl) ethanol and 16.5 g (0.04 mol) of di- (p-toluyl) -L-tartaric acid monohydrate. then proceed as in Example 1. The pressure is 4 x 10 ³ Pa and the humidity is 38 ° C. Weight: 4.7 g [α] D = -10.9 ”(c = 1, n HCl).

8. 3.2 g (0.02 mole) of the racemic N-methyl-α-pyrrolidinyl acetic acid methyl ester and 4.1 g of di- (p-toluyl) -L-tartaric acid monohydrate are weighed, followed by the procedure of Example 1. we act. The pressure of 10 ⁵ Pa and a vapor temperature of 54 ° C. The yield: 1.0 g, [?] D = 28.3 ° (c = 1, methanol).

9. Following the procedure of Example 7, 50 cm <^{3> of} 10% sodium hydroxide was added to the solid after distillation, and the resulting mixture was extracted with ³ x 50 cm <^{3> of} dichloromethane and then concentrated. Weight: 7.1 g [α] D = + 8.2 ° (c = 1.1, lHCl).

Claims (1)

PATIENT PERSONALITY Process for preparing enantiomeric mixtures of nitrogenous bases by breaking down a racemic composition, comprising mixing a racemic nitrogen-containing base with 0.2-0.9 molar equivalents of optically active acid, preferably O-acylated tartaric acid, and then removing the excess from the mixture by distillation. .