HU218218B - Stereoselective process for preparing optically pure isomers of 1-benzoyl-4-hydroxy-5-(1-phenylethyl)amino-1,2,2a,3,4,5-hexahydrobenz[c,d]indole - Google Patents

Abstract

The present invention relates to a process for the preparation of the superantiomeric compounds of formula (III ') wherein 1) is at least 98: 2? alpha isomers or up to 1: 99?:? and a mixture of the pure crystalline enantiomer of the compound of formula (III ') is selectively crystallized from the mixture. ŕ

Description

The present invention relates to a stereoselective process for the preparation of optical isomers of 1-benzoyl-4-hydroxy-5- (1-phenylethyl) amino-1,2,2a, 3,4,5-hexahydrobenz [cd] indole. These optical isomers are useful intermediates in the preparation of 4 amino-1,2,2a,3,4,5-hexahydrobenz [cd] indoles which can be used to treat various disorders of the central nervous system.

For example, U.S. Patent 4,110,339 discloses that 4- (di-propyl] amino-1,3,4,5-tetrahydrobenz [cd] indole may be used as a prolactin inhibitor and for the treatment of Parkinson's disease. U.S. Patent No. 6,193,196 to 6-Substituted 4-Dialkylaminol, 3,4,5-tetrahydrobenz [cd] indoles as active ingredients in anti-depressant and anti-anxiety formulations, Leanna et al., Tetrahedron Letters, 30: 3935 (1989). for the preparation of compounds of formula III.

Given that certain stereoisomers of the 4-amino-1,2,2a, 3,4,5-hexahydrobenz [cd] indoles are particularly effective, there is a need for stereoselective methods which provide pure optically active starting materials.

The present invention provides a stereospecific process for the preparation of the pure enantiomer of formula III 'in which

i) the carbon atoms 2a are in the R configuration, the 4 carbon atoms are in the R configuration, the 5 carbon atoms are in the R configuration, and the carbon atom marked with * is in the S configuration;

ii) the carbon atom 2a in the S configuration, the carbon atom 4

In the 5-configuration, the 5-carbon atoms are in the S-configuration and the carbon atoms marked with * are in the R-configuration;

iii) the carbon atom 2a is in the R configuration, the carbon atom 4 is in the S configuration, the carbon atom 5 is in the S configuration and the carbon atom marked with an * is in the R configuration; or iv) the C 2a is in the S configuration, the C 4 is in the R configuration, the C 5 is in the R configuration, and the carbon atom marked with * is in the R configuration.

According to the procedure

1) contacting a mixture of alpha-isomers of at least 98: 2 or beta: isomers of at most 1:99 of alpha: β of the compound of formula IV 'with a 1-phenylethylamine enantiomer, and

2) selectively crystallizing the pure crystalline enantiomer of compound III 'from the reaction mixture.

"III produced by reacting the appropriate compound of formula 'The compounds of formula IV to provide _the III _D stereoisomers wherein wherein R ¹ is benzoyl, R ² is hydrogen and R ³ 1-phenylethyl groups. III _a and III _b in the compound of formula I together with isomers, III _C, and III, compounds of formula _d with termed β-isomers.

Leanna et al., Tetrahedron Letters, 30: 3935 (1989) describe methods for the preparation of the corresponding epoxy compounds and the structure of the corresponding stereoisomers is described in great detail.

The reaction temperature is from about 50 ° C to about 150 ° C, and is preferably from about 80 ° C to about 100 ° C.

After completion of the reaction, as determined, for example, by thin layer chromatography or liquid chromatography, the desired amino alcohol is crystallized at a temperature in the range of about -20 ° C to about 40 ° C. The preferred temperature for crystallization is from about 0 ° C to about 15 ° C. A valuable feature of this method is that the reaction and separation of the stereoisomers are efficiently performed in a single step. By appropriate selection of the alpha or beta epoxide isomers and the R or S- (1-phenyl 1-ethyl) amine enantiomers, it is possible to determine which stereoisomer of compound III 'is precipitated from the reaction mixture. For example, a preferred stereoisomer of 1-benzoyl-4-hydroxy-5- (1-phenylethyl) amino-1,2,2a, 3,4,5-hexahydrobenz [cd] indole, (2a-R, 4 The -R, 5-R) -isomer can be prepared by reacting the alpha-epoxides with S1-phenylethylamine.

In the specification, examples and claims, temperatures are given in degrees Celsius. Parts, percentages, and ratios are by weight, by weight, and by weight, except for solvents, which are by volume unless otherwise indicated.

The following examples further illustrate the preparation of the compounds of the invention and their intermediates. The exemplary preparation illustrates the use of the process of the present invention to most preferably produce tetrahydrobenz [cd] indole.

Example 1 (2a-R, 4-R, 5-R) -1-Benzoyl-4-hydroxy-5-S- (1-phenylethyl) amino-1,2,2a, 3,4,5- hexahydrobenz [thiol

482.5 g (1.74 mol) of (2a-RS, 2a-a, 4-a, 5-a) -1-benzoyl-4,5-epoxy-1,2,2a, 3,4,5-hexahydrobenz [ cd] indole was dissolved in 4400 ml of n-butanol and distributed in two 5000 ml three-necked flasks fitted with a mechanical stirrer, an electric thermometer and a reflux condenser with nitrogen inlet on top. A total of 900 mL of 450-450 mL (6.98 mol) of (S) -1-phenylethylamine was added to each flask and the mixture was stirred at 90 ° overnight. A small amount is then removed, the n-butanol is removed in vacuo and the residue is subjected to thin layer chromatography (SiO ₂ , 1: 1 hexane / ethyl acetate). The assay showed no starting material in the mixture after 24 hours. The reaction mixture is then allowed to cool to room temperature, whereupon the desired amino alcohol crystallizes directly from the reaction mixture. The crystalline material is filtered off, each portion is washed with 2,000 to 2,000 ml of diethyl ether and dried. The amount of the first product, together with the quality fraction, was 168.26 g, which was used directly in the next reaction. A second product was obtained by evaporating the above filtrate to dryness, dissolving the residue in 200 mL of toluene, and adding 100 mL of hexane and 100 mL of diethyl ether. The resulting solution was allowed to stand in the refrigerator overnight to give an additional 39.2 g of desired product after filtration. The crystalline material was analyzed to give the following data.

PHYSICAL DATA Melting point: 158-160 °.

IR: 3480 (br), 1638 (s), 1610 (w), 1470 (s), 1457 (s),

1394 (s) cm -1.

NMR: (¹H, ppm, CDC1 _3): 7.02-7.56 (m, 13H);

4.21 (q, 1H, J = 6.6 Hz), 4.25 (br s, 1H), 3.63 (m,

2H), 3.42 (m, 2H), 2.72 (br s, 1H, exchange with D, O),

1.99 (m, 1H), 1.80 (m, 1H), 1.47 (d, 3H, J = 6.6 Hz). MS: m / e = 398, 355, 249, 145, 105.

UV:? _Max = 292 (ε = 8930), 265 (ε = 11400) in ethanol. TLC: _Rf = 0.68 _(SiO2, 42:42:16 ethyl acetate: hexane: triethylamine) = desired diastereomer

R _f = 0.62 (SiO ₂ , 42:42:16 ethyl acetate: hexane: triethylamine) = unwanted diastereomer R _f = 0.36 (SiO ₂ , hexane: ethyl acetate 1: 1) = amino alcohols (mixture).

Analysis

Calcd. For CΗΗ N: 78.37 6.58 7.03%: 78.14 6.67 6.77% [α] _D = -37.58 ° (589 nm).

Example 2 (2a-R, 4-S, 5-R) -1-Benzoyl-4-hydroxy-5- (R 1-phenylethyl) amino-1,2,2a, 3,4,5-hexahydrobenz [thiol

0.36 g (1.00 mmol) of (2a-RS, 2a-a, 4-a, 5-a) -1-benzoyl-4,5-epoxy-1,2,2a, 3,4,5-hexahydrobenz [ cd] indole was introduced into a 100 mL 1-neck round bottom flask. 50 ml of n-butanol are then added, followed by 0.65 ml (0.606 g, 5.0 mmol) of R-1-phenylethylamine in the flask. The reaction mixture was heated at reflux for about 72 hours. The reaction mixture was then analyzed by thin layer chromatography (silica, 42:42:16 ethyl acetate / toluene / triethylamine) to show the presence of two products. The solvent was removed in vacuo to give 0.60 g of a residue. The residue was applied to a silica gel column (230 x 400 mesh) (60 g) eluted with ethyl acetate / toluene / triethylamine (42:42:16). Fractions were collected, analyzed by thin layer chromatography and separated into two sections. Thus, two major components are separated in substantially pure form.

2a. Example 2a (2a-S, 4-S, 5-S)-diastereomer

The solvent from the eluate of Example 2 was removed in vacuo to give the previously eluted compound as a white foam (0.078 g). PHYSICAL DATA [α] _D = -40.78 ° (589 nm, tetrahydrofuran, 103 mg / ml), [α] _D = -269.9 ° (365 nm, tetrahydrofuran, 10.3 mg / ml). Analysis

C H N date: 65.41 5.28 5.87% found: 66.02 5.56 6.65%

2b. Example 2a (2a-R, 4-R, 5-R)-diastereomer The solvent of the eluate of Example 2 was removed in vacuo to give the subsequently eluted compound as a red oil (0.107 g). PHYSICAL DATA

NMR: The title compound was identified as described in Example 4b. similarly to the compound of example.

[α] _D = + 8.86 ° (589 nm, tetrahydrofuran, 10.6 mg / ml), [α] _D = + 54.14 ° (365 nm, tetrahydrofuran, 10.16 mg / ml). Analysis

Calculated for C C N 65.41 5.28 5.87% Found: 66.32 5.40 5.50%

Claims (2)

Patent Claim Point A process for the preparation of pure enantiomers of a compound of formula (III ') which comprises: 1) contacting a mixture of alpha-isomers of the compound of formula (IV ') of at least 98: 2 or beta-isomers of up to 1:99 of the alpha: β with the enantiomer of 1-phenylethylamine, and 2) selectively crystallizing the pure crystalline enantiomer of the compound of formula (III ') from the reaction mixture.