Production of the enantiomer-enriched form of (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide by a splitting process.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- AOP ORPHAN IP AG
- Filing Date
- 2024-05-15
- Publication Date
- 2026-06-09
Smart Images
Figure 2026518663000001_ABST
Abstract
Claims
1. Equation for enantiomer enrichment morphology (S-I) 【Chemistry 20】 (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS) represented by formula (I) 【Chemistry 21】 A method for producing rac-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (rac-SLS) represented by the following, a) Formula (II) of rac-SLS and enantiomer-enriched form in the first liquid medium 【Chemistry 22】 [wherein, R １ , R ２ , R ３ , R ４ and R ５ may be the same or different and each independently is H, C １ to C ４ -alkyl, halogen, C １ to C ４ -haloalkyl, -O-C １ to C ４ -alkyl and -O-C １ to C ４ -haloalkyl, and can be selected therefrom] A step of providing a first mixture containing the compound shown, b) Exposing the first mixture formed in step a) to conditions such that rac-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and the compound represented by formula (II) are at least partially dissolved in a first liquid medium to form an intermediate solution, c) A step of exposing the intermediate solution formed in step b) to conditions under which a cocrystalline solid intermediate product is formed, comprising (S)-SLS and a compound represented by formula (II), d) optionally, recrystallizing the solid intermediate product formed in step c) in a second liquid medium to provide a solid intermediate product comprising (S)-SLS and a compound represented by formula (II), in a cocrystalline, diastereomer-enriched form, e) A step of exposing the solid intermediate product formed in step c) or d) to a base to provide (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide represented by formula (S-I) in an enantiomer-enriched form. including, method.
2. In the compound represented by formula (II), R １ , R ２ , R ３ , R ４ and R ５ However, they may be the same or different, and independently, H and C １ ~C ４ - Alkyl, halogen and C １ ~C ４ - The method according to claim 1, which can be selected from haloalkyl groups.
3. In the compound represented by formula (II), R １ , R ２ , R ４ and R ５ However, H is R ３ However, C １ ~C ４ - The method according to claim 1 or 2, selected from alkyl groups.
4. The method according to any one of claims 1 to 3, wherein a first liquid mixture is provided with rac-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide represented by formula (I) and a compound represented by formula (I) in a molar ratio of about 1.5:1 to about 2.5:1, preferably about 1.9:1 to about 2.1:
1.
5. The first and / or second liquid medium is C １ ~C ４ The method according to any one of claims 1 to 4, comprising or essentially consisting of an alkyl acetate, for example ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tert-butyl acetate; an organic solvent or mixture of organic solvents selected from the group consisting of acetonitrile, methyl isobutyl ketone, and aromatic hydrocarbons, for example toluene.
6. The method according to any one of claims 1 to 5, wherein the first and second liquid media comprise or are essentially comprised of isobutyl acetate and acetonitrile.
7. Recrystallization according to process step d) d1) A step of providing a mixture of solid intermediate products into a second liquid medium containing or essentially consisting of a third solvent or solvent mixture, d2) A step of exposing the mixture formed in step d1) to conditions such that the solid intermediate product dissolves at least partially in the second liquid medium, d3) The method according to any one of claims 1 to 6, comprising the step of exposing a mixture formed in step d2) in which the solid intermediate product is at least partially dissolved in a second liquid medium to conditions under which the dissolved intermediate product, comprising (S)-SLS and a compound represented by formula (II), in a cocrystalline, diastereomer-enriched form, recrystallizes.
8. The method according to any one of claims 1 to 7, wherein, in step e), the base is selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, or hydroxides.
9. The method according to any one of claims 1 to 8, wherein, in step e), the base is sodium bicarbonate.
10. The method according to any one of claims 1 to 9, wherein, in step e), the base is used in an amount of at least 1.5 equivalents relative to the molar amount of the intermediate cocrystal of (S)-SLS and the compound represented by formula (II).
11. Crystalline formula (S-I) 【Chemistry 23】 (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide is represented by [the formula shown].
12. The (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide according to claim 11, having an enantiomer purity of at least 97% ee, at least 98% ee, or at least 99% ee.
13. (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (polymorph X) represented by the crystalline formula (S-I) according to claim 11 or 12, having an X-ray powder diffraction pattern including two-theta angular values (deviation ±0.2 degrees) of 16.4, 19.8, 21.9, and 32.6 degrees.
14. (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide ((S)-SLS), represented by the crystalline formula (S-I) according to any one of claims 11 to 13, for use as a pharmaceutical.
15. (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and formula (II) 【Chemistry 24】 [In the formula, R １ , R ２ , R ３ , R ４ and R ５ These may be the same or different, and independently, H and C １ ~C ４ - Alkyl, halogen, C １ ~C ４ -Haloalkyl, -O-C １ ~C ４ -Alkyl and -O-C １ ~C ４ - Can be selected from haloalkyl groups. It contains a tartaric acid derivative represented by and is in an enantiomer-enriched form. compound.
16. The compound according to claim 15, comprising (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide and a tartaric acid derivative represented by formula (II) in a molar ratio of 2:
1.
17. In the compound represented by formula (II), R １ , R ２ , R ４ and R ５ However, H is R ３ The compound according to claim 15 or 16, wherein the compound is methyl.
18. The compound according to any one of claims 15 to 17, which is crystalline, preferably cocrystalline.
19. The compound according to claim 18, having an X-ray powder diffraction pattern including two-theta angular values (deviation ±0.2 degrees) of 6.2, 10.7, 12.5, and 16.2 degrees.