Process for preparing optically active 2,3-dihydrobenzofuran compounds
View Patent ↗A process for preparing optically active 2,3-dihydrobenzofuran compounds which comprises subjecting a 2,3-dihydrobenzofuran compound represented by the general formula or a salt thereof to optical resolution with an optically active acid compound: [wherein R 1 and R 2 are each hydrogen or an optionally substituted hydrocarbon group; R 3 is an optionally substituted aromatic group; and C is a benzene ring which may further have a substituent in addition to the amino group]. The process enables industrially advantageous production of intermediates for the synthesis of optically active 2,3-dihydrobenzofuran compounds useful as preventive and/or therapeutic drugs for neurodegenerative diseases and so on.
1. A process for producing an optically active 2,3-dihydrobenzofuran compound or a salt thereof, comprising optically resolving a 2,3-dihydrobenzofuran compound represented by the formula:
wherein R 1 and R 2 are each a hydrogen atom or an optionally substituted hydrocarbon group, R 3 is an optionally substituted aromatic group, ring C is a benzene ring optionally having a substituent besides the amino group or a salt thereof, with an optically active acidic compound.
2. The process according to claim 1 , wherein R 1 and R 2 are each a C 1-6 alkyl group.
3. The process according to claim 1 , wherein R 3 is a phenyl group optionally having C 1-6 alkyl and/or halogen atom.
4. The process according to claim 1 , wherein the ring C is a benzene ring fully substituted with the substituents selected from a C 1-6 alkyl, a C 1-6 alkoxy and a C 1-3 alkylenedioxy besides the amino group.
5. The process according to claim 1 , wherein the compound represented formula (I) or a salt thereof is a compound represented by the formula:
wherein R 1′ and R 2′ are each a C 1-6 alkyl group, R 3′ is a phenyl group optionally having C 1-6 alkyl and/or halogen atom, R 4 , R 5 and R 6 are each a C 1-6 alkyl, a C 1-6 alkoxy or a C 1-3 alkylenedioxy, or a salt thereof.
6. The process according to claim 1 , wherein the optically active acidic compound is an optically active O,O′-diacyltartaric acid derivative.
7. The process according to claim 1 , wherein the optically active acidic compound is an optically active N-acylamino acid derivative.
8. The process according to claim 1 , wherein the optically active acidic compound is an optically active phosphoric acid derivative represented by the formula:
wherein Ar is an optionally substituted aromatic hydrocarbon group, R 1a and R 2a are each a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, a halogen atom or a nitro group, or R 1a and R 2a may be bound together to form an optionally substituted alkylene group or an optionally substituted methylenedioxy, and the symbol * shows the position of an asymmetric carbon.
9. The process according to claim 1 , wherein the optically active acidic compound is an optically active O,O′-di-(p-toluoyl)tartaric acid.
10. The process according to claim 1 , wherein the optically active acidic compound is an optically active N-(3,5-dinitrobenzoyl)-α-phenylglycine.
11. The process according to claim 8 , wherein the phosphoric acid derivative represented by the formula (II) is an optically active compound of 2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide.
12. The process according to claim 5 , wherein R 4 , R 5 and R 6 are each a methyl group.
13. A salt of a compound represented by the formula (I′):
wherein R 1′ and R 2′ are each a C 1-6 alkyl group, R 3′ is a phenyl group optionally having C 1-6 alkyl and/or halogen atom, R 4 , R 5 and R 6 are each a C 1-6 alkyl, a C 1-6 alkoxy or a C 1-3 alkylenedioxy
with an optically active O,O′-di-(p-toluoyl)tartaric acid, an optically active N-(3,5-dinitrobenzoyl)-α-phenylglycine or an optically active 2-hydroxy-5 ,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide.
14. A salt of (R)-(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine with (2S,3S)-O,O′-di-(p-toluoyl)tartaric acid.
15. A salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine with (2S,3S)-O,O′-di-(p-toluoyl)tartaric acid.
16. A salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine with (S)-N-(3,5-dinitrobenzoyl)-α-phenylglycine.
17. A salt of (+)-2,2,4,6,7-pentamethyl-3-[4-(1-methylethyl)phenyl]-2,3-dihydro-1-benzofuran-5-amine with (+)-2-hydroxy-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide.
18. A salt of (+)-2,2,4,6,7-pentamethyl-3-(4-bromophenyl)-2,3-dihydro-1-benzofuran-5-amine with (2S,3S)-O,O′-di-(p-toluoyl)tartaric acid.