2-methoxyacetic acid [2-[2-[3-(1H-benzimidazol-2-yl)propyl-methylamino]ethyl]-6-fluoro-1-propan-2-yl-3,4-dihydro-1H-naphthalen-2-yl] ester → N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide

HRID 443069Notes

Reaction equation

HRID 443069 reaction equation
COCC([O:6][C:7]1([CH2:21][CH2:22][N:23]([CH2:25][CH2:26][CH2:27][C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)[CH3:24])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[CH:8]1[CH:18]([CH3:20])[CH3:19])=O.FC1C=C2C(=CC=1)C(C(C)C)C(=[O:51])CC2.N1C2C=CC=CC=2N=C1CCCN(C)C(=O)C>>[NH:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[CH2:27][CH2:26][CH2:25][N:23]([CH3:24])[C:22](=[O:51])[CH2:21][C:7]1([OH:6])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[CH:8]1[CH:18]([CH3:20])[CH3:19]

Participants

4

Reactant 3

HCID 52302702-methoxyacetic acid [2-[2-[3-(1H-benzimidazol-2-yl)propyl-methylamino]ethyl]-6-fluoro-1-propan-2-yl-3,4-dihydro-1H-naphthalen-2-yl] esterHCID 110200276-Fluoro-1-(propan-2-yl)-3,4-dihydronaphthalen-2(1H)-oneHCID 11107182N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide

Product 1

HCID 10917130N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide

Procedure

A method of preparing 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting 6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with the dianion of N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide to form N-[3-(1H-benzirnidazol-2-yl) propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, reducing this to 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and treating the 2-[2-{[3-(1H-benzirnidazol-2-yl)propyl]methylarnino}ethyl]-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N-[3-(1H-Benzimidazol-2-yl)propyl]-N-methylacetamide, and the acetic acid solvate of 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-ol dioxalate, are new.

Sources & evidence

ORD record
ord-f3c750fcfc1549c8a398e591907d3081
Source dataset
uspto-grants-1999_04
Patent number
US05892055

Reaction notes

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