Methanesulfonyl chloride → ((1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-enyl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

HRID 901201Notes

Reaction equation

HRID 901201 reaction equation
[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[N:5][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:11]=2[CH:12]=1.[CH3:15][C:16]1[N:17]([C@H:22]2[CH2:26][C@@:25]([CH:30]([CH3:32])[CH3:31])([C:27](O)=[O:28])[CH:24]=[CH:23]2)[C:18]([CH3:21])=[CH:19][CH:20]=1.CS(Cl)(=O)=O>>[CH3:15][C:16]1[N:17]([C@H:22]2[CH2:26][C@:25]([C:27]([N:9]3[CH2:8][CH2:7][C:6]4[N:5]=[CH:4][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:12][C:11]=4[CH2:10]3)=[O:28])([CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23]2)[C:18]([CH3:21])=[CH:19][CH:20]=1

Participants

4

Reactant 3

HCID 31297Methanesulfonyl chlorideHCID 11402372(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-enecarboxylic acidHCID 114810975,6,7,8-Tetrahydro-3-(trifluoromethyl)-1,6-naphthyridine

Product 1

HCID 59700298((1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-enyl)(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

Procedure

N-((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)-N-[(cis-3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine, 1, is synthesized by sequentially coupling three building block compounds 4, 5 and 6 (Schemes 3, 4 and 5, below). An amidation reaction between 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine, 5, and (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)1-isopropylcyclopent-2-ene-1-carboxylic acid, 4, is carried out in the presence of methanesulfonyl chloride to afford 6-{[(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-en-1-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine. Deprotection of the pyrrole group was carried out at this stage using hydroxylamine as a through process to provide an amine salt. The amine salt and (3R)-3-methoxytetrahydro-4H-pyran-4-one, 6, are coupled through reductive amination, in the presence of a tributylamine buffer, and with NaBH(OAc)3 to afford (3S,4S)-N-((1S,4S)-4-isopropyl-4-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopent-2-en-1-yl)-3-methoxytetrahydro-2H-pyran-4-amine, 2. The cyclopentene moiety of compound 2 was then hydrogenated to form free base compound 1.

Sources & evidence

ORD record
ord-0428eb617c314a64a777551ae43b56a1
Source dataset
uspto-grants-2008_04
Patent number
US07361765B2

Reaction notes

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