1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide → 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt

HRID 1075425Notes

Reaction equation

[Br-:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:56])[C@:16]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])([OH:47])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([O:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])=[C:26]([CH3:46])[CH:25]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)#[N:3].[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].ClCCl>>[F:60][C:59]([F:62])([F:61])[C:57]([OH:63])=[O:58].[Br-:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([C@H:15]([CH3:56])[C@:16]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[F:55])([OH:47])[CH2:17][N:18]3[CH:22]=[N+:21]([CH2:23][C:24]4[CH:25]=[C:26]([CH3:46])[C:27]([O:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])=[C:28]([CH3:30])[CH:29]=4)[CH:20]=[N:19]3)[S:13][CH:14]=2)=[CH:8][CH:9]=1)#[N:3]

Participants

Reactant 2

HCID 110618711-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide

HCID 21863450Trifluoroacetic acid methylene chloride

Product 1

HCID 443265701-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt

Procedure

To a solution of 3 g of 3,5-dimethyl-4-hydroxybenzyl bromide in CH3CN(30 mL) was added 1.2 g of (1R,2R)-4-[2-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]thiazol-4-yl]benzonitrile and stirring was continued for 2 h at room temperature. The precipitate was filtered and washed with ether to give 1.37 g(81 %y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxy)benzyl-1H-[1,2,4]triazol-4-ium bromide(RoO9-3846) as a white solid. To a mixture of 30 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluoro-phenyl)-2-hydroxybutyl]-4-(3,5-dimethyl-4-hydroxybenzyl)-1H-[1,2,4]triazol-4-ium bromide, 10.9 g of Boc-(L)-proline and 2.8 g of N,N-dimethylaminopyridine in 1.2L of dichloromethane was added 17.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture was stirred for 1.5 h at room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (Wakogel C-200, solvent: CH2Cl2 /MeOH=14/1) to give 30.9 g(79%y.) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide as a white solid. 30.9 g of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(N-tert-butoxycarbonylpyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide was stirred in 600 mL of 10% TFA-dichloromethane for 5 h at room temperature and the solvent was removed in vacuo. The residue was diluted with ether and the precipitate was washed with ether to give 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-4-[(S)-3,5-dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]-1H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt as a white solid.

Workup

customthe solvent was removed in vacuo
additionThe residue was diluted with ether
washthe precipitate was washed with ether

Sources & evidence

ORD record: ord-08d7072018cc4d3296a06f263b1538e2
Source dataset: uspto-grants-1999_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US05900486

Reaction notes

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