(3R)-1-azabicyclo[2.2.2]octan-3-yl carbonochloridate hydrochloride → 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-((phenyl(((R)-quinuclidin-3 yloxy)carbonyl)amino)methyl)benzamido)ethyl)carbamoyl)-phenyl)sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide formate

HRID 520344Notes

Reaction equation

HRID 520344 reaction equation
[Cl:1][C:2]1[CH:3]=[N+:4]([O-:65])[CH:5]=[C:6]([Cl:64])[C:7]=1[CH2:8][C@@H:9]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH:56]([F:58])[F:57])=[C:51]([O:59][CH2:60][CH:61]2[CH2:63][CH2:62]2)[CH:50]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:48])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:47])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:34]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12].Cl.[C:67](Cl)(=[O:77])[O:68][C@@H:69]1[CH:74]2[CH2:75][CH2:76][N:71]([CH2:72][CH2:73]2)[CH2:70]1>N1C=CC=CC=1.Cl>[CH:11]([OH:12])=[O:10].[Cl:1][C:2]1[CH:3]=[N+:4]([O-:65])[CH:5]=[C:6]([Cl:64])[C:7]=1[CH2:8][C@@H:9]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH:56]([F:58])[F:57])=[C:51]([O:59][CH2:60][CH:61]2[CH2:62][CH2:63]2)[CH:50]=1)[O:10][C:11]([C@H:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:48])[NH:28][CH2:29][CH2:30][NH:31][C:32](=[O:47])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:67]([O:68][C@@H:69]4[CH:74]5[CH2:75][CH2:76][N:71]([CH2:72][CH2:73]5)[CH2:70]4)=[O:77])[CH:34]=3)[CH:22]=2)(=[O:19])=[O:20])[CH2:16][CH2:15][S:14]1)=[O:12]

Participants

5

Reactant 2

HCID 86676896(3R)-1-azabicyclo[2.2.2]octan-3-yl carbonochloridate hydrochlorideHCID 1185584733,5-Dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-(2-(3-((phenylamino)methyl)benzamido)ethylcarbamoyl)phenylsulfonyl)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide

Product 1

HCID 1185584863,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-((phenyl(((R)-quinuclidin-3 yloxy)carbonyl)amino)methyl)benzamido)ethyl)carbamoyl)-phenyl)sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide formateYield 30%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 1049PyridineSolvent

Procedure

3,5-Dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-(2-(3-((phenylamino)methyl)benzamido)ethylcarbamoyl)phenylsulfonyl)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (35 mg, 0.036 mmol) was dissolved in pyridine (2 ml). (R)-quinuclidin-3-yl carbonochloridate hydrochloride (described in the co-pending International Patent Application No. PCT/EP2013/075529 (published as WO 2104/086855) (8.15 mg, 0.036 mmol) was added, and the reaction was stirred at room temperature for 6 hrs to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The crude was purified by preparative HPLC to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-3-((3-((2-(3-((phenyl(((R)-quinuclidin-3 yloxy)carbonyl)amino)methyl)benzamido)ethyl)carbamoyl)-phenyl)sulfonyl)thiazolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide formate (12.65 mg, 10.81 μmol, 30% yield).

Workup

  1. additionPCT/EP2013/075529 (published as WO 2104/086855) (8.15 mg, 0.036 mmol) was added
  2. extractionextracted with ethyl acetate
  3. washThe organic phase was washed with water, brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated under vacuum
  6. customThe crude was purified by preparative HPLC

Sources & evidence

ORD record
ord-44ee8597935743b48e20c6c053ac7676
Source dataset
uspto-grants-2016_05
Patent number
US09326976B2

Reaction notes

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