(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 520344ノート

反応式

HRID 520344 の反応式
[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]

参加物

5

反応物 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

生成物 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 formate収率 30%

試薬・触媒・溶媒 2

HCID 313Hydrochloric Acid溶媒HCID 1049Pyridine溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-44ee8597935743b48e20c6c053ac7676
出典データセット
uspto-grants-2016_05
特許番号
US09326976B2

反応ノート

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