(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 520344노트

반응식

HRID 520344 반응식
[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]

참가 물질

5

반응물 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

생성물 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 formate수율 30%

시약·촉매·용매 2

HCID 313Hydrochloric Acid용매HCID 1049Pyridine용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-44ee8597935743b48e20c6c053ac7676
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09326976B2

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