Hydrochloric Acid → [(1S)-1-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl]1-[4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoyl]azetidine-3-carboxylate

HRID 520337노트

반응식

HRID 520337 반응식
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:21]=[C:22]([CH:41]=[CH:42][CH:43]=1)[O:23][CH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([N:31]3[CH2:34][CH:33]([C:35](OC)=[O:36])[CH2:32]3)=[O:30])=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2]2.[OH-].[Li+].Cl.[Cl:47][C:48]1[CH:49]=[N+:50]([O-:73])[CH:51]=[C:52]([Cl:72])[C:53]=1[CH2:54][C@@H:55]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH:64]([F:66])[F:65])=[C:59]([O:67][CH2:68][CH:69]2[CH2:71][CH2:70]2)[CH:58]=1)[OH:56].Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1>[CH:69]1([CH2:68][O:67][C:59]2[CH:58]=[C:57]([C@@H:55]([O:56][C:35]([CH:33]3[CH2:32][N:31]([C:29](=[O:30])[C:28]4[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:22]5[CH:41]=[CH:42][CH:43]=[C:20]([CH2:19][N:12]([C:10]([O:9][C@@H:3]6[CH:4]7[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]7)[CH2:2]6)=[O:11])[C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=6)[CH:21]=5)=[CH:40][CH:39]=4)[CH2:34]3)=[O:36])[CH2:54][C:53]3[C:52]([Cl:72])=[CH:51][N+:50]([O-:73])=[CH:49][C:48]=3[Cl:47])[CH:62]=[CH:61][C:60]=2[O:63][CH:64]([F:66])[F:65])[CH2:71][CH2:70]1

참가 물질

9

반응물 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 71092687(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxideHCID 118558450Methyl 1-[4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)-methyl]phenoxy]methyl]benzoyl]azetidine-3-carboxylate2회

생성물 1

HCID 102514695[(1S)-1-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl]1-[4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoyl]azetidine-3-carboxylate수율 13%

시약·촉매·용매 3

HCID 142844-(Dimethylamino)pyridine촉매HCID 887Methanol용매HCID 8028Tetrahydrofuran용매

실험 절차

A solution of methyl 1-[4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoyl]azetidine-3-carboxylate (Intermediate 7 above described) (190 mg, 0.32 mmol) in THF (3 mL) and methanol (3 mL) was added with an aqueous solution of 1N lithium hydroxide (0.64 mL, 0.64 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and acidified by addition of 2N hydrochloric acid dropwise to pH≈2-3. The mixture was allowed to warm to room temperature and the solvent removed in vacuo and azeotroped with toluene to dryness. The crude material was redissolved in dimethylformamide (3 mL). (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (161 mg, 0.38 mmol), 4-(dimethylamino)pyridine (20 mg, 0.16 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (123 mg, 0.64 mmol) were added, and reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water (50 mL) The organic phase was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified twice by preparative HPLC to yield the title compound as white solid (40 mg, 13% yield over two steps).

후처리

  1. temperatureThe mixture was cooled to 0° C.
  2. temperatureto warm to room temperature
  3. customthe solvent removed in vacuo
  4. customazeotroped with toluene to dryness
  5. dissolutionThe crude material was redissolved in dimethylformamide (3 mL)
  6. additionwere added
  7. customreaction mixture
  8. stirringwas stirred at room temperature for 18 hours
  9. customThe solvent was removed in vacuo
  10. customthe residue was partitioned between EtOAc (50 mL) and water (50 mL) The organic phase
  11. dry with materialwas dried over MgSO4
  12. filtrationfiltered
  13. customthe solvent was removed in vacuo
  14. customThe residue was purified twice by preparative HPLC

출처 및 근거

ORD 기록
ord-dd932ac83345466483fb660ff8d798ad
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09326976B2

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