Sodium hydride → {(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 2-fluoro-pyridin-3-yl ester

HRID 587403

반응식

HRID 587403 반응식
[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1C(O)=[CH:56][CH:55]=[CH:54][N:53]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[F:51][C:52]1[C:45]([O:44][C:43](=[O:49])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:56][CH:55]=[CH:54][N:53]=1

참가 물질

8

반응물 5

HCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 27627852-Fluoro-3-hydroxypyridineHCID 58303053[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone

생성물 1

HCID 53244726{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 2-fluoro-pyridin-3-yl ester수율 181.8%

시약·촉매·용매 2

HCID 6228Dimethylformamide용매2회HCID 8028Tetrahydrofuran용매

반응 조건

온도
45 °C

실험 절차

A mixture of 50 mg (0.11 mmol) [(3R,4S)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone, 16.2 mg (0.12 mmol) DIPEA and 11.8 mg (0.04 mmol) triphosgene in 5 mL THF at −78° C. was allowed to come to 0-5° C. during 2 h, concentrated under vacuum and dissolved in 1 mL DMF. A solution of 65.5 mg (0.57 mmol) 2-fluoropyridine-3-ol in 1 mL DMF was treated with 18.2 mg (0.45 mmol) NaH 55% in mineral oil and heated to 45° C. for 1 h. This solution was added to the activated amine in DMF and the mixture was shaken for 90 minutes at 80° C. The mixture was filtered and the filtrate was subjected to preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 42 mg (64%) of the title compound as off-white foam. MS m/e: 577.3 [M+H]+.

후처리

  1. concentrationconcentrated under vacuum
  2. dissolutiondissolved in 1 mL DMF
  3. filtrationThe mixture was filtered
  4. washeluting with a gradient
  5. customformed from acetonitrile, water and NEt3
  6. additionThe product containing fractions
  7. customwere evaporated

출처 및 근거

ORD 기록
ord-a4239f1394454fb88aa4a04cbe24a3d6
출처 데이터셋
uspto-grants-2016_01
특허 번호
US09226916B2

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