Diisopropylethylamine → Carbamic acid, [(1S,2R)-3-[(cyclohexyloxy)[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester

HRID 1166508

반응식

HRID 1166508 반응식
[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:15]([C@H:22]([NH:34][C:35](=[O:45])[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1)[C@H:23]([OH:33])[CH2:24][NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:15]([C@H:22]([NH:34][C:35](=[O:45])[O:36][C@@H:37]1[C@H:44]2[C@H:40]([O:41][CH2:42][CH2:43]2)[O:39][CH2:38]1)[C@H:23]([OH:33])[CH2:24][N:25]([O:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[S:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)(=[O:13])=[O:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1

참가 물질

6

반응물 3

HCID 81531DiisopropylethylamineHCID 27761692,3-Dihydro-1,4-benzodioxine-6-sulfonyl chloride2회HCID 59090777(3r,3As,6ar)hexahydrofuro[2,3-b]furan-3-yl(1s,2r)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate

생성물 1

HCID 6321057Carbamic acid, [(1S,2R)-3-[(cyclohexyloxy)[(2,3-dihydro-1,4-benzodioxin-6-yl)sulfonyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]-, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester수율 86%

시약·촉매·용매 2

HCID 218852-Dimethylaminopyridine촉매HCID 8028Tetrahydrofuran용매

실험 절차

A mixture of 1,4-benzodioxan-6-sulfonyl chloride (Eur. Pat. Appl. 583960, Feb 23, 1994; 60 mg; 0.253 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol), and diisoproylethylamine (0.042 mL, 0.242 mmol) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. A catalytic quantity of dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. An additional quantity of 1,4-benzodioxan-6-sulfonyl chloride (12 mg, 0.051 mmol) was added and the reaction was heated for an additional 30 minutes. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. After separating the phases, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 1:1 ethyl acetate:hexane. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]-2-hydroxypropylcarbamate (125 mg, 86%) as a white solid. HL-NMR (chloroform-D3): 1.20 (m, 6H), 1.60 (m, 5H), 2.07 (m, 2H), 2.90 (m, 4H), 3.09 (b, 1H), 3.67 (m, 2H), 3.90 (m, 4H), 4.23 (m, 1H), 4.31 (m, 4H), 4.82 (d, 1H), 5.01 (m, 1H), 5.64 (d, 1H), 6.95 (d, 1H) 7.25 (m, 7H). MS(ESI): 655(M+Na).

후처리

  1. temperaturethe reaction was heated
  2. temperatureat reflux for approximately 2 hours
  3. temperaturethe reaction was heated for an additional 30 minutes
  4. temperatureAfter cooling to ambient temperature
  5. customthe reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid
  6. customAfter separating the phases
  7. washthe organic layer was washed with brine
  8. dry with materialdried over anhydrous magnesium sulfate
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe residue was purified on a preparative TLC plate (20×20 cm, 500 μM)
  12. washeluting with 1:1 ethyl acetate
  13. customThe product band was removed
  14. washeluted with 3:1 methylene chloride
  15. filtrationmethanol, filtered
  16. customevaporated in vacuo
  17. customThe residue was triturated with water
  18. filtrationfiltered
  19. customdried under high vacuum

출처 및 근거

ORD 기록
ord-338af4af4edf49ffad6191ca992363da
출처 데이터셋
uspto-grants-2003_09
특허 번호
US06613743B2

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