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

反応式

HRID 1166508 の反応式
[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

参加物

6

反応物 3

HCID 81531DiisopropylethylamineHCID 27761692,3-Dihydro-1,4-benzodioxine-6-sulfonyl chloride2 回HCID 59090777(3r,3As,6ar)hexahydrofuro[2,3-b]furan-3-yl(1s,2r)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate

生成物 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 ester収率 86%

試薬・触媒・溶媒 2

HCID 218852-Dimethylaminopyridine触媒HCID 8028Tetrahydrofuran溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-338af4af4edf49ffad6191ca992363da
出典データセット
uspto-grants-2003_09
特許番号
US06613743B2

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