Diisopropylethylamine → N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamide

HRID 20953

反応式

HRID 20953 の反応式
[Si]([O:8][C@H:9]([C@H:39]1[CH2:43][C@@H:42]([O:44][CH2:45][CH2:46][CH3:47])[CH2:41][N:40]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:38])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][O:36][CH3:37])=[O:29])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=CC=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.COC[C@H]1CCCN1>ClCCl.CN(C=O)C.C(OCC)(=O)C>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:35][O:36][CH3:37])=[O:29])[CH:23]=2)[C@H:9]([OH:8])[C@H:39]2[CH2:43][C@@H:42]([O:44][CH2:45][CH2:46][CH3:47])[CH2:41][NH:40]2)[CH:17]=[C:16]([F:18])[CH:15]=1

参加物

9

反応物 5

HCID 81531DiisopropylethylamineHCID 671216(2R)-2-(Methoxymethyl)pyrrolidineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 673161403-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acidHCID 67316242(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

生成物 1

HCID 59346852N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamide収率 79%

試薬・触媒・溶媒 3

HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒

実験手順

Step 1 (D): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid (Step 1 (C), 50 mg, 0.074 mmol) in dichloromethane (2 mL) and DMF (5 mL) was added Hunig's base (28 mg, 0.222 mmol) to make a clear solution and HATU (36 mg, 0.0962 mmol) was then added. After stirring for 20 min, the reaction mixture was added (R)-2-(methoxymethyl)pyrrolidine (17 mg, 0.148 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O, dried and concentrated to give 45 mg of the title compound (79% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.83 (9H, s), 0.86-0.89 (3H, m), 1.48-1.51 (11H, m), 1.72 (1H, m), 1.91-2.07 (4H, m), 2.18 (1H, d, J=15 Hz), 2.64 (1H, dd, J=10, 15 Hz), 2.90-2.94 (1H, m), 3.02 (1H, brd s), 3.28-3.38 (6H, m), 3.48 (1H, m), 3.55 (1H, m), 3.67 (1H, m), 3.74 (1H, m), 3.98 (1H, m), 4.04-4.12 (2H, m), 4.42 (1H, m), 4.59 (1H, m), 6.57-6.60 (1H, m), 6.76 (2H, d, J=5 Hz), 7.41-7.44 (1H, m), 7.60-7.62 (1H, m), 7.88 (1H, d, J=5 Hz), 7.96 (1H, s), 8.08 (1H, brd s). MS (ESI) (M+H)+ 774.40.

後処理

  1. additionwas then added
  2. stirringthe reaction mixture was stirred at rt overnight
  3. washthe mixture was washed with Brine, H2O
  4. customdried
  5. concentrationconcentrated

出典と根拠

ORDレコード
ord-c0932e2aaacb4e24b2c1bda7a58d733c
出典データセット
uspto-grants-2010_06
特許番号
US07745470B2

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