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)-5-methylbenzamide

HRID 20961ノート

反応式

HRID 20961 の反応式
C([O:4][C@H:5]1[CH2:9][N:8](C(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:7]([C@@H:23]([OH:52])[C@@H:24]([NH:34][C:35](=[O:51])[C:36]2[CH:50]=[CH:49][CH:48]=[C:38]([C:39]([N:41]([CH2:45][CH2:46][CH3:47])[CH2:42][CH2:43]C)=[O:40])[CH:37]=2)[CH2:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)[CH2:6]1)C=C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=C(C)C=C(C(N2CCC[C@@H]2COC)=O)C=1)CC1C=C(F)C=C(F)C=1)([C:56](C)([CH3:58])[CH3:57])(C)C.[C:108]([O:112]C(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=C(C)C=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.[CH3:156]CN(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.C(OCC)(=O)C>[F:32][C:30]1[CH:31]=[C:26]([CH2:25][C@H:24]([NH:34][C:35](=[O:51])[C:36]2[CH:50]=[C:49]([CH3:156])[CH:48]=[C:38]([C:39]([N:41]3[CH2:45][CH2:46][CH2:47][C@@H:42]3[CH2:43][O:112][CH3:108])=[O:40])[CH:37]=2)[C@H:23]([OH:52])[C@H:7]2[CH2:6][C@@H:5]([O:4][CH2:57][CH2:56][CH3:58])[CH2:9][NH:8]2)[CH:27]=[C:28]([F:33])[CH:29]=1

参加物

9

反応物 6

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 593468483-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acidHCID 67316677(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 68497616N1-((1S,2S)-1-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide

生成物 1

HCID 11848581N-((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)-5-methylbenzamide収率 95%

試薬・触媒・溶媒 2

HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒

実験手順

Step 8 (A): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-methylbenzamido)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)-5-methylbenzoic acid (Preparation G, 28 mg, 0.038 mmol) in dichloromethane (1 mL) was added Hunig's base (14 mg, 0.114 mmol) to make a clear solution and HATU (19 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added (R)-2-(methoxymethyl)pyrrolidine (65 mg, 0.057 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 30 mg of the title compound (95% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.01 (3H, s), 0.06 (3H, s), 0.85 (9H, s), 0.88 (3H, t, J=5 Hz), 1.48-1.54 (11H, m), 1.73 (1H, m), 1.92-22.09 (5H, m), 2.18 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.96 (1H, m), 3.05 (1H, m), 3.26-3.39 (5H, m), 3.47 (1H, m), 3.58 (1H, m), 3.68 (1H, m), 3.76 (1H, dd, J=5, 15 Hz), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.11-4.14 (1H, m), 4.41 (1H, brd s), 4.56 (1H, m), 6.59 (1H, m), 6.76 (1H, s), 6.77 (1H, s), 7.43 (1H, s), 7.72 (1H, s), 7.74 (1H, s), 7.98 (1H, brd s). MS (ESI) (M+H)+ 788.61.

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-d8354cfb81f64f4bb8e709b2160bf320
出典データセット
uspto-grants-2010_06
特許番号
US07745470B2

反応ノート

読み込み中…