Trimethylaluminum → (r)-2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [3-methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenyl]-amide

HRID 601518Notes

Reaction equation

HRID 601518 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH2:10]1.C[Al](C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[S:38][C:39]3[C:45](=[O:46])[O:44][CH2:43][CH2:42][C:40]=3[N:41]=2)=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:25][C:45]([C:39]2[S:38][C:37]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)=[N:41][C:40]=2[CH2:42][CH2:43][OH:44])=[O:46])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:22]([CH3:24])[CH3:23])[CH:16]([CH3:18])[CH3:17])[CH2:10]1

Participants

4

Reactant 3

HCID 16682925TrimethylaluminumHCID 574214852-(4-Chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-oneHCID 57870268(R)-3-Methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenylamine

Product 1

HCID 57870257(r)-2-(4-Chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [3-methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenyl]-amideYield 118.1%

Procedure

Charge an oven-dried round bottom flask with (R)-3-methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenylamine (750 mg, 2.05 mmol), purge with nitrogen, and dilute with CH2Cl2 (11 mL). Add trimethylaluminum (2M in hexanes, 1.03 mL, 2.05 mmol) dropwise by syringe and stir 20 min at room temperature. Add solid 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (364 mg, 1.37 mmol) to the reaction mixture and stir overnight at ambient temperature. Absorb the reaction mixture on silica gel and purify by silica gel flash chromatography, using a gradient of EtOAc/hexane (0-100%) to give the title compound (1.02 g, 73%). MS (ES+) 630.1 (M+1)+. 1H NMR (CDCl3): δ 9.88 (bs, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.48 (bs, 1H), 7.37 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.69 (bs, 1H), 4.60-4.52 (m, 1H), 4.19-4.11 (m, 2H), 3.81 (s, 3H), 3.69-3.58 (m, 1H), 3.39-3.29 (m, 1H), 3.26 (t, J=5.3 Hz, 2H), 3.20-3.02 (m, 2H), 2.21-2.08 (m, 1H), 1.93-1.83 (m, 1H), 1.59 (bs, 1H), 1.12-0.95 (m, 21H).

Workup

  1. custompurge with nitrogen
  2. additiondilute with CH2Cl2 (11 mL)
  3. customAbsorb the reaction mixture on silica gel
  4. custompurify by silica gel flash chromatography

Sources & evidence

ORD record
ord-b49fb474786443809d1e616eb17a6ac0
Source dataset
uspto-grants-2011_03
Patent number
US07902356B2

Reaction notes

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