Dichloromethane → [(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamic acid benzyl ester

HRID 2089346Notes

Reaction equation

HRID 2089346 reaction equation
[CH2:1]([O:8][C:9](=[O:41])[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28](Br)[S:29][C:30]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C)C=O>[CH2:1]([O:8][C:9](=[O:41])[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:40])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:46]3[CH:45]=[CH:44][C:43]([F:42])=[CH:48][C:47]=3[F:49])[S:29][C:30]=2[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 162176522-(2,4-Difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 58464869((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester

Product 1

HCID 58464864[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamic acid benzyl esterYield 56.7%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Procedure

In a microwave vial was placed ((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester (78.2 mg, 0.12 mmol), 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101.3 mg, 0.42 mmol, 3.5 eq.), cesium carbonate (196.4 mg, 0.60 mmol, 5.0 eq), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexed with dichloromethane (1:1) (29.5 mg, 0.036 mmol, 0.30 eq), and anhydrous N,N-dimethylformamide (3.5 mL). The reaction mixture was degassed with N2 for 10 minutes and then subjected to microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and then filtered through a pad of Celite. The filtrate was washed with 50% brine/water, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via flash column chromatography eluted with 40 to 100% ethyl acetate/heptane to give 46.4 mg (56.5%) of desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.63 (s, 1H), 8.14-8.04 (m, 1H), 7.82 (s, 1H), 7.31 (s, 5H), 7.03-6.87 (m, 2H), 5.11-5.00 (s, 2H), 4.84-4.74 (m, 1H), 3.95-3.85 (m, 1H), 3.74 (s, 3H), 3.35-3.24 (m, 2H), 3.23-3.11 (m, 2H), 2.18-2.03 (m, 2H), 1.97-1.65 (m, 4H), 1.53 (s, 9H); MS (ESI) m/z: 682.6 [M+H]+.

Workup

  1. customThe reaction mixture was degassed with N2 for 10 minutes
  2. customirradiation at 100° C. for 30 minutes
  3. additionThe reaction mixture was diluted with ethyl acetate (50 mL)
  4. filtrationfiltered through a pad of Celite
  5. washThe filtrate was washed with 50% brine/water, water and brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude was purified via flash column chromatography
  10. washeluted with 40 to 100% ethyl acetate/heptane

Sources & evidence

ORD record
ord-8b77741911ac4298bc24ab38ae36c3d4
Source dataset
uspto-grants-2013_05
Patent number
US08436001B2

Reaction notes

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