Acetic Acid → N-{4-[4-(5-fluoro-2-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]cyclohex-3-en-1-yl}-3-methyl-L-valine

HRID 528008Notes

Reaction equation

HRID 528008 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][C:20](=O)[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.C(N(CC)CC)C.C(O)(=O)C.Cl.[NH2:38][C@@H:39]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42]C(C)(C)C)=[O:41]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][CH:20]([NH:38][C@H:39]([C:40]([OH:42])=[O:41])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 8471TriethylamineHCID 56776989tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochlorideHCID 904185524-(4-(5-fluoro-2-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)cyclohex-3-enone

Product 1

HCID 86271570N-{4-[4-(5-fluoro-2-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]cyclohex-3-en-1-yl}-3-methyl-L-valine

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a mixture of Example 83B (100 mg, 0.296 mmol), triethylamine (0.091 mL, 0.652 mmol), and acetic acid (0.085 mL, 1.482 mmol) in dichloromethane (3 mL) was added (S)-tert-butyl 2-amino-3,3-dimethylbutanoate hydrochloride (133 mg, 0.593 mmol) and MP-(CN)BH3 resin (Biotage, 2.17 mmol/g, 546 mg, 1.186 mmol). The reaction mixture was shaken on an orbital shaker overnight. The reaction mixture was diluted with 5 mL dichloromethane and the resin filtered off, rinsing with dichloromethane and methanol. The crude material was purified via column chromatography: Analogix Intelliflash™ 280, 12 g silica cartridge, 0-4% methanol/dichloromethane gradient over 30 minutes. The material was dissolved in 5 mL dichloromethane and treated with excess trifluoroacetic acid and stirred at room temperature overnight. The volatiles were removed in vacuo, the residue was dissolved in 5 mL methanol, and the mixture was treated with excess 2 M HCl/diethyl ether. The solution was stirred at room temperature for 20 minutes and then diluted with diethyl ether. The resultant solid was collected by filtration and dried under high vacuum to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H) 8.80-9.10 (m, 3H) 8.36 (s, 1H) 7.46-7.57 (m, 2H) 7.27-7.39 (m, 1H) 6.60-6.78 (m, 2H) 4.02 (d, J=10.07 Hz, 1H) 3.76-3.88 (m, 3H) 3.51-3.61 (m, 1H) 3.15-3.36 (m, 2H) 2.57-2.93 (m, 2H) 2.34 (s, 1H) 1.99-2.16 (m, 1H) 1.78-1.98 (m, 1H) 1.15 (s, 9H). MS (ESI+) m/z 453.2 (M+H)+.

Workup

  1. filtrationthe resin filtered off
  2. washrinsing with dichloromethane and methanol
  3. customThe crude material was purified via column chromatography
  4. waitAnalogix Intelliflash™ 280, 12 g silica cartridge, 0-4% methanol/dichloromethane gradient over 30 minutes
  5. dissolutionThe material was dissolved in 5 mL dichloromethane
  6. additiontreated with excess trifluoroacetic acid
  7. stirringstirred at room temperature overnight
  8. customThe volatiles were removed in vacuo
  9. dissolutionthe residue was dissolved in 5 mL methanol
  10. additionthe mixture was treated with excess 2 M HCl/diethyl ether
  11. stirringThe solution was stirred at room temperature for 20 minutes
  12. additiondiluted with diethyl ether
  13. filtrationThe resultant solid was collected by filtration
  14. customdried under high vacuum

Sources & evidence

ORD record
ord-d6420ed201f6416aaeca151bd927f84b
Source dataset
uspto-grants-2016_05
Patent number
US09346813B2

Reaction notes

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