Acetic Acid → N-{4-[4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]cyclohex-3-en-1-yl}-D-valine

HRID 1522005Notes

Reaction equation

HRID 1522005 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][C:20](=O)[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.C(N(CC)CC)C.C(O)(=O)C.Cl.[NH2:38][C@H:39]([CH:47]([CH3:49])[CH3:48])[C:40]([O:42]C(C)(C)C)=[O:41].C([BH3-])#N>ClCCl.ClCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][CH:20]([NH:38][C@@H:39]([C:40]([OH:42])=[O:41])[CH:47]([CH3:49])[CH3:48])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 8471TriethylamineHCID 498716Cyano-borohydrideHCID 45108216H-D-Val-OtBu hydrochlorideHCID 90413654US9796708, Example 805

Product 1

HCID 90412628N-{4-[4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]cyclohex-3-en-1-yl}-D-valine

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

To a mixture of Example 241B (125 mg, 0.372 mmol), triethylamine (0.114 mL, 0.818 mmol), acetic acid (0.106 mL, 1.858 mmol) and (R)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (0.401 mL, 1.858 mmol) in 4 mL 1:1 dichloromethane/methanol was added Biotage MP-cyanoborohydride resin (2.17 mmol/g, 678 mg, 1.487 mmol) and the mixture was shaken at room temperature overnight. The mixture was diluted with dichloromethane and the resin was filtered off, rinsing with dichloromethane and methanol. The crude material was purified by flash chromatography (Analogix280, eluting with a 0-4% methanol/dichloromethane gradient). The tert-butyl ester in 5 mL dichloromethane was treated with excess trifluoroacetic acid for 10 hours. The solvent was removed and the residue was dissolved in 5 mL methanol and treated with 2M hydrogen chloride in diethyl ether for 1 hour. The mixture was diluted with 50 mL diethyl ether and the solid was filtered and dried in vacuo to give the title compound as the hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 0.87-1.16 (m, 6H) 1.76-2.02 (m, 1H) 2.09-2.40 (m, 2H) 2.56-2.87 (m, 3H) 3.20-3.45 (m, 1H) 3.64-3.86 (m, 3H) 4.05 (s, 1H) 6.40 (s, 1H) 6.60 (s, 1H) 7.13-7.44 (m, 4H) 8.22-8.33 (m, 1H) 8.40 (d, J=1.83 Hz, 1H) 8.65-9.88 (m, 2H) 12.70 (d, J=3.97 Hz, 1H). MS (ESI): 438.1 (M+H)+.

Workup

  1. filtrationthe resin was filtered off
  2. washrinsing with dichloromethane and methanol
  3. customThe crude material was purified by flash chromatography (Analogix280
  4. washeluting with a 0-4% methanol/dichloromethane gradient)
  5. additionThe tert-butyl ester in 5 mL dichloromethane was treated with excess trifluoroacetic acid for 10 hours
  6. customThe solvent was removed
  7. dissolutionthe residue was dissolved in 5 mL methanol
  8. additiontreated with 2M hydrogen chloride in diethyl ether for 1 hour
  9. additionThe mixture was diluted with 50 mL diethyl ether
  10. filtrationthe solid was filtered
  11. customdried in vacuo

Sources & evidence

ORD record
ord-825383ae12224a719bb3aca19e7c4d0d
Source dataset
uspto-grants-2015_07
Patent number
US09073922B2

Reaction notes

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