Triethylamine → N-(4-(3-amino-4-hydroxycyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide

HRID 2046895Notes

Reaction equation

HRID 2046895 reaction equation
Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]2[CH2:33][CH:21]3[N:22](C(OC(C)(C)C)=O)C(=O)[O:24][CH:20]3[CH2:19][CH2:18]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:34].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:22][CH:21]1[CH:20]([OH:24])[CH2:19][CH2:18][CH:17]([C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:34])=[C:2]([C:37]3[C:36]([F:35])=[CH:41][CH:40]=[CH:39][C:38]=3[F:42])[N:7]=2)[CH2:33]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 27343362,6-Difluorophenylboronic acidHCID 59226599tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate

Product 1

HCID 59226417N-(4-(3-amino-4-hydroxycyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide

Reagents, catalysts & solvents 1

HCID 21863594Toluene ethanolSolvent

Procedure

A solution of tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv), 2,6-difluorophenyl boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting cyclic carbamate and Boc groups were deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, N-(4-(3-amino-4-hydroxycyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide as the TFA salt. LCMS (m/z): 443.2 (MH+); LC Rt=2.11 min.

Workup

  1. temperatureUpon cooling
  2. customremoval of the volatiles in vacuo
  3. customthe Suzuki product was directly purified by reverse phase HPLC
  4. customafter RP HPLC purification and lyophilization, N-(4-(3-amino-4-hydroxycyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide as the TFA salt

Sources & evidence

ORD record
ord-91e046e1b6f644df91ffa3e7b4e4e7f1
Source dataset
uspto-grants-2013_11
Patent number
US08592455B2

Reaction notes

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