Cesium carbonate → diethyl (4-{[4-({6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyridin-2-yl]amino}-3-methoxybenzyl)phosphonate

HRID 2279814Notes

Reaction equation

HRID 2279814 reaction equation
Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([C:24]([NH:26][CH3:27])=[O:25])=[N:11][C:12]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=3)=[CH:13][CH:14]=2)[C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][N:3]=1.[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=1[O:48][CH3:49].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[OH:23][CH2:22][CH2:21][CH2:20][N:18]1[CH:19]=[C:15]([C:12]2[N:11]=[C:10]([C:24](=[O:25])[NH:26][CH3:27])[C:9]([NH:8][C:6]3[C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][N:3]=[C:2]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[CH:7]=3)=[CH:14][CH:13]=2)[CH:16]=[N:17]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86653997Diethyl(4-amino-3-methoxybenzyl)phosphonate2×HCID 86697755HCID 86697755, compound2×

Product 1

HCID 86697754diethyl (4-{[4-({6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyridin-2-yl]amino}-3-methoxybenzyl)phosphonateYield 11.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 3-{[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino}-6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 36C, 158 mg, 0.35 mmol) and diethyl (4-amino-3-methoxybenzyl)phosphonate (Compound 1F, 104 mg, 0.38 mmol) in 1,4-dioxane (4.0 mL) was treated with Pd(II)(OAc)2 (3.90 mg, 0.017 mmol), Xantphos (20.1 mg, 0.035 mmol) and Cs2CO3 (226 mg, 0.70 mmol). The mixture was purged with N2 for 2 minutes, sealed and irradiated in a microwave reactor for 40 minutes at 120° C. The cooled reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to a brown residue which was taken purified using a Teledyne ISCO Combiflash® system (0%-5%-10% MeOH/DCM) to afford 27 mg of a brown foam (11%). 1H NMR (400 MHz, CDCl3) δ 10.91 (s, 1H), 8.38 (s, 1H), 8.23 (q, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.86-6.94 (m, 3H), 6.70 (s, 1H), 4.38 (t, J=6.3 Hz, 2H), 3.93-4.05 (m, 4H), 3.88 (s, 3H), 3.66 (q, J=5.5 Hz, 2H), 3.12 (d, J=21.2 Hz, 2H), 3.06 (d, J=5.1 Hz, 3H), 2.79 (t, J=5.2 Hz, 1H), 2.13 (quin, J=6.1 Hz, 2H), 1.21 (t, J=7.0 Hz, 6H).

Workup

  1. customThe mixture was purged with N2 for 2 minutes
  2. customsealed
  3. customirradiated in a microwave reactor for 40 minutes at 120° C
  4. customThe cooled reaction mixture
  5. extractionextracted twice with EtOAc
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated to a brown residue which
  10. customwas taken purified

Sources & evidence

ORD record
ord-5f05bbf3a0fd4e60b12d4b430320f094
Source dataset
uspto-grants-2015_09
Patent number
US09133224B2

Reaction notes

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