Cesium carbonate → (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester

HRID 1404222Notes

Reaction equation

HRID 1404222 reaction equation
[F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14](=[O:35])[CH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][O:13][C:14](=[O:35])[CH2:15][CH:16]1[CH2:17][CH2:18][CH:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[N:32][C:31]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=4)=[N:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:20][CH2:21]1

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 27377445-Amino-2-(trifluoromethyl)pyridineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86634684HCID 86634684, compound

Product 1

HCID 66615828(4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
150 °C

Procedure

To a glass vial add 6-trifluoromethyl-pyridin-3-ylamine (35 mg, 0.217 mmol), {4-[4-(2-chloro-pyrimidin-5-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (50 mg, 0.145 mmol), Pd(OAc)2(5 mg, 5% mol), X-Phos (7 mg, 10% mol), and Cs2CO3 (118 mg, 0.363 mmol). Flush with N2. Add tBuOH (0.25 mL), toluene (0.75 mL), and seal the tube. The reaction mixture is heated to 150° C. for 30 min by microwave irradiation. The reaction is diluted with EtOAc and filtered. The filtrate is concentrated and chromatographed on silica gel (25-50% EtOAc/Hexanes) to afford (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester as 90% pure. (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (45 mg, 0.096 mmol) is taken up in DMF (1.5 mL) and 4 M LiOH (0.5 mL) and stirred at room temperature for 16 h. The reaction is heated to 50° C. for 12 h and then heated to 70° C. for 8 h. The reaction is diluted with 1 N HCl (2 mL) and H2O (2 mL). The precipitate is collected by filtration and purified by HPLC (Xterra C8 30×100 mm, 22-50% ACN/H2O+ 5 mM NH4OH) to afford (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.18 (m, 2 H) 1.43-1.56 (m, J=12.95, 12.66, 12.66, 3.16 Hz, 2H) 1.68-1.87 (m, 6 H) 2.08 (d, J=6.57 Hz, 2 H) 7.35 (d, J=8.34 Hz, 2 H) 7.65 (d, J=8.34 Hz, 2 H) 7.85 (d, J=8.59 Hz, 1 H) 8.55 (dd, J=8.59, 2.02 Hz, 1 H) 8.91 (s, 2 H) 9.06 (d, J=2.27 Hz, 1 H) 10.42 (s, 1 H); (M+H)+ 457.0.

Workup

  1. customFlush with N2
  2. customAdd tBuOH (0.25 mL), toluene (0.75 mL), and seal the tube
  3. additionThe reaction is diluted with EtOAc
  4. filtrationfiltered
  5. concentrationThe filtrate is concentrated
  6. customchromatographed on silica gel (25-50% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-9989bd30148b4dec8dc245f523be93bc
Source dataset
uspto-grants-2014_12
Patent number
US08912208B2

Reaction notes

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