Nitrogen → 1-[5-(3-[(2,2,2-Trifluoroethyl)amino]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol

HRID 1040029Notes

Reaction equation

HRID 1040029 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=3)[CH:12]=[C:13]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:14]=2)O1.Br[C:34]1[S:38][C:37]([C:39]2([OH:43])[CH2:42][CH2:41][CH2:40]2)=[N:36][CH:35]=1.N#N.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.ClCCl>[F:20][C:17]([F:19])([F:18])[CH2:16][NH:15][C:13]1[CH:14]=[C:9]([C:34]2[S:38][C:37]([C:39]3([OH:43])[CH2:42][CH2:41][CH2:40]3)=[N:36][CH:35]=2)[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][N:23]=2)[CH:12]=1

Participants

8

Reactant 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 58456224HCID 58456224, compoundHCID 866730095-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)-N'-[4-(trifluoromethyl)pyrimidin-2-yl]benzene-1,3-diamine

Product 1

HCID 584564091-[5-(3-[(2,2,2-Trifluoroethyl)amino]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanolYield 69%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of the product of Step 4 (50 mg, 0.108 mmol), PdCl2(dppf) (as the dichloromethane adduct; 4.42 mg, 5.41 μmol) and Intermediate 1 (27.9 mg, 0.119 mmol) was degassed (alternating vacuum-N2 cycles). Dioxane (0.3 mL) and Na2CO3 (2.0 M, 162 μL, 0.325 mmol) were added. The mixture was degassed again and stirred at 85° C. for 2 hrs. The mixture was cooled to room temperature, diluted with ethyl acetate and gravity filtered on celite. After in vacuo concentration, the residue was purified by Chromatography on silica gel (0-100% ethyl acetate in hexanes) then briefly triturated in hexanes to give the 1-[5-(3-[(2,2,2-trifluoroethyl)amino]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol (36.4 mg, 0.074 mmol, 69% yield) as a white solid. MS ESI: [M+H]+ m/z 490.0. 1H NMR (500 MHz, CD3OD) δ 8.73 (d, J=4.9, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 7.15 (d, J=4.9, 1H), 6.69 (s, 1H), 3.88 (q, 9.2, 2H), 2.79-2.67 (m, 2H), 2.67-2.36 (m, 2H), 2.12-1.92 (m, 2H).

Workup

  1. customThe mixture was degassed again
  2. temperatureThe mixture was cooled to room temperature
  3. additiondiluted with ethyl acetate and gravity
  4. filtrationfiltered on celite
  5. concentrationAfter in vacuo concentration
  6. customthe residue was purified by Chromatography on silica gel (0-100% ethyl acetate in hexanes)
  7. customthen briefly triturated in hexanes

Sources & evidence

ORD record
ord-929dfd2d0f5a4204abdebe25d1683724
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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