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

HRID 1040029노트

반응식

HRID 1040029 반응식
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

참가 물질

8

반응물 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 584562241-(5-Bromothiazol-2-yl)cyclobutanolHCID 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

생성물 1

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

시약·촉매·용매 3

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 6344Dichloromethane용매HCID 312751,4-Dioxane용매

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온도
85 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-929dfd2d0f5a4204abdebe25d1683724
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08551984B2

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