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

HRID 1040029ノート

反応式

HRID 1040029 の反応式
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

参加物

8

反応物 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 6344Dichloromethane溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
85 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-929dfd2d0f5a4204abdebe25d1683724
出典データセット
uspto-grants-2013_10
特許番号
US08551984B2

反応ノート

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