Potassium Carbonate → (1S,3R)-3-(2-((4-Isopropylpyrimidin-5-yl)methylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)-2,2-dimethylcyclobutanol

HRID 1749412Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1749412
[CH3:1][C:2]1([CH3:20])[C@H:5]([NH:6][C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:10]=[C:9](SC)[N:8]=2)[CH2:4][C@@H:3]1[OH:19].ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+].CC1(C)[C@H](NC2C(C(F)(F)F)=CN=C(S(C)(=O)=O)N=2)C[C@@H]1O.CCN(C(C)C)C(C)C.Cl.Cl.[CH:71]([C:74]1[C:79]([CH2:80][NH2:81])=[CH:78][N:77]=[CH:76][N:75]=1)([CH3:73])[CH3:72]>C1COCC1.C(OCC)(=O)C.O1CCOCC1>[CH:71]([C:74]1[C:79]([CH2:80][NH:81][C:9]2[N:8]=[C:7]([NH:6][C@@H:5]3[CH2:4][C@H:3]([OH:19])[C:2]3([CH3:20])[CH3:1])[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:10]=2)=[CH:78][N:77]=[CH:76][N:75]=1)([CH3:73])[CH3:72]

Komponenten

10

Edukt 6

HCID 11430Potassium CarbonateHCID 70297m-Chloroperbenzoic acidHCID 81531DiisopropylethylamineHCID 118162070(4-Isopropylpyrimidin-5-yl)methanamine dihydrochlorideHCID 118162086(1S,3R)-2,2-dimethyl-3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutanolHCID 118162153(1S,3R)-2,2-Dimethyl-3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutanol

Produkt 1

HCID 118162201(1S,3R)-3-(2-((4-Isopropylpyrimidin-5-yl)methylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)-2,2-dimethylcyclobutanolAusbeute 39 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 8028TetrahydrofuranLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittel2×

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

In a round-bottomed flask, (1S,3R)-2,2-dimethyl-3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutanol (1.0 equiv.) and 3-chlorobenzoperoxoic acid (2.0 equiv.) were combined in THF (0.5 M). The reaction was stirred at 25° C. for 45 min. The mixture was diluted with ethyl acetate. To this solution was added potassium carbonate (4.0 equiv.). The mixture was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated to afford the crude product. A solution of (1S,3R)-2,2-dimethyl-3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutanol (1.0 equiv.), DIEA (3.0 equiv.) and (4-isopropylpyrimidin-5-yl)methanamine dihydrochloride (1.5 equiv.) were combined in dioxane (0.4 M) and stirred at ambient temperature. Additional dioxane was added to ensure solubility. After 1 h at room temperature, LCMS indicated the presence of some product. After 12 h, the reaction was heated to 75° C. for 6 h. Standard work-up afforded the title compound (39% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.97 (s, 1H) 8.32-8.68 (m, 1H) 8.03 (s, 1H) 7.26-7.93 (m, 1H) 6.07 (d, J=7.03 Hz, 1H) 4.79 (m, 1H) 4.54 (br. s., 2H) 3.80-3.96 (m, 1H) 3.37-3.59 (m, 1H) 2.15-2.41 (m, 1H) 2.05 (m, 1H) 1.06-1.24 (m, 6H) 0.67-0.92 (m, 6H); MS(ESI) m/z 411.3[M+1]+.

Aufarbeitung

  1. stirringThe mixture was stirred at room temperature for 30 min
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated
  4. customto afford the crude product
  5. stirringstirred at ambient temperature
  6. waitAfter 1 h at room temperature
  7. waitAfter 12 h
  8. temperaturethe reaction was heated to 75° C. for 6 h

Quellen und Nachweise

ORD-Eintrag
ord-46e8a7ecb2114709bf3ddfc698e0551c
Quelldatensatz
uspto-grants-2015_10
Patentnummer
US09156798B2

Notizen zur Reaktion

Wird geladen…