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

HRID 1749412Notes

Reaction equation

HRID 1749412 reaction equation
[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]

Participants

10

Reactant 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

Product 1

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

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
25 °C

Procedure

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]+.

Workup

  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

Sources & evidence

ORD record
ord-46e8a7ecb2114709bf3ddfc698e0551c
Source dataset
uspto-grants-2015_10
Patent number
US09156798B2

Reaction notes

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