Lithium Chloride → HCID 86684828, compound

HRID 1853129Notes

Reaction equation

HRID 1853129 reaction equation
Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:16][C:17]2([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C[Sn](C)C.C[Sn](C)C.[Li+].[Cl-].Br[C:39]1[S:40][C:41]([CH2:44][C:45]#[N:46])=[CH:42][N:43]=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O1CCOCC1>[C:11]([O:10][C:9](=[O:15])[N:8]([CH2:16][C:17]1([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19][CH2:18]1)[C:5]1[N:4]=[CH:3][C:2]([C:39]2[S:40][C:41]([CH2:44][C:45]#[N:46])=[CH:42][N:43]=2)=[CH:7][N:6]=1)([CH3:14])([CH3:13])[CH3:12]

Participants

9

Reactant 4

HCID 433294Lithium ChlorideHCID 6327618HexamethylditinHCID 67452886(2-Bromo-1,3-thiazol-5-yl)acetonitrileHCID 68232591HCID 68232591, compound

Product 1

HCID 86684828HCID 86684828, compoundYield 20.3%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalyst2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a 50 mL round bottom flask was added t-butyl 5-bromopyrimidin-2-yl((1-(3-chloropyridin-2-yl)cyclobutyl)methyl)carbamate (1.0 g, 2.2 mmol), Pd(PPh3)4 (0.25 g, 0.22 mmol), hexamethylditin (0.92 mL, 2.2 mmol), LiCl (0.25 g, 5.9 mmol), and dioxane (10 mL). The mixture was heated to 90° C. for 1 h. To the resultant dark brown solution was added 2-(2-bromothiazol-5-yl)acetonitrile (0.89 g, 4.4 mmol), Pd(PPh3)4 (0.076 g, 0.066 mmol), and CuI (4.2 g, 22.2 mmol). The reaction mixture was stirred at 90° C. for 1 h. The reaction was then cooled to rt, diluted with ethyl acetate (50 mL), and filtered through Celite. The filtrate was washed with water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 222 mg of t-butyl(1-(3-chloropyridin-2-yl)cyclobutyl)methyl(5-(5-(cyanomethyl)thiazol-2-yl)pyrimidin-2-yl)carbamate as a viscous brown oil. To this compound was added potassium carbonate (185 mg, 1.3 mmol) and DMSO (3 mL). The mixture was cooled to 0° C. and hydrogen peroxide (0.5 mL) was slowly added. The reaction was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc (75 mL) and washed three times with brine (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by reverse phase chromatography to afford 48 mg of t-butyl 5-(5-(2-amino-2-oxoethyl)thiazol-2-yl)pyrimidin-2-yl((1-(3-chloropyridin-2-yl)cyclobutyl)methyl)carbamate as a white solid. This compound was dissolved in 25% TFA/CH2Cl2 and stirred for 10 min. The reaction was then concentrated, dissolved in ethyl acetate (75 mL), and washed three times with saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4, filtered, and concentrated to give 39 mg of 2-(2-(24(1-(3-chloropyridin-2-yl)cyclobutyl)methylamino)pyrimidin-5-yl)thiazol-5-yl)acetamide as a white solid (M+H=415.1).

Workup

  1. temperatureThe reaction was then cooled to rt
  2. filtrationfiltered through Celite
  3. washThe filtrate was washed with water (30 mL) and brine (30 mL)
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. custompurified by silica gel chromatography (EtOAc/hex)

Sources & evidence

ORD record
ord-9511be5a5bfe4ac282404c1d4768404a
Source dataset
uspto-grants-2015_02
Patent number
US08962632B2

Reaction notes

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