Triethylamine → (2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol

HRID 1499808Notes

Reaction equation

HRID 1499808 reaction equation
Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH2:29][CH3:30])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[CH3:38][C@H:39]1[CH2:41][O:40]1>C(O)(C)C.C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH2:29][CH3:30])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:38][C@@H:39]([OH:40])[CH3:41])[CH2:6]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 146262(2S)-2-MethyloxiraneHCID 866777291-[1-(3-Azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride

Product 1

HCID 71510103(2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-olYield 23.6%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
90 °C

Procedure

To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (46 mg, 0.11 mmol) (from isomer 1) and triethylamine (50 μL, 0.4 mmol) in isopropyl alcohol (0.3 mL) was added (S)-(−)-methyloxirane (16 μL, 0.23 mmol). The resulting mixture was stirred at 90° C. for 3 h. After cooling, the mixture was diluted with acetonitrile and purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (12 mg, 23%). The product was isolated as a single diastereomer. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.38 (d, 1H), 6.15 (m, 1H), 4.26 (d, 1H), 3.76-3.60 (m, 6H), 2.99 (m, 2H), 2.48 (s, 3H), 2.22 (m, 2H), 1.62 (d, 3H), 1.25 (t, 3H), 0.93 (d, 3H) ppm; LCMS calculated for C22H29ClFN6O2 (M+H)+: m/z=463.2; Found: 463.2.

Workup

  1. temperatureAfter cooling
  2. custompurified by RP-HPLC (XBridge C18 column
  3. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min)

Sources & evidence

ORD record
ord-8cfa215b12fa4946b4be1cf13469f835
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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