4-Methylmorpholine → HCID 86677793, compound

HRID 1499868Notes

Reaction equation

HRID 1499868 reaction equation
FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:26]([C:28]3[C:29]([O:47][CH2:48][CH3:49])=[C:30]([CH:37]4[CH2:40][N:39]([C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43])[CH2:38]4)[C:31]([C:35]#[N:36])=[C:32]([Cl:34])[CH:33]=3)[CH3:27])[N:23]=[C:24]([CH3:25])[C:17]=12.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:26]([C:28]3[CH:33]=[C:32]([Cl:34])[C:31]([C:35]#[N:36])=[C:30]([CH:37]4[CH2:40][N:39]([C:41]([CH3:45])([CH3:46])[CH2:42][OH:43])[CH2:38]4)[C:29]=3[O:47][CH2:48][CH3:49])[CH3:27])[N:23]=[C:24]([CH3:25])[C:17]=12

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 86677791HCID 86677791, compound

Product 1

HCID 86677793HCID 86677793, compoundYield 4.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-15 °C

Procedure

A solution of 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoic acid bis(trifluoroacetate) (0.10 g, 0.16 mmol) in tetrahydrofuran (0.9 mL) was cooled to −25° C., treated with 4-methylmorpholine (0.072 mL, 0.65 mmol) and isobutyl chloroformate (0.085 mL, 0.65 mmol), and stirred at −15° C. for 15 min. The reaction mixture was filtered though a disposable filter cartridge into a separate round bottom flask. This solution was then cooled to −20° C. and a solution of sodium tetrahydroborate (0.031 g, 0.82 mmol) in a minimum amount of water was added dropwise. The reaction mixture was stirred at −15° C. for 30 min, poured into water, and extracted with ethyl acetate. The organic layer was separated, concentrated, diluted with methanol, and purified by preparative LCMS (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 (3.5 mg, 4%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.50 (s, 1H), 7.35 (br s, 2H), 6.23 (q, J=6.7 Hz, 1H), 4.44-4.35 (m, 1H), 4.04-3.88 (m, 1H), 3.86-3.73 (m, 1H), 3.72-3.57 (m, 3H), 3.12 (d, J=4.7 Hz, 2H), 2.54 (s, 3H), 1.71 (d, J=6.9 Hz, 3H), 1.31 (t, J=6.9 Hz, 3H), 0.80 (s, 6H). LCMS for C24H31ClN7O2 (M+H)+: m/z=484.2; Found: 484.2.

Workup

  1. filtrationThe reaction mixture was filtered though a disposable filter cartridge into a separate round bottom flask
  2. temperatureThis solution was then cooled to −20° C.
  3. stirringThe reaction mixture was stirred at −15° C. for 30 min
  4. extractionextracted with ethyl acetate
  5. customThe organic layer was separated
  6. concentrationconcentrated
  7. additiondiluted with methanol
  8. custompurified by preparative LCMS (XBridge C18 column
  9. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min)

Sources & evidence

ORD record
ord-48eee3f33d81425888db141d3c7b5059
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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