Formaldehyde → HCID 44467683, compound

HRID 2046967Notes

Reaction equation

HRID 2046967 reaction equation
[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(O[C:47]([N:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[C:54](O)=[O:55])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C=O.C([BH3-])#N.[Na+]>CN(C=O)C.CO.C1COCC1.CC(O)=O>[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:20][CH2:21][N:22]([C:54]([C@@H:50]5[CH2:51][CH2:52][CH2:53][N:49]5[CH3:47])=[O:55])[CH2:23][CH2:24]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1

Participants

11

Reactant 6

HCID 712FormaldehydeHCID 81531DiisopropylethylamineHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 5003444Sodium cyanoborohydrideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 248164386-(5-Chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one

Product 1

HCID 44467683HCID 44467683, compound

Reagents, catalysts & solvents 4

HCID 176Acetic AcidCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(piperidin-4-yl)isoindolin-1-one (52 mg, 0.09 mmol) in DMF (1.0 mL) was added (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (19 mg, 0.09 mmol), HATU (50 mg, 0.130 mmol), and DIEA (0.174 mmol, 30 μL) sequentially. The reaction mixture was stirred for 1 h, then partitioned between EtOAc and water. The organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was stirred in a solution of DCM (1 mL) and TFA (1 mL) for 1 h, then concentrated in vacuo. To the solution of the resulting crude product in 1 mL of MeOH and 1 mL of THF was added 3 drops of AcOH, formaldehyde (37 wt. % solution in water, 0.09 mmol, 7 mg). After stirring for 1 h, sodium cyanoborohydride (0.18 mmol, 11 mg) was added, and the reaction mixture was stirred for another 30 min. The reaction mixture was filtered and the resulting filtrate was purified by preparative RP-HPLC to afford (S)-6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)-pyrimidin-2-ylamino)-5-isopropoxy-2-(1-(1-methylpyrrolidine-2-carbonyl)piperidin-4-yl)isoindolin-1-one.

Workup

  1. custompartitioned between EtOAc and water
  2. dry with materialThe organic extracts were dried (Na2SO4)
  3. concentrationconcentrated in vacuo
  4. stirringThe crude product was stirred in a solution of DCM (1 mL) and TFA (1 mL) for 1 h
  5. concentrationconcentrated in vacuo
  6. stirringAfter stirring for 1 h
  7. stirringthe reaction mixture was stirred for another 30 min
  8. filtrationThe reaction mixture was filtered
  9. customthe resulting filtrate was purified by preparative RP-HPLC

Sources & evidence

ORD record
ord-421fa489f1864d89b206dfa6ceeffdf5
Source dataset
uspto-grants-2013_11
Patent number
US08592432B2

Reaction notes

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