2-Cyano-4-methylpent-2-enoic acid → 2-[2-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile

HRID 1778436Notes

Reaction equation

HRID 1778436 reaction equation
[C:1]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:4]([OH:6])=O)#[N:2].[NH:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([NH2:25])=[C:19]2[C:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][C:27]=2[F:39])=[N:17]1.C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:25][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:16]([CH2:15][CH:12]3[CH2:13][CH2:14][N:11]3[C:4]([C:3](=[CH:7][CH:8]([CH3:10])[CH3:9])[C:1]#[N:2])=[O:6])[N:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:28][C:27]=3[F:39])[C:19]=12

Participants

5

Reactant 3

HCID 2925472-Cyano-4-methylpent-2-enoic acidHCID 11038641((7-Azabenzotriazol-1-YL)oxy)tris(pyrrolidino)phosphonium hexafluorophosphateHCID 900012121-(Azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine

Product 1

HCID 1240076262-[2-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrileYield 39.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-cyano-4-methyl-pent-2-enoic acid (30.7 mg, 0.220 mmol), 1-(azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (57.5 mg, 0.150 mmol in DCM (2 mL) was added PyAOP (86.2 mg, 0.160 mmol) and TEA (0.06 mL, 0.440 mmol) and the resulting yellow solution stirred at rt for 1 h. LCMS showed that the reaction was complete and the crude mixture was directly loaded onto a silica gel cartridge for purification (3 to 5% MeOH: CH2Cl2). Removal of solvent from cleanest fractions afforded 30 mg of the desired compound 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile (30 mg, 0.0586 mmol, 39.8% yield) as judged by LCMS. (M+1=512).

Workup

  1. customthe crude mixture was directly loaded onto a silica gel cartridge for purification (3 to 5% MeOH: CH2Cl2)
  2. customRemoval of solvent from cleanest fractions

Sources & evidence

ORD record
ord-ec27c3c6939a4a0bbe57bf509723e84f
Source dataset
uspto-grants-2016_02
Patent number
US09266895B2

Reaction notes

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