Diisopropylethylamine → 4-[4-(6-Cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester

HRID 1931724Notes

Reaction equation

HRID 1931724 reaction equation
Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].FC(F)(F)C(O)=O.[F:17][C:18]1[C:19]([O:27][C:28]2[N:33]=[CH:32][N:31]=[C:30]3[N:34]([CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[N:35]=[CH:36][C:29]=23)=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[C:21]#[N:22].C(OC(N1CCC(N2C3=NC=NC(OC4C(C#N)=CC=C(F)C=4F)=C3C=N2)CC1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC1C=CC(OC2N=CN=C3N(C4CCNCC4)N=CC=23)=C(F)C=1)C.C(N(C(C)C)CC)(C)C>ClCCl.O>[CH:5]1([O:4][C:2]([N:40]2[CH2:39][CH2:38][CH:37]([N:34]3[C:30]4=[N:31][CH:32]=[N:33][C:28]([O:27][C:19]5[C:20]([C:21]#[N:22])=[CH:23][CH:24]=[C:25]([F:26])[C:18]=5[F:17])=[C:29]4[CH:36]=[N:35]3)[CH2:42][CH2:41]2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 2735892Cyclopentyl chloroformateHCID 579649274-[4-(6-Cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl esterHCID 669153124-(4-ethoxy-2-fluoro-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate saltHCID 690162343,4-difluoro-2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate salt

Product 1

HCID 579650264-[4-(6-Cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl esterYield 90%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Cyclopentyl chloroformate (3B Scientific Corporation, Libertyville, Ill., USA; 46 mg, 0.31 mmol) was added to a mixture of 3,4-difluoro-2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate salt (which was prepared from 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester [Example 49] following the procedure described for the preparation of Intermediate 29; 145 mg, 0.31 mmol), diisopropylethylamine (120 mg, 0.93 mmol) in dichloromethane (10 mL). The reaction was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (130 mg, 90%) as a white solid. Mass spectrum MH+=469.

Workup

  1. customto quench
  2. customthe reaction
  3. extractionthe aqueous layer was extracted three times with dichloromethane
  4. dry with materialThe combined organic layers were dried (sodium sulfate)
  5. filtrationfiltered
  6. customevaporated
  7. custompurified by flash chromatography on silica gel
  8. washeluting with 4% methanol/dichloromethane

Sources & evidence

ORD record
ord-2d14622cf0bd4b869419b94860cc3554
Source dataset
uspto-grants-2012_05
Patent number
US08188098B2

Reaction notes

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