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

HRID 1931629Notes

Reaction equation

HRID 1931629 reaction equation
ClC(OC(C)C)=O.FC(F)(F)C(O)=O.FC1C(OC2N=CN=C3N(C4CCNCC4)N=CC=23)=C(C=CC=1F)C#N.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([N:54]2[C:58]3=[N:59][CH:60]=[N:61][C:62]([O:63][C:64]4[C:69]([C:70]#[N:71])=[CH:68][CH:67]=[C:66]([F:72])[C:65]=4[F:73])=[C:57]3[CH:56]=[N:55]2)[CH2:50][CH2:49]1)=[O:47])(C)([CH3:43])[CH3:42].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:41]([O:45][C:46]([N:48]1[CH2:49][CH2:50][CH:51]([N:54]2[C:58]3=[N:59][CH:60]=[N:61][C:62]([O:63][C:64]4[C:69]([C:70]#[N:71])=[CH:68][CH:67]=[C:66]([F:72])[C:65]=4[F:73])=[C:57]3[CH:56]=[N:55]2)[CH2:52][CH2:53]1)=[O:47])([CH3:43])[CH3:42]

Participants

8

Reactant 5

HCID 7917Isopropyl chloroformateHCID 81531DiisopropylethylamineHCID 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 579649534-[4-(6-Cyano-2,3-difluoro-phenoxy)-pyrazolo-[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl esterYield 85%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Isopropyl chloroformate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 1M in toluene; 0.35 mL, 0.35 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; 180 mg, 0.35 mmol), diisopropylethylamine (136 mg, 1.06 mmol) in dichloromethane (6 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 isopropyl ester (147 mg, 85%) as a white solid. Mass spectrum MH+=443.

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-948ea6ec3e0e4e2cbd2967d533652021
Source dataset
uspto-grants-2012_05
Patent number
US08188098B2

Reaction notes

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