Toluene → 4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester

HRID 1931630노트

반응식

HRID 1931630 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OC(C)C)=O.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O.ClCCl.O1CCCC1>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]

참가 물질

8

반응물 4

HCID 1140TolueneHCID 7917Isopropyl chloroformateHCID 8471TriethylamineHCID 532576834-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

생성물 1

HCID 444698194-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester수율 61%

시약·촉매·용매 3

HCID 6344Dichloromethane용매HCID 6422Trifluoroacetic acid용매HCID 8028Tetrahydrofuran용매

실험 절차

A solution of 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 59; 400 mg, 0.84 mmol) in a mixture of trifluoroacetic acid (3 mL) and dichloromethane (7 mL) was stirred at room temperature for 45 min. The solvents were evaporated and the residue was co-evaporated three times with dichloromethane, dried under high vacuum, and then diluted with 1M aqueous sodium carbonate solution. The mixture was extracted twice with dichloromethane and twice with 10% methanol/chloroform. The combined organic layers were dried (sodium sulfate) and evaporated. A solution of the residue in tetrahydrofuran (6 mL) and triethylamine (0.23 mL, 1.65 mmol) was cooled to −20° C. under nitrogen and a solution of isopropyl chloroformate in toluene (1 M; 0.8 mL, 0.8 mmol) was added. The mixture was stirred at −10° C. to −20° C. for 45 min, then allowed to reach room temperature, and then filtered through a Millipore filter. The filter was washed with tetrahydrofuran and ethyl acetate and the combined filtrate and washings were evaporated. The crude material was purified on a flash silica column (30 mm×4″) eluting with 75-83% ethyl acetate/hexanes to give 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (235 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, 6H, J=6.3 Hz), 1.92-2.04 (m, 4H), 2.98-3.12 (m, 2H), 3.28-3.30 (m, methyl sulfone and water peak), 4.07-4.15 (m, 2H), 4.75-4.84 (m, 1H), 4.96-5.05 (m, 1H), 7.60-7.63 (m, 2H), 8.02-8.05 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum (ES) MH+=460.

후처리

  1. customThe solvents were evaporated
  2. customdried under high vacuum
  3. additiondiluted with 1M aqueous sodium carbonate solution
  4. extractionThe mixture was extracted twice with dichloromethane and twice with 10% methanol/chloroform
  5. dry with materialThe combined organic layers were dried (sodium sulfate)
  6. customevaporated
  7. stirringThe mixture was stirred at −10° C. to −20° C. for 45 min
  8. customto reach room temperature
  9. filtrationfiltered through a Millipore
  10. filtrationfilter
  11. washThe filter was washed with tetrahydrofuran and ethyl acetate
  12. customthe combined filtrate and washings were evaporated
  13. customThe crude material was purified on a flash silica column (30 mm×4″)
  14. washeluting with 75-83% ethyl acetate/hexanes

출처 및 근거

ORD 기록
ord-1ef376c203af44ea9747c08c9b69e53d
출처 데이터셋
uspto-grants-2012_05
특허 번호
US08188098B2

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