Dichloromethane → HCID 135409602, compound

HRID 2078722Notes

Reaction equation

HRID 2078722 reaction equation
C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]3)[CH:15]=2)[CH:10]=[C:9]1[C:28]1[C:29]2[S:42][C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:40][C:30]=2[N:31](C(OC(C)(C)C)=O)[N:32]=1)=O)(C)(C)C.C1(OC)C=CC=CC=1.ClCCl.FC(F)(F)C(O)=O>CO.CCOCC.CO>[C:43]1([C:41]2[S:42][C:29]3[C:28]([C:9]4[NH:8][C:16]5[C:11]([CH:10]=4)=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]4)[CH:15]=5)=[N:32][NH:31][C:30]=3[CH:40]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 7519AnisoleHCID 67098505HCID 67098505, compound

Product 1

HCID 135409602HCID 135409602, compoundYield 75%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 21864698Diethyl ether methanolSolvent

Conditions

Temperature
45 °C

Procedure

A mixture of 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [300 mg, 0.460 mmol, Intermediate (50)], 3-hydroxypiperidine (73.0 mg, 0.722 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (39.0 mg, 0.235 mmol), and anhydrous acetonitrile (5 mL) was heated at 70° C. with shaking at 200 rpm. After 20 hours, the reaction was cooled to ambient temperature, filtered, the insolubles washed with dichloromethane/methanol (5:1), and the filtrate concentrated under reduced pressure to give a dark residue. The residue was chromatographed on silica, eluting with 20% methanol/dichloromethane (20 mL) followed by 1 M ammonia in methanol/dichloromethane 1:9 (30 mL), to give 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-[3-(3-hydroxy-piperidin-1-yl)-propoxy]-indole-1-carboxylic acid tert-butyl ester (329 mg) as a brittle green foam. LC/MS: 673.3 (M+H), 74% UV purity). To a solution of 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-[3-(3-hydroxy-piperidin-1-yl)-propoxy]-indole-1-carboxylic acid tert-butyl ester (326 mg), anisole (1.0 mL), and dichloromethane (1.0 mL) at ambient temperature was added trifluoroacetic acid (1.0 mL) and the resulting amber solution heated at 45° C. After 2 hours, the reaction was cooled to ambient temperature and added to a Varian Mega Bond Elut SCX column (5 g) that was conditioned with methanol. The product was washed with methanol (30 mL) and eluted with a 1 M ammonia in methanol solution. Fractions with product were combined and concentrated under reduced pressure to give a white solid. Trituration of the solid with methanol/ether (1:4) provided 1-{3-[2-(5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-6-yloxy]-propyl}-piperidin-3-ol [163 mg, 75%, Example 56] as an off-white powder. TLC Rf 0.55 (silica, 20% 1 M NH3 in methanol/80% dichloromethane); mp: 213-216° C.; LC/MS: 473.2 (M+H), RT=2.67 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.31 (br s 1H), 11.39 (br s, 1H), 7.79 (m, 2H), 7.66 (s, 1H), 7.51-7.36 (m, 4H), 6.93 (d, J=2 Hz, 1H), 6.67 (dd, J=2, 8.5 Hz, 1H), 6.60 (d, J=1.5 Hz, 1H), 4.58 (d, J=5 Hz, 1H), 3.99 (t, J=6.5 Hz, 2H), 3.47 (m, 1H), 2.85 (dm, J=11 Hz, 1H), 2.68 (dm, J=11 Hz, 1H), 2.45 (m, 2H), 1.95-1.67 (m, 5H), 1.62 (dm, J=13.5 Hz, 1H), 1.40 (m, 1H), 1.07 (m, 1H).

Workup

  1. temperaturethe reaction was cooled to ambient temperature
  2. additionadded to a Varian Mega Bond Elut SCX column (5 g) that
  3. washThe product was washed with methanol (30 mL)
  4. washeluted with a 1 M ammonia in methanol solution
  5. concentrationconcentrated under reduced pressure
  6. customto give a white solid

Sources & evidence

ORD record
ord-62bf832d9fef456aa37c3b4cad15c475
Source dataset
uspto-grants-2011_04
Patent number
US07928231B2

Reaction notes

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