Pyridine → Toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl ester

HRID 2373880Notes

Reaction equation

HRID 2373880 reaction equation
[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[O:37](S(C1C=CC(C)=CC=1)(=O)=O)[S:38]([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)(=O)=[O:39]>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH:27]([CH2:29][O:30][S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:39])=[O:37])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 77773Toluene-p-sulphonic anhydrideHCID 11406927{3-[8-Amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol

Product 1

HCID 11215034Toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of {3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (23 mg, 0.057 mmol) in dry methylene chloride (3 mL) was charged with pyridine (0.1 mL) and Ts2O (21 mg, 0.063 mmol) at −20° C. under N2 atmosphere. The mixture was slowly warmed to rt overnight. The reaction was quenched with water (1 mL), diluted with ethyl acetate (20 mL), washed with sat. aq. NaHCO3 (10 mL) and brine (2×10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with EtOAc:MeOH=98:2→96:4), yielding the title compound as a white solid. Partial trans isomer was removed by chromatography and the ratio of cis and trans isomers raised to 8:1; MS (ES, Pos.): m/z 555 [MH+]. 1H NMR (CDCl3, 400 MHz) δ 2.27-2.35 (m, 2H), 2.41 (s, 3H), 2.55-2.62 (m, 2H), 2.80 (m, 1H), 3.66 (m, 1H), 4.07 (d, J=6.7 Hz, 2H), 5.01 (br s, 2H, NH2), 5.15 (s, 2H), 7.02-7.85 (m, 15H). Anal. Calcd for C31H30N4O4S.1/3H2O: C, 66.41; H, 5.51; N, 9.99. Found: C, 66.43; H, 5.44; N, 10.07.

Workup

  1. customThe reaction was quenched with water (1 mL)
  2. additiondiluted with ethyl acetate (20 mL)
  3. washwashed with sat. aq. NaHCO3 (10 mL) and brine (2×10 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe crude material was purified by silica gel column chromatography (eluting with EtOAc:MeOH=98:2→96:4)

Sources & evidence

ORD record
ord-ba9a4a75a20a4885b0f17d85bce88354
Source dataset
uspto-grants-2008_12
Patent number
US07459554B2

Reaction notes

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