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Ethyl Acetate → 2,2,2-trichloroethyl 3-[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate

HRID 45800
Notes
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Reaction equation

HRID 45800 reaction equation
[CH3:1][S:2][C:3]1[N:12]=[CH:11][C:10]2[CH:9]=[CH:8][C:7]3[C:13]([C:16]([NH2:18])=[O:17])=[N:14][NH:15][C:6]=3[C:5]=2[N:4]=1.CS(O[CH:24]1[CH2:30][CH:29]2[N:31]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[CH:26]([CH2:27][CH2:28]2)[CH2:25]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[C:16]([C:13]1[C:7]2[CH:8]=[CH:9][C:10]3[CH:11]=[N:12][C:3]([S:2][CH3:1])=[N:4][C:5]=3[C:6]=2[N:15]([CH:24]2[CH2:30][CH:29]3[N:31]([C:32]([O:34][CH2:35][C:36]([Cl:38])([Cl:39])[Cl:37])=[O:33])[CH:26]([CH2:27][CH2:28]3)[CH2:25]2)[N:14]=1)(=[O:17])[NH2:18]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10796Cesium carbonateHCID 86668393HCID 86668393, compoundHCID 178503380HCID 178503380, compound

Product 1

HCID 679754422,2,2-trichloroethyl 3-[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylateYield 70%

Reagents, catalysts & solvents

2
HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

8-(Methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 50 mg (0.193 mmol) in DMF (8 ml), were reacted with 2,2,2-trichloroethyl 3-[(methylsulfonyl)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 200 mg (0.52 mmol) and cesium carbonate 140 mg (0.43 mmol) at 90° C. for 4 hours. The mixture was cooled at r.t. and portioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The crude was purified by column chromatography eluting with DCM/EtOH 9/1 to provide 2,2,2-trichloroethyl 3-[3-carbamoyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate as a off-white solid 73 mg (70%). The compound (134 mmol) was dissolved in THF (5 ml), acetic acid (5 ml) and zinc dust 35 mg (0.536 mmol) were added. The mixture was heated up to 50° C. and stirred 18 hours. The volatiles were removed in vacuum and the residue was purified by chromatography eluting with DCM/MeOH 95/5. A further purification was required and was performed by prep-HPLC method 1, to obtain the title compound 25 mg (50%). LC/MS (254 nm) HPLC method 2 Rt 4.08 min. 1H NMR (401 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.25 (d, J=8.67 Hz, 1H), 7.62-7.79 (m, 3H), 7.52-7.60 (m, 1H), 6.21-6.54 (m, OH), 3.68 (br. s., 2H), 2.76 (s, 2H), 2.22-2.36 (m, 2H), 2.02 (br. s., 2H), 1.78-1.98 (m, 5H). HRMS (ESI) calcd for C18H20N6OS [M+H]+ 369.1492 found 369.15.

Workup

  1. washThe organic phase was washed with brine
  2. dry with materialdried over Na2SO4
  3. customevaporated
  4. customThe crude was purified by column chromatography
  5. washeluting with DCM/EtOH 9/1

Sources & evidence

ORD record
ord-2f92b727fdff4b139f7522c0091c8188
Source dataset
uspto-grants-2013_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08541576B2

Reaction notes

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