HOAt → HCID 53246869, compound

HRID 1476533Notes

Reaction equation

HRID 1476533 reaction equation
[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C1C=NC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[CH3:68][C:69]1[S:70][C:71]([CH2:74][N:75]2[C:80]3[CH:81]=[C:82]([C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)[S:83][C:79]=3[C:78](=[O:90])[N:77]([CH:91]3[CH2:96][CH2:95][NH:94][CH2:93][CH2:92]3)[C:76]2=[O:97])=[CH:72][N:73]=1>CCN(C(C)C)C(C)C>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:94]4[CH2:95][CH2:96][CH:91]([N:77]5[C:78](=[O:90])[C:79]6[S:83][C:82]([C:84]7[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=7)=[CH:81][C:80]=6[N:75]([CH2:74][C:71]6[S:70][C:69]([CH3:68])=[N:73][CH:72]=6)[C:76]5=[O:97])[CH2:92][CH2:93]4)=[O:22])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]

Participants

6

Reactant 4

HCID 181649HOAtHCID 2733286O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 67258342HCID 67258342, compoundHCID 672590924-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid

Product 1

HCID 53246869HCID 53246869, compound

Reagents, catalysts & solvents 1

HCID 81531DiisopropylethylamineSolvent

Procedure

A solution of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (199 mg; compound C10), TOTU (213 mg) and HOAT (102 mg) in DIPEA (259 mg) is stirred for 50 min at RT. Subsequently, 1-[(2-methyl-1,3-thiazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (276 mg; compound B44) is added and the reaction mixture is stirred for additional 60 min at RT. The solvent is removed under reduced pressure and to the resulting residue DCM (15 ml) and saturated aqueous sodium bicarbonate solution (3 ml) are added. The organic phase is separated and the aqueous phase is extracted with DCM (10 ml). The combined organic phases are applied to a phase separator, dried over magnesium sulfate and the solvent is removed under reduced pressure to give the crude title compound. The residue is first purified by flash chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)]. After a second purification step applying preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluent: EtOAc/triethylamine, 97/3 (v/v)] the title compound is obtained as a solid.

Workup

  1. customThe solvent is removed under reduced pressure and to the resulting residue DCM (15 ml) and saturated aqueous sodium bicarbonate solution (3 ml)
  2. additionare added
  3. customThe organic phase is separated
  4. extractionthe aqueous phase is extracted with DCM (10 ml)
  5. dry with materialdried over magnesium sulfate
  6. customthe solvent is removed under reduced pressure

Sources & evidence

ORD record
ord-aa5f2dc17c794a0a9ec10fee3019d3ac
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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