Diisopropylethylamine → 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-{[2-(methoxymethyl)-2H-tetrazol-5-yl]methyl}-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

HRID 1476539Notes

Reaction equation

HRID 1476539 reaction equation
C([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10](C3C=CC(C(O)=O)=CC=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)C.[B-](F)(F)(F)F.CCO[C:37]([C:39]([C:49]#N)=NOC(N(C)C)=[N+](C)C)=[O:38].[CH:51]1C=N[C:54]2N(O)N=N[C:53]=2[CH:52]=1.[CH3:61][CH2:62]N(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH3:77][O:78][CH2:79][N:80]1[N:84]=[N:83][C:82]([CH2:85][N:86]2[C:91]3[CH:92]=[C:93]([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=4)[S:94][C:90]=3[C:89](=[O:101])[N:88]([CH:102]3[CH2:107][CH2:106][NH:105][CH2:104][CH2:103]3)[C:87]2=[O:108])=[N:81]1>C(Cl)Cl>[CH2:61]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:52]3[CH:51]=[CH:49][C:39]([C:37]([N:105]4[CH2:106][CH2:107][CH:102]([N:88]5[C:89](=[O:101])[C:90]6[S:94][C:93]([C:95]7[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=7)=[CH:92][C:91]=6[N:86]([CH2:85][C:82]6[N:83]=[N:84][N:80]([CH2:79][O:78][CH3:77])[N:81]=6)[C:87]5=[O:108])[CH2:103][CH2:104]4)=[O:38])=[CH:54][CH:53]=3)=[N:9][C@@H:8]3[CH2:7][CH2:28][S:27][CH2:26][C@@H:25]3[C:6]=2[CH:5]=1)[CH3:62]

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 181649HOAt2×HCID 2733286O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate2×HCID 67258448HCID 67258448, compoundHCID 672590924-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid2×

Product 1

HCID 532471203-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-{[2-(methoxymethyl)-2H-tetrazol-5-yl]methyl}-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (251 mg; compound C10), TOTU (270 mg), HOAT (129 mg), DIPEA (327 mg) in DCM (8 ml) is stirred for 1 h at RT. To this mixture 1-{[2-(methoxymethyl)-2H-tetrazol-5-yl]methyl}-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (359 mg; compound B25) is added and the reaction mixture is stirred for additional 3 h at RT. Additional 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (125 mg; compound C10), TOTU (207 mg) and HOAT (86 mg) are added to drive the reaction to completion. After stirring for 1 h at RT the reaction is quenched by addition of DCM (10 ml) and a saturated aqueous solution of sodium bicarbonate (10 ml). The organic phase is separated and the aqueous phase is extracted with DCM (5 ml). The combined organic phases are applied to a phase separator and the solvent is removed under vacuum. The resulting residue is purified by flash column chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] to yield the title compound as a solid.

Workup

  1. stirringthe reaction mixture is stirred for additional 3 h at RT
  2. customthe reaction to completion
  3. stirringAfter stirring for 1 h at RT the reaction
  4. customis quenched by addition of DCM (10 ml)
  5. customThe organic phase is separated
  6. extractionthe aqueous phase is extracted with DCM (5 ml)
  7. customthe solvent is removed under vacuum
  8. customThe resulting residue is purified by flash column chromatography [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)]

Sources & evidence

ORD record
ord-fcd38bdffba6414b868275e818fe30ef
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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