1,2-Dichloroethane → 4-(4-((R)-(4'-chlorobiphenyl-2-yl)(dimethylamino)methyl)piperidin-1-yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide, hydrochloride salt

HRID 1476358Notes

Reaction equation

HRID 1476358 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([N:30]([CH3:32])[CH3:31])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Li].C(Cl)CCl.CCN(C(C)C)C(C)C.[O:47]1[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][C@@H:55]([NH:64][C:65]2[CH:70]=[CH:69][C:68]([S:71]([NH2:74])(=[O:73])=[O:72])=[CH:67][C:66]=2[S:75]([C:78]([F:81])([F:80])[F:79])(=[O:77])=[O:76])[CH2:56][S:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:49][CH2:48]1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CO.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([N:30]([CH3:32])[CH3:31])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:74][S:71]([C:68]4[CH:69]=[CH:70][C:65]([NH:64][C@H:55]([CH2:54][CH2:53][N:50]5[CH2:51][CH2:52][O:47][CH2:48][CH2:49]5)[CH2:56][S:57][C:58]5[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=5)=[C:66]([S:75]([C:78]([F:81])([F:79])[F:80])(=[O:77])=[O:76])[CH:67]=4)(=[O:72])=[O:73])=[O:26])=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1

Participants

11

Reactant 6

HCID 111,2-DichloroethaneHCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 3028194LithiumHCID 250584544-[[(1R)-3-(4-Morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]benzenesulfonamide2×HCID 131732793(R)-4-(4-((4'-chlorobiphenyl-2-yl)(dimethylamino)methyl)piperidin-1-yl)benzoate

Product 1

HCID 1317327924-(4-((R)-(4'-chlorobiphenyl-2-yl)(dimethylamino)methyl)piperidin-1-yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide, hydrochloride saltYield 35%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent2×

Procedure

(R)-4-(4-((4′-chlorobiphenyl-2-yl)(dimethylamino)methyl)piperidin-1-yl)benzoate, lithium salt (EXAMPLE 36, STEP 1, 0.105 g, 0.23 mmol), DMAP (56 mg, 0.46 mmol), and EDC (0.176 g, 0.92 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (4.5 ml) and DIPEA (0.08 ml, 0.46 mmol) were added, and the solution was stirred at r.t for 15 minutes. (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 0.127 g, 0.23 mmol) was added to the solution and the reaction mixture was stirred at r.t overnight. The reaction mixture was diluted with DCM and washed with 1N sodium bisulfate (aq.) followed by saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue which was purified by reverse phase HPLC (Gilson column, eluting with 30→50% H2O/ACN with 0.1% formic acid for 10 minutes) to provide a solid. The solid was dissolved in MeOH and the mixture was treated with 2N HCl in diethylether. Evaporation of the volatiles under reduced pressure provided the title compound (85 mg, yield: 35% for 2 steps).

Workup

  1. customflushed with nitrogen
  2. stirringthe reaction mixture was stirred at r.t overnight
  3. washwashed with 1N sodium bisulfate (aq.)
  4. dry with materialThe organic layer was dried (Na2SO4)
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customto give a residue which
  8. customwas purified by reverse phase HPLC (Gilson column, eluting with 30→50% H2O/ACN with 0.1% formic acid for 10 minutes)
  9. customto provide a solid
  10. customEvaporation of the volatiles under reduced pressure

Sources & evidence

ORD record
ord-b2ed97347c4b4b0e93641958c2edde44
Source dataset
uspto-grants-2015_04
Patent number
US09018381B2

Reaction notes

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