Potassium Carbonate → (2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl) phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile

HRID 1015547Notes

Reaction equation

HRID 1015547 reaction equation
[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:21][CH:17]4[CH2:18][CH:19]([CH2:20]2)[C:15]([NH2:22])([CH2:16]4)[CH2:14]3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]([N:34]1[CH2:38][C@@H:37]([F:39])[CH2:36][C@H:35]1[C:40]#[N:41])=[O:33]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:21][CH:17]4[CH2:16][C:15]([NH:22][CH2:31][C:32]([N:34]5[CH2:38][C@@H:37]([F:39])[CH2:36][C@H:35]5[C:40]#[N:41])=[O:33])([CH2:14]2)[CH:19]([CH2:18]4)[CH2:20]3)=[CH:11][CH:12]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 57518632(2S,4S)-1-(2-Chloroacetyl)-4-fluoropyrrolidine-2-carbonitrileHCID 670178591-[4-(1,1-Dioxidoisothiazolidin-2-yl) phenyl]tricyclo[3.3.1.03,7]nonan-3-amine

Product 1

HCID 24853220(2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl) phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrileYield 37%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred mixture of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.03,7]nonan-3-amine (as obtained in example 8 Step II) (0.17 g, 0.5 mmol) and K2CO3 (0.21 g, 1.5 mmol) in DMSO (2 mL) at an ice bath temperature was added (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.1 g, 0.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile as an off-white powder (0.09 g) in 37% yield as a 3:1 mixture of two rotomers. IR cm−1 3438, 2953, 2776, 1673, 1518, 1427, 1301, 1135, 1078, 955; m/z (M+1) 487; 1H NMR (CDCl3) 300 MHz δ 7.25 (d, J=6.2 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 5.42 (d (br), J=51.0 Hz, 0.8H), 5.34 (d (br), J=50.4 Hz, 0.2H), 5.15 (d, J=10.2 Hz, 0.2H), 4.98 (d, J=7.4 Hz, 0.8H), 4.0-3.50 (m, 4H), 3.76 (t, J=6.5H, 2H), 3.35 (t, J=6.5 Hz, 2H), 2.80-2.28 (m, 6H), 2.15-1.58 (m, 10H).

Workup

  1. customUpon completion of the reaction (checked by TLC)
  2. washwashed with water and brine
  3. dry with materialdried over Na2SO4
  4. customthe solvent was removed under reduced pressure
  5. customThe crude product was purified by column chromatography

Sources & evidence

ORD record
ord-e1cfa7a197854268a3009b3cb9452fb5
Source dataset
uspto-grants-2011_07
Patent number
US07985759B2

Reaction notes

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