1,2-Dichloroethane → 4-{(1R)-1-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-2-methylpropyl}-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

HRID 1627168Notes

Reaction equation

HRID 1627168 reaction equation
[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[O:29]=[S:26]1(=[O:30])[CH2:27][CH2:28][N:23]([C:13]([C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:24][CH2:25]1

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 12324096Thiomorpholine 1,1-dioxide hydrochlorideHCID 57389932(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid

Product 1

HCID 498423804-{(1R)-1-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-2-methylpropyl}-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-oneYield 47%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), thiomorpholine 1,1-dioxide hydrochloride (8.84 mg, 0.51 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (9.8 mg, 46.6%). 1H NMR (400 MHz, CD3OD) δ 0.92 (d, J=6.82 Hz, 3 H) 1.02 (d, J=6.32 Hz, 3 H) 2.60 (dt, J=10.61, 6.57 Hz, 1 H) 2.90-3.03 (m, 1 H) 3.03-3.25 (m, 3 H) 3.86-4.01 (m, 1 H) 4.13 (ddd, J=14.78, 8.59, 2.40 Hz, 1 H) 4.21-4.41 (m, 2 H) 4.92-5.06 (m, 1 H) 5.06-5.18 (m, 1 H) 5.57 (d, J=10.61 Hz, 1 H) 7.89 (s, 1 H) 8.18 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C18H21FN4O4S, 409; found, 409.3.

Workup

  1. customTo an 8 mL scintillation vial equipped
  2. stirringthe solution was stirred at 25° C. for 4 h
  3. customThe reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%)
  4. customThe fractions were collected

Sources & evidence

ORD record
ord-e6d8b5f3e25d4285b27e330ce398293f
Source dataset
uspto-grants-2014_07
Patent number
US08785429B2

Reaction notes

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