1-[4-(Tributylstannyl)-3,6-dihydropyridin-1(2H)-yl]ethan-1-one → 7-(1-Acetyl-1,2,3,6-tetrahydro-pyridin-4-YL)-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-B]quinoline-3,4-dione

HRID 1640957Notes

Reaction equation

HRID 1640957 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]3[C:17](=[O:18])[NH:16][S:15][C:8]=3[N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:20].[C:21]([N:24]1[CH2:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:21]([N:24]1[CH2:25][CH:26]=[C:27]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]4[C:17](=[O:18])[NH:16][S:15][C:8]=4[N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:20])[CH2:28][CH2:29]1)(=[O:23])[CH3:22]

Participants

5

Reactant 2

HCID 156368961-[4-(Tributylstannyl)-3,6-dihydropyridin-1(2H)-yl]ethan-1-oneHCID 599995297-Bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-B]quinoline-3,4-dione

Product 1

HCID 584268547-(1-Acetyl-1,2,3,6-tetrahydro-pyridin-4-YL)-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-B]quinoline-3,4-dioneYield 98%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

A mixture containing 7-bromo-9-cyclopropyl-6-fluoro-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7, 100.0 mg, 0.28 mmol), 1-acetyl-4-tributylstannyl-1,2,3,6-tetrahydropyridine (190.0 mg, 0.46 mmol), tetrakis(triphenylphosphine)palladium(0) (16.0 mg, 0.014 mmol), and dimethylformamide (6.0 mL) Is sparged with argon gas and irradiated with microwaves (5×10 min irradiations at 130° C.). (For cross-coupling experiments described previously using C with conventional thermal heating, see: (a) Laborde, E.; Kiely, J. S.; Culbertson, T. P.; Lesheski, L. E. J. Med. Chem. 1993, 36, 1964-1970. (b) Kiely, J. S.; Laborde, E.; Lesheski, L. E.; Bucsh, R. A. J. Heterocyclic Chem. 1991, 28, 1581-1585. (c) Laborde, E.; Kiely, J. S.; Lesheski, L. E.; Schroeder, M. C. J Heterocyclic Chem. 1990, 28, 191-198) The resulting yellow solution is evaporated to dryness under reduced pressure (−6 mm Hg, 60° C.). The recovered solid is dissolved in a mixture containing 10% methanol in methylene chloride (10 mL), precipitated via addition of hexanes (100 mL), and collected by filtration. This process is repeated once. The product is purified further by flash column chromatography (eluting with 10% methanol in methylene chloride, Rf 0.50) to give pure 26 as a yellow solid (98% purity by HPLC). mp 243-244° C. 1H NMR (CDC3/CD3OD (12:1 v/v), 50° C.): δ 1.32 (m, 2H, c-Pr CH2), 1.45 (m, 2H, c-Pr CH2), 2.18 (s, 3H, NC(O)CH3), 2.65 (m, 2H, NCH2CH2), 3.45 (m, 1H, c-Pr CH), 3.73 (m, 1H, NCH2CH2), 3.87 (m, 1H, NCH2CH2), 4.23 (m, 1H, NCH2CH), 4.31 (m, 1H, NCH2CH), 6.19 (m, 1H, NCH2CH), 7.88 (d, JH-F=6.0 Hz, 1H, quinolone H-8), 8.08 (d, JH-F=11.0 Hz, 1H, quinolone H-5). 19F{1H} NMR (CDCl3/CD3OD (12:1 v/v), 50° C.): δ −119.4 (s). NMR spectroscopic data collected at room temperature indicated that two conformational isomers were present. LCMS m/z calcd for C20H18FN3O3S ([M]+) 399. Found 400 ([M+H]+). HRMS m/z calcd for C20H18FN3NaO3S ([M+Na]+) 422.0951. Found 422.0951.

Workup

  1. customIs sparged with argon gas
  2. customirradiated with microwaves (5×10 min irradiations at 130° C.)
  3. custom1990, 28, 191-198) The resulting yellow solution is evaporated to dryness under reduced pressure (−6 mm Hg, 60° C.)
  4. dissolutionThe recovered solid is dissolved in a mixture
  5. additioncontaining 10% methanol in methylene chloride (10 mL)
  6. customprecipitated via addition of hexanes (100 mL)
  7. filtrationcollected by filtration
  8. customThe product is purified further by flash column chromatography (eluting with 10% methanol in methylene chloride, Rf 0.50)

Sources & evidence

ORD record
ord-e5d59f997dc447f0bdd086fd1ee9c0e1
Source dataset
uspto-grants-2012_02
Patent number
US08114888B2

Reaction notes

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