Sodium ethoxide → HCID 57590670, compound

HRID 1783824Notes

Reaction equation

HRID 1783824 reaction equation
CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=1)=O.Cl.[NH2:26]/[C:27](/[NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]1)=[N:28]/[H].[O-]CC.[Na+]>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:28]=[C:27]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]4)[N:26]=2)[CH:13]=[CH:12][S:11]3)=[CH:16][C:17]=1[O:22][CH3:23]

Participants

5

Reactant 3

HCID 2723922Sodium ethoxide2×HCID 68801242HCID 68801242, compoundHCID 178478974HCID 178478974, compound2×

Product 1

HCID 57590670HCID 57590670, compoundYield 86%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent3×

Procedure

A mixture of 3-(dimethylamino)-1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one (0.6 g, 1.74 mmol) and tert-butyl (3R)-3-{[(Z)-amino (imino)methyl]amino}piperidine-1-carboxylate hydrochloride (0.726 g, 2.61 mmol) was diluted with 13 ml of absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of sodium ethoxide in ethanol (875 μl) to form a reaction mixture. The reaction mixture was heated to reflux for 24 hours. HPLC revealed remaining starting enaminone. More tert-butyl (3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride (0.243 g, 0.87 mmol) was added followed by a 21% w/w solution of sodium ethoxide in ethanol (270 μl). The mixture was kept at reflux for an additional 15 hours. Volatiles were removed in vacuo and the residue was taken up in 50 ml of ethyl acetate and 50 ml of water. The phases were separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organic extracts were washed with 100 ml of water, and then with a saturated sodium chloride solution (100 ml). The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product was purified by flash chromatography on silica gel (gradient 50% to 75% ethyl acetate in hexanes) to yield 0.785 g of a pale yellow solid (86%). 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.72 (br. s, 1H), 8.13 (d, J=5.5 Hz, 1H), 7.41 (d, J=4.7 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.26 (dd, J=11.7, 8.6 Hz, 1H), 7.18-7.08 (m, 2H), 6.41 (d, J=5.5 Hz, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 3.85-3.75 (m, 1H), 3.72-3.63 (m, 1H), 3.00-2.88 (m, 2H), 2.04-1.94 (m, 1H), 1.82-1.73 (m, 1H), 1.62-1.50 (m, 1H), 1.50-1.38 (m, 1H), 1.34 (s, 9H). LCMS: 525 [M+H].

Workup

  1. customto form a reaction mixture
  2. temperatureThe reaction mixture was heated
  3. temperatureto reflux for 24 hours
  4. temperatureat reflux for an additional 15 hours
  5. customVolatiles were removed in vacuo
  6. customThe phases were separated
  7. extractionthe aqueous phase was extracted with 50 ml of ethyl acetate
  8. washThe combined organic extracts were washed with 100 ml of water
  9. dry with materialThe organic phase was dried with sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto give a brown oil
  13. customThe product was purified by flash chromatography on silica gel (gradient 50% to 75% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-30951136747f4a7ebbca4f4cc3e2b2ef
Source dataset
uspto-grants-2009_03
Patent number
US07501430B2

Reaction notes

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