Diethyl Ether → 4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}amide

HRID 493006Notes

Reaction equation

HRID 493006 reaction equation
[NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[S:57])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 218580(1S)-(+)-Camphor-10-sulphonic acidHCID 12454157Phenylacetyl isothiocyanateHCID 576777584-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(4-amino-2fluorophenoxy)pyridin-2-yl]amide

Product 1

HCID 576775574-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylthioureido)phenoxy]pyridin-2-yl}amideYield 43.3%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 1140TolueneSolventHCID 8058HexaneSolvent

Procedure

4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (60 mg) was dissolved in ethanol (1.5 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (101 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of phenylacetyl isothiocyanate in toluene (0.87 ml) was added thereto, followed by stirring for 13 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, ethyl acetate, then ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated under reduced pressure to give a residue, to which diethyl ether (2 ml) and hexane (2 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (37.2 mg, 43.3%) as white powder.

Workup

  1. stirringby stirring for 13 hrs
  2. customThe reaction mixture was partitioned between ethyl acetate (50 ml)
  3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was evaporated
  6. customto give a residue, which
  7. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent
  8. additionFractions containing the target compound
  9. concentrationwere concentrated under reduced pressure
  10. customto give a residue
  11. filtrationThe solid was filtered off
  12. customdried under aeration

Sources & evidence

ORD record
ord-dcffabb5062d4d61b544ea7d7cc39498
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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