Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → HCID 57677693, compound

HRID 492855Notes

Reaction equation

HRID 492855 reaction equation
[NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52]([N:54]=[C:55]=[S:56])=[O:53])=[CH:47][CH:46]=1.C(#N)C.C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[F:28][C:4]1[CH:3]=[C:2]([NH:1][C:55]([NH:54][C:52](=[O:53])[CH2:51][C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)=[S:56])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1

Participants

7

Reactant 4

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 516892Sodium BicarbonateHCID 23153597HCID 23153597, compoundHCID 57677632HCID 57677632, compound

Product 1

HCID 57677693HCID 57677693, compoundYield 37.8%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

After adding potassium thiocyanate (65.3 mg) and acetonitrile (4 ml) to 2-(4-fluorophenyl)acetyl chloride (58 mg) under a nitrogen atmosphere, the mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled to room temperature, and then ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture and stirring was continued for 30 minutes. After partitioning the reaction mixture, the separated organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to provide a crude product of 2-(4-fluorophenyl)acetyl isothiocyanate as a yellow oil. After dissolving 4-(azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (70 mg) in ethanol (2 ml), D-10-camphorsulfonic acid (43 mg) was added and the mixture was stirred for 5 minutes under a nitrogen atmosphere. Then, 2-(4-fluorophenyl)acetyl isothiocyanate-acetonitrile (0.5 ml×3) was added and the mixture was stirred for 2 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5), and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (0.5 ml) and hexane (4 ml) were added to the resultant residue to produce a suspension of the solid. After filtering the solid, it was subjected to aeration drying to provide the title compound (36.9 mg, 37.8%) as white powder.

Workup

  1. additionwas added
  2. stirringthe mixture was stirred for 2 hours
  3. customfor partition
  4. washthe organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml)
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5)
  8. additionfractions containing the target compound
  9. concentrationwere concentrated under reduced pressure
  10. additionDiethyl ether (0.5 ml) and hexane (4 ml) were added to the resultant residue
  11. customto produce
  12. additiona suspension of the solid
  13. filtrationAfter filtering the solid, it
  14. customdrying

Sources & evidence

ORD record
ord-d6f9e305aef04ea59f25254babf60fe4
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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