Sulfuric Acid → {rel-(3R,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ylsulfanyl}-acetonitrile

HRID 2178200Notes

Reaction equation

HRID 2178200 reaction equation
[SH:1][CH2:2][C:3]#[N:4].[CH3:5][O:6][C:7]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:8]=1[CH2:9][N:10]1[C@@:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([CH3:19])[C@@H:17]2[C@@H:13]([CH2:14][O:15][CH2:16]2)OS1(=O)=O.CN(C)C(N(C)C)=N.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:8]=1[CH2:9][NH:10][C@@:18]([C@H:17]1[CH2:16][O:15][CH2:14][C@@H:13]1[S:1][CH2:2][C:3]#[N:4])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])[CH3:19]

Participants

7

Reactant 5

HCID 1118Sulfuric AcidHCID 664601,1,3,3-TetramethylguanidineHCID 516892Sodium BicarbonateHCID 4346655MercaptoacetonitrileHCID 88876324(3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5,5-dioxide

Product 1

HCID 70654467{rel-(3R,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ylsulfanyl}-acetonitrileYield 97.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

2-Mercaptoacetonitrile (1.03 g, 14.1 mmol) was added dropwise to a solution of (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5,5-dioxide (4.1 g, 9.37 mmol) and 1,1,3,3-tetramethylguanidine (1.62 g, 14.1 mmol) in N,N-dimethylformamide (55 ml) at room temperature. The reaction mixture was then stirred at 60° C. for 12 hours. For the workup, the solvent was evaporated at reduced pressure, and the residue was dissolved in dichloromethane (50 ml). After addition of sulfuric acid (20%; 50 ml, 185 mmol) and stirring overnight, the mixture was poured onto a saturated solution of sodium hydrogencarbonate followed by the extraction (2×) with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The {rel-(3R,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ylsulfanyl}-acetonitrile (3.92 g, 97% yield) was obtained as a light brown oil. MS (ISP): m/z=431.2 [M+H]+.

Workup

  1. customFor the workup, the solvent was evaporated at reduced pressure
  2. dissolutionthe residue was dissolved in dichloromethane (50 ml)
  3. stirringstirring overnight
  4. extractionfollowed by the extraction (2×) with dichloromethane
  5. dry with materialThe combined organic layers were dried over sodium sulphate
  6. customevaporated
  7. customThe residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent

Sources & evidence

ORD record
ord-cd2e94626e9840d0aa404f071caf59d0
Source dataset
uspto-grants-2015_06
Patent number
US09067924B2

Reaction notes

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