Carbon Disulfide → (3R)-N-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide

HRID 1254378Notes

Reaction equation

HRID 1254378 reaction equation
[NH2:1][C@@H:2]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][N:4]([CH3:14])[C:5](=[O:13])[O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].[C:22](=[S:24])=S.[OH-].[Na+].ClC(OCC)=O.Cl[C:34]1[CH:35]=[C:36]([C@:40]([C@@H:48]2[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)([OH:47])[CH2:41][CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH:37]=[CH:38][CH:39]=1>C1COCC1.O.CC#N.CCOCC>[CH:16]1([CH2:15][C@H:2]([NH:1][C:22]([N:50]2[CH2:51][CH2:52][CH2:53][C@@H:48]([C@:40]([OH:47])([C:36]3[CH:35]=[CH:34][CH:39]=[CH:38][CH:37]=3)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH2:49]2)=[S:24])[CH2:3][N:4]([CH3:14])[C:5]([O:6][CH2:7][CH2:8][Si:9]([CH3:11])([CH3:12])[CH3:10])=[O:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1

Participants

10

Reactant 5

HCID 6348Carbon DisulfideHCID 10928Ethyl chloroformateHCID 14798Sodium HydroxideHCID 59382814(S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-olHCID 593829982-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylmethylcarbamate

Product 1

HCID 86626199(3R)-N-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamideYield 42.5%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

A stirred solution of (2-(trimethylsilyl)ethyl) (S)-2-amino-3-cyclohexylpropyl-methylcarbamate (484 mg, 1.54 mmol) and CS2 (96 μL, 1.62 mmol) in THF (5 mL) was cooled in an ice bath and a solution of NaOH (65 mg, 1.62 mmol) in water (0.15 mL) was added. The mixture was heated at reflux for 1.5 h, cooled to 40° C. and treated with ethyl chloroformate (0.155 mL, 1.62 mmol). The mixture was heated at 40° C. for 30 min, cooled and poured into ether (90 mL). The ether layer was washed with water (25 mL), brine (25 mL) and dried over MgSO4. Removal of the solvent left an oil (660 mg). An aliquot of this oil (83 mg) and (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (42 mg, 0.13 mmol) were dissolved in MeCN (1 mL) and heated at 100° C. in a microwave for 10 min. The mixture was concentrated to leave an oil which was applied to a 2-g silica SPE cartridge and eluted sequentially with 0, 10, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford six fractions. The third fraction was evaporated to afford (3R)-N-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbothioamide (35 mg) as an oil.

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 1.5 h
  3. temperatureThe mixture was heated at 40° C. for 30 min
  4. temperaturecooled
  5. washThe ether layer was washed with water (25 mL), brine (25 mL)
  6. dry with materialdried over MgSO4
  7. customRemoval of the solvent
  8. waitleft an oil (660 mg)
  9. temperatureheated at 100° C. in a microwave for 10 min
  10. concentrationThe mixture was concentrated
  11. customto leave an oil which
  12. washeluted sequentially with 0, 10, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each)
  13. customto afford six fractions
  14. customThe third fraction was evaporated

Sources & evidence

ORD record
ord-ab310b272113447e80a844c5ac0b16d0
Source dataset
uspto-grants-2013_06
Patent number
US08455521B2

Reaction notes

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