Hydrochloric Acid → HCID 86651623, compound

HRID 472694Notes

Reaction equation

HRID 472694 reaction equation
F[B-](F)(F)F.C[O+](C)C.[F:10][C:11]([F:52])([F:51])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:50])[C:25]([N:27]2[CH2:41][CH2:40][C@@:30]3([NH:34][C:33](=O)[CH2:32][CH:31]3[C:36]([O:38][CH3:39])=[O:37])[CH2:29][C@@H:28]2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C([BH3-])#N.[Na+].Cl.C([O-])(O)=O.[Na+]>ClCCl.CO>[F:52][C:11]([F:10])([F:51])[C:12]1[CH:13]=[C:14]([C@H:22]([N:24]([CH3:50])[C:25]([N:27]2[CH2:41][CH2:40][C@@:30]3([NH:34][CH2:33][CH2:32][CH:31]3[C:36]([O:38][CH3:39])=[O:37])[CH2:29][C@@H:28]2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[CH3:49])=[O:26])[CH3:23])[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 516892Sodium BicarbonateHCID 2735153Oxonium, trimethyl-, tetrafluoroborate(1-) (1:1)HCID 5003444Sodium cyanoborohydrideHCID 58169920HCID 58169920, compound2×

Product 1

HCID 86651623HCID 86651623, compoundYield 17.7%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of trimethyloxonium tetrafluoroborate (33.5 mg, 0.226 mmol) and methyl (5R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-4-carboxylate (Intermediate 40, 70 mg, 0.113 mmol) in Dichloromethane (DCM) (3 ml) was stirred at rt overnight. The mixture was washed with NaHCO3 saturated solution and the aqueous layer was extracted with DCM. The organic layers were combined, filtered through a phase separator tube and concentrated. The residue obtained was dissolved in Methanol (3 ml) and to the solution, cooled to 0° C., was added sodium cyanoborohydride (28.5 mg, 0.454 mmol). A solution of 1.25M HCl in MeOH was added maintaining the pH around 3-4 and the reaction was left stirring at rt for 2 hrs. To the solution NaHCO3 saturated solution and DCM were added and the aqueous layer was extracted with DCM. Organic layers were combined and filtered through a phase separator tube and concentrated. The crude was purified by SP4 (12M cartridge, eluting from 90%:10% to 50%:50% Cy:EtOAc). Relevant fractions were collected obtaining the title compound (12 mg, 0.020 mmol, 17.54% yield) as a single diasteroisomer. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (s, 1H) 7.68 (s, 2H) 7.13 (dd, 1H) 6.89 (dd, 1H) 6.76 (t, 1H) 5.20-5.40 (m, 1H) 4.43 (dd, 1H) 3.61 (s, 3H) 3.11-3.19 (m, 1H) 3.01-3.10 (m, 1H) 2.89-2.97 (m, 1H) 2.80-2.88 (m, 1H) 2.71 (s, 3H) 2.45-2.55 (m, 1H) 2.32 (s, 3H) 1.85-2.05 (m, 2H) 1.61-1.71 (m, 1H) 1.53-1.60 (m, 2H) 1.46 (d, 3H) 1.38-1.50 (m, 1H); Despite some signals' overlapping (H10 eq and H6 eq), causing missing information, stereochemistry could be assigned on the basis of the following noe data:

Workup

  1. washThe mixture was washed with NaHCO3 saturated solution
  2. extractionthe aqueous layer was extracted with DCM
  3. filtrationfiltered through a phase separator tube
  4. concentrationconcentrated
  5. customThe residue obtained
  6. temperaturemaintaining the pH around 3-4
  7. waitthe reaction was left
  8. extractionthe aqueous layer was extracted with DCM
  9. filtrationfiltered through a phase separator tube
  10. concentrationconcentrated
  11. customThe crude was purified by SP4 (12M cartridge, eluting from 90%:10% to 50%:50% Cy:EtOAc)
  12. customRelevant fractions were collected

Sources & evidence

ORD record
ord-543e114d5e854433bcf37b90f21844f6
Source dataset
uspto-grants-2014_01
Patent number
US08633214B2

Reaction notes

Loading…