Hydrochloric Acid → [(4R,5R)-5-(4-methylsulfonylphenyl)-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]methanol

HRID 1879341Notes

Reaction equation

HRID 1879341 reaction equation
C(O[C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])C.[BH4-].[K+].Cl.[OH-].[Na+].N[C@H](CO)[C@@H:27]([C:29]1[CH:34]=[CH:33][C:32](S(C)(=O)=O)=[CH:31][CH:30]=1)O>CO.O>[CH3:17][S:14]([C:11]1[CH:10]=[CH:9][C:8]([C@H:6]2[O:7][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18][C@@H:5]2[CH2:4][OH:19])=[CH:13][CH:12]=1)(=[O:15])=[O:16]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 4192641Potassium borohydrideHCID 6452441(R(R*,R*))-2-Amino-1-(p-(methylsulphonyl)phenyl)propane-1,3-diol2×HCID 34175685(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate

Product 1

HCID 14760452[(4R,5R)-5-(4-methylsulfonylphenyl)-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl]methanol

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) in methanol (about 100 mL) is reacted in a reaction vessel with potassium borohydride (about 1.1 g, 0.0207 moles) over about 6 hours while maintaining the temperature below about 60° C. The reaction is cooled to ambient room temperature and about 1N HCl and water (about 25 ml) are added, followed by neutralization with sodium hydroxide (about 25%) to generate (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) in situ. Next, the methanol is evaporated, followed by the addition of 1,2-dichloroethane (about 200 mL). Next, 2,2-dichloro-ethanimidic acid ethyl ester (Compound IV wherein R2 is dichloromethyl and R4 is ethyl) is added (about 10.9 g, 0.0696 moles) with heating up to about 85° C. for about 6 hours. The reaction is then cooled to below about 25° C. After cooling, glycerin is added (about 50 mL). Next, the 1,2-dichloroethane is distilled by heating to about 85° C., followed by continued heating to about 105° C. to about 110° C. for about 10 hours, then followed by cooling to below about 25° C. Thereafter, water is added (about 100 mL). The resulting solids are filtered and washed with water (about 10 mL) and isopropanol (about 10 mL) to yield (4R,5R)-2-(Dichloromethyl)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is dichloromethyl).

Workup

  1. temperaturewhile maintaining the temperature below about 60° C
  2. customNext, the methanol is evaporated
  3. additionfollowed by the addition of 1,2-dichloroethane (about 200 mL)
  4. additionNext, 2,2-dichloro-ethanimidic acid ethyl ester (Compound IV wherein R2 is dichloromethyl and R4 is ethyl) is added (about 10.9 g, 0.0696 moles)
  5. temperaturewith heating up to about 85° C. for about 6 hours
  6. temperatureThe reaction is then cooled to below about 25° C
  7. temperatureAfter cooling
  8. additionglycerin is added (about 50 mL)
  9. distillationNext, the 1,2-dichloroethane is distilled
  10. temperatureby heating to about 85° C.
  11. temperatureby continued heating to about 105° C. to about 110° C. for about 10 hours
  12. temperatureby cooling to below about 25° C
  13. additionThereafter, water is added (about 100 mL)
  14. filtrationThe resulting solids are filtered
  15. washwashed with water (about 10 mL) and isopropanol (about 10 mL)

Sources & evidence

ORD record
ord-5f88d37e90e54eeea34aebbaea9860f9
Source dataset
uspto-grants-2012_11
Patent number
US08314252B2

Reaction notes

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