Formaldehyde → (S)-3-(Biphenyl-4-yl)-2-[(diphenylphosphonomethyl)-amino]-propionic acid benzyl ester

HRID 1078690Notes

Reaction equation

HRID 1078690 reaction equation
Cl.[CH2:2]([O:9][C:10](=[O:26])[C@@H:11]([NH2:25])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:27](=O)(O)[O-].[Na+].C=O.[P:34]([O-:49])([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:2]([O:9][C:10](=[O:26])[C@@H:11]([NH:25][CH2:27][P:34]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:49])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1

Participants

8

Reactant 4

HCID 712FormaldehydeHCID 516892Sodium BicarbonateHCID 23418553DiphenoxyphosphanolateHCID 68805074(S)-benzyl 2-amino-3-(biphenyl-4-yl)propanoate hydrochloride

Product 1

HCID 54430803(S)-3-(Biphenyl-4-yl)-2-[(diphenylphosphonomethyl)-amino]-propionic acid benzyl ester

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred mixture of (S)-2-amino-3-(biphenyl-4-yl)-propionic acid benzyl ester hydrochloride (4.7 g, 12.8 mmol) in ethyl acetate (100 mL) and water (100 mL) at 5° is added sodium bicarbonate (1.13 g, 13.5 mmol). The solution is stirred for 5 minutes, then aqueous formaldehyde (37% aq., 1.25 mL, 16.6 mmol) is added. The mixture is allowed to warm slowly to room temperature while being stirred vigorously for 18 hours. The organic layer is separated and the aqueous layer extracted with ethyl acetate (50 mL). The combined organic phases are washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude hexahydrotriazine intermediate is obtained as a white solid that is dried under high vacuum. Some of that material (0.75 g, 2.18 mmol) is dissolved in toluene (10 mL) and kept under nitrogen. Diphenyl phosphite (0.5 mL, 2.62 mmol) is added and the solution is warmed in a bath pre-heated to 70°. After 2 hours, the reaction mixture is allowed to cool to room temperature. After evaporation of the solvent under reduced pressure, the residue is purified by flash-chromatography on silica gel, eluting with a gradient of ethyl acetate (50% to 90%) in hexane. The product is recrystallized from ether/hexane, affording (S)-3-(biphenyl-4-yl)-2-[(diphenylphosphonomethyl)-amino]-propionic acid benzyl ester as a while solid, m.p. 85°-86°; [α]D =+8.40 (c 1.04, CHCl3).

Workup

  1. stirringwhile being stirred vigorously for 18 hours
  2. customThe organic layer is separated
  3. extractionthe aqueous layer extracted with ethyl acetate (50 mL)
  4. washThe combined organic phases are washed with water (50 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe resulting crude hexahydrotriazine intermediate is obtained as a white solid
  9. customthat is dried under high vacuum
  10. temperaturethe solution is warmed in a bath
  11. temperaturepre-heated to 70°
  12. waitAfter 2 hours
  13. temperatureto cool to room temperature
  14. customAfter evaporation of the solvent under reduced pressure
  15. customthe residue is purified by flash-chromatography on silica gel
  16. washeluting with a gradient of ethyl acetate (50% to 90%) in hexane
  17. customThe product is recrystallized from ether/hexane

Sources & evidence

ORD record
ord-1522e25c83364b1384f4259781457645
Source dataset
uspto-grants-1996_08
Patent number
US05550119

Reaction notes

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