Benzenepropanoic acid,a-hydroxy-b-methoxy-b-phenyl-,methyl ester Chemical Properties

Melting point:

96-98°C

Boiling point:

440.7±40.0 °C(Predicted)

Density 

1.176

storage temp. 

2-8°C

solubility 

Chloroform (Slightly), DMSO (Slightly), Methanol (Very Slightly)

form 

Solid

pka

12.37±0.20(Predicted)

color 

White to Off-White

Safety Information

HazardClass 

IRRITANT

Benzenepropanoic acid,a-hydroxy-b-methoxy-b-phenyl-,methyl ester Usage And Synthesis

Uses

Ambrisentan intermediate.

Synthesis

1. 500 g (2.74 mol) of benzophenone was dissolved in 1200 mL of toluene and the reaction system was purged using nitrogen. Subsequently, 267 g (4.94 mol) of sodium methanol was added and stirred to form a suspension. 2. The suspension was cooled and 410 mL (4.68 mol) of methyl chloroacetate in toluene (300 mL) was slowly added dropwise over a period of 90 minutes, with the reaction temperature maintained at -8 to 4°C. The reaction temperature was maintained at -8 to 4°C. After the dropwise addition was completed, the reaction solution was cooled to 0°C and maintained for 1 hr. 3. 1000 mL of water was added and stirred for 15 minutes before liquid-liquid separation. The organic layer was washed with 1000mL of water. 4. The solvent was removed by distillation under reduced pressure and the resulting residue (methyl (RS)-3,3-diphenyl-2,3-epoxyacrylate) was dissolved in 1200 mL of methanol and cooled to 0°C. 5. A methanolic solution of 15 g (0.08 mol) of toluene sulfonic acid monohydrate (150 mL) was added slowly and dropwise over 30 min. The mixture was stirred at 0°C for 1.5 h. The precipitated crystals were collected by filtration. 6. The crystals were dissolved in 2500 mL of ethyl acetate and washed twice with 1000 mL of 5% aqueous sodium carbonate. 7. The solvent was removed by pressurized distillation and 1000 mL of hexane was added to the residue, suspended and stirred at room temperature for 1.5 hours, followed by stirring at 0°C for 1 hour. 8. The crystals were collected by filtration and dried under reduced pressure at 60 °C for 5 h to give 659 g (yield: 84%) of methyl (RS)-2-hydroxy-3-methoxy-3,3-diphenylpropionate.

References

[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 11, p. 2123 - 2128
[2] Patent: JP5700378, 2015, B2. Location in patent: Paragraph 0062
[3] Patent: JP2017/128528, 2017, A. Location in patent: Paragraph 0005; 0039
[4] Patent: WO2012/17441, 2012, A1. Location in patent: Page/Page column 10-11
[5] Patent: WO2010/70658, 2010, A2. Location in patent: Page/Page column 18

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