Browse Prior Art Database

SYNTHESIS OF A DIPHENYLPROPANOIC ACID DERIVATIVE

IP.com Disclosure Number: IPCOM000240324D
Publication Date: 2015-Jan-23
Document File: 14 page(s) / 71K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present document discloses a procedure for the synthesis of (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 9% of the total text.

Page 01 of 14

1

SYNTHESIS OF A DIPHENYLPROPANOIC ACID DERIVATIVE


[0001] The present document discloses a procedure for the synthesis of (2S)-2- [(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid, which is represented by Formula (I): O

O

N

O

O

H

N

(I)


[0002] The procedure for the synthesis of (2S)-2-[(4,6-dimethylpyrimidin-2- yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid is depicted in Scheme 1, below:

O

O

O

O

O

Cl

O

O

O

pTsOH

O

OH

O


(II)


(III)

KOH

O

N S

O

O

O

O

N

O

N

O

H

O

H

O

H

N

O

OH

O

OH

resolution


(I)

(S-IV)


(IV)

Scheme 1


[0003] The resolution step of the compound of formula (IV) comprises the reaction of the compound of formula (IV) with an optically active chiral amine base, either in (S) or (R) configuration, in a suitable solvent to obtain the diastereomeric salt of the compound of formula (S-IV) with high chiral purity.


Page 02 of 14

2


[0004] This diastereomeric salt of the compound of formula (S-IV) can be subsequently neutralized to give the compound of formula (S-IV) or alternatively can further be used for the preparation of the compound of formula (I).


[0005] The reaction of the diastereomeric salt of the compound of formula (S-IV) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine may be carried out in the presence of a suitable base in one or more suitable solvents. Suitable bases which can be used for above coupling may include one or more of lithium diisopropyl amide, lithium amide, sodium amide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate, lithium hexamethyldisilazane, potassium hexamethyldisilazane, potassium tert-butoxide, sodium tert-butoxide and the like. Suitable solvents which can be used may include one or more of dimethylsulfoxide, N,N-dimethylformamide, diethyl ether, 1,4-dioxane, 2-methyltetrahydrofuran, N,N-dimethylacetamide, dichloromethane, diisopropyl ether, tetrahydrofuran and the like or mixtures thereof.

Example 1. Methyl 2-hydroxy-3-methoxy-3,3-diphenylpropanoate (compound
III).


50.6 g of sodium methoxide were added over a solution of 100.0 g of benzophenone in 170 mL of tetrahydrofuran. The resulting suspension was cooled in an ice bath and 82 mL of methyl chloroacetate were added. After completion of the reaction, 300 mL of water were added and the organic solvent was distilled under vacuum. Then, 170 mL of methyl tert-butyl ether were added, the resulting biphasic mixture was separated and the organic layer was washed with brine. 670 mL of methanol were added to the resulting organic layer, and methyl tert-butyl ether was distilled off. To the obtained solution, 1.0 g of p-toluenesulfonic acid monohydrate were added and the resulting mixture was stirred at room temperature. After cooling in an ice bath, the solid was filtered, washed with methanol and dried until constant weight to obtain methyl 2-hydroxy-3-methoxy-3,3-diphenylpropanoate (compound III) as a white solid.

Example 2. (S)-2-hydroxy-3-methoxy-3,3-diphenyl...