Diisopropylethylamine → (R)-3-(4-carboxybutanoyl-amino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid methyl ester

A solution of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (1.28 g, prepared as described in Reference Example 31) in anhydrous dimethylformamide (50 ml), under an atmosphere of argon, was treated sequentially with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.55 g), diisopropylethylamine (1.35 ml) and a solution of (R)-3-(4-carboxybutanoyl-amino)-3-(4-aminophenyl)-propanoic acid methyl ester (1.25 g, prepared as described immediately hereinabove) in dimethylformamide (5 ml). After stirring for 2 hours at ambient temperature the reaction mixture was evaporated. The residue was treated with hydrochloric acid (50 ml, 1M) and extracted with ethyl acetate (100 ml). The combined organic extracts were washed with water (5 ml) and saturated aqueous potassium carbonate solution (50 ml) before being dried over magnesium sulphate and concentrated to dryness. The residue was subjected to flash chromatography on silica gel eluting with a mixture of methanol and dichloromethane (1:29, v/v) to give (R)-3-(4-carboxybutanoyl-amino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenyl-acetylamino}phenyl)-propanoic acid methyl ester a fawn solid (1.32 g). A solution of this material in tetrahydrofuran (40 ml) was heated to reflux and then treated with aqueous sodium hydroxide solution (34 ml, 2M). After stirring at reflux for a further 2.5 hours, the reaction mixture was cooled and then evaporated. The residue was diluted with water and the mixture acidified to pH 1.0 by addition of concentrated hydrochloric acid. The resultant white solid was washed with water, then dried in vacuo, then recrystallised from a mixture of ethanol and water (9:1 v/v) gave the title compound as a white crystalline solid (3.2 g), m.p. 220-222° C. MS: MH+ 591. [Elemental analysis:—C, 63.1; H, 5.3; N, 9.3%. Calculated for C31H34N4O8:—C, 63.0; H, 5.8; N, 9.5%]. >99% ee by HPLC analysis on a CHIRALPAK AD F294 column eluting with heptane: isopropanol:ethanol:trifluoroacetic acid (200:25:25:1) at a rate of 0.7 ml/min.

1. customwas evaporated
2. additionThe residue was treated with hydrochloric acid (50 ml, 1M)
3. extractionextracted with ethyl acetate (100 ml)
4. washThe combined organic extracts were washed with water (5 ml) and saturated aqueous potassium carbonate solution (50 ml)
5. dry with materialbefore being dried over magnesium sulphate
6. concentrationconcentrated to dryness
7. additionThe residue was subjected to flash chromatography on silica gel eluting with a mixture of methanol and dichloromethane (1:29

ORD record

ord-8929a7d5486d4d638a3b38a5a39bbbef

Source dataset

uspto-grants-2002_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06479519B1