L-Valine 5'-ester with 3-(2-deoxy-beta-D-erythro-pentofuranosyl)-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-2(3H)-one synthesis

Yield:956483-02-6 90%

Reaction Conditions:

Stage #1: 3-[2'-deoxy-5'-O-[N-(fluorenylmethoxycarbonyl)valyl]-β-D-ribofuranosyl]-6-(p-pentylphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-onewith 1,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane at 20; for 2 h;
Stage #2: with hydrogenchloride in dichloromethane;isopropyl alcohol at 5; pH=1 - 4;

Steps:

19

[00225] Example 19Preparation of ( )-((2R,3 ,5R)-(3-Hvdroxy-5-(2-oxo-6-(4-pentylphenyl)furor2,3- rf1pyrimidin-3(2H)-yl)-tetrahvdrofuran-2-yl)methyl 2-amino-3-methylbutanoate[00226] To a 500 mL flask was added DCM 200 mL, (S)-((2R,3S,5R)-3-hydroxy) 5-(2- oxo-6-(4-pentylphenyl)furo[2,3-(i]pyrimidin-3(2H)-yl)-tetrahydrofuran-2- yl)methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methylbutanoate 19.7 g (27.4 mmol), The reaction mixture was cooled, and 8.3 g DBU (54.8 mmol) was added to the reaction mixture. The reaction was stirred at rt for 2 h until TLC showed the end of the reaction.[00227] TLC: eluant: DCM/methanol=6: 1 ;(_lS^,)-((2R,35^,,5R)-3-hydroxy-5-(2-oxo-6-(4-pentylphenyl)furo[2,3-(i]pyrimidin- 3(2H)-yl)-tetrahydrofuran-2-yl)methyl2-(((9H-fluoren-9-yl)methoxy) carbonylamino)-3-methyl butanoate:R =0.55; (S)-((2R,3S,5R)- (3-hydroxy-5-(2-oxo- 6-(4-pentylphenyl)furo [2,3-J]pyrimidin-3(2H)-yl)-tetrahydrofuran-2-yl))methyl 2-amino- 3-methylbutanoate:R/=0.24.[00228] The above reaction mixture was cooled below 5 °C and was added with 20% ofHQ IPA solution until pH 1-4. The mixture was stirred for additional 1 h and was filtered. The filter cake was washed with dichloromethane. Desired crude product was obtained. The yield was 90% and the purity was 97%. The crude product was recrystallized with methanol/dichloromethane/MTBE to give the desired pure product.

References:

WO2012/48202,2012,A2 Location in patent:Page/Page column 51-52