2,6-Lutidine → 4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester

Temperature

0 °C

Triphenylphosphine (310 mg, 1.18 mmol) was dissolved in methylene chloride (4 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (238 mg, 1.34 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1; 259 mg, 0.79 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for another 30 min. After such time 4-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (182 mg, 0.79 mmol) and 2,6-lutidine (274 μL, 2.36 mmol) were added dropwise as a solution in methylene chloride (4 mL) and the reaction was stirred at 25° C. for 16 h. The reaction was then diluted with ethyl acetate (80 mL), washed with water (2×20 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 20% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) followed by recrystallization from 25% ethyl acetate/hexanes afforded the desired product. The reaction procedure was scaled up by a factor of two according to the same procedure. The combined batches afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (840 mg, 65%) as a beige powder: ESI-LRMS m/e calcd for C27H30ClN3O5S [M+] 543.2, found 544.5 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2H, CH2), 1.33-1.80 (m, 8H, 4×CH2), 1.99-2.19 (m, 1H, CH), 3.32 (s, 3H, SO2CH3), 3.82 (s, 3H, CO2CH3), 3.84-3.92 (m, 1H, CH), 5.28 (s, 2H, NCH2), 6.48 (d, J=2.2 Hz, 1H, Ar), 7.29 (d, Jo=8.5 Hz, 2H, Ar), 7.55 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.65 (d, Jm=1.7 Hz, 1H, Ar), 7.75 (d, J=2.2 Hz, 1H, Ar), 7.90 (d, Jo=8.5 Hz, 2H, Ar), 7.97 (d, Jo=8.2 Hz, 1H, Ar), 10.78 (s, 1H, NH).

1. dissolutionwas completely dissolved
2. stirringit was stirred at 0° C. for 20 min
3. temperaturewarmed to 25° C.
4. stirringstirred for another 30 min
5. stirringthe reaction was stirred at 25° C. for 16 h
6. washwashed with water (2×20 mL), saturated aqueous brine solution (1×20 mL)
7. dry with materialdried over magnesium sulfate
8. concentrationconcentrated in vacuo
9. customto give an orange oil
10. customPurification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 20% ethyl acetate/hexanes to 100% ethyl acetate/hexanes)
11. customfollowed by recrystallization from 25% ethyl acetate/hexanes

ORD record

ord-094520dcb742486dbae8bd6428dbef84

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935699B2