反应详情

Methylhydrazine is highly toxic, is a cancer suspect agent, is flammable and is potentially explosive. It should be handled with extreme care. Have spill kits, drying agents, liqua paks and fire extinguishers on hand during handling. Ensure air hoses are long enough to escape any accident scene. Since methylhydrazine can react with metal oxides, the reaction vessel was inspected to ensure that no metal surfaces were exposed prior to initiating the reaction. In a clean, glass-lined, nitrogen purged vessel, 4-oxo-3-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (prepared according to Preparation Five, Step D, 50.1 kg, 1.0 eq.) was dissolved in methyl-t-butyl ether (MTBE, 208 L) at 15° C. to 20° C. to form a solution. The reaction solution was charged with methylhydrazine (7.6 kg, 1.15 eq.). After stirring for about 30 minutes, acetic acid (13.0 kg, 1.5 eq.) was added. The reaction mixture was slowly heated to reflux temperature (53° C. to 57° C.) and held at reflux for 15 to 20 hours. The reaction was cooled to between 20° C. and 25° C. The reaction mixture was cooled to between 5° C. and 10° C. and slowly charged with 10% sodium bicarbonate solution in water (175 L). The biphasic mixture was separated and the organic layer was washed sequentially with water (175 L) and saturated sodium chloride solution (175 L). The aqueous wash layers should be combined and treated with bleach solution to destroy any residual methylhydrazine prior to disposal. The organic solution was concentrated to a volume between 130 and 170 L under partial vacuum. Addition of heptanes (174 L) to the mixture precipitated the product. The slurry was stirred for 2 hours at a temperature between 5° C. and 10C. The solids were isolated by filtration, washed with cold MTBE (34 L), and dried under vacuum at a temperature between 35° C. and 45° C. for 24 hours to give 47.1 kg of 2,3,3a,4,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid 1,1-dimethylethyl ester (95.1% yield). HPLC assay showed a product peak of 99.1% at about 5 minutes. HPLC conditions: Intersil C-8 column, 4.6×150 mm; mobile phase: 50%acetonitrile/water; aqueous phase: 1 L water, 3 mL triethylamine and 1 mL H3PO4 at pH 6.5; flow rate 1.0 mL/min.; detected by UV at 205 nm.

1. customdrying agents, liqua paks and fire extinguishers on hand
2. customSince methylhydrazine can react with metal oxides
3. customthe reaction
4. customto form a solution
5. temperatureThe reaction mixture was slowly heated
6. temperatureto reflux temperature (53° C. to 57° C.)
7. temperatureat reflux for 15 to 20 hours
8. temperatureThe reaction was cooled to between 20° C. and 25° C
9. temperatureThe reaction mixture was cooled to between 5° C. and 10° C.
10. customThe biphasic mixture was separated
11. washthe organic layer was washed sequentially with water (175 L) and saturated sodium chloride solution (175 L)
12. additiontreated with bleach solution
13. customto destroy any residual methylhydrazine
14. concentrationThe organic solution was concentrated to a volume between 130 and 170 L under partial vacuum
15. additionAddition of heptanes (174 L) to the mixture
16. customprecipitated the product
17. stirringThe slurry was stirred for 2 hours at a temperature between 5° C.
18. customThe solids were isolated by filtration
19. washwashed with cold MTBE (34 L)
20. customdried under vacuum at a temperature between 35° C. and 45° C. for 24 hours