Tert-buthyl Pitavastatin

tert-Buthyl Pitavastatin is the  metabolite of Pitavastatin. Pitavastatin is a potent HMG-CoA reductase inhibitor[1].

The compound prepared in (1.5 kg) was added to acetonitrile (16 L). A mixed solution of a 35percent HCl solution (0.91 kg) and purified water (9.5 kg) was slowly added over 2 hours to the mixture under stirring. The reaction mixture was stirred for additional 1 hour. After confirming with HPLC that the starting material was exhausted, the reaction was quenched. The reaction mixture was neutralized with sodium bicarbonate and then extracted with ethyl acetate. The separated organic layer was washed with a sodium chloride solution (1.5 kg) and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1.5 L) and then hexane (9 L) was slowly added thereto. The reaction mixture was cooled to about 10° C. and then stirred for 2 hours. The resulting precipitate was isolated by filtering under reduced pressure and then dried under reduced pressure at about 50° C. to give the titled compound (1.22 kg) as a white crystalline form (Yield: 88.4percent).[0062]HPLC percent Area: 98.555percentEXAMPLE-lOPREPARATION OF tert.-BUTYL (3R, 5S, 6E)-7-[2-CYCLOPROPYL-4-(4-• FLUOROPHENYL)QUINOLIN-3-YL]-3, 5-DfflYDROXY-6-HEPTENOATE [tertBUTYL PITAVASTATIN]Diprotected tert-butyl Pitavastatin (30 g, 0.058 mole) was suspended in acetonitrile (210 ml) and water (70 ml) at 25-30°C. The pH of the reaction mass was adjusted to 2.5 with dilute hydrochloric acid (0.1 molar). Thereafter, the reaction mass was heated to 50-55°C and progress of the reaction was monitored by HPLC After completion of reaction, pH of the reaction mass was adjusted to 8.5 with aqueous ammonia and stirred for 30 mm. Product was filtered and dried at 40-45°C under reduced pressure to obtain title compound.Yield: 27gChromatographic Purity (by HPLC): 99.6percent, Lactone diastereomer: 0.09percentThe compound prepared in (1.5 kg) was added to acetonitrile (16 L). A mixed solution of a 35percent HCl solution (0.91 kg) and purified water (9.5 kg) was slowly added over 2 hours to the mixture under stirring. The reaction mixture was stirred for additional 1 hour. After confirming with HPLC that the starting material was exhausted, the reaction was quenched. The reaction mixture was neutralized with sodium bicarbonate and then extracted with ethyl acetate. The separated organic layer was washed with a sodium chloride solution (1.5 kg) and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1.5 L) and then hexane (9 L) was slowly added thereto. The reaction mixture was cooled to about 10° C. and then stirred for 2 hours. The resulting precipitate was isolated by filtering under reduced pressure and then dried under reduced pressure at about 50° C. to give the titled compound (1.22 kg) as a white crystalline form (Yield: 88.4percent).[0062]HPLC percent Area: 98.555percentEXAMPLE-lOPREPARATION OF tert.-BUTYL (3R, 5S, 6E)-7-[2-CYCLOPROPYL-4-(4-• FLUOROPHENYL)QUINOLIN-3-YL]-3, 5-DfflYDROXY-6-HEPTENOATE [tertBUTYL PITAVASTATIN]Diprotected tert-butyl Pitavastatin (30 g, 0.058 mole) was suspended in acetonitrile (210 ml) and water (70 ml) at 25-30°C. The pH of the reaction mass was adjusted to 2.5 with dilute hydrochloric acid (0.1 molar). Thereafter, the reaction mass was heated to 50-55°C and progress of the reaction was monitored by HPLC After completion of reaction, pH of the reaction mass was adjusted to 8.5 with aqueous ammonia and stirred for 30 mm. Product was filtered and dried at 40-45°C under reduced pressure to obtain title compound.Yield: 27gChromatographic Purity (by HPLC): 99.6percent, Lactone diastereomer: 0.09percent250mL three-necked flask, Grilled smoked three times, Compound 8 (25.3 mmol, 1 eq) was added under a nitrogen atmosphere, THF (120 mL), MeOH (20 mL), Cooled to -40 C, 50% Et2BOMe / THF (10.1 g, 506 mmol, 2 eq) was added dropwise, -78 reaction 3h, NaBH4 (1.5 g, 40.5 mmol, 1.6 eq) was added at -40 C, -40 reaction 2h, AcOH (20 mL) / THF (20 mL) was added dropwise at -78 C, Completed, The temperature rose to 0 ~ 10 .THF was removed, MeOH (50 mL x 2) was added to azeotrope, H2O (80 mL) was added, DCM (80 mL), Liquid separation, The aqueous layer was extracted with DCM (50 mL × 2)The combined organic layers, Saturated NaCl wash, Dried over anhydrous Na2SO4, Spin dry, Product 9 (10.2 g, 84.4%) was obtained.To a 500 ml dry reaction flask, add anhydrous tetrahydrofuran (THF) 300 ml and anhydrous methanol 85 ml, add 6.3 gP-1, and replace the reaction system with nitrogen and stir until P-1 was completely dissolved.Cooled to -80 C to -85 C with liquid nitrogen, and 13.8 ml of a tetrahydrofuran solution of 1 M diethylmethoxyborane was added dropwise to control the rate of dropping to keep the temperature from -80 C to -85 C And the dropping time is about 30 min.Maintain the temperature between -80 ~ -85 , continue stirring 55 ~ 60min.And then evenly adding 0.6 g sodium borohydride in some parts, about 80 ~ 90min after adding, to maintain the temperature between -80 ~ -85 , this process requires 5.5 ~ 6h, the end of the reaction.And then heated to 20 C to 30 C in 2 hours. After 2 to 3 hours of continuous incubation, 1.2 g of glacial acetic acid was added, followed by distillation under reduced pressure at 45 C to 55 C to remove the organic solvent mixed with methanol and tetrahydrofuran to give an oil Things.After adding 50 ml of methanol to dissolve the oil, it was distilled under reduced pressure at 45 C to 55 C to remove methanol to obtain an oil.The mixture was further added with 50 ml of methanol to dissolve the oil and distilled under reduced pressure at 45 C to 55 C to remove methanol to give the final oil.Then, 50 ml of ethyl acetate and 50 ml of water were added to the final oil, and the mixture was stirred for 10 to 15 minutes. The mixture was allowed to stand and the aqueous layer was repeatedly extracted twice with ethyl acetate. Each time, 30 ml of acetic acid Ethyl ester, each stirring 10 ~ 15min, static liquid separation, and finally combined organic layer.The resulting organic layer was washed successively with 40 ml of a saturated aqueous solution of sodium bicarbonate and twice with a saturated aqueous sodium chloride solution, and the amount of the saturated aqueous sodium chloride solution was 40 ml each time for 10 to 15 minutes, Dispensing, discard the water layer.The organic layer was added with 2 g of anhydrous sodium sulfate and stirred for 30 min. The anhydrous sodium sulfate was removed by suction filtration. The filtrate was distilled at a temperature of 40 C to 50 C to remove the ethyl acetate organic solvent to obtain 6.1 g of P-2 Oil.

tert-Butyl Pitavastatin is used to prepare hemicalcium salt.

Molecular Weight:477.6
XLogP3:4.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:10
Exact Mass:477.23153666
Monoisotopic Mass:477.23153666
Topological Polar Surface Area:79.6
Heavy Atom Count:35
Complexity:725
Defined Atom Stereocenter Count:2
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes