| 71% |
With sodium hydrogen sulfate; copper(l) iodide; sulfuric acid; potassium tert-butylate; In diethylene glycol dimethyl ether; at 115℃; |
Step l[00285] Activated cuprous iodine: Cuprous iodide (1Og) and sodium bisulfate (lmol/L,50ml) were placed in a round-bottom flask. Sulfuric acid (lmol/L, 10) was added and the solution was stirred for 15 minutes at ambient temperature. The solution was filtered; the filter cake was washed with water (5OmL) and tetrahydrofuran (50mLx3), and then dried under reduced pressure.; Step 5[00289] 11 -Cvclopropyl-5.11 -dihvdro-4-methyl-6H-dipyridor3 ,2.-b :2 ' .3 ' -el 1.41- diazepin-2-one (Nevirapine): A solution of 7V-(2-chloro-4-methylpyridin-3-yl)-2-(cyclopropylamino)nicotinamide (1Og, 33.11 mmol, 1.00 equiv) in l-methoxy-2- (2- methoxyethoxy)ethane (300 ml) was placed in a 500 ml 3 -necked round-bottom flask. The reaction was purged with nitrogen and maintained under an inert atmosphere of nitrogen. Potassium 2-methylpropan-2-olate (1 Ig, 98 mmol, 3.00 equiv) and activated cuprous iodide (5 g, 26 mmol) were added to the solution. The solution was allowed to react overnight while maintaining the temperature at 115 C in an oil bath. The solution was filtered, the filter cake was washed with ethyl acetate (5OmL), and the filtrate was collected and concentrated in vacuo using a rotary evaporator. The residue was purified by flash chromatography on silica gel (10% ethyl acetate in petroleum ether). The final product (6.3g, purity: 98%, yield:71%) was obtained as a yellow solid. |
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With sodium hydride; In diethylene glycol dimethyl ether; o-xylene; at 135 - 140℃; for 1.16667 - 1.33333h; |
Sodium hydride (9.15 g, 65 % w/w) was suspended in o-xylene (187.5 ml) at 25- 300C under nitrogen atmosphere and slowly heated to 130-1350C. N-(2-chloro-4- methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide (25 g) was dissolved in diglyme (50 ml) at 70-800C and added to the above suspension over a period of 10-20 min at 135-138C and stirred for 1 h at 135-1400C. Thereafter the reaction mixture was cooled to 5C and acetic acid (8.75 ml) was added slowly below 15C. Then cold DM water (100 ml) was added to the reaction mixture slowly below 15C and pH of the reaction mixture was adjusted to 6.5 using acetic acid (4.25 ml) at 5-100C. The temperature of the reaction mixture was raised to 20-250C and stirred for 1 h at 20-250C and product crystallizes out. The product obtained was filtered and washed with DM water (75 ml) and then with cyclohexane (50 ml) and suck dried the product under suction for 10 min. The wet product (27.5 g) was suspended in a mixture of methanol (750 ml) and DM water (175 ml) and heated to reflux at 700C, a clear solution formed. Carbon (2.5 g) was added and stirred for 30 min at reflux. Filtered the carbon in hot condition and washed with hot methanol (50 ml, 60-650C). Filtrate was concentrated under reduced pressure at 50-550C up to residual weight attained is approximately 225 g. Thereafter cooled the concentrated mass to 5-100C and stirred for 30 min at 5-100C. The product obtained was filtered and washed with cold DM water (25 ml, 5-100C), suck dried and dried at 65-7O0C under reduced pressure. <n="11"/>Yield - 17.5 gHPLC purity - 99.92 %Moisture content - 0.08 % w/w |
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With sodium hexamethyldisilazane; In tetrahydrofuran; at 30 - 66℃; |
EXAMPLE 5 Preparation of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (Nevirapine) Using sodium Hexamethyldisilazane A reaction flask equipped with a magnetic stirrer, temperature controller thermodouple, addition funnel and condenser with an oil bubbler for exclusion of ambient air was inerted with nitrogen and charged with 3.02 g (0.010 mol) of <strong>[133627-47-1]N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide</strong> from Example 4 and 30 ml of anhydrous THF. A 40% solution of sodium hexamethyldisilazane in THF (12.7 ml, 0.025 mol) was added dropwise maintaining the temperature of the reaction mixture at no more than 30 C. When the addition of the NaHMDS solution was completed, the reaction mixture was heated to reflux temperature (about 63-66 C.).When the reaction was completed (HPLC analysis), the mixture was cooled to ambient temperature.The reaction mixture was treated with 1.55 g (0.050 mol) of methanol and 0.45 g of water (0.025 mol).The mixture was concentrated on a rotary evaporator at 25-30 in.Hg with a 50-60 water bath temperature.The residual product weighing 4.44 g was triturated with 50 ml of water and the PH 10-12 solution was acidified to PH 3 by adding 10% HCl solution.The solid product was collected by filtration and the filter cake rinsed three times with 10 ml portions of water.The filter cake was dried in a vacuum oven at 50-60 C. to obtain nevirapine. |
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With sodium hydride; In diethylene glycol dimethyl ether; mineral oil; at 80 - 130℃; |
EXAMPLE 6 Preparation of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (Nevirapine) Using sodium Hydride A 500 ml 4NRB flask with stirrer, temperature controller thermocouple, addition funnel and condenser with an oil bubbler to exclude air was inerted with nitrogen and charged with 15.00 g of 60% sodium hydride in a mineral oil slurry and 120 ml of diglyme.The mixture was heated to 130 C. and treated dropwise with a solution of 41.7 g (0.138 mol) of <strong>[133627-47-1]N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide</strong>, from Example 4, in 70 ml of diglyme at 80 C. The reaction mixture was heated at 130 C. until hydrogen evolution ceased.The mixture was cooled to ambient temperature and water (6.75 g) was added dropwise cautiously.When hydrogen evolution ceased, an additional 100 ml of water was added.Acetic acid (20 ml) was added to reduce the PH of the mixture from 11-13 to about 7.An additional 100 ml of water was added and the reaction mixture stirred under ambient conditions for 30 minutes while the product crystallized.The solid product was collected by filtration and the filter cake rinsed with 100 ml of water followed by 50 ml of cyclohexane to remove any residual mineral oil from the mineral oil-sodium hydride slurry.The wet cake was dried in a vacuum oven at 50 C. for 18 hours to obtain 35.58 g of nevirapine. |
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EXAMPLE 7Preparation of NevirapineSodium hydride (9.15 g, 65% w/w) was suspended in o-xylene (187.5 ml) at 25-30 C. under nitrogen atmosphere and slowly heated to 130-135 C. <strong>[133627-47-1]N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide</strong> (25 g) was dissolved in diglyme (50 ml) at 70-80 C. and added to the above suspension over a period of 10-20 min at 135-138 C. and stirred for 1 h at 135-140 C. Thereafter the reaction mixture was cooled to 5 C. and acetic acid (8.75 ml) was added slowly below 15 C. Then cold DM water (100 ml) was added to the reaction mixture slowly below 15 C. and pH of the reaction mixture was adjusted to 6.5 using acetic acid (4.25 ml) at 5-10 C. The temperature of the reaction mixture was raised to 20-25 C. and stirred for 1 h at 20-25 C. and product crystallizes out. The product obtained was filtered and washed with DM water (75 ml) and then with cyclohexane (50 ml) and suck dried the product under suction for 10 min. The wet product (27.5 g) was suspended in a mixture of methanol (750 ml) and DM water (175 ml) and heated to reflux at 70 C., a clear solution formed. Carbon (2.5 g) was added and stirred for 30 min at reflux. Filtered the carbon in hot condition and washed with hot methanol (50 ml, 60-65 C.). Filtrate was concentrated under reduced pressure at 50-55 C. up to residual weight attained is approximately 225 g. Thereafter cooled the concentrated mass to 5-10 C. and stirred for 30 min at 5-10 C. The product obtained was filtered and washed with cold DM water (25 ml, 5-10 C.), suck dried and dried at 65-70 C. under reduced pressure. Yield-17.5 g HPLC purity-99.92% Moisture content-0.08% w/w |
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