Ropinirole Synthesis
1.1 3 – nitro-o- Xylene Preparation In 500 mL three-neck flask by adding 122.0 mL (1mol) of o-xylene, cooled to -5 , after stirring to 180.5 mL with a good mixed acid (71.0mL 65% nitric acid and 109.5 mL 98% concentrated
Sulfuric acid ) In 10 ~ 5 instilled among xylene, continue stirring 30min, standing divided as to lower waste acid, followed by water, 5%
NaOH Solution, water washing, drying, fractionation was fraction 75.6 g, bp 128 ~ 130 (26.66 mbar),
1.2 2 – methyl -3 – nitro benzyl ester diacetate
With mechanical agitation in the three neck bottle by adding 5.3 mL (0.04mol) 3 – Nitro – o-xylene and 47 mL acetic anhydride, 57mL glacial acetic acid and stir until fully dissolved, in ice-salt bath to cool to 0 and dropping concentrated sulfuric acid, and then from 10.0g (0.1 mol) of chromium trioxide paired with a solution of 30mL of acetic anhydride in 5 ~ 10 instilled in the reaction solution under the conditions and the conditions to continue stirring 3h, after approach the same with the literature 3 . flakes are yellow transparent solid mp 84 ~ 86 .
1.3 2 – methyl -3 – nitrobenzaldehyde Preparation
In 250 mL round bottom flask followed by adding 21.05 g (0.079 mol) 2 – A? 3 – nitro-benzyl diacetate (4), 120 mL 50% ethanol and 5mL concentrated sulfuric acid was refluxed 3 h with reference to separate the literature 3 water layer handled the product;
1.4 2 – methyl -3 – nitro-benzyl nitrile of Preparation
Obtained 4.15 g (0.025 1 mol) of 2 – methyl -3 – nitrobenzaldehyde (5) dissolved in 60 mL of
Methanol In ice-water bath cooling to 5 , the 0.7 g batches of sodium borohydride solution by adding cold response after 1h, room temperature overnight, the reaction solution diluted in 120 mL ice water, the separation of oil, with 15mL dry benzene, divided into 3 times with water, vacuum distillation
Solvent Have oily (6) crude ; to the oily 3.59 g (0.02 mol) added to 35mL of anhydrous ether, 4 times total phosphorus trichloride was added dropwise 6 mL, back, end with the TLC detection of the end of reaction After the cold reaction solution into 50mL of ice water, the separation of water layer, washed with ether and ether layer dried with Na2SO4, vacuum concentration was Chlorides (crude). in the above (0.0099 mol) Chlorides by adding 1.0 g sodium cyanide and 97 mL 75% ethanol, reflux 2.5h, the reaction solution into 150 mL water, place overnight, was light yellow crystals,
Filter , Recrystallization, were colorless Powder Like solid, filtration, vacuum drying was the product, mp 80 ~ 81 ;
1.5 2 – methyl -3 – nitro Benzoic Acid (abbreviated)
1.6 2 – methyl -3 – nitro-benzoyl dipropyl acetamide Preparation
22 g 2 – methyl -3 – nitrobenzoic acid by adding 25ml of thionyl chloride, 75C reflux 1h, the reaction solution concentrated under vacuum, toluene extraction 3 to 5 times (about 100ml), mixed extracts, 10C to add 13gNa2CO3 (13g +150 ml water), and n-2-propanamine (150ml toluene containing 10.6g0.12moln-2-propanamine) slow stirring, 30min later, remove the ice bath and continue stirring 1h, adding 0.5g of solid Na2CO3, 15min After separating organic layer, 5% Na2CO3 wash, then wash with 2NHCl last water, organic liquid with Mg2SO4 drying, vacuum concentration, and solvent, to give 2 – methyl -3 – nitrophenyl-N, N-2 n-propyl-acetamide;
1.7 2 – methyl -3 – nitro-benzoyl 2 propylamine Preparation
2.105nmol2-methyl -3 – nitrophenyl-N, N-dipropyl acetamide dissolved in 250ml of anhydrous tetrahydro-
Furan Adding 1mol B2H6 Reagent 160ml, at room temperature for 1h, then back to 2h, cooling, excess reagent destroyed with methanol, vacuum concentration, residue acidified with 40ml6NHCl 1h, cooled, then 40% NaOH alkaline Ph = 8.0, ether extracted three times, mixed pumping extracts washed with brine, vacuum concentration, and vacuum distillation 0. 1mmHg 115-118 degrees under the recovery fraction. To give 2 – methyl -3 – nitrophenyl-N, N-di-propylamine;
1.8 6 – (2 – 2-n-propyl-amino ethyl) -2 – nitrophenyl b preparation of ethyl ketone
At 18. 51g (0.07mole) 2 – methyl -3 – nitro-benzoyl 2 propylamine, add 2. 38g (0.103 mol) CH3CH2ONa, stirring, then dropping 15.42 g (0.103mole) diethyl oxalate, in the N2 in the back 20min, cooled to 0C, extracted with 700ml ice water, 3N HCl equivalent acidification 10Min, adding a small amount of ether, a little stirring, solid sodium bicarbonate regulation Ph = 8.5, extracted with ether 3 times, mixed, saturated salt water washing, Mg2SO4 dry
Activated Carbon Bleaching, vacuum concentrated to near dry, adding petroleum ether, mixing, filtration, was 6 – (2 – 2-n-propyl-amino ethyl) -2 – nitrophenyl ethyl ketone B;
1.9 6 – (2 – 2-n-propyl-amino ethyl) -2 – nitrophenyl acetic acid preparation
At 10 , 10. 24g (28.1mmoles) 6 – (2 – 2-n-propyl-amino ethyl) -2-nitrobenzene dissolved in acetone and ethyl 196ml2% of NaOH in the stirring, dropping 30% The H2O2 is about 5ml, remove the water bath, slowly warming to continue to stir 1.5h, until the color more and more light to filter small Xu insoluble, concentrated HCl conditioning Ph = 1.5, at 45C under vacuum concentration, half-way with water twice. A smaller residue Xu HCl, filtered, dried in the air, was 6 – (2 – 2-n-propyl-amino ethyl) -2 – nitrophenyl acetic acid;
1.10 Preparation of Ropinirole 5.83g6-(2 – 2-n-propyl-amino ethyl) -2 – nitrophenyl acetic acid dissolved in 250ml of ethanol, adding 0. 6g5% Pd-C, hydrogenation 50psi pressure, stirred 6 hours, filtered remove Pd-C, Pd-C ethanol washing,
Filtrate
Vacuum concentration, and then 550ml of acetonitrile in the recrystallization of the final product
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