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Preparation method of rotigotine
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A technology of thiophene and solvent, applied in the new process field of rotigotine preparation, can solve the problems of increasing process steps and reducing yield, and achieve the effect of increasing yield and shortening synthesis steps
Active Publication Date: 2014-11-05
HENAN ACADEMY OF SCI CHEM RES INST CO LTD
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[0013] In the above-mentioned routes, it is inevitable to carry out chiral resolution in the synthesis process, which increases the process steps and reduces the yield
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[0035] For a better description of the present invention, the specific implementation is as follows:
example 1
[0037] (1) Take 3.52g (0.02mol) of 5-methoxy-2-tetralone, dissolve it in 20mL of dichloromethane, add 2 drops of glacial acetic acid dropwise, heat to 50°C for reflux reaction, and then slowly add 3.3 mL (0.04mol) n-propylamine, reacted for 5 hours. After the reaction was completed, filter and wash with 50 mL of isopropanol for 2 to 3 times to obtain 3.47 g of khaki solid compound imine (I).
[0038] (2) Dissolve 3.47g of compound imine (I), 5g of Hans ester 1,4-dihydropyridine (HEH) in toluene, add chiral 3,3′-(trifluoromethyl)phenylbis Naphthol phosphate 0.2g, Molecular sieve 3g, reflux at 60°C for 3 hours, filter, remove the solvent under pressure, the crude product is separated through a silica gel column, using chloroform and methanol as developing solvents to obtain a yellow solid, which is dried to obtain 2.10 g of chiral compound (II).
[0039] C 14 h 21 NO, 1 HNMR (400MHZ, DMSO): -CH 3 (δ=0.998,m,3H),-CH 2 (δ=1.718,m,3H),-NH(δ=2.294,m,1H),-CH 2 (δ=2.909,m,4H)...
example 2
[0044] (1) Take 1.056g (0.006mol) of 5-methoxy-2-tetralone, dissolve it in 5mL of dichloromethane, add 0.2mL of glacial acetic acid dropwise, heat to 70°C for reflux reaction, and then slowly add 1mL dropwise (0.012mol) n-propylamine, reacted for 5 hours. After the reaction was completed, filter and wash with 6 mL of isopropanol for 2 to 3 times to obtain 1.04 g of khaki solid compound imine (I).
[0045] (2) Dissolve 1.04g of compound imine (I), 1.2g of Hans ester 1,4-dihydropyridine (HEH) in toluene, add chiral 3,3'-(trisilylmethyl)phenyl Binaphthyl Phosphate 0.05g, Molecular sieve 1g, reflux at 40°C for 3.5 hours, filter, remove the solvent under pressure, the crude product was separated through a silica gel column, using chloroform and methanol as developing solvents to obtain a yellow solid, which was dried to obtain 0.63g of chiral compound (II). C 14 h 21 NO, 1 HNMR (400MHZ, DMSO): -CH 3 (δ=0.998,m,3H),-CH 2 (δ=1.718,m,3H),-NH(δ=2.294,m,1H),-CH 2 (δ=2.909,m,4H)...
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Abstract
The invention discloses a preparation method of rotigotine, and belongs to the technical field of medicine synthesis. According to the method, 5-methoxy-2-tetralone is used as a raw material for amination, asymmetric reduction, halogenation and methoxyl group removal four step reaction for synthesis of chiral rotigotine {(-)-(S)-2-(N-propyl-N-(2-(2-thiophene) ethyl] amino]-5-hydroxy-1, 2, 3, 4-tetralin}. According to the method, a simplex stereoscopic structural compound is synthesized by stereo selective chemical reaction, in the asymmetric reduction process, hantzsch ester 1, 4-dihydropyridine (HEH) is used as a reducing agent, and chiral phosphoric acid is used as a catalyst to synthesize an important intermediate (S)-2-(N-n-propyl) amido-5-methoxy tetralin (II) with a simplex stereoscopic structure, the use of a chiral reagent for splitting to obtain the simplex stereoscopic structural compound is avoided, the synthesis procedure is shortened, the yield is improveds, and the method is favorable for industrialized production.
Description
technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a new preparation process of rotigotine. Background technique [0002] Parkinson's disease (Parkinson disease, PD), also known as tremor paralysis, is a chronic neurodegenerative disease of the central nervous system. The main cause is that the brain cells that produce dopamine (DA) in the substantia nigra of the patient's brain gradually decline, leading to The DA gradually decreases, which affects the function of the human body to control motor nerves. The typical symptoms of the disease are resting tremor, muscle rigidity, slowness of movement and impaired postural reflexes, and severe patients are accompanied by symptoms such as memory impairment and dementia. At present, there are nearly 2 million cases of PD patients in my country, 1.7% of males and 1.6% of females are older than 65 years old. As my country accelerates into an aging society, and people'...
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