| Schizophrenia is a common mental illness, according to WHO estimates that lifetime prevalence of schizophrenia was about 3.8-8.4‰ in a word, US studies have shown that the lifetime prevalence rate of the disease is 13‰.According to the 2002 Ministry of Health informed of schizophrenia prevalence rate of 6.2‰. The disease causes complex, has not been fully elucidated. Multi-onset in young adults, showed perception, thinking, emotion,will conduct, and many other disorders, mental activity and the surrounding environment and inner experience uncoordinated, divorced from reality.General disorders and obviously unconscious mental retardation, may have attention, working memory, abstract thinking, and information integration and other aspects of cognitive impairment, duration and more persistent, recurrent,and some patients with varying degrees of mental activity and social functions of recession defects.Drug treatment is still the preferred treatment, Lurasidone hydrochloride compared with placebo for patients with schizophrenia have significant effects.Lurasidone hydrochloride does not exist in the treatment of schizophrenia gender differences in age, race, and the significant treatment effect. For bipolar disorder, when lurasidone hydrochloride monotherapy group,compared with placebo was significant difference. Lithium or valproate as an adjunct to the treatment of bipolar disorder, although the statistical analysis is not carried out,but reports have proven their effectiveness. Lurasidone hydrochloride by clinical favored the development of this product has broad prospects.Lurasidone hydrochloride is a new molecular entity, developed by Japan’s Sumitomo Pharmaceuticals, an atypical antipsychotic, has been marketed in the United States.Sumitomo Pharmaceutical Co., Ltd. first racemic 1,2-bis(methylsulfonyloxy) cyclohexane(racemate),(3a R,4S,7R,7a S)-7-methylene-1H- isoindole-1,3(2H)- dione and 3-(1-piperazinyl)-1,2-benzisothiazole racemic get through a three-step as the main raw material nucleophilic substitution reaction lurasidone followed by chiral resolution to give optically pure lurasidone. Sumitomo Corporation of Japan and then conducted a series of studies on chiral synthesis and split, research-based Sumitomo Pharma Co.,Tianjin Institute of Pharmaceutical patents CN102731512 A reported lurasidone lurasidone intermediates and preparation methods in 2011, while India’s Ranbaxy Laboratories Limited(Ranbaxy Laboratories Limited) also applied for patents related WO2012107890A2 in 2012,but all were in lurasidone chiral separation stage to obtain optically pure lurasidone, in 2001 Sumitomo pharmaceutical Co.,Ltd. in the 1,2-cyclohexanedimethanol phase chiral resolution to give(1R, 2R)- cyclohexane dimethanol, avoiding low yield chiral resolution, solvent consumption and other shortcomings.Obtain optically pure chemical lurasidone split method has many drawbacks,as patent US5532372, the highest closing rate reached 50%, a lower yield; resolving reagent consumption, the higher the cost. Therefore chiral(1R, 2R)- cyclohexanedimethanol as a starting material to synthesize lurasidone hydrochloride, is a simple and feasible synthetic route,while isomer introduced from the starting materials and ease of tracking control.In this thesis, the optical purity of(1R, 2R)-1,2- cyclohexanedimethanol as a starting material, since the proposed synthetic route, synthesis performed lurasidone hydrochloride.Objective: The source control, by controlling the optical purity of the starting material to synthesize lurasidone hydrochloride, effectively control the content of an optical isomer, optimize the best synthesis process to obtain high purity lurasidone hydrochloride, and lurasidone hydrochloride structure melting point, IR, MS, NMR diffraction means to confirm.Methods: lurasidone can be divided into segments 1, fragment 2 and fragment 3. Fragment 1 may be made of(3a R, 4S, 7R, 7a S)-7- methylene-1H- isoindole-1,3-(2H)-dione obtained; fragment 2 may be made of1,2-cyclohexanedicarboxylic derivative of methanol is introduced into lurasidone in; fragment 3 is heterocycles 3-(1-piperazinyl)-1,2-benzisothiazole. By suitable chemical reaction to fragment 1,2 and 3 combined to obtain a lurasidone, by salt formation with hydrochloric acid lurasidone hydrochloride.Take the technical route is as follows:Optically pure(1R,2R)-1,2-cyclohexane dimethanol(SM1) were sulfonylation reaction to give(1R,2R)-1,2-bis(methanesulfonyloxy methyl via methanesulfonyl chlorideyl) cyclohexane(INT1); INT1 and 3-(1-piperazinyl)-1,2-benzisothiazole(SM2) can occur twice a nucleophilic substitution reaction, to give(3a R, 7a R)-4’-(1,2-benzisothiazol-3-yl) octahydro-spiro [2Hisoindole-2,1’-piperazinyl] methanesulfonate(INT1); then with(3a R,4SR, 7a S)-7-methylene-1H-isoindole-1,3(2H)-dione(SM3) substituted lurasidone obtained; finally lurasidone hydrochloride to give the hydrochloride salt.The result:Melting point: 265 ℃~275 ℃2 The infrared absorption spectrum(IR), IR cm-1: 3064.99, 1562.39,1504.53, 777.34, 740.69, demonstrated the presence of a benzene molecule. IR cm-1: 2258.72, proved the existence of the hydrochloride salt molecules.3 The high resolution mass spectrometry data M + H peak(493.26318).4 The proton nuclear magnetic resonance spectroscopy(1H-NMR) in a total of 16 sets of peaks corresponding hydrochloride lurasidone structure 36 protons, is consistent with lurasidone hydrochloride number of protons in the molecule; Carbon NMR spectra(13C-NMR) proved lurasidone HCl molecule has 28 carbon atoms, where secondary carbon 15, carbon eight tertiary,quaternary carbon 5, in the 13C-NMR spectrum, each carbon attribution lurasidone hydrochloride individual carbon molecules coincide.5 The single crystal X-diffractogram proved lurasidone hydrochloride molecule contains six chiral centers, the absolute configuration was confirmed,and proves the sample molecules with HCl salt, the ratio of 1: 1.Conclusion: The optimal synthesis process optimization, prepared with high purity hydrochloric acid lurasidone, by melting point, IR, MS, NMR,single crystal diffraction means confirmed lurasidone hydrochloride structure. |
PDF Full Text Request