盐酸舍曲林性质与制备最新资料大全.doc

盐酸舍曲林中文名称：盐酸舍曲林英文名称：Sertraline hydrochloride别名名称：(1S-顺式)-4-(3,4-二氯苯基)-1,2,3,4-四氢-N-甲基-1-萘胺盐酸盐 盐酸舍曲林 舍曲林盐酸盐 (1S,4S)-4-(3,4-二氯苯基)-1,2,3,4-四氢-N-甲基-L-萘胺盐酸盐更多别名：(1s,4s)-4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-N-Methyl-1-Naphthalenamine Hydrochloride (1s,4s)-4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-N-Methyl-1-Napthalenamine Hydrochloride (1s,4s)-1-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-4-(Methylamino)Naphthale分子式：C17H18Cl3N 分子量：342.69目录 编号系统 物性数据 毒理学数据 生态学数据 分子结构数据 计算化学数据 性质与稳定性 贮存方法 合成方法 用途 安全信息 表征图谱编号系统CAS号：79559-97-0MDL号：MFCD00895772EINECS号：RTECS号：QJ0352070BRN号：PubChem号：24278601物性数据1. 性状：白色固体。2. 密度(g/mL,25/4)：未确定 3. 相对蒸汽密度(g/mL,空气=1)：未确定4. 熔点()：246-2495. 沸点(,常压)：未确定6. 沸点(,5.2kPa)：未确定7. 折射率：未确定8. 闪点()：未确定9. 比旋光度()：未确定10. 自燃点或引燃温度()：未确定11. 蒸气压(kPa,25)：未确定12. 饱和蒸气压(kPa,60)：未确定13. 燃烧热(KJ/mol)：未确定14. 临界温度()：未确定15. 临界压力(KPa)：未确定16. 油水(辛醇/水)分配系数的对数值：未确定17. 爆炸上限(%,V/V)：未确定18. 爆炸下限(%,V/V)：未确定19. 溶解性：溶于DMSO。毒理学数据1. 急性毒性：人(口服)TDLo： 7mg/kg/2W-I 人(口服)TDLo： 7mg/kg/7D-I 由于食盐的LD50是3,000 mg/kg，BPA的急性毒性程度与食盐同。2. 生殖毒性：女士(口服)TDLo：56mg/kg大鼠1世代生殖毒性试验：NOAEL：1,000ppm(相当于50 mg/kg/日)。没有任何影响。小鼠2世代生殖毒性试验：最低剂量2,500ppm(相当于437 mg/kg/日)，出现异常。肾脏、肝脏重量增加、雄性生殖器重量减少。由于给量过高，无法得出NOAEL。 生态学数据 通常对水是不危害的，若无政府许可，勿将材料排入周围环境。计算化学数据 1. 疏水参数计算参考值(XlogP)：2. 氢键供体数量：23. 氢键受体数量：14. 可旋转化学键数量：25. 拓扑分子极性表面积(TPSA)：126. 重原子数量：217. 表面电荷：08. 复杂度：3229. 同位素原子数量：010. 确定原子立构中心数量：011. 不确定原子立构中心数量：012. 确定化学键立构中心数量：013. 不确定化学键立构中心数量：014. 共价键单元数量：1性质与稳定性 指定条件下稳定，远离氧化物。贮存方法 存放在密封容器内，并放在阴凉，干燥处。合成方法1. 3,4-二氯苯甲酰氯在三氯化铝存在下，对苯酰化得到3,4-二氯二苯甲酮。再在叔丁醇钾作用下，和丁二酸二乙酯反应，得化合物()。()水解并脱羧，得化合物()。()还原得化合物()，再二氯亚砜氯化为其酰氯()。然后在三氯化铝作用下环合为化合物()，最后和甲胺作用，得消旋的舍曲林。经拆分，可得光学活性的盐酸舍曲林。2. 4-(3,4-二氯苯基)-3,4-二氢-1(2H)-萘酮的制备在反应瓶中加入邻二氯苯500ml和-萘酚144g(1mol),搅拌下分批加入无水三氯化铝200g(1.5mol),120下反应,搅拌反应过程中,深黄色固体悬浮物逐渐溶解,溶解逐渐变成绿色.搅拌反应3h后冷却,加水500ml终止反应,水层用少量邻二氯苯洗涤。合并有机层,将其用无水MgSO4干燥,过滤,滤液蒸除溶剂,得浅褐色固体290g, 用己烷500ml类白色固体4-(3,4-二氯苯基)-3,4-二氢-1(2H)-萘酮275g,收率95%,mp9699(文献5,6报道mp99101).3. N-4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘基-N-甲基甲酰胺的制备在反应瓶中加入4-(3,4-二氯苯基)-3,4-二氢-1(2H)-萘酮275g(0.95mol)和N-甲基甲酰胺168g(0.85mol),搅拌混合后分批加入甲酸30g(0.65mol),在195200反应5h后停止加热,冷却,蒸除过量的N-甲基甲酰胺,剩余物冷却后得到浅棕色胶状体.加入乙酸乙酯200ml后室温搅拌1h.过滤,滤饼干燥,得灰白色固体N-4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘基-N-甲基甲酰胺267g,收率84%,mp109110 .4. 舍曲林(1S,4S)-异构体的制备在反应瓶中加入正丁醇200ml和N-4-(3,4-二氯苯基)-1,2,3,4-四氢-1-萘基-N-甲基甲酰胺137g(0.5mol),于100 搅拌下分批加入KOH110g(1.96mol),热回流4h.冷却,加入水200ml静置分层,有机相(含舍曲林顺式外消旋体)中加入热D-(-)-扁桃酸76g(0.5mol)的正丁醇(100ml)溶液,搅拌15min后冷却,有固体析出,放置冰箱过夜.过滤,滤饼用少量正丁醇洗涤后干燥#,得白色舍曲林D-(-)-扁桃酸盐粗品110.5g,用正丁醇100ml重结晶,得纯品100.3g,收率36.7%,mp190192.(文献5,6报道190191).取纯品100g (0.2mol)溶于水/乙醚(1:1), 搅拌下滴入5mol/L NaOH溶液,调至pH11,水层用乙醚洗,合并乙醚相,得舍曲林(舍曲林1S,4S-异构体)的乙醚溶液待用.5. 盐酸舍曲林的合成在烧杯中加舍曲林(1S,4S)-异构体的乙醚溶液和过量的36%盐酸,搅拌混匀,有白色固体生成,静置过夜后过滤,滤饼用乙醚洗,常温减压干燥,得白色盐酸舍曲林粗品65g,收率95%,mp242244 .(文献5,6报道收率96%,mp243245).粗品用乙醇100ml重结晶2次,得纯品盐酸舍曲林58g,精制收率89%,纯度99.5%(HPLC归一化法).用途1.强效和特异性的5-羟色胺吸收抑制剂。用于治疗抑郁症，预防抑郁症早期发作的复发或病情加重的复发。2.本品为新型选择性5-羟色胺再摄取抑制剂(SSRI).用于治疗抑郁症,预防抑郁症早期发作的复发或病情加重的复发,1996年又批准用于治疗强迫性精神障碍等症.该药抑制神经递质回收的专一性好,具有长效、体内清除快、对肝脏毒性低、适合老年患者服用等优点。安全信息 安全标识：S22 S24/25以下摘自/databases/8_0_wthriwdctvndwamw.htmlSertraline, CP-51974-1, CP-5197401(hydrochloride), 79617-96 -2-药物合成数据库 发布时间：2004-10-25 来源：本站整理 【药物名称】Sertraline, CP-51974-1, CP-5197401(hydrochloride)【化学名】(1S-cis)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine; (1S,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine【CAS登记号】79617-96-2, 79559-97-0 (HCl) 【结构式】 【分子式】C17-H17-Cl2-N 【分子量】306.238【原研厂家】Pfizer (Originator) 【研发状态】Not Determined【作用类别】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors【合成情况】来源J Label Compd Radiopharm合成路线标题Synthesis of 7-3H-(IS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-I- naphthalenamine hydrochloride (7-3H-sertraline)合成方法A new synthesis of 7-3H-sertraline has been described: The optical resolution of 7-bromo-1-(methylamino)tetraline (I) with N-acetyl-D-phenylalanine gives the (R)-isomer (II), which is acylated with formic acid - acetic anhydride to the formamide (III). The oxidation of (III) with KMnO4 in acetone - water yields 6-bromo-4(R)-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (IV), which, by a Grignard condensation with 3,4-dichlorophenylmagnesium bromide (V) in ether - toluene, affords 6-bromo-1(S)-(3,4-dichlorophenyl)-4(R)-(N-methylformamido)-1,2,3,4-tetrahydronaphthalen-1-ol (VI). The reduction of (VI) with triethylsilane tetrafluoroborate in dichloromethane gives 6-bromo-1(S)-(3,4-dichlorophenyl)-4(R)-(N-methylformamido)tetraline (VII), which is hydrolyzed with HCl in isopropanol to the corresponding methylamine (VIII). Oxidation of (VIII) with NaClO NaOCH3 in methanol - water yields the imine (IX), which is reduced with NaBH4 in THF - methanol to 6-bromo-1(S)-(3,4-dichlorophenyl)-4(S)-(methylamino)tetraline (X), along with starting (VIII). After separation by column chromatography, (X) is reduced with H2 over Pd/C or with T2 over Pd/C in THF containing triethylamine.作者Williams, M.T.; Welch, W.M.参考Williams, M.T.; Welch, W.M.; Synthesis of 7-3H-(IS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-I-naphthalenamine hydrochloride (7-3H-sertraline). J Label Compd Radiopharm 1993, 33, 2, 119出处J Label Compd Radiopharm1993,33,(2):119备注A new synthesis of 7-3H-sertraline has been described: The optical resolution of 7-bromo-1-(methylamino)tetraline (I) with N-acetyl-D-phenylalanine gives the (R)-isomer (II), which is acylated with formic acid - acetic anhydride to the formamide (III). The oxidation of (III) with KMnO4 in acetone - water yields 6-bromo-4(R)-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (IV) which, by a Grignard condensation with 3,4-dichlorophenylmagnesium bromide (V) in ether - toluene, affords 6-bromo-1(S)-(3,4-dichlorophenyl)-4(R)-(N-methylformamido)-1,2,3,4-tetr ahydronaphthalen-1-ol (VI). The reduction of (VI) with triethylsilane tetrafluoroborate in dichloromethane gives 6-bromo-1(S)-(3,4-dichlorophenyl)-4(R)-(N-methylformamido)tetraline (VII), which is hydrolyzed with HCl in isopropanol to the corresponding methylamine (VIII). Oxidation of (VIII) with NaClO NaOCH3 in methanol - water yields the imine (IX), which is reduced with NaBH4 in THF - methanol to 6-bromo-1(S)-(3,4-dichlorophenyl)-4(S)-(methylamino)tetraline (X), along with starting (VIII). After separation by column chromatography, (X) is reduced with H2 over Pd/C or with T2 over Pd/C in THF containing triethylamine.来源Drugs Fut合成路线标题Sertraline合成方法The Friedel-Krafts reaction of benzene (I) and 3,4-dichlorobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3,4-dichlorobenzophenone (III), which is condensed with diethyl succinate (IV) by means of potassium tert-butoxide in tert-butyl alcohol yielding ethyl 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoate (V). Hydrolysis of (V) with HBr in refluxing acetic acid affords 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate giving 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (VII), which is converted into the corresponding acyl chloride (VIII) with refluxing SOCl2. Cyclization of (VIII) with AlCl3 in CS2 yields 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (IX), which is treated with methylamine and TiCl4 in THF affording the corresponding Schiff base (X). Finally, this compound is reduced with H2 over Pd/C in THF.作者Casta馿r, J.; Serradell, M.N.参考Casta馿r, J.; Serradell, M.N.; Sertraline. Drugs Fut 1984, 9, 4, 277出处Drugs Fut1984,9,(4):277备注Synthesis of 090172: The Friedel-Krafts reaction of benzene (I) and 3,4-dichlorobenzoyl chloride (II) by means of AICI3 in dichloromethane gives 3,4-dichlorobenzophenone (III), which is condensed with diethyl succinate (IV) by means of potassium tert-butoxide in tert-butyl alcohol yielding ethyl 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoate (V). Hydrolysis of (V) with HBr in refluxing acetic acid affords 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate giving 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (VII), which is converted into the corresponding acyl chloride (VIII) with refluxing SOCl2. Cyclization of (VIII) with AICI3 in CS2 yields 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (IX), which is treated with methylamine and TiCl4 in THF affording the corresponding Schiff base (X). Finally this compound is reduced with H2 over Pd/C in THF (1). (Scheme 09017202a) Description Crystals, m.p. 290-1?(1). Manufacturer Pfizer, Inc. (USA). Reference 1. Welch, W.M., Harbert, C.A., Koe, B.K. and Kraska, A.R. (Pfizer, Inc.); EP 30.081.来源Tetrahedron合成路线标题Selective functionalization of 1,2-dihydronaphthalenols leads to a concise, stereoselective synthesis of sertraline合成方法A stereoselective synthesis of sertraline has been described: The silylation of 1,2-dihydronaphthalen-1(R)-ol (I) with tert-butyldiphenylsilyl chloride (TBDPS-Cl) gives the corresponding silyl ether (II), which is brominated with Br2 and triethylamine (TEA) in dichloromethane yielding the 4-bromo-compound (III). The condensation of (III) with 3,4-dichlorophenyltrimethyltin (IV), by means of a palladium catalyst affords the silylated phenylnaphthalenol (V), which is deprotected with TBAF and acetic acid to provide 4-(3,4-dichlorophenyl)-1,2-dihydronaphthalen-1(R)-ol (VI). The regioselective hydrogenation with H2 over chiral iridium or rhodium catalysts gives the (1R-trans)-tetrahydronaphthol (VII), which is treated with diphenylphosphoryl azide (DPPA) and DBU in THF yielding the (1S-cis)-azide (VIII). The reduction of (VIII) with H2 over Pd/C in ethanol affords the corresponding amine (IX), which is treated with ethyl chloroformate to give the expected carbamate (X). Finally, this compound is reduced with LiAlH(OMe)3 in THF. 2,4-Dichlorophenyltrimethyltin (IV) is prepared by reaction of 3,4-dichlorophenol (XI) with triflic anhydride in pyridine/CH2Cl2 to give triflate (XII), which is converted to (IV) by reaction with hexamethylditin and Pd(PPh3)4 in THF. The silylated naphthalenol (V) can also be obtained by condensation of (III) with the phenylboronic acid (XIII) in the presence of a palladium catalyst.作者Rovis, T.; Lautens, M.参考Rovis, T.; Lautens, M.; Selective functionalization of 1,2-dihydronaphthalenols leads to a concise, stereoselective synthesis of sertraline. Tetrahedron 1999, 55, 29, 8967出处Tetrahedron1999,55,(29):8967备注Synthesis of 090172 A stereoselective synthesis of sertraline has been described: The silylation of 1,2-dihydronaphthalen-1(R)-ol (I) with tert-butyldiphenylsilyl chloride (TBDPS-Cl) gives the corresponding silyl ether (II), which is brominated with Br2 and triethylamine (TEA) in dichloromethane yielding the 4-bromo-compound (III). The condensation of (III) with 3,4-dichlorophenyl-trimethyltin (IV), by means of a palladium catalyst affords the silylated phenylnaphthalenol (V), which is deprotected with TBAF and acetic acid to provide 4-(3,4-dichlorophenyl)-1,2-dihydronaphthalen -1(R)-ol (VI). The regioselective hydrogenation with H2 over chiral iridium or rhodium catalysts gives the (1R-trans)-tetrahydronaphthol (VII), which is treated with diphenylphosphoryl azide (DPPA) and DBU in THF yielding the (1S-cis)-azide (VIII). The reduction of (VIII) with H2 over Pd/C in ethanol affords the corresponding amine (IX), which is treated with ethyl chloroformate to give the expected carbamate (X). Finally, this compound is reduced with LiAlH(OMe)3 in THF. 2,4-Dichlorophenyltrimethyltin (IV) is prepared by reaction of 3,4-dichlorophenol with triflic anhydride in pyridine/CH2Cl2 to give triflate (XII), which is converted to (IV) by reaction with hexamethylditin and Pd(PPh3)4 in THF. The silylated naphthalenol (V) can also be obtained by condensation of (III) with the phenylboronic acid (XIII) in the presence of a palladium catalyst. Description alpha(25?(D) = +39.7?(c 0.3, MeOH/HCl).来源Tetrahedron合成路线标题An expedient total synthesis of cis-(+)-sertraline from D-phenylglycine合成方法A new total synthesis of sertraline has been described: The reduction of N,N-dibenzyl-D-phenylglycine methyl ester (I) with LiAlH4 in THF gives alcohol (II), which is oxidized to aldehyde (III) with oxalyl chloride in dichloromethane. The condensation of (III) with the phosphorane (IV) in benzene yields the unsaturated ester (V), which is reduced with Mg in methanol affording the saturated methyl ester (VI). Reduction of (VI) with LiAlH4 in THF provides the corresponding butanol derivative (VII), which is oxidized to the aldehyde (VIII) with pyridinium dichromate (PDC) in dichloromethane. The Grignard reaction of (VIII) with 3,4-dichlorophenylmagnesium bromide (IX) in THF affords the secondary alcohol (X), which is cyclized by means of AlCl3 in dichloromethane yielding a mixture of the desired cis-isomer (XI) along with some trans-isomer separated by column chromatography. Debenzylation of (XI) by H2 over Pd(OH)2 in methanol, followed by protection with Boc2O yields the carbamate (XII), which is methylated with methyl iodide and NaH in THF to afford the protected intermediate (XIII). Finally, compound (XIII) is deprotected with TFA in dichloromethane.作者Chandrasekhar, S.; Reddy, M.V.参考Chandrasekhar, S.; Reddy, M.V.; An expedient total synthesis of cis-(+)-sertraline from D-phenylglycine. Tetrahedron 2000, 56, 8, 1111出处Tetrahedron2000,56,(8):1111来源Org Process Res Dev合成路线标题Improved industrial synthesis of antidepressant sertraline合成方法The condensation of 1-naphthol (I) with an excess of o-dichlorobenzene (II) at 100 C by means of anhydrous AlCl3 gives 4-(3,4-dichlorophenyl)-1-tetralone (III), which is allowed to react with N-methylhydroxylamine (IV) and NaOAc in refluxing ethanol, yielding the nitrone (V). The reduction of (V) with H2 over RaNi in methanol affords a racemic cis/trans (9:1) mixture of methylamines, which by crystallization of its hydrochloride in ethanol provides pure (racemic)-(cis)-(VI). Finally, the target (1S)-(cis)-compound is obtained by optical resolution of (VI) with (R)-(-)-mandelic acid.作者Vukics, K.; et al.参考Vukics, K.; et al.; Improved industrial synthesis of antidepressant sertraline. Org Process Res Dev 2002, 6, 1, 82出处Org Process Res Dev2002,6,(1):82来源J Org Chem合成路线标题The preparation and intra- and intermolecular addition reactions of acyclic N-acylimines: Applications to the synthesis of (?-sertraline合成方法The reaction of intermediate 4-(3,4-dichlorophenyl)-4-phenylbutyric acid (I) (see scheme number 09017202a intermediate (VII) with (COCl)2 in dichloromethane gives the acyl chloride (II), which is condensed with methyl carbamate (III) in hot toluene to yield N-4-(3,4-dichlorophenyl)-4-phenylbutyrylcarbamic acid methyl ester (IV). The reduction of (IV) with DIBAL in toluene/dichloromethane affords the hydroxybutyl derivative (V), which is cyclized by means of TiCl4 in dichloromethane to provide N-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylcarbamic acid methyl ester as a mixture of the cis and trans isomers, easily separated by chromatography. Finally, the desired cis isomer (VI) is reduced with LiAlH4 in THF to afford the target (rac)-sertraline.作者DeNinno, M.P.; et al.参考DeNinno, M.P.; et al.; The preparation and intra- and intermolecular addition reactions of acyclic N-acylimines: Applications to the synthesis of (?-sertraline. J Org Chem 2001, 66, 21, 6988出处J Org Chem2001,66,(21):6988备注来源EP 0030081; JP 1981086137; US 4536518合成路线标题Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphtalenamine合成方法The Friedel-Krafts reaction of benzene (I) and 3,4-dichlorobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3,4-dichlorobenzophenone (III), which is condensed with diethyl succinate (IV) by means of potassium tert-butoxide in tert-butyl alcohol yielding ethyl 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoate (V). Hydrolysis of (V) with HBr in refluxing acetic acid affords 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate giving 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (VII), which is converted into the corresponding acyl chloride (VIII) with refluxing SOCl2. Cyclization of (VIII) with AlCl3 in CS2 yields 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (IX), which is treated with methylamine and TiCl4 in THF affording the corresponding Schiff base (X). Finally, this compound is reduced with H2 over Pd/C in THF.作者Kraska, A.R.; Welch, W.M. Jr.; Koe, B.K.; Harbert, C.A. (Pfizer Inc.)参考Kraska, A.R.; Welch, W.M. Jr.; Koe, B.K.; Harbert, C.A. (Pfizer Inc.); Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphtalenamine. EP 0030081; JP 1981086137; US 4536518 出处EP 0030081; JP 1981086137; US 4536518,():备注Synthesis of 090172: The Friedel-Krafts reaction of benzene (I) and 3,4-dichlorobenzoyl chloride (II) by means of AICI3 in dichloromethane gives 3,4-dichlorobenzophenone (III), which is condensed with diethyl succinate (IV) by means of potassium tert-butoxide in tert-butyl alcohol yielding ethyl 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoate (V). Hydrolysis of (V) with HBr in refluxing acetic acid affords 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate giving 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (VII), which is converted into the corresponding acyl chloride (VIII) with ref