CN108047131A - 盐酸多奈哌齐杂质及其制备方法和用途 - Google Patents
盐酸多奈哌齐杂质及其制备方法和用途 Download PDFInfo
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- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
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- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
本发明公开了盐酸多奈哌齐杂质，即盐酸多奈哌齐杂质1、杂质2、杂质4；此外，还公开了杂质1、杂质2、杂质4、杂质5的制备方法和用途。本发明提供的盐酸多奈哌齐相关杂质及其制备方法为盐酸多奈哌齐中间体、原料药及其组合物的质量研究夯实了基础。
Description
技术领域
本发明属于药物合成技术领域，更具体地，涉及盐酸多奈哌齐相关杂质及其制备工艺。
背景技术
盐酸多奈哌齐是一种长效的阿尔茨海默病（AD）的对症治疗药。AD是一种以记忆减退为主要表现，伴有其他认知功能损害的获得性智能减退。近30年的研究表明：AD胆碱能神经元的进行性退变是记忆力减退、定向力丧失、行为和个性改变的原因，这种胆碱能理论已被组织学研究证实。盐酸多奈哌齐是第二代胆碱酯酶(ChE）抑制剂，其治疗作用是可逆性地抑制乙酰胆碱酯酶（AchE）引起的乙酰胆酰水解而增加受体部位的乙酰胆碱含量。多奈哌齐可能还有其他机制，包括对肽的处置、神经递质受体或Ca2+通道的直接作用。
盐酸多奈哌齐对AchE的选择亲和力比对丁酰胆碱酯酶（BchE）强1250倍，它能明显抑制脑组织中的ChE，但对心脏（心肌）或小肠（平滑肌）无作用，可能对胸部组织（横纹肌）有作用；对中枢神经毒性比他克林小。因此对盐酸多奈哌齐的研究具有广阔的前景。
根据盐酸多奈哌齐的合成工艺：
盐酸多奈哌齐杂质产生情况如下：
目前专利CN104892489报道了杂质6、7、8的定向合成方法，并在杂质6、杂质7的合成基础上可以进一步苄基化合成杂质10、杂质D；文献Sythetic Communications®,36:169-174,2006提及了杂质9的合成方法；专利CN102367236报道了杂质A的定向合成方法；CN102516156报道了杂质B及其定向合成的方法；专利CN105418488报道了杂质C及其定向合成的方法；文献Journal of Medicinal chemistry 51(12) 3588-3589,2008报道了杂质E及其定向合成的方法；文献RSC Advances,4(47)24619-24634;2014、文献SytheticCommunications®,36:169-174,2006分别报道了杂质杂质3、杂质H合成的方法；文献Medicinal Chemistry Research,21(6),726-733,2012报道了杂质F的合成方法；专利EP296560报道了杂质G的基本性质与氢谱特征、专利JP02169569提到了杂质G的制备；专利CN106631989报道了杂质I的合成方法。而杂质1、杂质2、杂质4及杂质5定向合成的方法未见相关报道；通过定向合成目标杂质，建立目标杂质的检测方法，对盐酸多奈哌齐原料药的质量进行有效控制具有重要的意义。
发明内容
本发明人首次提供了3种新物质：盐酸多奈哌齐杂质1、杂质2、杂质4，及杂质1、杂质2、杂质4、杂质5的制备方法；为盐酸多奈哌齐原料药的质量进行有效控制夯实了基础。
本发明的目的是提供盐酸多奈哌齐的杂质化合物。
本发明的另一个目的是提供上述杂质化合物的制备方法。
本发明的第三个目的是提供上述杂质化合物的用途。
具体地说，在本发明的实施方案中，本发明提供了3种盐酸多奈哌齐杂质，即杂质1、杂质2、杂质4，其化学结构式如下所示:
第二方面，本发明提供了盐酸多奈哌齐4种杂质的制备方法；其中，杂质1的制备方法，包括如下步骤：
将5,6-二甲氧基-1-茚酮（SM1）、4-吡啶甲醛（SM2）、质子类有机溶剂1和有机碱混合后，于10~40℃搅拌反应，SM1反应完全后，过滤反应液；收集滤饼用质子类有机溶剂2和非质子类有机溶剂1的混合溶剂结晶得杂质1：
。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质1的制备方法，其中，4-吡啶甲醛（SM2）用量为5,6-二甲氧基茚酮（SM1）1~2倍（摩尔比）。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质1的制备方法，其中，反应温度为10~40℃，更优选为20~30℃。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质1的制备方法，其中，所述有机碱选自三乙胺、苯胺、N,N-二异丙基乙胺、正丙胺、或二乙胺，优选地为三乙胺；所述有机碱与5,6-二甲氧基-1-茚酮（SM1）的摩尔比为1~2:1。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质1的制备方法，其中，质子类有机溶剂1，选自乙醇、甲醇、或异丙醇或者它们中的一种与水混合的溶液，优选地为甲醇；所述质子类有机溶剂2，选自乙醇、甲醇、或异丙醇，优选地为甲醇；所述非质子类有机溶剂1选自二氯甲烷、三氯甲烷、四氢呋喃、乙酸乙酯、二氧六环、或丙酮，优选为二氯甲烷。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质1的制备方法，其中，质子类有机溶剂2和非质子类有机溶剂1的混合溶剂为二氯甲烷和甲醇的混合溶剂，二氯甲烷与甲醇的体积比为1:3~1:6。
在本发明的实施方案中，本发明还提供了盐酸多奈哌齐杂质2的合成路线和方法，包括如下步骤：
将5,6-二甲氧基-1-茚酮（SM1），4-吡啶甲醛(SM2)，质子类有机溶剂3和无机碱混合后，搅拌并升温至50~65℃反应，反应完全；过滤、洗涤即得；
。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质2的制备方法，其中，所述4-吡啶甲醛（SM2）用量为5,6-二甲氧基-1-茚酮（SM1）1.0~2.0倍（摩尔比）；所述反应的反应温度为50~65℃，更优选为60~65℃；所述质子有机溶剂3选自甲醇、乙醇、异丙醇、或乙二醇等，优选为甲醇。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质2的制备方法，其中，所述无机碱为碱金属碳酸盐、或碱金属氢氧化物，优选地为氢氧化钠。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质4的合成路线和制备方法，包括如下步骤：
将杂质1、质子类有机溶剂4、钯炭和有机酸1混合后，密封于氢化釜中，通入氢气然后升温并搅拌反应，反应结束后，过滤；减压浓缩滤液至无溶剂，产物经过萃取和洗涤、干燥、过滤，再次减压浓缩滤液至无溶剂，产物用非质子类有机溶剂2打浆即得；
。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质4的制备方法，其中，质子类有机溶剂4选自甲醇、乙醇、或它们中的一种与水的混合物，优选为甲醇；钯炭规格为10%含量，用量为杂质1用量的5重量%~15重量%，优选为8重量%~12重量%；有机酸1选自对甲苯磺酸、冰乙酸，优选为冰乙酸，用量为杂质1的1.0~2.0倍当量（摩尔比），优选为1.1~1.5倍当量。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质4的制备方法，其中，反应温度为50~80℃，优选为70~80℃；产物打浆温度为50~65℃，优选为60~65℃，降温温度为20~30℃；所用非质子有机溶剂2选自甲苯、四氢呋喃、乙酸乙酯、二氧六环、丙酮等，优选为四氢呋喃。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质5的合成路线和制备方法，包括如下步骤：
将杂质4、非质子有机溶剂3、有机酸2混合，搅拌并升温反应，反应结束后，将反应液浓缩，产物经萃取、洗涤、干燥后，结晶即得；
。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质5的制备方法，其中，反应温度为100~111℃，优选为105~111℃。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质5的制备方法，其中，非质子类溶剂3选自甲苯、丙酮、四氢呋喃、二甲苯、二氧六环等，优选为甲苯；有机酸2选自对甲苯磺酸、冰醋酸、三氟乙酸等，优选为对甲苯磺酸。有机酸2的用量为杂质4的1.5~3.0倍当量，优选为2.0~2.5倍当量。
在本发明的实施方案中，本发明提供的盐酸多奈哌齐杂质5的制备方法，其中，杂质5的结晶溶剂为二氯甲烷/甲醇的混合溶剂，体积比为2:1~4:1，结晶温度0~20℃，优选为0~10℃。
第三方面，本发明提供了盐酸多奈哌齐杂质1、盐酸多奈哌齐杂质2、盐酸多奈哌齐杂质4、盐酸多奈哌齐杂质5作为盐酸多奈哌齐中间体、原料药及其复方制剂质量研究的对照品的用途。
本发明的有益效果在于：
首次提供了盐酸多奈哌齐杂质1、杂质2、杂质4、杂质5制备的方法；首次合成了新物质：盐酸多奈哌齐杂质1、杂质2、杂质4；且所述方法制备得到的盐酸多奈哌齐杂质1、杂质2、杂质4、杂质5的纯度均在95％以上，可以作为对照品用于盐酸多奈哌齐中间体、原料药及其相关制剂质量研究。
附图说明
图1表示的是盐酸多奈哌齐杂质1的液相图谱。
图2表示的是盐酸多奈哌齐杂质2的液相图谱。
图3表示的是盐酸多奈哌齐杂质4的液相图谱。
图4表示的是盐酸多奈哌齐杂质5的液相图谱。
具体实施方式
下面通过本发明实施例进行具体描述本发明的实施方案。
实施例1、盐酸多奈哌齐杂质1的制备
将SM1（20.0g ，104mmol）、甲醇510ml和SM2（12.2g ，114mmol）加入反应瓶，搅拌下滴加三乙胺（11.6g，114mmol）,滴毕，于20~30℃下搅拌反应, TLC监测反应(展开剂：二氯甲烷：甲醇=15：1)完全后，再冷却反应液至0~5℃搅拌30~40min，过滤，收集滤饼，用二氯甲烷：甲醇=3:1的溶剂200ml溶解后，滴加甲醇500ml，固体析出。降温至0~5℃搅拌1~2h，过滤，收集滤饼于40℃减压干燥得到类白色结晶性粉末20.4g，收率为65.5%，HPLC纯度：98.50%。1HNMR (600 MHz, CDCl3)1.79(S,1);2.75(m,1), 3.04(m,2), 3.88(s,3), 3.94(s,3),5.56(s,1), 6.83(s,1), 7.14(s,1), 7.38(d,2), 8.56(m,2)，MS(m/z)：322[M+Na]+为杂质1的分子离子峰。
色谱条件：用十八烷基硅烷键合硅胶为填充剂（Agilent ZORBAX SB-C18 4.6×250mm，5μm色谱柱适用），检测波长为215nm，流速为1.0ml/min，进样量5μl，柱温为30℃，以乙腈-1.0g/L十二烷基硫酸钠=35:65并用磷酸调节pH至2.5为流动相。专属性检测结果：
结论：溶剂不干扰各成分的检测，且各成分分离度均大于3.0，说明本方法专属性良好。
质谱检测条件：
氢谱检测条件：
实施例2、盐酸多奈哌齐杂质2的制备
将SM1（20.0g ，104mmol）、甲醇510ml和SM2（12.2g ，114mmol）加入反应瓶，搅拌下滴加三乙胺（11.6g，114mmol）,滴毕，于室温下搅拌反应, TLC监测反应(展开剂：二氯甲烷：甲醇=15：1)完全后，再冷却反应液至0~5℃搅拌30~40min，过滤，收集滤饼，用二氯甲烷：甲醇=3:1的溶剂200ml溶解后，滴加甲醇500ml，固体析出。降温至0~5℃搅拌1~2h，过滤，收集滤饼于40℃减压干燥得到类白色结晶性粉末20.4g，收率为65.5%，HPLC纯度：98.50%。1H NMR (600MHz, CDCl3)1.69（s,2），2.80（dd,2）,3.70(s,3),3.77(s,3), 3.84(s,3), 3.92(s,3),3.76(m,1),3.90(m,1),4.00(d,1),4.47(dd,1),6.377(s,1)6.383(s,1),7.02(s,1),7.17(s,1),7.18(m,2),7.24(d,2) ,8.39(d,2) ,8.46(d,2)；13C NMR (150 MHz, CDCl3): δ =203.11，201.33,156.49,156.27，150.63,150.15,150.05,149.26,147.76,146.07,129.75
,128.35,123.63,106.80,105.88,105.21,103.94,69.40,58.01,56.38,56.33,56.24,56.18,53.19,52.67,45.06,29.45 ppm.
色谱条件：用十八烷基硅烷键合硅胶为填充剂（Kromasil 100-5-C18，4.6mm×250mm，5μm色谱柱适用），检测波长为286nm，流速为1.0ml/min，进样量20μl，柱温50℃，以0.1%磷酸溶液（三乙胺调节pH值至6.6三乙胺调）作为流动相A，乙腈作为流动相B。洗脱方式为梯度洗脱：
专属性检测结果：
结论：从上述结果可知，溶剂不出峰，不干扰各杂质的检测，各组分分离效果良好。
质谱检测条件;
氢谱检测条件：
实施例3、盐酸多奈哌齐杂质4的制备
取杂质1（15.0g, 50.0mmol ）加入反应瓶，加入180ml甲醇溶解，加入10%钯炭1.75g，加入冰醋酸3.90g。加毕，用氢气置换体系空气5次并充1氢至8bar。在70~80℃下反应, TLC监测反应 (展开剂：甲醇：二氯甲烷=1:10) 完全后，冷却至20~30℃，过滤，滤液于45℃减压浓缩。残留物中加入纯化水85ml，用10%氢氧化钠调pH=12~13，用二氯甲烷50ml/次萃取6次，合并有机相，用饱和食盐水100ml洗涤，洗毕有机相中加入无水硫酸钠15.0g搅拌干燥，过滤，滤液于40℃减压浓缩。残留物用四氢呋喃65ml回流打浆半小时，降至20~30℃，过滤，收集滤饼于50℃减压干燥得白色结晶性粉末8.45g，收率为55.23%。HPLC纯度：98.42%。1H NMR(600 MHz, CDCl3)1.32(m,2),1.64(m,2),2.02(m,1),2.51(s,2),2.64(m,2),2.84(m,1)
,3.01(m,1),3.18(m,3),3.89(s,3),3.96(s,3),4.09(m,1),6.89(s,1),7.14(s,1),306[M+H]+为杂质4的分子离子峰。
色谱条件：用十八烷基硅烷键合硅胶为填充剂（Agilent ZORBAX SB-C18 4.6s,3),4，5μm色谱柱适用），乙腈-0.05mol/L磷酸二氢钾（磷酸调节至pH2.5）=13:87作为流动相，检测波长为208nm，流速1.0ml/min，柱温40℃，进样量5μl。专属性检测结果：
结论：溶剂不干扰各成分的检测,，各待测成分峰形良好。
质谱检测条件;
氢谱检测条件：
实施例4、盐酸多奈哌齐杂质5的制备
取杂质4（2.0g, 6.56mmol ）加入反应瓶，加入40ml甲苯溶解，再加入2.48g对甲苯磺酸。加毕，在回流下反应, TLC监测反应 (展开剂：甲醇：二氯甲烷=1:9) 完全后，冷却至20~30℃，过滤，滤液于45℃减压浓缩。残留物加入二氯甲烷20ml和纯化水20ml，用10%氢氧化钠调pH=12~13，分出水相，用二氯甲烷15ml/次萃取3次后合并有机相，依次用饱和碳酸氢钠溶液30ml和饱和食盐水溶液40ml洗涤，再用无水硫酸钠10.0g干燥，过滤，滤液于45℃减压浓缩。残留物用二氯甲烷/甲醇（v/v）=2/1的溶剂溶清，滴加异丙醚至体系浑浊，回流溶清，滴加异丙醚至固体析出；降至0~10℃搅拌30~40min，过滤，收集滤饼于50℃减压干燥得灰白色结晶性粉末0.5g，收率为26.6%。HPLC纯度：97.53%。1H NMR (600 MHz, CDCl3)7.26(s,1),6.90(s,1)6.62(s,1),3.97(s,3),3.91(s,3),3.60(s,2),3.60(d,2),3.04(m,2),2.63(m,1),2.00(m,4), 288[M+H]+为杂质5的分子离子峰。
色谱条件：用十八烷基硅烷键合硅胶为填充剂（Agilent ZORBAX SB-C18 4.6m,1),2，5μm色谱柱适用），乙腈-0.05mol/L磷酸二氢钾（磷酸调节至pH2.5）=13:87作为流动相，检测波长为208nm，流速1.0ml/min，柱温40℃，进样量5μl。专属性检测结果：
结论：溶剂不干扰各成分的检测，各待测成分峰形良好。
质谱检测条件;
氢谱检测条件：
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管通过参照本发明的优选实施例已经对本发明进行了描述，但本领域的普通技术人员应当理解，可以在形式上和细节上对其作为各种各样的改变，而不偏离所附权利要求所限定的本发明的精神和范围。
Claims (12)
1.一种盐酸多奈哌齐杂质1，其结构如下：
。
2.一种盐酸多奈哌齐杂质2，其结构如下：
。
3.一种盐酸多奈哌齐杂质4，其结构如下：
。
4.权利要求1所述盐酸多奈哌齐杂质1的制备方法，包括如下步骤：
将5,6-二甲氧基-1-茚酮（SM1）、4-吡啶甲醛（SM2）、质子类有机溶剂1和有机碱混合后，于10~40℃搅拌反应，SM1反应完全后，过滤反应液；收集滤饼用质子类有机溶剂2和非质子类有机溶剂1的混合溶剂结晶得杂质1
。
5.如权利要求4所述盐酸多奈哌齐杂质1的制备方法，其中，5,6-二甲氧基-1-茚酮与4-吡啶甲醛的摩尔比为1：1~2，有机碱与5,6-二甲氧基-1-茚酮的摩尔比为1~2:1；或
所述质子类有机溶剂1，选自乙醇、甲醇、或异丙醇或者它们中的一种与水混合的溶液，优选地为甲醇；所述质子类有机溶剂2，选自乙醇、甲醇、或异丙醇，优选地为甲醇；所述非质子类有机溶剂1选自二氯甲烷、三氯甲烷、四氢呋喃、乙酸乙酯、二氧六环、或丙酮，优选为二氯甲烷；所述有机碱，选自三乙胺、苯胺、N，N-二异丙基乙胺、正丙胺、或二乙胺；
所述质子类有机溶剂2和非质子类有机溶剂1的混合溶剂为二氯甲烷和甲醇的混合溶剂，二氯甲烷与甲醇的体积比为1:3~1:6；
反应温度为10~40℃，优选为20~30℃。
6.权利要求2所述盐酸多奈哌齐杂质2的制备方法，包括如下步骤：
将5,6-二甲氧基-1-茚酮（SM1），4-吡啶甲醛(SM2)，质子类有机溶剂3和无机碱混合后，搅拌并升温反应，反应完全；过滤、洗涤即得；
。
7.如权利要求6所述盐酸多奈哌齐杂质2的制备方法，其中，4-吡啶甲醛（SM2）用量为5,6-二甲氧基-1-茚酮（SM1）1.0~2.0倍（摩尔比）；所述反应的反应温度为50~65℃，更优选为60~65℃；所述质子类有机溶剂3选自甲醇、乙醇、异丙醇、或乙二醇，优选为甲醇；无机碱选自氢氧化钠、氢氧化钾、或碳酸钾，优选地为氢氧化钠。
8.如权利要求3所述盐酸多奈哌齐杂质4的制备方法，包括如下步骤：
将杂质1、质子类有机溶剂4、钯炭和有机酸1混合后，密封于氢化釜中，通入氢气然后升温并搅拌反应，反应结束后，过滤；减压浓缩滤液至无溶剂，产物经过萃取和洗涤、干燥、过滤，再次减压浓缩滤液至无溶剂，产物用非质子类有机溶剂2打浆即得；
。
9.如权利要求8所述盐酸多奈哌齐杂质4的制备方法，其中，所述质子类有机溶剂4选自甲醇、乙醇、或它们中的一种与水的混合物，优选为甲醇；钯炭规格为10%含量，用量为杂质1用量的5重量%~15重量%，优选为8重量%~12重量%；有机酸1选自对甲苯磺酸、冰乙酸，优选为冰乙酸，用量为杂质1的1.0~2.0倍当量（摩尔比），优选为1.1~1.5；
反应温度为50~80℃，优选为70~80℃；产物打浆温度为50~65℃，优选为60~65℃，降温温度为20~30℃；所用非质子有机溶剂2选自甲苯、四氢呋喃、乙酸乙酯、二氧六环、丙酮等，优选为四氢呋喃。
10.盐酸多奈哌齐杂质5的制备方法，包括如下步骤:
将杂质4、非质子有机溶剂3、有机酸2混合，搅拌并升温反应，反应结束后，将反应液浓缩，产物经萃取、洗涤、干燥后，结晶即得；
。
11.如权利要求10所述盐酸多奈哌齐杂质5的制备方法，其中，所述非质子类有机溶剂3选自甲苯、丙酮、四氢呋喃、二甲苯、二氧六环等，优选为甲苯；有机酸2选自对甲苯磺酸、冰醋酸、三氟乙酸等，优选为对甲苯磺酸；
对甲苯磺酸的用量为杂质4的1.5~3.0倍当量，优选为2.0~2.5倍当量；反应温度为100~111℃，优选为105~111℃；所述结晶的溶剂为二氯甲烷/甲醇的混合溶剂，体积比为2:1~4:1，结晶温度0~20℃，优选为0~10℃。
12.如权利要求1、2、或3所述盐酸多奈哌齐杂质1、2、或4作为盐酸多奈哌齐中间体、原料药及其处方制剂质量研究的对照品的用途。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007108011A2 (en) * | 2006-03-20 | 2007-09-27 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure donepezil |
| CN102367236A (zh) * | 2011-11-30 | 2012-03-07 | 陕西方舟制药有限公司 | 一种盐酸多奈哌齐的合成工艺 |
| CN103992263A (zh) * | 2014-05-22 | 2014-08-20 | 浙江海正药业股份有限公司 | 一种多奈哌齐的纯化方法 |
-
2017
- 2017-12-08 CN CN201711290480.XA patent/CN108047131A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007108011A2 (en) * | 2006-03-20 | 2007-09-27 | Ind-Swift Laboratories Limited | Process for the preparation of highly pure donepezil |
| CN102367236A (zh) * | 2011-11-30 | 2012-03-07 | 陕西方舟制药有限公司 | 一种盐酸多奈哌齐的合成工艺 |
| CN103992263A (zh) * | 2014-05-22 | 2014-08-20 | 浙江海正药业股份有限公司 | 一种多奈哌齐的纯化方法 |
Non-Patent Citations (2)
| Title |
|---|
| HACHIRO SUGIMOTO ET AL.: "Synthesis and Anti-Acetylcholinesterase Activity of 1-Benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine hydrochloride (E2020) and Related Compounds", 《BIOORGONIC & MEDICINAL CHEMISTRY LETTERS》 * |
| XINZHENG CHEN ET AL.: "Blue-light-promoted carbon–carbon double bond isomerization and its application in the syntheses of quinolines", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105862A (zh) * | 2020-08-29 | 2022-03-01 | 浙江华海药业股份有限公司 | 盐酸多奈哌齐杂质及其制备方法 |
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