CN110183375A - 一种高纯度盐酸多奈哌齐中间体的制备方法 - Google Patents
一种高纯度盐酸多奈哌齐中间体的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract description 6
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 title abstract description 6
- 229960003530 donepezil Drugs 0.000 title abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- 230000008025 crystallization Effects 0.000 claims abstract description 3
- IHMQOBPGHZFGLC-UHFFFAOYSA-N 5,6-dimethoxy-2,3-dihydroinden-1-one Chemical compound C1=C(OC)C(OC)=CC2=C1C(=O)CC2 IHMQOBPGHZFGLC-UHFFFAOYSA-N 0.000 claims description 60
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 229960003135 donepezil hydrochloride Drugs 0.000 claims description 24
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 claims description 24
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 239000002798 polar solvent Substances 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 abstract description 6
- -1 piperidines acetate Chemical class 0.000 abstract description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 2
- 238000000275 quality assurance Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 102100033639 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229940022698 acetylcholinesterase Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
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- 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
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Abstract
本发明涉及一种高纯度盐酸多奈哌齐中间4‑[(5,6‑二甲氧基‑1‑茚酮)‑2‑亚甲基]哌啶醋酸盐的制备方法。该方法为4‑[(5,6‑二甲氧基‑1‑茚酮)‑2‑亚甲基]‑甲基吡啶经钯炭催化加氢，反应完毕得到4‑[(5,6‑二甲氧基‑1‑茚酮)‑2‑亚甲基]哌啶的醋酸盐溶液，过滤钯炭后浓缩、析晶，过滤及烘干得到液相纯度大于99.8%的4‑[(5,6‑二甲氧基‑1‑茚酮)‑2‑亚甲基]哌啶醋酸盐。本发明方法得到的4‑[(5,6‑二甲氧基‑1‑茚酮)‑2‑亚甲基]哌啶醋酸盐纯度高，为下步制备高质量的盐酸多奈哌齐提供了质量保障；另外，收率高、反应条件较为简单、操作方便，适合工业化大批量生产。
Description
技术领域
本发明属于医药技术领域，涉及一种医药中间体的合成方法，具体涉及一种高纯度盐酸多奈哌齐中间体4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法。
背景技术
盐酸多奈哌齐是美国FDA批准的用于治疗阿尔茨海默病的药物，主要成分是5,6-二甲氧基-2-[(1-苯甲基-4-哌啶基)-甲基]-2,3-二氢-1H-茚酮盐酸盐。盐酸多奈哌齐是第二代胆碱酯酶抑制剂，其治疗作用是可逆性的抑制乙酰胆碱酯酶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它机制，包括对肽的处置、神经递质受体或Ca2+通道的直接作用。
4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐是合成盐酸多奈哌齐的主要中间体，文献一般报道是4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]吡啶加氢完毕，得到4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶的醋酸盐醇溶液，不经处理和纯化直接进行下步反应；但是制备高纯度4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的方法没有相关的文献报道。
发明内容
本发明公开了一种高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，该方法为4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶经钯炭催化加氢，反应完毕得到4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶的醋酸盐溶液，过滤钯炭后浓缩、析晶，过滤及烘干得到液相纯度大于99.8%的4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐。本发明方法得到的4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐纯度高，为下步制备高质量的盐酸多奈哌齐提供了质量保障；另外，收率高、反应条件较为简单、操作方便，适合工业化大批量生产。
本发明是通过下述的技术方案来实现的：
一种高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，包括以下步骤：
（1）4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶加入极性溶剂和乙酸，混合溶液以5%钯炭加氢还原至原料反应完全；
（2）反应液过滤钯炭，滤液减压浓缩至近干，趁热加入溶剂，降温析晶，过滤、烘干得到4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐。
反应路线如下：
其中，
所述步骤（1）中极性溶剂为甲醇、乙醇中的一种或两种，优选为甲醇。
所述步骤（1）中极性溶剂与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为2-10:1，乙酸与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶摩尔比为0.2-0.6:1，5%钯炭与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为1:10-100。
优选的，所述步骤（1）中极性溶剂与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为5-8:1，乙酸与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶摩尔比为0.4:1，5%钯炭与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为1:20-50。
所述步骤（1）反应温度为30-80℃，加氢还原所用氢气压力为0.2-2MPa。优选为60-65℃。
优选的，所述步骤（1）反应温度为50-65℃，加氢还原所用氢气压力为0.5-1.6MPa。
所述步骤（2）中溶剂为乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、正己烷中的一种或多种，所述溶剂与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为2-15:1。
优选的，所述步骤（2）中溶剂为乙酸乙酯，所述溶剂与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为5-10:1。
所述步骤（2）析晶温度为-5-20℃，优选为0-10℃。
上述的高纯度高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，详细步骤如下：
（1）300kg 4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶溶于1500kg甲醇，抽入120kg乙酸混合液，加5%钯炭6kg，抽真空，氮气置换三次，加氢至0.6-0.8MPa，升温至50-55℃，至原料反应完全；
（2）反应液过滤，滤液减压浓缩至近干，趁热加入乙酸乙酯1800kg，降温至0-5℃搅拌析晶，过滤、烘干得到4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐301.8kg，收率81.0%，液相纯度99.87%。
本发明的有益效果在于：
1．本发明的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，将4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶以高纯度醋酸盐的形式析晶，过滤得到的固体与母液分离，可以得到纯度大于99.8%的4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐，显著提高了4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶的质量。
2. 本发明的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐在乙酸乙酯析晶，得到高纯度的中间体(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐，高纯度的中间体有利于制备高质量的盐酸多奈哌齐，为下步制备高质量的盐酸多奈哌齐提供了质量保障。
3. 本发明的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法为中试及大生产规模的高纯度4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，该方法用来生产4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐安全可靠，反应条件较为简单、操作方便，收率高达81%以上，适合工业化大批量生产。
具体实施方式
下面结合具体实施例对本发明作更进一步的说明，以便本领域的技术人员更了解本发明，但并不因此限制本发明。
实施例1
（1）反应过程：
300kg 4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶溶于1500kg甲醇，抽入120kg乙酸混合液，加5%钯炭6kg，抽真空，氮气置换三次，加氢至0.6-0.8MPa，升温至50-55℃，至原料反应完全；
（2）后处理：
反应液过滤，滤液减压浓缩至近干，趁热加入乙酸乙酯1800kg，降温至0-5℃搅拌析晶，过滤、烘干得到4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐301.8kg，收率81.0%，液相纯度99.87%。
实施例2
（1）反应过程：
将300kg 4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶溶于1800kg甲醇，抽入120kg乙酸混合液，加5%钯炭7.5kg，抽真空，氮气置换三次，加氢至0.8-1.0MPa，升温至55-60℃，至原料反应完全；
（2）后处理：
反应液过滤，滤液减压浓缩至近干，趁热加入乙酸乙酯1500kg，降温至0-10℃搅拌析晶，过滤、烘干得到4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐312.3kg，收率83.8%，液相纯度99.90%。
实施例3
（1）反应过程：
将500kg 4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶溶于2000kg甲醇，抽入200kg乙酸混合液，加5%钯炭10kg，抽真空，氮气置换三次，加氢至1.2-1.4MPa，升温至60-65℃，至原料反应完全；
（2）后处理：
反应液过滤，滤液减压浓缩至近干，趁热加入乙酸乙酯2000kg，降温至0-10℃搅拌析晶，过滤、烘干得到4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐514.9kg，收率82.9%，液相纯度99.85%。
Claims (10)
1.一种高纯度盐酸多奈哌齐中间体4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，包括以下步骤：
（1）4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶加入极性溶剂和乙酸，混合溶液以5%钯炭加氢还原至原料反应完全；
（2）反应液过滤钯炭，滤液减压浓缩至近干，趁热加入溶剂，降温析晶，过滤、烘干得到4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐。
2.如权利要求1所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（1）中极性溶剂为甲醇、乙醇中的一种或两种。
3.如权利要求2所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（1）中极性溶剂为甲醇。
4.如权利要求1所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（1）中极性溶剂与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为2-10:1，乙酸与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶摩尔比为0.2-0.6:1，5%钯炭与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为1:10-100。
5.如权利要求4所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（1）中极性溶剂与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为5-8:1，乙酸与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶摩尔比为0.4:1，5%钯炭与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为1:20-50。
6.如权利要求1所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（1）反应温度为30-80℃，加氢还原所用氢气压力为0.2-2MPa。
7.如权利要求6所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（1）反应温度为50-65℃，加氢还原所用氢气压力为0.5-1.6MPa。
8.如权利要求1所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（2）中溶剂为乙酸乙酯、乙酸甲酯、乙酸丙酯、乙酸丁酯、正己烷中的一种或多种，所述溶剂与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为2-15:1。
9.如权利要求8所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（2）中溶剂为乙酸乙酯，所述溶剂与4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]-甲基吡啶质量比为5-10:1。
10.如权利要求1所述的高纯度盐酸多奈哌齐中间4-[(5,6-二甲氧基-1-茚酮)-2-亚甲基]哌啶醋酸盐的制备方法，其特征是，所述步骤（2）析晶温度为-5-20℃，优选为0-10℃。
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| CN102702078A (zh) * | 2012-05-29 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | 盐酸多奈哌齐的制备方法 |
| US20140128613A1 (en) * | 2011-03-25 | 2014-05-08 | Piramal Enterprises Limited | A process for preparation of intermediates of donepezil hydrochloride |
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| CN102060750A (zh) * | 2009-11-16 | 2011-05-18 | 天津必佳药业集团有限公司 | 一种盐酸多奈哌齐的制备方法 |
| US20140128613A1 (en) * | 2011-03-25 | 2014-05-08 | Piramal Enterprises Limited | A process for preparation of intermediates of donepezil hydrochloride |
| 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 |
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