CN115960035A - 一种盐酸多奈哌齐制备过程中杂质的控制方法 - Google Patents
一种盐酸多奈哌齐制备过程中杂质的控制方法 Download PDFInfo
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- indanone
- donepezil
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- 229960003135 donepezil hydrochloride Drugs 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 15
- 239000012535 impurity Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 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 abstract description 19
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- 239000002994 raw material Substances 0.000 claims 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 claims description 18
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种盐酸多奈哌齐的制备方法,其特征在于通过控制原料5,6‑二甲氧基‑1‑茚满酮中茚满酮二聚物杂质的含量≤0.15%,优选为≤0.10%。本发明提供的方法可以有效地解决盐酸多奈哌齐产品外观不合格的问题。
Description
技术领域
本发明涉及盐酸多奈哌齐合成过程中杂质的控制方法,属化工和化学医药领域。
背景技术
盐酸多奈哌齐,化学名是1-苄基-4-[(5,6-二甲氧基茚满酮-2-基)甲基]哌啶盐酸盐,它是同日本卫材公司开发的,适用于轻度或中度阿尔茨海默型痴呆症状的治疗。它具有高度选择性,剂量小,半衰期长,不良反应小,无肝脏毒性等优点。盐酸多奈哌齐结构式如下:
目前工业上应用有多条路线,其中应用较广的路线可以参考中国专利CN101321729A,即由5,6-二甲氧基-1-茚满酮(II)与1-苄基-4-哌啶甲醛(III)缩合得到多奈哌齐缩合物(IV),再经氢化、成盐得到盐酸多奈哌齐,合成路线如下所示:
盐酸多奈哌齐在中国药典的规定中性状为白色或类白色结晶性粉末,然而本发明人发现在生产盐酸多奈哌齐的过程中,偶尔出现盐酸多奈哌齐颜色偏绿,导致成品外观也不合格。
发明内容
本发明的目的是改进盐酸多奈哌齐的制备工艺,从而彻底解决盐酸多奈哌齐的外观不合格的现象。
本发明提供了一种盐酸多奈哌齐的制备方法,其特征在于控制原料5,6-二甲氧基-1-茚满酮(II)的茚满酮二聚物的含量≤0.15%,优选为≤0.10%。
所述茚满酮二聚物(本说明书中也称二聚物杂质)结构式如下所示:
根据本发明的一种具体实施方式,其包括如下步骤:
a)将上述的原料5,6-二甲氧基-1-茚满酮(II)和1-苄基-4-哌啶甲醛(III)在碱性条件下反应得到多奈哌齐缩合物(IV);
b)多奈哌齐缩合物(IV)经氢化,加盐酸成盐得到盐酸多奈哌齐,
合成路线如下所示:
对步骤a)所述反应中使用的溶剂没有特别限定,只要其可用于式(II)化合物与式(III)化合物的缩合反应中。所述溶剂包括例如卤代烃、醇溶剂、酯溶剂、醚溶剂、脂族烃溶剂、芳族烃溶剂。所述卤代烃包括二氯甲烷。所述醇溶剂包括例如甲醇、乙醇、2-丙醇和叔-丁醇。所述酯溶剂包括例如乙酸甲酯和乙酸乙酯。所述醚溶剂包括例如二乙醚、二异丙醚、叔-丁基甲基醚、四氢呋喃、1,2-二甲氧基乙烷和二噁烷。所述脂族烃溶剂包括例如戊烷、己烷、庚烷和环己烷。所述芳族烃溶剂包括例如苯、甲苯和二甲苯。
步骤a)所述反应中优选使用的溶剂选自二氯甲烷,甲苯和二甲苯。
对步骤a)使用的碱没有特别限定,只要其可用于所述缩合反应。例如,优选碱金属化合物例如碱金属氢氧化物、碱金属碳酸盐、碱金属氨化物、碱金属氰化物、碱金属C1-C4醇盐等。特别地,优选碱金属氢氧化物或碱金属C1-C4醇盐。碱金属氢氧化物包括例如氢氧化钠或氢氧化钾。C1-C4醇盐包括例如甲醇盐、乙醇盐、丙醇盐和丁醇盐。
步骤a)使用的碱优选为金属氢氧化物或碱金属C1-C4醇盐,进一步优选氢氧化钠或氢氧化钾。
步骤b)的反应溶剂可选自四氢呋喃,乙酸乙酯,甲苯,甲醇,乙醇异丙醇。
步骤b)可用选自雷尼镍,钌,铑或钯金属的金属催化剂下进行催化氢化,优选为钯/碳。反应温度为约20℃至约60℃。最优选在约30℃至35℃。在反应完成后,过滤催化剂,蒸馏除掉溶剂。然后将蒸馏的残余物加入盐酸溶液转化为盐酸多奈哌齐。
本发明通过在控制原料5,6-二甲氧基-1-茚满酮(II)中茚满酮二聚物的含量,有效地解决了盐酸多奈哌齐产品外观不合格的问题。通过本发明提供的方法,得到的盐酸多奈哌齐产品外观均为白色。
具体实施方式
以下制备盐酸多奈哌齐的实施例说明了本发明的性质,并且仅用于说明目的,不应解释为限制本发明的范围:
5,6-二甲氧基-1-茚满酮(II)的液相分析条件:
仪器:高效液相色谱配备UV检测器
色谱柱:ACE UltraCore Super C18 150mm*4.6mm,2.5μm
流动相:0.1%磷酸水溶液:乙腈=80:20(V/V)
柱温:35℃ 流速:1.0mL/min 检测波长:254nm
进样量:10μl 运行时间:30min
多奈哌齐缩合物液相分析条件:
仪器:高效液相色谱仪配备紫外检测器
色谱柱:Thermo Hypersil BDS-C8 250×4.6mm 5μm
流动相:1.36g磷酸二氢钾溶于1000mL水,加2mL三乙胺,用磷酸调pH6.0:
乙腈=70:30(V/V)
柱温:30℃ 检测波长:230nm 流速:1.0mL/min
进样量:10μl 运行时间:30min
本发明及实施例中所述的“含量”均为HPLC检测的峰面积比,代表各物质的相对百分含量。
制备例:茚满酮二聚物的制备
称取19.2g茚满酮,然后加入到500ml三口烧瓶中,加热至熔融状态,然后加入26.7g三氯化铝,反应3-5小时,然后降温至常温,加入300ml水淬灭,然后过滤,滤饼通过自动过柱机即可分离得到茚满酮二聚物杂质。
实施例1:
将20g 1-苄基-4-哌啶甲醛,200ml二氯甲烷,17g含有二聚物杂质含量为0.05%的5,6-二甲氧基-1-茚满酮(II),3.2g氢氧化钠放于500ml三口瓶中,回流反应24小时,冷却,加入水洗涤分层。有机层蒸馏至干,加入100ml乙醇室温打浆1h,过滤烘干得30g多奈哌齐缩合物(IV)(茚满酮二聚物杂质含量N.D,缩合物外观为白色)。
将得到的19g多奈哌齐缩合物加入到200ml四氢呋喃中,Pd/C下氢化,氢化结束后,减压蒸馏至干,加入50ml甲醇和7g盐酸,再加入异丙醚反析晶,过滤,烘干得13g粗品,将13g粗品用甲醇和水精制得到12g成品,杂质含量为N.D,外观为白色。
重复实施例1,将不同含量的二聚物杂质含量的茚满酮(II)代替实施例1的原料5,6-二甲氧基-1-茚满酮(II),结果如下所示:
Claims (9)
2.根据权利要求1所述的方法,其特征在于控制起始原料5,6-二甲氧基-1-茚满酮中茚满酮二聚物杂质的含量≤0.10%。
4.根据权利要求3所述的方法,步骤a)所述反应中使用的溶剂选自二氯甲烷,甲苯和二甲苯。
5.根据权利要求3所述的方法,步骤a)使用的碱优选金属氢氧化物或碱金属C1-C4醇盐。
6.根据权利要求5所述的方法,所述为氢氧化钠或氢氧化钾。
7.根据权利要求3所述的方法,步骤b)的反应溶剂可选自四氢呋喃,乙酸乙酯,甲苯,甲醇,乙醇异丙醇。
8.根据权利要求2所述的方法,步骤b)的氢化所用的催化剂选自雷尼镍,钌,铑或钯金属的金属催化剂下进行催化氢化。
9.根据权利要求8所述的方法,步骤b)的氢化所用的催化剂为钯/碳。
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