CN101341122B - 生产高纯度多晶型(ⅰ)盐酸多奈哌齐的方法 - Google Patents
生产高纯度多晶型(ⅰ)盐酸多奈哌齐的方法 Download PDFInfo
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- 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 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 34
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- 229960003135 donepezil hydrochloride Drugs 0.000 title abstract 3
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000013078 crystal Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 53
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Natural products O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 229960003530 donepezil Drugs 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
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- ILXHUZNXWKFGHY-UHFFFAOYSA-N 2,3-dihydroinden-1-one;hydrochloride Chemical compound Cl.C1=CC=C2C(=O)CCC2=C1 ILXHUZNXWKFGHY-UHFFFAOYSA-N 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
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- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 abstract 1
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- 230000000877 morphologic effect Effects 0.000 abstract 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 1
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- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 5
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- 239000007787 solid Substances 0.000 description 5
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- QDUXDCXILAPLAG-UHFFFAOYSA-N hydron;1-methylpiperidine;chloride Chemical compound Cl.CN1CCCCC1 QDUXDCXILAPLAG-UHFFFAOYSA-N 0.000 description 2
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- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
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- FXFCQBKRSKWLPE-UHFFFAOYSA-N 1-benzoylpiperidine-4-carbaldehyde Chemical compound C1CC(C=O)CCN1C(=O)C1=CC=CC=C1 FXFCQBKRSKWLPE-UHFFFAOYSA-N 0.000 description 1
- NZVZVGPYTICZBZ-UHFFFAOYSA-N 1-benzylpiperidine Chemical class C=1C=CC=CC=1CN1CCCCC1 NZVZVGPYTICZBZ-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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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
本发明提供了新的、工业上可实现和经济上优选的生产高纯度多晶型(I)形态学晶型(I)的1-苄基-4-[(5,6-二甲氧基-1-茚满酮)-2-基]甲基哌啶盐酸盐,即在下列反应方案中显示的盐酸多奈哌齐。在该方法的关键步骤之一中,在氢化过程中,将5,6-二甲氧基-2-(吡啶-4-基亚甲基)茚满-1-酮盐酸盐使用Pd碳饱和,以获得超过9 7%HPLC纯度的4-[(5,6-二甲氧基-1-茚满酮)-2-基]-甲基哌啶。在结晶步骤中,使多奈哌齐-盐酸盐从含水醇溶剂中结晶以获得至少99.95%HPLC纯度的多晶型(I)。
Description
技术领域
本发明涉及用于制备高纯度多晶型(I)形态学晶型的盐酸多奈哌齐(donepezil),即,式I的1-苄基-4-[(5,6-二甲氧基-1-茚满酮)-2-基]甲基哌啶盐酸盐。
背景技术
式I的盐酸多奈哌齐因其优良的抗乙酰基胆碱酯酶活性而为人所知,并且它是用于治疗和预防疾病例如阿尔茨海默病和老年性痴呆的药物制剂中的有效活性成分。
已知有数种用于制备盐酸多奈哌齐的方法。它们中的大多数包括侧链中或/和吡啶环的乙烯双键(“叶立德”(ylide)键)的催化氢化。这些方法的一部分在苄化后应用氢化。根据欧洲专利No.296,560的实施例4,如在下一个方案中所示,通过还原1-苄基-4-[(5,6-二甲氧基-1-茚满酮)-2-基idenyl]-甲基-哌啶盐酸盐,获得盐酸多奈哌齐。根据该专利的实施例3,在-70℃,在丁基锂存在下,在工业上冗长的反应中,使5,6-二甲氧基-1-茚满酮与复杂且昂贵制备的N-苄基-哌啶(pyperidin)-4-甲醛反应,形成1-苄基-4-[(5,6-二甲氧基-1-茚满酮)-2-亚基(idenil)]-甲基-哌啶盐酸盐。
根据该专利中公开的另一种方法,使5,6-二甲氧基-1-茚满酮与 N-苯甲酰基-哌啶-4-甲醛反应,并且在形成的“叶立德”化合物饱和后,去除苯甲酰基,并通过N-苄化作用获得终产物。这些方法的共同缺点是昂贵的原料、极端的反应条件(-70℃)和低收率。
欧洲专利No.296,560中也揭示了通常使用的活性成分形式,多奈哌齐盐酸盐。将反应混合物通过柱色谱法纯化,然后将碱溶解于二氯甲烷中,然后将其用盐酸乙酸乙酯处理,接着在减压下蒸发至干燥。将结晶物质从二异丙醚中重结晶。
在PCT公开文本No.WO 97/46,526和WO 97/46,527中,根据更早的欧洲专利No.296,560可获得的盐酸多奈哌齐的晶型被命名为多晶型(I),并且其特征为在KBr压片中获得的下列IR谱带:463,502,563,589,604,701,750,759,799,860,922,947,972,1012,1012,1038,1104,1120,1128,1175,1192,1218,1250,1267,1316,1368,1410,1433,1440,1455,1472,1502,1591,1606,1644,1684,2412,2530,2559,2595,2620,2717,2840,2858,2924,3004,3074,3259,3373,3547,3589cm-1。
PCT公开文本No.WO 97/22,584中描述了下面复杂的九步合成,完成它同样非常困难:
在一部分合成方法中,将包括饱和侧链和哌啶环的中间体转变成终产物。
在PCT公开文本No.WO 00/09,483中,描述了同样复杂的七步合成,其中在苄化后,通过环化饱和的中间体形成吲哚环。
根据欧洲专利申请No.EP 1,386,607,通过将1-苄基-4-[{(5,6-二甲氧基-2-乙氧羰基-茚满-1-酮)-2-基}甲基]-哌啶去乙氧羰基化,获得多奈哌齐碱。
在PCT公开文本No WO 05/03,092中的相似程序中,同样在最后步骤中除去过量的基团(Y):
因为上述方法收率低,所以不能将它们考虑作为工业化方法。
下面方法的共同缺点是大量使用昂贵的亚当斯(Adam′s)催化剂(PtO2)。
在欧洲专利申请No.1,047,674中,首先由5,6-二甲氧基-1-茚满酮产5,6-二甲氧基-2-乙氧基羰基-2-[(4-吡啶基(piridyl))-甲基-]-1-茚满酮,接着去乙氧基羰基化,然后将其转换为苄基-卤化物季盐。通过氢化作用由季盐获得终产物。
根据欧洲专利申请No.711,756中描述的方法,在缩合反应中,由5,6-二甲氧基-1-茚满酮-4-醛(aldehide)制备4-[(5,6-二甲氧基-1-茚满酮)-2-亚基]-甲基-吡啶,用苄基-卤化物将其季铵化。将该季盐在催化环境中氢化:
上述方法的主要缺点是大规模使用昂贵的催化剂。我们的研究经验证明,在这些情况中,会出现大量的不需要的脱苄基化和过氢化的衍生物(例如环己酮(cyclohexyl one))。
在这些方法中,没有报告产物的纯度,并且没有给出盐酸盐的生产方法。
同样,在美国专利No.6,649,765中使用了4-[(5,6-二甲氧基-1-茚满酮)-2-亚基]-甲基-吡啶。在此,在存在10%(m/m)亚当斯催化剂下,将原料还原,然后将产生的吡啶衍生物苄化。
在PCT公开文本No.WO 04/082,685 A1中发现了相似的方法。在该方法中,借助于钯催化剂,将“叶立德”键氢化,然后将10%亚当斯催化剂用于吡啶环的氢化:
在Bioorganic & Medicinal Chemistry Letters 2 (2002) 2565-2568和Journal of Pharmaceutical and BiomedicinalAnalysis 35(2004)1047-1058中发表了在钯催化剂存在下的“叶立德”双键的饱和。后一篇论文描述了在基础培养基中,4-[(5,6-二甲氧基-1-茚满酮)-2-亚基]-甲基-吡啶产生了四种不同的产物,从该产物中可以制备多奈哌齐的杂质。
在这两项申请中,将4-[(5,6-二甲氧基-1-茚满酮)-2-亚基]-甲基-吡啶碱还原。在PCT公开文本No.WO 04/082,685中,提到但没有详细说明不仅可以适当还原碱,而且可以还原它的盐。然而,该申请没有报告关于所产生的产物的表观纯度差异。
在再现实验中,我们也确认了Journal of Pharmaceutical andBiomedicinal Analysis这篇论文的成立。在碱的还原过程中,令人遗憾的是,不仅“叶立德”双键和吡啶环被饱和,而且至少部分地5,6-二甲氧基-1-茚满酮的酮基团也被饱和。
根据PCT公开文本No.WO 05/076,749,多奈哌齐是在下面的反应方案中获得的:
在美国专利申请No.04/143,121中发现的方法中,将4-[(5,6-二甲氧基-1-茚满酮)-2-亚基]-甲基-吡啶氢化形成4-[(5,6-二甲氧基-1-茚满酮)-2-基]-甲基-哌啶,接着苄化得到多奈哌齐。根据我们的经验,以这种方法,通过碱的氢化作用,不能以工业化规模生产足够纯的多奈哌齐。
在PCT公开文本No.WO 05/044,805中,多奈哌齐是根据下面的反应方案进行制备的:
基本上已知氢化步骤影响终产物的纯度。关于氢化作用,虽然原则上该说明书根据实施例2和6确定了广泛多种的催化剂,但在实践中,仅限于明显使用PtO2催化剂。该催化剂的应用不仅使得该方法太昂贵,而且还涉及不能完全控制氢化以及不能避免产生氢化不足和过氢化的产物的风险。对甲苯磺酸盐的应用也有缺点,这可见于列表于这篇文章实施例1和2中的比较结果。
发明内容
本发明提供了新的、工业上可实现的而且经济上优选的生产高纯度多晶型(I)形态学晶型的1-苄基-4-[(5,6-二甲氧基-1-茚满酮)-2-基]甲基哌啶盐酸盐,即,在下列反应方案中所显示的盐酸多奈哌齐。
在该方法的关键步骤之一中,在氢化作用过程中,将5,6-二甲氧基-2-(吡啶-4-基亚甲基)茚满-1-酮盐酸盐使用Pd碳饱和,以得到超过97%HPLC纯度的4-[(5,6-二甲氧基-1-茚满酮)-2-基]-甲基哌啶。在结晶步骤中,使多奈哌齐-盐酸盐从含水醇溶剂中结晶,以获得至少99.95% HPLC纯度的多晶型(I)。
在我们的实验工作期间,我们意外地发现,如果在较不昂贵、工业上适用并且活性较低的钯碳催化剂存在下,在低温将相当反应活性的4-[(5,6-二甲氧基-1-茚满酮)-2-亚基]-甲基-吡啶盐酸盐(V)还原,那么能够以一个步骤、以适当的纯度和良好的收率获得想要的粗制4-[(5,6-二甲氧基-1-茚满酮)-2-基]-甲基-哌啶(V)。因为在后一步骤中建立苄基,所以可避免形成甲基-环己基过氢化污染。在该氢化方法中,达到了超过99.0% HPLC纯度。该早期中间体的高纯度确保了后面中间体的高纯度、多奈哌齐盐酸盐的高纯度,最后从中以希望的多晶型(I)晶型生成了非常纯的盐酸多奈哌齐,该终产物几乎没有任意一种溶剂残留。
结果,根据上述反应方案,可以确保产物的高纯度,其中使5,6-二甲氧基-1-茚满酮(II)和吡啶-4-醛(III)在缩合反应中反应,以得到4-[(5,6-二甲氧基-1-茚满酮)-2-亚基]-甲基-吡啶碱,然后将后者(IV)的盐酸盐在50-70℃温度和5巴压力下在乙酸中氢化,获得4-[(5,6-二甲氧基-1-茚满酮)-2-基]-甲基-哌啶(V)。用已知的方法从该中间体,通过苄化,接着为了进一步纯化进行包括相交换的盐-形成,产生盐酸多奈哌齐。从该物质,在含水醇溶解并沉积后,获得了特别纯的多晶型(I)盐酸多奈哌齐,几乎无溶剂残留。我们认识到这样高纯度的终产物只能在下列条件下获得:适当地确定所有连续步骤,特别是在氢化和结晶这两个关键的步骤中,令人意外的是使用了比先前更好的方法。
多奈哌齐盐酸盐的多晶型(I)的首次描述可以在欧洲专利No.296,560中发现,根据该专利,它是通过用柱色谱法纯化反应混合物形成的,将所述碱溶解于二氯甲烷中,然后将溶解的多奈哌齐碱用盐酸乙酸乙酯处理,接着在真空中蒸发。使用甲醇和异丙醚使结晶物质重结晶。
后来,在PCT公开文本No.′s WO 97/46,526和WO 97/46,527(欧洲专利No.′s 1,019,374和1,211,243)中,将该变体称为多晶型(I),其特征是从KBr压片获得的该物质的红外光谱吸收带。在这些文献中也描述了新晶型II、III、IV和V的表征。美国专利No.6,140,321描述了多晶型物(III)。PCT申请No.WO 04/87,660提供了无定形变体的制备方法。
根据PCT公开文本No.WO 97/46,527(和欧洲专利No.′s.1,019,374和1,211,243)的教导,盐酸多奈哌齐的多晶型(I)可以在实验室环境中制备。
在优选的方法之一(No.1-7)中,将多奈哌齐碱溶解于低碳数醇中,用盐酸或氯化氢形成盐,然后用叔丁基甲基醚(实施例29)或用二异丙基醚(实施例30)或用乙酸乙酯(实施例31)使需要的多晶型(I)沉淀。从不可处理的浆液中不能很好地过滤多晶型(I)。在工业 化规模中,不能应用该方法。在另一个优选的方法(No.1-9)中,通过重结晶进行制备盐酸多奈哌齐的多晶型(I)。将盐酸多奈哌齐溶解于低碳数醇中(有利地是溶于甲醇中),然后用不同的沉淀剂如叔丁基甲基醚(实施例39)或乙酸乙酯(实施例40)或正己烷(实施例41)降低其溶解度,并且将结晶物质过滤和干燥。在所有这些说明书中,将沉淀剂添加到多奈哌齐或多奈哌齐-盐酸盐的溶液中。该说明书没有报告多奈哌齐-盐酸盐(I)的溶剂残留数据。
值得注意的是,在这些实例中,一方面,所应用的溶剂不适于大规模生产(二乙基-醚的闪点是40℃),另一方面,仅在特别得到证明的情况下(如在二异丙基-醚的情况下)才允许它们在制药工业中使用。从文献(PCT公开文本No.WO 1997/46527)中也已知,甲基叔丁基醚也适合于生产多晶型(I)盐酸多奈哌齐。该说明书没有报告反向添加成,并且没有处理溶剂残留。
根据我们对大量实验数据的研究,我们得出如下结论:与所述添加顺序(将二乙基醚加入盐酸多奈哌齐甲醇溶液或相反)无关,多晶型物(III)能结晶出来,而不是需要的多晶型物(I)。经济工业化程序不能基于这种不确定的技术。在已知的程序中,使几乎都包含1mol结合水的多晶型(I)从无水溶剂中结晶出来。在实验期间,可以知道在60-80℃盐酸多奈哌齐可丢失该水,但在室温和40-60%相对湿度-它从空气中快速吸回水。我们得出如下结论:根据已知的程序,首先产生多晶型(I)的不稳定无水过渡变体,并且在处理过程中,该过渡形式变为稳定的含水多晶型(I)晶体变体。在大规模处理中,这种不受控制的形成是不容许的,因为在药物生产中,良好的再现性是一种基本要求。
令人意外地发现,所述产物的溶剂残留浓度非常依赖于成分的添加顺序。所以如果将盐酸多奈哌齐的无水甲醇溶液滴加到包含多晶型(I)晶种的甲基叔丁基醚溶剂中,那么产物的甲基叔丁基醚残留为大约2500ppm。相反,当将甲基叔丁基醚滴加到包含晶种的无水甲醇盐酸多奈哌齐溶剂中,那么甲基叔丁基醚的残留为大约6500ppm。
根据我们的研究,正如根据EP 1211243可以预期的,可以将应用 的醇的含水量进一步增加到某一界限而没有形成多晶型物(IV)的问题。如果溶液中的含水量是理论上1mol的2-20倍,形成了带有必需的1mol含水量的多晶型(I)。我们令人意外地体验到,溶剂残留数据非常依赖于所用醇的含水量。我们认为,如果将盐酸多奈哌齐溶解于包含2-18%水的甲醇中(有利地是包含4%的水),那么污染的溶剂残留将减少一个数量级,只有200-300ppm。通过将多晶型(I)晶种悬浮于沉淀溶剂(它难以溶解盐酸多奈哌齐),有利地确保了多晶型(I)的结晶。
我们进一步的研究揭示,多晶型(I)的形成需要适当调整温度。与成分的添加顺序无关,在20℃以上,多晶型物(III)结晶,降低温度有利于多晶型(I)的形成。然而,在太低的温度下,溶剂残留的量增加。
具体实施方式
实施例
实施例1:根据PCT公开文本No.WO 2005/044805 A1中实施例2制备2-(4-哌啶基甲基)-5,6-二甲氧基-1-二氢茚酮对甲苯磺酸盐的再现实验:
将4.02克2-(4-吡啶基(piridyl)亚甲基)-5,6-二甲氧基-1-二氢茚酮对甲苯磺酸盐溶解于300毫升无水甲醇中,接着添加330毫克PtO2催化剂,并在大气压、室温搅拌下,将混合物氢化10.5小时。将固体滤出,用50毫升无水甲醇洗涤。将液相蒸发至干燥,将残留物溶解于150毫升无水异丙醇中,同时加热,然后将溶液冷却以结晶,获得2.02克标题化合物。将母液蒸发至15毫升体积,再得到0.46克物质。将两部分合并,获得2.86克标题化合物。
关于产物含量的HPLC分析结果显示在下表中,其中也证明了进行更长反应时间的实验结果。
实施例2:根据PCT公开文本No.WO 2005/044805 A1中实施例2制备2-(4-哌啶基甲基)-5,6-二甲氧基-1-二氢茚酮盐酸盐的再现实验:
将3.17克2-(4-吡啶基亚甲基)-5,6-二甲氧基-1-二氢茚酮盐酸盐溶解于300毫升无水甲醇中,接着添加330毫克PtO2催化剂,并在大气压、室温搅拌下,将混合物氢化10.5小时。将固体滤出,用50毫升无水甲醇洗涤。将液相蒸发至干燥,将残留物溶解于150毫升无水异丙醇中,同时加热,然后将溶液冷却到0℃以结晶,获得2.02克标题化合物。将母液蒸发至15毫升体积,再得到1.11克物质。将两部分合并,获得3.13克标题化合物。
关于产物含量的HPLC分析的结果显示在下表中。也证明了进行更长反应时间的实验结果。
实施例3:将200升乙酸、2.2千克包含10%混悬于22升乙酸中的钯的炭和22.24千克4-[(5,6-二甲氧基-1-茚满酮)-2-亚基]-甲基-吡啶盐酸盐(IV)测量到500升惰性化氢化高压釜中,并且在68-72℃,5大气压超压,同时剧烈搅拌下,将混合物氢化,直到压力降低到结束为止。将高压釜冷却到20-25℃,滤出催化剂。滤液在真空中浓缩到66升体积,然后在搅拌下向其中滴加72升甲基-异丁基-酮。将结晶物质滤出,并用甲基-异丁基-酮洗涤。将该湿的物质溶解于210升沸腾的甲醇中,然后将它冷却到0-5℃。将结晶物质滤出,洗涤并干燥后,获得15.12千克4-[(5,6-二甲氧基-1-茚满酮)-2-基]-甲基-哌啶(V)。
关于产物含量的TLC分析的结果显示在下表中:
实施例4.:将500升乙酸、32.58千克4-[(5,6-二甲氧基-1-茚满酮)-2-基]-甲基-哌啶(V)、27.60千克碳酸钾和6.5升水测量到1000升容积高压釜中,然后向其中滴加40升乙酸乙酯中的12.5升苄基溴。将该反应混合物在25-30℃强烈搅拌4小时。在检查反应完成后,将固体滤出。将300升水和12升乙酸加到滤液中并在搅拌后分离各相。用50升水洗涤有机层,再次分离各相。产物在联合的水相中,向其中加入200升乙酸乙酯并向其中滴加100升含10.0千克NaOH的水溶液。在搅拌后分离各相,用新部分的100升乙酸乙酯洗涤水相,并用水洗涤有机相。分离的有机相在无水硫酸钠上进行干燥,并过滤。将滤液在真空中浓缩到50升,添加50升甲醇,使之均匀并蒸发,然后加新 的50升甲醇,并再次蒸发。
在搅拌下将残留物溶解于140升甲醇中并冷却到5-10℃。向其中滴加38升盐酸甲醇(10.46千克cc盐酸和23.75千克甲醇的混合物)。通过滴加包含多晶型(I)晶种的280升甲基叔丁基醚,使结晶完成。将产物滤出,用35升甲基叔丁基醚洗涤两次并在35-40℃在空气中干燥,获得30.7千克多晶型(I)盐酸多奈哌齐活性成分。它的分析数据显示在下表中:
实施例5.:将34.5升甲醇、1.5升软化水、9.00千克盐酸多奈哌齐(原则上任意多晶型物变体都是适合的)测量到150升容积的配备有搅拌器和冷凝器的高压釜中。当混悬液的温度升到50-55℃,固体再次溶解。将溶液冷却到25-30℃并过滤到无纤维。将90升甲基叔丁基醚和90克多晶型(I)盐酸多奈哌齐测量到150升容积高压釜中,将混悬液温度降至5-10℃之间,并且在持续剧烈搅拌下在30分钟期间内均匀地加入盐酸多奈哌齐溶液。在另外搅拌30分钟后,滤出结晶的固体并用9升甲基叔丁基醚洗涤。在35-40℃干燥结晶物质,获得8.7千克包含低溶剂残留的多晶型(I)盐酸多奈哌齐。甲基叔丁基醚残留的特征性浓度为150-750ppm,而其它污染的溶剂残留成分都在检出限以下。
Claims (6)
1.制备高纯度式I的多晶型(I)盐酸多奈哌齐的方法,
该方法通过氢化IV的5,6-二甲氧基-2-(吡啶-4-基亚甲基)茚满-1-酮盐中间体,随后苄化获得的式V的4-[(5,6-二甲氧基-1-茚满酮)-2-基]-甲基哌啶中间体,随后通过使式VI的多奈哌齐碱反应进行成盐步骤,并随后从包含甲醇的溶液中使获得的式I的盐酸多奈哌齐重结晶来进行,
该方法包括:
a.在炭Pd催化剂存在下,完成所述式IV的5,6-二甲氧基-2-(吡啶-4-基亚甲基)茚满-1-酮盐酸盐的氢化,
b.通过使式VI的多奈哌齐碱与乙酸反应完成所述成盐步骤,然后将乙酸盐萃取到水相中,然后在碱存在下,将它再次转化为多奈哌齐碱,然后在氯化氢存在下将后者转化为式I的盐酸多奈哌齐,以及
c.通过从包含2-18%水的含水醇溶液中沉淀多晶型(I)盐酸多奈哌齐产物,完成所述重结晶。
2.根据权利要求1的方法,其中所述氢化包括应用作为催化剂的包含5-15%钯的炭。
3.根据权利要求2的方法,其中所述氢化进一步包括应用4-6大气压超压和60-80℃的温度。
4.根据权利要求1的方法,其中所述成盐步骤包括使多奈哌齐碱与乙酸在乙酸乙酯溶液中反应,并将多奈哌齐乙酸盐转移到水相中。
5.根据权利要求1的方法,其中所述重结晶包括在含有3-5%(v/v)水的含水甲醇中溶解盐酸多奈哌齐。
6.根据权利要求1的方法,其中所述重结晶包括将盐酸多奈哌齐的含水甲醇溶液添加到包含多晶型(I)晶种的甲基叔丁基醚沉淀剂中。
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CN (1) | CN101341122B (zh) |
CA (1) | CA2630512A1 (zh) |
EA (1) | EA012911B1 (zh) |
HU (1) | HU227474B1 (zh) |
UA (1) | UA98102C2 (zh) |
WO (1) | WO2007072087A2 (zh) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100113793A1 (en) * | 2006-03-20 | 2010-05-06 | Ind-Swift Laboratories Limited | Process for the Preparation of Highly Pure Donepezil |
WO2008117123A2 (en) * | 2006-10-16 | 2008-10-02 | Medichem, S.A. | Process for preparing donepezil hydrochloride polymorphic form i |
CN101397270B (zh) * | 2007-09-28 | 2012-03-28 | 天津和美生物技术有限公司 | 多奈哌齐盐的多晶型物及其制备和应用 |
CN101723879B (zh) * | 2009-11-16 | 2011-12-28 | 华东师范大学 | 一种合成(r)-3-哌啶乙酸乙酯盐酸盐的方法 |
CA2803559A1 (en) | 2010-06-21 | 2011-12-29 | Teva Pharmaceutical Industries Ltd. | Nilotinib salts and crystalline forms thereof |
CN103038227A (zh) * | 2010-06-21 | 2013-04-10 | 特瓦制药工业有限公司 | 尼洛替尼盐及其晶形 |
CN101906066B (zh) * | 2010-08-08 | 2015-03-11 | 浙江华海药业股份有限公司 | 一种制备盐酸奈哌齐晶型i的方法 |
US20140128613A1 (en) * | 2011-03-25 | 2014-05-08 | Piramal Enterprises Limited | A process for preparation of intermediates of donepezil hydrochloride |
WO2013005094A1 (en) * | 2011-07-05 | 2013-01-10 | Torrent Pharmaceuticals Ltd | Acid addition salt of donepezil and pharmaceutical composition thereof |
JP5832558B2 (ja) | 2011-07-28 | 2015-12-16 | 大塚製薬株式会社 | ベンゾ[b]チオフェン化合物の製造方法 |
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 |
CN102633779B (zh) * | 2012-04-26 | 2014-01-22 | 齐鲁制药有限公司 | 法舒地尔乙酸盐及其制备方法和应用 |
CN103923064A (zh) * | 2013-01-11 | 2014-07-16 | 重庆华邦制药有限公司 | 一种纯化2-[(4-氯苯基)(哌啶-4-氧基)甲基]吡啶的方法 |
US9359315B2 (en) | 2013-09-10 | 2016-06-07 | Arrien Pharmaceuticals Llc | Substituted 2,3-dihydro-1H-inden-1-one retinoic acid-related orphan nuclear receptor antagonists for treating multiple sclerosis |
BR102013030928A2 (pt) * | 2013-11-29 | 2015-09-22 | Cristália Produtos Químicos Farmacêuticos Ltda | processo para a preparação de cloridrato de donepezila formas i e iii; e de um composto intermediário do mesmo |
CN109651234B (zh) * | 2018-12-29 | 2021-01-01 | 山东罗欣药业集团股份有限公司 | 一种盐酸多奈哌齐的合成方法 |
CN110183374A (zh) * | 2018-12-31 | 2019-08-30 | 山东诚汇双达药业有限公司 | 一种盐酸多奈哌齐中间体的制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1524851A (zh) * | 2003-02-27 | 2004-09-01 | 天津药物研究院 | 工业化生产盐酸多奈哌齐的工艺方法 |
CN1613848A (zh) * | 2003-11-05 | 2005-05-11 | 天津和美生物技术有限公司 | 合成多奈哌齐及其衍生物的新方法 |
CN1699343A (zh) * | 1996-06-07 | 2005-11-23 | 卫材株式会社 | 盐酸多奈哌齐的多晶型物及其制备方法 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI95572C (fi) * | 1987-06-22 | 1996-02-26 | Eisai Co Ltd | Menetelmä lääkeaineena käyttökelpoisen piperidiinijohdannaisten tai sen farmaseuttisen suolan valmistamiseksi |
DE4439822A1 (de) * | 1994-11-08 | 1996-08-29 | Bayer Ag | Verfahren zur Herstellung von Benzyl-piperidylmethyl-indanonen |
TW513409B (en) * | 1996-06-07 | 2002-12-11 | Eisai Co Ltd | Polymorphs of donepezil hydrochloride |
CA2252806C (en) * | 1996-06-07 | 2005-11-22 | Eisai Co., Ltd. | Polymorphs of donepezil hydrochloride and process for production |
WO1999036405A1 (en) * | 1998-01-16 | 1999-07-22 | Eisai Co., Ltd. | Process for production of donepezil derivative |
IL125809A (en) * | 1998-08-17 | 2005-08-31 | Finetech Lab Ltd | Process and intermediates for production of donepezil and related compounds |
US7148354B2 (en) * | 2002-07-24 | 2006-12-12 | Dr. Reddy's Laboratories Limited | Process for preparation of donepezil |
IL150982A (en) * | 2002-07-30 | 2007-02-11 | Ori Lerman | Process for making Donafzil |
US6649765B1 (en) * | 2003-02-12 | 2003-11-18 | Usv Limited, Bsd Marg. | Process for the preparation of 1-benzyl-4(5,6-dimethoxy-1-indanon)-2-yl) methyl piperidine hydrochloride (Donepezil HCL) |
US7439365B2 (en) * | 2003-11-17 | 2008-10-21 | Usv, Ltd. | Pharmaceutical salt of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl] methyl piperidine (Donepezil) |
WO2004082685A1 (en) * | 2003-03-21 | 2004-09-30 | Ranbaxy Laboratories Limited | Process for the preparation of donepezil and derivatives thereof |
WO2004087660A1 (en) * | 2003-04-02 | 2004-10-14 | Hetero Drugs Limited | A novel process for amorphous form of donepezil hydrochloride |
WO2004099142A1 (en) * | 2003-05-05 | 2004-11-18 | Ranbaxy Laboratories Limited | Hydrobromide salt of benzyl-piperidylmethyl-indanone and its polymorphs |
WO2006015338A2 (en) * | 2004-07-30 | 2006-02-09 | Dr. Reddy's Laboratories Ltd. | Crystalline form of donepezil hydrochloride |
IL171137A (en) * | 2004-09-29 | 2012-01-31 | Chemagis Ltd | Use of purified malt donfazil for the preparation of pure pharmaceutical amorphous donfazil hydrochloride |
EP1858847A1 (en) * | 2005-02-28 | 2007-11-28 | Ranbaxy Laboratories Limited | Stable form i donepezil hydrochloride and process for its preparation and use in pharmaceutical compositions |
GB0515803D0 (en) * | 2005-07-30 | 2005-09-07 | Pliva Hrvatska D O O | Intermediate compounds |
-
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- 2006-12-18 WO PCT/HU2006/000115 patent/WO2007072087A2/en active Application Filing
- 2006-12-18 EP EP06831515.9A patent/EP1966136B1/en active Active
- 2006-12-18 UA UAA200806699A patent/UA98102C2/ru unknown
- 2006-12-18 CN CN200680048057.2A patent/CN101341122B/zh not_active Expired - Fee Related
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1699343A (zh) * | 1996-06-07 | 2005-11-23 | 卫材株式会社 | 盐酸多奈哌齐的多晶型物及其制备方法 |
CN1524851A (zh) * | 2003-02-27 | 2004-09-01 | 天津药物研究院 | 工业化生产盐酸多奈哌齐的工艺方法 |
CN1613848A (zh) * | 2003-11-05 | 2005-05-11 | 天津和美生物技术有限公司 | 合成多奈哌齐及其衍生物的新方法 |
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EA200801518A1 (ru) | 2008-10-30 |
EP1966136B1 (en) | 2014-02-26 |
EA012911B1 (ru) | 2010-02-26 |
EP1966136A2 (en) | 2008-09-10 |
US20080306271A1 (en) | 2008-12-11 |
HU227474B1 (en) | 2011-07-28 |
HUP0501167A2 (en) | 2007-09-28 |
HU0501167D0 (en) | 2006-02-28 |
CN101341122A (zh) | 2009-01-07 |
WO2007072087A3 (en) | 2007-09-07 |
UA98102C2 (ru) | 2012-04-25 |
CA2630512A1 (en) | 2007-06-28 |
WO2007072087A2 (en) | 2007-06-28 |
HUP0501167A3 (en) | 2008-03-28 |
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