- Industrially scalable synthesis of anti-alzheimer drug donepezil
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This paper describes a simple, efficient and industrially scalable total synthesis of donepezil hydrochloride. The article also reported the X-ray studies of the 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one, an intermediate in the synthesis of donepezil. The crystal structure analysis of 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one shows that it crystallizes in monoclinic class under the space group P121/c1 with cell parameters, a = 17.2992(7) ?, b = 10.1999(4) ?, c = 11.9539(5) ?, β = 103.450(2)°, V = 2051.42(15) ?3 and Z = 4.
- Gaonkar, Santosh L.,Nadaf,Bilehal, Dinesh,Shetty, Nitinkumar S.
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Read Online
- Efficient and industrially viable synthesis of donepezil
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An efficient, economically viable process has been developed for large-scale preparation of donepezil HCl (1), an anti-Alzheimer's agent. The process involves the condensation of 5,6-dimethoxy-1-indanone (3) and 1-benzyl-4-piperidinecarboxaldehyde (4) in the presence of alkalimetal carbonates at elevated temperature to yield 1-benzyl-4-[(5,6-dimethoxy-1- indanone)-2-yidenyl] methyl piperidine (2), the key intermediate in the synthesis of donepezil. Hydrogenation of 2 yields donepezil. Copyright Taylor & Francis Group, LLC.
- Rao, R. Janaki Rama,Rao, A. K. S. Bhujanga,Murthy
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Read Online
- New synthesis of donepezil through palladium-catalyzed hydrogenation approach
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A new, economical, and efficient process has been developed for large-scale synthesis of donepezil 1, an anti-Alzheimer's drug. The process involves palladium-catalyzed hydrogenation of (2E)-5,6-dimethoxy-2-(pyridin-4- ylmethylene)indan-1-one 6 to provide 5,6-dimethoxy-2-(piperidin-4-ylmethyl) indan-1-one 8 as a key step. Copyright Taylor & Francis LLC.
- Elati, Chandrashekar R.,Kolla, Naveenkumar,Chalamala, Subrahmanyeswara Rao,Vankawala, Pravinchandra J.,Sundaram, Venkataraman,Vurimidi, Himabindu,Mathad, Vijayavitthal T.
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Read Online
- Bisulfite Addition Compounds as Substrates for Reductive Aminations in Water
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Highly valued products resulting from reductive aminations utilizing shelf-stable bisulfite addition compounds of aldehydes can be made under aqueous micellar catalysis conditions. Readily available α-picolineborane serves as the stoichiometric hydride source. Recycling of the aqueous reaction medium is easily accomplished, and several applications to targets in the pharmaceutical industry are documented.
- Bailey, J. Daniel,Iyer, Karthik S.,Leahy, David K.,Li, Xiaohan,Lipshutz, Bruce H.,Thakore, Ruchita R.
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p. 7205 - 7208
(2021/09/22)
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- A metal-free method for the facile synthesis of indanonesviathe intramolecular hydroacylation of 2-vinylbenzaldehyde
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A facile method for the synthesis of indanones was developed under metal- and additive-free conditions, whereinl-proline served as an efficient and environmentally benign catalyst. Compared with previously synthesized indanones, synthesis by the transition-metal-catalyzed intramolecular hydroacylation of 2-vinylbenzaldehyde provided a more green synthetic pathway to indanone scaffolds with good to excellent yields. More importantly, it could be used to synthsize the anti-AD drug donepezil.
- He, Guoxue,Ma, Jinyu,Zhou, Jianhui,Li, Chunpu,Liu, Hong,Zhou, Yu
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supporting information
p. 1036 - 1040
(2021/02/09)
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- Can Heteroarenes/Arenes Be Hydrogenated Over Catalytic Pd/C Under Ambient Conditions?
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Hydrogenation of over a dozen aromatic compounds, including both heteroarenes and arenes, over palladium on carbon (Pd/C, 1–100 molpercent) with H2-balloon pressure at room temperature is reported. Analyses using pyridine as a model substrate revealed that acetic acid was the best solvent, as using only 1 molpercent Pd/C provided piperidine quantitatively. Substrate scope analysis and density functional theory calculations indicated that reaction rates are highly dependent on frontier molecular orbital characteristics and the steric bulkiness of substituents. Moreover, the established method was used for the concise synthesis of the anti-Alzheimer drug donepezil (Aricept?).
- Tanaka, Nao,Usuki, Toyonobu
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p. 5514 - 5522
(2020/07/24)
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- Method for synthesizing donepezil in water
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The invention discloses a method for synthesizing donepezil. The method comprises the following steps: adding 5,6-dimethoxyindanone, (1-benzyl-4-piperidyl)methanol, a metal iridium catalyst and potassium hydroxide into a reaction vessel, carrying out heating for a reaction for several hours, the carrying out cooling to room temperature, spin-drying a solvent, and carrying out column separation toobtain the target compound. According to the method, under the catalytic action of the metal iridium catalyst, 5,6-dimethoxyindanone reacts with (1-benzyl-4-piperidyl)methanol to directly synthesize donepezil; a commercialized reagent is used as a raw material for the reaction, and alcohol is an environment-friendly and low-toxicity chemical reagent; a by-product of the reaction water, so environmental pollution is avoided; the atom economy of the reaction is high; and reaction is conducted in water. Therefore, the reaction meets the requirements of green chemistry and has a wide development prospect.
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Paragraph 0012; 0020-0023
(2020/08/17)
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- METHOD FOR PRODUCING DONEPEZIL BY FLOW REACTION USING IMMOBILIZED CATALYST
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PROBLEM TO BE SOLVED: To provide a method for producing donepezil in which, as the required amount can be produced when required while precisely controlling the reaction time and temperature, and the post-reaction neutralization, separation operation, intermediate isolation and purification steps can be omitted, the labor force and operation time can be significantly reduced. SOLUTION: Provided is a method for producing donepezil, including a step of Aldol condensation for yielding 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yliden] methylpiperidine by Aldol condensation reacting 5,6-dimethoxy-1-indanone and 1-benzyl-4-formylpiperidin, and a step of hydrogenation for yielding donepezil by hydrogenation reacting 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yliden] methylpiperidine, and in which at least one of the aldol condensation step and the hydrogenation step is continuously carried out by a flow method using a reactor in which the catalyst is immobilized. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPO&INPIT
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Paragraph 0069-0074; 0076-0081; 0083-0089; 0091-0094
(2021/01/08)
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- Basic Anion-Exchange Resin-Catalyzed Aldol Condensation of Aromatic Ketones with Aldehydes in Continuous Flow
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A general method for the aldol condensation of aromatic ketones with aldehydes was developed under continuous-flow conditions using a commercially available, strongly basic anion-exchange resin (A26) as catalyst. This procedure, in addition to exhibiting a wide substrate scope, promoted carbon-carbon bond formation under mild conditions using a quasi-stoichiometric ratio of starting reagents with good to excellent yields, thereby forming a limited amount of waste and allowing the process to be applied to sequential-flow systems. A proof of concept was developed in the first fully heterogeneously catalyzed two-step flow synthesis of donepezil, which is a blockbuster commercial anti-Alzheimer's drug.
- Laroche, Benjamin,Saito, Yuki,Ishitani, Haruro,Kobayashi, Shū
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p. 961 - 967
(2019/05/02)
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- Purification method for Donepezil
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The invention relates to a purification method for Donepezil and belongs to the technical field of preparation of raw pharmaceutical materials. The purification method for the Donepezil or pharmaceutically acceptable salts thereof, provided by the invention, comprises the steps: firstly, adding a hydrophobic organic solvent and water into the Donepezil or pharmaceutically acceptable salts thereof,so as to obtain a mixed solution, wherein the hydrophobic organic solvent is selected from dichloromethane, ethyl acetate, toluene and mixtures thereof; adjusting an aqueous phase pH of the mixed solution to be not smaller than 9 with alkali, and separating an organic phase from an aqueous phase; and subjecting the organic phase obtained in the step (3) to depressurized concentration, thereby obtaining purified Donepezil. According to the purification method for the Donepezil or pharmaceutically acceptable salts thereof, provided by the invention, high-quality raw pharmaceutical materials areprovided for preparations.
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Paragraph 0027; 0028
(2019/12/25)
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- The α-alkylation of ketones with alcohols in pure water catalyzed by a water-soluble Cp?Ir complex bearing a functional ligand
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A water-soluble dinuclear Cp?Ir complex bearing 4,4′,6,6′-tetrahydroxy-2,2′-bipyrimidine as a bridging ligand was found to be a highly effective catalyst for the α-alkylation of ketones with alcohols in pure water. In the presence of catalyst (0.5 mol%), a series of desirable products were obtained with high reaction economy under environmentally benign conditions. The importance of the hydroxy group in the ligand for catalytic hydrogen transfer was confirmed by mechanism experiments. Furthermore, the application of this catalytic system for the synthesis of a biologically active molecule donepezil in pure water has been accomplished. Notably, this research would facilitate the progress of C-C bond-forming reactions in water catalyzed by water-soluble metal-ligand bifunctional catalysts.
- Meng, Chong,Xu, Jing,Tang, Yawen,Ai, Yao,Li, Feng
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p. 14057 - 14065
(2019/09/18)
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- Iron-Catalyzed Ligand Free α-Alkylation of Methylene Ketones and β-Alkylation of Secondary Alcohols Using Primary Alcohols
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Herein, we demonstrate a general and broadly applicable catalytic cross coupling of methylene ketones and secondary alcohols with a series of primary alcohols to disubstituted branched ketones. A simple and nonprecious Fe2(CO)9 catalyst enables one-pot oxidations of both primary and secondary alcohols to a range of branched gem-bis(alkyl) ketones. A number of bond activations and formations selectively occurred in one pot to provide the ketone products. Coupling reactions can be performed in gram scale and successfully applied in the synthesis of an Alzehimer's drug. Alkylation of a steroid hormone can be achieved. A single catalyst enables sequential one-pot double alkylation to bis-hetero aryl ketones using two different alcohols. Preliminary mechanistic studies using an IR probe, deuterium labeling, and kinetic experiments established the participation of a borrowing-hydrogen process using Fe catalyst, and the reaction produces H2 and H2O as byproducts.
- Alanthadka, Anitha,Bera, Sourajit,Banerjee, Debasis
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p. 11676 - 11686
(2019/10/02)
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- Polysilane-Immobilized Rh-Pt Bimetallic Nanoparticles as Powerful Arene Hydrogenation Catalysts: Synthesis, Reactions under Batch and Flow Conditions and Reaction Mechanism
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Hydrogenation of arenes is an important reaction not only for hydrogen storage and transport but also for the synthesis of functional molecules such as pharmaceuticals and biologically active compounds. Here, we describe the development of heterogeneous Rh-Pt bimetallic nanoparticle catalysts for the hydrogenation of arenes with inexpensive polysilane as support. The catalysts could be used in both batch and continuous-flow systems with high performance under mild conditions and showed wide substrate generality. In the continuous-flow system, the product could be obtained by simply passing the substrate and 1 atm H2 through a column packed with the catalyst. Remarkably, much higher catalytic performance was observed in the flow system than in the batch system, and extremely strong durability under continuous-flow conditions was demonstrated (>50 days continuous run; turnover number >3.4 × 105). Furthermore, details of the reaction mechanisms and the origin of different kinetics in batch and flow were studied, and the obtained knowledge was applied to develop completely selective arene hydrogenation of compounds containing two aromatic rings toward the synthesis of an active pharmaceutical ingredient.
- Miyamura, Hiroyuki,Suzuki, Aya,Yasukawa, Tomohiro,Kobayashi, Shu
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supporting information
p. 11325 - 11334
(2018/09/06)
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- Chemoselective Alkylation of Aminoacetophenones with Alcohols by Using a Palladacycle-Phosphine Catalyst
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The development of efficient and environmentally benign palladacycle-phosphine catalyzed process to enable the formation of chemoselective C-alkylated or N-alkylated aminoacetophenones with alcohols is described. This methodology proved to be tunable by variation of the base and the temperature, which allows for the isolation of structurally diverse C-alkylated and N-alkylated aminoacetophenones. Moreover, this methodology has been applied to the synthesis of biologically and industrially important donepezil.
- Mamidala, Ramesh,Subramani, M. Siva,Samser, Shaikh,Biswal, Priyabrata,Venkatasubbaiah, Krishnan
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p. 6286 - 6296
(2018/11/23)
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- Method for synthesizing donepezil
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The invention discloses a method for synthesizing donepezil. The method comprises the following steps: adding ketone, alcohol, a metal iridium catalyst and alkaline into a reaction container; performing reflux reaction; cooling to room temperature after reaction is ended; spin-drying a solvent; and performing column separation to obtain a target compound. Compared with the original method, the method has the advantages of being low in toxicity, high in atom utilization rate, simple in step and high in yield.
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Paragraph 0012; 0020-0021; 0023-0032
(2018/03/24)
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- NNN pincer Ru(II)-complex-catalyzed α-alkylation of ketones with alcohols
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A series of novel ruthenium(II) complexes supported by a symmetrical NNN ligand were prepared and fully characterized. These complexes exhibited good performance in transfer hydrogenation to form new C-C bonds using alcohols as the alkylating agents, generating water as the only byproduct. A broad range of substrates, including (hetero)aryl- or alkyl-ketones and alcohols, were well tolerated under the optimized conditions. Notably, α-substituted methylene ketones were also investigated, which afforded α-branched steric hindrance products. A potential application of α-alkylation of methylene acetone to synthesize donepezil was demonstrated, which provided the desired product in 83% yield. Finally, this catalytic system could be applied to a one-pot double alkylation procedure with sequential addition of two different alcohols. The current protocol is featured with several characteristics, including a broad substrate scope, low catalyst (0.50 mol %) loadings, and environmental benignity.
- Cao, Xiao-Niu,Wan, Xiao-Min,Yang, Fa-Liu,Li, Ke,Hao, Xin-Qi,Shao, Tian,Zhu, Xinju,Song, Mao-Ping
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p. 3657 - 3668
(2018/04/14)
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- Donepezil synthesis method
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The invention discloses a donepezil synthesis method which comprises the following steps: sequentially putting 5,6-dimethoxy indanone, 1-benzyl-4-piperidine methanol, a catalyst, an alkali and a solvent into a reactor; in an argon atmosphere, performing a magnetic stirring reaction in an oil bath pot sufficiently, after the reaction is completed, performing vacuum rotation evaporation and spectrumseparation, and drying, thereby obtaining a target product. By adopting the method disclosed by the invention, the problem that a great amount of byproducts are generated as reagents are used in a conventional synthesis method is solved since the components are cheap, easy to preserve and environmental-friendly and are renewable petroleum base replaceable compounds. An NNN type pincerlike metal ruthenium (II) compound is adopted as a catalyst for catalyzing reactions in the method, the reactions are completed at one step, the method is simple and convenient to operate and high in reaction efficiency, and requirements of sustainable development of environmental-friendly chemicals are met.
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Paragraph 0017; 0019
(2018/05/01)
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- Nickel-Catalyzed Hydrogen-Borrowing Strategy for α-Alkylation of Ketones with Alcohols: A New Route to Branched gem-Bis(alkyl) Ketones
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The α-alkylation of ketones using an earth-abundant and nonprecious NiBr2/L1 system is reported. This nickel-catalyzed reaction could be performed in gram scale and successfully applied in the synthesis of donepezil (Alzheimer's drug) and functionalization of steroid hormones and fatty acid derivatives. Synthesis of N-heterocycles, methylation of ketones, and one-pot double alkylation to bis-hetero aryl ketones using two different alcohols with a single catalyst broadens the scope of the catalytic protocol. Preliminary mechanistic studies using defined Ni-H species and deuterium-labeling experiments established the participation of the borrowing-hydrogen strategy.
- Das, Jagadish,Singh, Khushboo,Vellakkaran, Mari,Banerjee, Debasis
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supporting information
p. 5587 - 5591
(2018/09/25)
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- Mn(ii)-catalysed alkylation of methylene ketones with alcohols: Direct access to functionalised branched products
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Herein an operationally simple alkylation of methylene ketones with primary alcohols is reported. Use of an inexpensive and earth abundant Mn/1,10-phenanthroline system enables direct access to a series of functionalised branched ketones including one-pot sequential double alkylation and Alzheimer's drug donepezil. Preliminary mechanistic investigation, determination of the rate and order of reactions and deuterium labeling experiments support the participation of the hydrogen-borrowing strategy for the ketone alkylation.
- Kabadwal, Lalit Mohan,Das, Jagadish,Banerjee, Debasis
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supporting information
p. 14069 - 14072
(2019/01/03)
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- Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil
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A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer's disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer's disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC50value of 0.03 ± 0.07 μM against acetylcholinesterase with no cytotoxicity observed (IC50of >100 μM, SH-SY5Y cell line). In comparison donepezil had an IC50of 0.05 ± 0.06 μM and an observed cytotoxicity IC50of 15.54 ± 1.12 μM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase.
- van Greunen, Divan G.,Cordier, Werner,Nell, Margo,van der Westhuyzen, Chris,Steenkamp, Vanessa,Panayides, Jenny-Lee,Riley, Darren L.
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p. 671 - 690
(2017/02/10)
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- Isolation and Characterization of Regioisomers of Pyrazole-Based Palladacycles and Their Use in α-Alkylation of Ketones Using Alcohols
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Regioisomers of 3,5-diphenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-based palladacycles (1 and 2) were synthesized by the aromatic C-H bond activation of N/3-aryl ring. The application of these regioisomers as catalysts to enable the formation of α-alkylated ketones or quinolines with alcohols using a hydrogen borrowing process is evaluated. Experimental results reveal that palladacycle 2 is superior over palladacycle 1 to catalyze the reaction under similar reaction conditions. The reaction mechanisms for the palladacycles 1 and 2 catalyzed α-alkylation of acetophenone were studied using density functional theoretical (DFT) methods. The DFT studies indicate that palladacycle 2 has an energy barrier lower than that of palladacycle 1 for the alkylation reaction, consistent with the better catalytic activity of palladacycle 2 seen in the experiments. The palladacycle-phosphine system was found to tolerate a wide range of functional groups and serves as an efficient protocol for the synthesis of α-alkylated products under solvent-free conditions. In addition, the synthetic protocol was successfully applied to prepare donepezil, a drug for Alzheimer's disease, from simple starting materials.
- Mamidala, Ramesh,Samser, Shaikh,Sharma, Nishant,Lourderaj, Upakarasamy,Venkatasubbaiah, Krishnan
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p. 3343 - 3351
(2017/09/18)
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- Novel method for preparing donepezil
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The present invention relates to a method for preparing Donepezil, comprising the steps of: (a) making 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carbonitrile represented by chemical formula 3 react with a benzylpiperidine compound represented by chemical formula 4 to provide 2-((1-benzylpiperidine-4-yl)methyl)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carbonitrile represented by chemical formula 2; and (b) subjecting 2-((1-benzylpiperidine-4-yl)methyl)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carbonitrile represented by chemical formula 2 to decyanation reaction, thereby providing Donepezil represented by chemical formula 1.COPYRIGHT KIPO 2017
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- Use of a Cyclometalated Iridium(III) Complex Containing a N∧C∧N-Coordinating Terdentate Ligand as a Catalyst for the α-Alkylation of Ketones and N-Alkylation of Amines with Alcohols
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A cyclometalated iridium(III) complex containing a N∧C∧N-coordinating terdentate ligand [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 was found to be a general and highly effective catalyst for the α-alkylation of ketones and N-alkylation of amines with alcohols. In the presence of catalyst (1 mol % Ir) and base (0.2-0.5 equiv), a variety of desirable products were obtained in good yields under an air atmosphere. Notably, this research exhibited the new potential of Ir(III) complexes bearing non-Cp? ligand and will facilitate the progress of the hydrogen autotransfer process.
- Liu, Pengcheng,Liang, Ran,Lu, Lei,Yu, Zhentao,Li, Feng
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p. 1943 - 1950
(2017/02/26)
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- Preparation method of donepezil hydrochloride
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The invention relates to a compound synthesis method, in particular to a preparation method of donepezil hydrochloride. The method consists of: (1) adding thionyl chloride into benzyl alcohol dropwise and carrying out heating reaction; (2) adding anhydrous ethanol, sodium bicarbonate and 2, 3-dihydro-5, 6-dimethoxy-2-(4-piperidyl)methyl-1-indanone, carrying out reaction, cooling and pumping filtration; (3) performing washing with ethyl acetate, combining the filtrate, then conducting washing with brine, collecting the organic phase, and conducting concentration; (4) performing cooling, adding saturated hydrogen chloride ethyl acetate solution to adjust pH, further conducting stirring, filtering, washing and drying, thus obtaining a crude product; and (5) conducting dissolution with methanol, then adding activated carbon to conduct decoloration, performing cooling crystallization, carrying out filtering, washing the filter cake with methanol, then adding anhydrous ethanol and performing stirring, conducting filtration and washing, soaking the filter cake with ethyl acetate, and carrying out filtering and drying, thus obtaining a donepezil hydrochloride refined product. The method provided by the invention is green and environmental friendly, has high yield, and can prepare donepezil hydrochloride with high purity, thus being suitable for industrial production.
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Paragraph 0035; 0041; 0043; 0044
(2016/10/09)
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- Ruthenium-NHC Catalyzed α-Alkylation of Methylene Ketones Provides Branched Products through Borrowing Hydrogen Strategy
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The α-alkylation of a broad range of methylene ketones was achieved using a ruthenium(II)-NHC catalyst under borrowing hydrogen conditions. Primary alcohols served as alkylating agents and could be used in a one-to-one stoichiometry with respect to the ketone. The selectivity of the process for methyl over branched ketones enabled a one-pot double alkylation protocol utilizing two different alcohols with a single catalyst. Moreover, this methodology could be applied directly to the one-step synthesis of donepezil, the best-selling drug for the treatment of Alzheimer's disease.
- Schlepphorst, Christoph,Maji, Biplab,Glorius, Frank
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p. 4184 - 4188
(2016/07/12)
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- Direct carbocyclizations of benzoic acids: Catalyst-controlled synthesis of cyclic ketones and the development of tandem aHH (acyl Heck-Heck) reactions
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The formation of exo-methylene indanones and indenones from simple ortho-allyl benzoic acid derivatives has been developed. Selective formation of the indanone or indenone products in these reactions is controlled by choice of ancillary ligand. This new process has a low environmental footprint as the products are formed in high yields using low catalyst loadings, while the only stoichiometric chemical waste generated from the reactants in the transformation is acetic acid. The conversion of the active cyclization catalyst into the Hermman-Beller palladacycle was exploited in a one-pot tandem acyl Heck-Heck (aHH) reaction, and utilized in the synthesis of donepezil. Carboxylic acids in aHH: Simple ortho-allyl benzoic acid derivatives have been utilized in an acyl Heck (aH) reaction to selectively form indanones and indenones. The conversion of the active cyclization catalyst into the Hermman-Beller palladacycle was exploited in a one-pot tandem acyl Heck-Heck (aHH) reaction to form two sp 2-sp2 bonds of (E)-trisubstituted olefins.
- Miles, Kelsey C.,Le, Chi,Stambuli, James P.
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p. 11336 - 11339
(2014/10/16)
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- Tetra-n-butylammonium bromide: A simple but efficient organocatalyst for alcohol oxidation under mild conditions
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A simple but efficient organocatalytic system with 5 mol% tetra-n-butylammonium bromide (TBAB) as the catalyst has been identified for alcohol oxidation for the first time. This organocatalytic system is compatible with a broad range of benzylic/allylic alcohols with various catalytically reactive groups. Besides, it shows excellent selectivity for secondary benzylic alcohols over aliphatic alcohols, and good selectivity over the primary benzylic alcohol site in 4-(1-hydroxyethyl)benzyl alcohol. Thus, the features of simplicity, high efficiency, selectivity and mildness of reaction conditions associated with this TBAB organocatalytic system suggest its potential for widespread use in synthetic chemistry.
- Ma, Xinyi,Li, Zhongfeng,Liu, Feijie,Cao, Shengli,Rao, Honghua
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supporting information
p. 1741 - 1746
(2014/06/09)
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- Method for making donepezil
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The method in accordance with the present invention has: mixing E2M, an organic solvent, a weak base, sodium dithionite, and a phase transfer catalyst to obtain an E2M mixture solution; heating the E2M mixture solution and adding water to obtain a heated E2M aqueous solution having an organic layer; and extracting the organic layer from the heated E2M aqueous solution, and condensing and drying the organic layer to obtain donepezil. Employing sodium dithionite as a reducing agent improves safety over hydrogen gas used in conventional methods and lowers the cost in contrast to the conventional noble metal catalysts that are extremely expensive. Furthermore, the method of the present invention requires only 60 minutes of reaction time to synthesize donepezil with a promising yield more than 85%, which greatly raises the efficiency and economic value of the manufacture of donepezil.
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- Method For Making Donepezil
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The method in accordance with the present invention has: mixing E2M, an organic solvent, a weak base, sodium dithionite, and a phase transfer catalyst to obtain an E2M mixture solution; heating the E2M mixture solution and adding water to obtain a heated E2M aqueous solution having an organic layer; and extracting the organic layer from the heated E2M aqueous solution, and condensing and drying the organic layer to obtain donepezil. Employing sodium dithionite as a reducing agent improves safety over hydrogen gas used in conventional methods and lowers the cost in contrast to the conventional noble metal catalysts that are extremely expensive. Furthermore, the method of the present invention requires only 60 minutes of reaction time to synthesize donepezil with a promising yield more than 85%, which greatly raises the efficiency and economic value of the manufacture of donepezil.
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- Novel Pharmaceutical Forms, and Methods of Making and Using the Same
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Crystalline salts, polymorphs, solvates, and hydrates of bicalutamide, 5-fluorouracil, donepezil, anastrozole, nelfinavir, mirtazapine, lansoprazole, and tamsulosin, or derivatives thereof are provided by the subject invention. Methods of making and using the same are also provided.
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Page/Page column 10
(2012/02/01)
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- Effect of benzothiazole/piperazine derivatives on intracerebroventricular streptozotocin-induced cognitive deficits
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Background: In this study, benzothiazole-piperazine compounds were synthesized by condensing the functional groups of donepezil (DNP), FK-960, and sabeluzole, which are known to have therapeutic potential against Alzheimer's disease, with the aim of obtaining new and potent anti-Alzheimer agents. Methods: Initially, acetylcholinesterase/butyrylcholinesterase enzyme inhibition activities of the synthesized test compounds were investigated by Ellman's method. Effects of the compounds on a streptozotocin (STZ) model of Alzheimer's disease (SMAD) were investigated in rats. SMAD was established by intracerebroventricular (icv) injection of STZ (3 mg/kg), bilaterally. The elevated plus maze, Morris water maze, and active avoidance tests were used to examine the effects of test compounds (1, 5, and 10 mg/kg) on learning and memory parameters of icv STZ-injected rats. Effects of the test compounds on spontaneous locomotor activities of rats were examined with the activity cage test. Results: The compounds B2-B5 and DNP exhibited significant selective inhibitory potencies against acetylcholinesterase. Compounds B2 and B3 at 10 mg/kg doses and compounds B4 and B5 at 5 and 10 mg/kg doses, as well as the reference drug DNP (1 and 3 mg/kg), significantly improved the learning and memory parameters of animals in all cognition tests. None of the test compounds changed spontaneous locomotor activities. Conclusion: Results of the present study revealed that compounds B2-B5 repaired the parameters related to the learning and memory deficits of icv STZ-injected rats. Potencies of these test compounds were comparable to the activity of DNP. Copyright
- ?zkay, ümide Demir,Can, ?zg?ur Devrim,Oz?kay, Yusuf,Oz?türk, Yusuf
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p. 834 - 847
(2013/01/15)
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- A PROCESS FOR THE PREPARATION OF DONEPEZIL HYDROCHLORIDE
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The present invention is directed to an improved industrially viable, cost effective process for manufacturing 1 -benzyl-4-(5,6,-dimethoxyindanone-2-yl)methylpiperidine hydrochloride commonly known as donepezil hydrochloride in a substantially pure form with a purity level of greater than 99.9% and a novel crystalline form of 1- benzyl-4-(5,6,-dimethoxyindanone-2-yI)methylpiperidine in a substantially pure form.
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Page/Page column 10-11
(2011/05/11)
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- A new commercially viable synthetic route for donepezil hydrochloride: Anti-Alzheimer's drug
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An economical new process has been developed for the synthesis of donepezil hydrochloride (1) an anti-Alzheimer's drug. The process involves Darzen reaction of pyridine-4-carboxaldehyde and 2-bromo-5,6-dimethoxy indanone affording epoxide 5,6-dimethoxy-3-(pyridine-4-yl)spiro[indene-2,2′-oxiran] -1(3H)-one (4) as a key intermediate. The one-pot deoxygenation of 4 and hydrogenation of the aryl moiety in high yield improved the overall yield of the process.
- Dubey, Shailendra Kumar,Kharbanda, Manita,Dubey, Sushil Kumar,Mathela, Chandra Shekhar
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experimental part
p. 1157 - 1160
(2010/11/18)
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- INDANONE INHIBITORS OF ACETYLCHOLINESTERASE
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The present invention relates to new indanone inhibitors of acetylcholinesterase, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 15
(2010/06/19)
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- POLYMORPHIC CRYSTAL OF DONEPEZIL AND PROCESS FOR PRODUCING THE SAME
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[Problem] A novel polymorphic crystal (F) of donepezil that is a precursor for production of donepezil hydrochloride having an excellent effect as a medicine and is an active principle, which has excellent handling properties, and an industrial process for producing the novel polymorphic crystal (F). [Solution] The novel polymorphic crystal (F) of the present invention is characterized by a powder X-ray diffraction pattern, an IR absorption peak, a solid NMR spectrum, and the like, of donepezil represented by the following formula (I).
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Page/Page column 15-16
(2010/08/05)
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- ANTI-AMNESIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
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The present invention relates to the use of at least one compound of formula (I) as follows: or of at least one pharmaceutically acceptable salt thereof for the preparation of a drug for the prevention or treatment of memory disorders.
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- IMPROVED PROCESS FOR THE PREPARATION OF (1-BENZYL-4-(5,6,- DIMETHOXYIND ANONE-2-YL)METHYLPIPERIDINE) HYDROCHLORIDE-FORM III
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The present invention is directed to an improved industrially viable, cost effective process for manufacturing pure racemic crystalline anhydrous form of (1-benzyl-4-(5,6,- dimethoxyindanone-2yl)methylpiperidine) hydrochloride Form III commonly known as Donepezil hydrochloride with a purity level of greater than 99.9%.
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Example 2; scheme VII
(2009/08/14)
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- Highly chemoselective metal-free reduction of tertiary amides
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This communication describes the chemoselective metal-free reduction of tertiary amides to the corresponding amines. Hantzsch ester is used as a mild reducing agent for the reduction of trifluoromethanesulfonic anhydride activated amides providing the tertiary amines with high functional group tolerance. Copyright
- Barbe, Guillaume,Charette, Andre B.
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- NOVEL POLYMORPHIC FORMS OF l-BENZYL-4-[(5,6-DIMETHOXY-l-INDANONE)-2-YL]METHYL PIPERIDINE [DONEPEZIL] AND PROCESS FOR PREPARING THE SAME
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Disclosed herein novel crystalline polymorphic forms of 1-benzyl-4-(5,6-dimethoxy-1-indanon-2-yl)methylpiperidine (Donepezil) base having higher stability. Said polymorphic forms are designated as Form D and E and characterized by employing analytical tools such as infrared absorption spectrum, X-ray powder diffraction pattern, thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC) and/or melting point. The present invention also disclosed a process for preparing said polymorphic forms. Further an improved process for preparing polymorphic form B of 1-benzyl-4-(5,6-dimethoxy-1-indanon-2-yl)methylpiperidine (Donepezil) base is also disclosed.
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Page/Page column 13-14
(2008/12/05)
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- Novel Process for Production of Highly Pure Polymorph (I) Donepezil Hydrochloride
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The present invention provides a novel, industrially realizable and economically preferable process for production of highly pure 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl piperidine hydrochloride, i.e., donepezil hydrochloride shown in the following reaction scheme, in Polymorph (I) morphological crystal form. (I) In one of the key steps of the process, during the hydrogenation 5,6-dimethoxy 2-(pyridine-4-yhnethylene)indan-1-one hydrochloride is saturated using Pd carbon to get 4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine at more than 97% HPLC purity. In the crystallization step donepezil-hydrochloride is crystallized from an aqueous alcoholic solvent to get Polymorph (I) in at least 99.95% HPLC purity.
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Page/Page column 9
(2009/01/20)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DONEPEZIL
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An improved, novel and simple industrial process for the preparation of Donepezil of formula (I) and its pharmaceutically acceptable salts manufactured by the condensation of 5,6-dimethoxy indanone of formula (III) with 1-benzyl-4-piperidine carboxaldehyde of formula (IV) to give 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl] methyl piperidine in the presence of base in organic solvents or an aqueous solvent or mixture thereof followed by the reduction carried out using at least one metal borohydride in the presence of catalytic amount of cobalt salts and suitable solvent or mixture thereof.
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Page/Page column 17-18
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF DONEPEZIL AND INTERMEDIATE COMPOUNDS THEREOF AS WELL AS HYDRATES OF DONEPEZIL
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The present invention relates to a new process for the preparation of intermediate compounds useful in the manufacture of donepezil, or a pharmaceutically-acceptable salt thereof, and also relates to processes for preparing donepezil and to the novel intermediates per se. In addition the invention relates to various hydrated forms of donepezil.
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Page/Page column 21
(2008/06/13)
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- Novel process for preparing dopenzil and its derivatives
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A process for producing a Donepezil derivative represented by the formula (I), wherein R1, R2, R3, and R4 each independently represents H, F, an alkyl having from 1 to 4 carbon atoms, or an alkoxy having from 1 to 4 carbon atoms; R5 represents a phenyl or a substituted phenyl; and n is an integer from 0 to 2, characterized in that the process comprises: (a) a reaction of 4-pyridinecarboxaldehyde with a compound of formula (II) in the presence of a strong acid HX to form a compound of formula (III); (b) a catalytic hydrogenation of a compound of formula (III) or a compound of formula (V) to yield a compound of formula (IV); and (c) an alkylation reaction of a compound of formula (IV) to yield a compound of formula (I).
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Page/Page column 4-5
(2010/11/26)
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- Process for producing 1-benzyl-4-[ (5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or hydrochloride thereof
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1-Benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or hydrochloride thereof, which is useful as a drug, can be produced in high purity by safer and easier operations suitable for industrial production by subjecting 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidene]methyl-piperidine or a solvate thereof to catalytic hydrogenation in the presence of a palladium-alumina catalyst and if necessary, converting the thus obtained compound to its hydrochloride.
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Page/Page column 5
(2008/06/13)
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- PROCESSES FOR PRODUCING 1-BENZYL-4-[(5,6-DIMETHOXY-1-INDANON)-2-YL] METHYLPIPERIDINE AND HYDROCHLORIDE THEREOF
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Processes for prepering 1-benzyl-4-[(5,6-dimethoxy-lindanon)-2-yl]methylpiperidine (donepezil), which is useful as an intermediate for medicines, and for producing 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride (donepezil hydrochloride), which is useful as a medicine. The process for donepezil hydrochloride production comprises catalytically hydrogenating the compound represented by the structural formula (III) [1-benzyl-4-[(5,6-dimethoxy-lindanon)-2-ylidene]methylpiperidine] with a Raney nickel catalyst under mild conditions and subsequently treating it with hydrochloric acid. Thus, impurities are further diminished. The operations are simple and the process is suitable for industrial production.
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Page/Page column 8-9
(2008/06/13)
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- NERVE REVENERATION PROMOTER
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A nerve regeneration stimulator comprising a compound having a cholinesterase inhibitory activity, a pharmacologically acceptable salt thereof or a solvate thereof.
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Page/Page column 32
(2010/11/27)
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- PROCESS FOR PRODUCING 1-BENZYL-4-[(5,6-DIMETHOXY-1-INDANON-2-YL)METHYL] PIPERIDINE OR ITS SALT THEREOF VIA NOVEL INTERMEDIATE
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Disclosed herein the process for producing 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine or its salt thereof employing novel intermediates.
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Page/Page column 13
(2008/06/13)
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- STABLE FORM I DONEPEZIL HYDROCHLORIDE AND PROCESS FOR ITS PREPARATION AND USE IN PHARMACEUTICAL COMPOSITIONS
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The present invention provides stable polymorphic Form I donepezil hydrochloride, processes for its preparation, use in pharmaceutical compositions and methods of treating Alzheimer's disease using the pharmaceutical compositions.
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Page/Page column 6-7
(2008/06/13)
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- CRYSTALLINE FORM OF DONEPEZIL HYDROCHLORIDE
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A process for preparing crystalline form I of donepezil hydrochloride comprises: a) condensing 5,6-dimethoxy-2-piperidin-4-yl-methyl-indan-1-one with benzyl bromide and reacting a condensation product with hydrobromic acid to form donepezil hydrobromide; and b) hydrolyzing donepezil hydrobromide, followed by reacting with aqueous hydrochloric acid.
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Page/Page column 6
(2008/06/13)
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- Therapeutic agent for overactive bladder resulting from cerebral infarction
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An agent for treating overactive bladder resulting from cerebral infarction, comprising administrating a compound having a cholinesterase inhibitory activity or a pharmacologically acceptable salt thereof.
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Page/Page column 19
(2008/06/13)
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