- New synthetic approach to memantine hydrochloride starting from 1,3-dimethyl-adamantane
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A short and practical method for the synthesis of 1-amino-3,5-dimethyl- adamantane (Memantine hydrochloride) was established by using tertiary butyl alcohol under Ritter conditions to give 1-acetamido-3,5-dimethyl-adamantane. The 1-acetamido-3,5-dimethyl-adamantane is hydrolyzed using alkali to give free base which was then converted into its hydrochloride acid.
- Madhra, Mukesh K.,Sharma, Mukesh,Khanduri
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- Process Safety Evaluation to Identify the Inherent Hazards of a Highly Exothermic Ritter Reaction Using Adiabatic and Isothermal Calorimeters
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This paper describes the process safety studies that were carried out prior to the scale-up for the initial process containing the reaction of 1,3-dimethyladamantane with sulfuric acid and acetonitrile. The reaction temperature is set at 13 C followed by heating to 23 C for progress of the reaction. Thermal screening studies showed the exotherm onset to occur at 30 C, which is very close to the desired final process temperature, with high rate of temperature rise and pressure rise. Also understood was the better option for selecting the sequence of reagent addition, i.e., either acetonitrile or sulfuric acid. These thermal hazard evaluation results helped to redesign the process temperature at 38 ± 2 C, which was evaluated for safety aspects to prevent the untoward situation using an adiabatic calorimeter and an isothermal reaction calorimeter.
- Veedhi, Srinivasarao,Babu, Subramani Ramesh
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- Decarboxylative Ritter-Type Amination by Cooperative Iodine (I/III)─Boron Lewis Acid Catalysis
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Recent years have witnessed important progress in synthetic strategies exploiting the reactivity of carbocations via photochemical or electrochemical methods. Yet, most of the developed methods are limited in their scope to certain stabilized positions in molecules. Herein, we report a metal-free system based on the iodine (I/III) catalytic manifold, which gives access to carbenium ion intermediates also on electronically disfavored benzylic positions. The unusually high reactivity of the system stems from a complexation of iodine (III) intermediates with BF3. The synthetic utility of our decarboxylative Ritter-type amination protocol has been demonstrated by the functionalization of benzylic as well as aliphatic carboxylic acids, including late-stage modification of different pharmaceutical molecules. Notably, the amination of ketoprofen was performed on a gram scale. Detailed mechanistic investigations by kinetic analysis and control experiments suggest two mechanistic pathways.
- Narobe, Rok,Murugesan, Kathiravan,Schmid, Simon,K?nig, Burkhard
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p. 809 - 817
(2022/01/15)
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- Two Step Cost-Saving Process for Industrial Scale Production of 1-Amino-3,5-dimethyladamantane Hydrochloride (An Anti-Alzheimer's Drug)
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This work presents a predominant cost-saving process for the industrial scale synthesis of memantine hydrochloride (1) from 1,3-dimethyladamantane (2) by a two-step method in which both steps were carried out in one-pot. The conversion of 2 to N-(3,5dimethyladamantane-1-yl)acetylamide (3) was synthesized first in mixture of sulfuric acid 96-98% and nitric acid 64-65% at 25 oC for 2.5 h and then in acetonitrile at 40 oC for 3.5 h as a key step. The yield of this process reached to 98%. Next, the deacetylation of 3 with potasium hydroxide in mixture of water-ethylene glycol at 140 oC for 15 h to get memantine base which was then converted into memantine hydrochloride (1) by aq. HCl 14% (yield of 93%). Overall yield of this synthetic route was 91.65%. The advantages of this process is saving time, solvents, reagents and giving a higher yield as compared to reported procedures.
- Le, Viet Duc,Ngo, Sy Thinh,Nguyen, Thi Hong Tham,Nguyen, Thi Hong Thanh,Phan, Dinh Chau,Vu, Binh Duong
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p. 251 - 255
(2022/01/21)
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- Green preparation method of memantine
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The method comprises the following steps: (1) mixing 1 - chlorine -3 and 5 - dimethyl adamantane with acetamide to obtain 1 -acetylamino -3 and 5 -dimethyladamantane. (2) The 1 -acetylamino -3, 5 -dimethyladamantane was deacetylated in a hot-water system to obtain a memantine. The preparation method provided by the invention is simple to operate. The method is safe, environment-friendly, high in yield and purity, cost-saving, low in production cost and beneficial to industrial production.
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Paragraph 0047; 0049; 0051; 0053; 0055
(2021/09/15)
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- Preparation method of medicine for treating neurological function diseases
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The invention discloses a preparation method of a medicine for treating neurological function diseases, which comprises the following steps: 1) adding 1-bromo-3,5-dimethyl adamantane, acetonitrile, acatalyst 1 and a catalyst 2 into a reaction kettle, stirring to react, adding a certain amount of water into the reaction solution, cooling to precipitate a solid, adding the solid into a certain proportion of an alcohol water solution, and carrying out hot melting and cold precipitation to obtain 1-acetamido-1,3-dimethyl adamantane; and (2) carrying out high-temperature reaction on 1-acetamido-1,3-dimethyl adamantane and sodium hydroxide in ethylene glycol, adding a certain amount of purified water, extracting by adopting dichloromethane, concentrating under reduced pressure, adding an ethylacetate hydrochloride solution into the concentrated solution, cooling to allow crystal growing, carrying out suction filtration, and drying to obtain memantine hydrochloride. According to the method,the catalyst 1 and the catalyst 2 are used as reaction catalysts, so that the operation risk caused by the use of concentrated sulfuric acid is avoided, the reaction time is shortened, and the side reaction is reduced. The post-treatment is simple, the reaction yield is high, and the product purity is good.
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Paragraph 0022-0024; 0026-0028; 0030-0032; 0034-0036
(2020/11/23)
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- Memantine hydrochloride synthesis method
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The invention provides a memantine hydrochloride synthesis method, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: carrying out a substitution reaction on 1-bromo-3,5-dimethyladamantane and acetamide to obtain 1-acetamido-3,5-dimethyladamantane, mixing the 1-acetamido-3,5-dimethyladamantane, an alcohol and an alkali, carrying out an alcoholysis reaction to obtain 1-amino-3,5-dimethyladamantane, and finally carrying out an acidification reaction on the 1-amino-3,5-dimethyladamantane and hydrochloric acid to obtain memantine hydrochloride. According to the method of the invention, 1-bromo-3,5-dimethyl adamantane and acetamide are used as the starting raw materials, so the sources of the raw materials are wide, the use of acetonitrile is avoided, and no pollution is caused to the human body and the environment; the use of catalysts is avoided in the whole reaction process, the reaction product is easy to separate, and the yield of the obtained memantine hydrochloride is high; and the method is mild in reaction condition and suitable for industrial production.
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Paragraph 0061-0066; 0074-0074; 0088-0093
(2020/03/09)
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- Memantine hydrochloride impurity compound and preparation method thereof
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The invention discloses a preparation method of a memantine hydrochloride impurity compound 1-nitro-7-hydroxy-3,5-dimethyl adamantane. According to the preparation method, 1-bromo-3,5-dimethyl adamantane is taken as a raw material and carries out a substitution reaction with acetamide in a molten state, then hydrolysis and salt forming happen in an alkaline environment, and finally the target product is prepared after hydroxylation and oxidation. The impurity compound is used as a reference substance for memantine hydrochloride quality control.
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Paragraph 0040-0042; 0047-0048
(2020/06/20)
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- Preparation method of memantine hydrochloride impurity C
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The invention discloses a preparation method of a memantine hydrochloride impurity C. The preparation method comprises a step of hydrolyzing an intermediate D under an acidic condition to obtain the impurity C. The preparation method has the advantages of novelty, usage of easily available raw materials, simple synthesis and good practicability.
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Paragraph 0037; 0038
(2020/04/17)
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- Method for synthesizing N-alkanoyl memantine
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The invention discloses a method for synthesizing N-alkanoyl memantine. The method comprises the steps that (a) memantine hydrochloride reacts with a formylation reagent or an acetylation reagent in areactive solvent; (b) after the reaction is completed, separation is carried out to obtain a target product. The method for synthesizing the N-alkanoyl memantine has the advantages that the operationis simple, the raw materials are easy to obtain, the preparation yield and product purity are higher, and the method is suitable for rapid preparation in analytical laboratories.
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Paragraph 0056; 0057
(2019/07/04)
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- Synthesis, molecular docking studies, and antimicrobial evaluation of new structurally diverse ureas
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A series of new urea derivatives (3a-p) have been synthesized from readily available isocyanates and amines in good to high yields. All synthesized compounds were fully characterized using 1H NMR, 13C NMR, IR, and mass spectrometry. Additionally, the structure of the compound (3n) was confirmed by single-crystal X-ray diffraction. Furthermore, all compounds were evaluated for antimicrobial activity against five bacteria and two fungi. Last but not the least, molecular docking studies with Candida albicans dihydropteroate synthetase were performed and the results are presented herein.
- Patil, Mahadev,Poyil, Anurag Noonikara,Joshi, Shrinivas D.,Patil, Shivaputra A.,Patil, Siddappa A.,Bugarin, Alejandro
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supporting information
p. 302 - 311
(2019/03/26)
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- A hydrochloric acid just preparation method
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The invention discloses a method for preparing memantine hydrochloride. The method is characterized in that the method provided by the invention uses 1-bromo-3,5-dimethyladamantane (represented by a general formula IV in the description) as a starting material which is subjected to an amination reaction with acetamine to obtain a key intermediate 1-actamido-3,5-dimethyladmantane (represented by a general formula III in the description); the compound represented by the general formula III is subjected to alcoholysis in a mixture system of inorganic base and n-butyl alcohol for deacetylated to obtain memantine; memantine is treated using hydrochloric acid in a ketone solvent to obtain memantine hydrochloride. The method provided by the invention overcomes deficiencies in the prior art and has the advantages that the raw materials are simple and readily available, the reaction steps are simple and short, and the operations are convenient and fast, therefore, the method is suitable for industrial production.
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Paragraph 0038; 0049; 0062; 0063; 0070; 0077
(2018/04/02)
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- Preparation method of memantine hydrochloride
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The invention relates to a preparation method of memantine hydrochloride. According to the preparation method, crude 1-acetylamino-3,5-dimethyladamantane is prepared via direction reaction of a system composed of 1,3-dimethyladamantane, acetonitrile, and concentrated sulfuric acid; the crude 1-acetylamino-3,5-dimethyladamantane is subjected to hydrolysis without purifying directly; ethanediol is taken as a solvent, and crude memantine is obtained via hydrolysis under alkaline conditions; crude memantine is extracted with hydrocarbon solvents such as n-heptane; concentrated hydrochloric acid or an organic solution of hydrochloric acid is added into an obtained extracted solution directly so as to obtain a crude memantine hydrochloride solid; and recrystallization is carried out with an alcohol-ethyl acetate system so as to obtain refined memantine hydrochloride. Operation of the preparation method is simple; the preparation method is simplified; yield is high; production cost is low; and the preparation method is suitable for industrialized production.
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Paragraph 0018
(2017/10/12)
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- A Namenda preparation method
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The invention relates to a preparation method of memantine hydrochloride, which comprises the following steps: reacting 1-bromo-3,5-dimethyladamantane with acetamide to obtain 1-acetamino-3,5-dimethyladamantane, reacting the 1-acetamino-3,5-dimethyladamantane with sodium methoxide and ethylene glycol, extracting, acidifying with hydrochloric acid to generate the target compound memantine hydrochloride, and recrystallizing the memantine hydrochloride crude product to obtain the memantine hydrochloride final product. By using the 1-acetamino-3,5-dimethyladamantane as the raw material, the method reduces the consumption of toxic, harmful and dangerous raw materials, has the advantages of high yield of the final product and lower cost, and is suitable for industrial production.
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Paragraph 0049; 0050
(2017/01/02)
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- PRODUCTION METHOD OF 1-AMINO-3,5-DIMETHYLADAMANTANE HYDROCHLORIDE
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PROBLEM TO BE SOLVED: To provide a production method of 1-amino-3,5-dimethyladamantane hydrochloride with a high yield, of which the amount of predetermined impurities (trimethyl analog and monomethyl analog) is reduced, which has high purity, and which can be used for pharmaceutical application as it is. SOLUTION: 1-amino-3,5-dimethyladamantane hydrochloride is crystallized from a mixed solution of: a protic solvent such as an organic acid, an alcohol; an aprotic solvent such as ketones, esters, nitriles; and water. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPO&INPIT
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Paragraph 0043
(2017/05/17)
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- MANUFACTURING PROCESS FOR MEMANTINE
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A method for manufacturing 3,5-dimethyl-1-adamantanamine of the present invention comprises: (i) a step of reacting 3,5-dimethyl-1-adamantanol with an acid and nitrile in an organic solvent to obtain a reaction solution; (ii) a step of adding water to the reaction solution obtained in step (i) to obtain 1-amido-3,5-dimethyladamantane; and (iii) a step of hydrolyzing 1-amido-3,5-dimethyladamantane obtained in step (ii) in the presence of an alcohol-containing solvent and an inorganic base.
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Paragraph 0063
(2015/12/18)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF MEMANTINE HYDROCHLORIDE
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The present invention relates to an improved process for the preparation of memantine hydrochloride. Memantine hydrochloride is used in the treatment of Alzheimer's and Parkinson's disease.
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Page/Page column 10
(2014/03/21)
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- Synthesis and IR/MS study of 3,5-dimethyladamantanamine hydrochloride salt
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This paper studied the synthesis of memantine hydrochloride characteristics by optimizing the synthetic route in the bromination of acid hydrolysis under the conditions of acetonitrile and the final salt formation reaction, so that memantine hydrochloride in an overall yield of the products from the 67.3 % reported in the literature increased to 81.5 %. Compared to 1,3-dimethyl adamantane and 3,5-dimethyladamantanamine, the infrared spectra showed the characteristic absorptions of 3,5-dimethyl-adamantanamine hydrochloride. Especially by the use of ESI method Spray ionization mass spectrometry analysis of fragments of memantine hydrochloride mass characteristics of ammonia compounds. By IR and MS studies to determine the spectrum of memantine hydrochloride microscopic molecular structure of ammonia.
- Ren, Huixue,Ying, Hanjie,Ouyang, Pingkai,Lin, Jimao,Jing, Liu
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p. 5107 - 5110
(2012/10/08)
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- PROCESS FOR THE PREPARATION OF MEMANTINE HYDROCHLORIDE
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The present invention provides an improved process for the preparation of 1-bromo-3,5-dimethyladamantane. The present invention also provides a process for preparing free flowing solid of 1-acetamido-3,5-dimethyladamantane. The present invention further provides a process for the preparation of memantine hydrochloride substantially free of 1-amino-3,5,7-trimethyladamantane hydrochloride and/or 1-amino-3-methyladamantane hydrochloride impurity.
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Page/Page column 8
(2011/10/31)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF 1-BROMO-3,5-DIMETHYL ADAMANTANE
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The present invention relates to an improved process for the preparation of 1-bromo-3,5-dimethyl adamantane of formula (III), which is an useful intermediate for synthesis of 1-amino-3,5-dimethyl adamantane of formula (I) or pharmaceutically acceptable salt thereof.
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Page/Page column 6-7
(2010/07/02)
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- IMPROVED PROCESS FOR MEMANTINE HYDROCHLORIDE
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The present invention provides an improved eco-friendly process for the preparation of memantine hydrochloride compound of formula (1). The present invention also provides one-pot process for the preparation of memantine hydrochloride compound of fomula (1) from 1,3 -dimethyl adamantane without isolating any intermediates.
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Page/Page column 9-11
(2009/06/27)
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- PROCESS FOR PREPARING MEMANTINE HYDROCHLORIDE SUBSTANTIALLY FREE OF !MPURITIES
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A process for preparing memantine hydrochloride free from impurities comprises (a) reacting 1,3-dimethyladarnantane with acetontitrile and sulphuric acid to produce 1- acetamido-3,5-dimethyl adamantane; (b) treating l-acetamido-3,5-dimethyl adamantane with base in the presence of solvent to produce memantine; (c) reacting memantine with alcoholic HCl in the presence of solvents to produce memantine hydrochloride; and purification of memantine hydrochloride using aliphatic solvents.
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- PROCESS FOR THE PREPARATION OF MEMANTINE
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A process for the preparation of Memantine of formula (I) or its pharmaceutically acceptable salts is disclosed. The process comprises formula (I): (a) reacting halogenated-3, 5 -dimethyl adamantine of formula (III) with acetamide in presence of sulfuric acid to provide l-Acetamido-3,5-dimethyl adamantine of formula (II), wherein X is Cl or Br. Formula (III), (II): (b) treating l-Acetamido-3,5-dimethyl adamantine of formula (II) with base in presence of solvent to obtain Memantine of formula (I) (c) optionally converting Memantine of formula (I) in to pharmaceutically acceptable salts.
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Page/Page column 13-17
(2008/12/05)
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- A PROCESS FOR THE PREPARATION OF MEMANTINE HYDROCHLORIDE
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3,5-Dimethyladamantane is reacted with bromine to form l-bromo-3,5,- dimethyladamantane of formula (I), it is reacted with acetonitrile in the presence of acid to form l-acetamido-3,5-dimethyladamantane of formula (II). Optionally formula (II) is treated with an organic acid to form the corresponding salt of formula (Ill), which is setting free of salt in the presence of base to get the pure formula (II). A formula (II) is subjected to hydrolysis followed by in-situ reaction with hydrochloric acid to form memantine hydrochloride. The memantine hydrochloride is treated with base to get the pure memantine base.
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- γ-aminoadamantanecarboxylic acids through direct C-H bond amidations
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Utilizing bromine-free, direct C-H bond amidations we have synthesized a large variety of adamantane amides. Depending on the precursors used these amides directly yield pharmaceutically active aminoadamantanes or γ-aminoadamantanecarboxylic acids after hydrolytic cleavage. These rigid analogues of γ-aminobutyric acid (GABA) were protected at the C- and N-termini and we synthesized a number of peptides incorporating γ-aminoadamantanecarboxylic acids in solution as well as via solid phase peptide synthesis. These peptides are promising scaffolds for applications in medicinal chemistry as well as in organocatalysis. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Wanka, Lukas,Cabrelle, Chiara,Vanejews, Maksims,Schreiner, Peter R.
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p. 1474 - 1490
(2008/09/19)
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- PROCESS FOR PREPARING MEMANTINE HYDROCHLORIDE SUBSTANTIALLY FREE OF IMPURITIES
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The present invention encompasses processes for preparing Memantine hydrochloride and its derivatives, substantially free of impurities.
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Page/Page column 20-21
(2008/06/13)
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- AMINO ADAMANTANE DERIVATIVES, METHODS FOR THE PRODUCTION AND USE THEREOF
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The invention relates to 1-amino adamantane derivatives and 3-amino adamantane-1-carboxylic acid derivatives, wherein the 5th and/or 7th position of the adamantane base frame can be substituted in any particular manner. The invention also relates to methods for the production of said inventive compounds, in addition to methods for linking the thus obtained monomer 3-amino adamantane-1-carboxylic acid derivatives in order to form oligomers. The inventive compounds are suitable for use as anti-viral active substances, artificial ion channels and for the therapy, diagnosis and prophylaxis of diseases, wherein a defect of the GA-BA-system occurs.
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Page/Page column 44
(2010/02/15)
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- Process for synthesising aminoadamantanes
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The present invention concerns a new process for synthesising aminoadamantanes of formula I in which R1 and R2 are identical or different and are H or a straight or branched alkyl group comprising from 1 to 6 carbon atoms, and addition salts thereof with inorganic or organic acids, in particular memantine hydrochloride (1-amino-3,5-dimethyladamantane hydrochloride).
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Page/Page column 4-5; figure 1
(2008/06/13)
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- Process for synthesising aminoadamantanes
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The present invention concerns a new process for synthesising aminoadamantanes of formula I in which R1 and R2 are identical or different and are H or a straight or branched alkyl group comprising from 1 to 6 carbon atoms, and addition salts thereof with inorganic or organic acids, in particular memantine hydrochloride (1-amino-3,5-dimethyladamantane hydrochloride).
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Page/Page column 7; 13
(2008/06/13)
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- DERIVATIVES OF ADAMANTANE. II. USE OF TRIFLUOROACETIC ACID IN THE RITTER REACTION
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For the case of 1-substituted adamantanes it was possible to realize the synthesis of amides by the Ritter reaction with high yields using trifluoroacetic acid as catalyst and solvent.This makes it possible to realize the process in a homogenous phase and to remove the excess of the nitrile and the excess of the acid itself from the reaction mass by hydrolysis of the intermediate immonium comples.On account of the mild conditions labile nitriles and aminonitriles, in particular, can be used in the reaction.
- Plakhotnik, V.M.,Kovtun, V.Yu.,Yashunskii, V.G.
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p. 867 - 871
(2007/10/02)
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