LV13186B - Method for producing 1-amino-3,5-dimethyladmantane hydrochloride - Google Patents

Abstract

Invention relates to a method for producing 1-amino-3,5-dimethyladamantane hydrochloride (memantine or akatinol). The method provides for a reaction of 1,3-dimethyladamantane with nitric acid followed by addition of urea and heating the reaction mixture. The nitric acid is added to pre-prepared emulsion of hydrocarbon in acetic acid at 10 to 300C temperature. Further 30 - 55% water solution of urea is added at molar ratio of dimethyladamantane - acetic acid - urea as 1:3-4:9-12:2,5-5,0. Final product is separated by neutralization of reaction mixture with 30 - 45% sodium alkali solution, extraction by toluene at 50 - 850C temperature adding hydrochloric acid and by filtering and crystallizing from water.

Description

This method has its disadvantages:

1. Potentially explosive properties of the process in the first step of the process - Dissolution of hydrocarbon in 98-100% nitric acid. If the molar ratios of adamantane hydrocarbon to fuming nitric acid are greater than 1: 10, a practically ideal ratio of fuel-oxidant formation and reaction mass is detonator-capable (sensitive to the initiation pulse, E.IO.OpnoBa, xhmm? -Jl: Xmmhh, 1973, 388).

2. Low technological feasibility, personnel hazards and fire hazards of the method during the addition of hard urine. Oxidation of 1,3-dimethyladamantane with nitric acid in the first stage releases nitrogen dioxide (2 moles per 1 mole of hydrocarbon) which dissolves in the reaction mass and exists as a dimer.

R H + 3 HNO ₃ = [R-ONO 2] + ₂ NO ₂ + H ₂ O

The addition of the first two moles of urea in the reaction mass results in a rapid urea decomposition reaction through nitrosation of the nitrogen dioxide dimer. The reaction proceeds with a very high heat effect and an intense release of gas.

Dosing of solid urea is technologically very difficult to achieve. Effective local ventilation is required, staff are required to work in gas masks, and the cost of ecologically maintaining the process is increasing. Due to uneven dosing of solid urea, it is difficult to maintain a constant heat regime of the process. When solid urea reacts with nitrogen dioxide and nitric acid vapors in the gaseous phase on the reactor walls, solid phase particles consisting of urea nitrate, nitroso and nitro urea are formed in the lid and dosing unit. These compounds are highly flammable and explosive. Nitroso derivatives of urea are well-known as carcinogens and mutagens (Oinafl opraHMHecnaa χμμμα, no. Fl.BapTOHa M / a. Onnuca, vol. environment and personnel, the technological process becomes more expensive, additional investment in production infrastructure is required.

3. The method does not achieve the quality characteristics of 1-amino-3,5-dimethyladamantane hydrochloride which meet the requirements of medical preparations. Oxidation at the third carbon atom (Κπμμομκμη K) is known to occur when heating adamantane compounds in a nitric acid environment .H. m FLP., Te3MCbi flOKnaflOB BcecoiO3HOM κοΗφβρβΗμΜΜ 'TlepcneKTMBbi ρ33βμτμπ χμμμμ KapKacHbix οοθ ^ μηθημμ m mx πρμμθηθημθ b HapoflHOM xo3RižiCTBe, KyM6bimeB 1989 r., 102-103). This is due to the fact that at elevated temperatures nitric acid decomposes to form atomic oxygen.

HNO ₃ ► 2 NO ₂ + 1/2 O ₂ + H ₂ O

The amination of 1,3-dimethyladamantane under the conditions shown in the prototype resulted in the formation of a further oxidation product impurity, 1-amino-3-hydroxy-5,7-dimethyladamantane (Κπμμομκμη KO.H .. stom οοηοβθ .flMCcepTauMR Ha οομοκθημθ yneHOM οτβπβΗΜ flOKTopa χμμμμθοκμχ HayK, CaMapa, 1999, 166). This is demonstrated by a comparative example. The end product yields given in the prototype description are for the non-recrystallized product, but the GH assay conditions do not provide for a reliable determination of impurities. Data on the content of the parent substance are given without listing the impurity indicated.

4. The method of isolation of the final product in the description of the prototype specified is non-technological and cannot be used on an industrial scale (neutralization with solid sodium alkali, use of flammable ether for extraction, use of dry hydrogen chloride, etc.).

Technical result - ensuring explosion protection of production, simplification of the technological process, raising the quality indicators of the final product to the level that meets the requirements of the pharmaceutical. Technical result of the process for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride by reaction of 1,3-dimethyladamantane with nitric acid, followed by addition of urea and heating of the reaction mass, by addition of nitric acid at 10-30 ° C to the previously prepared hydrocarbon emulsion 30-55% molar ratios of aqueous solutions of urea

1,3-dimethyladamantane - acetic acid - nitric acid - urea 1: 3-4: 9-12: 2.5-5.0; but isolation of the final product is accomplished by neutralizing the reaction mass with a 30-45% aqueous solution of sodium hydroxide, extracting with toluene at 50-85 ° C, adding conc. hydrochloric acid by filtration and recrystallization of 1-amino-3,5-dimethyladamantane hydrochloride from water.

Distinctive features:

1. Addition of nitric acid in an emulsion of 1,3-dimethyladamantane in acetic acid.

2. Addition of an aqueous solution of urea.

3. Reduced levels of acetic and nitric acid.

4. Neutralization of the reaction mass with 30-45% aqueous sodium hydroxide solution and extraction with toluene at 50-85 ° C.

The invention has the following advantages:

Addition of nitric acid to the previously obtained hydrocarbon emulsion in acetic acid provides an explosion-proof process. In this case, the oxidant, i.e. nitric acid is always in the minority relative to fuel. In addition, the required balance of initiation pulse sensitivity to the fuel, oxidant, is not achievable, since acetic acid is always in a superior position in the reaction mass. The technological process is simplified as a result of better control of heat flows, eliminating flammable and environmentally harmful operations. This is mainly achieved by dosing the urea in the reaction mixture in the form of an aqueous solution, as well as by using sodium hydroxide solution for neutralization and toluene for extraction. Reducing acetic and nitric acid contributes to reducing production costs and wastewater. The quality of 1-amino-3,5-dimethyladamantane hydrochloride is ensured in accordance with the requirements of the pharmaceutical preparation. This is due to the elimination of excessive oxidant excess and local overheating as a result of the addition of nitric acid to the previously prepared hydrocarbon emulsion in acetic acid and the dosing of urea in aqueous solution. In addition, the presence of water in the reaction mixture rapidly decreases the acidity of the environment, reduces the possibility of the final decomposition reaction of nitric acid and thus eliminates the possibility of impurities forming further oxidation products in the adamantane structure. Extraction with a non-polar solvent, toluene, allows the elimination of even trace amounts of polar impurities in the final product.

The proposed method is approbated on an industrial scale and the quality of the resulting pharmaceutical preparation is fully in accordance with the requirements of the Pharmacopoeia.

Method acquisition examples

Analysis was performed using a chromato-mass spectrometer HP GC / MS 5971A with ionization electron energy of 70 eV and a quartz capillary column, 50 m long with immobilized SE-30 phase.

1. Example

Introduce into the 1000 ml flask 68 ml (60.5 g) of 1,3-dimethyladamantane, 62 ml of acetic acid and 142 ml of nitric acid at 25-30 ° C, keep the reaction mass for 3 hours and add 100 g of 55% aqueous urea solution 20- At 25 ° C, stand for 2 hours at 25 ° C, warm to 1 ° C for 125 hours and stand at given temperature for 3 hours. The reaction mass is then cooled, added to 320 ml of 30% sodium hydroxide solution at 50 ° C, extracted with 500 ml of toluene, the toluene layer is separated, 30 ml of hydrochloric acid is added, dried and recrystallized from water. 64 g (82%) of 1-amino-3,5-dimethyladamantane hydrochloride are obtained, m.p. 324-328 ° C. IR spectrum, cm. 2080, 1600, 1498, 1315, 967. Mass spectrum m / z (%): 179 (16), 122 (93), 108 (100). The quality meets the requirements of the pharmacopoeia. ²

2. Example

Into a 1000 ml flask, charge 68 ml (60.5 g) of 1,3-dimethyladamantane, 82 ml of acetic acid and add 190 ml of nitric acid at 10 to 15 ° C, keep the reaction mass for 1 hour and add 365 g of 30% aqueous urea solution at 20 °. At C, hold for 1 hour at 20 ° C, heat to 90 ° C for 3 hours, and stand at given temperature for 1 hour. The reaction mass is cooled, added with 400 ml of 45% sodium hydroxide solution at 85 ° C, extracted with 800 ml of toluene, the toluene layer is separated, 35 ml of hydrochloric acid is added, dried and recrystallized from water. 68 g (87%) of 1-amino-3,5-dimethyladamantane hydrochloride are obtained, m.p. 324-328 ° C. IR spectrum, cm ^-1 ; 2080, 1600, 1498, 1315, 967. Mass spectrum m / z (%): 179 (16), 122 (93), 108 (100). The quality meets the requirements of the pharmacopoeia.

Example 3

Introduce into the 1000 ml flask 68 ml (60.5) g of 1,3-dimethyladamantane, 70 ml of acetic acid and add 180 ml of nitric acid at 15-20 ° C, keep the reaction mass for 2 hours and add 140 g of 50% aqueous urea solution 20- At 25 ° C, stand for one hour at 25 ° C, heat for two hours to 110 ° C and stand for one hour at that temperature. The reaction mass is cooled, added to 400 ml of 30% sodium hydroxide solution at 70 ° C, extracted with 700 ml of toluene, the toluene layer is separated, 30 ml of hydrochloric acid is added, dried and recrystallized from water. 72 g (92%) of 1-amino-3,5-dimethyladamantane hydrochloride are obtained, m.p. 324-328 ° C. IS spectrum, cm ^-1 : 2080, 1600, 1498, 1315, 967. Mass spectrum m / z (%): 179 (16), 122 (93), 108 (100). The quality meets the requirements of the pharmacopoeia.

Example 4 (Comparative)

Place 250 ml of 98-100% nitric acid in a 1000 ml flask and add 50 ml

1,3-dimethyladamantane at 15 to 20 ° C, reaction mass for 3 hours at 20 ° C, add 100 ml acetic acid and 50 g urea, heat and stand for 4 hours at 80 ° C. The reaction mass is cooled, sodium hydroxide is added to pH> 10, extracted with 2000 ml ether. The ether extracts are dried over sodium hydroxide and saturated with hydrogen chloride gas. The precipitate is filtered off and dried to constant weight. 72 g (92%) of 1-amino-3,5-dimethyladamantane hydrochloride are obtained, m.p. > 300 ° C. IS spectrum, cm ^-1 : 2080, 1600, 1498, 1315, 967. Mass spectrum m / z (%): 179 (16), 122 (93), 108 (100). The content is 97.6% based on chromato-mass spectra. The sample contains heavy impurity with mass spectrum characteristics, m / z (%): 195 (18), 180 (7), 124 (100). After elution of the product part using a silica gel column (benzene - 2-propanol - 25% ammonia = 10: 10: 1), the isolated impurity identified as 3-amino-5,7-dimethyl-1-adamantanol, m.p. ° C (2-propanol); IS spectrum, cm ^-1 : 3305, 2630, 2060, 1620, 1510, 1335, 1195; NMR ¹ H δ, dd: 0.98 c (6H, CH ₃ ), 1.15-2.15 m (13H, Ad + OH), 8.64 c (3H, NH ₃ ⁺ ); Found:% C 62.84, H 10.01, N 5.98, C 12 H 21 NO x HCl, calculated% C 62.75, H 9.58, N 6.10.

Claims (1)

INVENTION FORMULA Method for the preparation of 1-amino-3,5-dimethyladamantane hydrochloride by reaction of 1,3-dimethyladamantane with nitric acid followed by addition of urea and heating of the reaction mass, characterized in that the addition of nitric acid is carried out at a temperature of 10-30 ° C with previously obtained hydrocarbon emulsion, further add 30-55% aqueous solution of urea in molar ratio 1,3-dimethyldiamantane - acetic acid - nitric acid - urea 1: 3-4: 9-12: 2.5-5.0 respectively, but isolation of the final product is carried out by neutralizing the reaction mass with 30-45% sodium hydroxide solution by extraction with toluene at 50-85 ° C, addition of hydrochloric acid, filtration and recrystallization from water.