4-methoxyethyl-2-tert.butylphenol as intermediates in the synthesis of metoprolol and its analogues
(57) Abstract:The invention relates to 4-methoxyethyl-2-tert.-butylphenol (1) (alkyl = ethyl-, propyl-), which is obtained by processing 4-chloroalkyl-2,6-di-tert.-butylphenols the sodium methylate or sodium hydroxide solution in methanol) under heating, followed by thermolysis of the resulting 4-methoxyethyl-2,6-di-tert. -butylphenol at 280 - 290oC. Advantages of compounds 1: more technological way of getting 1, a greater purity of the subsequent intermediates and metoprolol, the possibility of obtaining analogues of metoprolol. The invention relates to new derivatives of tert.-butylphenol, specifically to 4-(-methoxyethyl)-2-tert.-butylphenol formula:
< / BR>as intermediates in the synthesis of metoprolol and its analogues, which are known drugs for the prevention of arrhythmias and myocardial infarction.Compounds 1A,b are not described in literature.Object of the invention is improved method of producing metoprolol and its analogues, which will produce the desired products with high degree of purity and a more simple technological scheme.The described connection 1 use the camping metoprolol and its analogues according to scheme I:
< / BR>according to which compound 1 is subjected to thermolysis at 290 300oC and obtained with the yield of 70 77% 4-( -methoxyethyl)phenols (II) alkylate with epichlorohydrin under 100oC. After evaporation of epichlorohydrin, taken in excess, get the mixture in the amount of 90 94%) 3-[4-( w-methoxyethyl)phenoxy]-1-chloropropanol-2 (III) and 1,2-epoxy-3-[4-(w-methoxyethyl)phenoxy]propane (IV), which, without separating, heated with Isopropylamine and get metoprolol (VA) with yields of 80% or its analogs. Then in complex with tartaric acid is prepared tartrate metoprolol, which is the current top of the dosage form.Previously metoprolol (VA) was obtained according to scheme 2, according to which the phenol (II) was synthesized from nitro-derivatives (VI) 
< / BR>Recovery VI with hydrogen leads to the amine (VII). This amine diasterous and received diazoketone (VIII) hydrolyzing, which leads to 4-(2-methoxyethyl)phenol IIA with the release of 40%  Subsequent stages leading to metoprolol, chemistry similar to the previously proposed scheme I [2,3]
The main disadvantage of the circuit 2 is a low yield of 4-(2-methoxyethyl)phenol.Known intermediate nitrosoaniline (VI) produced by two different schemes. Implemented a method of obtaining it from 2-femilet is Ali, getting microproduct VI with the release of 55% of the disadvantages of this scheme include low yield of the target product VI, as well as the difficulties associated with separation of p-isomer formed from a mixture of o-, m - and p-isomers.Known another approach to the synthesis of microproduct VI interaction 4-bromonitromethane and methylvinylether ether, followed by reduction with hydrogen condensation products of [2,4,5] the Process is carried out according to the scheme:
< / BR>The main disadvantage of the scheme is the absence in Russia production of both components, and the synthesis metilfenidato ether technologically harmful  in Addition, the presence of stage synthesized requires regeneration of bromine and stage nitration thorough cleaning from isomers.In these examples, the synthesis of metoprolol loss products associated with the introduction of the hydroxyl group in the aromatic fragment intermediates reach 75%
New intermediate compounds 1, obviously containing in its structure a hydroxyl group, get on the scheme:
< / BR>according to which 4-( -chloroalkyl)-2,6-di-tert.-butylphenol (IX) derived from 2,6-di-tert. -butylphenol  is heated with sodium methylate or sodium hydroxide in methanol, the oC leads to compounds 1 (example 2), further heating which at 290 300oC gives 4-methoxyaniline (example 3) with the output 70 of 77% Technologically transformation of compounds X in methoxyacetophenone II is carried out in the same vessel (example 4).Thus obtained, the compound (II) possess a high degree of purity. So, technical 4-(2-methoxyethyl)phenol (II-a) with a basic substance content (OWLS) 97% melts in the range of 35 of the 37oC, and purified by crystallization from toluene has so pl. 41 43oC. In the literature, this connection is known as oil  or as a solid with so pl. 27 29 oC  This difference in the purity of the products is a natural consequence of the chosen scheme of synthesis, in which there are no processes leading to the formation of isomers.The use of more pure compounds II in the synthesis of metoprolol resulted in cleaner metoprolol with so pl. 47.0 48.5oC (described as oil [3,8]) and tartrate obtained on its basis, so pl. 117 118oC (cf. with so pl. 114 -116oC) 
New intermediate compound I in the synthesis of metoprolol and its analogues in comparison with the known intermediate product VI have the following advantages:
in a more technical way poluchaiutsea product II,and, and the metoprolol obtained with lower cost;
more ease and simplicity of obtaining 4-methoxyacetophenone, which is of independent interest [II]
the ability to obtain analogues of metoprolol and dosage forms based on them.Example 1. Getting 4-(2-methoxyethyl)-2,6-di-tert.-butylphenol (X,a).In the autoclave Vishnevsky with a capacity of 1.5 liters of load 322 g of 4-(2-chloroethyl)-2,6-di-tert. -butylphenol (IX, a) with OWLS 94% and 70 g of sodium methylate in 1 l of methanol. The reaction mass is heated with stirring for 6 h at 100oC, cooled to room temperature and the contents are neutralized with hydrochloric acid. The precipitated sodium chloride is filtered off and the filtrate evaporated. The remainder of 310 g distilled in vacuum, collecting the fraction wikipaedia in the range of 140 to 150oC/2 3 mm RT.article Receive 250 g of compound X,and so pl. 52 54oC (OWLS 97%).Example 2. Getting 4-(2-methoxyethyl)-2-tert.-butylphenol (I,a).In the flask is heated under reflux 264 g (1 mol) of 4-(2-methoxyethyl)-2,6-di-tert. butylphenol (X, a) for 8 hours at a temperature of 285 295oC. Receive 214 g of colorless oil, containing according to GC 95% of product I, and which is dissolved in toluene, washed with 2% alkaline solution.article Get the product I,and in the form of oil. Found: M/z 208.1460. C13H20O3. Calculated: M/z 208,1463. Range PMR (CCL, d M. D. from TMS): 1.33 (C. 9H, C4H9); 2.74 (t, J=7 Hz, 2H, -CH2Ar); 3.33 (C. 3H, CH3O-); 3.54 (t, J=7 Hz, 2H, -CH2O-); 5.95 (S. IH, -OH); 6.31 (doctor of Jortho=8 Hz), 6.72 (m, Jortho8 Hz, Jmeta=2 Hz), 6.94 (doctor of Jmeta=2 Hz) band signals of the protons of the aromatic ring, 3H).Example 3. Getting 4-(2-methoxyethyl)phenol (II-a) from compound I,and.In a distillation flask with a reflux condenser are placed 191 g of compound 1,and (OWLS 95% ) and heated in a stream of nitrogen at the temperature of the reaction mass 295 - 300oC for 36 hours and Then the extract continue for another 12 h with the selection of products, wikipaedia not higher than 270oC. Obtain 120 g of oil containing 75% of compound (11), and. It is dissolved in toluene and shaken with 1 l of 4% aqueous solution of alkali. In toluene solution is separated and evaporated, receiving compound 1,a (COS 90%).The aqueous layer was acidified with hydrochloric acid, extracted with toluene and the extract evaporated. The remainder (95 g of oil) is distilled under vacuum, collecting the fraction with so Kip. 130 135oC/2 3 mm RT.article Get 75 g of compound (11) and (OWLS 97%). Yield 60%
Example 4. Getting 4-(2-methoxyethyl)phenol (11) of the compounds X and I,and.remaut in a weak stream of nitrogen at 290 300oC for 30 hours and Then the shirt distillation column is heated to 280oC and begin to pick a faction, wikipaedia at 271 273oC. Reflux number 6. The distillation continued for 18 hours Obtain 110 g of compound (II), and (OWLS 92%). Vakuumnaya by distillation VAT residue receive an additional 12 g of product II,and (OWLS 80%). The remote sites are combined and distilled under vacuum, collecting the fraction with so Kip. 131 135oC/2 3 mm RT.article Get 110 g II, and (OWLS 97% ), so pl. 33 35oC. After crystallization from toluene so pl. 41 43oC.From VAT residue by vacuum distillation allocate 12.5 g I,and faction with so Kip. 140 160oC/2 3 mm RT.cent.).Exit II,and, considering the new reaction products, is 77%
Example 5. Receiving metoprolol (V,a).A mixture of 141 g (0.9 mol) of 4-(2-methoxyethyl)phenol (II,a), 570 ml epichlorohydrin and 1.5 ml of piperidine is heated with stirring 4 h at 100oC. Then the reaction mass is distilled off, the epichlorohydrin to the content in the reaction mass is not more than 5% Receive 223 g of oil containing 12% of 1,2-epoxy-3-[4-(2-methoxyethyl)phenoxy] -propane and 79% 3-[4-(2-methoxyethyl)phenoxy]-1-chloropropanol-2. This mixture is placed in a rotating autoclave along with 300 ml of Isopropylamine and 350 ml of isopropanol and vydareny the solution washed with 10% alkali solution, then water and dried with magnesium sulfate. After evaporation of the solvent receive 176,7 g hard metoprolol (V,a) with so pl. 39 -46oC, after crystallization from hexane with the addition of methylene chloride so pl. 47,0 - 48,5oC.In isopropanol mix 154 g of metoprolol (V,a) with so pl. 39 46 oC and to 38.8 g of tartaric acid and heated while stirring at 50oC for 0.5 h, cooled to room temperature and incubated for 12 hours the precipitation is filtered off and dried in air to constant weight. Get 143,6 g tartrate metoprolol with so pl. 116 118oC (according to  T. pl. 114 - 116oC).Example 6. Getting 4-(3-methoxypropyl)-2,6-di-tert.-butylphenol (X,b).In steel rotating autoclave with a capacity of 0.2 l placed 60 g (0,264 mol) of 4-(3-chlorpropyl)-2,6-di-tert.-butylphenol (IX,b) and 13.5 g (0.25 mol) of sodium methylate in 70 ml of methanol, maintained at a rotating autoclave for 8 hours at 135oC. After cooling to room temperature the reaction mass is neutralized with hydrochloric acid, the precipitated sodium chloride is filtered off and the solvent evaporated. Obtain 57 g of 4-(3-methoxypropyl)-2,6-di-tert.-butylphenol (OWLS 86% ), which is clear, turning in a vacuum. Collect the fraction with so Kip. 155 160oC/4 mm RT.article and receive 4-(3-methoxypropyl)phenol (II,b).In the cube distillation column load 211 g (0.75 mol) of 4-(3-methoxypropyl)-2,6-di-tert.-butylphenol and stand in a stream of nitrogen at 295 -300oC (the temperature of the reaction mass). After aging the reaction mass is then cooled, dissolved in 150 ml of toluene and vigorously shaken with a solution of 30 g of alkali in 0,5 l of water. From the toluene layer emit connection I,b, and water-II,b.The balance of 30 g, obtained after evaporation of toluene layer is distilled in vacuum, collecting the fraction with so Kip. 165 170 oC/5 mm RT.article Obtain 18 g of 4-(3-methoxypropyl)-2-tert. -butyl-phenol (I, b) (COS 98% ). Found: M/z 222,1622. C14H22O2. Calculated: M/z 222,1619. Range PMR (CCl4d M. D. from TMS): 1,34 (C. N, C4H9-tert.); is 1.81 (m, 2H, -CH2-); 2,53 (so J=7 Hz, 2H, -CH2Ar); 3,31 (C. 3H, CH3O); to 3.38 (t, J=7 Hz, 2H, -CH2O-); 6,05 (S. IH, OH); 6,40 (doctor of Jortho8 Hz), of 6.68 (m, Jortho=8 Hz, Jmeta=2 Hz), 6.90 to (doctor of Jmeta=2 Hz) band signals of the protons of the aromatic ring, 3H. UV spectrum (C2H5OH, lmax(lg nm): 279,5 (3,2).To obtain a compound (II), b the aqueous layer was acidified with hydrochloric acid to pH 5.0 and the product II,b is extracted with toluene. After evaporation of the solvent to obtain 95 g of 4-(3-methoxypropyl) phenol (OWLS 95%), oil yield was 73% PMR Spectrum (CCl4d M. D. from TMS): 1,82 (m, 2H, -CH2-); of 2.58 (t, J=7 Hz, 2H, ArCH2-); 3,34 (C. 3H, CCH3); 3,39 (so J=7 Hz, 2H, -CH2-); 4,93 (S. IH, -OH); 6,70 6,90 and system AA'BB', 4H, Ar-H).Example 8. The intermediate formation of compound I,b in the synthesis of 4-(3-methoxypropyl) phenol (II,b).Thermolysis of a sample of 4-(3-methoxypropyl)-2,6-di-tert.-butylphenol (X,b) at a temperature of 295 300oC under the conditions of example 7 through 14 hours gave a product containing data GC 2% of the parent compound X,b, 19% of compound (II), b and 74% of 4-(3-methoxypropyl)-2-tert.-butylphenol (I,b).Example 9. Getting 1 isopropylamino-3-[4-(3-methoxypropyl)-phenoxy]propanol-2 (V,b).A mixture of 15.2 g (0.1 mol) of 4-(2-methoxypropyl)phenol, 65 ml of epichlorohydrin and 0.17 ml of piperidine is heated with stirring 4 h at 100oC. Then the reaction mass is distilled off, the epichlorohydrin to the content in the reaction mass is not more than 5% Gain of 29.3 g of oil containing 24% of 1,2-epoxy-3-[4-(2-methoxypropyl)phenoxy] -propane and 59% 3-[4-(2-methoxypropyl)phenoxy]-1-chloropropanol-2. This mixture is placed in a rotating autoclave along with 35 ml of Isopropylamine and 45 ml of isopropanol and incubated for 12 h at 100oC. and Then distilled off the mixture of Isopropylamine and solvent, the residue is dissolved in ether. The ether solution is washed bukta V,b so pl. 40 50oC, after crystallization from hexane with the addition of dichloroethane so pl. 53 54oC. Found? C 67,54; H 9,26; N 5,04. Calculated C 67,39; H 9,42; N 5,23. Range PMR (CCl4d M. D. from TMS); 1,05 (D. 6N); to 1.75 (m, 2H); 2,55-2,77 (m, 2H); 3,23 (C. 3H); of 3.77-3,88 (m, 3H); 6.73 x-6,97 (system AA'BB', 4H).Example 10. Getting tartrate V,b.A mixture of 2.0 g of product V,b and 0.5 g of tartaric acid in 15 ml of isopropanol is heated, stirring, for 15 minutes at 50 to 60oC. the resulting solution was cooled to room temperature and was incubated for 6 hours the precipitation is filtered off, washed with isopropanol and air-dried to constant weight. Get 1.9 grams (80,5%) tartrate product V,b so pl. 106 - 107 oC. Found; C 61,18; H 8,62; N 3,86. Calculated C 60,88; H By 8.22; N 3,93.Literature.1. Synthesis and analytical study of 4-(2-methoxyethyl)phenol Tyrazol// Rutkowska-Olma E. Sazala W. Kulawinek J. M.// Barwniki Srodki Pomocnicze 1988 at M.V.Lomonosov 32 (3) p. 55-61 // Chem. Abstr. 1989 111 - 57149v.2. Preparation of salts of ()-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy] -2-propanol, especially the tartrate of ()-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy] -2-propanol// Zjawiony J. Kaczur-Kaczynski E. at al.//Pol. PL 158.497 (Cl. C 07 C 217/32)// Chem. Abstr. 1993 119 203128w.3. Phenoxy-hydroxypropylamines, metod and pharmaceutiical preparations for treating cardiovascular diseases // A. E. Brandstrom, P. A. E. Carlsson at al. // Pat. US 3928601 (US Cl. 424/300, 424/330. Int Cl2A 61 K 31/27) - 1975.4. Preparation of 2-methoxyethenyl-nitrobenzenes// Hallberg A. B. Holm her// Hallberg A. Westfelt L. Anderssonlarl M.// Synth. Commun. 1985 15 (13) -p. 1131-1136.6. Organikum. Workshop on organic chemistry, I. I. M. Mir, S. 356-357.7. The method of obtaining 4-haloalkyl-2,6-di-tert.-butylphenol// Patent of the Russian Federation (the class C 07 C 39/24, 37/62), N 1376511, 1985.8. Synthesis of cabon-14-labelled metoprolol //N. Chaudhuri K. Ball, T. J. // J. Labelled Comp. Radiopharm, 1981, 18 (9) p. 1273-1281.9. The evaluation of a biogenetically based approach to the synthesis of octahydro-1H-benzofuro[3,2-e] isoguinolines//Ajao J. F. C. W. Bird Chauhan Y.-P.// Tetrahedron 1985 41 (6-7) p. 1367-1372.10. Patent USSR, N 1170968, class C 07 C 93/06, 1985.11. Synthesis and physical properties of alkoxymethylene substituted phenyl cyclohexanecarboxylates// Kitamura Teruo, Mukoh Akio at al.// Mol. Cryst. Liq. Cryst. 1985 130 (3-4) p. 231-243. 4-Methoxyethyl-2-tert.butylphenol formula I
< / BR>as intermediates in the synthesis of metoprolol and its analogues.
FIELD: medicine, narcology.
SUBSTANCE: method involves alternating comatose therapy and electroshock therapy every other day. In day carrying out the comatose therapy eserine ointment is placed in conjunctival sacs to patient and in 30 min 2-2.5 mg scopolamine hydrobromide solution is administrated as its 0.5% solution. Then in 3-5 h of comatose state patient is recovered from coma and 15-30 mg of physostigmine, 6 g of pyracetam, 7.5 g of magnesium sulfate and 400 ml of sodium hypochlorite are administrated by intravenous drops. In each next séance of comatose therapy dose of scopolamine hydrobromide is increased by 0.5 mg and brought about to 5-6 mg. In day carrying out electroshock therapy 1 ml of 0.1% solution of atropine sulfate and 2 ml of cordiamine are administrated and preliminary narcosis is carried out by intravenous administration of 200-300 mg of sodium thiopental or 100 mg of ketamine with simultaneous administration of 3-4 ml 2% ditiline solution and electroshock therapy is carried out followed by artificial lungs ventilation. Method provides enhancing effectiveness of treatment and to prolong the remission period.
EFFECT: enhanced effectiveness of treatment.
FIELD: medicine, otorhinolaryngology.
SUBSTANCE: invention relates to substances causing fresh and relieving sense in mouth cavity, pharynx and respiratory ways, to compositions containing these compounds and to using these compounds. Compounds represent acyclic ethers. Using proposed compositions allows eliminating bitter taste of medicines, they are stable and their effect in using is more continuous.
EFFECT: improved and valuable properties of agent.
18 cl, 4 ex
SUBSTANCE: in formula I Rf is an alkyl group containing 1-2 carbon atoms, in which 1-5 hydrogen atoms are substituted with 1-5 fluorine atoms, and R is an amine group or an amine group substituted with an amino acid residue of general formula NH(COCHR'NH)-H, where R' is hydrogen, a side chain of natural amino acid which is C1-C4alkyl, possibly substituted with a hydroxy group, a hydroxyl group, disodium or an ammonium phosphate group. The invention also relates to versions of the method of producing compounds of formula I, involving the following steps: fluoroalkylation of 4-hydroxy-3-methoxybenzaldehyde or 4-hydroxybenzaldehyde in the presence of an interphase transfer catalyst, to obtain 4-fluoroalkoxy-3-methoxybenzaldehyde (V) or 4-fluoroalkoxybenzaldehyde (VII), respectively, subsequent selective demethylation (V) with lithium diphenylphosphine and a protection of a hydroxy group or nitration (VII) in the 3rd position. The obtained compounds undergo Wittig reacton using a ylide of 3,4,5-trimethoxybenzyltriphenylphosphonium and the desired product is extracted.
EFFECT: obtaining novel combretastin derivatives of formula (I), having angiogenesis inhibiting activity, which can be used as anticancer and/or antiangiogenic agents.
6 cl, 17 ex, 4 dwg
SUBSTANCE: invention refers to medicine, specifically to dermatology, and can be used for treating the patients suffering eczema. The method involves comprehensive drug therapy including administration of antihistamines and glucocorticosteroids, and also prescription of Cytoflavinum orally 2 tablets twice a day 30 minutes before meals. In the evening, the drug is taken not later than 18 o'clock. Length of the therapeutic course is 25 days.
EFFECT: method enables higher clinical effectiveness in the patients suffering eczema due to relief of core symptoms of eczema and correction principal pathogenic mechanisms of said pathology, and also faster regression of clinical presentation, improved endotoxicosis values, immunological values, stimulated antioxidant protection and albumin status factors.
1 dwg, 17 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry, particularly to polyvitamin kit for women. The polyvitamin kit for women containing herbal microelements and micronutrients and comprising 2 formulations; the first formulation potentiates an oestrogen phase of menstrual cycle; the second form potentiates a progesterone phase of menstrual cycle with the first and second formulations containing specific ingredients taken in specific proportions.
EFFECT: kit is effective for stimulating menarche in disturbed menstrual function formation, rehabilitation of female adolescents and adults of reproductive age with menstrual dysfunction for preventing and treating ovarian-menstrual irregularities.
7 cl, 2 dwg, 2 tbl, 8 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical and cosmetic industry, particularly an agent applied to skin. A vesicle applied to skin containing α,ε-bis(γ-N-(C10-30)acylglutamyl)lysine and/or its salt; ceramide and/or its derivative; and one or more ethers selected from glycerin ether of fatty acid, polyglycerin ether of fatty acid and glycerin ether of pyroglutamic acid taken in certain proportions. The therapeutic agent for external application to skin containing a certain amount of the vesicle.
EFFECT: vesicle and based therapeutic agent are stable, effectively encapsulates an active ingredient that allows it reaching true skin, effectively suppress transepidernal dehydration.
6 cl, 13 tbl, 8 ex
SUBSTANCE: invention refers to pharmaceutical and food industry, namely a method for producing alkyl-glycerol esters of sea fats. The method for producing alkyl-glycerol esters of sea fats involving hydrolysis of sea fat, acidation of a fatty mixture, water washing, first crystallisation of the mixture of acetone and hexane, filtration, second crystallisation of the residue of acetone or hexane, filtration and drying of an end product under certain conditions.
EFFECT: method enables reducing a time of technological process.
2 cl, 21 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, namely to experimental pharmacology and may be used for the placental microcirculation correction in pregnant women. Substance of the method involves simulating gestosis in Wistar rats by the daily intraperitoneal introduction of L-nitro-arginine-methyl ester 25 mg/kg for 14th to 20th day of pregnancy. For the purpose of the placental microcirculation correction, what is used is a single 10-minute hind-limb ischemia by clamping the femoral artery in the upper one-third followed by reperfusion on the 21 days of pregnancy, 90 minutes prior to the microcirculation recording.
EFFECT: use of the declared method allows correcting the placental microcirculation disorders during the simulated pathology.