How to obtain tramadol
(57) Abstract:Getting tramadol is performed in the Grignard reaction. The Grignard reaction between m-halogenation, magnesium and 2-(dimethylaminomethyl)cyclohexanone is carried out in a medium of an organic solvent with donor properties. As m-halogenase use m-bromoanisole or m-chloroanisole. The reaction is carried out with the activation of magnesium 1,2-dehalogenation. As 1,2-dehalogenating use 1,2-dibromoethane, 1,2-dichloroethane or 1-bromo-2-chlorate. Specified 1,2-dehalogenated take in the amount of from 0.01 to 0.95 molar amount of m-halogenase. As the organic solvent with donor properties use ethers or amines. The improved method provides a higher yield of the target product and expanding the resource base at the expense of use as the original m-halogenase m-chloroanisole. 14 C.p. f-crystals. The invention relates to the chemistry of aminoalcohols, in particular, to an improved process for the preparation of tramadol - 2-dimethyl aminomethyl-1-(3-methoxyphenyl)cyclohexanol.Tramadol (in the form of cleaners containing hydrochloride salt) is an effective analgesic with a low toxicity to warm-blooded animals (1).< / BR>The described method is reorganizes compounds (Grignard reagent, derived from magnesium and m-bromoanisole) (1,2).Getting substituted aminomethylphenol - tramadol by the Grignard reaction is presented in scheme 1 (see the end of the description).Known for an improved method of obtaining aminoalcohols by the Grignard reaction and their separation from the reaction mixture (3). According to this method, the reaction mixture was subjected to acid and then alkali treatments, thereby increasing the yield of the target product.However, according to patent documents the scope of the Grignard reaction is limited by the use of expensive product m-bromoanisole, which is several orders of magnitude more expensive than the corresponding chlorinated.The number of known techniques to obtain a Grignard reagents from light aryl halides. So, when using the magnesium chloride-potassium iodide potassium Grignard reagents can be obtained with high yields (4), but the system with metallic potassium is flammable and explosive and may not be used to produce pharmaceutical substances in the industrial scale.The use of the system magnesium-1,2-dibromethane allows you to get magyarkanizsa connections from and tend to the formation of insoluble deposits on the surface of magnesium and as a consequence, exhibit inertia (7). Therefore, even the approach formulated above with the above substituents interact with magnesium in the presence of 1,2-dibromethane only 36 - 56% (8-10).As the closest analogue (prototype) the selected method of obtaining the tramadol, which consists in the interaction m-bromoanisole, magnesium and 2-dimethylaminomethylene in absolute tetrahydrofuran (THF) (2). According to example 1 of the said patent shavings of magnesium added in portions to a solution of m-bromoanisole in absolute tetrahydrofuran, maintaining the boil, and boil until dissolved magnesium. To the thus obtained Grignard reagent is added 2-dimethylaminomethylphenol, maintaining the temperature of the reaction mixture to -10...0oC. as a result, the output of the reasons tramadol is 78,6% in terms of 2-dimethylaminomethylene. The target product can be transferred to the cleaners containing hydrochloride salt in hydrochloric acid or gaseous hydrogen chloride in the presence of an organic solvent selected from ethers, ketones or aromatic esters.Under these conditions, m-chloroanisole shows inert and does not interact with MAGN the AI known way for tramadol.The technical result, which can be obtained by carrying out the invention is expressed in the increase in the yield of the target compounds in expanding the resource base through the use of a cheaper source connection, m-chloroanisole and expansion of the range of the used solvents.The proposed method for obtaining the tramadol is in the interaction m-halogenase with magnesium and 2-dimethylaminomethylene in the environment of an organic solvent with donor properties in the presence of 1,2-dehalogenating, taken in an amount from 0.01 to 0.95 molar amount of m-halogenase. The target product is released in the form of a base or cleaners containing hydrochloride salt.As m-halogenase used as m-bromoanisole and m-chloroanisole.As 1,2-dehalogenating use 1,2-dibromethane in number, it is from 0.01 to 0.5, and preferably of 0.05 to 0.3 molar quantity of the specified m-halogenase.As 1,2-dehalogenating use of 1,2-dichloroethane in number, preferably from 0.25 to 0.95 molar quantity of the specified m-halogenase.As 1,2-dehalogenating you can use 1-bromo-2-chlorate.As the solution is propyl ether, glyme or diglyme, or a cyclic ether, for example tetrahydrofuran. You can use as a solvent with donor properties of the amine, preferably a tertiary amine, such as triethylamine or pikolines.In the absence of additives, activating the magnesium - specified 1,2-dehalogenating, the yield of the target compounds will be reduced to 10% when used as a solvent diethyl ether.In the presence of 0.1-0.25 mol of 1,2-dibromethane when using as starting compound m-chloroanisole exit reasons tramadol is 50 to 75% depending on the solvent. When using m-bromoanisole output rises to 85% in diethyl ether, and slightly increased (up to 87-90%) when the number of 1,2-dibromethane. On the contrary, in the case of m-chloroanisole further increase in the amount of 1,2-dibromethane (from 0.25 to 0.95 moles) causes a gradual increase in the yield of the Foundation of tramadol.The use amount of 1,2-dehalogenating more of 0.95 moles impractical because not lead to a noticeable increase in the yield of the target product.Replacement 1,2-dibromethane 1-bromo-2-chlorate virtually no effect on the process, and the transition to a 1,2-dichloroethane leads to some reduction is of tramadol in the interval from -10 to 100oC.Translation grounds of tramadol in cleaners containing hydrochloride salt is carried out by traditional methods.The essence of this invention is illustrated by, but is not limited to the following examples.Example 1. To 3.1 g (0.13 mol) of magnesium shavings add a solution of 18.7 g (0.1 mol) of m-bromoanisole and 4.7 g (0,025 mol) of 1,2-dibromethane in 60 ml of diethyl ether, so that the ether was quietly seething. Then boil for 1 hour, cooled to room temperature and added 12.4 g (0.08 mol) of 2-dimethylaminomethylene. Stirred for 0.5-1 hour and add 50 ml of saturated solution of ammonium hydrochloride. Layers divide, the water layer is extracted. The combined extract the solvent is distilled off, the residue is distilled in vacuum. Obtain 17.9 g (1), yield 85%, so Kip. 152-155oC/2 mm RT.art., so plvl. hydrochloride 177-178oC.Example 2. Analogously to example 1 from 18.7 g (0.1 mol) of m-bromoanisole, 3.6 g (0.15 mol) of magnesium, 9.4 g (0.05 mol) of 1,2-dibromethane, 12.4 g (0.08 mol) of 2-dimethylaminomethylene and 60 ml of diethyl ether to obtain 18.7 g (1), yield 89 %, so Kip. 142-145oC/1 mm RT.article.Example 3. Analogously to example 1 from 14.3 g (0.1 mol) of m-chloroanisole, 4.8 g (0.2 mol) of magnesium, 18,8 g (0,095 mol) of 1,2-dibromethane, 12.4 g (0.08 mol) of 2-dimethylaminomethyl is R 4. Analogously to example 1 from 14.3 g (0.1 mol) of m-chloroanisole, 3.1 g (0.13 mol) of magnesium, and 1.9 g (0.01 mol) of 1,2-dibromethane, 12.4 g (0.08 mol) of 2-dimethylaminomethylene and 80 ml of tetrahydrofuran gain of 12.6 g (1), yield 60 %, so Kip. 165-170oC/5 mm RT.article.Example 5. Analogously to example 1 from 14.3 g (0.1 mol) of m-chloroanisole, 3.1 g (0.13 mol) of magnesium, 4.7 g (0,025 mol) of 1,2-dibromethane, 12.4 g (0.08 mol) of 2-dimethylaminomethylene and 60 ml of diethyl ether receive a 10.5 g (1), the yield is 50%, so Kip. 165-170oC/5 mm RT.article.Example 6. Analogously to example 1 from 18.7 g (0.1 mol) of m-bromoanisole, 4.8 g (0.2 mol) magnesium, 18,8 g (0,095 mol) of 1,2-dichloroethane, 12.4 g (0.08 mol) of 2-dimethylaminomethylene and 60 ml of diethyl ether to obtain 16.6 g (1), yield 79%, so the bales. 142-145oC/1 mm RT.article.The spectral parameters and physico-chemical constants of 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol and its cleaners containing hydrochloride salt obtained in the examples are identical.Thus, the proposed method allows to obtain higher outputs tramadol, based on both m-bromoanisole and m-chloroanisole using a wide range of organic solvents.Sources of information
1. U.S. patent N 3652589, C 07 D 27/04, publ. 28.03.1972.
8. G. R. Peftet, M. F. Bauman, K. N. Rangamnal. J. Med. Pharm. Chem., 1962, v. 5, p. 800.9. G. W. H. Cheeseman, R. C. Poller. J. Chem. Soc., 1962, p. 5277.10. A. Nudelman, D. J. Cram. J.Org. Chem., 171, v. 36, p.335.1 1. How to obtain tramadol - 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol by the reaction of m-halogenase, magnesium and 2-(dimethylaminomethyl)cyclohexanone in the environment of an organic solvent with donor properties with the separation of the target product in the form of a base or cleaners containing hydrochloride salt, characterized in that as m-halogenase use m-bromoanisole or m-chloroanisole, and the reaction is carried out with the activation of magnesium 1,2-dehalogenation, taken in an amount from 0.01 to 0.95 molar quantity of the specified m-halogenase.2. The method according to p. 1, characterized in that as 1,2-dehalogenating use 1,2-dibromethane.3. The method according to p. 2, characterized in that the 1,2-dibromethane used in an amount of 0.01 to 0.5 molar quantity of the specified m-halogenase.4. The method according to p. 3, characterized in that the 1,2-dibromethane used in quantities of 0.05 to 0.3 Molinos is ohinata use of 1,2-dichloroethane.6. The method according to p. 5, characterized in that the 1,2-dichloroethane is used in amounts of from 0.25 to 0.95 molar quantity of the specified m-halogenase.7. The method according to p. 1, characterized in that as 1,2-dehalogenation using 1-bromo-2-chlorate.8. The method according to any of paragraphs.1 to 7, characterized in that the organic solvent with donor properties use the ether.9. The method according to p. 8, characterized in that the ether used as an acyclic ether.10. The method according to p. 9, characterized in that as the acyclic ether using diethyl ether, di-isopropyl ether, glyme or diglyme.11. The method according to p. 8, characterized in that the ether used as a cyclic ether.12. The method according to p. 11, characterized in that the cyclic ether used tetrahydrofuran.13. The method according to any of paragraphs. 1 to 7, characterized in that the solvent with donor properties of the used amine.14. The method according to p. 13, characterized in that used as an amine tertiary amine.15. The method according to p. 14, characterized in that the tertiary amine using triethylamine or picoline.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes compound of the formula (I):
as a free form or salt wherein Ar means group of the formula (II):
wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
13 cl, 3 tbl, 35 ex
FIELD: medicine, neurology.
SUBSTANCE: the present innovation describes arylalkylamines that specifically affect certain types of receptor-operated Ca2+-canals, their application and pharmaceutical compositions for treating neurological disorders or diseases.
EFFECT: higher efficiency.
55 cl, 29 ex, 11 tbl
FIELD: medicine, dermatology.
SUBSTANCE: invention proposes an anti-infectious preparation comprising the combination of active substances with topical and systemic antifungal agents and a water-insoluble film-forming agent. The systemic antifungal agent is taken among the group including intraconazole, terbinafine and fluconazole or their salts. The topical antifungal agent is taken among the group including ciclopirox, 6-(2,4,4-trimethylpentyl)-1-hydroxy-4-methyl-2(1H)-pyridone, amorolfine and butenafine or their salts. The preparation is used as lacquer for nails in therapy of onychomycosis. The lacquer preparation provides high concentration of systemic antifungal agents in nails after its topical applying. The significant advantage of the preparation involves short time in treatment of anychomycosis.
EFFECT: enhanced effectiveness and valuable medicinal properties of preparation.
6 cl, 6 ex
FIELD: medicine, gastroenterology, surgery, endoscopy.
SUBSTANCE: method involves injection of adrenaline hydrochloride 0.01% solution that is administrated in the amount 10 ml and injection is carried out from 4-6 points in the dose 1.6-2.5 ml per a point, and dalargin in the dose 1 mg diluted in 2 ml of physiological solution, and the preparation is injected from 4 points in the dose 0.5 ml per a point. These medicinal agents are administrated into submucosa periulcerogenic zone wherein the preparation "TakhoKomb" is used for application that is pressed to the bottom of ulcer defect for 2 min, not less. Invention promotes to diminish the amount of bleeding relapses in early post-hemorrhagic period due to the combined effect of "TakhoKomb", adrenaline and dalargin. Invention can be used in carrying out the endoscopic hemostasis in bleeding-complicated chronic gastroduodenal ulcers.
EFFECT: improved method for hemostasis.
FIELD: medicine, infectious diseases, psychotherapy.
SUBSTANCE: method involves antiviral therapy, immune correction with thymus hormones and interferon inductors. Since the first day the relapse symptom method involves prescription of antiox+ (1 capsule per a day) and detox+ (1 capsule, 2 times per a day) for 30 days, profluzak (20 mg, 3 times per a day for 5 days) and then in the dose 20 mg, 1 time per a day for 20 days. Derinate is prescribed topically as installation into urethra in the dose 3-5 ml or with tampon into vagina and with simultaneous prescription of microenemas in the dose 10-40 ml for 10 days. Since 10-14 day in exacerbation period in the proliferative stage of an antiherpetic immune response derinate is prescribed by intramuscular injections in the dose 5 ml, 1 time in a day, 10 injections in total number. Then since 6-th day of exacerbation and intake of profluzak psychotherapy seances are carried out. The first seance of rational psychotherapy involves explanation to a patient in available form mechanism of the disease, the necessity of prolonged treatment and motivation for treatment is enhanced by suggestion. The second psychotherapy seance involves neurolinguistic programming wherein a patient colorful and detailed description of desirable function when he imagines achievement of the desire result, and positive emotional and vegetative symptoms are notes and the conditional-reflect association is formed by tactile contact. Under psychotherapist control a patient imagines "part of person" responsible for achievement of the desire result the patient attention is accented for the desire result and arisen physiological responses are fixed by using tactile contact. Also, new behavior methods are proposed to take for a patient that are directed for achievement of the desire result - avoiding sexual contacts during exacerbation of genital herpes in one of partner and during every month hormonal cycles, avoiding stress situations, and in case of each stress situation significant for patient profluzak has to be intake in a single dose 40 mg, using a condom in sexual contact in the exacerbation period. Patient analyzes the proposed new behavior methods that help avoiding relapses, provide good state of health, promotes to recovery process of genitals recovery and selects at least three the most rationally available for him behavior methods. In the case of the positive response that is controlled by physiological symptoms the result is fixed by tactile contact. The third seance involves the suggestive psychotherapy directed for fixing the attained result. The suggestive therapy seance is carried out once per a week for 6 months. Method provides declining the treatment time, to reduce relapse frequency of genital herpes and to recover the emotional state of patient.
EFFECT: improved treatment method.
2 cl, 3 tbl, 1 ex
FIELD: medicine, phthisiology, in particular chronotherapy of patients suffering from disseminated pulmonary tuberculosis with β2-agonists.
SUBSTANCE: two doses β2-agonists, namely salbutamol and fenoterol are administered at 11, 17 and 23 o'clock.
EFFECT: improvement of external respiration in early period; preventing severe blockages of bronchial tree; improvement of patient quality of life.
FIELD: medicine, narcology, biochemistry, pharmacy.
SUBSTANCE: invention proposes using the combination of dextromethorphan and the second medicine (quinidine, yohimbin, haloperdol, adjmaline, lobeline, pipamperon, fluoxetine, labetalol, chlorpromazine, domperidone, nortryptiline, quinine, oxyprenolol, propranolol, timolol, methaprolol, diphenhydramine, papaverine, mexiletine or their salts or isomers) for removing addiction to opiates, opioids or synthetic narcotics with exception cocaine and barbiturates (help in refusal in their using) or in case of chronic using antidepressant and corresponding treatment methods. The proposed combination of drugs reduces pain and relieves the withdrawal syndrome on the background of reducing morphine dose (antidepressant) up to the complete removing their intake.
EFFECT: enhanced effectiveness and valuable medicinal properties of medicine combinations.
54 cl, 2 ex
SUBSTANCE: invention relates to two-layered solid composition including a) the first layer of direct action containing effective antiallergic amount of desloratadine and at least one pharmaceutically acceptable carrier and b) the second layer of prolonged action containing effective amount of nasal anti-oedema agent and pharmaceutically acceptable carrier, wherein composition contains less than 2 % of desloratadine deterioration products. Composition is stable in administration of one or two times per day.
EFFECT: new composition for treatment and/or amelioration of prodromes or symptoms associated with common cold and allergic and/or phlogistic skin or pipe conditions.
28 cl, 1 dwg, 6 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of amidines possessing properties of inhibitors of phosphatases, and to a pharmaceutical composition comprising indicated compounds. Invention provides enhancing effectiveness of treatment.
EFFECT: valuable medicinal and biochemical properties of compounds.
4 cl, 1 dwg, 33 ex