Method for bromination of α- and β-ergocryptines
FIELD: chemical-pharmaceutical industry, chemical technology.
SUBSTANCE: invention relates to a method for preparing neurohormonal agent - abergin (α- and β-bromoergocryptines). Bromination of mixture of α- and β-ergocryptines is carried out with 50% excess of N-bromosuccinimide in chloroform medium with addition of dioxane (10:1). Method involves using dioxane with peroxide content in the amount 0.011-0.0145 mole part with respect to amount of alkaloids in the reaction medium wherein the parent concentration of ergotoxine alkaloids is 0.125-0.150 mole/l. Method provides enhancing yield of the end substance at the key stage of the bromination reaction.
EFFECT: improved preparing method.
1 tbl, 2 dwg, 1 ex
The invention relates to pharmaceutical industry, and in particular to methods of obtaining compositions with neurohormonal activity - aubergine.
A method of obtaining abelina , according to which the horns of ergot ergocryptine strain is extracted with dichloroethane, the precipitated amount of alkaloids, conduct cleanup fees by chromatography through a layer of fine sorbent with suction, crystallized alkaloids from benzene and then hold bromination of the cleared amount. In the known method are bromination with N-bromosuccinimide in a mixture of dioxane-chloroform 1:10 without heating for 0.5 hour, then the reaction mass is passed through a bed of sorbent and the product is crystallized from acetone. The resulting basis alkaloids transferred to salt methansulfonate standartnym way.
The disadvantage of this method is the low yield of 2-bromo-α,β-ergocryptine stage synthesized (38%).
The objective of the invention was to increase the yield of the target substance in bromirovanii N-bromosuccinimide.
The reaction of the synthesized of ergot alkaloids flows is ambiguous due to the high chemical lability of the molecules of these natural compounds (I) and is accompanied near side transformations (see diagram).
Usually in the course of dissolution, in the process of carrying out the reaction and purification of the target product is epimerization occurs in position 8 molecules of alkaloidal education α thatβ-ergocryptine (II) and 2-bromo-α,β-ergocryptine (III). In order to accelerate the reaction of the synthesized and avoid formation of epimeres (II, III), apply the excess N-bromosuccinimide (to 1.5 mole per mole of alkaloid). Otherwise, the part of the original grounds (I) will not react and will complicate the purification of the target substance (IV). Large excess brainwashes agent is undesirable because it causes the formation polipoprotein. In reaction mass should not be present in water and alcohols, because it leads to the formation of intensely colored impurities resulting photopresenter double bond With9-C10(V) and photooxidation of 2-position of the indole ring (VI). Under these conditions, the main condition of successful technology must be fast and directional conducting the reaction of the synthesized with minimum side transformations.
Bromination reaction is radical type and therefore requires the presence in the reaction medium initiators, such as gidroperekisi. This is due to the necessity of presence in the environment of the reaction of dioxane containing a certain amount of hydroperoxides. It is considered that the hydroperoxide concentration of about 0.01% sufficient for this reaction. Given the above, we have proposed a method of carrying out the reaction of the synthesized α and β-ergocryptine alkaloids in pin is aireamh content of peroxides conditions. When carrying out the reaction of synthesized on an industrial scale (on the order of large industrial load than the laboratory), we establish that the yield of the reaction is higher, the closer the content of peroxides in dioxane to optimal with respect to the amount of substance in the reaction medium (see table). The optimum molar relationship initiator to brainwave substance was found by conducting a series of downloads in real production conditions. Turned out to be (see the drawing)that the dependence of the yield of 2-bromo-α,β-ergocryptine this parameter has a bell-shaped form. At low values until 0,010 in the reaction mass remains the original connection and the yield of the target substance is low. It also decreases with excess peroxides, when the molar ratio exceeds 0,015, due to the occurrence of side reactions, type polibromirovannyh and someproducts. It was shown that it is advantageous to use more concentrated solutions of the original substance in the range from 0.125 to 0,150 m/l α,β-ergocryptine while maintaining the ratio of chloroform - dioxane in the environment of the reaction of 10:1 instead of the above concentrations of about 0.1 M/L. this reduces the consumption rates of the absolute highly purified solvents and productivity is increased due to the increase in single downloads 16 times compared to the prototype, the Upper limit of 0.15 M/l is limited by the solubility of all components in the reaction mixture and norms of mechanical losses during subsequent processing of highly concentrated solutions.
|The results of the synthesized α,β-ergocryptine 50% excess of N-bromosuccinimide environment chloroform-dioxane (10:1) (reaction time 30 minutes)|
|No.||α,β-EC. mol||Conc. α,β-EC. m/l CHCl3||Hydrophilicity in dioxane mol||The concentration of peroxides in dioxane %||The ratio of 4:2 M/m||The yield of 2-Br-α,β-EC.||The concentration of starting materials in the reaction product, %|
|P = prototype|
Compliance with the proposed method the criterion of "novelty" is that using the optimal molar ratio of peroxides in dioxane to the original amount of the mixture α,β-ergocryptine taken in response, and increased concentration ergocryptine in the reaction medium.
Compliance with the proposed method the criterion of "inventive step" is that identified the nature of the dependence of the yield of the reaction between the reactive substance - initiated reactions of radical type, which ensures optimization of process parameters of synthesized in a certain interval conditions and high preparative you the od process synthesized.
The essence of the invention is demonstrated by the example.
Example: 1000 g of purified sum reason α,β-ergocryptine in the form of a solvate with 2 moles of benzene (1.37 m) dissolved in 10 l of dry chloroform and added to 1.0 l of dioxane (content of peroxides 0,185%) (0,015 mol). The molar ratio of alkaloids to the initiator 0,0113. Within 30 minutes are added under stirring and a temperature of 20°With 370 g of N-bromosuccinimide. After 30 minutes the reaction mass is treated with 6 l of a 1M solution of Na2SO4, 12 l (2×6 l) 1M solution of Na2CO3and 2×4 l H2O. Dried over sodium sulfate, filtered and passed with suction through a layer of 4 kg of silica gel (particle size of from 10 to 60 μm firm "Slavich", Russia), washed with chloroform. Fractions containing 2-bromo-α,β-ergocryptine, evaporated to dryness and dissolved in 600 ml of acetone. After 12 hours at 0°With precipitation, which is separated and get 560 g (62.6 per cent) of the crystal amount of 2-bromo-α,β-ergocryptine. From the Queen cells will receive an additional 51 g of residue which is subject to additional cleaning.
The use of the proposed method in comparison with the known will provide the following benefits:
1. By choosing the optimal parameters of the reaction, the synthesized output target substance increased from 38% to 62.6%.
2. Reduced consumption of sorbent 4 times due to the mind is isenia amounts of impurities and complete the passage of the reaction.
3. Increased productivity and reduced expenses on highly purified solvents due to the increase in single boot 16 times. On the basis of the claimed method increased production of drug amergin at CJSC "Farmcentr VILAR" 2-3 times.
The source of information
1. Patent No. 2106148 (RF) dated 10.03.1998 g priority from 06.10.1995, BI No. 7, 1998, "a Method of obtaining neurohormonal means" Bykov V.A., zvonkova E.N., Tregubov V.M., Monakhov IE, Burma I., Anufrieva CENTURIES, Pineau S.A., Sahin S., Shevchenko V.I.
The way the synthesized α and β-ergocryptine alkaloids using N-bromosuccinimide in a mixture chloroform-dioxane 10:1, wherein the number of peroxides that are made with dioxane, is to 0.011-0,0145 mole fractions on the number of alkaloids, and initial concentration of alkaloids equal 0,125-0,150 mol/L.
FIELD: organic chemistry, medicine, hematology.
SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.
EFFECT: valuable medicinal properties of compounds.
13 cl, 1 tbl, 195 ex
< / BR>where X Is N or CY and Y denotes H or halogen; R1is amino or a protected amino group; R2is hydrogen or optionally substituted (ness.)alkyl; R3denotes hydrogen or lower alkyl; R4indicates Bogoroditse optionally substituted (NISS
FIELD: genetic engineering, proteins, medicine, pharmacy.
SUBSTANCE: invention relates to a method for preparing a fused protein representing immunoglobulin Fc-fragment and interferon-alpha and can be used in treatment of hepatitis. Method involves construction of a fused protein comprising immunoglobulin Fc-fragment prepared from Ig G1 or Ig G3 in direction from N-end to C-end and the end protein comprising at least one interferon-alpha. Fc-fragment and the end protein are joined directly or by a polypeptide bridge. The fused protein is used for preparing a pharmaceutical composition used in treatment of liver diseases and in a method for targeting interferon-alpha into liver tissues. Invention provides preparing the fused protein eliciting with biological activity of interferon-alpha providing its concentrating in liver and showing enhanced solubility, prolonged half-time life in serum blood and enhanced binding with specific receptors.
EFFECT: improved targeting method, valuable biological properties of fused protein.
10 cl, 5 dwg, 9 ex
where n= 1-4, R7Is F, Cl, C1-C4alkyl, R2Is h, Cl, Br, I, C1-C4alkyl, C1-C4alkylthio, R3- H, C1-C4alkyl, R4(i) a group of formula (C), (d), where R8- N, NO2and R11- C1-C4alkyl, C2-C8alkenyl or (ii) a group of formula (d), (e), R5and R6- H or together form an additional bond
FIELD: medicine, pharmacy.
SUBSTANCE: invention describes analgesic compositions containing buprenorphine in the level of subclinic analgesic doses in combination with naloxone, naltrexone or nalmephene. The mass ratio buprenorphine to naloxone is in the range from 12.5:1 to 27.5:1, and the mass ratio buprenorphine to naltrexone or to nalmephene is in the range from 12.5:1 to 22.5:1. Compositions are prepared as the parenteral or sublingual medicinal formulation or as a medicinal formulation that can be delivered through mucosa. Analgesic effect of buprenorphine is enhanced by low dose of naloxone, naltrexone or nalmephene.
EFFECT: enhanced effectiveness of compositions, valuable medicinal properties.
7 cl, 3 dwg, 21 ex