Method of obtaining 3,5-diamino-6-(2,3-dichlorphenyl)-1,2,4-triazine of high purity grade
FIELD: chemistry.
SUBSTANCE: invention claims a new method of obtaining 3,5-diamino-6-(2,3-dichlorphenyl)-1,2,4-triazine of high purity degree by reaction of 2,3-dichlorbenzoylcyanide with 1-2 mol equivalents of dimethylase aminoguanidine salt in the presence of 3-6 mol equivalents of methanesulfoacid, with further addition of 2-5 mol equivalents of magnesium oxide to the reaction mix. The process is performed at 50-80°C, and target product is recrystallised from acetone.
EFFECT: improved efficiency of compounds.
5 cl, 3 ex
The technical field to which the invention relates.
The present invention relates to a new method of producing high-purity 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of the formula (I).
The level of technology
It is well known that 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, also known as lamotrigine, is the active component of some pharmaceutical compositions used for the treatment of various Central nervous system diseases (e.g. epilepsy).
The synthesis of substituted 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine known from the prior art. The following publication describes the General synthesis of substituted derivatives - Agr. Res. Serv.3188 (1966) and J. Med. Chem.8859 (1972), in accordance with which benzylcyanide reacts with aminoguanidine in an acidic medium, and the thus obtained adduct cyclist in basic conditions. In accordance with the method described in EP 21121, similar to the way, opened higher, 2,3-dichlorobenzidine reacts with bicarbonate salt aminoguanidine in dimethyl sulfoxide as a solvent, in the presence of 8 N nitric acid for 7 days. The obtained adduct cyclist using methanolic solution of potassium hydroxide to yield the final product 15% in the calculation of the original product. Close essentially the method described in EP 142306. The disadvantages of these methods are extremely durable, is extremely aggressive environment of the reaction, a long reaction time and a very low output.
EP 247842 reveals the way in which the condensation reaction instead of 8 N nitric acid using 8 M solution of sulfuric acid and conduct a reaction period of 48 hours the Reaction of cyclization is carried out in n-propanol at boiling point. The output is 41%. The disadvantages of this method are low output and the aggressive environment of the reaction.
Close essentially the method described in US 6111101, in which the condensation is carried out in a mixture of dilute sulfuric acid and acetonitrile for 60 h, then the cyclization is carried out with a 1% aqueous solution of potassium hydroxide. The output is 44%. The crude product is purified by recrystallization from methanol using a clarifier. The disadvantages of the method are in a hostile environment, low output and very long reaction times.
Modification of this method is described in EP 963980, in which the cyclization reaction is carried out in n-propanol at boiling point. The yield is 60%. The product was then purified by recrystallization from n-propanol. The disadvantages of this method are the long reaction time and the aggressive environment of the reaction.
In accordance with WO 96/20934 intermediate product, which is obtained with great difficulty, in turn lamotrigine by cyclization in a photochemical reactor with yields of 80%. The disadvantage of this method is that it is e can be used on an industrial scale.
WO 96/20935 describes the synthesis of the six stages, which is complex to implement and difficult feasible on an industrial scale, the yield of the final product is very low. The disadvantages of the method are complex synthesis, the use of hazardous reagents and low output.
Disclosure of inventions
From the above facts it is seen that in accordance with known methods lamotrigine and intermediate adduct can be synthesized only with low yield with the use of aggressive reagents, long reaction time. The objective of the invention was to develop an industrially applicable method in which use simple industrial operations in which high-purity lamotrigine can be synthesized with good yield, economically, in a short reaction time without the use of hazardous reagents.
Unexpectedly, it was found that, on the one hand, the conversion of 2,3-dichlorobenzothiazole formula (II) adduct of formula (IV) can be carried out within one hour using methansulfonate as acidic environment, in almost quantitative yield of the adduct of formula (IV), so use a large amount of mineral acid is not necessary, on the other hand, the reaction can be carried out with almost quantitative yield by applying new dimesale the Noah salt aminoguanidine formula (III). In addition, it was found that the yield can be increased through the use of magnesium oxide as a base in the reaction of cyclization without increasing reaction time, as well as that of the formation of by-products can be avoided. In the known methods used or a strong base, so the product always contained hydrolyzed by-product (for example, a product synthesized in accordance with the method of the EP 963980)or base generally not used, so the cyclization reaction was not complete. The use of magnesium oxide eliminate all these drawbacks.
During the development stage of recrystallization was found that, using acetone as solvent, the product can be obtained with more than 99.9% purity and with 70% yield.
Thus, the object of the invention is a new method for synthesis of high-purity 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of the formula (I) using 2,3-DICHLOROSILANE as starting substances, which are subjected to interaction with the new dimesylate salt aminoguanidine formula (III) in the presence of methansulfonate with subsequent conversion of the obtained adduct of formula (IV) without isolation with the help of magnesium oxide in lamotrigine. In this case, the resulting crude lamotrigine recrystallized from acetone using activated coal is as a clarifier.
The method of the present invention has several advantages in comparison with known methods. The main advantage of the method of the present invention is to obtain high purity of the final product with almost quantitative yield. The following advantages of this method are the exception aggressive, dangerous reagents and short reaction time compared with conventional methods. An important advantage of this method is besides the fact that it does not require complex manufacturing equipment of expensive structural material.
In accordance with the present invention the reaction of formation of the adduct is carried out at a temperature of 30-100°With, in the presence of 3-6 molar equivalents of methansulfonate, with 1-2 molar equivalents aminoguanidine salt (both calculated on the original 2,3-dichlorobenzidine). The cyclization reaction is conducted without isolation of the adduct at a temperature of 50-80°in the presence of 2-5 molar equivalents of magnesium oxide. The crude product can be recrystallized from a suitable organic solvent with the use of activated carbon as a clarifier.
In accordance with the present invention the reaction of formation of the adduct can preferably carried out at a temperature of 70°With, in the presence of 4.2 molar equivalents methanesulfonic is the notes using a 1.3 molar equivalents dimesylate salt aminoguanidine and acetonitrile as co-solvent, and reaction time of one hour. The product, without isolation, is subjected to contact with an aqueous suspension of 3.75 molar equivalents of magnesium oxide, preferably at a temperature of 70°C for 4 hours. Salt magnesium hot filtered and the filtrate is concentrated by distillation. The selected product is filtered. The raw output levels of lamotrigine is 90-95%, 2,3-dichlorobenzidine.
In this case, the obtained product is recrystallized from acetone using activated carbon as a clarifier with obtaining high-purity 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine with a total amount of impurities amounting to less than 0.1%.
The invention is illustrated by the following non-limiting examples.
EXAMPLE 1
Dimesylate aminoguanidine
13,61 g (0.1 mol) of hydrogen aminoguanidine suspended in 36 ml of methanol at 20-22°in a round bottom flask of 250 ml, equipped with a magnetic stirrer, thermometer, reflux condenser and addition funnel. Added dropwise 21,14 g (0.22 mol) of methansulfonate to suspension for 1.5 hours, allowing the reaction temperature to rise to 40-45°C. After the addition the resulting solution was stirred at 65-70°15 min, then cooled to (-3)-(-5)°C and stirred at this temperature for 1 h the Precipitated crystals filtered and washed with 6.8 m the methanol at the (-3)-(-5)° C.
The resulting crystalline product is dried in a vacuum oven at 45-50°and 6-10 kPa obtaining 23,46 g (88,10%) of the named compound as white crystals. Melting point: 147.5 to°C.
EXAMPLE 2
3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine
A suspension of 24.0 g methansulfonate and 21.0 g (0.079 mol) damisela aminoguanidine heated to 65-70°in a round bottom flask of 500 ml equipped with a stirrer, thermometer and addition funnel. The mixture becomes homogeneous after 15 min, then added dropwise a solution of 12.0 g (0.06 mol) of 2,3-dichlorobenzothiazole in 10 ml of acetonitrile. The resulting mixture was stirred at 65-70°1 h a Mixture of 9 g (0,223 mol) of magnesium oxide and 60 ml of water is stirred for 5 min and the resulting suspension is added to the reaction mixture within 10 minutes
The temperature of the reaction mixture was raised to 70°C and kept at this temperature for 3 hours, the Reaction mixture was hot filtered, add 90 ml of water to the filtrate and concentrate. Add 60 ml of water to the precipitate and the suspension is stirred at 0-5°C, then filtered. The product is washed with water and dried at 60-70°to yield 14.3 g (93.1%) are crude titled compound. Melting point: 212-216°C.
EXAMPLE 3
Crystallization of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine
10 g of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine are dissolved in 400 ml and is of etona at boiling point, then add 0.5 g of activated charcoal and the mixture is heated in a flask with reflux condenser 5 minutes Clarifier is filtered off and the filtrate is cooled to 0-5°C. the Precipitated crystals are filtered and dried at 90°in vacuo to yield 7.0 g (70%) of product. Melting point: 215-219°C.
1. The way to obtain 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of the formula (I)
characterized by the fact that they are carrying out the reaction between 2,3-dichlororesorcinol and dimesylate salt aminoguanidine in the ratio of 1-2 molar equivalent per mole of 2,3-DICHLOROSILANE in the presence of 3-6 molar equivalents of methansulfonate and then adding to the reaction mixture 2-5 molar equivalents of magnesium oxide and selection of the target product, and the process is carried out at a temperature of 50-80°and the target product is subjected to recrystallization from acetone.
2. The method according to claim 1, characterized in that use is 1.3 molar equivalent of dimesylate aminoguanidine.
3. The method according to claim 1, characterized in that use is 4.2 molar equivalent methansulfonate.
4. The method according to claim 1, characterized in that use is 3.75 molar equivale is that of magnesium oxide.
5. Dimesylate aminoguanidine formula (III)
where R represents hydrogen or CO2CH(CH3)2
FIELD: chemistry.
SUBSTANCE: invention claims a new method of obtaining 3,5-diamino-6-(2,3-dichlorphenyl)-1,2,4-triazine of high purity degree by reaction of 2,3-dichlorbenzoylcyanide with 1-2 mol equivalents of dimethylase aminoguanidine salt in the presence of 3-6 mol equivalents of methanesulfoacid, with further addition of 2-5 mol equivalents of magnesium oxide to the reaction mix. The process is performed at 50-80°C, and target product is recrystallised from acetone.
EFFECT: improved efficiency of compounds.
5 cl, 3 ex
FIELD: chemistry.
SUBSTANCE: invention relates to compounds of general formula III and their pharmaceutically acceptable salts, A represents (C1-C6)alkyl-O-, phenyl-(C1-C6)alkyl-O-; aryl, selected from phenyl, naphthyl,
and
which is possibly substituted by 1-3 substituents, given in the invention formula; or heteroaryl, which has four or five carbon atoms and one heteroatom, selected from oxygen, nitrogen and sulphur, which is possibly substituted by 1-3 substituents, given in the invention formula; B represents phenyl, possibly substituted by 1-3 substituents, where substituents are selected from (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O-, hydroxy, amino and halogeno; and R1 and R2 independently represent (C1-C6)alkyl, phenyl-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl, (C3-C7)cycloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; on condition that R1 is different from R2; where absolute configuration of asymmetric R1 and R2 -carrying carbon atom is mainly R-configuration. Invention also relates to pharmaceutical composition, possessing ability to modulate gene expression, methods of modulation of gene expression in host cell, method of regulating expression of endogenous or heterologous gene in transgenic subject, method of regulating transgenic expression in transgenic subject, method of polypeptide production and to method of obtaining formula IV
compound. Method includes stages: a) interaction of formula V compound with formula IV compound with obtaining formula VII compound; b) reduction of formula VII compound with obtaining formula VIII compound, b) interaction of formula VIII compound with formula B-CO-LG compound, where B has values, given above, and LG is leaving group representing -F, -Cl or -Br, with formation of formula IX compound, d) removal of group R7CO2- from formula IX compound with obtaining formula X compound, e) interaction of formula X compound with formula A-CO-LG compound, where A has values, given above, and LG is leaving group, representing -F, -Cl or -Br, with obtaining formula IV compound ( compounds of formulas V, VI, VII, VIII, IX, X are given in the invention formula).
EFFECT: obtaining formula III compounds, possessing ability to modulate gene expression.
19 cl, 4 ex, 2 tbl, 78 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a compound presented by formula
,
wherein A1 means benzene or heterocycle specified in a group consisting of pyridine, pyrazine, imidazole, thiazole, pyrimidine, thiophen, pyridazine, benzoxazine and oxobenzoxazine; A2 means benzene, if needed substituted by fluorine, or thiophen; B1 means hydrogen, lower alkyl, if needed substituted by piperazinyl or morpholino, halogen-substituted lower alkyl, lower alkoxy substituted by carbamoyl, acylamino, carbamoyl or lower alkylcarbonyloxy (provided A1 means thiazole, B1 does not mean acylamino); B2 means hydrogen or a functional group containing at least one nitrogen atom specified in a group consisting of acylamino, pyrrolidinyl, morpholino, piperidinyl, if needed substituted by acyl, piperazinyl, if needed substituted by lower alkyl or acyl, pyrazolyl, diazabicyclo[2.2.1]heptyl, if needed substituted by acyl, and di-(lower alkyl)amino, if needed substituted by amino or acylamino (provided A1 means thiazole, B2 does not mean acylamino); Y means a group presented by formula
,
wherein J means ethylene or lower alkynylene; L means a bond; M means a bond; X means -(CH2)m-, -(CH2)m-O- or -(CH2)m-NR2- (wherein m is an integer of 0 to 3, and R2 means hydrogen); D means -NR3-, wherein R3 means hydrogen; and E means amino, or its pharmaceutically acceptable salt. The compounds of formula (I) are used for preparing a pharmaceutical agent or a pharmaceutical composition for treating or preventing the VAP-1 related diseases.
EFFECT: benzene or thiophen derivative as a VAP-1 inhibitor.
13 cl, 25 tbl, 125 ex
FIELD: chemistry.
SUBSTANCE: invention relates to agriculture. The compound is selected from a group including formula 1, formula 2, formula 3, formula 4, formula 5 and formula 6. Formula 1 is , where R1 = isobutyl, sec-butyl or tert-butyl-CH2; R2=H; n=0-25. Formula 2 is
, where R1 = sec-butyl or tert-butyl-CH2; R2=H. Formula 3 is
, where R1 = isobutyl, sec-butyl or tert-butyl-CH2; R2=H. Formula 4 is
, where R1 = isobutyl; R2=H; R3 = n-alkyl containing 2-25 carbon atoms, except n-heptyl and n-undecyl, branched alkyl containing 4-25 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-25 carbon atoms, or substituted or unsubstituted arylalkyl containing 12-26 carbon atoms; or R1 = sec-butyl or tert-butyl-CH2; R2=H; R3 = n-alkyl containing 1-25 carbon atoms, branched alkyl containing 3-25 carbon atoms, substituted or unsubstituted cycloalkyl containing 7-25 carbon atoms, or substituted or unsubstituted arylalkyl containing 7-25 carbon atoms; or R1 = isobutyl; R2 = methyl; R3 = n-alkyl, containing 2, 3, 6 and 12-25 carbon atoms, branched alkyl containing 3-25 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-25 carbon atoms, or substituted or unsubstituted arylalkyl containing 7-25 carbon atoms. Formula 5 is
, where R4=H, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy or haloalkythio, each containing 1-4 carbon atoms, or halogen, hydroxyl group, nitro group, carboxylic acid group or cyano group; an either R1 = sec-butyl or tert-butyl-CH2; and R2=H; or R1 = isobutyl; and R2 = methyl; and formula 6 is
, where R4 = H, alkyl, haloalkyl, alkoxy, alkythio, haloalkoxy, haloalkylthio, each containing 1-4 carbon atoms, or halogen, hydroxyl group, nitro group; carboxylic acid group or cyano group; and either R1 = isobutyl, sec-butyl or tert-butyl-CH2; R2=H; or R1 = isobutyl; and R2 = methyl. Said compounds are used to attract zoospores of plant pathogenic oomycetes of fungi or control plant diseases.
EFFECT: invention increases treatment efficiency.
17 cl, 2 dwg
FIELD: chemistry.
SUBSTANCE: invention relates to a compound of formula I, where R1 is -OR7; R2 is H; X is selected from a pyrazole, triazole, benzotriazole, tetrazole, oxazole, isoxazole, thiazole, pyridazine, pyrimidine and pyridyl triazole; R3 is absent or is selected from H; halogen; -C0-5alkylene-OH; -C1-6alkyl; -C3-7cycloalkyl; -C0-2alkylene-O-C1-6alkyl; -C(O)R20; -C0-1alkylene-COOR21; -C(O)NR22R23; -NHC(O)R24; =O; phenyl, optionally substituted with one or two groups independently selected from halogen, -OCH3, -NHC(O)CH3 and phenyl; naphthalenyl; pyridinyl; pyrazinyl; and R3, when present, is bonded to carbon atom; R4 is selected from H; -OH; -C1-2alkylene-COOR35; -pyridinyl; and phenyl or benzyl, optionally substituted by one or more groups selected from halogen and -OCH3; and R4, when present, is bonded to carbon atom or a nitrogen atom; a equals 0 or a equals 1; and R5 is selected from halogen and -CN; b is equal to 0 or 1, and R6 is selected from Cl, F, -OH, -CH3, -OCH3 and -CF3; or b is equal to 2, and R6 each is independently selected from halogen, -OH, -CH3, or -OCH3, or b is equal to 3, and R6 each is independently selected from halogen or -CH3; R7 is selected from H, -C1-8alkyl, -C1-3alkylene-C6-10aryl, -C0-6alkylene morpholinyl or dioxol-2-one methyl, of formula (a); or a pharmaceutically acceptable salt thereof. Compounds of formula (I) are obtained by condensation of compound of formula 1 with a compound of formula 2, where P1 is H or tert-butoxycarbonyl; and wherein method further includes removal of protective group of compound of formula 1, when P1 is tert-butoxycarbonyl. Also compound of formula (I) is obtained by removing protective group of compound of formula (6) or salt thereof; where R1P is -O-P3, where P3 is methyl. Invention also relates to intermediate compounds of formulae (1) and (6). Compounds of formula (I) are intended for inhibiting neprilysin activity.
EFFECT: compounds having neprilysin inhibiting activity.
19 cl, 9 ex
,
(а),
,
FIELD: biotechnology.
SUBSTANCE: invention relates to a method for preparation of an enantiomerically enriched compound with Formula III , wherein A is (C1-C6)alkyl-O-, phenyl- C1-C6)alkyl-O-; aryl selected from phenyl, naphthyl, benzo 1,3]dioxole, 2,3-benzo[1,4]dioxin which is optionally substituted by 1 to 3 substituents, where the substituents are selected from (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6)alkyl-O-, hydroxy, amino and halo; or heteroaryl having four or five carbon atoms and one heteroatom selected from oxygen, nitrogen and sulfur, which is optionally substituted by 1 to 3 substituents, where the substituents are selected from (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O-, hydroxy, amino and halo; B is phenyl optionally substituted by 1 to 3 substituents, where the substituents are selected from (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-O-, hydroxy, amino and halo; and R1 and R2 independently represent (C1-C6)alkyl, phenyl-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl, (C3-C7)cycloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; provided that R1 differs from R2; where the absolute configuration of the asymmetric carbon atom carrying R1 and R2, is an R-configuration; including (a) reaction of Formula XI
acylhydrazine with Formula XII
ketone to form a compound of Formula XIII
, where R1 differs from R2, (b) reduction of the Formula XIII compound in the presence of a chiral catalyst to form a Formula R-XIV compound and (c) reaction of the Formula R-XIV
compound with the Formula B-CO-LG compound, wherein LG is a leaving group, forming a compound with Formula III.
EFFECT: chiral diacylhydrazine ligands for genome modulation.
6 cl, 25 dwg, 11 tbl
FIELD: chemistry.
SUBSTANCE: invention claims a new method of obtaining 3,5-diamino-6-(2,3-dichlorphenyl)-1,2,4-triazine of high purity degree by reaction of 2,3-dichlorbenzoylcyanide with 1-2 mol equivalents of dimethylase aminoguanidine salt in the presence of 3-6 mol equivalents of methanesulfoacid, with further addition of 2-5 mol equivalents of magnesium oxide to the reaction mix. The process is performed at 50-80°C, and target product is recrystallised from acetone.
EFFECT: improved efficiency of compounds.
5 cl, 3 ex
FIELD: chemistry.
SUBSTANCE: invention relates to method of obtaining unknown before 3-amino-6-aroylmethyl-5-hydroxy-1,2,4-triazines of general formula: , where: R= CH3, CH3O, C2H3O, Cl which lies in the following: aminoguanidine hydrocarbonate is subjected to interaction withcorresponding 5-aryl-2,3-dihydrofurane-2,3-dione or aroylpyruvic acid at boiling in water-free dioxane during 25-30 minutes.
EFFECT: high output of novel compounds, which demonstrate anti-inflammatory and analgesic activity.
2 cl, 2 tbl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: described are novel derivatives of 1,2,4-triazine-6-one of general formula (I) or their pharmaceutically acceptable acid-additive salts, or stereochemically isomeric forms, where rings A and B represent phenyl; values of other radicals are given in formula of invention.
EFFECT: development of efficient method of obtaining composition and application of novel compounds for treatment or prevention of HIV-infection.
22 cl, 2 tbl, 6 ex
