The method of obtaining 5-(1,2,4-triazole-1-yl)tryptamine compounds and 2-[5-(1,2,4-triazole-1-yl - methyl)-1h-indol-3 - yl ethyl alcohol


(57) Abstract:

N,N-Dimethyl-2-[5-(1,2,4-triazole-1-yl-methyl)-1H-indol-3-yl]-ethylamine is obtained by interaction of 2-[5-(1,2,4-triazole-1-yl-methyl)-1H-indol-3-yl] ethanol with methylchloride at -20 C in dry THF followed by treatment received in situ intermediate nelfinavir 40% aqueous dimethylamine. The method does not require the use of triphenylphosphine and lithium chloride and eliminates the tendency triazolines polymerization. 2 S. and 9 C.p. f-crystals, 1 table.

The present invention relates to the production of class 5-heterocyclic substituted tryptamines, such as 5-(1,2,4-triazole-1-yl)tryptamine compounds, therapeutically active as caused agents. The invention relates to an improved process for the preparation of these derivatives of 5-heterocyclic substituted tryptamine, which includes catalyzed by palladium coupling and ring closure.

A brief description of the literature data

Complex physiological and pathophysiological processes of the neurotransmitter serotonin (5-HT) are becoming more and more clear.1(Links, denoted by superscripts are listed at the end). In accordance with one of her roles serotonin acts shall otential as a pharmaceutical agent, however, limited due to its rapid metabolism in vivo. In the last few years many attempts have been devoted to the development of N, N-dialkylamino as agonists of the receptor 5-HT1Dto achieve the desired activity and selectivity in the treatment of migraine. Sumatriptan is the first of this class of drugs approved for this purpose.2MK-0462 (developed by Merck & Co.) described in U.S. patent 5298520 and is also a potent agonist of the receptor 5-HT1D, which runs clinical trials.

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Usually this class of compounds obtained using the indole reaction Fisher to obtain the structure of N, N-dimethyltryptamine. The use of this technique for the synthesis of MK-0462, however, is inefficient and gives a low yield due to the instability benzilmidazole residue to the reaction conditions, which usually leads to polymerization triazole residue, giving oligomers. Desired in this area is a highly effective way of obtaining N, N-dimethyltryptamine, MK-0462(1), which eliminates the undesirable tendency to polymerization triazolyl.

Larock et al. showed that cyclization godnlenora fragment existing in structutes.3Smith et al. also demonstrated that 4-pyrimidinamine and pyridinyl derivatives of indol-3-yl-alkylpiperazine, as shown in the publication EP 0548831 A1. Two other applications of this technique prodemonstrirovany in the synthesis heterodontosaurid pyrrole4aand tryptophanol4b. However, all these methods require triphenylphosphine as part of the catalyst system, which is dangerous for the environment.

The technique catalyzed by palladium linking to the specific synthesis of 5-triazolyl N, N-dimethyltryptamine ring system has not been described previously.

Brief description of the invention

We found that MK-0462 can be synthesized with high yield using catalyzed by palladium binding/ring closure of 3-iodine-4-aminobenzotriazole protected appropriately derived butanol and the corresponding tryptophol with subsequent transformation hydroxyethylene balance in dimethylaminoethyl. The advantage of this new method is that it does not require the use of triphenylphosphine, and tetrabutylammonium chloride and lithium chloride and eliminates the tendency triazolines polymerization taking place in indolin the 5-Deputy represents triazolyl, triazolylmethyl, imidazolyl, imidazolylalkyl, tetrazolyl or tetrazolyl.

According to the present invention is a process comprising a stage of bringing into contact of the compounds of Structure I with a compound of Structure II to form a compound of Structure III:

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the process is carried out in a dry inert organic solvent for Structures I and II at a temperature in the range from about 70o120oC in the presence of a palladium catalyst, soluble in the said solvent is present in an amount of from 0.5 to 5 molar percent relative to I, and in the presence of inorganic or organic compounds amine, which acts as a proton acceptor, i.e. catcher acid which does not react chemically with the aforementioned catalyst,

where X1and X2are, independently, a ring nitrogen atoms or carbon; halogen is Br or I; n is an integer 0-1; p is an integer 1-4; R3is H or a linear or branched C1-C4by alkyl; R1is H or a radical that acts as a hydroxy protective group which can be removed by the hydrolysis of a weak acid, namefunction as a final protective group limit carbon acetylene, which can be removed by the hydrolysis of a weak acid, for example, when contacting with a mixture of HCL/MeOH, for example 1:1 2 N. HCL/MeOH at 0-30oC.


The synthesis of MK-462(1) is illustrated in the following Scheme 1 below.

A key element of the synthesis is to obtain predecessor tryptophol 7, which can be obtained by linking 3-iodine-4-aminobenzotriazole 3 respectively protected derivative butanol 5.


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aReaction conditions: (a) ICl, CaCO3, MeOH-H2O; b) 2 molar% Pd(OAc)2, Na2CO3, DMF, 100oC; (C) MeOH-HCL; (d)1. MsCl, Et3N, THF; 2. 40% HNMe2; (e) Benzoic acid, isopropanol, room temp.

The synthesis of MK-462(1) start with getting itanyone 3. 4 - Aminobenzotriazole 2 available using a 3-stage method with a total yield >90% of 4-nitrobenzylamine and 4-amino-1,2,4 - triazole using modified procedures known from the literature.5The reaction of 2 with monochloride iodine in the presence of CaCO3in aqueous methanol gives 4-triazolylmethyl 3 yield 91%; there is some additional accession of iodine, giving 1-3% didanosine 4. More the tx2">

It was found that catalyzed by palladium binding/ring closure between joanina 3 and butanolom 5 flows smoothly with unexpectedly high yield in the absence of a standard required reactants of triphenylphosphine, tetrabutylammonium chloride and literorica, and in the absence of any induced triazolam polymerization.

The binding reaction between joanina 3 and various derivatives of 3-buten-1-ol have been thoroughly studied in detail (table). It was found that to prevent binding of the end carbon of the acetylene necessary silyl protection.3Silyl group injected with education dianion with BuLi followed by quenching with 2 equivalents of similiarity. In the case of TBDMS-protected (tertiary butyldimethylsilyl) alkyne bis-similarobama suddenly goes to the end; and the result is a mixture of 1:1 5d and 5e. Found that the alternative Of protection may be effected by selective hydrolysis of the O-silyl group; for example 5a in turn 5b with a quantitative yield using diluted HCl in aqueous methanol. The hydroxy-group 5c can then be protected TBDMS or TNR group, giving alkynes 5f and 5g, respectively, in quantitative yields.

The simplest projeciton 9 (5%) (see below figure 1). Formed also other impurities. It is believed that those responsible for these by-products and low output is the TMZ group. We have found unexpectedly that a more stable TES and TBDMS group on alkyne give indoles 6A and 6d8accordingly, with higher outputs (numbers 1 and 4). Although more stable C-protection gives the best results, bulky TBDMS Butin associated significantly slower; therefore, we have found that particularly useful protecting group in this particular synthesis is TES, because it gives an acceptable rate of binding and stability.

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Disilylgermane United indoles 6a and 6b in MeOH-HCL gives tryptophol 78with a total yield of 70-80% after treatment and crystallization (Scheme 1). Disilylgermane 2-similarbank of indoles can also be implemented with other acids such as alcamovia acid, AlCl3, methansulfonate acid and other sulfonic acid. However, we found that the system MeOH-HCI is decidedly more useful and convenient to use, especially from the point of view of environmental protection. Turning 3 and 5a 7 directly without allocating 6. Regioisomer 9 (6%) during crystallization 7 is removed from the mother liquor.

is ethylamine, giving free base MK-0462 88with the release of 79%. We unexpectedly found that mesilate is prone to polymerization due to intramolecular alkylation of the triazole; therefore mesilate process directly 40% dimethylamine. Selected tryptamine then purified by adding a solution of benzoic acid to the free base, receiving MK-0462 as benzoate salt with a yield of 95%.

This new synthesis of MK-0462(1), characterized catalyzed by palladium coupling itanyone 3 and bis-TES-butanol 5a with the formation of the indole ring, is an effective process that can be zoomed in, so that despite the formation of several impurities, unexpectedly does not require chromatographic cleanings as opposed to the standard indole synthesis, Fischer.


1. Glennon T. A.; Darmani, N. A; Martin, B. R. Life Sciences 1991, 48,2493.

2. (a) Feniuk W.; Humpherey P. P. A. Drug Dev. Res. 1992, 26, 235; (b) S. J. Hopkins Drug of Today 1992, 28, 155.

3. Lorack R. C.; Yum, E. K. J. Am.Chem.Soc. 1991, 113, 6689.

4. (a) Wensbo D.; Eriksson Jeschke, T.; Annby U.; Gronowitz.; Cohen L. A. Tetrahedron Lett. 1993, 34, 2823. (b) Wensbo D.; Eriksson Jeschke So; Annby U.; Gronowitz.; Cohen L. A. Tetrahedron Lett. 1993, 34, 6471.

5. Astleford C. A., Goe G. L.; Keay, J. G.; Scriven, E. F. V. J. Org.Chem. 1989, 54, 731-732.

6. (a) 5c was kuplu1H-NMR,13C-NMR and elemental analysis. Election data (1H-NMR at 250 MHz,13C-NMR at 62.5 MHz);

Indole 6b: 1H-NMR(CDCl3) : of 0.90 (m, 15H), 1,60 (t, J=5,2 Hz, 1H), 3,09 (t, J=7.9 Hz, 2H), 3,85 (dt, J=7,9, and 5.2 Hz, 2H), of 5.40 (s, 2H), 7,10 (DD, J= 8,3, and 1.4 Hz, 1H), 7,35 (d, J=8,3 Hz, 1H), 7,60 (d, J=1.4 Hz, 1H), 7,92 (s, 1H), 7,98 (s, 1H), 8,10 (s, 1H);13C-NMR (MeOH-d4) : 152,1, 144,5, 140,5, 134,0, 130,3, 126,2, 123,0, 122,3, 119,9, 112,7, 64,5, 55,3, 30,9, 7,9, 4,6; Calculated: C19H27N5OSi: C 64,18; H 7,66; N 15,76 Found: C Expenses 63.81; H 7,87; N 16,15.

Tryptophol 7: so pl. 131-132oC;1H-NMR (DMSO-d6) : of 2.81 (t, J=7.4 Hz, 2H), 3,63 (dt, J= 7,4, a 5.3 Hz, 2H) and 4.65 (t, J=5.3 Hz, 1H), 5,43 (s, 2H), 7,00 (DD, J=8,4, and 1.4 Hz, 1H), 7,15 (d, J=2.0 Hz, 1H), 7,51 (s, 1H), 7,94 (s, 1H), to 8.62 (s, 1H), 10,85 (s, 1H);13C-NMR (DMSO-d6) 151,3, 143,6, 135,7, 127,3, 125,8, 123,6, 121,1, 118,3, 111,7, 111,4, 61,5, 53,0, 28,7; Calculated: C13H14N4O: C 64,44; H Of 5.82; N 23,12, Found: C 64,38; H Of 5.85; N 23,28.

Tryptamine 8: so pl. 120-121oC;1H(DMSO-d6) : of 2.34 (s, 6H), 2.63 in (m, 2H), 2,93 (m, 2H), 5,43 (s, 2H), 7,05 (m, 2H), 7,31 (d, J=8,3 Hz, 1H), 7,56 (s, 1H), of 7.97 (s, 1H), to 7.99 (s, 1H), 8,49 (s, 1H);13C-NMR (CDCl6) : 151,7, 142,8, 136,4, 127,7, 124,5, 123,1, 121,9, 119,1, 113,9, 112,0, 60,2, 54,6, 45,3, 23,5; Calculated: C15H19N5: C 66,89; H 7,11; N 26,00 Found: C 66,89; H 7,20; N To 26.04.

The above specific synthesis of MK-462 can also be extended to other active analoog nitrogen, through a methylene group or attached directly to the 5 position of the indole ring as illustrated in the following diagram:

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At the initial stage of the process Structure Ia is subjected to reaction with palodiruyut agent, forming a Structure I, at a temperature of from about -10 to 10oC in a suitable solvent and in the presence of a suitable proton acceptor.

Palodiruyut agent can be, for example, monochloride iodine, N-jodatime, N-bromosuccinimide, and the like.

The term "halogen", as used here, is denoted by Br or I.

Values for n are 0, 1, and values for p are 1, 2, 3 and 4.

Solvent at this stage can be MeOH, MeOH-H2O, EtOH, THF-H2O, CH2Cl2and similar, and a useful solvent is 95% MeOH-H2O.

Useful proton acceptors that can be used include: CaCO3, K2CO3, Na2CO3, Li2CO3, LiOH, KOH, NaOH, NaHCO3and similar. When using N-bromosuccinimide or N - jodatime, separate the proton acceptor is not required.

A useful set of reaction conditions for stage haloiding is MeOH-H2O (95%)th pressure in an inert atmosphere, for example in an atmosphere of dry N2in the presence of calcium carbonate.

Structure II, which is protected 1-Akinola, obtained by reaction of the original 1-alkanol IIa, which can be selected from 2-propyne-1-ol (propargilovyh alcohol), 3-buten-1-ol, 4-pentyn - 1-ol and 5-hexyne-1-ol:

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where p= 1-4, in a suitable inert organic ether solvent such as tetrahydrofuran, dioxane, diethyl ether, 1,2 - dimethoxyethane and the like, in a dry atmosphere, for example in an atmosphere of dry N2at a temperature of from -50oC to -10oC when a small excess of n-botellita of about 2.1 moles per mole of alkanol, in sufficient time, for example 2 to 8 hours, for a full generation militiania Akinola. Then the protective group is attached by adding a predecessor, such as chlorotrimethylsilane, also with a slight excess of about 2.1 moles per mole of litigarion Akinola, and allows mixing within 1-4 hours to complete the reaction. The reaction mixture is processed using normal procedures, giving diseasesandy of alkanol II.

R1the protective group can be selectively removed by using a weak acid hydrolysis oC, and the selection of the product. The resulting alcohol can be selectively protect one protective group, R1by following the above procedure, protection, giving II, where R1and R2are different protective groups.

Similitudine agents that can be used are usually the halogenated trihydroxybenzene, such as chlorotriethylsilane.

Tetrahydropyranyl, THF, the protective group can be applied using the original connection dihydropyran as the precursor in the presence of an acid catalyst, for example p-CH3PhSO2OH, to convert Akinola in TNR ether.

Structure I is then associated with the Structure II to obtain the Structure III with reactions catalyzed by palladium, in a dry inert organic solvent containing a soluble palladium catalyst and in the presence of a proton acceptor, representing an aromatic amine, alkylamine or inorganic base, which does not poison the catalyst, at a temperature of from about 70 to 120oC.

In Structure III, R3is H or C1-C4linear or branched alkyl, including methyl, ethyl, n-Phnom group, selected from silyl ligand SiR3awhere each Raindependently selected from linear or branched C1-C4the alkyl (as described above) or phenyl; and tetrahydropyranyl.

Representative examples of radicals SiR3ainclude trimethylsilyl, triethylsilyl, tributyrin, triphenylsilane, dimethyl-tert-Boticelli, dimethylphenylsilane, diphenylmethylsilane, triisopropylsilyl and the like.

R2behaves as a protective group of the end carbon atom of acetylene and has the same structure as described above SiR3a.

As R1and R2are removed by hydrolysis with a weak acid, for example, by contacting with a mixture of solvents 2 N. HCI/MeOH about 1: 1 by volume at a temperature of about 0-30 oC for 1-24 hours to completely remove the R1, R2radicals.

The organic solvent suitable for these stages binding/ring closure, there should be a solvent in which the Structure I, Structure II and palladium catalyst are soluble and compatible and which are chemically inert under the reaction conditions.

Classes of solvents suitable for this Rea is>C6cyclic mono - or diesters, di (C1-C4alkoxyamine, C6-C10aromatic hydrocarbons, mono - or dichloro C1-C4alkanes, alternately and similar or mixtures thereof.

Typical representatives of solvents include dimethylformamide, dimethylacetamide, diethylether, dipropylamine, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, benzene, toluene, o - xylene, m - xylene, p - xylene, acetonitrile, propionitrile and similar or mixtures thereof.

The temperature maintained within the range of from 70 to 120oC. a Suitable temperature is in the range of about 90-100oC. Usually the reaction is carried out in dry N2at atmospheric pressure.

Palladium catalyst useful in the reaction can be selected, for example, of the following classes: Pd alkanoate, Pd acetonate, Pd halides, Pd halide complexes, Pd - benzylideneacetone complexes and similar. Representative examples include Pd (II) acetate, Pd(II) acetylacetonate, Pd(O)bis-dibenzylidene acetone, Pd(II)bromide, Pd (II) chloride, Pd (II) iodide, Pd (II) sulfate, Pd (II) triptorelin, Pd(II)Cl2(CH3CN)2and similar. A suitable catalyst is palladium acetate.

Palladium catalyst using IMEMO from 2 to 3 molar percent of a soluble palladium catalyst towards itanyone 1.

The proton acceptor, suitable at this stage, is the primary connection, which may be organic or inorganic, acts as a proton acceptor and is not "poison the catalyst. Using the term "catalyst poison" refers to the interaction with the catalyst, which inhibits its catalytic activity and prevents this link/ring closure between Structures I and II.

Suitable classes of proton acceptors include bonds alkylamines, aromatic amines, heterocyclic amines, carbonates, bicarbonates, phosphates, biphosphate alkali metals of Group I and alkaline earth metals of Group II and similar.

Representative compounds include lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, triethylamine, diisopropylethylamine, pyridine, N,N - dimethylaniline, 4-dimethylaminopyridine and the like.

Removing the protective groups R1and R2from III is usually performed with the help of weak acid hydrolysis without separate allocation III. When linking/ring closure is completed, the solvent is usually removed under reduced pressure. A mixture of 2 N. HCl/MeOH about 1:1 by volume add is, the example at 0-30oC for 2-4 hours for complete removal of both R1and R2protective groups by obtaining IV.

The substitution of hydroxyl in the fourth dialkylamino obtaining V is usually carried out in two stages in a single reaction vessel.

Alcohol IV may be reacted with methylchloride, (CF3SO2)2O and similar in a dry inert organic solvent, for example tetrahydrofuran, dioxane, diethylether, 1,2 - dimethoxyethane, dichloromethane and similar, at a temperature of from about -30 to -10oC in an atmosphere of dry N2in the presence of a proton acceptor, representing soluble aliphatic or aromatic amine, such as triethylamine, pyridine, Diethylenetriamine, diisopropylethylamine, tributylamine, 4 - dimethylaminopyridine and similar, with the formation of intermediate nelfinavir or sulfonate in situ.

Dialkylamino similar V can then be obtained by simply adding dialkylamino to mutilatory content in the reaction vessel and subsequent stirring at room temperature for 1 hour.

The resulting Structure V can be separated as it is or subjected to reaction with the appropriate farmatsevticheskii, maleic acid and similar, obtaining the appropriate additive salt of the acid.

Typical examples of the Structure of V, which can be obtained using this process are:

N,N-Dimethyl-2- [5- (1,2,4-triazole-1-ylmethyl) -1H-indol-3-yl] -ethylamine;

N,N-Dimethyl-2- [5- (1,3-imidazol-1-ylmethyl) -1H-indol-3-yl] - ethylamine;

N, N-Dimethyl-2- [5- (5-methyl-1,2, 3, 4-triazole-1-ylmethyl) - 1H-indol-3-yl] ethylamine;

N,N-Dimethyl-2- [5- (1,3,4-triazole-1-ylmethyl) -1H-indol-3-yl] - ethylamine;

N,N-Dimethyl-2- [5- (I, 3,4-triazole-1-yl) -1H-indol-3-yl] ethylamine;

N,N-Diethyl-2- [5- (1,2,4-triazole-1-ylmethyl) -1H-indol-3 - yl] -ethylamine;

N,N-Diethyl-2- [5- (1,3-imidazol-1-ylmethyl) -1H-indol-3-yl] - ethylamine;

N, N-Diethyl-2- [5- (5-methyl-1,2,3,4-tetrazol-1-ylmethyl) -1H - indol-3-yl] ethylamine;

N,N-Diethyl-2- [5- (1,3,4-triazole-1 - ylmethyl) -1H-indol-3-yl] -ethylamine;

N,N-Diethyl-2- [5- (1,3,4-triazole-1-yl) -1H-indol-3-yl] ethylamine;

N,N-Dimethyl-[5- (1,2,4-triazole-1-ylmethyl) -1H-indol-3-yl] - methylamine;

N,N-Dimethyl- [5- (1,3-imidazol-1-ylmethyl) -1H-indol-3-yl] - methylamine;

N, N-Dimethyl- [5- (5-methyl-1,2,3,4-tetrazol-1-ylmethyl) -1H - indol-3-yl] methylamine;

N,N-Dimethyl- [5- (1,3,4-triazole-1 - ylmethyl) -1H-indol-3-yl] -methylamine;

N,N-Dimethyl- [5- (1,3,4-triazole-1-yl) -1H-indol-3-yl] methylamine;

N, N-D is operamin;

N, N-Diethyl-3- [5- (5-methyl-1,2,3,4-tetrazol-1-ylmethyl) -1H - indol-3-yl] Propylamine;

N, N-Dimethyl-3- [5- (1,3,4-triazole-1-ylmethyl) -1H-indol-3-yl] -Propylamine;

N,N-Diethyl-3- [5- (1,3,4-triazole-1-yl) -1H-indol-3-yl] Propylamine;

N,N-Dimethyl-4- [5- (3-methyl-1,2,4,5-tetrazol-1 - ylmethyl) -1H-indol-3-yl] butylamine;

N,N-Dimethyl-4- [5- (2-ethyl-1,3-ethyl-imidazol-1-ylmethyl) -1H - indol-3-yl] butylamine;

N, N-Dimethyl-4- [5- (5-ethyl-1,2,3,4-triazole-1-ylmethyl) -1H - indol-3-yl] butylamine;

N, N-Dimethyl-4- [5- (2-methyl-1,3,4-triazole-1-ylmethyl) -1H - indol-3-yl] butylamine;

N, N-Dimethyl-4- [5- (2-ethyl-1,3,4-triazole-1-yl) -1H-indol-3-yl] butylamine.

Also included alcohol analogs of the above amines, including, for example,

2- [5- (1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl] ethanol;

2- [5- (1,3-imidazol-1-ylmethyl)-1H-indol-3-yl] ethanol;

2-[5- (5-methyl-1,2,3,4-tetrazol-1-ylmethyl) -1H-indol-3-yl] ethanol;

2- [5- (1,3,4-triazole-1-ylmethyl) -1H-indol-3-yl] ethanol;


[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl]methyl alcohol;

3-[5- (1,3-imidazol-1-ylmethyl)-1H-indol-3-yl]propyl alcohol;

4 -[5- (5 - methyl-1,2,3,4-tetrazol-1-ylmethyl) -1H-indol-3-yl] butyl alcohol;

2-[5- (2-methyl-1,3,4-triazole-1-ylmethyl) -1H-indol-3-yl] -lustrious the invention as it is represented by the inventors and is not intended to limit the scope or substance of the present invention.

Stage 1. To a mixture of comminuted into a powder of calcium carbonate (34 g, 0.34 mol) and aniline 2 (30.0 g, to 0.17 mol) in methanol (240 ml) and water (12 ml) is added at 0oC in nitrogen atmosphere a solution of monochloride iodine (30,3 g at 0.19 mol) in methanol (120 ml) for 0.5 hour.

The mixture is heated to room temperature and quenched with polysystem solution of sodium thiosulfate (5 ml). The mixture is stirred for 30 minutes. The solid product is filtered and washed with ethyl acetate (100 ml).

The filtrate was concentrated in vacuo to 100 ml, diluted with ethyl acetate (250 ml), washed with polysystem sodium thiosulfate (200 ml), dried over magnesium sulfate and concentrated to 100 ml Add hexane for deposition itanyone 3 in the form of a pale reddish-brown solid product (48,5 g, 91%).

Recrystallization itanyone 3 (24 g) from ethanol gives stanlin 3 (14.5 g, 60% extraction) as a white powder; so pl. 114-115oC.

Stage 2. Dry tetrahydrofuran (15,9 l) loaded into a flask equipped with a mechanical stirrer and a thermocouple in a nitrogen atmosphere, and loaded into the flask 3-buten-1-ol (958,5 g, 13,68 mol). The mixture is cooled to -30oC and added dropwise over 4 hours n-BuLi (17,1 l, 27,36 mol), keeping the temperature the lower 55-60 minutes chlorotriethylsilane (4,218 kg, 28,04 mol), keeping the reaction mixture at a temperature below 10oC. Then the mixture was allowed to warmed to room temperature. The reaction is finished after 1.5 hours at approximately 22oC.

The solution is cooled to -10oC and add 1% (weight/weight) Na2CO3(8.4 litre) for 25 minutes at a temperature <0C. Add heptane (10 l) and the layers separated. The aqueous layer was extracted with heptane (10 l). The organic layers are combined and washed with water (22 l), and concentrated to a pale orange-yellow oil, getting the product 5a (output 98,1%, purity 93,8% wt.).

Stage 3. To dry dimethylformamide (12 ml) add a solution of bis-TES-butanol 5a in heptane (24.5 g, to 31.5 mmol, 40% by weight). The mixture was concentrated in vacuo to a volume of 22 ml of the concentrate added dimethylformamide (78 ml), stanlin 3 (9 g, 30 mmol) and sodium carbonate (15.9 g, 0.15 mol) in powder form. The mixture Tegaserod with vacuum/nitrogen pumping.

Add palladium acetate (RUR 134.4 mg, 0.6 mmol) and the mixture heated to 100oC for 4 hours.

The mixture of products is cooled to room temperature and filtered through Solka-Floc. The cake is washed with dimethylformamide (30 ml). The combined filtrate and washing liquid is distilled p is (50 ml) to the distillation residue. The resulting mixture is filtered through 2 g Solka-Folc, and the cake washed with isopropylacetate (15 ml). The combined filtrates washed with water (50 ml) and concentrated to 50 ml.

The above concentrate is diluted with methanol (35 ml), and after 20 minutes, add 2 N. HCl (30 ml, 2 EQ), maintaining the temperature of the reaction mixture below 30oC. the Mixture was kept at room temperature for 2 hours or until the reaction is complete.

Add heptane (36 ml) and heptane-isopropylacetate layer is separated. The methanol-water layer, containing the product 7, concentrated in vacuo to 65 ml by removal of methanol (20 ml).

Add to the mixture isopropylacetate (50 ml). The mixture is cooled to 18oC followed by the addition of saturated aqueous sodium carbonate (24 ml) for 10 minutes. Add to the mixture isopropylacetate (50 ml). The aqueous layer was separated and extracted with isopropylacetate (100 ml). The combined organic solution (200 ml), treated with Darco G-60 (0.5 g). The mixture is stirred for 5 hours and filtered. The filtrate is concentrated to 100 ml, receiving fine suspension, followed by the addition of heptane (34 ml). The suspension is incubated at room temperature in the course is the learn tryptophol 7 (5.5 g, 75%). The NMR data and analytical data for C, H, N above References and notes".

Stage 4. Tryptophol 7 (4,87 g) is suspended in dry tetrahydrofuran (97 ml) and add dried on a molecular sieve triethylamine (2.64 g, and 26.1 mmol). The suspension is cooled to -20oC and add methanesulfonanilide (2.30 g, 20,1 mmol) at a temperature of <-15C for 45 minutes. The reaction mixture was incubated for 30 minutes at -20oC.

The suspension is filtered at a temperature of <-15C and the filtered cake was washed with cold anhydrous tetrahydrofuran (25 ml).

Aqueous solution of dimethylamine (40%, V/V, 49 ml to 0.39 mol) is added to the combined filtrates. The reaction mixture is allowed the opportunity to be warmed to room temperature.

A large part of the THF removed by vacuum distillation at a temperature <30C (final volume 60 ml). Add isopropylacetate (50 ml) and saturated aqueous potassium carbonate solution (5 ml). Layers are well mixed and divided. The aqueous layer was extracted with isopropylacetate (50 ml).

The combined organic layers washed with saturated aqueous potassium carbonate (10 ml). To the diluted organicheskimim using traps Dean-stark. The solution is cooled and treated with Darco G-60 (0.5 g) for 60 minutes and the mixture filtered. The filtrates are concentrated to 20 ml by distillation in vacuum, make the seed and left to crystallize for > 1 hour. To the deposited layer for 1 hour add heptane (64 ml) and the suspension cooled to 0oC. After 1 hour exposure, the suspension is filtered. The product is washed with cold 4:1 heptane-isopropylacetate (2 x 10 ml) and dried in vacuum at 40oC. the Free base MK-0462 (8) will get krivokrasov solids (4,30 g, yield 73%). NMR data, and C, H, N analytical data presented above in the "References and notes".

Stage 5. To a solution of free base MK-0462 (10 g, purity 89% by weight) in isopropyl alcohol (80 ml) at room temperature for 10 minutes, add a solution of benzoic acid (4.5 g, to 36.8 mmol) in isopropylacetate (20 ml). The mixture was kept at room temperature for 0.5 hours, cooled to 0-5oC and filtered. The cake is washed with isopropylacetate (10 ml) and dried, obtaining raw benzoate salt MK-0462 (13,1 g, purity 95% by weight, the output according to the analysis of 96%). Recrystallization from EtOH gives pure solid salt MK-0462 (13,1 g, purity 95% by weight, the output according to the market consistent with the proposed structure.

1. The method of obtaining N,N-dimethyl-2-[5-(1,2,4-triazole-1-yl-methyl)-1H-indol-3-yl]-ethylamine of the formula V

< / BR>
characterized in that it comprises a stage of processing 2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl]- ethanol of the formula IV

< / BR>
methylchloride at -20C in dry tetrahydrofuran, in a period of time sufficient for the formation in situ intermediate nelfinavir and a subsequent stage of processing intermediate nelfinavir 40% aqueous dimethylamine in a period of time sufficient for the formation of compounds of formula V.

2. The method according to p. 1, characterized in that the compound of formula IV is obtained by treatment of 3-halogen-4-amino-benzilate formula I

< / BR>
where halogen represents Br or J-protected butenolide derivative of the formula II

< / BR>
where R1represents H, SiR3a;

R2is SiR3a;

R3arepresents a linear or branched C1-C4alkyl or tetrahydropyranyl, and the process is carried out in DMF at 70 to 120C in the presence of palladium acetate and in the presence of inorganic compounds, acting as a proton acceptor and non-interacting chemically with the catalyst, followed by removal of simitsis fact, that the specified represents a halogen J.

4. The method according to p. 2, characterized in that the said SiR3aradical selected from trimethylsilyl, triethylsilyl, tributylamine, triisopropylsilyl, dimethyl-tertbutylamine.

5. The method according to p. 2, wherein the specified temperature is in the range of about 90 to 110C.

6. The method according to p. 2, characterized in that the palladium acetate is present in the amount of 0.5 to 5.0 mol.% regarding the compounds of structure I.

7. The method according to p. 2, characterized in that the proton acceptor selected from carbonates of alkali metals of group I and carbonates of alkaline earth metals of group II.

8. The method according to p. 7, characterized in that said proton acceptor is sodium carbonate.

9. The method according to p. 2, characterized in that the 3-halogen-4-aminobenzotriazole formula I

< / BR>
produced by interaction of 4-amino-benzilate formula Ia

< / BR>
with a halogenation agent in a mixture of 95% Meon/N2O in the presence of calcium carbonate.

10. The method according to p. 9, characterized in that said halogenation agent is monochloride iodine.

11. The connection representing 2-[5-(1,2,4-triazole-1-the


Same patents:

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The invention relates to new N-substituted azabicycloalkanes

The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof

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The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted 1-pyridyl-2-azolyl-1-(2-phenylethenyl)ethan-1-ols having general formula I:

where Py denotes 2-, 3-, or 4-pyridyl, Z nitrogen atom or CH group, and R1 and R2, independently from each other, are hydrogen or halogen atom, or trifluoromethyl group. Claimed compounds are applied as agricultural, industrial, medical, or veterinarian fungicides for controlling harmful fungi.

EFFECT: enhanced fungi control efficiency.

2 cl, 3 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of 4-(heteroarylmethyl)halo-1-(2H)-phthalazinones, particularly 4-(4-pyridylmethyl)-1-(2H)-phthalazinone. Claimed method includes interaction between substituted phthalidyl-3-triphenylphosphonium and aldehyde of formula Ar-CHO, wherein Ar is pyridine, pyrazine, or pyrimidine, in presence of base followed by reaction with hydrazine hydrate optionally under acidic conditions.

EFFECT: environmental friendly and safe method.

4 cl, 1 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to the improved method for preparing (R)-5-(2-benzenesulfonylethyl)-3-N-methylpyrrolidine-2-ylmethyl)-1H-indole of the formula (I): or its pharmaceutically acceptable salt. Method involves hydrolysis of compound of the formula (II): that is prepared by catalytic reduction of compound of the formula (III): . The claimed method excludes formation of dimer in the end product used in medicine.

EFFECT: improved method for preparing.

18 cl, 3 sch, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 1-aziridino-1-hydroxyiminomethyl of the general formula (I):

wherein R means a single bond or organic radical that can bind aziridinoxime groups by a covalent bond and taken among the group including saturated or unsaturated alkanes with normal or branched chain and comprising up to 6 carbon atoms, substituted azino-group -(R')C=N-N=C(R'') wherein R' and R'' represent independently of one another hydrogen atom or lower alkyl, heterocyclic compounds comprising from 3 to 6 atoms in ring and up to 4 heteroatoms taken among -N- and -O-, and aromatic compounds comprising up to 8 atoms in ring; R1 and R2 mean independently of one another -H, -COOH, -COOCH3, -COOC2H5 or -CONH2; n means a whole number 2 or 3; with exception the compound wherein R represents a single bond and R1 and R2 are both hydrogen atom, and also with exception the compound wherein R represents a single bond and one of substitutes is hydrogen atom among the group R1 and R2. Also, invention describes a method for their preparing and medicinal preparations comprising these compounds that possess an antitumor effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds and preparations.

7 cl, 3 tbl, 19 ex