Method for preparing 3-amino-derivatives of rifamycin s

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-aminorifamycin S of the formula (I) , eliciting antibiotic properties wherein X means NH2; Y = Z and mean hydrogen atom (H) or (CH3)2C<, or C6H5CH<, or C6H10<. Method for preparing 3-amino-derivatives of rifamycin S involves stirring 3-halogen-derivative of rifamycin S in solvent medium wherein solvent represents simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the following series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 with hydrazoic acid salt wherein sodium azide is used and stirring is carried out for 0.5-2 h. Then method involves the following conversion of obtained 30azido-derivative of rifamycin S to the end product using a reducing agent wherein mixture of zinc or iron with acetic acid is used, or hydrogen in the presence of palladium catalyst followed by treatment with oxidizing agent wherein ferric (III) chloride or manganese (IV) oxide is used, or hydrogen peroxide, or persulfates, or air. Extraction of the end product is carried out by extraction with organic solvent not mixing with water or by dilution of reaction mixture with water followed by crystallization of product. Invention provides the enhancement of method for preparing 3-amino-derivatives of rifamycin S due to elevating yield of the end product and process for it isolating.

EFFECT: improved preparing method.

1 tbl, 4 ex

 

The present invention relates to the field of chemical technology of organic substances, and in particular to methods of obtaining derivatives of 3-aminoaniline S having the properties of antibiotics.

3-amino-rifamycin S formula I,

where X=NH2Y=Z=H, or (CH3)2With<, or6H5CH<, or6H10<,

interest and as an independent antibacterial agents (antibacterial activity higher than that of rifamycin S), and as a starting compound to obtain numerous semisynthetic analogues of rifamycin S, which are used, for example, as an effective anti-TB drugs.

There are several ways to obtain 3-amino-rifamycin S. the German Patent N 1670377, 1974, reports a 3-aminoaniline S direct aminating rifamycin S (formula I, X=Y=Z=H), but the outputs of this method are extremely low (about 1%) and the product emit column chromatography, which makes this method unsuitable for industrial use. In U.S. patent N 4217277, C 07 D 413/04, describes a method for 3-aminoaniline's recovery of zinc with acetic acid 3-nitroaniline S (formula I, X=NO2Y=Z=H), which, in turn, is obtained from 3-bromoaniline S (formula I, X=Br, Y=Z=H). Despite all the part of the high yield of the target compounds the disadvantage of this method is that, while getting 3-nitroaniline's use dimethylformamide, which is highly toxic and relatively difficult on an industrial scale connection.

Closest to the claimed technical essence and the achieved result is a method of obtaining 3-aminoaniline S (U.S. Pat. USA N 4007169, C 07 D 498/08, 1975, prototype), including the interaction of rifamycin S with sodium azide in a solvent by stirring the reactants at a temperature from 0C to 100C for at least 0.5 hours. As solvents which are especially suitable for carrying out this reaction, marked dimethylformamide, methylformamide, dimethylsulfoxide, pyrrolidone and other solvents belonging to the group of bipolar aprotic solvents. After the reaction the product emit using either preparative column chromatography or fractional crystallization. The yield of the target product is 25-30%.

The disadvantages of the known method of obtaining 3-aminoaniline S should be attributed to the low yield of the product, and the use of highly toxic and expensive solvents. In addition, if the reaction is the formation of a significant number of by-products. It should also be noted that the solutions of rifamycin derivatives in solvents such as dimethylformamide, present a heightened danger for workers in chemical plants because dimethylformamide greatly increases the permeability of cell membranes. The disadvantages also include the use of column chromatography for separation of the target product that requires special equipment and usage is quite expensive sorbents, and also creates the problem of recycling (regeneration) of the spent sorbent.

The objective of the proposed technical solution is to increase the efficiency of the method of preparation of 3-amino-rifamycin S due to the increase of the yield of the target product and facilitate its excretion.

The task is achieved in that in a method of producing 3-amino-rifamycin S formula I

where X=NH2Y=Z=H, or (CH3)2With<, or6H5CH<, or6H10<comprising obtaining 3-acidproducing rifamycin S by mixing 3-halogenated derivatives of rifamycin S in the medium of the solvent, which is used as a simple aliphatic alcohols with carbon atoms of 1 to 5 or acetonitrile or a mixture of water and water-immiscible organic solvent selected from the range: ethyl acetate, methyl acetate, benzene or mono - or dimethyl analogues, chlorinated what's hydrocarbons with carbon atoms of 1 to 3, salt of the nitrogen-hydrogen acid, which use sodium azide or potassium azide, at a temperature from 0C to 100C for 0.5-2 hours, with subsequent conversion of the obtained 3-acidproducing rifamycin S in the target product by using the recovery agent, which is used as a mixture of zinc or iron with acetic acid, or hydrogen in the presence of a palladium catalyst, followed by treatment of the oxidizing agent, which is used as the iron chloride (III)or manganese oxide (IV), or hydrogen peroxide or persulfates, or air, removing a target product is performed by extraction of water-immiscible organic solvent or by dilution of the reaction mixture with water followed by crystallization of the product.

The scheme of conversion of 3-halogenated derivatives of rifamycin S (formula I, where X=Br, Cl, I; Y=Z=H, or (CH3)2With<, or6H5CH<, or6H10<) 3-amino-rifamycin S (formula I, X=NH2Y=Z=H, or (CH3)2With<, or6H5CH<, or6H10<) below.

From the chemical literature it is known that the halogen atom in the halogen-quinones, which is 3-halogenseparating S, quite mobile and may be substituted by suitable substituent (see, for example, ouben Weil, Metoden der Organische Chimie). In addition, asiagraph in organic compounds can be restored to the amino group under mild conditions using various healing agents (Houben Weil, Metoden der Organische Chimie, V. IV, p. 533).

We have found that the interaction of 3-halogenated derivatives of rifamycin S with the salt of the nitrogen-hydrogen of the acid is carried out in the present conditions, leads to the rapid formation of 3-azidoaniline S high yield, and the connection does not require treatment and can be used directly for further transformation into 3-amino-rifamycin S and restoring azido - amino group occurs smoothly under mild conditions using a recovery agent, as a mixture of zinc or iron with acetic acid or hydrogen in the presence of palladium catalyst.

The proposed solution is new, involves an inventive step and is industrially applicable.

The essence of the proposed method is illustrated by examples of its implementation.

Example 1.

In a glass reactor equipped with a thermometer and stirrer was placed 1500 ml of methanol and added with stirring 86.2 g (0.1 mol) 21,23 isopropylidenebis derived 3-iodipamide S, obtained according to the method described in German patent N 2548128, and then a solution of 9.7 g (0.15 mol) of sodium azide in 30 ml of water. Re eshivot the reaction mass at a temperature of 20C for 2 hours, then to the reaction mass is added palladium catalyst (10% Pd on alumina) and hydronaut at a pressure of 1 ATM and 20C until complete recovery 3-azidoaniline S, is filtered from the catalyst and mix the filtrate with 40 g of active manganese oxide (IV) within 30 minutes. Filtered off from the precipitate, and the filtrate is diluted with 2000 ml of water, and the resulting product is filtered off, washed several times with water and dried.

Output 21,23 isopropylidene derivative-3-aminoaniline S 67.5 g (90%).

Data CHN analysis corresponds to the formula C40H50N2O12

range PMR: there is no signal for the proton at C(3) and the signal is present 2 protons NH2group at 5.7-6.7 ppm

High-performance liquid chromatography (HPLC): the product is homogeneous.

Example 2

In a glass reactor equipped with a thermometer and a stirrer, was placed 500 ml of ethyl acetate and added with stirring 73.0 g (0.1 mol) 3-chlorophenesin S, obtained according to the method described in German patent N 2548128, and then a solution of 12.1 g (0.15 mol) of potassium azide in 100 ml of water. Stirred the reaction mass at a temperature of 20C for 2 hours, after which the 3-azithrimycin S extracted with ethyl acetate, the organic phase is washed with water and dried with anhydrous sodium sulfate. To the obtained solution under stirring and temp is the temperature of 40C, add 13 g of zinc dust and 5 ml of acetic acid and stirred for 2 hours. Filtered off from the precipitate and stirred filtrate for 1 hour with a solution of 50 g of iron chloride (III) in 200 ml of water. The organic phase is washed 3 times with water, dried with anhydrous sodium sulfate and evaporated under vacuum.

Output 3-aminoaniline S 61.8 g (87%).

Data CHN analysis corresponds to the formula C37H46N2O12

UV-spectrum λmax (∈) (226(4.47), 265(4.5), 31.1(4.1), 365(3.87), 520(3.04)), which corresponds to literature data (Kump W., H. Bickel, Hev. Chem. Acta, Vol. 56, Fasc. 7(1973) Nr. 244, p. 2348-2377):

range PMR: there is no signal for the proton at C(3) and the signal is present 2 protons NH2group at 5.7-6.7 ppm

High-performance liquid chromatography (HPLC): the product is homogeneous.

Example 3

Process for the preparation of 3-amino-rifamycin S carried out analogously to example 2. As a 3-halogen derivative of rifamycin S take 86.3 g (0.1 mol) 21,23 benzylidene derived 3-bromelain S. as chloroform solvent used instead of zinc to take 15 g of iron powder, and as an oxidizer use the oxygen in the air.

Output 21,23 benzylidene derivative-3-aminoaniline S 73.5 g (92%).

Data CHN analysis corresponds to the formula C44H50N2O12

range PMR: there is no signal for the proton at C(3) and the signal is present 2 protons NH2group at 5.7-6.7 ppm

Vysokoe the effective liquid chromatography (HPLC): the product is homogeneous.

Example 4

Process for the preparation of 3-amino-rifamycin S carried out analogously to example 2. As a 3-halogenated derivatives of rifamycin S take 85.5 g (0.1 mol) 21,23 cyclohexylidene derived 3-bromelain S. In the solvent used methylene chloride.

Output 21,23 cyclohexylidene derived 3-aminoaniline S 74.4 g (94%).

Data CHN analysis corresponds to the formula C43H54N2O12

range PMR: there is no signal for the proton at C(3) and the signal is present 2 protons NH2group at 5.7-6.7 ppm

High-performance liquid chromatography (HPLC): the product is homogeneous.

The process of obtaining derivatives of 3-amino-rifamycin S in examples 5-6 carried out analogously to example 1 and in examples 7-12 analogously to example 2. Reagents and process parameters listed in the table.

As can be seen from the table, the inventive method allows for 65% to increase the yield of the target product as compared with the method of the prototype. In addition, as shown by the results obtained by the reaction between 3-halogenated derivatives of rifamycin S and salts of nitrogen-hydrogen acid in homogeneous or heterogeneous conditions, and converting the obtained 3-acidproducing rifamycin S, 3-amino-rifamycin S, target product formed quickly under mild conditions and with high yield, which allows St. the STI to minimize the formation of by-products and to obtain the target product of high quality.

Table
N exampleX*Y, Y*azideTemperature, °solventthe restorerthe oxidizing agentthe product yield, %
1I(CH3)2With<NaN320methanolH3/PD(Al2O3)MnO290
2ClHKN340the ethyl acetateZn/AcOHFl387
3VGWith6H5SN<NaN320chloroformFe/AcOHthe oxygen in the air92
4BrWith6H10<NaN320methylene chlorideZn/AcOHFl394
5VG(CH3)3With<NaN330ethanolH2/Pd(C)MnO286
6Br(CH3)2With<NaN320propanol-1H2/Pd(BaSO4)MnO285
7Br(CH3)2With<NaN325acetonitrileZn/AcOHH2O291
8Br(CH3)2With<NaN340benzeneZn/AcOHK2S2O887
9Br(CH3)2With<NaN330tolueneZn/AcOHNa2S2O893
10Br(CH3)2With<NaN320o-xyleneZn/AcOH(NH4)2S2O886
11Br(CH3)2With<NaN330the acetateZn/AcOHFeCl388
12Br(CH3)2With<NaN3 40dichloroethaneZn/AcOHMnO292
the placeholderHNNaN30-100DMF

25-30
* General formula 3-halogenseparating S (see formula I)

Method for the preparation of 3-amino-rifamycin S formula I

where X=NH2Y=Z=H or (CH3)2With< or (C6H5CH< or (C6H10<comprising obtaining 3-acidproducing rifamycin S by mixing 3-halogenated derivatives of rifamycin S in the medium of the solvent, which is used as a simple aliphatic alcohols with carbon atoms of 1 to 5 or acetonitrile or a mixture of water and water-immiscible organic solvent selected from the range: ethyl acetate, methyl acetate, benzene or mono - or dimethyl analogues, chlorinated hydrocarbons with carbon atoms of 1 to 3, with salt, attestations acid, which use sodium azide or potassium azide, at a temperature of 0-100° for 0.5-2 h, the subsequent conversion of the obtained 3-acidproducing rifamycin S in the target product by using the recovery agent, who when asked which use a mixture of zinc or iron with acetic acid, or hydrogen in the presence of a palladium catalyst, followed by treatment of the oxidizing agent, which is used as the iron chloride (III)or manganese oxide (IV), or hydrogen peroxide or persulfates, or air, and removing the target product is performed by extraction of water-immiscible organic solvent or by dilution of the reaction mixture with water followed by crystallization of the product.



 

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< / BR>
A new connection can be used as an antibacterial and antituberculosis drug

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-aminorifamycin S of the formula (I) , eliciting antibiotic properties wherein X means NH2; Y = Z and mean hydrogen atom (H) or (CH3)2C<, or C6H5CH<, or C6H10<. Method for preparing 3-amino-derivatives of rifamycin S involves stirring 3-halogen-derivative of rifamycin S in solvent medium wherein solvent represents simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the following series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 with hydrazoic acid salt wherein sodium azide is used and stirring is carried out for 0.5-2 h. Then method involves the following conversion of obtained 30azido-derivative of rifamycin S to the end product using a reducing agent wherein mixture of zinc or iron with acetic acid is used, or hydrogen in the presence of palladium catalyst followed by treatment with oxidizing agent wherein ferric (III) chloride or manganese (IV) oxide is used, or hydrogen peroxide, or persulfates, or air. Extraction of the end product is carried out by extraction with organic solvent not mixing with water or by dilution of reaction mixture with water followed by crystallization of product. Invention provides the enhancement of method for preparing 3-amino-derivatives of rifamycin S due to elevating yield of the end product and process for it isolating.

EFFECT: improved preparing method.

1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to methods for preparing derivatives of 3-aazidorifamycin S eliciting antibiotic properties. Method for preparing 3-azido-derivatives of rifamycin S involves interaction rifamycin S derivative with hydrazoic acid salt in solvent medium by stirring reagents at temperature from 0oC to 100oC for 0.5-2 h followed by extraction of the end product. 3-Halogen-derivative of rifamycin S is used as rifamycin S derivative. Simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 is used as a solvent. Sodium azide or potassium azide is used as hydrazoilc acid salt. Extraction of the end product is carried out by extraction with solvent not mixing with water or by dilution of reaction mixture with water followed by filtration. The claimed method provides enhancing the yield of the end product by 63-71% and to simplify the process of it isolating. Invention provides the enhancement of effectiveness of method for preparing 3-azido-derivatives of rifamycin S due to elevating yield of the end product and simplifying the process of its isolating.

EFFECT: improved preparing method.

1 tbl, 13 ex

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EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

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73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new layers of acidic compounds with Formula I , where R2 is C1-6alkyl (possibly substituted and/or ending with one or more substitute, chosen from -OH, halogen, cyano, nitro and aryl) or aryl, where each aryl group, if not specifically mentioned, is possibly substituted by one or more substitutes, including -OH, cyano, halogen, nitro, C1-6alkyl, C1-6alkoxy, -N(R14a)R14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14e)R14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2Rl3c and/or -OS(O)2R13d, where radicals from R13b to Rl3d independently represent C1-6alkyl; R14a and R14b independently represent H, C1-6alkyl, or jointly represent C3-6alkene, as a result, yielding a four-heptatomic nitrogen containing ring; radicals from R14c to R14m independently represent H or C1-6alkyl; A represents , where R16 represents unsubstituted C1-4alkyl, C1-4perfluoroalyl or phenyl, where the last group can be substituted with one or more substitutes, chosen from C1-6alkyl, halogen, nitro and C1-6alkoxy. The invention also relates to the method of obtaining Formula II compounds.

EFFECT: obtaining of new intermediate compounds and their use in special obtaining of formula II oxabispidin compounds, which can be used in the treatment of cardiac arrhythmia.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

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55 cl, 421 ex, 1 tbl

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14 cl, 6 dwg, 63 ex

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32 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

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8 cl, 160 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel intermediate compounds - methyl 7-aryl-4,9-diaroyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]none-3,8-diene-8-carboxylates of formula III Ar1=Ar2=Ph, Ar3=C6H4Me-n (IIIa); and Ar1=C6H4Br-n, Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IIIb), for synthesis of methyl 6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-6-ene-8-carboxylates of formula IV where Ar1=Ar2=Ph, Ar3=C6H4Me-n (IVa); Ar1=C6H4Br-n Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IVb), which exhibit antimicrobial activity and are used as precursors for synthesis of novel heterocyclic systems, and a method for synthesis of said compounds.

EFFECT: compounds have high effectiveness.

5 cl, 1 tbl, 5 ex

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