The method of obtaining derivatives benzothiophenes and aminoalcohols (options)

 

(57) Abstract:

The invention relates to a method for producing derivatives benzothiophenes formula I, including the interaction of amerosport formula (II) or its salt with the compound of the formula (III) or its reactive derivative, the oxidation of the resulting product in the presence of 2,2,6,6-tetramethylpiperidine-1-oxide and then liaising with ridom in the conditions of a Wittig reaction with subsequent optional unprotect. Also described methods of obtaining intermediate aminoalcohols of formula II. The compounds I can be used as drugs in the treatment of systemic mastocytosis, asthma and other diseases. The claimed method requires simple operations and little time, safe as used in the reaction solvents are water and ethyl acetate. 4 C. and 5 C.p. f-crystals.

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The technical field to which the invention relates

The invention relates to the production of derivatives benzothiophenes which are useful as antagonists of prostaglandin D2(hereinafter referred to as "PGD2").

Background of the invention

Derivatives benzothiophenes the od or the alkyl and the double bond is E or Z-configuration, are antagonists PGD2specific PGD2receptors, and are useful as pharmaceutical compounds for treating diseases associated with dysfunction of mastocyte (fat cells), caused by excessive production of PGD2(WO 97/00853, PCT/JP 97/04527 (WO 98/25919)). Therefore, the compounds of the above formula can be used as medicines for the treatment of systemic mastocytosis, violations of system activation of mast cells, tracheal spasm, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, damage caused by ischemic reperfusion, inflammation and atopic dermatitis. Among these compounds, a compound in which OR represents 5-hydroxy, X is hydrogen and the double bond is Z-configuration (hereinafter referred to as "compound a"), exhibits a particularly high antagonistic effect on PGD2possesses excellent activity against nasal occlusion and is expected to be a promising drug for the treatment of nasal occlusion.

Disclosure of the invention

The compound (I) and methods of its production are known from the literature (WO 97/00853, PCT/JP 97/04527 (WO 98/25919)). However, the known methods are not the Cove and the environment and efficient use of resources for the following, for example, reasons:

1) using chromatography on silica gel, is not suitable for mass production;

2) low output and high consumption of time;

3) the presence of complex processes of separation and purification of the reaction product;

4) associated release of harmful gas and odor and/or the generation of hazardous waste liquids; and/or

5) the need as starting compounds, reagents and/or solvents materials, hazardous or difficult to handle.

In accordance with this invention proposes a method of obtaining compounds of formula (I)

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where R represents hydrogen or hydroxyamino group, X represents hydrogen or alkyl and the double bond is E or Z configuration, or its pharmaceutically acceptable salt or hydrate, including the interaction of amerosport formula (II)

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or its salt with the compound of the formula (III)

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where R represents hydrogen or hydroxyamino group, or its reactive derivative with obtaining the compounds of formula (I-2)

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where R is as defined above; oxidation of compound (I-2) halogenosilanes in the presence of compounds of 2,2,6,6-tetramethylpiperidine-1-oxides with connection f is in the conditions of the Wittig reaction and, if you unprotect the reaction product.

The best option of carrying out the invention

In a preferred embodiment of the present invention the compound of formula (I-2)

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where R is as defined above, are oxidized by halogenosilanes in the presence of 2,2,6,6-tetramethylpiperidine-1-oxides with obtaining the compounds of formula (I-3)

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where R is as defined above.

In another preferred embodiment, the compound of the formula (II-2):

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where R2is alkyl and R3represents hydrogen or alkyl, restore, using the system of the reducing agent is a Lewis acid, to obtain amerosport formula (II) or its salt.

In accordance with the preferred option is used, the reducing agent is chosen from the group consisting of borohydrides, substituted alkali or alkaline earth metal and a Lewis acid selected from the group consisting of a halide of tin, aluminum, titanium, boron, zirconium or Nickel and their complexes with ethers.

In one preferred embodiment, the compound of the formula (II-2)

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where R2and R3such as defined above, is converted into the alcohol of formula (II-3)

The
cue sodium-alcohol or reducing agent is a Lewis acid with getting amerosport formula (II) or its salt.

Below for a definition of terms used in this description.

The term "hidroxizina group" means an alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl substituted silyl, alkoxycarbonyl, aryloxyalkyl, Uralelectromed or tetrahydropyranyl.

The term "alkyl" means C1-C20unbranched or branched alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, monodecyl and icosyl, preferably is C1-C6alkyl. As the alkyl for R2preferred is C1-C3alkyl.

The term "alkoxy" means C1-C6unbranched or branched alkoxy, in particular methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentylamine, neopentylene, sec-pentyloxy, tert-pentyloxy, n-hexyloxy, neosaxitoxin, isohexyl, sec-hexyloxy, tert-hexyloxy and the like, and preferred is alkoxygroup, and includes methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl, methoxypropyl and the like.

The term "acyl" means C1-C11acyl derived from an aliphatic or aromatic carboxylic acid. Examples of acyl aliphatic acid include acetyl, chloroacetyl, trichloroacetyl, propionyl, butyryl, valeryl and the like, and examples of the aromatic acyl acid include benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, toluoyl, naphtol and the like.

The term "aryl" means phenyl, naphthyl or polycyclic aromatic hydrocarbon group and the like. In addition, the aryl can be substituted by the following substituents.

Examples of substituents include alkyl, such as methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or tert-pentyl, lower alkoxy, such as methoxy or ethoxy, halogen, such as fluorine, chlorine, bromine or iodine, nitro, hydroxy, carboxy, cyano, sulfonyl, amino, lower alkylamino, such as methylamino, dimethylamino, ethylmethylamino or diethylamino, and the like. The aryl group may have one or more substituents at any possible positions. Concrete is Il, 4-carboxyphenyl, 4-acetylphenyl, 4-(N, N-dimethylamino)phenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-forfinal, 4-chlorophenyl, 4-itfeel the like.

Aryl group described below in "aralkyl", "arylsulfonyl", "aryloxyalkyl" or "uraltrackservice" may have the substituents similar to defined above.

The term "aralkyl" means alkyl group, substituted aryl group, and includes benzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, naphthylmethyl, phenethyl and the like.

The term "alkylsulfonyl" means sulfonyloxy group, substituted alkyl group, and includes methanesulfonyl, econsultancy and the like.

The term "arylsulfonyl" means sulfonyloxy group, substituted aryl group, and includes benzazolyl, p-toluensulfonyl and the like.

The term "alkyl substituted silyl" means mono-, di - or trialkylamines silyl, for example methylsilyl, dimethylsilane, trimethylsilyl, tert-butyldimethylsilyl and the like.

The term "alkoxycarbonyl" means methoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and the like.

The term "aryloxyalkyl" means fenoxycarb the P CLASS="ptx2">

As hydroxyamino group represented by the symbol R, is preferable alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl substituted silyl, alkoxycarbonyl, aryloxyalkyl, Uralelectromed or tetrahydropyranyl, and more preferred is arylsulfonyl.

Examples of salts of compounds of General formula (I) include alkali metal salts such as lithium salt, sodium salt or potassium salt and the like, salts of alkaline earth metals such as calcium salt and the like, ammonium salt, salts with organic bases, such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylsilyl, tri-n-butylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexane, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamino, 4-methoxybenzylamine, 1-naphthalenemethylamine, divinylbenzene, triphenylamine, 1-naphtylamine, 1-aminoanthracene, 2-aminoanthracene, dehydroabietylamine, N-methylmorpholine or pyridine, or amino acid salts such as lysine salt and arginine salt.

Salts of aminoalcohols, formulas chloromethane acid, sulfuric acid, etc.

The target compound of the present invention represented by the General formula (I), in which the double bond alkenylamine side chain (i.e., 5-heptanedionato circuit) may be in the E - or Z-configuration.

The method according to the present invention is described in more detail below. If you have a substituent(s) may hinder(them) reaction, it is possible appropriately to protect and at the desired stage to release from protection. Such protection or removal of protection can be realized by a method known in this technical field.

I. Obtaining the compound (I) (see scheme I in the end of the description).

[Stage 1]

This phase deals with obtaining amide (I-2) by acylation of amerosport (II) or its salt of carboxylic acid (III) or its reactive derivative.

Carboxylic acid (compound III) used in the acylation may be synthesized by a method known in the literature [e.g., Nippon-Called Zasshi, I. 88, 7, 758-763 (1967); Nippon-Called Zasshi, I. 86, 10, 1067-1072 (1965); J. Chem. Soc. (C), 1899-1905 (1967); J. Heterocycle. Chem. so 10, 679-681 (1973)]. The term "reactive derivative" of carboxylic acid (III) refers to the corresponding acid halides (e.g. acid chloride, bromohydrin,s), activated esters (for example, Succinimidyl) and the like and includes alleluya agents commonly used for the acylation of the amino group. For example, to obtain the acid halides, carboxylic acid is subjected to interaction with thionylchloride (e.g., thionyl chloride), phosphorous halide (for example, phosphorous trichloride, phosphorous pentachloride), oxaliplatin (for example, oxalylamino) or the like in accordance with a known method (for example, Shin-jikken Called Koza, T. 14, page 1787 (1978); Synthesis, 852-854 (1986); Shin-jikken Called Koza, T. 22, page 115 (1992)).

The acylation can be carried out under normal conditions used for the acylation of the amino group. For example, when using a carboxylic acid halide, the reaction is carried out according to the method commonly known as "the reaction of the Schotten's-Bauman". Typically, the carboxylic acid halide is added dropwise to the aqueous alkaline amine solution under stirring and cooling with removal of the resulting acid with alkali. In accordance with another variant, when carboxylic acid is used in the form of the free acid, but not its reactive derivative, the reaction can be performed traditionally in the presence of Illogicalities (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-carbonyldiimidazole.

[Stage 2]

This stage refers to the oxidation of the alcohol (I-2) to give the aldehyde (I-3). Until now, such a reaction was carried out using an oxidizing agent from the family of chromic acid, such as Jones reagent (J. Org. Chem., 40, 1664-1665 (1975)), the Collins reagent (J. C. S. Chem. Comm., 1972, 1126) or pyridineboronic (Tetrahedron Lett. , 2646-2650 (1975)). Also known a method using manganese dioxide (Helv. Chim. Acta., 39, 858-862 (1956)) or DMSO (Swern oxidation, J. Org. Chem., 43, 2480-2482 (1978)). However, these existing methods have drawbacks. For example, chromic acid toxic to humans and must be disposed of after use. In addition, the oxidation will Roll (Swern) using a mixture of dimethyl sulfoxide-oxalicacid not suitable for large scale production because it is accompanied by release of carbon monoxide, which is dangerous for workers, and the smell of sulfur and besides, it must be carried out at low temperature, for example between -50oC and -78oC.

In accordance with the method of the present invention the alcohol (I-2) are oxidized using an oxidant(s), such(them) as halogenoalkane, in the presence of 2,2,6,6-tetramethylpiperidine-volumes of existing methods. Examples include TEMPO 2,2,6,6-tetramethylpiperidine-1-oxide, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxide, 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxide, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxide and 4-cyano-2,2,2,2-tetramethylpiperidine-1-oxide. Examples of halogenation include sodium hypochlorite, hypobromite sodium, bromic sodium and higher bleach. The oxidizer solution can be increased, for example, to a pH of 8.5 to 9.5 by addition of mineral acid, such as sodium bicarbonate, hydrochloric acid or sulfuric acid. In accordance with another variant of the solution of the oxidizing agent may be added in the presence of sodium bicarbonate. The reaction can be carried out at the time from several minutes to several tens of minutes at a temperature from temperature cooling with ice to room temperature in a solvent such as ethyl acetate, acetonitrile or dichloromethane.

The advantage of the new oxidation method of the present invention is characterized by the following:

1) the method requires simple steps and a little time, since the reaction yields a product with a high yield in a short reaction time without maintaining very low temperatures;

2) how safe as used in Soshestvii using only extraction;

4) the oxidation is carried out, using a cheap reagent, sodium hypochlorite, and only a very small amount of catalyst TEMPO at 1-0,2% molar equivalent of the alcohol (I-2);

5) the method allows the operator to work in the best environment, because, in contrast to the oxidation will Roll (Swern), the reaction gives a small selection of carbon monoxide or smell and, in addition, the sodium chloride formed from sodium hypochlorite, used in the oxidation, it is not necessary to neutralize.

[Stage 3]

This stage is associated with the formation of double bonds by the interactions of the compounds of formula (I-3) with ridom (PH3R=CH(CH2)3COOH). The reaction of formation of the double bond can be carried out traditional Wittig reaction. Used in the reaction of ylides can be synthesized in the presence of a base by processing postnasal salt synthesized from triphenylphosphine, and alkylhalogenide with required for condensation of the alkyl group, such as 5-bromopentanoate acid. Examples of the base include diminati, demirkale, sodium hydride, n-utility, tert-piperonyl potassium and diisopropylamide lithium. The reaction is carried out in a few hours xitan or dimethylsulfoxide.

[Stage 4]

At this stage produce unprotect the compound (I) in which R represents hydroxyamino group to obtain compound (I-1). The reaction can be carried out in the traditional way using as catalyst, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, or barium hydroxide, or the like. The reaction is carried out in a period of time from several tens minutes to several hours under heating in a solvent such as methanol-water, ethanol-water, acetone-water, acetonitrile-water or the like, preferably dimethyl sulfoxide-water. Grouping OR can be in any of the positions 4, 5, 6 and 7, although it is preferable that it is at position 5.

II. Obtaining the compound (II)

Original material in this process, amerosport (II) can be obtained in a known manner from, for example, (-)-myrtenol. Predecessor product, complex methoxymethyl formula (II-2), where R3represents methyl, then restore metallic sodium in isopropanol to obtain the corresponding amerosport (II) (Hagishita, et al., Chem. Pharm, Bull., 37(6), 1524-1533 (1989)). However, this method has disadvantages such as low yield (author of esters to alcohols, known borohydride sodium (J. Org. Chem., 28, 3261 (1982)), sociallyengaged (Org. Syn., 63, 140), borohydride lithium (J. Org. Chem. , 47, 4702 (1982)) and the like. In addition, as methods of recovery Asimov to amines using already known catalytic reduction (Syn. Comm. , 27, 817 (1997); Org. Syn., collection of T. 5, 376 (1973)) or the ways in which use of the reducing agent(s) so(s) as DIBORANE (J. Org. Chem., 30, 2877 (1965)), borohydride sodium (J. Org. Chem., 48, 3412 (1983)), sociallyengaged (Tetrahedron, 51, 8363 (1995)), the system borohydride sodium-chloride titanium (IV) (Synthesis. 1980, 695), the system borohydride sodium-Nickel chloride (II) (Chem. Ber., 117, 856 (1984)) or the like. None of these references, however, are not described method of recovering at the same time slices as complex ether and oxime in one molecule such as a compound of the formula (II-2), at a high yield and high stereobitrate.

The creators of the present invention has succeeded in restoring complex oximeter formula (II-2) to the target amerosport (II) at a high yield and with high selectivity by using the reducing agent is a Lewis acid (in particular, borohydride sodium-Lewis acid) as shown in scheme II (see below).

alcohol (II-3) to produce amerosport (II) or its salt. The reducing agents used in the above reaction include borohydride, substituted alkali or alkaline earth metal (borohydride sodium, borohydride lithium, borohydride calcium and so on).

Examples of the Lewis acid include the halides of tin, aluminum, boron, titanium, zirconium or Nickel (for example, chloride tin(II) chloride tin(IV), aluminum chloride, titanium tetrachloride, boron TRIFLUORIDE, zirconium tetrachloride, Nickel dichloride, and so on) or their ether complexes (for example, bis(2-methoxyethoxy)aluminiumhydride sodium and so on).

Examples of the solvent include ethers (e.g. diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, dimethyl ether of diethylene glycol, and so on), hydrocarbons (e.g. toluene, xylene and so on), and mixed solvents containing ethers, and hydrocarbons. As for the recovery of alcohol (II-3) to amerosport (II) or its salt, there is also the way in which, in addition to the above system, the reducing agent is a Lewis acid, use metallic sodium-alcohol. Examples of the alcohol include methanol, ethanol, n-propanol, isopropanol and the like. Examples of solvents include hydrocarbons (such as toluene, xylene and so on).

NII II-2b), dissolve in 2 or more volumes of solvent. To the solution add 2 or more molar equivalents of a reducing agent and then 0.1 to 0.4 molar equivalent (relative to the reductant) Lewis acid at 0oC-150oC. In accordance with another option may be added to the mixture, prepared by mixing the Lewis acid and solvent. In addition, can be changed to add the source material (complex oximeter), a reducing agent and a Lewis acid. Then the reaction mixture is subjected to interaction at 0oC-150oC for a time ranging from several minutes to several hours. The reaction solution can be treated by adding water and dilute mineral acid (e.g. dilute chloroethanol acid), followed by stirring, allowing the reducing agent is decomposed. In accordance with another variant of the reaction solution can be poured into dilute mineral acid.

Then the solution is neutralized with alkali (e.g. sodium hydroxide) and extracted with an organic solvent (e.g. ethyl acetate). After removal of the solvent receive amerosport (II). If necessary, the product may be the benzoic acid and then neutralizing the alkali with getting amerosport (II).

As described above according to the present invention, the target amerosport (II) can be obtained with high yield (about 89%) at high stereotypicality (99% or higher).

Although the method of obtaining the compounds of formula (II) shown in the above scheme II, is new and useful to obtain the compound (II) as such, it also helps to ensure the safe and efficient receipt of the compound (I), i.e. the final product, when combined with the method of obtaining the compound (I).

To further illustrate the present invention further examples, which should not be considered in any limiting scope of the invention. Used in the examples, the abbreviations have the following meanings:

PH: phenyl

AC: acetyl

TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl.

Reference example 1

Obtain ethyl[(1R, 3R, 5S)-2-methylidene-10-morphinan-3-yl]acetate (2) (see diagram 1 at the end of the description).

A mixture of (-)-myrtenol (1) (6,44 g of 42.3 mmol), triethylorthoformate (23 ml, 126 mmol) and hydroquinone (27 mg) was heated with stirring at 165oC for 2 hours at 185oC for 2 hours at 195oWith over 25 hours and drove derived ethanol. The resulting oil deposits (2). Output: 81,4%.

IR (Film): 3070, 2980, 2921, 2869, 1737, 1638 cm-1.

1H NMR (CDCl3), 300 MHz: 0,76 and of 1.24 (each 3H, each s), 1,20 (1H, d, J=9.9 Hz), of 1.27 (3H, t, J=7.2 Hz), of 1.52 (1H, m), from 2.00 (1H, m), 2,23-of 2.50 (3H, m) to 2.66 (1H, DD, J=5.1 and 15.3 Hz), 3,03 (1H, m) to 4.16 (2H, q, J=7.2 Hz), 4,71 (2H, D., of 11.4 Hz).

Elemental analysis for C14H22ABOUT2.

Calculated (%): C, 75,63; N, Becomes 9.97.

Found (Percent): C, 75,61; N, 9,99.

[]D24+29,1o(s=1,05, CH3IT)

Reference example 2

Getting 5-benzolsulfonate[b]thiophene-3-carbonylchloride (6) (see diagram 2 at the end of the description).

5-Hydroxybenzo[b] thiophene-3-carboxylic acid (11) (M. Martin-Smith et al. , J. Chem. Soc (C), 1899-1905 (1967), 8,63 g, 44.4 mmol)) was dissolved in aqueous tetrahydrofuran (water content 20%; 160 ml) and 1 called sodium hydroxide (44 ml). To the solution was added dropwise 0,56 n sodium hydroxide (87 ml) and benzosulphochloride (6.2 ml, 48,4 mmol) under stirring and cooling on ice, maintaining the pH at 11-12. After the reaction mixture was diluted with water, podslushivaet and washed with toluene. The aqueous layer was slightly acidified by adding concentrated hydrochloric acid with stirring and the precipitated precipitated crystals were filtered off, washed with water and high"ptx2">

NMR (CDCl3), 300 MHz: 7,16 (1H, DD, J=2.7 and 9.0 Hz), 7,55-to 7.61 (2H, m), 7,73 (1H, m), 7,81 (1H, d, J=9.0 Hz), of 7.90-7,94 (2H, m), 8,16 (1H, d, J= 2.7 Hz), at 8.60 (1H, s).

IR (Nujol): 3102, 2925, 2854, 2744, 2640, 2577, 1672, 1599, 1558, 1500, 1460, 1451 cm-1.

Elemental analysis for C15H10O5S2.

Calculated (%): C, 53,88; N, 3,01; S, MT 19: 18.

Found (Percent): C, 53,83; N, 3,03; S, 19,04.

5-Benzolsulfonate[b] thiophene-3-carboxylic acid (12) (5,582 g, and 16.7 mmol), obtained as described above was heated under reflux for 1.5 hours with dimethylformamide (1 drop), thionyl chloride (3,57 ml, 50 mmol) and toluene (22 ml). Removing under reduced pressure the solvent, received of 5.89 g of target compound (6).

EXAMPLE 1

Getting amerosport

(1) stage 1: obtain ethyl [(1R, 3R, 5S)-2-oxo-10-morphinan-3-yl]acetate (3) (see scheme 3 in the end of the description).

Connection (2) (333,5 g, 1.5 mol) obtained in reference example 1 was dissolved in dichloromethane (3,340 l) and methanol (660 ml). The mixture was cooled to a temperature of from -70oC to -73oWith and was able to introduce nitrogen gas for 4 hours. After administration within 1 hour of gaseous nitrogen was added triethylphosphite (265 ml of 2.26 mol) and gave the reaction mixture to warm to room toty (300 g). The organic layer was washed with water (1.2 l), 2% sodium sulfite (1.2 kg) and water (1.2 l). The aqueous layer was extracted with ethyl acetate (1,11 l). The organic layers were combined and the solvent drove under reduced pressure to get 456,51 g of oil which was then dissolved in tetrahydrofuran (1.05 liters). After adding cold 14% aqueous ammonium hydroxide (106,8 g) obtained pale-yellow solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with ice water (750 ml). After adding ethyl acetate (1.1 l) and the mixture was stirred and separated into two layers. The same procedure was repeated again, and the aqueous layer was again extracted with ethyl acetate. The combined organic layer washed with 10% brine (750 ml), dried over anhydrous magnesium sulfate and then drove away under reduced pressure the solvent. The oil obtained was dissolved in toluene (500 ml) and kept under reduced pressure, the solvent is getting 347,96 g of oil. Crude yield: 103.4 percent.

1H NMR (CDCl3), 300 MHz: 0,95 and 1.34 (each 3H, each s) of 1.27 (3H, t, J=7.0 Hz), 1,40 (1H, d, J=9.9 Hz), 1,67 (1H, m), of 2.25 (1H, m), 2,33-to 2.42 (2H, m), 2,56-to 2.65 (2H, m), 2,86-to 3.02 (2H, m), 4,14-is 4.21 (2H, m).

(2) stage 2 (see figure 4 at the end of the description).

(Yali in ethanol (45 ml). To the solution was added gidroxinimesoulid (4,99 g, to 71.9 mmol) and pyridine (4,7 ml, to 58.1 mmol) and the mixture was heated at 60oC for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with hydrochloric acid, after which the mixture was extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate and then drove away under reduced pressure, the solvent receipt of 10.72 g is specified in the header of the compound (4A) as a colourless oil. Crude yield: 100%.

[]D24+55,3o(c=l 01, CH3IT)

(2) to Obtain ethyl [(1R, 3R, 5S)-2-methoxyimino-10-morphinan-3-yl]acetate (4b) (see figure 5 at the end of the description).

Connection (3) (107,0 g, 477 mmol) was dissolved in ethanol (500 ml). To the solution was added O-methylhydroxylamine (50,1 g, 600 mmol) and pyridine (47,5 g, 600 mmol) and the mixture was heated under reflux for 3 hours under stirring. The reaction mixture was concentrated under reduced pressure, diluted with water, acidified with hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed in under reduced pressure the solvent. The obtained colorless oil was distilled under reduced pressure to get 106,1 g specified in the connection header (4b). Boiling point: 118-123o(Low pressure 1.2 mm RT. column). Output: 87,8%.

IR (film): 1738, 1630 cm-1.

Elemental analysis for C14H23NO3.

Calculated (%): C, 66,37; N, To 9.15; N, Of 5.53.

Found (Percent): C, 65,92; N, 9,13; N, The Ceiling Of 5.60.

[]D24+69,5o(C=1.00%, in CH3IT)

(3) stage 3: obtain the benzoic acid salt [(1R, 2R, 3R, 5S)-2-amino-10-morphinan-3-yl]ethanol (II') (see diagram 6 in the end of the description).

1) preparation of compound (4b)

Borohydride sodium (799 mg, 21.1 mmol) suspended in 1,2-dimethoxyethane (5 ml). To the suspension was added with stirring and ice cooling, the suspension of aluminofluoride (507 mg, 3.8 mmol) in 1,2-dimethoxyethane (5 ml), and then a solution of the compound (4b) (1.07 g, 4.2 mmol) in 1,2-dimethoxyethane (3 ml) and the mixture was heated in a bath at 70oC for 3 hours. Then to the reaction mixture were added water (4 ml), 2 N. hydrochloric acid (8 ml) and concentrated hydrochloric acid (1 ml) under stirring and ice cooling, after which the mixture was stirred at room temperature for 40 minutes. Then reactio layer was dried over anhydrous magnesium sulfate and drove away the solvent under reduced pressure to obtain 789 mg specified in the header of the compound (II) as a colourless oil. The product was dissolved in diethyl ether (5 ml). To the solution was added a solution of benzoic acid (516 mg, 4.2 mmol) in ether (5 ml) and the mixture was stirred. Precipitated precipitated crystals were filtered off, washed with ether, and dried to obtain 1,146 g colorless benzoic acid salt of amerosport (II'). Yield: 89% (purity: 99.2 percent), so pl. 183-185oC. the Purity of benzoic acid salt of amerosport (II') was determined by converting the salt into benzamide in the presence of condensing agents, such as dicyclohexylcarbodiimide (DCC, DCC) and 1-hydroxybenzotriazole (NOUT, HOBT) in tetrahydrofuran, and determine the purity of the obtained amide using high-performance liquid chromatography (HPLC).

IR (KBR): 3420, 2600 (W), 1621, 1523, 1386 cm-1.

1H NMR (CDCl3), 300 MHz: 0,72 (1H, d, J=9.9 Hz), 1.06 and of 1.13 (each 3H, each s) of 1.40 (1H, m), 1.56 to of 1.92 (3H, m), 2,12-of 2.36 (4H, m), 3,29 (1H, m), 3,62 (1H, m), of 3.78 (1H, m), 7,32-7,47 (3H, m), 7,97-of 8.04 (2H, m).

Elemental analysis for C18H27NO3.

Calculated (%): C, 70,79; N, 8,91; N, 4,59.

Found (Percent): C, 70,54; N, 8,93; N, 4,56.

[]D25+27,6o(C=1.00%, in CH3IT)

Reference values: so pl. 180-183oC []D26+27,lo(Chem. Pharm. Bull., 37, 1524 (1989)).

[AO is Vigna phase: acetonitrile-water (1:1); retention time: 5,23 minutes.

2) Receiving from the compound (4A) (part 1)

Borohydride sodium (1.55 g, 41,0 mmol) suspended in dimethyl ether of diethylene glycol (13 ml). To the suspension was added with stirring and ice cooling for 10 minutes athirat of boron TRIFLUORIDE (1,71 ml, 13.5 mmol) and the mixture was stirred at room temperature for 20 minutes. After adding a solution of the compound (4A) (1,015 g, 4.1 mmol) in dimethyl ether of diethylene glycol (8 ml) and the mixture was stirred at room temperature for 20 minutes. Then the mixture was heated in a bath at 110oWith stirring for 2 hours. The solution was processed as described above in paragraph 1, with the receipt of 741 mg of benzoic acid salt of amerosport (II'). Yield: 59% (purity: 99.2 percent), so pl. 178-180oC.

3) Receiving from the compound (4A) (part 2)

Borohydride sodium (1,00 g of 26.4 mmol) suspended in 1,2-dimethoxyethane (10 ml). To the suspension was added with stirring and ice cooling compound (4A) (1,00 g, a 4.03 mmol) and the complex of titanium tetrachloride-1,2-dimethoxyethane (1:1) (700 mg, 2.51 mmol). The mixture was stirred at room temperature for 30 minutes and then was heated in a bath at 70oC for 3 hours. The mixture was processed as described above in the

(4) stage 4: obtain [(1R, 3R, 5S)-2-methoxyimino-10-morphinan-3-yl] ethanol (5) (see scheme 7 at the end of the description).

The compound (4b) (23,8 g, 94 mmol) was dissolved in toluene (111 ml). To the solution was added a solution of 70% bis(2-methoxyethoxy)aluminiumhydride sodium in toluene (34.4 g, 119 mmol) at a temperature below the 25oC for 20 minutes and continued the stirring for 30 minutes at the same temperature. To the reaction mixture was added acetone (7 g) for the decomposition of the reagent, after which was added water (30 ml) and then 48% aqueous sodium hydroxide solution (43,8 g). Resulting two layers were separated and the aqueous layer was extracted with toluene (111 ml). The combined organic layer was washed with water (330 ml). The organic layer was dried over anhydrous magnesium sulfate and then drove away under reduced pressure, the solvent receipt of 18.9 g is specified in the header of the compound (5) as a colourless oil. Output: 95,1%. The product was used in subsequent reactions without purification.

IR (l3): 3619, 3502, 3020, 2974, 2937, 2872, 2818, 1623, 1460 cm-1.

[]D23,5+86,4o(C=1.00%, in CH3IT)

(5) stage 3': obtain the benzoic acid salt [(1R, 2R, 3R, 5S)-2-amino-10-morphinan-3-yl]ethanol (II') (see figure 8 at the end of the description).

The connection is whether sodium metal (7.47 g, 325 mmol) in portions at reflux for 25 minutes. After 1 hour, added additional sodium metal (1,15 g, 50 mmol) and continued stirring for 1 hour at reflux. The reaction mixture was cooled and separated into two layers by adding ice water (39 ml) and toluene (95 ml). The aqueous layer was extracted with toluene (95 ml). The combined organic layer was washed with brine (395 ml) and dried over anhydrous magnesium sulfate, and then drove away under reduced pressure, the solvent is getting 8,4 g is specified in the header of the compound (II) as a colourless oil. The compound (II) (8,4 g, with 45.8 mmol) was dissolved in toluene (33.3 ml) and acetone (111 ml) and the solution was heated to 50oC. After addition of a solution of benzoic acid (4,82 g, 39,47 mmol) in acetone (22,2 ml) and the mixture was stirred at the same temperature for 1 hour. Precipitated precipitated crystals were filtered off, washed with cold acetone (33.3 ml) and dried with getting 9,155 g colorless benzoic acid salt (II') amerosport. Output: 65,8%.

IR (Nujol): 3428, 2999, 2921, 2864, 2727, 2633, 2596, 2107, 1663, 1623, 1592, 1555, 1523, 1456, 1444 cm-1.

[]D23,5+27,lo(C=1.01 per cent, CH3IT), so pl. 181-183oC.

Salt (+)-2-[(1R, 2R, 3R, 5S)-2-amino-10-morphinan-3-yl]ethanol benzosulfimide acid (II', 5,1 g, and 16.7 mmol) obtained in example 1, suspended in water (10 ml). To the suspension was added 1 N. HCl (17 ml) and the precipitated benzoic acid was removed by extraction with ethyl acetate. The organic layer was washed with water (10 ml). To the combined aqueous layer was added a 4 n solution of sodium hydroxide (9,2 ml, to 36.8 mmol)

while cooling with ice and then added dropwise within 15 minutes with stirring, a solution of 5-benzolsulfonate[b]thiophene-3-carbonylchloride (6) (of 5.89 g, and 16.7 mmol) obtained in reference example 2 in tetrahydrofuran (36 ml). After stirring for a further 1 hour at the same temperature, was added 1 N. hydrochloric acid (4 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then drove away under reduced pressure, the solvent is getting 8.00 g (95,6%) specified in the header of the compound (7) in the form of a colorless amorphous substance.

1H NMR (CDCl3), 300 MHz as 0.96 (1H, d, J=9.9 Hz), and 1,12 1,26 (each 3H, each s), 1,50-2,42 (N, m), 3,69-3,82 (2H, m), and 4.40 (1H, m), 6,21 (1H, d, J= 8.1 Hz), 7,06 (1H, DD, J=2.4 and 8.7 Hz), 7,51-7,56 (2H, m), to 7.67 (1H, m), 7,73
(2) stage 2: obtain [3-[(1R, 2R, 3R, 5S)-3-formylmethyl-10-morphinan-2-yl] carbamoylated[b]thiophene-5-yl]benzosulfimide (8) (see scheme 10 at the end of the description).

Compound (7) (9,72 g, and 18.3 mmol) was dissolved in ethyl acetate (70 ml). To the solution was added TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), 14.3 mg, 0.005 equivalent) and potassium bromide (218 mg, 0.1 equivalent). Was added dropwise over 3 minutes under stirring with maintaining the internal temperature in the range of -1oWith up to -6oFrom 0.41 N. aqueous sodium hypochlorite (45 ml solution, brought to pH 9.5 sodium bicarbonate, 1 equivalent). After 10 minutes of incubation at the same temperature two layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then drove away under reduced pressure, the solvent is getting 9,10 g (100%) specified in the header of the compound (8) as a colorless amorphous substance.

IR (SNS3); 3443, 3093, 3066, 3030, 3016, 2925, 2871, 2828, 2729, 1720, 1655, 1599, 1558, 1513, 1377 cm-1.

1H NMR (CDC13), 300 MHz: 0,97 (1H, d, J=10,2 Hz), 1.17 and 1.28 (in each 3H, each s) of 1.46 (1H, m), 2,03 (1H, m), 2,22 (1H, m), a 2.36-2,60 (3H, m), 2,69 (1H, DDD, J=1,2, of 8.7 and 17.4 Hz), 3,14 (1H, DD, J=4,5 and 17.4 Hz), 4,28 (1H, m), 6,18 (1H, d, J=8.1 Hz), to 7.09 (1H, DD, J=2,23+31,8o(C=1.00%, in CH3IT).

(3) stage 3: obtaining (5Z)-7-[(1R, 2R, 3S, 5S)-2-(5-benzolsulfonate[b] thiophene-3-ylcarbonyl)-10-morphinan-3-yl] -5-heptenophos acid (9) (see scheme 11 in the end of the description).

4-Carboxyvinyltransferase (12,17 g, 27.5 mmol) and tert-piperonyl potassium (7,19 g, 64.1 mmol) suspended in tetrahydrofuran (64 ml) and was stirred for 1 hour while cooling on ice. To the reaction mixture was added over 15 minutes a solution of compound (8) (9,11 g, and 18.3 mmol) obtained in the above stage 2, in tetrahydrofuran (27 ml) and the mixture was continuously stirred 2 hours at the same temperature. The reaction mixture was diluted with water (80 ml) and washed with toluene (2105 ml). After adjusting the aqueous layer to pH 8.1 by adding 5 N. hydrochloric acid (4.8 ml) was added anhydrous calcium chloride (8.1 g, 73 mmol) dissolved in water (16 ml) and the mixture was extracted with ethyl acetate (2100 ml). The organic layer was added water (100 ml) and the aqueous layer was brought to pH below 2 by adding 5 N. hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and then drove away under reduced pressure, the solvent receiving 11,benzo[b] thiophene-3-ylcarbonyl)-10-morphinan-3-yl] -5-heptenophos acid (10) (Compound a) (see scheme 12 in the end of the description).

Compound (9) (11,06 g, and 18.3 mmol) obtained in the above stage (3), was dissolved in dimethyl sulfoxide (22 ml). To the solution was added 4 n sodium hydroxide (27.5 ml) and the mixture was heated at 55oC for 2 hours under stirring. The reaction mixture was diluted with water (130 ml) and washed with toluene (265 ml). The aqueous layer was acidified 5 N. hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and drove away under reduced pressure, the solvent is getting compared to 8.26 g of the crude target compound (10). The product was dissolved in methanol (40 ml) and water (16 ml) and the mixture strassle and gradually cooled while stirring. Precipitated precipitated crystals were filtered off and washed with a mixture of water-methanol (2: 5) obtaining of 6.35 g of target compound (10). Output: 78,6%. The crystals were dissolved in methanol (40 ml) and to the solution was added water (12 ml) for 7 minutes under stirring. After adding seed crystals to the solution was continuously stirred at 25oC for 1 hour. Added additional water (7 ml) for 40 minutes and continued the stirring for 1.5 hours at 25oC. Precipitated precipitated crystals OTF (10). Output: 76,0%, etc., 145-146oC.

IR (Nujol): 3313, 3096, 3059, 3001, 1717, 1627, 1603, 1548, 1469, 1440 cm-1.

1H NMR (SO3), 300 MHz: 1,02 (1H, d, J=10,2 Hz), and 1,12 1,24 (each 3H, each s), 1.56 to 2,55 (14N, m), the 4.29 (1H, m), 5,32-the 5.51 (2H, m), of 6.20 (1H, d, J= 9.3 Hz), 7,01 (1H, DD, J=2.4 and 9.0 Hz), 7,66 (1H, d, J=9.0 Hz), 7,69 (1H, s), 8,03 (1H, d, J=2,4 Hz).

[]D24+50,70(C=1.01 per cent, CH3IT).

Elemental analysis for C25H31NO4S.

Calculated (%): C, 68,00; H, Was 7.08; N, 3,17; S, 7,26.

Found (Percent): C, 67,84; H, Was 7.08; N, 3,24; S, 7,31.

1. The method of obtaining the compounds of formula (I)

< / BR>
where R represents hydrogen or hydroxyamino group;

X represents hydrogen or alkyl and the double bond is E or Z-configuration,

or its pharmaceutically acceptable salt or hydrate, including the interaction of amerosport formula (II)

< / BR>
or its salt with the compound of the formula (III)

< / BR>
where R represents hydrogen or hydroxyamino group

or its reactive derivative with obtaining the compounds of formula (I-2)

< / BR>
where R is as defined above,

oxidation of compound (I-2) halogenosilanes in the presence of compounds of 2,2,6,6-tetramethylpiperidine-1-oxides with getting nogo the compound (I-3) with ridom under the reaction conditions of the Wittig and if you unprotect the reaction product.

2. The method according to p. 1, in which hydroxyamino group is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl substituted silyl, alkoxycarbonyl, aryloxyalkyl, Uralelectromed or tetrahydropyranyl.

3. The method according to p. 1, in which hydroxyamino group is arylsulfonyl.

4. The method of obtaining the compounds of formula (I-3)

< / BR>
where R represents hydrogen or hydroxyamino group

including the oxidation of compounds of formula (I-2)

< / BR>
where R is as defined above,

halogenosilanes in the presence of 2,2,6,6-tetramethylpiperidine-1-oxide.

5. The method according to p. 1, which additionally includes a step of obtaining amerosport formula (II) or its salt by reaction of the recovery of the compounds of formula (II-2)

< / BR>
where R2is alkyl;

R3represents hydrogen or alkyl,

using the system of the reducing agent is a Lewis acid.

6. The method according to p. 5, in which the reducing agent is chosen from the group consisting of borohydrides, substituted alkali or alkaline earth metal and a Lewis acid selected from the group consisting of halide oenia of amerosport formula (II) or its salt, including the restoration of the compounds of formula (II-2):

< / BR>
where R2is alkyl;

R3represents hydrogen or alkyl,

using the reducing agent is a Lewis acid.

8. The method according to p. 1, which additionally includes the stage of transformation of compounds of formula (II-2)

< / BR>
where R2and R3such as defined above,

in the alcohol of the formula (II-3)

< / BR>
where R3such as defined above,

and recovery of the resulting alcohol using metal sodium-alcohol or reducing agent is a Lewis acid.

9. The method of producing amerosport formula (II) or its salt, which comprises converting a compound of the formula (II-2)

< / BR>
where R2and R3such as defined above,

in the alcohol of the formula (II-3)

< / BR>
where R3such as defined above,

and recovery of the alcohol by using metal sodium-alcohol or reducing agent is a Lewis acid.

 

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FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a method for preparing derivatives of benzoxazine and describes a method for preparing compound represented by the formula . Method involves of compound represented by the formula (I): with compound represented by the formula (II-1-a): in the presence of a base to form compound represented by the formula (III-1-a): followed by reduction of this compound to compound represented by the formula (IV-a): , interaction of this compound with compound represented by the following formula: to form compound represented by the formula (V-a): and the following treatment of this compound in the presence of a base to obtain compound represented by the formula (VI-a): , treatment of this compound with compound of boron trifluorine and its conversion by this manner to the boron chelate compound represented by the following formula: followed by reaction of this compound with 4-methylpiperazine to obtain compound represented by the following formula: followed by cleavage and elimination of boron chelate of this compound. In each of above given formulas X1, X2 and X3 represents independently halogen atom; R1 represents a leaving group; R3 represents hydrogen atom or carboxyl-protecting group; R4 represents hydroxyl-protecting group; each R5 and R6 represents independently alkyl group comprising 1-6 carbon atoms; R7 represents carboxyl-protecting group; Y represents alkoxy-group comprising 1-6 carbon atoms, halogen atom or dialkylamino-group (wherein alkyl groups can be similar or different and each represents alkyl group comprising 1-6 carbon atoms). Also, invention describes variants above described method, methods for preparing intermediate compounds and intermediate compound. Invention provides industrially favorable methods for preparing intermediate compounds that are useful for preparing compounds with antibacterial properties.

EFFECT: improved preparing methods, valuable properties of compounds.

96 cl, 102 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention proposes new compounds - 4-isononylphenoxypolyethoxyethyl-bis-(2-hydroxyethyl)amine mono- and disodium salts and a method for their preparing. 4-Isononylphenoxypolyethoxyethyl-bis-(2-hydroxyethyl)amine mono- and disodium salts are prepared by interaction of oxyethylated alkylphenol, triethanolamine and sodium hydroxide taken in the mole ratio - (1.0-1.1):1.0:(1.0-2.0), respectively, at temperature 20-80°C for 2-10 h in solvent medium. As a solvent method involves using aliphatic (C2-C3)-alcohols or water taken in the amount 0-70 wt.-%. 4-Isononylphenoxypolyethoxyethyl-bis-(2-hydroxyethyl)amine mono- and disodium salts can be used as surface-active substances in different branches of industry.

EFFECT: improved preparing method, valuable technical properties of substances.

6 cl, 3 tbl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

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