The method of obtaining (s)-enantiomers

 

(57) Abstract:

In the invention the methods of obtaining compounds of formula (I) or (Ia),

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where R is 5-indayla or a group protecting the carboxyl group, or their amine salts, consisting of hydrogenation /E/-allyl simple ester of the formula (II) or (IIa), respectively, in the presence of a stereoselective rhodium or ruthenium bifosfonatov catalyst and the proton of the solvent, with the efficient education of these enantiomers used for medical preparations. 2 C. and 8 C.p. f-crystals.

The invention relates to the production of compounds which are useful as intermediates for obtaining spirotaenia derivatives of glutarimide, especially in connection with a registered brand name candoxatril and systematic name /S/-CIS-4-/1-[2-/5-intenrational/-3-/2-methoxyethoxy/propyl] -1 - cyclopentanecarboxylic/-1 cyclohexanecarbonyl acid. This connection is mentioned among others in U.S. patent US-A-5192800 as inhibitors of neutral endopeptidase E. C. 3,4.24.11, the enzyme that is useful as a diuretic agent for the treatment of hypertension, congestive heart nedostigeniya /S/-enantiomers of the compounds of formula (I)

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where

R is a 5-indayla or protective carboxyl group, benzyl ether of CIS-4-aminocyclohexanecarboxylic acid, followed by hydrogenation to remove the benzyl group. When R is 5-indanernas group, get candoxatril; when R is other group, it can be removed and replaced by 5-indenolol group of traditional ways.

The compound of formula (I) is /S/-enantiomer chiral specified derived glutaric acid, and almost optically pure enantiomer is required to obtain candoxatril, which in itself is an enantiomer of chiral compounds. As described in U.S. patent US-A-5192800 (example 431 et seq. ), (S)-enantiomers of the formula (I) can be obtained by separation of the racemate using /1S,2S-/+/-pseudoephedrine. This process of separation of the isomers is ineffective.

The present invention provides a method of obtaining /S/-enantiomers of compounds of formula (I) by asymmetric hydrogenation of the corresponding /E/-allyl simple ether.

According to the invention proposes a method of obtaining /S/-enantiomers of the compounds of formula (I)

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or its amine salt, where R is 5-indayla or Gruppo)

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or its amine salt, where R is as defined for formula (I), in the presence of a stereoselective chiral rhodium or ruthenium bifosfonatov catalyst capable of catalyzing the specified hydrogenation, and proton solvent.

R may be a straight or branched C1-C4is an alkyl group, such as tert.-bucilina group.

Known to some chiral biphosphine catalysts containing rhodium or ruthenium, they are commercially available or can be obtained by known methods. They contain rhodium or ruthenium centers, komplektovanie with chiral biphosphine ligands, such as 2,2'-bis-/diphenylphosphino/-1,1'-binaphthyl (usually called B1NAP), tert.-butyl-4-/diphenylphosphino/-2-/diphenylphosphino/- 2-/diphenylphosphinomethyl/-1-pyrrolidinecarboxylic (known as BPPM) and 1,2-bis-/diphenylphosphino/-propane (known as PROPHOS). Being chiral, these ligands exist in /R/ and /S/-forms and their complexes with metals such as rhodium and ruthenium, are themselves chiral. It was found that some, but not all of these catalysts can result in stereoselective recovery simple allyl ethers of the formula (II).

The hydrogenation can be carried out in a known manner, i.e. by treatment of a solution of allyl ether with gaseous hydrogen, typically at a pressure of about 60 lbs/inch2(= 414 kPa) in the presence of a catalyst. Typically, a suitable temperature is up to 50oC, at higher temperatures may occur decarboxylation of the acid of formula (II). Solvent used should be proton solvent: suitable were found methanol and aqueous methanol. Recovery is hardly taking place in an aprotic solvent, such as toluene and dimethylformamide.

R may be C1-C4is an alkyl group, such as tert.-butyl.

One group of catalysts which can be used are biphosphonate complexes B1NAP with rhodium and ruthenium, such as complexes B1NAP and p-zimola with ruthenium chloride and B1NAP with 1.5-cyclooctadiene and rhodium chloride. It was found that the /R/-/+/-enantiomer bifosfonatov ligand is required to obtain the target /S/-enantiomers of the compounds of formula (I), when the catalyst contains ruthenium; /S/-/-/-enantiomer is required in the case of rhodium.

Among other known types of catalyst complex of rhodium chloride with /S/-/-/-BPPM also results in untimely the compounds of formula (I) with a large number of S-enantiomer. However, the complex of rhodium with /S, S/-/+/-2,3-O-isopropylidene-2,3-dioxy-1,4-bis-/diphenylphosphino/- Bhutan provides a greater amount of R-enantiomer.

It was also found that the choice of acid or amine is important for hydrogenation reactions. With /R/-B1NAP-retinolum catalyst, when R1is tert. -bootrom obtained compound of the formula (II) is predominantly an /S/-enantiomer when the source material is the acid of formula (II) or its amine salt; when using /S/-B1NAP-rhodium catalyst, salt gives a high yield of /S/-enantiomer of formula (II), but of the free acid of the formula (II) does not.

Suitable amine salts are tsiklogeksanona and /1S,2S/-pseudoefedrina salt.

Another aspect of the present invention is a method for /S/-enantiomers of the compounds of formula (Ia)

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which is the hydrogenation /E/-allyl simple ester of the formula (IIa)

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in the presence of a stereoselective chiral rhodium or ruthenium bifosfonatov catalyst capable of catalyzing the specified hydrogenation, and proton solvent.

The latter aspect of the present invention, the preferred catalyst is /R/-B1NAP/ n-cimal I obtain the compounds of formula (I).

Starting materials (II) for the above synthesis can be obtained by the following reaction scheme:

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In stage 1 of this scheme, the compound of formula (III), where R has the meaning indicated above for formula (II), enter into reaction with p-toluensulfonate, and then treated with base, such as triethylamine, to remove iodine hydrogen to get vinylsulfonic (IV). p-Toluensulfonate can be formed in situ from iodine and benzosulfimide acid or its salts such as sodium salt and the reaction can be carried out in a solvent such as ethyl acetate. This reaction is stereospecific, and the stereochemistry of the compound (IV) is TRANS-/E/, which is confirmed by x-ray analysis.

The compound (IV) can be isolated by conventional means, and in stage 2 it is converted into a compound (II) in the processing of modified zinc dianin cyclopentanecarbonyl acid with the subsequent removal of the p-toluensulfonate salt. This reaction can be carried out by the processing cyclopentanecarbonyl acid diisopropylamide lithium in an inert solvent, such as tetrahydrofuran, a solution of zinc chloride in diethyl ether, followed by compound (V) in restorantski solvent to obtain the compound (II). This reaction is highly stereoselective and takes place with retention of configuration, leading to /E/-enantiomer allyl simple ether (II).

In this synthesis of p-toluensulfonate can be replaced by its aryl analogs such as benzene, 4-chlorobenzene, 4-Brabanthal and 4-nitrobenzenesulfonamide.

Starting compound (III) can be obtained by the interaction of the acrylate compounds CH2Br C(CH2) CO2R 2-methoxyethanol in the presence of potassium carbonate. Suitable conditions are described in EP-A-391673 (preparation 6).

The above allyl ether (IIa) can be obtained from compounds of formula (II), where R is labile acid protecting group such as tert.-butyl, according to the following reaction scheme:

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In stage 1 of this scheme, the compound of formula (II) may be treated with thionyl chloride, and then benzyl-CIS-4-amino-1 - cyclohexanecarboxylate-p-toluensulfonate in the presence of a base, such as triethylamine, in a solvent such as ethyl acetate. The product can be isolated and then treated in a strong acid, such as triperoxonane acid, in stage 2 to remove the groups R and obtain the compounds (IIa).

Obtaining compounds SOG is prigotovleniya.

Example 1. /S/-1-[2-(tert.-butoxycarbonyl)-3-(2-methoxyethoxy)- -propyl] -1-cyclopentanecarbonyl acid, cyclohexylamine salt.

Download 50 g (0,117 mol) cyclohexylamine salt /E/-1-[2-/tert.-butoxycarbonyl /-3-/2-methoxyethoxy/ prop-1-enyl] -1 - cyclopentanecarbonyl acid and 108 mg (0.11 mmol) of [(R)-/+/-2,2'-bis-/diphenylphosphino/-1,1'-binaphthyl] chloro(p-timal)-rotaryglobe in a glass flask with a capacity of 500 ml, containing a magnetic stirrer rod, the upper part of which is closed with a rubber septum. The system is rinsed with nitrogen, is injected with 300 ml of methanol and 100 ml obeskislorozhennaja demineralized water and in a mixture of 2 h bubbled hydrogen. The mixture hydronaut inside a steel vessel at 60 lb/inch2(=414 kPa) and 45 - 50oC for 19 hours, the Solvent is distilled off under reduced pressure and the crude product is dissolved in 345 ml of ethyl acetate by boiling under reflux, diluted with 345 ml of hexane and allowed to cool to room temperature. Precipitated precipitated salt granularit for 16 h at room temperature and collecting, receiving 33,33 g of target compound (68%) ratio (S : R 99 : 1), so pl. = 120 - 122oC, Rf= 0,3 (ethyl acetate/hexane, 1 : 1 + 1% acetic acid).

13C-NMR (75,4 Hz, CDCl3): = 24,69; 25,10; to 25.15 the Il/-3-/2-methoxyethoxy/ propyl]-1-cyclopentanecarbonyl acid, cyclohexylamine salt.

Download 5.0 g (11.7 mmol) cyclohexylamine salt /E/-1-[2-/tert.-butoxycarbonyl/-3-/2-methoxyethoxy/ prop-1-enyl]-1-cyclopentanecarbonyl acid and 10.9 mg (to 0.011 mmol) [/R/-/+/-2,2'-bis-/diphenylphosphino/-1,1'-binaphthyl] chloro-/p-timol/-rotaryglobe in a glass flask with a capacity of 100 ml and closes its upper part with a rubber septum. The system is bubbled dry hydrogen, add 50 ml of methanol and rinsed the mixture for 3 h in nitrogen. The mixture hydronaut inside a steel vessel at 60 lb/inch2(=414 kPa) at 45 - 50oC for 50 hours, the Methanol is distilled off under reduced pressure and dissolve the crude product in 35 ml of ethyl acetate by boiling under reflux, diluted with 35 ml of hexane and allowed to cool to room temperature. Precipitated precipitated salt granularit for 16 h at room temperature and collect, receive the target connection, identical to the compound of example 1 (3,17 g, 63%) ratio (S: R 99: 1), Rf= 0,33 (ethyl acetate/hexane 1 : 1 + 1% acetic acid).

Example 3. /S/-1-[2-/tert.-butoxycarbonyl/-3-/2- -methoxyethoxy/propyl] -1-cyclopentanecarbonyl acid.

Download /E/-1-[2-/tert.-butoxycarbonyl/-3-/2-methoxyethoxy/ prop-1-enyl] -1-cyclopentanecarbonyl acid (0.2 g, moorabin closed with a rubber septum. The system is rinsed with nitrogen, was added 5 ml of methanol and the mixture was bubbled nitrogen for 3 hours the Mixture hydronaut inside a steel container at 414 kPa (60 lb/in2) at 45 - 50oC for 26 hours, the Methanol is distilled off under reduced pressure to obtain the target compound (67% according to NMR) ratio (S : R 98 : 2), Rf= 0,29 (ethyl acetate/hexane, 1 : 1 + 1% acetic acid).

1H-NMR spectrum (300 MHz, CDCl3): = USD 1.43 (s, 9H); 1,45 - of 1.57 (m, 2H); 1,65 by 1.68 (m, 4H); 1,80 (DD, 1H); 1,99 (DD, 1H); 2,09 - of 2.16 (m, 2H); 2.57 m) - 2,66 (m, 1H); to 3.36 (s, 3H); 3.40 in - 3,61 ppm (m, 6H).

13C-NMR-spectrum (75,4 MHz, CDCl3): = 24,54; 24,90; 27,93; 35,10; 36,61; 37,38; 44,56; 53,46; 58,91; 70,16; 71,81; 73,30; 80,56; 173,98; 183,41 MRP.

Example 4. /R/-1-[2-(tert.-butoxycarbonyl)-3-(2-methoxyethoxy) propyl] -1-cyclopentanecarbonyl acid.

Load of 0.1 g (0.22 mmol) cyclohexylamine salt /E/-1-[2-/tert.-butoxycarbonyl/-3-/2-methoxyethoxy/ propyl-1-enyl] -1-cyclopentanecarbonyl acid and 8.5 mg (0,0061 mmol) HCl R [(S)-2,2'-bis-/diphenylphosphino/1,1'-binaphthyl]2in a glass flask equipped with a magnetic stirrer rod, and close the throat rubber septum. System purge with argon, was added to 2.5 ml of methanol and the mixture hydronaut inside a steel vessel at 345 kPa (50 lb/in2) at room temp is I. The crude product is partitioned between 10 ml of hexane and 10 ml of 1.0 M aqueous hydrochloric acid solution and separated layers. The aqueous layer was then extracted with 2 to 10 ml of hexane and dried the combined hexane extracts over magnesium sulfate, filtered and concentrated, to obtain the target compound in the form of oil (37 mg, 51%) ratio (S : R 9 : 91).

Example 5. /S/-1-[2-/tert-butoxycarbonyl/-3-/2-methoxyethoxy/ propyl]-1-cyclopentanecarbonyl acid, cyclohexylamine salt.

Loads of 15.2 mg (0.03 mmol) of the dimer chloro-/1, 5cyclooctadiene/-rhodium/1/ and 42.2 mg (0.06 mmol) /S/-/-/-2,2'-bis-/diphenylphosphino/-1,1'-binaphthyl in a three-neck flask with a capacity of 50 ml, equipped with lines for supplying and discharging gas, and a third throat closed with a rubber septum. The system is rinsed with nitrogen, add 10 ml of methanol and the mixture is rinsed for 30 min with nitrogen. The reaction mixture hydronaut at atmospheric pressure at room temperature for 1 h Then add a solution of 0.5 g (1,17 mmol) cyclohexylamine salt /E/-1-[2-(tert. -butoxycarbonyl)-3-(2 - methoxyethoxy) prop--1-enyl]-1-cyclopentanecarboxylic acid in 10 ml of methanol, the mixture hydronaut at atmospheric pressure and room temperature for 5 days. The reaction mixture is blown with nitrogen and concentrate when pony is up from 3.5 ml of ethyl acetate and 3.5 ml of hexane, get 0,37 g (74%) of the target product.

Ratio (S : R 92 : 8), Rf= 0,29 (ethyl acetate/hexane, 1 : 1 + 1% acetic acid).

Example 6. /1S,2S/-/+/-pseudoefedrina salt /S/-1-[2-/tert.-butoxycarbonyl/-3-/2-methoxyethoxy/ propyl]-1 - cyclopentanecarboxylic acid.

Loaded into a glass flask of 3.0 mg (0.006 mmol) of the dimer chlorine/1, 5cyclooctadiene/rhodium/1/ and 3.8 mg (0.006 mmol) /S/-/-/-2,2'-bis-/diphenylphosphino/1,1'-binaphthyl and the neck is closed with a rubber septum. System purge with argon, was added 10 ml of methanol, then the solution of 0.1 g (0.2 mmol) /1S,2S/-/+/-pseudoephedrine salt /E/-1-[2-/tert.-butoxycarbonyl/-3- -/2-methoxyethoxy/ prop-1-enyl]-1-cyclopentanecarboxylic acid in 1.5 ml of methanol. The mixture hydronaut inside a steel vessel at 345 MPa (50 lb/in2) and at room temperature for 48 hours the Reaction mixture is blown with nitrogen and distilled off methanol under reduced pressure to obtain the target compound in the form of oil (0.1 g, quantitative crude yield) ratio (S : R 90 : 10).

1H-NMR spectrum (300 MHz, CDCl3): = 1,02 (d, 3H); 1,40 - 1,49 (m, 2H); USD 1.43 (s, 9H); 1,59 - to 1.67 (m, 4H); or 1.77 (DD, 1H); of 1.88 (DD, 1H); 2.06 to to 2.18 (m, 2H); 2.57 m (s, 3H); 2,61 - a 2.71 (m, 1H); 2,86 - of 2.97 (m, 1H); 3,29 (s, 3H); 3,43 - 3,59 (m, 6H); 4,47 (d, 1H); 6,17 (Shir. s, 3H); 7,27 - 7,38 (m, 5H), MRP.

Analysis of C27H45NO7:

Found, %: C 65,53; H 9,17; N 3,22.

Calculated, %: C 65,43; H 9,15; N 2,83.

Example 7. /S/-1-[2-/tert.-butoxycarbonyl/-3-/2-methoxyethoxy/- propyl] -1-cyclopentanecarbonyl acid.

Download 100 mg (0.22 mmol) cyclohexylamine salt /E/-1-[2-/tert.-butoxycarbonyl/-3-/2-methoxyethoxy/ prop-1-enyl] -1-cyclopentanecarboxylic acid, 3.0 mg (0,0006 mmol) of the dimer chlorine /1, 5cyclooctadiene/-rhodium/1/ and 7.6 mg (0,013 mmol) /2S, 4S/tert.-butyl-4-/diphenylphosphino/-2-diphenylphosphino/-2- /diphenylphosphinomethyl/-1 pyrrolidinecarboxylic in the glass bulb and the neck is closed with a rubber septum. System purge with argon, was added to 2.5 ml of methanol and purge the mixture with argon for 30 minutes, the Reaction mixture hydronaut at 104 kPa (15 lb/in2) at room temperature for 20,5 hours, the Reaction mixture is blown with nitrogen, was added 100 mg of ion exchange resin Dowex 50W-X2 (200 mesh), the mixture is stirred for 15 minutes Ion-exchange resin is filtered, distilled methanol under reduced pressure to obtain the target compound in the form of oil (73 mg, quantitative yield) ratio (S : R 61 : 39), Rf= 0,3 (ethyl acetate/hexane, 1 : 1 + 1% acetic acid).

Example t 50 mg (0.11 mmol) cyclohexylamine salt /E/-1-[2-/tert.butoxycarbonyl/-3-/2-methoxyethoxy/ prop-1-enyl]-1-cyclopentanecarboxylic acid in a glass flask and the neck is closed with a rubber septum. Added 0.33 ml of ethanol, then 2.0 mg (0,004 mmol) of the dimer chlorine (1, 5cyclooctadiene) rhodium/1/ and 3.9 mg (0,008 mmol) /+/-2,3-0-isopropylidene-2,3-dioxy - 1,4-bis-/diphenylphosphino)-butane in 0.17 ml of toluene, the mixture was bubbled nitrogen. The mixture hydronaut in a steel vessel at 345 kPa (50 lb/in2) and room temperature for 24 h, diluted with 50 ml ethyl acetate and 50 ml of 2.0 N. aqueous solution of hydrochloric acid and separated layers. An ethyl acetate layer is passed through a column of silica gel and concentrated under reduced pressure to obtain the target compound as a yellow-brown oil (37 mg) ratio (R : S 62 : 38), Rf= 0,3 (ethyl acetate/hexane, 1 : 1 + 1% acetic acid).

Example 9. /S/-1-[2-/tert.-butoxycarbonyl/-3-,2-methoxyethoxy/ propyl] -1-cyclopentanecarbonyl acid.

Download 50 mg (0.11 mmol) cyclohexylamine salt /E/-1-[2-/-tert.-butoxycarbonyl/-3-/2-methoxyethoxy/ prop-1-enyl] -1-cyclopentanecarboxylic acid, 3.2 mg (0,008 mmol) /R/-/+/-1,2-bis-/diphenylphosphino)-propane and 2.0 mg (0,004 mmol) of the dimer chlorine /1,5-cyclooctadiene/ rhodium/1/ in a glass flask and the neck is closed with a rubber septum. System purge with argon, was added 0.5 ml of methanol and hydronaut the mixture in a steel vessel at 345 kPa (50 lb/in2) when Komarom (1% acetic acid), receive after the merger and evaporation of appropriate fractions of the target compound in the form of oil (22 mg, 61%) ratio (S : R 54 : 46), Rf= 0,3 (ethyl acetate/hexane 1 : 1 + 1% acetic acid).

Example 10. /S/-Benzyl-CIS-4-{1-[2-carboxy-3-(2-methoxyethoxy) propyl] -1-cyclopentanecarboxylic}-1-cyclohexanecarboxylate.

Download 100 mg (0.2 mmol) /E/-benzyl-CIS-4-{1-[2-carboxy-3- /2-methoxyethoxy/ prop-1-enyl]-1-cyclopentanecarboxylic}-1- -cyclohexanecarboxylate and 3.8 mg (0,004 mmol) [/R/-/+/-2,2'-bis-/diphenylphosphino/1,1'-binaphthyl] chloro /p-timol/ rotaryglobe in a vessel equipped with a magnetic rod stirrer, and close the mouth with a rubber septum. The system is rinsed with nitrogen and add 5 ml of methanol and the mixture was bubbled nitrogen for 2 hours the Mixture hydronaut inside a steel vessel at 414 kPa (60 lb/in2and at 45 - 50oC for 26 hours, the Methanol is distilled off under reduced pressure to obtain the target compound (113 mg, quantitative yield) ratio (S : R 85 : 15).

The sample preparation. /E/tert. -butyl-2-/2-methoxyethoxymethyl/- -3-/benzazolyl/-acrylate.

To the suspension to 7.59 g (46.2 mmol) of sodium salt benzosulfimide acid and 10.0 g (46.2 mmol) of tert.-butyl-2-/2-methoxyethoxymethyl/ - is l) of iodine and stirred mixture of 3 days. After 2 days additionally added 50 ml of ethyl acetate. The reaction mixture was cooled to 0oC and dropwise added triethylamine (9,67 ml and 69.3 mmol). The reaction mixture was stirred at 0oC for 2 h and at room temperature for 16 h, diluted with 100 ml of distilled water and 50 ml of ethyl acetate. Separated the layers and the aqueous layer was additionally extracted with 25 ml ethyl acetate. United an ethyl acetate extracts are washed with 1.0 M aqueous hydrochloric acid solution and 5% aqueous sodium thiosulfate solution (2 100 ml), filtered to remove the three products and the filter cake washed with ethyl acetate. The combined filtrate and wash water washed with 50 ml of distilled water and concentrated under reduced pressure, get 14,85 g of brown oil. The crude product is purified by chromatography on silica, elwira hexane/ethyl acetate (2: 1), obtained after combining and evaporation of appropriate fractions of the target compound in the form of oil (5,09 g, 30,8%), which crystallized upon standing, so pl. 46 - 48oC, Rf= 0,25 (silica, hexane/ethyl acetate 2:1), (MH+357,05, 1,7%).

1H-NMR spectrum (300 MHz, CDCl3): = of 1.47 (s, 9H); at 3.35 (s, 3H); 3,35 - of 3.53 (m, 2H); 3,63 - 3,66 (m, 2H); 4.75 V (s, 2H); 7.03 is (s, 1H); 7,54 - to 7.59 (m, 2H); 7,663,89 MRP.

Analysis of C17H24O6S:

Found, %: C 57,11; H 7,08.

Calculated, %: C 57,29; H 6,79.

/E/-tert.-butyl-2-/2-methoxyethoxymethyl/-3-/p-toluensulfonyl/ acrylate.

To a solution of 19,39 g (of 68.7 mmol) of p-toluensulfonate in 50 ml of dichloromethane at room temperature under nitrogen atmosphere add to 9.91 g (45,8 mmol) /tert.-butyl-2-/2-methoxyethoxymethyl/ acrylate. The mixture is stirred for 16 h at room temperature, cooled to 0oC and added dropwise to 12.7 ml (to 91.6 mmol) of triethylamine. The reaction mixture was stirred 0.5 h at 0oC and 4 h at room temperature, diluted with 100 ml of distilled water and separated layers. The aqueous layer was additionally extracted with 25 ml of dichloromethane and the combined organic extracts washed with 100 ml of 1.0 M aqueous solution of hydrochloric acid, 25 ml of 5% aqueous sodium thiosulfate solution and 50 ml of distilled water. Dichloromethane phase was concentrated under reduced pressure, get 17,48 g (quantitative yield) of a brown oil. The crude product is purified by chromatography on silica with gradient elution with mixtures of hexane/ethyl acetate, after pooling and evaporation of appropriate fractions obtain the target compound in the form of light-relegalized 2 : 1).

1H-NMR spectrum (300 MHz, CDCl3): = of 1.47 (s, 9H); of 2.45 (s, 3H); to 3.36 (s, 3H); 3,51 - of 3.54 (m, 2H); 3,63 - to 3.67 (m, 2H); 4.75 in (lat. s, 2H); 7,02 (Shir. s, 1H); to 7.35 (d, J = 9 Hz, 2H); to 7.84 (d, J = 9 Hz, 2H) ppm.

13C-NMR-spectrum (75,4 MHz, CDCl3): = 21,65; 27,84; 58,87; 62,90; 70,34; 71,66; 83,24; 128,04; 130,08; 137,29; 137,90; 142,37; 145,23; 163,96 MRP.

Analysis of C18H26O6S:

Found, %: C 58,51; H 7,20.

Calculated, %: C 58,36; H 5,93.

/E/tert. -butyl-2-/2-methoxyethoxymethyl/-3-/4-chlorobenzenesulfonyl/ acrylate.

To a solution of 4.95 g (16.4 mmol) of 4-chlorobenzenesulfonamide in 12 ml of dichloromethane at room temperature was added a 2.36 g (10.9 mmol) of tert. -butyl-2-/2-methoxyethoxymethyl/ acrylate. The mixture is stirred at room temperature for 23 h, cooled to 0oC and added dropwise to 2.9 ml (to 21.8 mmol) of triethylamine. The reaction mixture was stirred for 1.25 h at 0oC, diluted with 25 ml of distilled water and 12 ml of dichloromethane and separated layers. The aqueous layer was additionally extracted with 10 ml dichloromethane and the combined organic extracts are washed with 25 ml of 1.0 M aqueous hydrochloric acid, 25 ml of 5% aqueous sodium thiosulfate solution and 10 ml of distilled water. Dichloromethane phase was concentrated under reduced pressure, get 4,46 g brown the donkey Association and evaporation of appropriate fractions of the target compound in the form of oil (3.50 g, 82%), Rf= 0,38 (silica, hexane/ethyl acetate 2 : 1).

1H-NMR spectrum (300 MHz, CDCl3): = to 1.48 (s, 9H); 3,37 (s, 3H); 3,51 - of 3.54 (m, 2H); 3,64 - 3,68 (m, 2H); 4,74 (s, 2H); 7,02 (s, 1H); 7,53 (d, J = 9 Hz, 2H); a 7.92 (d, J = 9 Hz, 2H).

13C-NMR-spectrum (75,4 MHz, CDCl3): = 27,71; 58,84; 62,56; 70,34; 71,51; 83,50; 129,51; 129,73; 137,37; 138,32; 140,88; 142,84; 163,58 MRP.

Analysis of C17H23ClO6S:

Found, %: C 52,26; H 5,91.

Calculated, %: C 52,24; H 5,93.

/E/tert. -butyl-2-/2-methoxyethoxymethyl/-3-/4 - brabanthallen/ acrylate.

To a solution of 1.06 g (3,15 mmol) in 4.5 ml of dichloromethane at room temperature was added 0.45 g (2.1 mmol) of tert.- butyl-2-/2-methoxyethoxymethyl/ acrylate. The mixture is stirred for 2.5 h at room temperature, cooled to 0oC and added dropwise of 0.58 ml (4.02 mmol) of triethylamine. The reaction mixture was stirred at 0oC for 0.5 h and 1.0 h at room temperature, diluted with 20 ml of water and 15 ml of dichloromethane and separated layers. The aqueous layer was additionally extracted with 2 5 ml dichloromethane and the combined organic extracts washed with 20 ml of 1.0 M aqueous solution of hydrochloric acid, 20 ml of 5% aqueous sodium thiosulfate solution and 20 ml of distilled water. The dichloromethane phase is dried over magnesium sulfate, fotografia on silica with a gradient elution with mixtures of hexane/ethyl acetate, after pooling and evaporation of appropriate fractions obtain the target compound as a yellow oil (0.75 g, 83%), Rf= 0,39 (silica, hexane/ethyl acetate 2 : 1).

1H-NMR spectrum (300 MHz, CDCl3): = of 1.47 (s, 9H); 3,37 (s, 3H); 3,50 - 3,55 (m, 2H); 3,63 - to 3.67 (m, 2H); 4,71 (s, 2H); 7,01 (s, 1H); of 7.70 (d, J = 8 Hz, 2H) and a 7.85 (d, J = 8 Hz, 2H) ppm.

Analysis of C17H22BrO6S:

Found, %: C 46,71; H 5,26.

Calculated, %: C 46,90; H 5,33.

/E/tert. -butyl-2-/2-methoxyethoxymethyl/-3-/4 - nitrobenzenesulfonyl/ acrylate.

To a solution 1,49 g (4,65 mmol) of 4-nitrobenzenesulfonamide in 6 ml of dichloromethane at room temperature was added 0.68 g (3.1 mmol) of tert.-butyl-2-/2-metasilicates/ acrylate. The mixture is stirred for 3.5 h at room temperature and added dropwise to 0.88 ml (6.2 mmol) of triethylamine. The reaction mixture was stirred for 16 h, diluted with 25 ml of distilled water and 10 ml of dichloromethane and separated layers. The aqueous layer was additionally extracted with 5 ml dichloromethane and the combined organic extracts washed with 20 ml of 1.0 N. aqueous solution of hydrochloric acid, 20 ml of 5% aqueous sodium thiosulfate solution and 20 ml of distilled water. The dichloromethane phase is dried over magnesium sulfate, filtered and con is the silicon oxide gradient elution with mixtures of hexane/ethyl acetate, get after combining and evaporating the appropriate fractions 0,78 g of target compound as a yellow oil (61,9%), Rf= 0,33 (silica, hexane/ethyl acetate 2 : 1), (MH+402,88, 1,07%).

1H-NMR spectrum (300 MHz, CDCl3): = to 1.48 (s, 9H); 3,37 (s, 3H); 3,51 - of 3.54 (m, 2H); 3,66 at 3.69 (m, 2H); 4,74 (s, 2H); 7,05 (s, 1H); 8,21 (d, J = 9 Hz, 2H); 8,39 (d, J = 9 Hz, 2H) ppm.

13C-NMR-spectrum (75,4 MHz, CDCl3): = 27,83; 58,93; 62,71; 70,76; 71,67; 83,88; 124,57; 129,65; 136,58; 144,65; 145,67; 150,96 and 163,32 MRP.

Analysis of C17H23NO8S:

Found, %: C 50,75; H 5,80; N Of 3.46.

Calculated, %: C 50,86; H 5,77; N 3,49.

/E/-1-[/2-/tert. -butoxycarbonyl/-3-/2-methoxyethoxy/ prop-1-enyl]-1-cyclopentanecarbonyl acid, cyclohexylamine salt.

To a solution of 216 ml (1.54 mol) of Diisopropylamine in 4.0 l of anhydrous tetrahydrofuran at -10oC in nitrogen atmosphere are added dropwise over 35 min to 9.66 ml (1.54 mol) of 1.6 M solution of n-utility in hexane. The reaction mixture is stirred at -10oC for 15 min and allowed to warm to 0oC for 45 minutes At this point was added for 30 min 84 ml (0.77 mol) cyclopentanecarbonyl acid, keeping the temperature below 0oC with external cooling. The reaction mixture is allowed to warm to room the silt live within 10 minutes The reaction mixture was stirred at 0oC for 25 min, cooled to -20oC and add a solution of 260 g (0.70 mol) /E/-tert.-butyl-2-/2 - methoxyethoxymethyl/-3-/p-toluensulfonyl/ acrylate in 530 ml of anhydrous THF. The reaction mixture was stirred at -20oC and 0oC for 16 h, diluted 214 ml of concentrated hydrochloric acid and establish pH 5 with 2 ml of 5.0 N. aqueous sodium hydroxide solution. The mixture is filtered to remove insoluble products, extracted with 1.3 l of ethyl acetate and separated layers. An ethyl acetate layer was washed with 2.6 liters of 1.0 M aqueous hydrochloric acid solution, 2 to 2.6 liters of distilled water and concentrated under reduced pressure, get 259,8 g of oil. The crude product is dissolved in 2.25 liters of hexane boiling with reflux condenser, remove the heat and add 78.5 per ml of 0.68 mol) cyclohexylamine. The mixture is diluted 1.13 liters of hexane and the precipitated salt is cooled to 0oC, granularit for 1 h, and collect, receive 209,9 g of target compound (70%), so pl. = 106 - 108oC, Rf= 0,28 (ethyl acetate/hexane 1 : 1 + 1% acetic acid).

1H-NMR spectrum (300 MHz, CDCl3): = 3,36 (s, 3H); 3,50 - of 3.53 (m, 2H); to 3.58 - 3,61 (m, 2H); 4,24 (s, 2H); 6,98 (s, 1H) ppm.

13C-NMR-spectrum (75,4 MHz, CDCl3): = RUB 24.55; 25,06; 28,12; hidano, %: C 64,54; H 9,42; N 3,31.

Calculated, %: C 64,61; H 9,66; N 3,28.

/E/-Benzyl-CIS-4-{ 1-[2-/tert. -butoxycarbonyl/-3-/2 - methoxyethoxy/ prop-1-enyl]-1-cyclopentanecarboxylic}-1 - cyclohexanecarboxylate.

To a solution of 1.0 g (totaling 3.04 mmol) /E/-1-[2-/tert.-butoxycarbonyl/ -3-/2-methoxyethoxy/ prop-1-enyl]-cyclopentanecarbonyl acid 10.6 ml of ethyl acetate under nitrogen atmosphere at room temperature was added 1 drop of dimethylformamide, of 0.49 ml (between 6.08 mmol) of pyridine and 0.28 ml (3.95 mmol) of thionyl chloride and stirred the mixture at room temperature for 40 minutes Added 1.29 g (3,19 mmol) benzyl-CIS-4-amino-1-cyclohexanecarboxylate p-toluensulfonate at room temperature, then of 1.27 ml (9,12 mmol) of triethylamine and the mixture is stirred for 3 h at room temperature. The reaction mixture is diluted with 50 ml of distilled water and 50 ml of ethyl acetate and separated layers. An ethyl acetate layer was washed with 2 50 ml of distilled water, 50 ml of 1.0 M aqueous hydrochloric acid, dried over magnesium sulfate, filtered concentrated under reduced pressure, get 1,552 g of brown oil. The crude product is purified by chromatography on silica by elution with hexane/ethyl acetate (1 : 1), obtained after combining and evaporating relevant ,97; 28,95; 38,95; 39,66; 46,71; 55,59; 58,73; 65,19; 66,01; 70,25; 71,55; 80,98; 127,89; 128,06; 128,46; 133,06; 148,91; 174,06; 174,63 MRP.

Analysis of C13H45NO7:

Found, %: C 68,18; H 8,23; N To 2.57.

Calculated, %: C 68,48; H A 8.34; N 2,58.

/E/-Benzyl-CIS-4-{ 1-[2-carboxy-3-/2-methoxyethoxy/ prop-1-enyl] -1-cyclopentanecarboxylic}-1-cyclohexanecarboxylate.

Added dropwise 1.7 ml triperoxonane acid to 1.0 g (1,83 mmol) /E/-benzyl-CIS-4{ -1[2-(tert.-butoxycarbonyl)-3-(2-methoxyethoxy) prop-1-enyl]-1-cyclopentanecarboxylic}-1-cyclohexanecarboxylate at 0oC, the resulting solution was stirred at room temperature for 24 h, the Reaction mixture was concentrated under reduced pressure and the residue is distilled with toluene (3 10 ml) to remove additional triperoxonane acid. The residue is dissolved in 50 ml of tert.-butyl methyl ether and washed with 6 to 10 ml of distilled water.

The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 0,835 g of brown oil. The crude product is purified by chromatography on silica by elution with ethyl acetate/hexane (2 : 1) + 1% acetic acid to obtain after integration and evaporation of appropriate fractions of the target connected>Analysis of C27H37NO7:

Found, %: C 66,37; H Of 7.48; N 2,85.

Calculated, %: C 66,51; H 7,65; N 2,87.

1. The method of obtaining the compounds of formula I

< / BR>
where R is 5-indanyl or an alkyl group, a carboxyl protecting group,

or its amine salt, wherein hydronaut (E)-allyl simple ester of the formula II

< / BR>
where R has the meanings indicated for the formula I,

or its amine salt, at a temperature from room temperature up to 50oC and a pressure of from atmospheric to 450 KPa in the presence of a stereoselective chiral catalyst capable of catalyzing the specified hydrogenation, which is a rhodium or ruthenium centers, skomplikowanie with beforenov ligand and proton solvent.

2. The method according to p. 1, wherein the R - C1- C4is an alkyl group.

3. The method according to p. 2, wherein R is tert.butyl.

4. The method according to PP.1, 2 or 3, characterized in that the said catalyst is a rhodium catalyst and the hydrogenation is subjected to amine salt of the compounds of formula II.

5. The method according to p. 4, characterized in that the amine salt is a salt of cyclohexylamine or (1S, 2S) - (+)-pseudoephedrine.

7. The method according to PP. 1, 2 or 3, characterized in that the said catalyst is a ruthenium catalyst and gidriruemyi compound is the acid of formula II or its cyclohexylamine or (1S, 2S)-(+)-pseudoephedrine salt.

8. The method of obtaining the compounds of formula Ia

< / BR>
characterized in that hydronaut compound of formula IIa

< / BR>
at a temperature of from room temperature up to 50oC and a pressure of from atmospheric to 450 KPa in the presence of a stereoselective chiral catalyst capable of catalyzing the specified hydrogenation, which is a rhodium or ruthenium centers, skomplikowanie with beforenov ligand and proton solvent.

9. The method according to p. 8, characterized in that the catalyst is a ruthenium catalyst containing biosyntony ligand R-(+)-2,2' -bis(diphenylphosphino)-1,1'-binaphthyl.

10. The method according to any of paragraphs. 1 to 9, characterized in that the proton solvent is methanol or aqueous methanol.

 

Same patents:

The invention relates to the field of organic chemistry, namely to new chemical compound gross formula

< / BR>
where x= CF2or bond, the sum n + m + C 3 10

How prelinlinary // 2051143
The invention relates to a method for producing 4-aminobenzamide, which is an intermediate in the production of lightfastness and heat-resistant pigments

FIELD: biochemistry, medicine.

SUBSTANCE: invention relates to phenylalanine derivatives of formula I , wherein X1 and X2 are halogen; Q is CH2 or -(CH2)-; Y is C1-C6-alkyl; CO2R is carboxylic group which may be transetherified; or pharmaceutically acceptable salts thereof. Pharmaceutical composition is disclosed having inhibition activity against α4-integrine mediated cell adhesion. Said composition includes therapeutically effective amount of claimed derivative or pharmaceutically acceptable salt thereof in mixture with pharmaceutically acceptable carrier or diluent. Derivatives of present invention or pharmaceutically acceptable salt thereof are useful as active therapeutic agent inhibiting α4-integrine mediated cell adhesion. Also disclosed are application of phenylalanine derivatives of formula I or pharmaceutically acceptable salts thereof to produce drug for treatment of diseases associated with α4-integrine mediated cell adhesion. Method for treatment or prophylaxis diseases associated with α4-integrine mediated cell adhesion includes administrating to patient effective amount of phenylalanine derivatives of formula I or pharmaceutically acceptable salt thereof. Further methods (variants) for production of target derivatives are disclosed.

EFFECT: α4-integrine inhibiting phenylalanine derivatives.

20 cl, 42 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to synthesis of hydrazocarbonamide used as raw in producing foaming materials. Method for synthesis of hydrazocarbonamide involves the following steps: preparing monochlorobiuret metallic salt of the formula (2) or (3) wherein M means metal and X means chlorine atom by reaction of biuret of the formula (1) with metal hypochlorite or by reaction of biuret of the formula (1) with a chlorinating agent and a base, and reaction of synthesized monochlorobiuret metallic salt with ammonia. Hydrazocarbonamide is formed in the presence of catalyst comprising bromine or iodine atom and bromine or iodine ion formed in the process of the reaction and chosen from the group consisting of metal bromide, metal iodide, bromine-containing organic compound, iodine-containing organic compound and their mixtures. The amount of catalyst is from 0.001 to 1 mole per 1 mole of monochlorobiuret and/or monochlorobiuret metallic salt. As a solvent method involves using a mixture of water and hydrophobic organic solvent chosen from the group consisting of chlorinated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, acetate, ether and their mixtures. Invention provides reducing time of the process, enhancing yield of the end product and improvement of economic and ecological indices.

EFFECT: improved method of synthesis.

6 cl, 7 tbl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns chemistry of adamantane derivatives, namely to a new method of obtaining of dialkylamides of 3-brome-1-adamantilalkancarbon acids of the general formula:

R1,R2=H:R3=N(C2H5)2

R1, R2=CH3:R3=N(C2H5)2

which can be of interest as semiproducts in synthesis of some biologically active substances possessing antiviral activity. Method lies in interaction of 1,3-dehydroadamantane with dialkylamides of α-bromalkancarbon acids from the row: diethylamide of α-bromacetic acid, piperidide of α-brompropionic acid, diethylamide of α-bromo-isobutyric acid at mole ratio of reagents peer accordingly 1:3-4, in the environment of the initial dialkylamides of α-bromalkancarbon acids, at temperature of 80-90°C within 4-6 hours.

EFFECT: obtaining of bonds of declared structural formula, excluding reception stage adamantilealkanecarbon acids.

3 ex

FIELD: chemistry.

SUBSTANCE: invention concerns chemistry of adamantane derivatives, particularly new method of obtaining N,N-dialkyl-substituted amides of adamantylalkylcarboxylic acids of the general formula

which can be of interest as semiproducts in synthesis of some bioactive substances with antivirus effect. Method involves interaction of adamantane derivative with carboxylic acid dialkylamide, where 1,3-dehydroadamantane is used as adamantane derivative, and N,N-dimethylacetamide, N,N-diethylacetamide, N-acethylpiperidine, N-propionylpiperidine, N-(2-methyl)propionylpiperidine are used as carboxylic acid dialkylamides, and process runs at reagent mol ratio of 1:2-3 respectively, in original carboxylic acid dialkylamide medium at 120-130°C for 5-6 hours.

EFFECT: alternative method of obtaining compounds of the claimed structural formula, with omitted stage of obtaining adamantylalkylcarboxylic acids.

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel improved method of obtaining benzylamine derivative of general formula (3)

and method of obtaining from the latter of carbamate derivative of general formula (6) where X1 represents halogen atom and R1 represents acyl group selected from C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and aromatic acyl group, R3 represents alkyl group. Methods include interaction of benzyl derivative of general formula (1)

with halogen compound of general formula (2): where X2 represents halogen atom, and R2 represents acyl group selected from C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and aromatic acyl group, in presence of Lewis acid. From obtained compound of general formula (3) carbamate derivative of general formula (6) is obtained. For this purpose compound of general formula (3) is subjected to hydrolysis obtaining aminoderivative of general formula (4)

which is further subjected to interaction with ester of halogen-formic acid of general formula (5) where X1 and R2 are determined above, X3 represents halogen atom, and R3 represents alkyl group, in presence of base. Invention also relates to novel acylbenzylamine derivatives of general formula (7):

where X1 represents halogen atom, each of R2 and R4 independently represents C1-C7-linear or branched aliphatic acyl group, C3-C6-cycloalkylcarbonyl group, and R can additionally represent hydrogen atom. Benzylamine derivatives of formula (3) and formula (7) can be used as intermediate products for obtaining agricultural or garden bactericide based on formula (6) carbamate.

EFFECT: elaboration of improved method of obtaining benzylamine derivative.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing chlorine-substituted diaminobenzanilides such as 21 -chloro-4,41-diaminobenzanilide and 21,61-dichloro-4,41-diaminobenzanilide - monomers used in production of heat-resistant, fire-resistant and high-strength fibre. The method involves acylation of 2-chloro-4-nitroaniline or 2,6-dichloro-4-nitroaniline with nitrobenzoyl chloride taken in excesses, using ferric chloride as a catalyst in an organic solvent medium while heating in the presence of an anhydride of 4-nitrobenzoic acid, after which the chlorine-substituted dinitrobenzanilide formed is separated through crystallisation and filtration and reduced in an aqueous solution of an amide solvent with subsequent separation of the chlorine-substituted dinitrobenzanilide through crystallisation and filtration. After separating the chlorine-substituted dinitrobenzanilide or chlorine-substituted diaminobenzanilide, the mother solution is completely or partially returned to the corresponding process stage.

EFFECT: method enables to achieve high output (86-95%) of chlorine-substituted 4,41-diaminobenzanilides and minimise amount of wastes.

5 cl, 22 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds of the general formula (I) , where R1, R2 are independently H or C1-C6-alkyl; R3, R4 are independently H or C1-C6-alkyl; R5 is halogen, CN; n, m or o are 0, 1 or 2; and to pharmaceutically acceptable salts thereof.

EFFECT: compounds with monoaminooxidase B inhibition properties applicable in obtainment of pharmaceutical drugs with relevant effect.

14 cl, 3 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: method of producing partially fluorinated aromatic amines which contain at least one hydrogen atom in the ortho-position of the amino group, having general formula 1, , X = F (1a) or H (1b), is distinguished by that pentafluoroaniline is functionalised on the amino group through treatment with a derivative of aliphatic or aromatic mono- or dicarboxylic acid to obtain the corresponding derivative of pentafluoroaniline as a substrate which undergoes hydrodefluorination under the effect of a reducing metal in the presence of a proton source and in the presence of a catalyst - complex compound of nickel and/or cobalt with ligands selected from heterocyclic nitrogen-containing compounds or phosphorus-containing compounds in a medium of an aprotic dipolar solvent with subsequent alkaline or acid hydrolysis of the reaction mixture to form the corresponding amine.

EFFECT: improved method.

7 cl, 1 dwg, 6 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of compounds of general formula IV. The method involves (1) reaction of a compound of formula I with a compound of formula II in basic conditions where the phenol hydroxy group is present in at least partially deprotonated form, and in an aprotic solvent to form a compound of formula III, (2) if necessary the group R7 is converted to a carboxy group, (3) if necessaty, the product obtained at step (1) or (2) is treated with an acid to form a compound of formula IV. n equals 1-8, m equals 1-4, R1 is selected from a group comprising C1-C6alkyl with a straight or branched chain, a carboxy-activating group and a peptide condensing reagent, each R2 can be independently selected from a group comprising -OH, NR3R4, halogen, C1-C4 alkyl, halogen (C1-C4) alkyl, C1-C4 alkoxy, C2-C4 alkenyl, each R5 and each R6 is independently selected from a group comprising hydrogen, -OH, NR3R4, halogen, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, where each R5 and each R6 are optionally identical, R3 and R4 are each independently selected from a group comprising hydrogen, -OH, C1-C4 alkyl, halogen(C1-C4)alkyl, C1-C4 alkoxy, C2-C4 alkenyl, and R7 denotes a carboxylic acid or any group which can be converted to a carboxy group, for example an amide or nitrile.

EFFECT: invention enables to obtain N-substituted salicylamides which can be used in compositions for delivering active agents into an organism.

19 cl, 3 ex

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