Method for production of alpha-arylalkanecarboxylic acids

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of m- or p-substituted α-arylalkanecarboxylic acids of general formula I

from respective α-hydroxylated derivatives using inexpensive reagents and without converting of any reducible groups such as ester or ketone ones in side chains. In formula R is hydrogen, C1-C6-alkyl; R1 is hydrogen, linear or branched C1-C6-alkyl, phenyl, p-nitrophenyl, alkali or earth-alkali cation or cation of pharmaceutically acceptable ammonia salt: A is C1-C4-alkyl, aryl, optionally substituted with one or more alkyl, hydroxy, etc., aryloxy, arylcarbonyl; A is in m- or p-sites; P - linear or branched C1-C6-flkyl, phenyl, nitrophenyl. Claimed method includes the next steps: a) converting of compounds of formula II to compound of formula III either by reaction of II with compound of formula in presence of organic or inorganic base or by reaction of II with thiophene of formula and followed by reaction of obtained product with HNRaRb, wherein Ra andRb are as defined above; b) thermal rearrangement of III to form IIIb ; c) catalytic dehydration of IIIb to form IIIc ; and d) optional hydrolysis of IIIc to obtain target compound of formula I. Also are disclosed new compounds of formulae III and IIIb.

EFFECT: new α-arylalkanecarboxylic acids and intermediates thereof.

6 cl, 5 ex

 

The present invention relates to a method for meta - or para-substituted α-arylalkylamines acids.

More specifically, the invention relates to a method for producing compounds of formula (I):

where:

R represents hydrogen, C1-C6alkyl; R1represents hydrogen, linear or branched C1-C6alkyl, phenyl, p-nitrophenyl, alkaline cation or the cation of the alkaline earth metal, or a pharmaceutically acceptable ammonium salt; a represents C1-C4alkyl, aryl, aryloxy, arylcarbamoyl, 2-, 3 - or 4-iridocorneal, aryl, optionally substituted by one or more alkyl, hydroxy-, amino-, cyano-, nitro-, alkoxygroup, halogenation, halogenlampe; And is in the meta - or para-positions on the basis of compounds of the formula (II):

where R represents a linear or branched C1-C6alkyl, phenyl, p-nitrophenyl.

Currently, removal of phenolic hydroxyl derivatives arylalkylamines acids use different strategies based on the derivatization and subsequent elimination of this derived during recovery, but in most cases, these methods have several disadvantages such as expensive reagents or insufficient behold aktivnosti.

In the British patent 2025397 (Chinoin) described the use of various derivatives of phenolic hydroxyl, such as phenylenecarbonyl, 1-phenyl-5-tetrazolyl, 2-benzo-oxazolyl, -SO2OMe, and the restoration of that derivative with hydrogen on Pd/C catalyst.

In the application WO 98/05632 in the name of the applicant describes the use of performcalculation, in particular of triptoreline, with subsequent recovery of formic acid and triethylamine in the presence of a complex of palladium acetate/triphenylphosphine.

Currently, he found the way to obtain the aryl-propionic acids on the basis of appropriate α-hydroxylated derivatives using inexpensive reagents that do not involve any reducible groups such as ester or ketone, in side chains of the original molecules.

In accordance with the method of the invention the compounds of formula (I) receive the following stages:

a) the conversion of compounds of formula (II) into compounds of the formula (III):

where Ra and Rb represent C1-C6alkyl, preferably methyl;

b) thermal rearrangement of compound (III) with the formation of (IIIb)

c) catalytic hydrogenation of (IIIb) with the formation of (IIIc)

d) transformation (IIIc) is (I).

The compounds of formula (II) can be obtained as described in WO 98/05623. In short, based on arylolefins formula (IV)

where a and R have the same meaning as described above, by peregruppirovki of Clausena get a connection (V)

which can be subjected to oxidative cleavage, for example by ozonolysis or by using potassium permanganate in the interfacial conditions, receiving a product of the corresponding carboxylic acid. The latter can be converted to compound (II) esterification of the corresponding alcohol.

Stage (a) can be done in two ways.

In the first case, the compound of formula (II) enter into interaction with

where Ra and Rb same as defined above, in the presence of inorganic bases such as carbonate of alkali or alkaline earth metal, or an organic base such as triethylamine or pyridine,

Alternatively the compound of formula (II) enter into interaction with thiophosgene,

receiving the compound (IIIa)

which is then injected into the interaction with HNRaRb, in which Ra and Rb same as defined above.

The conversion of phenol in the 0-aryl-dialkyldithiocarbamate reacties RaRbNCSCl and subsequent thermal puregroove (stage b) 0-aryl-dialkyldithiocarbamate with the formation of compound (IIIb) described by Newman and Karnes, “The conversion of phenols”, J. Org. Chemistry, Vol.31, 1966, 3980-3982.

On the other hand, as far as getting 0-aryl-dialkyldithiocarbamate by the interaction of phenol with thiophosgene and then the resulting product with an amine RaRbNH, you can follow the method reported in Can. J. Chem., 38, 2042-52 (1960).

At the stage (C) catalytic hydrogenation of S-aryl-dialkyldithiocarbamate (IIIb) with education (S) can be carried out with Raney Ni as catalyst.

Compound (IIIc) can be easily translated in (I) conventional methods of hydrolysis of the ester group and an optional subsequent re-esterification or obtain a salt of carboxyl group.

The method of the invention has been particularly useful in the case when group a in the General formula (I) represents an optionally substituted arilou group, in that the carbonyl function is retained when you restore thiocarbamoyl derived. For example, when a represents a benzoyl, used in the experiment is not observed recovery of the ketone. Moreover, as already noted, the method of the invention is based on the use of reagents low cost, provides good outputs, does not require purification of the intermediate compounds and has a small impact on the environment.

The following examples illustrate the invention in more detail.

Example 1

Receiving the amylovora ether 2-(3’-benzoyl-2’-hydroxy-phenyl)-propionic acid (2)

To a solution of 2-(3’-benzoyl-2’-acetoxyphenyl)-propionic acid (1) (6.2 g) in methanol (35 ml) was added concentrated H2SO4(0.3 ml). The mixture was stirred at room temperature for 15 hours to extinction (1) and intermediates of the reaction. The solvent was evaporated in vacuum and the residue was dissolved in ethyl acetate (30 ml) and washed with water. The organic layer was treated with NaOH solution (100 ml), and the basic phase was acidified with 4 N Hcl and was extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with saturated salt solution, dried over Na2SO4and evaporated in vacuum. The crude product (4.3 g) was dissolved in isopropyl ether (5 ml) and filtered yellowish precipitate. To the residue was added n-hexane (25 ml) and stirred the mixture overnight. After filtration obtained 3.2 g (2) (0.11 mol; yield 70% based on 4) in the form of a whitish precipitate (melting point 108-111°).

TLC (CH2Cl2/MeOH 9:1 Rf=0,45)

Elemental analysis calculated for C17H16About3: 71,81, N 5,67.

Found: 71,16, N 5,63.

NMR1H (CDCl3) δ 8.4V (HE, 1H); a 7.85-to 7.3 (m, 7H); 7,0 (d, 1H, J=7 Hz); of 3.95 (q, 1H, J=8 Hz); and 3.8 (s, 3H); 1,6 (d, 3H, J=8 Hz).

Example 2

Obtain methyl ester of 2-(3’-benzoyl-2’-O-diethylthiocarbamoyl)-propionic acid (3)

To a solution of (2) (3.2 g, to 0.011 mol) in acetone (25 ml) priba is or potassium carbonate (1.65 g, 0.012 mol) and stirred the mixture at room temperature for 15 minutes To the boiling mixture for 2 hours was added dropwise a solution of N,N-diethylthiocarbamoyl chloride (1.51 g, 0.012 mol) in acetone (5 ml). After cooling to room temperature the precipitated inorganic salt was filtered, and the solvent was evaporated in vacuum. The residue was dissolved in ethyl acetate (25 ml) and washed with water (2×10 ml) and saturated salt solution (2×10 ml). The organic phase was dried over Na2SO4and was evaporated in vacuum, obtaining of 3.45 g (3) as a dark oil, sufficiently pure for use in the next stage.

TLC (n-hexane/EtOAc 8:2 Rf=0,25)

Elemental analysis calculated for C20H22NO4S: 64,49, N 5,95, N 3,76, S 8,61.

Found: 64,17, N Of 5.92, N 3,82, S 8,60.

NMR1H (Dl3) δ 7,95 one-7.8 (m, 4H); 7,6 to 7.4 (m, 3H); to 7.2 (d, 1H, J=7 Hz); of 3.9 (q, 1H, J=8 Hz); 3,7 (s, 3H); 3,6 (s, 3H); 3,4 (s, 3H); 1,6 (d, 3H, J=8 Hz).

Example 3

Obtain methyl ester of 2-(3’-benzoyl-2’-S-diethylthiocarbamoyl)-propionic acid (4)

Connection (3) (3,45 g) was heated in a flask at 210°C (external temperature, oil bath) for 2 hours under stirring. After cooling to room temperature and evaporation in vacuum got to 3.45 g 4) (0,0054 mol), sufficiently pure for use without further purification.

TLC (n-hexane/ethyl acetate 8:2 Rf=0,2)

E. emanny analysis, calculated for C20H22NO4S: 64,49, N 5,95, N 3,76, S 8,61.

Found: 64,17, N Of 5.92, N 3,82, S 8,60.

NMR1H (DCl3) δ 7,9-7,8 (m, 3H); 7,7-to 7.3 (m, 5H); 4,4 (kV, 1H, J=8 Hz); the 3.65 (s, 3H); of 3.2 and 2.9 (broad d, 6N); 1,6 (d, 3H, J=8 Hz).

Example 4

Obtain methyl ester of 2-(3’-benzoylphenyl)-propionic acid (5)

To Ni-Raney (50% in water, 20 ml) was added acetone (50 ml) and removed the mixture of water/acetone. The above treatment was carried out 3 times. Thereafter, the catalyst was suspended in acetone (30 ml) and boiled for 30 hours.

Added dropwise a solution of (4) (3,45 g) in acetone (4 ml) and boiled the mixture during the night. After cooling to room temperature the catalyst was filtered and washed with acetone (15 ml). The filtrate was evaporated in vacuum, obtaining 2.4 g (5) in the form of a brownish oil.

TLC (n-hexane/ethyl acetate 9:1 Rf=0,7)

Elemental analysis calculated for C17H16About3: 76,10, N 6,01.

Found: 75,99, N 6,03.

NMR1H (Dl3) δ of 7.9 to 7.4 (m, 8H); and 3.8 (q, 1H, J=8 Hz); the 3.65 (s, 3H); 1,6 (d, 3H, J=8 Hz).

Example 5

Getting 2-(3’-benzoylphenyl)-propionic acid (6)

To a solution of (5) (2.4 g, 0,009 mol) in methyl alcohol (25 ml) was added 1 N NaOH (13.5 ml) and left the mixture under stirring for 8 hours at room temperature. After evaporation of the solvent the residue was diluted with water and was added to this mixture dropwise 5%monotony sodium phosphate d is I bring the pH to 5. Then the aqueous layer was extracted with methyl acetate (2×100 ml). The combined organic extracts were dried over Na2SO4and was evaporated in vacuum, after which he led from a mixture of benzene/petroleum ether 6:20, after receiving 2,05 g (6) (0,0081 mol; yield 90%) as a white solid melting point 92-92° (C) after crystallization.

TLC (l3/CH3HE 95:5 Rf=0,2)

Elemental analysis calculated for C16H14About3: 75,57, N 5,55.

Found: 75,19, N Of 5.53.

NMR1H (Dl3) δ to $ 7.91 to 7.75 (d, 3H); 7,74-7,51 (m, 2H); 7,50-7,35 (m, 4H); of 3.85 (q, 1H, J=10 Hz); was 1.58 (d, 3H, J=10 Hz).

1. The method of obtaining meta - or para-substituted α-arylalkylamines acids of the formula (I)

where

R represents hydrogen, C1-C6alkyl; R1represents hydrogen, linear or branched C1-C6alkyl, phenyl, p-nitrophenyl, alkaline cation or the cation of the alkaline earth metal, or a pharmaceutically acceptable ammonium salt; a represents C1-C4alkyl, aryl, aryloxy, arylcarbamoyl, aryl, optionally substituted by one or more alkyl, hydroxy-, amino-, cyano-, nitro-, alkoxygroup, halogenation, halogenlampe; And is in the meta or paraprotex; R represents a linear or branched C1-C6alkyl, Anil, nitrophenyl, characterized in that the method includes the following stages:

a) the conversion of compounds of formula (II)

where R represents a linear or branched C1-C6alkyl in the compound of formula (III)

where Raand Rbsubmit C1-C6alkyl;

or by reaction of the compound of formula (II) with the connection

in the presence of organic or inorganic bases; or by reaction of the compound (II) with thiophosgene

and subsequent reaction of the obtained product with HNRaRbwhere Raand Rbdefined above;

C) thermal rearrangement of compound (III) with the formation of (IIIb)

(C) catalytic hydrogenation of (IIIb) with education (S)

d) followed, if necessary, by hydrolysis transformation (S) to obtain the compounds of formula (I)in which R1means hydrogen, which, if necessary, can be re-preterition to obtain the corresponding complex ester, or converted into the corresponding salt of the alkali or alkaline earth m is metal or pharmaceutically acceptable ammonium salt.

2. The method according to claim 1, characterized in that the said organic base selected from triethylamine and pyridine, and said inorganic base is selected from carbonates of alkaline or alkaline earth metals.

3. The method according to claim 1, characterized in that the hydrogenation in stage (C) is performed with the use of Ni-Raney.

4. The method according to any of the above paragraphs, wherein the group of formula (I) is a meta-benzoyl, a R is the stands.

5. The compound of the formula

where

R represents hydrogen, C1-C6alkyl; a represents C1-C4alkyl, aryloxy, arylcarbamoyl, aryl, optionally substituted one or more by alkyl, nitro, alkoxygroup, And is located in the meta or paraprotex; R represents a linear or branched C1-C6alkyl, phenyl, nitrophenyl; Raand Rbsubmit C1-C6alkyl as intermediate compounds.

6. The compound of the formula

where R is hydrogen, C1-C6alkyl; a represents C1-C4alkyl, aryloxy, arylcarbamoyl, aryl, optionally substituted one or more by alkyl, nitro, alkoxygroup, And is located in the meta or paraprotex; R represents a linear or once lvlany C 1-C6alkyl, phenyl, nitrophenyl; Raand Rbsubmit C1-C6alkyl, as an intermediate connection.



 

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FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of m- or p-substituted α-arylalkanecarboxylic acids of general formula I

from respective α-hydroxylated derivatives using inexpensive reagents and without converting of any reducible groups such as ester or ketone ones in side chains. In formula R is hydrogen, C1-C6-alkyl; R1 is hydrogen, linear or branched C1-C6-alkyl, phenyl, p-nitrophenyl, alkali or earth-alkali cation or cation of pharmaceutically acceptable ammonia salt: A is C1-C4-alkyl, aryl, optionally substituted with one or more alkyl, hydroxy, etc., aryloxy, arylcarbonyl; A is in m- or p-sites; P - linear or branched C1-C6-flkyl, phenyl, nitrophenyl. Claimed method includes the next steps: a) converting of compounds of formula II to compound of formula III either by reaction of II with compound of formula in presence of organic or inorganic base or by reaction of II with thiophene of formula and followed by reaction of obtained product with HNRaRb, wherein Ra andRb are as defined above; b) thermal rearrangement of III to form IIIb ; c) catalytic dehydration of IIIb to form IIIc ; and d) optional hydrolysis of IIIc to obtain target compound of formula I. Also are disclosed new compounds of formulae III and IIIb.

EFFECT: new α-arylalkanecarboxylic acids and intermediates thereof.

6 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 2-amino-2-phenylalkanol derivatives possessing analgesic activity. In formula (I):

R1 represents a hydrogen atom, alkyl radical containing 1 to 4 carbon atoms in a linear or branched chain, alkyl radical containing 2 to 4 C in a linear or branched chain, substituted hydroxy, alkoxy, alkylthio, acyloxy, amino, alkylamino, dialkylamino, alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido, R2 represents -CO-R radical, -CO-Y-R4 radical, or R2 represents an alkyl radical containing 2 to 4 C, substituted hydroxy, alkoxy, alkylthio, acyloxy, amino, alkylamino, dialkylamino with alkyl residues thereof forming together with a nitrogen atom whereto attached, a heterocycle having 5 or 6 members, optionally carrying another heteroatom specified in oxygen or nitrogen, or substituted by alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido. It will be appreciated that the above substituted alkyl radical represents a linear or branched chain, and contains at least 2 carbon atoms between a nitrogen atom carrying R2 and a substitute; R3 represents an alkyl radical containing 1 to 4 carbon atoms in a linear or branched chain. The radical values R, R4, R5, Y are presented in the patent claim.

EFFECT: what is presented is a method for preparing said compounds and a pharmaceutical composition containing them.

6 cl, 17 ex

FIELD: pharmacology.

SUBSTANCE: in formula , R1 and R2 are independently selected from the group consisting of C12-C18 alkyl, C12-C18 alkenyl and oleyl group; R3 and R4 are independently selected from the group consisting of C1-C6 alkyl and C2-C6 alkanol; X is selected from the group consisting of -CH2- and -S-, or absent; Y is selected from -(CH2)n and -S(CH2)n , where n is 1 to 4; a=1-4; b=1-4; c=1-4 and Z is a counter ion. The invention also relates to a star-cell-specific drug carrier comprising a star-cell-specific amount of a retinoid molecule and a cationic lipid consisting of a compound of formula I.

EFFECT: improved delivery of therapeutic drugs and increased activity thereof.

31 cl, 16 dwg, 14 tbl, 43 ex

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