Novel method of producing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid of formula (I) through a Suzuki reaction between 3-adamantyl-4-methoxyphenylcarboxylic acid of formula (II) and 6-bromo-2-naphthoic acid of formula (III), wherein the reaction between compounds (II) and (III) is carried out at temperature between 60 and 110°C for between 30 minutes and 24 hours in an inert gas atmosphere in the presence of a palladium catalyst and a base in a polar solvent, followed by treatment with an acid. The invention also relates to use of compounds of formulae (II) and (III) to produce a compound of formula (I).

EFFECT: single-step method enables to obtain desired product with high output.

13 cl, 2 dwg, 3 ex

 

The present invention relates to a new process for the preparation of 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid of the formula (I):

retinoid protivougrevoe agent for local purposes, used in pharmaceutical compositions, in particular, to treat certain types of acne.

The compound of formula (I) is described in particular in patent EP 0199636. Patent EP 0199636 describes how to obtain this compound in accordance with the following scheme 1.

Scheme 1

In this method, 2-(1-substituted)-4-bromoanisole turns, in the first stage (a), magyarkanizsa connection and then tsinkorganicheskih connection through the action of zinc chloride (ZnCl2), and then connects with methyl-6-bromination. This reaction is catalyzed by transition metal (palladium or Nickel) or one of its complexes with various phosphines. Synthesis of 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid of the formula (I), as described in patent EP 0199636 (scheme 1), thus, is a three-stage method with yield 63%, of 2-substituted-4-bromoanisole.

One disadvantage of this reaction is the formation of impurities. One of these impurities is obtained by reaction tsinkorganicheskih connection obtained "in situ", with 2-substituted-4-bro what anisole with the formation of 3,3'-di(1-substituted)-4,4'-dimethoxy-1,1'-biphenyl, having the following structure:

Another impurity is also formed during the conversion of the zinc-containing compounds 2-substituted-4-bromoanisole in methyl-6-brominated and interaction of this new zinc-containing compounds with methyl-6-bromination with the formation of the product of dimerization with the following structure:

This product leads, after saponification (stage (b)) and acidification (stage (C)), the following impurities:

The third impurity formed during the hydrolysis reaction medium. Indeed, during the hydrolysis of unreacted tsinkorganicheskih connection 2-substituted-4-bromoanisole gives a mixture having the following structure:

In industrial scale separation of these impurities from the target product is time consuming, and often requires an additional stage of recrystallization.

Moreover, some catalysts, such as chloride, [1,2-bis(diphenylphosphino)ethane]Nickel (NiCl2(dppe)) must be prepared separately, which increases the number of process steps.

At the time of combination reaction in the first stage (a) an acidic functional group protected, turning it into methyl ester and subsequent regeneration. Thus, vtoro the stage (b) methyl 6-[3-(1-substituted)-4-methoxyphenyl]-2-aftout its shades by treatment with base, such as sodium hydroxide (NaOH) or potassium hydroxide (KOH), in alcohol, such as methanol, boiling under reflux.

Upon acidification of the reaction medium with hydrochloric acid at the third stage (C) is formed of 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid. It should also be noted that in this method, the methyl ester of 6-bromatology acids must be obtained in one stage from the corresponding acid. Thus, it can be seen that the method known in the art, is a complex and unsatisfactory.

In this context one of the objectives of the present invention is the provision of a method of obtaining 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid, which would be much easier and more economical. The method, in accordance with the present invention, should be more suitable on an industrial scale, in particular in terms of cost and compliance with Good Manufacturing Practices. One of the objectives of the present invention is to provide a new method of obtaining the compound (I), which does not require at the last stage unprotect acid functional groups, eliminates the formation of impurities mentioned above and makes it possible to reduce the number of stages of the synthesis.

In this context, the present invention relates to a method for producing 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic sour the s of the formula (I):

through one of the Suzuki reaction of 3-substituted-4-methoxyphenylacetic acid of formula (II):

and 6-bromo-2-naphthoic acid of the formula (III):

The present invention also relates to the use of compound (II), on the one hand, and the application of compound (III), on the other hand, to obtain the compounds of formula (I).

In accordance with the method of the present invention, therefore, it is possible to combine in a single stage (1-substituted)phenyl part and naftalina part 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid.

Obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid, in accordance with the method of the present invention, is illustrated below in scheme 2.

Scheme 2

Obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid (I) is performed by a Suzuki reaction between 3-substituted-4-methoxyphenylacetic acid (II) (obtained, in particular, in accordance with the method similar to that described in patent applications WO 02/072009 A2 and WO 03/011808 A1)and commercially available 6-bromatology acid (III). Obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid of the formula (I), as described, in a new way, in accordance with scheme 2, is performed in two stages of 2-(1-substituted-4-bromoanisole (IV) (received for example, in accordance with EP 0199636), which is significantly higher than was obtained in the manner already known in the art. As shown in the example below, the method corresponding to the present invention, the output can be in the order of 95% or above.

In the context of the present invention, the Suzuki reaction is performed through a combination of compounds (II) and (III) in the presence of a palladium catalyst and a base in a polar solvent followed by treatment with acid.

Usually the Suzuki reaction can be performed in the presence of a palladium catalyst such as palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0), palladium on charcoal or dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), in an aprotic polar solvent (e.g. acetonitrile, N,N-dimethylformamide, dimethoxyethane or tetrahydrofuran) or proton polar solvent (for example, n-propanol, ISO-propanol or mixtures of these solvents with water. The amount used of the solvent is equal 7-13 volumes used 6-bromo-2-naphthoic acid (III), and the volume of water used is equal 7-13 volumes used 6-bromo-2-naphthoic acid (III).

Mainly, the palladium catalyst may contain a ligand selected from triphenylphosphine, tri-o-tolylphosphino, three-m-tolylphosphino or three-p-tolylphosphino. In an hour the particular the preferred catalysts are palladium(II) acetate and palladium on carbon, which makes it possible to obtain particularly fast reaction kinetics. The palladium(II) acetate may be preferred when used in combination with 2-(dicyclohexylphosphino)biphenylene type of ligand (J.P. Wolfe et al., J. Am. Chem. Soc.,1999, 121, 9550-9561).

These catalysts can also be encapsulated, such as Pd EnCatTMtype catalysts. Mostly the reaction is performed in the presence of inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide or in the presence of a tertiary amine such as triethylamine or diisopropylethylamine. Especially preferred bases are potassium carbonate, potassium hydroxide and diisopropylethylamine.

Preferably, the Suzuki reaction is performed in an atmosphere of inert gas, for example in an atmosphere of argon or nitrogen. The reaction mixture is predominantly heated to a temperature of from 60 to 110°C for from 30 minutes to 24 hours. Processed in an acid medium, for example in the presence of HCl. In accordance with the conditions used in example 1 and 2, it will be seen that the kinetics of the reaction is very rapid, and the reaction is finished after 2 hours. Specialists in this field will have the opportunity to modify these terms, at the hour of the activity, by applying variants of the Suzuki reaction, which are described in the literature (N. Miyaura & A. Suzuki, Chem. Rev., 1995, 95, 2457-2483; A. Suzuki, J. were obtained. Chem., 1999, 576, 147-168). Therefore, the method in accordance with the present invention is simple and economical and makes it possible to directly obtain the compound (I) with high yield, close to quantitative.

This new method also makes it possible to obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid with a high degree of purity, in which impurities are formed in ways that are known in this field, are completely absent. The following examples of the preparation demonstrate the method of the present invention.

Example 1

a) obtaining a 3-substituted-4-methoxyphenylacetic acid (II)

100 g (0,311 mol) of 2-(1-substituted)-4-bromoanisole (IV) and 500 ml of THF (tetrahydrofuran) is introduced into the nitrogen atmosphere in a 2-liter three-neck reactor. The reaction medium is cooled to -75°C. Add 137 ml (0,342 mol) of a 2.5 M solution of n-BuLi. After stirring for 1 hour at -70°C. add 80 ml (0,342 mol) of tri-ISO-propiverine. After setting at room temperature carry out the hydrolysis reaction mixture 1 liter of 1,2 N. HCl. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with 1 liter of saturated NaCl and then with 1 liter of water. The organic phase is dried over sodium sulfate and viparivartate. Formed 88,37 g of a white solid residue, which is triturated in 440 ml of heptane. After filtration of the precipitate washed with heptane and then dried under reduced pressure at 35°C, until constant weight. Get 84,4 g of 3-substituted-4-methoxyphenylacetic acid as a white solid (yield = 94,8%; TPL = 263°C).

1H-NMR (CDCl3): δ 1.77 in (s, 6H), 2,10 (m, 3H), of 2.20 (s, 6H), 3,91 (s, 3H), of 7.00 (d, 1H, J1=8.0 Hz), with 8.05 (DD, 1H, J2=1.5 Hz and J1=8.0 Hz), 8,15 (d, 1H, J=1.5 Hz).

b) Receiving 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid (I)

20 ml of tetrahydrofuran (12 volumes), 2 g (7 mmol) of 3-substituted-4-methoxyphenylacetic acid (II), 1.65 g (6.6 mmol) of 6-bromo-2-naphthoic acid (III) and 20 ml of 2 M aqueous solution of potassium carbonate are placed in a round bottom flask equipped with a stirrer, in a stream of nitrogen. Then give 15 mg (1%) of palladium acetate and 46 mg (2%) 2-(dicyclohexylphosphino)biphenyl. The medium is heated under reflux for 2 hours. Kinetic monitoring using liquid chromatography shows that % of the formed 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid reaches 94% after one hour and 98% after two hours.

After setting at room temperature, the catalyst was filtered through the cartridge and then slowly poured 30 ml of 1 N. aqueous solution of hydrochloric acid.

The medium is stirred for one the th hour. The precipitate is filtered, washed with water and then dried under reduced pressure. Gain of 2.68 g of 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid as a white solid, purity of which was determined using liquid chromatography, amounted to 99.9% (output = 94,8%, TPL= 321°C).

In the literature following the melting temperature (TPL): TPL = 319-322°C (B. Charpentier et al., J. Med. Chem., 1995, 38, 4993-5006) and TPL = 325-327°C (EP 0199636).

Example 2

Obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid (I)

80 g (0,319 mol) of 6-bromo-2-naphthoic acid, or 95.7 g (0,335 mol, of 1.05 equiv.) 3-substituted-4-methoxyphenylacetic acid, 0.8 g of 5% palladium on coal (50% VL., type Degussa E105CA/W) and 800 ml of tetrahydrofuran (10 volumes) is placed in a 4-liter reactor. The medium is heated to 55°C. and 85 g (1.05 mol, 3.3 EQ.) potassium hydroxide (85% dissolved in 240 ml of water (3 volumes).

The resulting solution was poured to the reaction medium. The addition is exothermic. The temperature of the reaction medium reaches a temperature phlegmy. Boiling under reflux is maintained for approximately 2 hours.

The reaction medium is filtered at approximately 35-40°C through the cartridge and washed with 400 ml of a mixture of tetrahydrofuran/water (1/1).

The medium is cooled to 20°C and add 100 ml of HCl 35% in 600 ml of water. Precipitated 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid. Sediment Phil is trout and washed with 4 liters of water. The level of pH of about 6-7. The product is dried in vacuum at 100°C for 24 hours.

Forms 131 g of 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid (crude yield = 99%).

This crude product is dissolved in 15-22 volumes of tetrahydrofuran at boiling under reflux. After filtration while hot add from 15 to 22 volumes of heptane and the medium is cooled to approximately 5°C over a period of time from 1 to 2 hours.

6-[3-(1-Substituted)-4-methoxyphenyl]-2-naphthoic acid is filtered through a sintered glass filter and washed with 1 or 2 volumes of heptane.

Obtain 108 g of 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid as a white solid, purity of which was determined using liquid chromatography, amounted to 99.9% (yield = 82%, TPL = 320 - 322°C).

Example 3

Obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid (I)

20 ml (12 volumes) tetrahydrofuran, 2 g (7 mmol) of 3-substituted-4-methoxyphenylacetic acid (II), 1.65 g (6.6 mmol) of 6-bromo-2-naphthoic acid (III) and 20 ml of 2 M aqueous solution of potassium carbonate are placed in a round bottom flask equipped with a stirrer, in a stream of nitrogen. Then add 0.7 g (5%) 10% palladium on coal (50% VL., type Heraeus-0218).

The medium is heated under reflux for 8 hours. The catalyst was filtered through the cartridge and ZAT is slowly poured 30 ml of 1 N. an aqueous solution of hydrochloric acid.

The medium is stirred for 1 hour. The precipitate is filtered, washed with water and then dried under reduced pressure. Get to 2.06 g of 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid as a white solid, purity of which was determined using liquid chromatography, amounted to 99.9% (yield = 79%, TPL = 321°C).

1. The way to obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid of the formula (I):

through the Suzuki reaction between 3-substituted-4-methoxyphenylacetic acid of formula (II):

and 6-bromo-2-naphthoic acid of the formula (III):
,
moreover, the interaction between the compounds (II) and (III) is conducted at a temperature in the range from 60 to 110°C., for from 30 min to 24 h in an atmosphere of inert gas, in the presence of a palladium catalyst and a base, in a polar solvent followed by treatment with acid.

2. The method according to claim 1, characterized in that the catalyst is selected from palladium (II)acetate, palladium on charcoal, dichloro[1,1'-bis(diphenylphosphino)ferrocen]palladium(II)and palladium complexes containing phosphine ligand.

3. The method according to claim 2, characterized in that the phosphine ligand is selected from 2-(dicyclohexylphosphino)biphenyl, triphenylphosphine, tri-o-tolylphosphino, three-m-is oligospora or three-p-tolylphosphino.

4. The method according to claim 2, characterized in that the catalyst is a palladium(II) acetate or palladium on charcoal.

5. The method according to claim 4, characterized in that the catalyst is a palladium(II) acetate in the presence of ligand 2-(dicyclohexylphosphino)biphenyl.

6. The method according to claim 2 to 5, characterized in that the base is an inorganic base selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, or a tertiary amine selected from triethylamine and diisopropylethylamine.

7. The method according to claim 6, characterized in that the amount used of the solvent is equal 7-13 volume 6-bromo-2-naphthoic acid (III), and the volume of water used is equal 7-13 volume of used 6-bromo-2-naphthoic acid (III).

8. The method according to claim 6, wherein the polar solvent is selected from acetonitrile, N,N-dimethylformamide, dimethoxyethane, tetrahydrofuran, n-propanol, isopropanol or mixtures of these solvents with water.

9. The method according to claim 6, characterized in that the acid treatment is performed with hydrochloric acid.

10. The method according to claim 8, characterized in that the acid treatment is performed with hydrochloric acid.

11. The method according to claim 8, characterized in that the amount used of the solvent is equal 7-13 volume 6-bromo-2-naphthoic acid (III), and the volume of water used is equal 7-13 volume using the Anna 6-bromo-2-naphthoic acid (III).

12. The use of 3-substituted-4-methoxyphenylacetic acid of formula (II)

to obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid of the formula (I):

according to claim 1.

13. The use of 6-bromo-2-naphthoic acid of the formula (III):

to obtain 6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid of the formula (I):

according to claim 1.



 

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9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), including its pharmaceutically acceptable salts, solvates, ethers and amides, possessing ability to bind ERα- and ERβ-estrogen receptors, to pharmaceutical composition based on them, to versions of applying claimed compounds in medication preparation and to method of binding ERα- and ERβ-estrogen receptors. (I), where R1 represents H, OH or C1-12alkoxy, or halogen; R2 represents H, OH or halogen; R3 represents C1-12alkyl, halogeno-C1-12alkyl, C3-10cycloalkyl, C1-12alkoxy or C1-12alkoxyC1-12alkyl; R4 represents H or C1-12alkoxy; R5 represents H, halogen or halogeno-C1-12alkyl; R6 represents -(Y)z-R7; R8 represents phenyl or 5- or 6-member heteroaryl, containing N, O or S as heteroatom, where said phenyl and heteroaryl are possibly substituted with OH, halogeno, halogenoC1-12alkyl or C1-12alkoxy. Values R7, Y and z are presented in invention formula.

EFFECT: novel compounds possess useful biological properties.

19 cl, 7 dwg, 1 tbl, 70 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: organic chemistry, pharmacy, pharmacy.

SUBSTANCE: invention relates to novel compounds designated for delivery of active substances to tissues of the following formula: wherein values of radicals R1-R7 are determined in claim 1 of the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to compositions designated for delivery of active substances to tissues and containing: (A) active substance and (B) at least one compound designated for delivery of active substance to animal tissues of the formula: wherein values of radicals R1-R7 are determined in claims 3-5 of the invention claim. Also, proposed invention relates to a standard medicinal formulation designated for delivery of active substances to body tissues and to a method for preparing indicated compositions and administration of substances for their delivery to body tissues.

EFFECT: valuable properties of compounds.

23 cl, 11 tbl, 11 ex

The invention relates to compounds of the formula

< / BR>
in which R1and R2each independently represents CNS group containing 1 to 4 carbon atoms, R3- H or acylcarnitine group containing 2 to 5 carbon atoms, R4- CNS group containing 1 to 4 carbon atoms, in free form and also, if such exist, in the form of salt

The invention relates to organic chemistry, in particular to a method for producing an aromatic dicarboxylic acid, 2,6-naphthaleneboronic acid, 4,4-diphenylcarbinol, 4,4-diphenylcarbinol acid, 4,4-diphenylmethanediisocyanate acid, which is used in the production of liquid-crystalline thermoplastics

FIELD: chemistry.

SUBSTANCE: present invention relates to a reesterification catalyst and its preparation method. The invention describes a reesterification catalyst of general formula: Zn3M2(CN)n(ROH)·xZnCl2·yH2O, where R is tertiary butyl and M is a transition metal ion selected from Fe, Co and Cr; x lies between 0 and 0.5, y lies between 3 and 5 and n equals 10 or 12. Described is a method of preparing the catalyst, involving the following steps: a) dissolving ZnCb in a mixture of water and tertiary butanol, b) adding the said solution obtained from step a) to an aqueous solution of K4Fe(CN)6 while stirring, c) adding a ternary block copolymer of poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (EO20-PO70-EO20; molecular weight of approximately 5800), dissolved in a mixture of tert-butanol and water, to the above mentioned mixture obtained at step (b) while stirring and at temperature 25°C-70°C, d) filtering the reaction mixture obtained at step (c) to obtain a solid product ad then washing with distilled water and drying at temperature 20-50°C and e) activating the said dried solid product at temperature 150-200°C to obtain the desired reesterification catalyst.

EFFECT: ensuring high catalyst activity even in moderate conditions during reesterification of glycerides, esters of fatty acids and cyclic carbonates during reaction with alcohols; leaching of metal ions from the solid catalyst is not observed.

12 cl, 2 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing lower alkyl ether of lower aliphatic alcohol having formula R1-COO-R2, involving reaction of a pre-dried lower alkyl ether having formula R1-O-R2, in which R1 and R2 independently denote C1-C6alkyl groups, provided that the total number of carbon atoms in groups R1 and R2 ranges from 2 to 12, or R1 and R2 together form a C2-C6 alkenyl group, with material which contains carbon monoxide, in the presence of a catalyst which contains mordenite and/or ferrierites in anhydrous conditions. The invention also relates to a method of producing carboxylic acids through hydrolysis of esters obtained using the method given above.

EFFECT: high output and selectivity of end product.

29 cl, 3 tbl, 9 dwg

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