The way to obtain 2,2-dimethyl-5-(2,5-dimethylphenoxy)- pentanol acid

 

(57) Abstract:

The inventive product - 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanol acid BF SNO. Tpl57 - 58oC. The Yield Was 70%. Reagent 1: halogenated ester of formula X

< / BR>
in which X is halogen, and Z is a straight or branched chain WITH1-8-alkalinous group, substituted with one or two 2,2-dimethyl-5-halogenocarboxylic, in which the halogen represented by chlorine or bromine, ethylene group, one or two methylene groups can be replaced by heteroatom(s) or diatomic heterocyclic group. Reagent 2: salt (alkali metal) of 2,5-dimethylphenol formula

< / BR>
or aired last formed with the lower alanovoy acid, and hydrolysis of the resulting arylacetamides ether of General formula

1 C. p. F.-ly, 1 table.

The invention relates to a new process for the preparation of 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanol acid of the formula (I)

O COOH

(I) This connection is used for regulating the level of blood lipids.

A method of obtaining this compound on the basis of isobutyl ether somaclonal acid. However, this method is quite complex and not Mae is inane formula (I) with high yield and quality, suitable for direct drug application.

Provides a way to obtain 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentane-howl acid of the formula I, which includes the interaction of halogenated polyhydric ether of the formula (III)

X COOZOOC X where X is represented by the halogen is chlorine, bromine or iodine, and Z is a straight or branched chain WITH1-8-alkalinous group, possibly substituted by one or two 2,2-dimethyl-(5-halogenaryloxy group(s) in which the halogen represented by chlorine or bromine. In alkalinous group one or two methylene groups can be replaced by any heteroatom(s), mainly oxygen and/or nitrogen, and the latter can be substituted by phenyl or C1-4the alkyl, possibly substituted 2,2-dimethyl-5-halogenaryloxy group, or diatomic heterocyclic group such as piperazine-1,4-diyl group, with salt (alkali metal) of 2,5-dimethylphenol formula (II) H is possible in the presence of alkali metal iodide as catalyst and hydrolysis of the resulting arylacetamides ether of General formula (IV)

O COOZOOC O

where Z presents a straight or branched chain1-8-alkalinous group, possibly substituted by one or which may be substituted or heteroatom(s), mainly oxygen and/or nitrogen, and the latter can be substituted by phenyl or C1-4-alkyl, possibly substituted 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanoate-group or two-atom heterocyclic group, such as a piperazine-1,4-diyl, without isolation directly in the reaction mixture in which it was received.

According to another aspect of the invention provides a method of obtaining 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanol acid of the formula (I), which comprises the interaction of a polyhydric ether of General formula (III), where X is represented by a halogen (chlorine, bromine or iodine), and Z presents a straight or branched chain1-8alkalinous group, possibly substituted by one or two 2,2-dimethyl-5-halogenaryloxy group(s), where the halogen is chlorine or bromine, and in alkalinous group one or two methylene groups can be replaced by heteroatom(s) mainly by oxygen and/or nitrogen, and the latter may be substituted by phenyl or C1-4-alkyl, substituted 2,2-dimethyl-5-halogenaryloxy group, 2,5-dimethyl-phenyl ester,

OCOR where R is C1-5-alkyl, in a polar, aprotic solvent, in the presence of alkali metal iodide as catalyst, site, where Z presents a straight or branched chain1-8-alkalinous group, possibly substituted by one or two 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanoate group(s). In alkalinous group one or two methylene groups may be replaced by heteroatoms, mainly oxygen and/or nitrogen, and the latter can be substituted by 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanoate group, without isolation, directly in the reaction mixture in which it was received.

In accordance with the above mentioned advantages of the invention polyhydric ether of General formula (III) reacts with potassium or sodium salt of 2,5-dimethylphenol. Salt can be obtained either in a separate operation or in situ. If you get it separately, it can be obtained, for example, by addition of suitable compounds of potassium or sodium, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, etc. ) to a solution of 2,5-dimethylphenol in a suitable solvent (e.g. methanol, ethanol, propanol, butanol, tetrahydrofuran, acetonitrile and similar). The mixture was then stirred until dissolved and the solvent is distilled off. Thus obtained salt can be C the sodium or potassium compound, described above. As solvents can be applied to polar solvents (such as dimethylformamide or dimethylacetamide) or alcohols (such as ethanol, n-propanol or n-butanol). If the salt is obtained using sodium hydroxide formed during neutralization, the water can be removed from the reaction mixture a suitable method, but you can use salt at a later stage, and without removing the water. If required, water can be removed, for example, by azeotropic distillation. In this case, the formation of a lead salt in a solvent suitable for the specified distillation, such as benzene, toluene, xylene, chlorobenzene and the like.

For the further reaction of the obtained salt of phenol (at least part of it) it is advisable to dissolve. With this objective, the above solvents may be added in a strong polar auxiliary solvent (such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, hexamethylphosphoric triamide, N-methyl-pyrrolidone, and others) in an amount of about 5-30. with another solvent. Salt of a phenol of the formula (II) can interact with the compound of General formula (III), mainly in the presence of alkali metal iodide (e.g. sodium iodide or potassium) as kata is alseny polyhydric ether can be isolated by known methods, for example, solvent extraction, clarification and/or chromatography, and then in a separate operation, is subjected to hydrolysis, but is preferable to conduct directly hydrolysis and isolation of only the resulting end product of the formula (I). The hydrolysis may be performed either in an acidic or alkaline reaction medium, preferably using alkali metal hydroxide such as sodium hydroxide. The final product can be isolated and purified convenient methods (for example, solvent extraction, clarification and crystallization).

Known for the selection of the final product, including the acidification of alkaline solution followed by filtration, leads to more contaminated product, than in the proposed method, when the acidification is carried out in the presence of a suitable organic solvent and the obtained product is transferred into the organic phase, followed by purification by lightening. For clarification of use, for example, activated carbon, silica gel, alumina, and other similar substances. After concentrating the clarified solution obtained crude product can be purified by simple recrystallization. Recrystallization can be p is onitrile, ethyl acetate, n-hexane, methanol, ethanol, isopropanol, 2-methoxyethanol, 2-ethoxyethanol and others). In the case of mixing with the water solvent can be applied to their water mixture.

P R I m e R 1. To the mixture 6,92 g (0,048 mol) of 2,5-dimethylphthalate sodium, 50 ml of dimethylformamide and 0.75 g (0,005 mol) of sodium iodide in 100aboutWith added 9.0 g (0,0253 mol) of pure 1,2-bis-(2,2-dimethyl-5-herpetologic)-ethane. The mixture was stirred at 115-120aboutC for 2 hours Then the mixture is cooled to 100aboutWith add 4.0 g (0.1 mol) of sodium hydroxide and 2 ml of water, stirred for 2 hours at a temperature of 115-120aboutC. Further, when 100aboutWith added 4.0 g (0.1 mol) of sodium hydroxide, continuing the stirring at a temperature of 115-120aboutWith another 2 h, the Reaction mixture was cooled to room temperature, poured 150 ml of water and washed twice with toluene (30 ml each time). The aqueous phase is acidified with 20% hydrochloric acid to pH 1 in the presence of 50 ml of hexane (cooling ice bath). The aqueous phase is separated and the extraction is carried out with toluene (twice 30 ml). The hexane phases are combined, washed three times with 30 ml of water and distilled under reduced pressure the solvent. The result of 9.9 g of the desired compound in the form of almost colorless TV and water. In this case, the gain of 8.4 g of the above compound in the form of colorless crystals. Output 70,0% Tpl.57-58aboutC. the Purity of the thus obtained product meets the requirements specified in the Pharmacopoeia.

Sodium salt of 2,5-dimethylphenol used in this synthesis can be obtained, for example, by the following methods.

M e t o d A. To a solution of 12.2 g (0.1 mol) of 2,5-dimethylphenol in 100 ml of ethanol is added at room temperature 4.1 g (0.1 mol) of solid sodium hydroxide (purity 98%). The reaction mixture is stirred until complete dissolution of alkali. Under reduced pressure the solvent is distilled off, the residue is dried in a desiccator to constant weight. Get to 14.4 g of the desired product as a solid gray matter. Output 100% Tpl.> 250aboutC.

M e t o d b To 100 ml of tetrahydrofuran at room temperature was added 0.9 g (0.03 mol) of 80% sodium hydride, and then with stirring 3,66 g (0.03 mol) of 2,5-dimethylphenol. The mixture is stirred for 30 min at room temperature, and then heated for further 30 minutes under reflux. The solvent is distilled off under reduced pressure, the solid residue is washed with benzene and dried under reduced pressure. Get as a result of 3.64 g trichodea substances 1,2-bis-(2,2-dimethyl-5-herpetologic)-ethane.

In this case, the product yield (net) 67,1%

P R I m e R 3. Carry out the operations described in example 1, using instead of 1,2-bis-(2,2-dimethyl-5-herpetologic-this - 12.0 g (0,025 mol) of crude 1,3 - bis-(2,2-dimethyl-5-herpetologic)-propane. Total crude yield for two reaction stages, designed for 1,3-bis-(2-methylpropyloxy)-propane, equal to 55.2% After recrystallization from a mixture (7:3) of ethanol and water get the desired product in pure form with the release of 41,4%

P R I m e R 4. Stage a): 1,3-bis-(2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanoyl-oxy)-propane. To a mixture of 2.9 g (0.02 mol) of 2,5-dimethylphthalate sodium, 50 ml of dimethylformamide and 0.3 g (0.002 mol) of sodium iodide in 100aboutWith and with stirring was added 5.0 g (0,0104 mol) of crude 1,3-bis-(2,2-dimethyl-5-herpetologic)-propane. The mixture is stirred at a temperature of 115-120aboutC for 2 h, cooled, poured 150 ml of water and extracted three times with 30 ml of toluene. Toluene phase is extracted three times with 10 ml ice-cold 1 n sodium hydroxide solution, washed with water until neutral environment, dried over sodium sulfate and the solvent is distilled off under reduced pressure. Get 4,74 g of the desired product diapir in the form of a dark yellow oil. The yield, calculated on the source link is the quality of the solvent mixture (80:20) of hexane and diethyl ether. The result 2,63 g of analytically pure desired compound. According to the analysis by thin-layer chromatography performed with a specified mixture of solvents, Rf0,5. The output is the 36,0%

Stage b): 2,2-Dimethyl-5-(2,5-dimethylphenoxy)-pentane acid. 10.8 g (0.02 mol) of pure diapir, obtained according to stage and add to the mixture of 200 ml of ethanol and 50 ml of 2n. an aqueous solution of sodium hydroxide. The reaction mixture is heated under reflux for 3 hours the Mixture is cooled, evaporated under reduced pressure, the solvent (ethanol), the residue is mixed with 200 ml of water and washed twice with 50 ml diethyl ether. The ether phase is dried over sodium sulfate and the solvent is distilled off, receiving 0.5 g of unreacted educt. From the aqueous phase under reduced pressure to remove the organic solvent and the aqueous solution is acidified to pH 1 20% hydrochloric acid. The precipitated substance is filtered, washed with water and dried at room temperature, receiving 7.9 g of product with a melting point of 56-57aboutC. Exit 82%

P R I m e R 5. To the mixture 4,89 g (0.04 mol) of 2,5-dimethylphenol and 100 ml of dimethylformamide with stirring 1.26 g (0,042 mol) of 80% sodium hydrate. The mixture was stirred at 50-60aboutTo terminated the sodium and 9.6 g (0.02 mol) of crude 1,3-bis-(2,2-dimethyl-5-herpetologic)- propane. The mixture was stirred at 115-120aboutC for 2 h, cooled to 100aboutTo give 3.2 g (0.08 mol) of sodium hydroxide and 2 ml of water, then continue to mix at 115-120aboutWith another 2 hours and Then at 100aboutWith added 3.2 g (0.08 mol) of sodium hydroxide and again continue stirring at 115-120aboutWith another 2 h, the Reaction mixture was treated as described in example 1. Gain of 5.3 g of the desired product. The yield, calculated on 1,3-bis(2-methylpropanoate)-propane and 40.8%

P R I m e R 6. To a mixture of 4.4 g (being 0.036 mol) of 2,5-dimethylphenol, 50 ml of n-butanol and 1.6 g (0.04 mol) of sodium hydroxide in 100aboutWith successively added 0.54 g (0,0036 mol) of sodium iodide and 8.7 g (0.018 mol) of crude 1,3-bis-(2,2-dimethyl-5-herpetologic)-propane. The reaction mixture is stirred for 2 h under reflux, cooled to 90aboutWith and add 2,88 g (0,072 mol) of sodium hydroxide. Stirring is continued (at reflux) for another 2 h, and then at reduced pressure the solvent is distilled off. The residue is dissolved in 100 ml of water and extracted twice with 200 ml of toluene each time). The aqueous phase in the presence of 50 ml of hexane under cooling with ice bath, acidified with 20% hydrochloric acid to pH 1. The aqueous phase is separated and diatom sodium, lighten with 0.5 g of silica gel and under reduced pressure, the solvent is distilled off. The result of 4.9 g of crude product as a solid with the yield of 41.6% calculated on 1,3-bis-(2,2-dimethyl-5-herpetologic)-propane. After recrystallization from acetonitrile gain of 3.05 g of the desired substance in pure form with the release of 25.9%

P R I m e R 7. The mixture 9,41 g (0,077 mol) of 2,5-dimethylphenol, 3.3 grams (0,0825 mol) of sodium hydroxide, 100 ml of toluene and 10 ml of dimethyl sulfoxide is stirred at reflux for 2 hours For permanent removal of formed water using appliance Dean-stark. Then add to 1.16 g (0,0077 mol) of sodium iodide and 18.5 g (0,0385 mol) of crude 1,3-bis-(2,2-dimethyl-5-herpetologic)-propane. The reaction mixture was stirred at reflux for 2 hours, cooled to 100aboutWith and added 5.8 g (0,145 mol) of sodium hydroxide. Continue mixing while heating under reflux for another 2 h, then the mixture is cooled, add 100 ml of water, separating the aqueous phase and washed twice with 30 ml of toluene. The mixture in the presence of 100 ml of hexane (cooling ice bath) and acidified to pH 1 with 40 ml of 20% hydrochloric acid. The aqueous phase is separated, the extraction is carried out twice GE is the atrium. The dried solution lighten under stirring with 1 g of silica gel for 30 min, and then at reduced pressure the solvent is distilled off. The result of 15.8 g of crude product as a nearly colorless solid. The yield, calculated on 1,3-bis-(2-methyl-propenyloxy)-propane, 63,0% After recrystallization from 32 ml of a mixture (7:3) of methanol and water gain of 13.1 g of the desired product in pure form. Tpl.56-58aboutC.

P R I m e R 8. Carry out the operations described in example 7, using as the starting material 1,3-bis-(2,2-dimethyl-5-herpetologic)-propane.

P R I m e R 9. Conduct operations according to the description of example 7, using as the starting material 1,3-bis- (2,2-dimethyl-5-herpetologic)-propane. After recrystallization get the desired product with a yield of 64.6 per cent calculated on 1,3-bis-(2,2-dimethyl-5-chlorphen - tanooki)-propane.

P R I m e R 10. Conduct operations according to the description of example 7, using as the starting material of 19.5 g (0.019 mol) of crude 1,3-bis-(2,2-dimethyl-5-herpetologic)-propane.

The result is the desired connection with the release of 32.8 per cent

P R I m e R 11. Carry out the operations described in example 7, using as the source misestimate get the desired product in the form of colorless crystals with access 37,0% in two reaction stages, designed for 1,3-bis-(2,2 - dimethyl-4-pentenoate)-propane. After recrystallization from a mixture (7:3) of ethanol and water get the desired product with a yield of 20.4%

P R I m e R 12. Carry out the operations described in example 7, using crude 1,2-bis-(2,2-dimethyl-5-bromopentanoate)- ethane instead of 1,3-bis-(2,2-dimethyl-5-herpetologic)-propane as the original substances. The result is the desired compound in the form of colorless crystals with a yield of 30%

P R I m e R s 13-24. Carry out the operations described in example 7, instead of using 1,3-bis-(2,2-dimethyl-5-herpetologic)- propane compounds of the formula (III) in which Z has the values shown in the table.

1. The WAY to OBTAIN 2,2-DIMETHYL-5-(2,5-DIMETHYLPHENOXY)-PENTANOL ACID formula 1

< / BR>
by reacting halogenated ester with an alkaline salt of 2,5-dimethylphenol formula II

< / BR>
in the presence of catalyst of alkali metal iodide in the environment of the solvent, characterized in that, to increase the yield of the target product as a halogenated ether used ether of the General formula III

< / BR>
where X is halogen; Z is a linear or branched Allenova group1- C8in which one or two methylene groups may be the which in turn, can be substituted diatomic heterocyclic group such as piperazine-1,4-diyl group and the solvent used or aliphatic alcohol such as n-butanol or an aromatic hydrocarbon such as toluene, or an aprotic polar solvent such as dimethylformamide, or dimethyl-sulfoxide or a mixture thereof, followed by hydrolysis of the resulting ester directly in the reaction mixture, where it was obtained, or allocate the obtained ether structural formula IV

< / BR>
where Z is a linear or branched Allenova group1- C8in which one or two methylene groups can be replaced by oxygen and/or nitrogen, and the latter may be substituted by phenyl or C1- C4-alkyl, which, in turn, can be substituted diatomic heterocyclic group such as piperazine-1,4-zielgruppe,

and then perform the hydrolysis.

2. The way to obtain 2,2-dimethyl-5-(2,5-dimethylphenoxy) - pentanol acid of the formula I

< / BR>
by reacting halogenated ether derivative of 2,5-dimethylphenol in the presence of iodide of an alkali metal as a catalyst in the environment of the solvent, characterized in that, with t the

where X is halogen;

Z is a linear or branched Allenova group1- C8in which one or two methylene groups can be replaced by heteroatoms, such as oxygen and/or nitrogen, and the latter may be substituted by phenyl or C1- C4-alkyl,

as a derivative of 2,5-dimethylphenol use its alkaline salt or its ester with a lower alanovoy acid, as solvent - dimethylsulfoxid and the process is carried out in the case of the use of ether in the presence of a strong base is potassium hydroxide or tert-butoxide potassium, followed by hydrolysis of the resulting ester directly in the reaction mixture, where he was received or allocate the obtained ether structural formula IV

< / BR>
where Z is a linear or branched alkylenes group1- C8in which one or two methylene groups can be replaced by heteroatoms, such as oxygen and/or nitrogen, and the latter may be substituted by phenyl or C1- C4-alkyl,

and then conducting hydrolysis.

 

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