The method of obtaining of ester 2-alkylidene-4 - bromocatechol acid

 

(57) Abstract:

The invention relates to an improved process for the preparation of ester 2-alkylidene-4-bromocatechol acid of the formula (3), where R1and R2each independently from each other represent a lower alkyl group with 1-5 carbon atoms, which is used as an intermediate connection upon receipt of the substances for pharmaceutical purposes, such as antibiotics. The method involves the interaction of ester 4-bromocatechol acid of formula (1), where R1has the specified values, with the aldehyde of formula (2): R2CHO, where R2has the above significance, in an inert organic solvent in the presence of a secondary amine and carboxylic acid. The method allows to obtain the target product in one stage, with significantly greater clarity to 96.4% and with a good yield up to 92%. 4 C. p. F.-ly.

The scope of the invention

The present invention relates to a process for the preparation of ester 2-alkylidene-4-bromocatechol acid, which can be used as an intermediate connection upon receipt of the substances for pharmaceutical purposes, specifically as an intermediate connection p is otstoyam him Russian patent 2071963 C1.

Art

In the Japan patent 2618119 and Russian patent 2071963 C1 describes a method for complex ester 2-alkylidene-4-bromocatechol acid, whereby methyl ether 2-propylidene-4-chloroacetoacetic acid is subjected to the exchange reaction of halogen with the bromide of sodium, and specified methyl ether 2-propylidene-4-chloroacetoacetic acid is produced by or methyl ester 4-chloroacetoacetic acid and propionic aldehyde using as catalysts of acetic acid and piperidine.

This method, however, is not quite satisfactory, because it is based on exchange reactions of Halogens, the degree of conversion which is unsatisfactory, and the use of methyl-4-chloroacetoacetate, the cost of which is high.

Therefore, desirable new ways of obtaining this compound.

The essence of the invention.

The object of the invention is a method comprising obtaining the target compound - complex ester 2-alkylidene-4-bromocatechol acid using as a starting compound of ester 4-bromocatechol acid, which can be easily obtained from the complex ether acetoxy the
the method of obtaining of ester 2-alkylidene-4-bromocatechol acid of the formula (3)

< / BR>
where R1and R2each independently of one another represent lower alkyl with 1-5 carbon atoms, including interaction of ester 4-bromocatechol acid of formula (1):

< / BR>
where R1have the above significance, with an aldehyde of formula (2)

R2CHO (2)

where R2have the above meanings, in an inert organic solvent in the presence of amine and carboxylic acid.

Description of the preferred embodiments of the invention

Ester 4-bromocatechol acid of the formula (I) used in this invention can be easily obtained by the reaction of acetoacetic ester of the acid of formula (4):

< / BR>
where R1have the above meanings, with bromine in the presence of an organic solvent according to the method described in J.Org. Chem., 12, 342 (1947), Helvetica Chemica Acta, 66, 1475 (1983), or similar.

Although ester 4-bromocatechol acid, obtained as described above, can be used as starting material in this invention after purification by distillation or other similar means, koncentrira the et be used without purification.

Examples of the lower alkyl groups with 1-5 carbon atoms for R1in a complex ester of 4-bromocatechol acid of formula (1) are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n-pentyl.

Specific examples of ester 4-bromocatechol acid of formula (1) are methyl-4-bromoacetate, ethyl-4-bromoacetate, n-propyl-4-bromoacetate, isopropyl-4-bromoacetate, n-butyl-4-bromoacetate, tert-butyl-4-bromoacetate, n-pentyl-4-bromoacetate etc.

Examples of the lower alkyl groups with 1-5 carbon atoms for R2the aldehyde of formula (2) in this invention are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and n-pentyl.

Specific examples of the aldehyde of formula (2) are acetaldehyde, propionic aldehyde, butyric aldehyde, somerley aldehyde, valeric aldehyde, trimethylacetaldehyde, hexanal etc.

The amount of the aldehyde of formula (2), which should be used is generally 1 to 10 mol, preferably 1.2 to 5 mol per mol of ester 4-bromocatechol acid of formula (1).

The reaction according to the invention is carried out in the presence of amine and carboxylic acid, taken as UB>-C20-bonds alkylamines (for example, methylamine, ethylamine and n-Propylamine),

secondary amines, such as di(C1-C20-alkylamino in which alkali may be the same or different and may contain a heteroatom, such as oxygen or nitrogen (e.g., dimethylamine, diethylamine, piperidine and morpholine),

- tertiary amines, for example three(C1-C20)alkylamino in which alkali may be the same or different (e.g., triethylamine), and (C5-C9aromatic tertiary amine (e.g. pyridine), or a mixture thereof. It is preferable to use secondary amines.

Specific examples of carboxylic acids include (C2-C6)alcamovia acid, for example acetic, propionic, butyric, valeric and Caproic acid, and mixtures thereof.

The amount of amine, which should be used is usually from 0.001 to 1 mol, preferably 0.01 to 0.5 mol per mole of ester 4-bromocatechol acid of formula (1).

The number of carboxylic acid, which should be used is usually from 0.1 to 10 mol, preferably 0.5 to 5 mol per mol of amine.

The reaction is usually carried out in an inert organic solvent. Such inert organicheskimi examples include aromatic hydrocarbons, for example, toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and heptane, halogen-containing hydrocarbons, such as dichloromethane, dichloroethane, chloroform, 1-chlorobutane and chlorobenzene, ethers, such as diethyl ether, tert-butyl methyl ether and tetrahydrofuran, ketones such as methyl ethyl ketone and methyl isobutyl ketone, etc.

These organic solvents may be used alone or as a mixture of two or more of them. The amount of inert organic solvent, which should be used is not particularly limited and is usually from 0.5 to 100 parts, preferably 1-30 weight. parts per 1 weight. part of ester 4-bromocatechol acid of formula (1).

The reaction temperature is usually from -80 to 30oWith the preferred range from -50 to 0oC.

Download method of starting compounds and catalysts for the reaction are important from the point of view of monitoring for adverse reactions, such as samarangense molecules of the aldehyde of formula (2), etc., and achieving high output.

The reaction is usually carried out by adding the amine to a solution of ester 4-bromocatechol acid of formula (1), the aldehyde of formula (2) and is arranged as follows, successfully (from the point of view of production) facilitates temperature control of the reaction, which proceeds as exothermic;

the reaction can be performed simultaneously by adding an ester of 4-bromocatechol acid of General formula (1), the aldehyde of formula (2) and the amine to a solution of carboxylic acid as a catalyst in an inert organic solvent; or

the reaction is carried out by simultaneous addition of ester 4-bromocatechol acid of formula (1), the aldehyde of formula (2), amine and carboxylic acid to an inert organic solvent.

Upon completion of the reaction, the reaction mixture is, for example, washed with water, etc. and the solvent evaporated to obtain the target of ester 2-alkylidene-4-bromocatechol acid of the formula (3). A solution of ester 2-alkylidene-4-bromocatechol acid of the formula (3) after washing, it is preferable to use, as it is.

According to the method of the present invention an ester of 2-alkylidene-4-bromocatechol acid, which can be used as an intermediate substance in obtaining substances for pharmaceutical purposes, etc. can be obtained with a good yield and a rather profitable obrazuyut the invention, however, it may not be limited to these examples.

Example 1 methyl ester 4-bromocatechol acid

In 679 g of dichloromethane was dissolved 116 g of methyl ester of acetoacetic acid, and cooled to -5oC. To this mixture was added dropwise 160 g of bromine at 0 to 5oWith in an hour. The mixture was stirred at this temperature for another one hour, then heated to 20oC and kept at this temperature for another 2 hours. After purging air from the reaction mixture for one hour evaporation of the mixture under vacuum gave 212 g of oil residue. Distillation of this oil residue under reduced pressure gave to 54.5 g of methyl ester 4-bromocatechol acid with a purity of 95.6% of.

Example 2 methyl ether 4-bromocatechol acid

In 2613 g 1-chlorobutane was dissolved 523 g of methyl ester of acetoacetic acid and cooled to 0oC. To this mixture was added dropwise 719 g of bromine at 55oC for one hour and the mixture was left at this temperature for 4 hours. The reaction mixture was washed 1161 g of a 10% salt solution.

After separating a mixture of aqueous and organic layers by the process of evaporation of organic layer under vacuum at a temperature of 40oC or lower was received 782,9 is the actual content of the methyl ester 4-bromocatechol acid in the crude product was 72% (564 g, yield 64%).

Example 1.

34 g of dichloromethane was dissolved 5.0 g (net weight 4,78 d) methyl ester of 4-bromocatechol acid, obtained in example a 1, of 2.23 g of propionic aldehyde and 0.15 g of acetic acid and cooled to -30oC. To the mixture was added dropwise a mixed solution of 0.26 g of piperidine and 1.18 g of dichloromethane at -272oC for 30 minutes.

After keeping at this temperature for 3.5 hours to the reaction mixture were added 15 g of a 0.7% aqueous solution of Hcl and heated it to 3oC. the Mixture was separated into aqueous and organic layers.

The organic layer is washed with 15 g of 1% aqueous solution of sodium bicarbonate and 15 g of water in a specified sequence at 0-5oWith and evaporated in vacuum at a temperature of 15oOr lower with getting to 8.57 g of concentrated solution of methyl ester 2-propylidene-4-bromocatechol acid.

High-performance liquid chromatography showed that the concentrated solution contained 5.31g methyl ester 2-propylidene-4-bromocatechol acid (yield 92%, the ratio of E/Z=49/51).

Example 2.

A mixed solution containing 39.9 g of isobutyl ketone and 2,61 g of acetic acid, cooled to -27oC for 6 hours. At the end of the addition the mixture was stirred at this temperature for 2 hours and then to the mixture was added 68,85 g of a 1.4% aqueous solution of model HC1 and 85,13 g of isobutyl ketone. The resulting mixture was heated to 3oWith and separated into aqueous and organic layer. Analysis of the organic layer using HPLC showed that this layer contained 29,56 g of methyl ester of 2-propylidene-4-bromocatechol acid (yield 89.4 per cent, the ratio E/Z=54/56).

Example 3.

First and 39.9 g of the mixture was cooled to -27oWith and to them was added dropwise at the same time of 38.1 g (net weight 27,43 g) of the crude methyl ester 4-bromocatechol acid obtained in example getting 2, 25,44 g of propionic aldehyde, a solution obtained by dissolution of 2.30 g of piperidine in 2,63 g of isobutyl ketone, and 2,61 g of acetic acid at -272oC for 6 hours. At the end of the addition the mixture was stirred at this temperature for 2 hours, then to the mixture was added 68,85 g of a 1.4% aqueous solution of model HC1 and 85,13 g of isobutyl ketone. The temperature of the vet layer using HPLC showed this layer contained 29,56 g of methyl ester of 2-propylidene-4-bromocatechol acid (output 88,2%, the ratio E/Z=53/47).

Example 3 methyl ether 4-bromocatechol acid

22.7 kg methyl ester of acetoacetic acid was dissolved in 113,3 kg 1-chlorobutane and was cooled to 0oC. To this mixture was added dropwise to 31.4 kg of bromine in 5oC for 2 hours and then the mixture was stirred at this temperature for 8 hours. The reaction mixture was cooled to -10oC and added dropwise to 22.7 kg of water at a temperature of 10oC or lower within 2 hours, then washed and separated the organic layer. The obtained organic layers were evaporated under reduced pressure at 40oWith or following the receipt of 42.0 kg of the crude methyl ester 4-bromocatechol acid. Gas chromatographic analysis showed that the content of methyl ester 4-bromocatechol acid in the crude product amounted to 65.3% (27,4 kg, yield 72%), whereas the content of 1-chlorobutane was 19.7 percent.

Example 4.

38,0 kg of the crude methyl ester 4-bromocatechol acid obtained in example getting 3 and containing 24,8 kg specified connection, 16,5 kg propionic aldehyde and 1.22 kg of piperidine 2,55 kg of acetic acid, pre-cooled to -27oC, and the resulting solution was kept at this temperature for 3 hours. Then the reaction mixture was added to 36,1 kg 1,4% hydrochloric acid and was subjected to separation. 78,8 kg the resulting organic layer was analyzed by HPLC, which showed that the content of methyl ester 2-propylidene-4-bromocatechol acid was 25.9 kg (output 86,6%, the ratio E/Z=55/45).

Comparative example 1

In 16,98 g of isobutyl ketone was dissolved 12,04 g of methyl ester 4-chloroacetoacetic acid, 6,97 g of propionic aldehyde and, of 0.48 g of acetic acid and the mixture was cooled to -30oC. To the resulting solution was added dropwise a mixed solution of 0.41 g of piperidine and 0.54 g of isobutyl ketone at -272oC for 30 minutes. After keeping at this temperature for 3 hours to the resulting solution was added 48 g of 0.35% aqueous Hcl and heated to 3oS, after which the mixture was separated into aqueous and organic layers. The organic layer was washed 48 g of 1% aqueous solution of sodium bicarbonate and 48 g of water in a specified sequence at 0-5oWith and evaporated in vacuum at 15oC or lower to obtain 31,17 g of concentrated solution of methyl ester 2-about the PRS contained to 12.44 g of methyl ester of 2-propylidene-4-chloroacetoacetic acid (yield of 81.6%, the ratio E/Z=46/54).

In 10,23 g of N, N-dimethylformamide was dissolved of 11.45 g of concentrated solution (net weight methyl ester 2-propylidene-4-chloroacetoacetic acid of 4.57 g) and cooled to 10oC. To this mixture was added 6,17 g of sodium bromide, and then heated until the 22oC and vigorously stirred at 222oC for 2 hours. The resulting reaction solution was cooled to 5oC and washed with 20 g of water, after which the mixture was stratified on the water and organic layers. Analysis of the organic layer is carried out using HPLC showed that this layer consisted of 4.66 g of methyl ester of 2-propylidene-4-bromo-acetoacetic acid (yield of 82.6%, the ratio E/Z=52/48) and 9.7% of the remaining original methyl ester 2-propylidene-4-chloroacetoacetic acid.

Comparative example 2 - a method according to EN 2071963.

To a solution of complex methyl ester 4-chloroacetoacetic acid (72,28 g, 750,0 mmol), Propionaldehyde (43,56 g, 750,0 mmol) and acetic acid (3.00 g, 50.0 mmol) in dichloromethane (335 ml) add a solution of piperidine (2.55 g, 30.0 mmol) in dichloromethane (2.6 ml) and the mixture is stirred at a temperature of -27oC for 240 minutes, the Reaction mixture was washed with diluted hydrochloric acid and water and the end of the R-2-propylenecarbonate acid (crude yield 100,85, The crude product contained 81,69 g (428,5 mmol) of methyl ether 4-chloro-2-propylenecarbonate acid, which corresponds to the output net of 85.7%).

To a solution of complex methyl ether 4-chloro-2-propylenecarbonate acid (3,93 g, 20.3 mmol) in dimethylformamide (10,8 ml) add sodium bromide (6,17 g, 60,0 mmol) and the mixture is stirred at a temperature of 22oC for 2 h to obtain a complex solution of methyl ester 4-bromo-2-propylenecarbonate acid. The crude yield of the target product 21,13 g (in solution). In the latter contained of 3.78 g (16,1 mmol) of a compound methyl ester 4-bromo-2-propylenecarbonate acid. The net output is 78,0% (based on methyl ester 4-chloro-2-propylenecarbonate acid). 16,6% (0.64 g, 3.4 mmol) downloaded difficult methyl ether 4-chloro-2-propylenecarbonate acid remained unspent. The total yield of the target product from the original complex methyl ester 4-chloroacetoacetic acid is 66,8%.

Analysis of the reaction solution by means of liquid chromatography high resolution showed that the area of the chromatographic peak of the methyl ester of 4-bromo-2-propylenecarbonate acid was $ 78.2%, and sootvetstvujushij solvents.

The analysis was performed under the following conditions.

Column: SUMIPAX ODS A-212 ( 6 mg cm, 5 μm), produced by Sumika Analysis Service Company, Limited.

The temperature of column: 0oC.

Eluent: 0.1% of triperoxonane acid-water : acetonitrile=50:50.

Flow rate: 0.1 ml/min

Detection: UV, 220 nm.

Comparative example 3 - a method according to the present invention.

To a solution of complex methyl ester 4-bromocatechol acid (4,88 g 25,0 mmol), Propionaldehyde (2,18 g, 37.5 mmol) and acetic acid (0.15 g, 2.5 mmol) in dichloromethane (27,1 ml) add a solution of piperidine (of 0.13 g, 1.5 mmol) in dichloromethane (2.0 ml) and the mixture is stirred at a temperature of -27oWith over 300 minutes, the Reaction mixture was washed with diluted hydrochloric acid and water and concentrated under reduced pressure at a temperature below 15oWith obtain 5.35 g of the crude complex methyl ester 4-bromo-2-propylenecarbonate acid containing 3,79 g (16,1 mmol) of methyl ester of 4-bromo-2-propylenecarbonate acid. Output net: 64,5%, based on methyl ether 4-bromocatechol acid.

Analysis of the reaction solution with pomade chromatographic peak of the methyl ester of 4-bromo-2-propylenecarbonate acid was 96,4%.

Thus, the method according to the present invention allows to obtain the target product as compared with the known method described in the Russian patent 2071963, in one stage, with significantly greater clarity to 96.4% and with a good yield up to 92%.

1. The method of obtaining of ester 2-alkylidene-4-bromocatechol acid of the formula (3)

(3)

where R1and R2each independently from each other represents a lower alkyl group with 1-5 carbon atoms,

which involves the interaction of ester 4-bromocatechol acid of formula (1)

(1)

where R1have the above values,

with an aldehyde of formula (2)

R2CHO, (2)

where R2have the above values,

in an inert organic solvent in the presence of a secondary amine and carboxylic acid.

2. The method according to p. 1, in which the ester 4-bromocatechol acid of formula (1), the aldehyde of formula (2) and the secondary amine simultaneously added to a solution of carboxylic acid in an inert organic solvent.

3. The method according to p. 1, in which the ester 4-bromocatechol acid of formula (1), aldehyde u.

4. The method according to p. 1, in which the secondary amine used di(C1-C20)alkylamino, piperidine or morpholine, and as a carboxylic acid is used (C2-C6)alanovoy acid.

5. The method according to p. 4, in which the secondary amine is piperidine, and the carboxylic acid is an acetic acid.

 

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11 cl, 7 ex

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17 cl, 13 ex

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6 ex

FIELD: chemistry.

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1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a stereoselective method of obtaining a fluorinated molecule having a fluorine atom with asymmetrical carbon (R) or (S) configuration in the α position relative an ester or ketone group in which: (i) a fluorosulphite compound of given configuration on C* which carries the fluorosulphite group of formula (III) is put into a reactor, (2i) the fluorosulphite compound is thermally decomposed in the presence of a nucleophilic catalyst which contains a tertiary nitrogen atom, at temperature ranging from 60°C to 180°C, (3i) a fluorinated molecule having reverse configuration of formula (IV) is obtained, provided that: -R1 denotes alkyl, alkenyl, alkynyl, where these groups can be straight or branched, aryl, cycloalkyl, alkylcycloalkyl, CO2R5, - (CH2)n-CO2R5, -COR5, -SOR5, -SO2R5, where n is an integer from 1 to 12, R5 denotes hydrogen or alkyl, alkenyl, alkynyl, where these groups can be straight or branched, cycloalkyl, alkylcycloalkyl, aryl, particularly substituted aryl; R1 can also form an aromatic or not a heterocycle containing, instead of one or more carbon atoms, one or more heteroatoms selected from oxygen, sulphur or nitrogen; -R2 denotes hydrogen or a group corresponding to definition given for R1; - R1 and R2 are different; - R3 denotes hydrogen or a R6 or -OR6 group, where R6 is selected a list given for R5; where R6 and R1 can be identical or different.

EFFECT: use of the present method enables to stereoselectively obtain fluorinated molecules with good output using cheap and reagents which do not lead to large amounts of effluent.

40 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: method involves combined synthesis of 1'-alkyl-1'-ethylformyl-(C60-Ih)[5,6]fullero[2':,3':1,9]cyclopropanes and 1'a-alkyl-1'a ethylformyl-1'a-carba-1'(2')a-homo(C60-Ih)[5,6]fullerenes of general formula

, where Alkyl =Et, i-Pr, i-Bu, Bn, where C60-fullerene reacts with α-alkyldiazoacetic ether of general formula N2C(alkyl)COOEt, where alkyl = Et, i-Pr, i-Bu, Bn, in o-dichlorobenzene in the presence of a three-component catalyst {Pd(acac)2:2PPh3:4Et3Al}, taken in molar ratio C60-fullerene: α-alkyldiazoacetic ether: Pd(acac)2:PPh3:Et3Al=0.01:(0.05-0.15):(0.0015-0.0025):(0.003-0.005):(0.006-0.01), preferably 0.01:0.1:0.002:0.004:0.008, at temperature of 40°C for 0.25-1.0 hours. 1'-alkyl-1'-ethylformyl-(C60-1h)[5,6]fullero[2',3':1,9]cyclopropanes (1) and 1'a-alkyl-1'a ethylformyl-1'a-carba-1'(2')a-homo(C60-Ih)[5,6]fullerenes (2) are obtained in ratio of 1:1 and total output of 55-79%.

EFFECT: high yield.

1 tbl, 10 ex

FIELD: process engineering.

SUBSTANCE: invention relates to catalysis. Proposed catalyst contains alcoholate of alkaline metal in solution of monohydroxy alcohol. Note here that said monohydroxy alcohol represents isobutyl alcohol, while alcoholate of alkaline metal represents potassium isobutyl with the following ratio of components in wt %: potassium isobutyl - 10-25; isobutyl alcohol - 75-90.

EFFECT: production of biodiesel from various vegetable oils, simplified process.

18 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a method of producing a phenylpropionic acid derivative of general formula: or salt thereof, where R2a is a methoxy group or ethoxy group; R3b is a cyclopentyl group and R5 is a methyl group which can be substituted with one or more phenyl groups, or an oxygen-containing heterocyclic group used as an intermediate compound during synthesis of 3-{5-[4-(cyclpentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid (T-5224), having anti-arthritic action and osteoclast inhibitory action. One of the versions of the method involves reaction of a benzophenol derivative of general formula: 3 , where R2a and R3b are as described above, or salts thereof with a 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-one derivative of general formula: , where R5 is as described above, and X is a halogen atom. The disclosed method can be used as a method for simple and safe synthesis of T-5224 with high output. The invention also relates to methods of producing intermediate compounds and novel intermediate compounds.

EFFECT: high efficiency of the composition.

28 cl, 23 ex

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