RU2529190C1 - Method of producing 2-hydroxy-2-carboxyalkyladamantanes - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing α-hydroxycarboxylic acids, particularly a novel method of producing 2-hydroxy-carboxyalkyladamantanes of general formula

where R=H, CH₃, which can be used as intermediate products in synthesis of adamantyl-containing amino acids and heterocyclic compounds. The method includes reacting adamantanone-2 with dilithium salts of acetic or propionic acid, obtained in situ by reacting lithium acetate or propionate with lithium hexamethyldisilylamide, obtained beforehand from hexamethyldisilazane and phenyllithium, in the medium of dry tetrahydrofuran at 20-45°C and molar ratio hexamethyldisilazane: lithium acetate or propionate: adamantanone-2 of 1.3-1.4:1.8-2.1:1.

EFFECT: wider range of compounds of the disclosed structural formula and obtaining products with high output and high degree of purity.

2 ex

Description

The invention relates to a method for producing α-hydroxycarboxylic acids, in particular to a new method for producing 2-hydroxy-2-carboxylalkylamantanes of the general formula

where R = H, CH _3,

which are used as intermediates in the synthesis of adamantyl-containing amino acids and heterocyclic compounds.

A known method of producing 2-hydroxy-2- (2-pyridyl) methyladamantane in 93% yield by reaction of adamantanone-2 with 2-methylpyridine in the presence of an equimolar amount of n-butyllithium at -20 ° C [Setaki D., Tataridis D., Stamatiou G., Kolocouris A., Foscolos G. B., Fytas G., Kolocouris N., Padaiko E., Neyts J., De Clercq E. // Bioorganic Chemistry, vol. 34, nb. 5, (2006), p. 248-273].

The disadvantage of this method is the use of low temperatures and inaccessible n-butyl lithium. In this way, compounds of the claimed structural formula were not obtained.

A known method for producing 2-hydroxy-2-adamantylacetonitrile by the reaction of acetonitrile with n-butyl lithium in tetrahydrofuran at -80 ° C, further interaction of the lithium intermediate with adamantanone-2 and subsequent hydrolysis of the intermediate. The target product was obtained in 97% yield [Zoidis G., Kolocouris N., Kelly J.M., Prathalingam S.R., Naesens L., De Clercq E. // European Journal of Medicinal Chemistry, vol. 45, nb. 11, (2010), p.5022-5030]. A similar product was obtained by the reaction of adamantanone-2 with acetonitrile in the presence of sodium hydride in dimethyl sulfoxide in 60% yield [Skomorokhov M.Yu., Leonova MV, Shiryaev AK, Klimochkin Yu.N. // ZhORKh, 2003. - T. 36, Issue 9, - p. 1432-1433].

The disadvantages of these methods are the need to use low temperatures and inaccessible n-butyl lithium in the first case and a low yield of the product in the second. By these methods, it is impossible to obtain compounds of the claimed structural formula.

A known method of producing methyl ester of 2-hydroxy-2-adamantanecarboxylic acid in 51% yield by reaction of adamantanone-2 with 2,5-dihydro-2,2-dimethoxy-5,5-dimethyl-1,3,4-oxadiazole in toluene [Romanski. Jaroslaw, Mioston. Grzegorz, Heimgartner. Heinz, Helvetica Chimica Acta, vol. 90, nb. 7, (2007), p.1279-1283].

The disadvantage of this method is the use of inaccessible 2,5-dihydro-2,2-dimethoxy-5,5-dimethyl-1,3,4-oxadiazole. In this way, compounds of the claimed structural formula cannot be obtained.

A known method of producing ethyl 2-hydroxyadamantyl-2-acetic acid by the reaction of adamantanone-2 with ethyl bromoacetate trimethylchlorosilane and zinc in diethyl ether [Zhao Mei-Xin, Wang Mei-Xi-ang, Yu Chu-Yi, Huang Zhi-Tang, Fleet George WJ // Journal of Organic Chemistry, vol. 69, nb. 3, (2004), p.997-1000].

The disadvantage of this method is that with its help it is possible to obtain only esters of 2-hydroxy-2-carboxylalkylamantanes, the preparation of acids by this method is impossible.

A known method for producing 2-hydroxy-2-adamantyl- (2,2-dimethyl) acetic acid by the reaction of adamantanone-2 with isobutyric acid and two equivalents of diisopropylamine and n-butyllithium in a mixture of n-heptane - absolute tetrahydrofuran at 0 ° C in yield 75% [Moersch GW, Burkett AR // Journal of Organic Cnemistry, vol. 36, (1971), p.1149-1151].

The disadvantages of this method are the use of a large number of expensive n-butyl lithium and diisopropylamine, the need for cooling the reaction mixture.

The objective of the proposed method is to develop a technologically advanced method for producing 2-hydroxy-2-carboxyalkylamantanes from readily available reagents in mild conditions.

The technical result is the expansion of a number of compounds of the claimed structural formula and the receipt of products with high yields and a high degree of purity.

The set result is achieved in the method for producing 2-hydroxy-2-carboxyalkylamantanes of the general formula

where R = H, CH _3,

consisting in the interaction of adamantanone-2 with dilithium salts of acetic or propionic acid, obtained in situ by the reaction of lithium acetate or propionate with lithium hexamethyldisilylamide, previously obtained from hexamethyldisilazane and phenyl lithium, in an environment of dried tetrahydrofuran at a temperature of 20-45 ° С an lithium acetate or propionate: adamantanone-2, equal to 1.3-1.4: 1.8-2.1: 1.

The essence of the invention is to obtain lithium salts of 2-hydroxy-2-carboxyalkylamantanes by reacting adamantanone-2 with dilithium salts of acetic or propionic acid. Dilithium salts of acetic or propionic acid are synthesized in situ by the reaction of lithium acetate or propionate with lithium hexamethyldisilylamide. In this case, lithium hexamethyldisilylamide is obtained from phenyl lithium and hexamethyldisilazane. The entire synthesis process takes place in a single reactor in the medium of dried tetrahydrofuran at a temperature of 20-45 ° C for 5 hours with the sequential addition of lithium, bromobenzene, hexamethyldisilazane, lithium acetate or propionate and adamantanone-2 in molar ratios of 2.5: 1.2: 1.3-1.4: 1.8-2.1: 1.

R = H, CH ₃

The method is as follows. To a mixture of finely chopped lithium metal in anhydrous tetrahydrofuran at 20-25 ° C, a solution of bromobenzene in tetrahydrofuran is added in portions at a rate that does not allow heating of the reaction mass above 40 ° C, which takes 1 hour. After the phenyl lithium solution is formed, hexamethyldisilazane is added portionwise to it and the reaction mass is maintained for 2 hours. Then, lithium acetate or propionate is added to the reaction mass. Then (or simultaneously with lithium acetate or propionate), adamantanone-2 is added. The reaction mixture is kept for 2 hours, after which excess water is added, while the salts of the target products are transferred to the aqueous phase. The lower aqueous layer is acidified with dilute sulfuric acid to a slightly acidic reaction, whereby 2-hydroxy-2-carboxyalkylamantanes precipitate, which are filtered off and dried.

The reaction proceeds in a single reaction volume with successive addition of available reagents without the use of low temperatures. The target 2-hydroxy-2-carboxylalkylamantanes are isolated as a result of the decomposition of the reaction mass with water, while the lithium salts of 2-hydroxy-2-carboxyalkylamantanes are transferred to the aqueous phase, and all organic impurities remain in the organic layer. The action of dilute sulfuric acid on an aqueous solution of lithium salts of 2-hydroxy-2-carboxyalkylamantanes liberates the corresponding 2-hydroxy-2-carboxyalkylamantanes. Thus, the proposed method is characterized by simplicity in the synthesis and isolation of reaction products. The yield of 2-hydroxy-2-carboxyalkyladamantanes is 76 and 87%, respectively.

As our studies have shown, the most convenient way to carry out the reaction is to carry out the reaction with an excess of hexamethyldisilazane relative to bromobenzene to increase the speed and completeness of the transmetallation reaction. Otherwise, the side reaction of unreacted phenyl lithium with other components of the reaction mass actively occurs. One of these reactions, associated with the formation of 2-phenyladamantanol-2 alcoholate, leads to a decrease in the yield of 2-hydroxy-2-carboxyalkylamantanes.

It is rational to add an excess of lithium acetate (propionate) relative to hexamethyldisilazane and adamantanone-2 (molar ratio 1.8-2.1: 1.3-1.4: 1, respectively), since in this case a more complete conversion of adamantanone-2 proceeds. A further increase in the excess of lithium acetate (propionate) does not lead to an increase in the yield of 2-hydroxy-2-carboxylalkylamantanes.

It was found that the use of other carboxylic acids instead of acetic and propionic from the series: butyric, isobutyric, and valerianic does not lead to the formation of the corresponding hydroxy derivatives. Apparently, this is due to steric obstacles arising from the attack by organolithium compounds adamantanone-2.

The invention is illustrated by the following examples.

Example 1

6.38 g (0.04 mol) of bromobenzene are added portionwise to 0.58 g (0.083 mol) of intensely mixed finely chopped lithium metal in 20 ml of dried tetrahydrofuran at such a rate as to prevent a strong temperature increase. Then the stirred mixture is heated to 45 ° C for 30-40 minutes, cooled to room temperature and 7.5 g (0.047 mol) of hexamethyldisilazane are added in portions. The mixture is kept for 2 hours, after which 4.4 g (0.067 mol) of lithium acetate are added, then a solution of 5 g (0.033 mol) of adamantanone-2 in 20 ml of tetrahydrofuran is added to it. With stirring, the mixture is heated at 45 ° C for 2 hours. After cooling, organolithium compounds decompose 25 ml of water. The mixture is separated into layers. The aqueous extract is treated with dilute sulfuric acid to a slightly acidic reaction. The precipitate is filtered. After drying, 5.3 g (0.025 mol) of 2-hydroxy-2-carboxymethyladamantane are obtained. Yield 76%, mp 124-127 ° C. ¹ H NMR spectrum, δ, ppm: 1.32-2.15 m (14H, _2.2- Ad); 2.50 s (2H, -CH ₂ ).

Example 2

To 0.35 g (0.05 mol) of intensely mixed finely chopped lithium metal in 15 ml of dried tetrahydrofuran, 3.77 g (0.024 mol) of bromobenzene are portionwise added at such a rate as to prevent a sharp increase in temperature. Then the stirred mixture is heated to 45 ° C for 30-40 minutes, cooled to room temperature and 4.2 g (0.026 mol) of hexamethyldisilazane are added in portions. The mixture is kept for 2 hours, after which 2.9 g (0.036 mol) of lithium propionate are added and a solution of 3 g (0.02 mol) of adamantanone-2 in 10 ml of tetrahydrofuran is added. With stirring, the mixture is heated at 45 ° C for 2 hours. After cooling, organolithium compounds decompose 25 ml of water. The mixture is separated into layers, the aqueous extract is treated with dilute sulfuric acid to a slightly acidic reaction. The precipitate is filtered. After drying, 3.9 g (0.017 mol) of product are obtained. Yield 87%, mp 138-141 ° C. ¹ H NMR, δ, ppm .: 0.91d (SH, -CH _3); (1.31-2.18 m 14H, _2.2- Ad); 2.87k (1H, -CHC (O)).

Thus, a new method has been developed for the synthesis of 2-hydroxy-2-carboxyalkyladamantanes, which consists in the reaction of adamantanone-2 with dilithium salts of acetic or propionic acid, proceeding in a single reactor at a temperature of 20-45 ° C for 5 hours.

Claims (1)

The method of obtaining 2-hydroxy-2-carboxyalkylamantanes of the General formula

where R = H, CH _3,
consisting in the interaction of adamantanone-2 with dilithium salts of acetic or propionic acid, obtained in situ by the reaction of lithium acetate or propionate with lithium hexamethyldisilylamide, previously obtained from hexamethyldisilazane and phenyl lithium, in an environment of dried tetrahydrofuran at a temperature of 20-45 ° С with manol: lithium acetate or propionate: adamantanone-2, equal to 1.3-1.4: 1.8-2.1: 1.