The method of obtaining the ethyl ester- bromsulfaleinovy acid

 

(57) Abstract:

The invention allows to obtain not optically active ethyl ester of a-bromsulfaleinovy acid - a substance for preparation of cardiorespiratory. The method includes the following stages: 1) synthesis of isovalerianic aldehyde by hydroformylation isobutylene; 2) direct bromination of the resulting aldehyde to bromohydrin a-bromsulfaleinovy acid; 3) the etherification of bromohydrin ethyl alcohol. 3 table.

The invention relates to the field of organic and petrochemical synthesis, namely, to obtain ethyl ester-bromsulfaleinovy acid (EEBIC), used in the manufacture of drugs, such as Corvalol, valocordin.

A method of obtaining EEBIC [1] of isovalerianic acid (CPI) by its complex halogenation first processing excess PCl3then bromirovanii obtained acid chloride of bromine and, finally, the interaction of the acid chloride a-bromsulfaleinovy acid with ethyl alcohol. Waste of such a process is phosphoric acid, phosphoric anhydride and formed during chlorination of a stable emulsion phosphoric acid in the acid chloride. The process loot purity of the original CPI. The CPI for this process is produced by oxidation reaction isovalerianic aldehyde synthesized by the oxidative dehydrogenation of oxygen-containing gas isoamyl alcohol at 450-500oC in the presence of silver-containing catalyst [2] thus Obtained aldehyde and, accordingly, the acid is optically active products, which negatively affects the properties of drugs, prepared on the basis of EEBIC.

A method of obtaining mentolovogo ether isovalerianic acid by hydrocarbonsoluble of isobutene metilovam alcohol in the presence of synthesis gas [3] the Reaction is carried out in the presence of a catalyst PdCl2(PPh3)2containing free triphenylphosphine when the ratio P/Pd 10, a temperature of 130oC and with the addition of conc. HCl.

This method is convenient, because it allows one to obtain a final product of an ester of isovalerianic acid in one stage, however, it is not suitable for obtaining poslednego isovalerianic anhydride. It also requires time-consuming purification of the obtained product from the catalyst and triphenylphosphine.

A known method of obtaining the ethyl ester of a-bromsulfaleinovy acid by DV is under bromine and PCl3when 70-80oC for 10 to 20 h and at the second stage in the presence of an additional amount of bromine at 100 - 105oC for 1.5 to 2 hours Received a-brasoveanu acid is transferred to the acid chloride, which is subjected to the esterification of ethyl alcohol [4] the prototype. The disadvantage is the presence of optically active impurities in the final product.

The task of the invention to develop the method of obtaining not optically active EEBIC of the available raw materials.

This is achieved by a method of obtaining EEBIC, which includes: synthesis of isovalerianic aldehyde from isobutene by hydroformylation, followed by direct bromination of the aldehyde with the formation of bromohydrins a-posledney isovalerianic acid and the esterification of the product with ethyl alcohol.

The method is as follows:

Hydroformylation of isobutene carried out in an autoclave with stirrer at 90-130oC in the medium of organic solvent synthesis gas composition H2/CO 1-2,2 at a constant pressure of 30 to 90 bar and the concentration of isobutene 25-30% under the action of carbonylative catalyst modified with phosphorus-containing ligand (preferably three(n-nonylphenyl)postitem) at a molar ratio P/R is as organic solvent, it is advisable to use a join not having a strong donor properties and having a boiling point of 100oC, for example o-xylene, mixture of isomers of xylene, dioxane or the products of synthesis.

When carrying out process with circulation isobutan continuously injected into the reactor with a circulating gas, which is saturated with the olefin by ozonation through it at a given temperature. The process is carried out with recycled synthesis gas at a volume ratio of circulating synthesis gas and an additional input, equal 10-35 (depending on the reaction temperature when the content of inert gases in the synthesis gas 2-30% and reaction products from the circulating gas).

Obtained at this stage, the product contains isovalerianic aldehyde (exit 95 - 97%), unreacted isobutene, a small amount of isobutane, resulting from the hydrogenation of isobutene, 2,2-DIMETHYLPROPANE, the condensation products of aldehyde and solvent. After rectification get WILLOW with purity 99.8 99.9% of

Received isovalerianic aldehyde bromilow as follows.

To a solution of the aldehyde in an organic solvent (hexane, heptane, chloroform, carbon tetrachloride) in the dark at peremeshautsa temperature interval reactions which is within 20-35oC. At this stage forms a-Posledny aldehyde. After bleaching reaction mixture include lighting (incandescent lamp), increase the temperature to 40 to 60oC and enter another 0.6-1.0 mol of bromine per mole of aldehyde. After bleaching raise the temperature to 70oC, enter the ethanol in the amount of 1-1,5 mol per mol of aldehyde and carry out the esterification reaction.

At the end of the selection HBr reaction mixture is maintained at 70-75oC for 5-10 min under stirring, then cooled to room temperature or below (up to 10oC), injected approximately equal in volume, the amount of water, separate the organic layer, dry it and fractionary.

The proposed method satisfies the criteria of novelty, because the process of obtaining the ethyl ester of a-bromsulfaleinovy acid is unknown.

The proposed method differs from the known fact that the isobutylene hydroformylation synthesis gas (CO H21 1 1 2) under the action of carbonylative catalyst modified by teenliterotica at a molar ratio of P/Rh 3-25, in the presence of a stabilizing additive selected from the group difficult phenols, at constant pressure 30-90 the oC, then exposed to light at 40-60oC, and then add ethanol, conduct the esterification reaction and produce ethyl ester of a-posledney acid.

In the literature there is a method of obtaining isovalerianic aldehyde by hydroformylation of isobutene in the presence of a complex catalyst based on rhodium carbonyl in the presence of organic phosphites [4] However, in this process are adverse reactions, in particular, accumulate unwanted condensation products of aldehydes. In the invention the addition of BHT to the catalytic system at a molar ratio of BHT/Rh 0,1-0,2 contributes to the reduction of the yield of the condensation products of aldehydes with long-term work with recycling of the catalyst.

In the proposed method, the process of hydroformylating carried out at a ratio of ligand/Rh from 3 to 25 (preferably 7-12). At a lower content of P/Rh a decrease in the reaction rate when recycling due to deactivation of the catalyst, and at a higher there is a noticeable decrease in the reaction rate due to the formation of catalytic complexes with a high degree of substitution of the carbonyl groups of the ligand (less active catalytic complexes). The process is executed when the op is licinii concentration of the catalyst is violated proportionality dependence of the reaction rate on the concentration of rhodium, what makes it inappropriate to work with high concentrations of rhodium. Variation of the composition of the gas in the direction of increasing the ratio of H2/CO to 2.2 allows to increase the temperature stable reaction up to 130oC. If you increase the specified ratio >2,2 observed largely hydrogenation of isobutene, and when the ratio of <1 significantly decreases the reaction rate.

Isovalerianic aldehyde obtained in the 1st stage of the proposed method is not optically active, while the aldehyde used to prepare the CPI in the known method [1] is the optical rotation angle 12o.

I. Receiving isovalerianic aldehyde

Example 1. In the reactor-autoclave with a capacity of 0.25 l load 60 ml of o-xylene, 6.9 mg acetylacetonato complex of rhodium acac2Rh(CO)2, 165,6 mg three(H-nonylphenyl)phosphite (molar ratio of P/Rh 9/1), 6,2 mg 2,6-decret. butylphenol (BHT) (molar ratio BHT/rhodium=1). The autoclave rinsed synthesis gas composition CO H21 1, the pressure of the synthesis gas is brought to 60 bar, the reaction mixture is heated to 115oC, enter 14.8 g of isobutene and conduct hydroformylation at constant pressure and temperature for 2 hours as you groove to restore the operating pressure. About the speed of turning isobutene judged by the pressure drop in the calibration vessel, the degree of conversion of isobutene the amount of absorbed gas. After 2 h, the autoclave is cooled, relieve pressure and unload the produce. Gain of 22.8 g of the aldehyde, while the share of isovalerianic aldehyde is 98,9% conversion isobutene 95% degree of hydrogenation of isobutene of 0.2% After rectification allocate isovalerianic aldehyde with a purity of 99.9%

Examples 2-5. Hydroformylation of isobutene carried out as in example 1, but varying pressure and temperature. The results are shown in table. 1.

Examples 6-8. Hydroformylation carried out as in example 1, but changing the ratio of H2/Co. the results are shown in table.2.

Example 9. Hydroformylation of isobutene carried out in a continuous mode with recycled synthesis gas. In the autoclave load 60 ml of o-xylene, 6.9 mg of rhodium acetylacetonate, 165,6 mg three(n-nonylphenyl)phosphite, 6,2 mg of ionol; the autoclave is rinsed with an inert gas, and then served cleansed from the impurities of oxygen and moisture in the synthesis gas (CO/H2=1,1), containing 4% nitrogen, to a pressure of 68 bar and 14.8 g of isobutene. After that, include a circulation pump, ensuring the circus is Isobutanol, than supply the reactor mixture composition of CO:H2:ISO-C4H8=1:1:1. After the reactor circulating gas passes the cooler-condenser, which condenses the liquid products of the synthesis, the solvent and neprevyshenie isobutene. After you enable the circulation of the autoclave in the specified mode heated to 110oC and the process is carried out without Ottawa to complete the forming of the catalyst and nitrogen accumulation by up to 25% In the future, the constant pressure in the reactor is supported by revenues synthesis gas, instead expended from the calibration vessel, equipped with a regulator after themselves. Then turns otbw synthesis gas 1.8 l/h and perform a stationary process for 500 hours, the Degree of transformation of isobutene is 95% Share in WILLOW aldehyde fraction 70% hard/n 98,5, the amount of the condensation products of aldehydes 2% At the end of the run there is a decrease in productivity by 15% during a run in the reactor to maintain a constant concentration of isobutene 5% Coefficient of circulation in the experiment is equal to 23. After rectification allocate WILLOW with a purity of 99.9%

Example 10 (comparative). Hydroformylation of isobutene conducted according to example 9, but without the addition of BHT. After osushestvleniu the condensation products of aldehydes 10% at the end of the run there is a decrease in performance by 20%

Examples 11-15. Hydroformylation of isobutene conducted according to example 9, to vary the molar ratio of P/Rh, the content of BHT constant of 6.2 mg of the Obtained results are shown in table.3.

11. Obtaining the ethyl ester of a-posledney isovalerianic acid.

Example 16.

In a reactor equipped with a stirrer, reflux condenser, thermometer and addition funnel with a tube reaching to the bottom, placed 12 ml (0.1 mol) of 2-methylbutanal (isovalerianic aldehyde) of 18 ml of hexane and in the dark with stirring, add 5 or (0.1 mol) of bromine at 20oC. the First 3 drops of bromine colorless within 1 min, and the temperature rises to 28oC. the entire quantity of bromine (5 ml) was added over 5 minutes Highlighting HBrvery low basic weight of methyl hydrogen remains in the reaction mass. thermal effect is negligible. After bleaching temperature was raised to 50oC, include the incandescent lamp 40 W and injected 3 ml (60% of theory.) bromine within 4 minutes of the Last drops of bromine fade slowly. Then the reaction mass is heated to 70oC and injected with 8 ml of ethanol for 2-3 minutes At the end of the selection HBR mixture is maintained at 70oC more n is Oset into a separating funnel, separate the organic layer, dried with anhydrous sodium sulfate and distilled under vacuum. Obtain 12.0 g (58% of theory.) ether so Kip. 75-83o/15 mm, n2D01,448.Repeated distillation get ethyl ester-bromsulfaleinovy acid so Kip. 76o/15 mm, n2D01,4478, d2401,2643, MPD44,25 (calc. 43, 81).

Found, wt. C 40,55; H 6.42 per; Br 37,8;

Calculated wt. C 40,21; H 6,27; Br 38,22

Example 17. Charged to the reactor 24 ml (0.2 mol) isovalerianic aldehyde and 30 ml of heptane, 30oC in the dark under stirring was added dropwise 9 ml of bromine (0.18 mol). After bleaching the temperature was raised to 42oC when tungsten lighting introduced gradually and 7.7 ml of bromine (0.15 mol). The solution is stirred until the discoloration of the reaction mass is heated to 70oC and injected 10 ml of ethanol. Further, all operations are performed as in example 1 (water add 50 ml). Get to 22.5 g (54% of theory.) ethyl ether-bromsulfaleinovy acid so Kip. 75-78oC/15 mm, n2D01,4560. By repeated distillation of pure ethyl ester-bromsulfaleinovy acid so Kip. 77-78oC/15 mm, n2D01,4495, d2401,2813.and

The method of obtaining e is lordsadomaso connection and esterification of galodamadruga ethyl alcohol, characterized in that as the oxygen-containing compounds used isovalerianic aldehyde obtained by hydroformylation of isobutene synthesis gas with a molar ratio of N2/CO 1 2.2 in the presence of acetylacetonato complex carbonitride modified three(n-nonyl)phosphate, at a molar ratio of P/Rh 3 25 and taken in an amount of 5 to 10-310 10-3wt. in the calculation of Rh, and in the presence of a stabilizing additive selected from the group of space-constrained phenol, such as BHT, when the molar ratio BHT/Rh 0.1 to 0.2, and the process is carried out at a temperature of 90 to 130oC and a pressure of 30 to 90 bar, after which the resulting aldehyde is subjected to bromirovanii with the first stage is carried out in the dark at 20 35oC and a molar ratio of bromine/aldehyde 0,8 1,0, and the second stage is performed on the light when 40 60oC and a molar ratio of bromine/aldehyde 0,6 - 1,0 with the formation of bromohydrins isovalerianic acid, which is subjected to esterification.

 

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