The method of obtaining riboflavin

 

(57) Abstract:

The invention relates to the production of Riboflavin (vitamin B2). To simplify the technological process, reducing time and increasing the yield of the target product condensation azeribajan with barbituric acid in the medium aliphatic alcohol in the presence of acetic acid at the boiling temperature of the mixture is carried out in the presence of additives water, taken in a mass ratio of barbituric acid: water 1: (0,6 - 1,2). As the aliphatic alcohol is preferable to use alcohols having an acidity equal to or higher than the acidity of isopropanol. It allows to conduct the process in a homogeneous phase, to exclude from the process using the absolute solvents, to intensify the process of condensation and to improve the yield of the target product by reducing decomposition and resinification of azeribajan and Riboflavin. 1 C.p. f-crystals, 1 table.

The invention relates to an improved method of obtaining Riboflavin (vitamin B2), which finds application as medicines and nutritional supplements.

Known [1] a method of producing Riboflavin by condensation of azeribajan with barb is islote boiling, output technical Riboflavin 70%

The disadvantage of this method is the low yield of the target product, as in the purification and recrystallization of the product is lost on average 8% to 10% of Riboflavin.

A known method of producing Riboflavin by condensation of 3,4-xylyl-6-phenyl-azo-D-arbitraria (azeribajan) with barbituric acid in an anhydrous environment in a mixture of lower aliphatic alcohols C2-C5and aromatic hydrocarbon o-xylene and/or toluene) in the presence of a catalytically acting acetic acid with continuous distillation of the formed water azeotrope [2] Output technical Riboflavin 84 - 86,1%

The disadvantage of this method is the difficulty of obtaining Riboflavin pharmacopoeial quality and the use of two solvents.

Known [3] the method of obtaining Riboflavin with a sufficiently high yield of the target product pharmacopoeial quality (71,5 74,2%), which is chosen as a prototype. Target product, according to atoi method, obtained by condensation of azeribajan with barbituric acid in absolute aliphatic alcohol (butanol) in the presence of acetic acid at the boiling temperature of the mixture with continuous azeotropic the kind in acidic medium, precipitation with water, washing and drying of the target product.

Used in the way the prototype of the absolute solvent is not possible to conduct the reaction in a homogeneous environment, as barbituric acid in alcohols and esters of acetic acid is not soluble. Reaction mass is heterogeneous, which leads to local overheating, and, consequently, to decrease the yield of the target product.

The disadvantage of this method is the complexity of the technological process consisting of a preliminary dehydration of aliphatic alcohols and carrying out the condensation in a heterogeneous environment, the duration of the technological process and not a high yield of the target product.

The purpose of the invention increase the yield of the target product, simplifying the process and reducing its duration.

This is achieved by condensation of azeribajan with barbituric acid in the medium aliphatic alcohol by boiling the addition of water, taken in a mass ratio of barbituric acid: water 1: (0,6oC1,2), then cooled and the release of a technical product, the processing of hydrogen peroxide in an acidic medium by precipitation with water, washing and slotosch, equal acidity isopropanol or higher.

Distinctive features of the proposed method are additive in the reaction mixture of water mass ratio of barbituric acid: water 1: (0,6 1,2). The use of water allows the process in homogeneous phase, because barbituric acid soluble in hot water [4] and azeribajni in hot alcohols [5] While heating the reaction mass in an aqueous-alcoholic medium azeribajni and barbituric acid into solution, which creates favorable conditions of flow of the reaction and increases the speed of its passing.

Experimental work has shown that when the ratio of barbituric acid: water 1: more than 1.2, the decrease of the output (example 4), as excess water reduces the reaction rate, which can be explained, firstly, by reducing the solubility of azeribajan, and, secondly, by shifting the equilibrium of the reaction to the left, as water is one of the products of the condensation reaction.

When carrying out the condensation at a ratio of barbituric acid: water below the lower limit or in absolute solvent also observed a decrease in the output (examples 5, 7, 9, 11 and 14), due to the decreased solubility barbecue alcohols or mixtures thereof, moreover, it is preferable to use aliphatic alcohols with high acid numbers (equal to or more than acidity isopropanol).

The acidity of these alcohols catalyzes the reaction of condensation as used organic acids. Known [6] the relative scale of acidity of alcohols:

Ethanol 740

Propanol 760

amyl 800

Butanol 830

Isobutanol 860

Isopropanol 920

Tertiary butanol 1100

In a series of solvents ethanol-n-butanol-isopropanol-tertiary butanol yield of Riboflavin under other equal conditions as with additives and without additives water increases, and it was confirmed by experimental data (examples of 13.8, 1,15 and 14.9).

It should be noted that carrying out the condensation of azeribajan with barbituric acid by adding water at the beginning of the condensation process is not so obvious and simple, although the solubility of barbituric acid in hot water has long been known. The fact that the second source reactant azeribajni not soluble in water and up to the present time, it was thought that the presence of water in the condensation process of azeribajan with barbituric acid is not desirable [7] which explains the COI is us relations provides solubility barbituric acid, do not reduce the solubility of azeribajan and does not shift the equilibrium of the reaction to the left.

The presence at the beginning of the condensation process additives water and use as a medium of aliphatic alcohols with high acidity allows to increase the yield of the target product to 83 86,6% due to homogenization of the environment and intensification of the process of condensation, which in turn leads to a reduction in the degree of decomposition of the sugar components of azeribajan.

Increase the yield of the target product is also achieved by improving the solubility of Riboflavin in acidic aqueous-alcoholic medium at the time of its formation, which provides a uniform supply of heat, prevents local overheating and loss of initial reagents with the decomposition products and resinification.

The reaction mass after completion of the condensation process is uniform and transportable, which eliminates clogging of pipes and fittings and associated loss of the target product.

In addition, the use of water additives allows to simplify the technological process, as this eliminates the need to use absolute solvents and prior alkoxy is STI. It is new, because applicants are not aware of any sources that provide data on the use of additives water by condensation of azeribajan with barbituric acid.

It has an inventive step, since it is not clear from the prior art, since in the literature there are no data about the positive influence of addition of water on the reaction of condensation of azeribajan with barbituric acid.

The invention is industrially applicable, because its implementation does not require any special equipment or inaccessible and expensive raw materials.

The method is illustrated by the following examples, the main results of which are shown in the pivot table.

In the examples 1, 2, 3, 6, 8, 10, 12, 13 and 15 presents the results obtained according to the invention in the claimed range. The deviation from the set parameters of the condensation process (examples 4, 5, 7, 9, 11 and 14) reduces the yield of the target product. Example 16 in terms of the prototype using absolute aliphatic alcohol with continuous distillation of the water azeotrope. The yield of the target product is significantly lower in comparison with the invention.

Yah, with the content of the basic substance, respectively 97,5% 98,0%

Example 1. A mixture of 10 g (0,028 mol) of azeribajan, 4.7g (being 0.036 mol) of barbituric acid and 13.3 ml of acetic acid, 70 ml of 95% isopropanol (ratio of barbituric acid: water 1 0,6) is heated with stirring in a sealed reactor at 105 110oC for 4 h under a pressure of 1 MPa At the end of the reaction mass is then cooled to 20oC and filtered. Technical vitamin on the filter is washed with 20 ml of isopropanol, then with hot water until a light yellow wash water.

The resulting Riboflavin dissolved in 32 ml of hydrochloric acid, to the solution was added 0.7 ml of a solution of hydrogen peroxide, diluted by half with water to change the color of the solution from dark green to yellow-brown.

The solution is filtered from nerastvorim impurities, the filter cake washed with 15% hydrochloric acid (4 ml). Hydrochloric acid, the filtrate is poured into a 10-fold amount (350 400 ml) of hot (90 95oC) water with stirring, there is a selection of Riboflavin. The resulting suspension is allowed to stand for 1 h under stirring at a temperature of 90 95oC, then cooled to 20oC, allowed to stand for 1 h, and filtered. The precipitate vitamin on the filter is washed with hot water (80 ml) to the absence of acidic p is 4.3% per azeribajni).

Example 2. A mixture of 10 g (0,028 mol) of azeribajan, 4.7g (being 0.036 mol) of barbituric acid and 13.3 ml of acetic acid, 70 ml of 92% isopropanol (ratio of barbituric acid: water 1 0,95) is heated with stirring in a sealed reactor at 105 110oC for 3.5 h at a pressure of 1 MPa. Upon completion of the reaction mass is then cooled to 20oC and filtered. Further treatment is carried out as in example 1.

The medical Riboflavin 8,79 g (84,0%).

Example 3. A mixture of 10 g (0,028 mol) of azeribajan, 4.7g (being 0.036 mol) of barbituric acid and 13.3 ml of acetic acid, 70 ml of 90% isopropanol, the ratio (barbituric acid water 1 1,2) is heated with stirring in a sealed reactor at 105 110oC for 4 h under a pressure of 1 MPa At the end of the reaction mass is then cooled to 20oC and filtered. Further processing is as in example 1.

The medical Riboflavin 8,68 g (83%).

Example 4 (comparative). A mixture of 10 g (0,028 mol) of azeribajan, 4.7g (being 0.036 mol) of barbituric acid and 13.3 ml of acetic acid, 70 ml of 85% isopropanolamine (barbituric acid: water 1 1,8) is heated with stirring in a sealed reactor at 100 110oC for 4 h under a pressure of 1 MPa At the end of the reaction mass is then cooled to 24%).

Example 5 (comparative). Was carried out analogously to example 1, under the same loading main components using 98% isopropyl alcohol. The ratio of barbituric acid: water 1 0,24.

The medical Riboflavin 8,19 g (78,3%).

Example 6. Was carried out analogously to example 1,as the aliphatic alcohol used a mixture of isopropanol and n-amyl alcohol (2 1) with a water content of 5%

The medical Riboflavin 8,63 g (82.5 per cent).

Example 7 (comparative). Was carried out analogously to example 1, as the aliphatic alcohol used absolute mixture of isopropanol and n-amyl alcohol (2 1).

The medical Riboflavin of 7.96 g (76,1%).

Example 8. Was carried out analogously to example 1, as the aliphatic alcohol used 95% n-butanol. The ratio of barbituric acid water 1 0,6.

The medical Riboflavin of 8.37 g (80,0%).

Example 9 (comparative). Was carried out analogously to example 1, as the aliphatic alcohol used absolute n-butanol.

The output of medical vitamin 7,66 g (73.2 per cent).

Example 10. Was carried out analogously to example 1, as the aliphatic alcohol used was a mixture of the ptx2">

Example 11 (comparative). Was carried out analogously to example 1, as the aliphatic alcohol used absolute mixture of n-butanol and isoamyl alcohol (1 1). The medical Riboflavin 7.6 g (72.6 per cent).

Example 12. Was carried out analogously to example 1,as the aliphatic alcohol used a mixture of amyl alcohols with a water content of 5%

The medical Riboflavin of 7.96 g (76,1%).

Example 13. Was carried out analogously to example 1, as the aliphatic alcohol used 95% ethanol.

The medical Riboflavin 7,56 g (72,3%).

Example 14 (comparative). Was carried out analogously to example 1, as the aliphatic alcohol used absolute ethanol.

The output of medical vitamin 7,11 g (68%).

Example 15. Was carried out analogously to example 1, as the aliphatic alcohol used 95% tertiary butanol. The ratio of barbituric acid water 1 0,6.

The medical Riboflavin 9,06 g (86.6 per cent).

Example 16 (the prototype). A mixture of 10 g (0,028 mol) of azeribajan, 4.7g (being 0.036 mol) of barbituric acid and 13.3 ml of acetic acid and 70 ml of absolute n-butanol is heated under stirring to a boil, formed during Rea is concani reaction mass is then cooled and filtered. Further processing is as in example 1.

The medical Riboflavin 7,74 g (74,0%).

Literature

1. USSR author's certificate N 93306 class. C 07 D 57/32, 18.01.80.

2. Patent Czechoslovakia N 156800 class. C 07 C 51/50, 19.11.73.

3. Chemical and pharmaceutical journal. M. 1986, N 1, c. 102 105.

4. Chemical encyclopedia, M. 1988, vol 1, S. 240.

5. Shneidman L. O. Production of vitamins. M. 1973, S. 121.

6. Kraskov A. P. Acid-base titration in nonaqueous solutions. M. 1967, S. 57.

7. Patent Czechoslovakia N 131622 class. C 07 C 51/50, 15.03.69 (prototype).

A method of producing Riboflavin by condensation of 3,4-xylyl-6 - phenylazo-D-arbitraria with barbituric acid in the medium aliphatic alcohol in the presence of acetic acid at the boiling temperature of the mixture, then cooling the reaction mass and the selection of a technical product, process hydrogen peroxide in an acidic environment, sedimentation of water, rinsing, and drying of the target product, wherein the condensation is carried out in the presence of additives water, taken in a mass ratio of barbituric acid water 1 0,6 1,2.

2. The method according to p. 1, characterized in that aliphatic alcohol use aliphatic alcohols with acid

 

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