RU2126792C1 - Process for preparing 1,2,3,4-tetrahydro-2-methyl-1,4- dioxonaphthalene-2-sulfoacid sodium salt (vicasol) - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: process for preparing 1,2,3,4-tetrahydro-2-methyl-1,4-dioxonaphalene- 2-sulfoacid sodium salt (vicasol) comprises reacting 2- methyl-1,4-napthoquinone (menadione) with sodium bisulfite (NaHSO₃) aqueous solution. Reaction is carried out in two-phase system consisting of aqueous phase and incombustible organic solvent. Aqueous phase is essentially sodium bisulfite solution having concentration from 4 to 6.5 mole/l, and organic phase is menadione solution. Reaction is carried out at temperature of not higher than 40 C. These conditions simplify and make cheaper technology of regeneration of organic solvents and also method of purification and recovery of vicasol. The resulting product comprises 0.5-2 wt % Na₂S₂O₅ which stabilizes vicasol and maintains its proper storage and light resistance. EFFECT: more efficient preparation process. 5 cl

Description

 The present invention relates to the field of fine organic synthesis, and in particular to methods for producing the sodium salt of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxonaphthalene-2-sulfonic acid (pharmacopoeial name vikasol) of the formula BC.

Викасол (ВС) является биологически активным соединением, широко применяемым в сельском хозяйстве и медицине. Он является наиболее используемой формой витамина K₃.

Vikasol (VS) is a biologically active compound widely used in agriculture and medicine. It is the most used form of vitamin K ₃ .

Водный раствор бисульфита натрия обычно получают растворением в воде твердого метабисульфита натрия Na₂S₂O₅ по реакции (2)
Na₂S₂O₅ + H₂O __→ 2NaHSO₃
Викасол в промышленности получают с использованием Na₂S₂O₅ [Регламент. Синтез β-метилнафтохинона. Объединение "Биостимулятор", Одесса, 1981].A known method of producing Vikasol, based on the interaction of 2-methyl-1,4-naphthoquinone (menadione, MD) with an aqueous solution of sodium bisulfite NaHSO ₃ according to reaction (1) [US patent N 2367302, CL. 514-682, 1945]:

An aqueous solution of sodium bisulfite is usually obtained by dissolving in water solid sodium metabisulfite Na ₂ S ₂ O ₅ according to reaction (2)
Na ₂ S ₂ O ₅ + H ₂ O __ → 2NaHSO ₃
Vikasol in industry is obtained using Na ₂ S ₂ O ₅ [Regulation. Synthesis of β-methylnaphthoquinone. Association "Biostimulant", Odessa, 1981].

This process has a number of disadvantages: 1) non-stoichiometric composition of Na ₂ S ₂ O ₅ , which contains up to 5% of harmful impurities Na ₂ SO ₃ , which reduces menadione with the formation of the reactive semiquinone radical, which initiates the formation of resins; 2) the use in the technology of a 2.6-fold excess of Na ₂ S ₂ O ₅ ; 3) a high reaction temperature (70 ^o C), leading to partial isomerization of vicasol with the formation of 1,4-dioxo-2-methylnaphthalene-3-sodium sulfonate, which does not have biological activity.

Closest to the proposed method is the method described in the patent [Russian patent N 1822554, class. C 07 C 309/44 // A 61 K 31/185; BI, 1996, N 16, p. 193]. In this method, vikasol is obtained from menadione and a pre-prepared aqueous solution of Na ₂ SO ₃ with a concentration of 1.0 to 3.0 mol / L, containing 5 to 10% excess SO ₂ . A NaHSO ₃ solution is prepared starting from Na ₂ SO ₃ and gaseous SO ₂ ; Na ₂ SO ₃ can be replaced with Na ₂ CO ₃ or NaHCO ₃ . A certain amount of dry pure menadione is poured with the calculated amount of an aqueous solution of NaHSO ₃ (ratio of NaHSO ₃ : menadione = 1). The resulting suspension is stirred at 40-60 ^o C in a stream of inert gas (CO ₂ , Na ₂ , argon) until the menadione is completely dissolved, which takes 1-3 hours. Water is evaporated from the resulting solution in a vacuum rotary evaporator at 40 ^o C to ≈ 1/3 of the original volume; isopropanol is added to the evaporated solution to the initial volume. Precipitated white Vikasol crystals are filtered off and washed with isopropanol. The mother liquor is again evaporated at 40 ^o C to ≈ 1/3 of the original volume; isopropanol is again added to the evaporated solution to obtain the next portion of vicasol, which is less pure. Isolation of vicasol is repeated 3-4 times. The yield of vicasol during the first isolation of crystals is 64-69 wt. %, the total yield is 81 - 85 wt.%. Isopropanol can be replaced with ethanol or acetone.

 The reduced yield of the aircraft, however, does not take into account the losses of the MD during cleaning (12–15 wt.%). Taking into account these losses, the aircraft’s yield on the full amount of MD does not exceed 75 wt.%.

 The disadvantages of the prototype method are the complexity, high cost and incompleteness of the selection of the product (BC), as well as the presence of production waste.

1) The main disadvantage of the prototype method was the presence in the solution of free (excess) SO ₂ . Excess SO ₂ slightly increases the yield of the aircraft, but its presence greatly complicated and increased the cost of the technology. To isolate the BC, an aqueous solution containing BC and an excess of SO ₂ was evaporated in vacuo at 40 ^o C to ≈ 1/3 of the initial volume, then a part of the BC was precipitated with an isopropanol volume of ≈ 2/3 from the original, and the BC was separated by filtration. Evaporation in vacuo and dropping the aircraft with isopropanol was repeated 3-4 times. As a result, water-isopropanol solutions containing dissolved SO _{2 were} evaporated.

2) Despite the complexity of the isolation procedure, it was not possible to completely extract the BC from the solution due to the high water solubility of the BC. In the solution always remained from 15 to 25 wt. % Of the aircraft, which osmolilas and turned into waste. As a result, the prototype method was not wasteless. Isopropanol was regenerated from a water-isopropanol solution containing SO ₂ and reused. The high cost of the method is due to both the high cost of vacuum evaporation and the need to use special steels for equipment, since aqueous and alcoholic solutions of SO ₂ are highly corrosive.

 3) A disadvantage of the known prototype method is also the use of pure MD in dry form. Isolation and purification of MD are associated with additional energy costs and significant losses of MD (at least 12-15 wt.%).

4) The next disadvantage of the known method was the choice of the stoichiometric ratio of NaHSO ₃ : MD = 1. This ratio gave a very clean aircraft, but this aircraft is very unstable; it is poorly stored due to oxidation in air and quickly decomposes in the light. In crystals of BC, a small excess (0.5 ^o C3 wt.%) Of Na ₂ S ₂ O _{5 is} required, providing sufficient stability of the BC in storage and use in the light and in the air.

5) The selected temperature range for the reaction (1) - 40 ^o C60 ^o C - turned out to be too wide, since at 60 ^o C the reaction (3) of isomerization of BC to menadiol-3-sulfonate (MS) without vitamin properties.

Настоящее изобретение решает задачу создания более эффективного способа синтеза викасола. Задача решается следующим образом. Викасол получают взаимодействием 2-метил-1,4-нафтохинона (менадиона) с водным раствором бисульфита натрия в двухфазной системе. Органической фазой является раствор технического менадиона в хлороформе, трихлорэтилене или другом негорючем растворителе, не смешивающемся с водой. Водной фазой является раствор NaHSO₃ концентрации от 4,0 до 6,5 моль/л. Раствор NaHSO₃ готовят заранее, исходя из Na₂SO₃ или Na₂CO₃ или NaHCO₃ и газообразного SO₂.К определенному количеству раствора менадиона добавляют рассчитанное количество раствора NaHSO₃. Полученную смесь перемешивают при температуре не выше 40^oC в токе инертного газа до полного превращения менадиона. Образующийся викасол кристаллизуется из водной фазы уже в процессе его синтеза. Полученную суспензию викасола фильтруют. Для удаления растворенных примесей осадок викасола на фильтре промывают растворителем, используемым для растворения менадиона. Фильтрат, состоящий из двух фаз - водной и органической - отделяют. Затем осадок викасола на фильтре промывают несколькими порциями изопропанола до получения бесцветного фильтрата. Полученные кристаллы продукта сушат на воздухе. Выход викасола составляет от 75 до 79 мас.%. Полученный викасол содержит 0,5^oC2 мас. % Na₂S₂O₅, который является стабилизирующей примесью. Поэтому викасол с Na₂S₂O₅ обладает лучшей хранимостью по сравнению с викасолом без стабилизатора.

The present invention solves the problem of creating a more efficient method for the synthesis of vicasol. The problem is solved as follows. Vikasol is prepared by reacting 2-methyl-1,4-naphthoquinone (menadione) with an aqueous solution of sodium bisulfite in a two-phase system. The organic phase is a solution of technical menadione in chloroform, trichlorethylene or another non-combustible solvent that is not miscible with water. The aqueous phase is a solution of NaHSO ₃ concentration from 4.0 to 6.5 mol / L. A NaHSO ₃ solution is prepared in advance based on Na ₂ SO ₃ or Na ₂ CO ₃ or NaHCO ₃ and gaseous SO _2. A calculated amount of NaHSO ₃ solution is added to a certain amount of menadione solution. The resulting mixture is stirred at a temperature not exceeding 40 ^o C in a stream of inert gas until the complete conversion of menadione. The resulting vicasol crystallizes from the aqueous phase already during its synthesis. The resulting suspension of Vikasol is filtered. To remove dissolved impurities, the Vikasol precipitate on the filter is washed with the solvent used to dissolve the menadione. The filtrate, consisting of two phases - aqueous and organic - is separated. Then the Vikasol precipitate on the filter is washed with several portions of isopropanol until a colorless filtrate is obtained. The obtained crystals of the product are dried in air. The yield of vicasol is from 75 to 79 wt.%. The resulting Vikasol contains 0.5 ^o C2 wt. % Na ₂ S ₂ O ₅ , which is a stabilizing impurity. Therefore, Vikasol with Na ₂ S ₂ O ₅ has better storage compared to Vikasol without a stabilizer.

Thus, the hallmarks of the present invention are:
1) The implementation of the synthesis reaction of vikasol in a two-phase system consisting of a concentrated (4 ^° C6.5 molar) aqueous solution of NaHSO ₃ and a solution of MD in a non-combustible organic solvent that is not miscible with water. These conditions simplify and reduce the cost of the technology for the regeneration of organic solvents, as well as the method of purification and separation of aircraft.

2) The reaction of synthesis of BC at temperatures not higher than 40 ^o C, which prevents decomposition of BC during synthesis.

 The essence of the method is illustrated by the following examples.

Example 1. In a liter glass cylindrical shaking reactor having 3 necks, of which one wide (at least 30 mm), pour 200 ml of a chloroform solution of crude (90%) menadione (MD) containing 66.4 g (0.347 praying) MD. To the reactor add 105 ml of an aqueous solution of NaHSO ₃ with a concentration of 5.62 mol / L. The reactor was purged with an inert gas (CO ₂ ) and shaking was started (400 strokes per minute with an amplitude of 20 mm). From this moment, reaction (1) begins to occur, accompanied by heating (from room temperature to 40 ^o C) and a gradual thickening of the mixture due to the accumulation of dispersed BC particles. Stagnant zones in the suspension are eliminated by periodically changing the direction of shaking, achieved by turning the reactor. Reaction (1) ends after 120 minutes; this is judged by the absence of MD in the sample of a chloroform solution taken from the mixture. A suspension having the consistency of thick sour cream is discharged through the wide neck of the reactor onto the filter, sucked off and squeezed from the liquid phase. A light brown precipitate of BC on the filter was washed with 40 ml of CHCl ₃ to remove the residue of resins soluble in CHCl ₃ . The liquid filtrate consists of two phases: chloroform (lower layer) - 180 ml and an aqueous layer - 50 ml. Further washing from the resin precipitate on the filter is carried out in portions (20 ml) of anhydrous isopropanol. Washing is completed when the effluent iC ₃ H ₇ OH remains colorless. 4 to 6 washes are required. The washed precipitate (yellowish white) is dried in air at room temperature to constant weight (8-10 hours). The BC powder is sieved through a 0.2 mm sieve, packaged in a dark container and analyzed. The output of the aircraft is 88.26 g (75 wt.%); BC composition: 96.3 wt.%, NaHSO ₃ - 0.8 wt.%, Na ₂ SO ₄ - 2.7 wt.%, i.e. the drug meets the requirements of the State Pharmacopoeia.

Example 2. Similar to example 1, the difference is that the solvent MD is trichlorethylene (C ₂ HCl ₃ ).

In the reaction (1), 141 ml of a 6.5 molar aqueous solution of NaHSO _{3 are used} . A solution of 112 g of technical MD (88 wt.%) In C ₂ HCl ₃ with a volume of 394 ml has a concentration of 0.25 g MD / ml.

Get 152.61 g of a product containing 95.5 wt. % BC, 1.1 wt.% Na ₂ S ₂ O ₅ , 3.4 wt.% Na ₂ SO ₄ , which meets the requirements of the State Pharmacopoeia. The output of the sun is 77 wt.% Of theory. This example shows that increasing the yield of BC and increasing the content of stabilizing impurity Na ₂ S ₂ O ₅ in the product contributes to a decrease in the amount of water in the system, which is achieved by increasing the concentration of NaHSO ₃ in the aqueous solution.

Example 3. Similar to example 1, the difference is that the reaction is carried out at a lower ratio of NaHSO ₃ : MD. Use 161 ml of a 6.5 molar aqueous solution of NaHSO ₃ (1.05 mol) and 582 ml of a solution of technical (88 wt.%) MD in C ₂ HCl ₃ with a concentration of 0.221 g MD / ml (146 g MD). Get 216.7 g of a product containing 90 wt. % BC, 2.1 wt.% Na ₂ S ₂ O ₅ and 7.9 wt.% Na ₂ SO ₄ , which corresponds to a yield of BC equal to 79 wt.%. The product is suitable as a vitamin supplement in animal feed. This example confirms that the yield of BC, its content in the product, as well as the concentration of the stabilizing component Na ₂ S ₂ O ₅ vary depending on the concentration of NaHSO ₃ and the ratio of NaHSO ₃ : MD at the stage of BC synthesis. The last two parameters should be the basis for the optimal method of synthesis of aircraft, depending on the purpose of the product.

Example 4. Similar to example 1, only MD in trichlorethylene is present during the reaction in the form of a suspension. In this experiment, from 200 ml of C ₂ HCl ₃ and 94.32 g (88 wt%) of MD (0.482 mol) at 55 ^° C, 250 ml of a solution of MD with a concentration of 0.377 g of MD / ml are prepared. A hot MD solution is poured into the reactor, and there it is cooled to 23 ^o C. Due to the fact that the solubility of MD in C ₂ HCl _{3 is} highly dependent on temperature, a significant part (up to 30 wt.%) Of MD is released from the solution in the form of a mass of small crystals MD suspended in C ₂ HCl ₃ . To the resulting suspension was added 111 ml of a 6.5 molar NaHSO ₃ solution. Next, the experiment and the selection of the aircraft is carried out, as in example 1. Allocate 132.9 g of the product containing 92.6 wt. % BC, 0.72 wt.% Na ₂ S ₂ O ₅ and 6.4 wt.% Na ₂ SO ₄ . The output of the aircraft is 77.4 wt. % This experiment shows that the synthesis of BC by reaction (1) can be carried out not only from dissolved, but also from solid MD suspended in an organic solvent. It is necessary that MD be at least partially soluble in it.

Thus, as can be seen from the above examples, the proposed method for the preparation of vicasol in a two-phase system greatly simplifies and cheapens the method of purification and separation of aircraft, as well as the technology of regeneration of organic solvents. The resulting BC contains 0.5 - 2 wt.% Na ₂ S ₂ O ₅ , which stabilizes the BC and ensures its satisfactory storage and light fastness. The reaction of the synthesis of vicasol at a temperature below 40 ^o C prevents its isomerization during synthesis. The possibility of synthesizing BC from suspensions significantly expands the range of organic solvents applicable for carrying out reaction (1), since it allows the synthesis of vicasol from three-phase systems.

Claims (4)

1. The method of obtaining the sodium salt of 1,2,3,4-tetrahydro-2-methyl-1,4-dioxonaphthalene-2-sulfonic acid (Vikasol) by the interaction of 2-methyl-1,4-naphthoquinone (menadione) with an aqueous solution of sodium bisulfite (NaHSO ₃ ) obtained by reacting sodium sulfite with sulfur dioxide (SO ₂ ) in water, followed by isolation of the target product, characterized in that the reaction is carried out in a two-phase system consisting of immiscible aqueous and organic phases.  2. The method according to claim 1, characterized in that the aqueous phase is a solution of sodium bisulfite with a concentration of 4 to 6.5 mol / L.  3. The method according to claim 1, characterized in that the organic phase is a solution of menadione in a non-combustible solvent. 4. The method according to PP.1 and 2, characterized in that the reaction is carried out at a temperature not exceeding 40 ^o C.