RU2063968C1 - Method of dihydroergocristine synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: ergocristine is hydrogenated over Raney nickel catalyst without addition of external hydrogen to reaction mixture. Catalyst is prepared by heating at 45-50 C for 1 hr followed by washing with water for 7-10 min up to pH = 7-8. EFFECT: improved method of synthesis.

Description

 The invention relates to the pharmaceutical industry, and in particular to methods for producing medicines from plants, in particular from ergot horns, the pharmacological activity of which is due to the presence of alkaloids called ergoalkaloids.

 Natural ergoalkaloids, for example ergometrine and ergotamine, are widely used in gynecological practice, and their dihydro derivatives for the treatment of peripheral circulation disorders.

 Recently, dihydroergocristine has become widely used abroad to treat cerebrovascular disorders.

Several methods have been proposed for the preparation of dihydroergocristine from ergocristine, which differ in the type of catalyst, as well as in the conditions for hydrogenation [1-3]
As you know, the most affordable catalyst is Nickel. Unlike other catalysts in the presence of Ni-Raney catalyst, hydrogenation can occur both in the presence of molecular hydrogen introduced into the reaction mixture and without it due to the hydrogen adsorbed on the catalyst that is formed at the time of preparation of the catalyst.

According to published data, the yield of the final product upon hydrogenation over a Ni catalyst under conditions of introducing molecular hydrogen at normal pressure is only 40% [2]
When hydrogenated with adsorbed hydrogen, i.e. remaining on the skeletal Ni catalyst at the time of its preparation from the Ni-Raney alloy, it was possible to increase the yield to 86% when hydrogenated in dioxane-methanol 9: 1 with a ratio of catalyst to ergocristine 2: 1 [4] This method was taken as a prototype.

 A positive factor of this method, in addition to a high yield, is that hydrogenation is carried out at normal pressure and without additional introduction of molecular hydrogen into the reaction mixture. A significant drawback of this method is the need to use large amounts of Ni-catalyst, namely 1 part of ergocristine must be taken 2 parts of Ni-Raney catalyst, in addition, the incomplete yield of the final product is 86% and the use of dioxane, which must be previously purified by distillation and dehydrated. Taking into account the easy flammability of dioxane, as well as its ability to form explosive mixtures with air, this solvent is undesirable in the factory.

 The aim of the present invention is to increase the yield of the target product, as well as reducing the amount of catalyst and the exclusion of dioxane.

This goal was achieved by the fact that:
1. The preparation of the Ni-Raney catalyst is carried out under mild conditions in order to maximize the saturation of the catalyst with hydrogen at the time of aluminum leaching from the Ni-Raney alloy. The prepared catalyst is used for hydrogenation immediately after preparation no later than 30 minutes after its preparation.

2. Hydrogenation is carried out in an environment of only one methanol, which allows to reduce the hydrogenation temperature by almost 40 ^o C (boiling point of dioxane 101 ^o C, methanol only 64 ^o C) and, thus, to avoid the rapid release of adsorbed hydrogen on the catalyst. Under these conditions, one double bond in the ergocristine molecule is completely restored.

 It is known [5–9] that the activity of a Ni-Raney catalyst depends on the conditions for its preparation, but especially on the temperature and time of leaching of aluminum, as well as on the duration and method of washing with water.

 If the literature describes in detail the methods for producing a Ni-Raney catalyst of varying degrees of activity for hydrogenation in the presence of molecular hydrogen introduced into the reaction mixture, the conditions for the preparation of a Ni-Raney catalyst for hydrogenation due to hydrogen adsorbed on the catalyst are not usually given.

 Experimentally, we found such conditions for the preparation of the catalyst that completely restored one double bond without affecting other structural units, which was also promoted by the low hydrogenation temperature by replacing the 9: 1 mixture of dioxane-methanol with methanol.

В таблице приведены данные по нахождению оптимальных условий приготовления катализатора из сплава Ni-Ренея и проведения гидрирования.Reaction scheme

The table shows the data on finding the optimal conditions for the preparation of the catalyst from Ni-Raney alloy and hydrogenation.

It was found that in the preparation of the catalyst, the optimal leaching temperature (bath temperature) is 45-55 ^o C (see examples 1 and 2); higher temperature (see example 3) leads to a decrease in the yield of the target product due to the loss of adsorbed hydrogen, lower temperature (see example 4) leads to insufficient saturation of the catalyst adsorbed by hydrogen, which also leads to a decrease in the yield of the target product.

 The optimal leaching time is 60 minutes (see examples 1-2), a longer duration leads to a loss (volatilization of adsorbed hydrogen (see example 5), which leads to a decrease in the yield of the target product; a shorter duration leads to insufficient saturation of the catalyst with adsorbed hydrogen, which also leads to a decrease in the yield of the target product (see example 6).

 The optimal duration of washing the catalyst with water is 7-10 minutes (see examples 1 and 2), a longer washing time leads to a decrease in the activity of the catalyst due to leaching of adsorbed hydrogen, i.e. to reduce the yield of the target product (see example 7); shorter washing time leads to insufficient purity of the catalyst, which, in turn, leads to by-products (see example 8).

 The optimal time for taking the catalyst into operation is no more than 30 minutes from the moment of its preparation (see examples 1-2), a longer interval leads to a decrease in the activity of the catalyst due to the volatilization of adsorbed hydrogen, i.e. to reduce the yield of the target product (see example 9).

 The possibility of reproducing the method of preparing the catalyst according to the prototype is excluded, since important cooking parameters (bath temperature, duration of heating, duration of washing with water, time of taking the catalyst to work) are not indicated.

 The table also contains data on finding the optimal conditions for hydrogenation (the substance-methanol-catalyst ratio and hydrogenation duration), from which it follows that one double bond is completely restored in ergocristine with the substance-methanol-catalyst ratio 1: 14: 0.5 (see examples 1-2), and the ratio of the substance-methanol-catalyst are interconnected. An increase in the amount of methanol does not give complete hydrogenation (the starting product remains, see Example 10), a decrease in the amount of methanol leads to the appearance of by-products (see Example 11).

 A decrease in the amount of catalyst does not give complete hydrogenation (see example 12), an increase in the amount of catalyst gives unambiguous data as in examples 1 and 2, i.e. the increase in the amount of catalyst is not economically feasible (see example 13).

 The optimum hydrogenation temperature is 30 minutes (see examples 1 and 2). Reducing the hydrogenation time does not give complete hydrogenation (see example 14), and increasing the hydrogenation time is not economically feasible (see example 15).

Optimal parameters
Example 1. 7.0 g of a Ni-Raney alloy is carefully added to 40 ml of freshly prepared 20% sodium hydroxide solution over an hour while cooling with ice water, after which the reaction mixture is heated in a water bath at a bath temperature of 45-55 ^o C for 60 minutes. The alkaline solution is drained by decantation, the black powder (Ni-Raney catalyst) is washed with water for 7-10 minutes with gentle stirring until a slightly alkaline reaction (pH between 7-8 according to the universal indicator), then 2 times also carefully washed with methanol. Using 30 ml of methanol, the catalyst was transferred to a hydrogenation flask in which 4.0 g of ergocristine were previously dissolved in 26 ml of methanol. The reaction mixture is boiled for 30 minutes under reflux and with stirring. According to thin-layer chromatography, the substance was completely hydrogenated. The catalyst is filtered off, the solvent is completely distilled off in a water bath under vacuum, the residue is dissolved in chloroform, 20 g of basic aluminum oxide III tbsp. Are passed through a layer. activity to remove catalyst residues, evaporated to a volume of 10-12 ml, left in the refrigerator for 3-4 hours, the crystals are filtered off, washed with benzene, dried in a vacuum oven for 6 hours at 30-32 ^o C and get 3.84 g white crystals with so pl. 200-201 ^o C, which corresponds to the literature data for dihydroergocristine [3] by TLC one substance without impurity in the NMR spectrum is dihydroergocristine. The yield of the target product 96%
Outrageous parameters.

Example 4. 7.0 g of Ni-Raney alloy is carefully added to 40 ml of a 20% sodium hydroxide solution over an hour while cooling with ice water, after which the reaction mixture is heated in a water bath at a bath temperature of 40-45 ^o C for 60 minutes. Further, as in example 1.

According to TLC, 90% was hydrogenated (there is a spot of the starting substance). The yield of the target product 80%
Example 8. 7.0 g of a Ni-Raney alloy is carefully added to 40 ml of a 20% sodium hydroxide solution overnight with cooling with cold water, after which the reaction mixture is heated in a water bath at a temperature of 45-55 ^o C for one hour. The alkaline solution is drained by decantation, the black powder is washed with water for 3-5 minutes with gentle stirring until an alkaline reaction (pH about 9 according to the universal indicator), then 2 times with methanol. Further, as in example 1. According to TLC, 89% was hydrogenated (many by-products). The yield of the target product 70%
Example 11. 7.0 g of the Ni-Raney alloy is carefully added to 40 ml of freshly prepared 20% sodium hydroxide solution over an hour while cooling with ice cold water, after which the reaction mixture is heated in a water bath at a bath temperature of 45-55 ^o C for 60 minutes The alkaline solution is drained by decantation, the Ni-Raney catalyst (black powder) is washed with water for 7-10 minutes with gentle stirring until a slightly alkaline reaction (pH between 7-8 according to the universal indicator), then 2 times also carefully washed with methanol. Using 30 ml of methanol, the catalyst was transferred to a hydrogenation flask in which 4.0 g of ergocristine were previously dissolved in 22 ml of methanol. Further, as in example 1.

According to TLC, 98% of the starting material was hydrogenated. However, along with this, 2% of by-products are formed, which are very difficult to separate from the target product. The yield of the target product 85%
The novelty in the claimed method is the special conditions for the preparation of the Ni-Raney catalyst, which reduced by 4 times its costs for the hydrogenation reaction, as well as hydrogenation in only one without dioxane.

A significant difference of the proposed method from the prototype is to increase the yield of the final product (dihydroergocristine) by 10
According to the proposed method, the technological regulations for the production of dihydroergocristine in industrial production are developed. TTT1 TTT2

Claims (1)

A method of producing dihydroergocristine, comprising hydrogenating ergocristine over a Ni-Raney catalyst, characterized in that the hydrogenation is carried out at a ratio of ergocristine-methanol-catalyst 1: 14: 0.5 over a catalyst obtained no later than 30 minutes before the reaction, wherein the catalyst is obtained by heating at 45-50 ^o C for 60 ', followed by washing with water for 7-10 minutes to a pH of 7-8.

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