HU194265B - Process for producing 1,4-3,6-dianhydro-d-gluate-5-nitrate - Google Patents

Abstract

In a novel prepn. of 1,4-3,6-dianhydro- D-glucitol-5-nitrate, 1,4-3,6-dianhydro- D-glucitol-2-acetate is nitrated to a 2-acetate-5-nitro deriv. Selective hydrolysis of the nitro deriv. follows without isolating it, using 1.0-1.6 mole alkaline carbonate per 1 mole of starting material in a medium contg. water and alkanol (1-3C) and in this case also a chlorinated solvent at 20-80 deg.C.

Description

The present invention relates to a novel process for the preparation of 1,4-3,6-dihydro-D-glucinate-5-nitrate, to nitration of 1,4-3,6,6-dianhydro-D-glucitol-2-acetate, and to the resulting 2-acetate. By hydrolysis of 5-nitro number derivatives.

The compound of the present invention is a nitrite formulation for the treatment of coronary heart and heart disease which is better than the corresponding 2,5-dinitrate derivative (Arzneim.-Forsch. 34, 1779 (1984)).

There are several methods known in the art for the preparation of 1,4-3,6-dianhydro-D-glucitol-5-nitrate.

One group of methods is not suitable for protecting a hydroxyl group at position 2. This method was used to work on the application of No. 3,028,289. The authors of US Patent Publication No. 1,4,3,6-dianhydro-D-glucitol were used as starting material which was known to be nitrated with 65% nitric acid in acetic anhydride glacial acetic acid and to form 2-nitrate and 5-nitrate. -nitrate isomers were separated by cumbersome chromatography. The yield of the 5-nitrate derivative is only 23%. The disadvantage of this process is that additional isomers such as 2,5-dinitrate are also produced, which results in low yields and poor purification.

The authors of U.S. Patent No. 2,221,080 also obtained the 5-nitrate derivative from the resulting nitrate isomers by chromatography. The disadvantage of the process is the complex and inefficient cleaning.

Another method starts with a 2,5-dinitrate derivative using a nitrate ester protecting group. Such a procedure was implemented in U.S. Patent No. 3,261,256. The authors of the German patent patent, when 2,5-dinitrate was partially reduced with hydrazine hydrate to a mixture of 2- and 5-mininitrates. The disadvantage of this process is that the highly explosive 2,5-dinitrate was used as starting material and at the end of the reaction, an isomeric mixture was formed which was not the main product of the 5-nitrate derivative.

A third group of methods are those which use a carboxylic acid (aliphatic, aromatic) or trityl group to negate the hydroxyl group at position 2. For example, the authors of Spanish Patent No. 518807 used p-nitrobenzoyl as a protecting group. The 2- (4-nitrobenzoyl) compound thus obtained was nitrated with acetyl nitrate and deprotected with an alcoholic potassium hydroxide. For recrystallized pure material, the specification does not include production data. The disadvantage of this method is that it does not yield pure uniform glucitol-2-p-nitrobenzylate. This product was nitrated to give a mixture containing glucitol-2-p-nitrobenzoate-5-nitrate, which needed further purification.

Starting from isomannide and employing a benzoate protecting group, U.S. Pat. Authors of publication document in the Federal Republic of Germany. The isomannide-2-p-toluenesulfonate obtained in the first step was converted to 1,4-, 3,6-dihydro-D-glucit-2-benzoate by Wladen inversion. This compound was nitrated with acetyl nitrate, re-esterified in ethanol to remove the 2-benzoate group in the presence of potassium potassium hydroxide, or hydrolysed with aqueous sodium hydroxide solution. The disadvantages of the process are the long synthesis route and the unpleasant fact that the two oily intermediates obtained cannot be purified.

No. 18,385/58. The authors of the Japanese patent application (unpublished) used a trityl protecting group for selectivity. Their procedure was described for an experiment containing only a mg of material, which is unsuitable for industrial implementation.

No. 3,028,873. In the German Patent Publication, a mixture of 2-acetate, 5-acetate, 2,5-diacetate formed from acylation with 1,4 -,6-dianhydro-D-glucitol with acetic acid anhydride was nitrated with acetyl nitrate and then formed with 2-acetate. The 5-nitrate derivative was isolated and hydrolyzed in aqueous medium with half equivalent of sodium hydroxide. The disadvantage of their method is very low production.

No. 3,102,947. The authors of the German patent application nitrated the 2-acetate derivative with acetyl nitrate and then extracted the 2-acetate-5-nitrate derivative with dichloromethane. After evaporation of dichloromethane, the 2-acetyl group was removed by transesterification in methanol in the presence of a catalytic amount of sodium methylate. The disadvantage of the process is that solvent exchange had to be performed before the transesterification was carried out. The process, even with the pure 2-acetate-5-nitrate derivative, yields only 60% yield.

No. 3,117,612. The authors of US Patent Publication No. 1,4-3,6-dianhydro-D-glucitol used as a starting material, first acylated with acetic acid, then nitrated with acetyl nitrate without isolation and, after extraction with dichloromethane, in the presence of 0.2 equivalents of potassium hydrate. in an alcoholic solution, the 2-acetyl group was removed by transesterification. Reproduction, in 60% yield, gave a mixture of acetate derivatives containing a significant amount of 2-acetate (47%) 5-acetate. This corresponds to a yield of 28.2% of the starting material, so that in practice the described 42% yield of 5-nitrate derivative cannot be achieved or approached. This was clearly demonstrated in our experimental data.

It was further found that the transesterification and / or hydrolysis reaction is not selective and cannot be controlled due to its rapid reaction progress. When hydrolysis is carried out with an equivalent of aqueous alkali, it produces only 26.9% yield (see German Patent Publication No. 3,117,612). A similar procedure was used by the authors of German Patent Publication No. 3,128,102, except that 0.4 molar equivalents of potassium hydroxide were used instead of 0.2 molar equivalents. According to the data, this process is extremely difficult to follow and is not selective.

Summarizing the processes known so far, it can be seen that several steps were required, with surprisingly low yields and a lack of uniformity in the supply of 1,4- 3,6-dianhydro-D-glucititrate nitrate. selective and highly controllable

It is therefore an object of the present invention to provide a process which, purely in a technological step and in good yield, provides purely 1,4-3,6-dianhydro-D-glucitol-5-nitrate in a process which is easy to carry out.

The present invention is based on the discovery that the product obtained by nitration of 1,4-3,6-dianhydro-D-glucitol-2-acetate: 1,4,4,6,6-dianhydro-D-glucitol-2-acetyl-. 5-nitrate need not always be recovered from the reaction mixture, but also its chlorinated hydrocarbon solution, preferably dichloromethane, in which the nitration reaction actually takes place, is capable of removing the 2-acyl group by hydrolysis,

The present invention is further based on the discovery that hydrolysis with non-alkali metal hydroxides (e.g.

194.265 sodium hydroxide or potassium hydroxide), but must be performed with an alkali metal carbonate in aqueous solution in the presence of alkanols. It has been found that, for example, when potassium carbonate is used, the hydrolysis is selective, i.e., only the acetyl group at position 2 is hydrolyzed. This finding is surprising because it was not expected that the hydrolysis would be so selective in the given system, that is, the nitro group would remain unchanged.

Accordingly, the present invention provides a process for the preparation of 1,4-3,6-dianhydro-D-glucitol-5-nitrate, the nitration of 1,4-, 3,6-dianhydro-D-glucitol-2-acetate and the resulting 2-acetate-5-nitrate. hydrolysis of the nitro number derivative, which comprises obtaining, after conventional nitration, 1,4-3,6-dianhydro-D-glucit-2-acetate-5-nitrate, optionally without direct isolation from the reaction mixture, It is selectively hydrolyzed at a temperature of 20 ° C to 80 ° C with 1.0 to 1.6 mol of alkali metal carbonate per mole of starting material in a mixture of water and C 1 -C 4 alkanol and optionally chlorinated hydrocarbon.

In a preferred embodiment of the process according to the invention, the alkali metal carbonate is potassium or sodium carbonate.

Ethanol and methanol have been found to be the most preferred C 1-4 alkanols for hydrolysis. Alternatively, after nitration in a chlorinated hydrocarbon, without hydrolysis of the solvent, hydrolysis can be carried out directly in a reaction medium supplemented with a year of water and an alkanol, preferably water and ethanol.

Thus, according to the invention, a solution of 1 mole of 1,4-3,4,6-dianhydro-D-glucit-2-acetate in dichloromethane is nitrated with 1 to 1.2 moles of acetyl nitrate, and the remaining trituration agent is decomposed and dichloromethane and the dichloromethane solution is hydrolyzed with 1.0-1.6 molar potassium carbonate in aqueous ethanol. The hydrolysis is carried out at 20-80 ° C, preferably 60 ° C. The product is obtained by extraction after removal of the organic solvents.

The advantages of the process according to the invention can be summarized as follows:

1. The process does not require any special technological equipment and is very simple to carry out.

2. The procedure is simple to carry out and involves few steps.

3. The reaction is selective and well controlled, and a good quality end product is available.

The invention is illustrated by the following non-limiting examples.

Example 1 A 10 cm ³ glacial acetic acid and 6.12 g (5.66 cm ³ , 0.06 mol) of acetic anhydride were weighed into a ^three -necked 50 cm ³ round-bottom flask equipped with a thermometer, a dropping funnel and a calcium chloride tube. The mixture was cooled to -5 ° C with external salt-ice cooling and 3.78 g (2.41 cm ³ , 0.06 mol) of 100% nitric acid was added dropwise with stirring, so that the internal temperature was 0 ° C. not higher. Another

9.4 g (0.05 mol) of 1,4,4,3,6-diandihydro-G-glucitol-2-acetate in 40 cm ^{3 of} anhydrous dichloromethane were weighed into a 150 cm ³ necked flask. The flask is equipped with a reflux condenser, a dropping funnel and a thermometer. The previously prepared 0 ^e C nitrating mixture

15-20 ° C with stirring. After completion of the reaction, the mixture was poured into 50 cm ^{3 of} ice-water. The two phases are separated and the aqueous phase is extracted with 10 cm ^{3 of} dichloromethane. The combined organic phases> 0 were washed; 40 cm ^{3 of} 10% sodium bicarbonate solution. The organic phase was poured into 250 cm ³ gömlombikba and treated with 100 cm ³ of ethanol and treated with potassium carbonate (10.4 g, 0.075 mol) in 40 cm ³ of water. Stir for 16 hours at 60-70 ° C. After completion of the reaction, the reaction mixture was neutralized with a 1: 1 dilute hydrochloric acid solution and concentrated. The residue was dissolved in 40 cm ^{3 of} water and extracted twice with 30 cm ^{3 of} dichloromethane. The organic layers were combined, dried and evaporated. The residue was crystallized from chloroform-carbon tetrachloride.

Yield: 5.69 g (59.6%) of 1,4,4,3,6-D-glucitol-5-nitrate. M.p. 88-90 ° C [ ^α ] D 20 = -173 ° (c = 1.0 methanol).

Example 2

1,4-3,4,6-Dianhydro-D-glucitol-2-acetate-5-nitrate (2.33 g, 0.01 mol) was dissolved in 20 cm ^{3 of} ethyl alcohol and 1.39 g (0.01 mol) of potassium was added. carbonate in 2 cm ^{3 of} water. The mixture was stirred at 50 ° C for 1 hour, and after the reaction was complete, neutralized with hydrochloric acid (1: 1) and concentrated. The residue is taken up in 20 cm ^{3 of} water and extracted twice with 20 cm ^{3 of} dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated. The residue was crystallized from chloroform-carbon tetrachloride (3: 1).

Yield: 1.45 g (75.9%) of 1,4,4,3,6-D-glucitol-5-nitrate, m.p. 88-89 ° C.

[α] ²⁰ D = + 174 ° (c = 1.0 methanol)

Claims (3)

40 Claims A process for the preparation of 1,4-6,6-dianhydro-D-glycity-5-nitrate, nitration of 1,4-, 3,6-dianhydro-G-glucitol-2-acetate, and the resulting 2-acetate-5nitrate derivative. hydrolysis, characterized in that the nitration 1,4-3,6-dianhydro-D-glucitol-2-acetate-5-nitrate obtained after 45, optionally with 1.0-1.6 moles of alkali metal carbonate per mole of starting material without direct isolation from the reaction mixture, water and is optionally hydrolyzed in a mixture of C 1 -C 4 alkanol and optionally chlorinated hydrocarbon at a temperature of 20 ° C to 80 ° C. Process according to claim 1, characterized in that the alkali metal carbonate is potassium or sodium carbonate. Process according to claims 1 and 2, characterized in that the C 1 -C 6 alkanols are methanol, ethanol, chlorinated hydrocarbon-dichloromethane, chloroform without