DE3405663A1 - Process for the preparation of scyllo-inositol - Google Patents

Abstract

A process for the preparation of scyllo-inositol from myo-inositol via myo-inosose, in which the mixture obtained after the oxidation is subjected to an esterification in which a well-crystallising ester of myo-inosose is formed, which is then converted into scyllo-inositol by reduction and hydrolysis.

Description

Process for the production of scyllo-inositol

Process for the preparation of scyllo-inositol The invention relates to a process for the production of scyllo-inositol from myo-inositol.

A whole series of display methods for the in Flora and fauna widely known natural substance scyllo-inositol [for example through biological oxidation of myo-inositol to myo-insosis and reduction (Th. Posternak, Helv. Chim. Acta, 24, 1045 (1941); by hydrogenation of hexahydroxybenzene (R.C. Anderson and E.S. Wallis, J. Am. Chem. Soc. 70: 293 (1948); by reducing Pentaacetyl-myo-inosose with NaBH4 and saponification (N.Z. Stanazev and M. Kates, J. Org. Chem. 26, 912 (1961); by basic condensation of "D-xylo-Hexos-5-ulose" on myo-inososis and reduction (D.F. Kiely and H.G. Fletscher, J. Am. Chem. Soc. 90, 3289 (1968) and by nucleophilic opening of cis-trioxatris-a-homobenzene (R. Schwesinger, H. Fritz and H. Prinzbach, Angew. Chem. 85, 1110 (1973) 1.

The method of selective, catalytic oxidation of the axial hydroxyl group des myo-inositol with Pt / 02 [K. Heyns and H. Paulsen, Chem. Ber. 86, 833 (1953) or Applied

Chem. 69, 600 (1957)] on myo-inososis and its reduction [D. Reymond, Helv. Chim. Acta, 59, 492 (1957) 3 appeared in as few synthetic and purification stages, starting from cheap and easily accessible raw materials, lead to the desired product.

Since, however, only sales of 75-80% are achieved, is a separation of the unreacted starting material necessary to obtain scyllo-inositol in high purity during the subsequent reduction obtain. The method proposed by Heyns and Paulsen via the phenylhydrazone the myo-inososis is not justifiable on a semi-industrial or technical scale Effort can be carried out and, moreover, would result in undesirable wastewater pollution to lead. Our own tests also showed that the phenylhydrazone method is extraordinary was difficult to reproduce.

The object of the present invention was now to provide an improved process for the synthesis of scyllo-inositol and for the separation of unreacted myo-inositol from its myo-inosose containing oxidation products that contain the described No disadvantages or only to a lesser extent.

This problem has been solved by doing that after the oxidation the mixture obtained from the myo-inosite is subjected to esterification and the myo-inososis selectively crystallized out as a well-crystallizing ester. These esters can subsequently converted into scyllo-inositol by reduction and hydrolysis.

The invention thus provides a method for producing scyllo-inositol from myo-inositol via myo-inosose, characterized in that the subjecting the mixture obtained after the oxidation to an esterification, at which creates a well-crystallizing ester of myo-inosose, which subsequently is converted into scyllo-inositol by reduction and hydrolysis, and a process for the separation of unreacted myo-inositol from its myo-inosose containing Oxidation products, characterized in that the myo-Inosose as well crystallizing Ester is selectively crystallized out.

The oxidation of myo-inositol can in principle according to all known Processes are carried out, for example by biological oxidation or by selective oxidizing agents such as N-bromosuccinimide, silver carbonate / Celite or chlorine / pyridine. The oxidation is preferably carried out in aqueous solution at 30-800, in particular at 45-60 ° as catalytic dehydrogenation with noble metal catalysts, preferably Platinum catalysts, and oxygen.

The reaction mixture can be esterified without further purification operations will. The reaction mixture is preferably evaporated after the catalyst has been removed. The residue is esterified with an acid or one of its reactive derivatives. Acid halides, above all, are particularly suitable as reactive derivatives the chlorides and bromides, anhydrides (also mixed anhydrides), also azides or Esters, especially alkyl esters with 1-4 carbon atoms in the alkyl group.

The esterification can be carried out in the presence of an inert solvent will. Amides such as dimethylformamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone or phosphoric acid hexamethyltriamide and sulfoxides such as dimethyl sulfoxide or sulfolane. The esterification can also be beneficial in the absence a solvent, e.g. B. by simply mixing the components, possibly in the presence of a strong acid. The reaction temperature is usually between -200 and 800, preferably between 0 ° and 50 ".

The esterification reactions are usually at these temperatures Finished in 15 minutes to 48 hours.

In detail, the reaction conditions for the esterification largely depend on the nature of the acids (or their reactive derivatives) used. So a free carboxylic acid is usually in the presence of a strong acid, for example a mineral acid such as hydrochloric acid or sulfuric acid. A preferred one The reaction is the conversion of an acid anhydride (preferably a carboxylic acid anhydride such as acetic anhydride, propionic anhydride or butyric anhydride) or one Acid chloride with the reaction mixture. This implementation is preferably done in one acidic environment, the acids being mineral acids such as hydrochloric acid or sulfuric acid, Organic acids such as p-toluenesulfonic acid or Lewis acids are important.

The implementation can, however, also in a basic medium, for example in the presence of alkali metal carbonates or bicarbonates such as sodium carbonate, Sodium hydrogen carbonate, potassium carbonate or potassium hydrogen carbonate, alkali metal acetates such as sodium or potassium acetate, alkaline earth metal hydroxides such as calcium hydroxide or organic bases such as triethylamine, pyridine, lutidine, collidine or quinoline.

In particular, aliphatic carboxylic acids (for example Acetic acid, propionic acid, butyric acid) or aromatic carboxylic acids (for example Benzoic acid). Substituted benzoic acids can also be used.

The esterification reaction mixture is carried out in a manner known per se worked up and the ester derivative of myo-inosose by crystallization from a suitable solvent obtained. Particularly suitable solvents are Ethers such as diethyl ether, di-isopropyl ether, di-n-propyl ether or di-n-butyl ether, Ketones such as acetone or methyl ethyl ketone, alcohols such as methanol, ethanol, n-propanol or isopropanol, esters such as ethyl acetate or mixtures of such solvents. Particularly Solvent mixtures which predominantly consist of ethers and 1 to are preferred 10, in particular 2 to 5% by volume of alcohol.

The well-crystallizing ester derivatives of myo-inosose are largely free of ester derivatives of myo-inositol and can be used for representation without further purification by scyllo-inositol or for other purposes. One further recrystallization usually leads to a lowering of the melting point.

The reduction and hydrolysis of the ester derivatives of myo-inosose too In principle, scyllo-inositol can be carried out by all known methods, preferably through a modification or combination of known regulations [A. Kirsch, C. von Sonntag and D. Schulte-Frohlinde, J. Chem. Soc., Perkin II, 1975, 1334 and N.Z. Stanazev and M. Kates, J. Org. Chem. 26, 912 (1961)]. The ester derivative of myo-inososis is reduced with sodium borohydride / methanol. To separate the borate, the After acidification, the reaction mixture is mixed several times with methanol and the same without Distilled off under vacuum. Crystallization turns the residue into pure scyllo-inositol obtain.

The following example is intended to explain the invention without limiting it: Presentation of the platinum catalyst: 8.5 g of platinum (II) oxide are dissolved in 125 ml of water hydrogenated with stirring at room temperature under normal pressure until hydrogen uptake has practically ended or slowed down significantly (approx. 24 h). This is an overhydration, identified by the deposition of a metal mirror or metal flakes, to be avoided, otherwise the effectiveness will decrease. The platinum suspension thus obtained is by multiple Evacuation of hydrogen freed and can go directly to the following regulation can be used.

The catalyst can be used for several reaction cycles.

Penta-O-acetyl-myo-inosose: In a mixture of 700 ml of water, 16.0 g myo-inositol and the Pt catalyst obtained from 8.5 g platinum (II) oxide by hydrogenation a stream of oxygen is passed in with stirring at 50-55 ° C. for 5 hours. Of the Catalyst is then filtered off and can be used repeatedly. The filtrate is evaporated and the reaction product is cooled with ice with a mixture from 106 ml of acetic anhydride and 6 ml of conc. Sulfuric acid added and 24 hours Room temperature stirred. The reaction mixture is poured onto 500 ml of water, three times extracted with ethyl acetate and the combined organic phases are each three times washed with 100 ml of saturated sodium hydrogen carbonate and sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue is initially with 10 ml of methanol and then mixed with 300-400 ml of ether and over Chilled out at night. The crystal precipitate formed is filtered off with suction and washed with ether rewashed.

Yield: 4-6 g, m.p .: 205-209 OC.

The pentaacetate obtained in this way still shows little in the 400 MHz NMR spectrum Contamination by the hexaacetate of myo-inositol, but can occur without further purification can be used to represent scyllo-inositol.

Scyllo-Inositol: To a suspension of 5.0 g of pentaacetate of myo-inosose in 125 ml absolute Methanol becomes the solution of 0.75 while stirring at room temperature g sodium borohydride in 125 ml absol. Added dropwise methanol and a further 30 min at room temperature touched. The solution is acidified with 2N hydrochloric acid and concentrated to 20 ml. To the Separation of the borate is mixed several times with 200 ml of methanol and distilled off. It is then evaporated to dryness, the residue is dissolved in 30-50 ml of water, filtered through a cation exchange column (100 g Levatit SC 102 H) and washed with water washed until the filtrate reacts neutrally. The aqueous solution is up to about 20 ml concentrated, mixed with 200-250 ml of methanol and placed cold.

The scyllo-inositol deposited as fine, colorless crystals becomes suctioned off and washed with methanol.

Yield: 1.6-1.8 g, m.p .: 345-347 OC.

Concentration of the mother liquor produces a second, less pure crystallizate can be obtained.

Claims (3)

Claims 4, 'Process for the production of scyllo-inositol myo-inositol over myo-inosose, characterized in that it is done after the oxidation The mixture obtained is subjected to an esterification, in which a well crystallizing Ester of myo-inosose is formed, which is then converted into scyllo-inositol is transferred. 2. The method according to claim 1, characterized in that the Performs esterification with carboxylic acids or their reactive derivatives. 3. Process for the separation of unreacted myo-inositol its myo-inosose-containing oxidation products, characterized in that the myo-inosose is selectively crystallized out as a well-crystallizing ester.