SE204636C1 - - Google Patents

Description

CLASS INTERNATIONAL SWEDISH C07 d12 p: 11/01 PATENT AND REGISTRATION WINK Ans. 4551/1964 was received on 13/4 1964 issued on 27/9 196 CIBA SA, BASEL, SWITZERLAND Set for the preparation of an ether of reserve acid methyl ester and salts thereof with sedative and ataractic effect Inventor: MM Robison and RA Lucas Priority requested! The present invention relates to a process for the preparation of the novel 18-O-methylreserpyric acid methyl ester and its salts.

Salts of the new compound are especially therapeutically useful addition salts, especially of inorganic acids, e.g. mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric or phosphoric acids, or organic acids, such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, citric acid, citric acid, citric acid hydroxymaleic acid or dihydroximalic acid, or benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid or 2-acetoxybenzoic acid, or methanesulfonic acid, 2-sulfonic acid toluenesulfonic acid.

The new ether may be in the form of the racemate or in the form of the antipodes. Preferably it has the configuration corresponding to that of the hare's reserpine, which is extracted from plants of Rauwolfia species, i.e., it is present in its wintering form.

The new compound, especially in the form of an antiseptic antipode, and its salts have a predominantly sedative effect and ataractic properties, respectively, and only a weak, antihypertensive effect. They stand out in particular by the fact that, in contrast to the natural alkaloids with their slowly occurring and often undesirably long-lasting, pharmacological effects, they develop their effects significantly earlier and over a limited period of time, ie. the medication thus becomes easier to control. The therapeutically useful salts of the new compound, especially the addition salts of mineral acids, are also relatively inefficient and thus of excellent importance for the preparation of aqueous injection solutions or orally applicable preparations, such as elixirs. This is especially true of 18-O-methylreserpymmethyl ester hydrochloride.

The compounds prepared according to the present process can therefore be used as medicaments for human or veterinary medicine, in particular as sedative and ataractic agents for the treatment of hyperactivity, tension and irritation. Had they been able to e.g. used in the form of pharmaceutical preparations containing these compounds 1. ex. together with pharmaceutical, organic or inorganic, solid or liquid carrier materials suitable for enteral use, 4. ex. oral, or parenteral administration. For Mil-fling of the same questionable such subjects, which do not react with the new associations, e.g. water, gelatin; milk sugar, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, cholesterol or other carbide intermediates. The pharmaceutical preparations can e.g. available in the form of tablets, dragees; capsules or in liquid form as solutions, suspensions or emulsions. They may be sterilized and / or contain excipients, such as preservatives, stabilizers, wetting or emulsifying agents, salts for altering the osmotic pressure or buffer buffer. They may also contain other therapeutically valuable substances, e.g. hypotensive agents. The content 2 of the new active substance is suitably at 0.05-10%.

However, the new compounds can also be used in conjunction with ordinary feed responses. bar material such as animal feed or mom veterinary medicine. They can also serve as intermediates for the preparation of other, valuable compounds.

The new 18-O-methyl-serpyric acid methyl ester is obtained by the fact that 18-O-methyl-reserpic acid ester of the formula HH .11 140 DEG C. per se edge was transesterified with methanol in the presence of an inorganic or organic acid, an alkali metal, alkaline earth metal or aluminum alcoholate or an alkali metal allyanide or a strong, quaternary ammonium base and then 18-0-methyl-reserve acid methyl ester or salts1 thereof extracted and. the free base obtained may be converted to salts or salts obtained are converted to the free base. An acidic or basic substances are used as transesterification catalysts, e.g. inorganic acids, sasona tungstic acid, or organic acids, sasoin p-toluenesulfonic acid, but preferably alkali metal alcoholate, such as lithium, sodium or potassium alcoholate, alkaline earth metal, such as strontium or barium alcoholate, or the aluminum alcoholane, alkali metal cyanides, such as potassium cyanide, or strong quaternary ammonium bases, such as benzyl-trimethylammonium hydroxide. In addition to the methanol used as a reactant, other inert solvents or diluents can be used, e.g. aromatic hydrocarbons, such as benzene or toluene. The transesterification is carried out at room temperature, if required, at elevated temperature, and / or at elevated pressure and / or in the presence of an inert gas, e.g. kvave.

The preparation of the 18-O-methyl-reservoic acid esters or their salts as starting material is described e.g. in each German patent 1,1002.

The starting material using the 18-O-methylreserpic acid ester or the salts of these compounds may be dangerous in the form of racemates or in the form of antipodes. Preferably here they are the configuration corresponding to that of the winter-turning reserve, extracted from plants of Rauwolfia species.

The new 18-O-methyl-reserve acid methyl ester and its salts can also, like the starting product, be present either in the form of racemates or in the form of the optical antipodes. Rheematic 18-O-methyl-reserve acid methyl ester can be separated, for example, in the following manner: or chloroform, is reacted with an optically active acid and the salts obtained are separated, e.g. by their various solubilities, in the diastereomers, from which the antipodes of the new base can be released by the action of alkaline agents. Particularly useful optically active acids are the D- and L-forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, 10-camphorsulfonic acid or quinic acid.

Optically active forms of the above-mentioned compounds can also be obtained by means of biochemical methods.

Depending on the conditions of the process and the starting materials, the new compound is obtained in free form or in the form of its salts. Thus, for example, basic, neutral, acidic or mixed salts can be prepared, and possibly also hemi-, mono-, sesqui- or polyhydrate thereof. The salts of the new compound can be transferred to the free base, e.g. by reaction with a basic agent, e.g. aqueous ammonia. The free base can on the other hand be transferred to acid addition salts e.g. by reacting with one of the above-mentioned inorganic or organic therapeutically useful acids, optionally in the presence of a diluent, e.g., a. alkanol, such as methanol, ethanol, n- or i-propanol, a halogenated aliphatic carbonate, such as anethylene chloride or chloroform, or in a mixture thereof, optionally also in the presence of water.

The invention is described in more detail in the following examples. The temperatures are given in ° C.

Example 1. A mixture of 0.5 g of (-) - 18-0-methyl-reservoic acid ethyl ester, 50 ml of methanol and a few drops of benzyl-trimethylamine monium hydroxide is allowed to boil for some time under reflux. The residue is concentrated and the resulting 18-O-methylreserpic acid methyl ester is crystallized from a mixture of benzene-cyclohexane. Melting point 235-237 °. [a] 2; = 111 ° (in chloroform).

Example 2. To a solution of 1.5 g of (-) - 18-0-methyl-reserve acid methyl ester in 25 ml of acetone. Concentrated hydrochloric acid was added dropwise at room temperature with stirring, until the wrap of Congo root was obtained. The crystals of (-) - 18-O-methyl-reserve-acid methyl ester hydrochloride separated by scraping on the male rocks are filtered off and washed with cold acetone. Melting point 237-2420 (special division).

Claims (1)

1. Patent claim Process for the preparation of an ether of reserve acid methyl ester and salts thereof with sedative and ataractic action, characterized in that 18-O-methyl-reserve acid ester of the formula "11000 / \ / \ N / \ H / H 13100C \>, / OC1-13 H OCH3 or salts thereof, van denotes an alcohol residue with more than one carbon atom, pi per se edge salt is transesterified with methanol in the presence of an inorganic or organic acid, an alkali, metal, alkaline earth metal or aluminum carbonate or an alkali metal allyanide or a strong, quaternary ammonium base, to form 18-O-methyl-reservoir acid ethyl ester of the formula 1 1-13CO / \ / \ N / \ \ L 117 \ OCH3 or salts thereof, and that the resulting free base may be converted to salts or salts obtained are converted to the free base.