DE1072248B - Process for the preparation of quinuclidine-3-carboxylic acid esters and their salts - Google Patents

Description

GERMAN

070 02

C 11874 IVb / 12 ρ

A N M E L D E T AG: SEPTEMBER 27, 1955

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: DECEMBER 31, 1959

The invention relates to a method of manufacture of quinuclidine-S-carboxylic acid esters and their salts. These compounds are persistent and therapeutically effective. So they show pronounced sympathicomimetic ones Properties that are of practical importance for a therapeutic effect on the disturbed intestinal function are. They are said to be used as remedies.

The new compounds are obtained if one reacts quinuclidone (3) with hydrocyanic acid in converts the nitrile group of the cyanohydrins obtained into an esterified carboxyl group in a manner known per se, wherein the 3-oxy group at any stage of the process by treatment with dehydrating agents Means is removed, the formed l-azabicyclo- (2,2,2) -octen- (2) -carbqnsäureester- (3) catalytically hydrogenated and optionally obtained bases with inorganic or converts organic acids or produces the free bases from the salts obtained.

These reactions can be illustrated, for example, by the following equation:

N '

HCl

OH

COOCH,

COOCH,

In the addition of hydrocyanic acid to quinuclidone- (3), it is advantageous to start from a salt the hydrocyanic acid, such as the potassium or sodium salt, and sets the acid in a weakly acidic reaction medium In freedom. A quinuclidone salt, such as a hydrohalic acid, is used in particular Salt, in aqueous solution. The conversion of the nitriles into the carboxylic acid esters takes place in a manner known per se Way, e.g. B. by hydrolyzing and esterifying or acidic alcoholysis. The esterification of a preserved Carboxylic acid happens z. B. by implementing the ent manufacturing process

of Chmuclidine-S-carboxylic acid esters

and their salts

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority: Switzerland of October 8, 1954

Dr. Cyril A. Grob, Basel (Switzerland), has been named as the inventor

speaking acid chloride with alcohols, preferably with lower alcohols. Let out of the oxy compounds at any stage of the process by dehydration, e.g. B. with thionyl chloride, the corresponding 2,3 unsaturated quinuclidine derivatives whose double bonds react with hydrogen, such as catalytically Let excited hydrogen, especially in the presence of a platinum catalyst, saturate.

Depending on the embodiment of the process, the quinuclidine-3-carboxylic acid esters are obtained in the form of free bases or their salts. The bases can be obtained from the salts in the usual way; free bases can be converted into their salts by known methods. They are suitable for the formation of therapeutic Usable salts those with inorganic acids, such as hydrohalic acids, sulfuric acids, nitric acid, Phosphoric acids, hydrofluoric acid, or with organic acids such as acetic acid, propionic acid, oxalic acid, Malonic acid, succinic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, oxyethanesulfonic acid, Benzene or toluenesulfonic acid.

The 3-quinuclidones mentioned as starting materials are known or can be produced in a manner known per se.

The invention is further illustrated in the following examples explained.

example 1

To an ice-cold solution of 18 g of quinuclidone-3-hydrochloride in 22.5 cm ^{3 of} water, a solution of 7.3 g of potassium cyanide in 22.5 cm ^{3 of} water is added in the course of

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Claims (2)

Added dropwise for 15 minutes. The crystalline cyanohydrin which soon separates out is stirred for a further hour at 0 ° C., nitrated off and washed with a little ice water. After drying, 16 g of the colorless S-Oxy-S-cyano-quinuclidine are from. F. 153 to- 155 °; G- er- _ hold. The compound crystallizes in colorless prisms from dioxane. 159 ° C (decomposition). ., In a very pure ..state .. it melts at 172 to .173 ° C (decomposition): 1 ": ■" '- "" l 9.5 g S-Oxy-S-cyano-quinuclidine ■ are dissolved in 130 cm8 of concentrated hydrochloric acid and left to stand for 48 hours at room temperature. Then it is completely evaporated in vacuo, the crystalline residue (F. des · S-oxy-quinuclidine-ß-carboxylic acid hydrochloride after crystallization from ethanol-ether 252 to 255 ° C), with, 130: cm ^ at 0oiC; Absolute methanol saturated with hydrogen chloride is added and the mixture is left to stand for 48 hours at 20 ° C. with occasional shaking. Evaporation gives 12.5 g of the strongly hygroscopic hydrochloride of S-oxy-S-carbmethoxy-quinuclidine. This salt is obtained directly if the cyanohydrin is treated with hydrous, methanolic hydrogen chloride in the manner indicated. To isolate the free ester base, ice-cold, concentrated potassium carbonate solution is added to the salt and the "precipitated" base is extracted with chloroform. The chloroform solution is dried over potash and evaporated, 8.9 g of S-oxy-S-carbmethoxyquinuclidine remaining. This crystallizes from chloroform-pentane in rosettes with a melting point of 122 ° C. 8.8 g of S-oxy-S-carbmethoxy-quinuclidiri are introduced in portions into 50 cm3 of ice-cooled thionyl chloride, and the solution is then refluxed for 48 hours. The resulting dark yellow solution is completely evaporated in vacuo and the crystalline residue is taken up in hot acetone, boiled with a little animal charcoal and filtered. When the acetone solution is concentrated, 7 g of hydrochloride des '3-carbmethoxyl-azabicyclo- (2; 2,2) -octene- (2) crystallize in colorless needles with a temperature of 178 to 179 ° C.: ^' / '; "; {^ r \ ^: ^ -V ^ - U :. ik-k To isolate the free / ester base, ice-cold concentrated potassium carbonate solution is added to 2g1 of this salt, and the base which has separated out is extracted with chloroform. The chloroform solution is dried over potash and evaporated, 1.1 g (65 ° / 0) of 3-carbmethoxy-1-azabicyclo- (2,2,2) -octen- (2) remaining, which is distilled in vacuo: bp 114 ° C. at 15 mm pressure. In the refrigerator, the distillate crystallizes in colorless crystals. A solution of 6.4 g of 3-carbomethoxy-1-azabicyclo- (2,2,2) -octen- (2) -hydrochloride in 50 cm3 of methanol is hydrogenated in the presence of 0.3 g of platinum at room temperature and normal pressure, the calculated amount of hydrogen being absorbed. The solution is filtered and evaporated and the residue is recrystallized from acetone, 6 g of the S-carbmethoxy-quinuclidine being obtained as a slightly hygroscopic hydrogen chloride with a temperature of 167 ° to 169 ° C. The reduction can be carry out the same result in the presence of a palladium catalyst, such as palladium alone or palladium on a carrier, for example palladium on activated carbon, with the same result: A solution of 22.3 g of the free 3-carbmethoxyl-azabicyclo- (2,2,2) -octene - (2) in 150 cm3 of methanol is hydrogenated in the presence of 1.0 g of platinum at room temperature and normal pressure, the calculated amount of hydrogen being taken up. The solution is nitrated and evaporated and the residue is distilled in vacuo, where 15.8 g of free 3-carbmethoxy: quinuclidine with a boiling point of 110 ° C at 15: mm pressure. '' '■' ■ '■,:';; ·: ';' -! ':: ■ :. ■: ■■ ■■ Example, don (3) hydrochloride were obtained in 100 cm3 of methanol saturated with hydrogen chloride for 24 hours1 at 20 ° C 'and then refluxed for 3 hours. It is then evaporated in vacuo, the residue is dissolved in a little water, made strongly alkaline with concentrated potassium carbonate solution and extracted with chloroform. After drying over potassium carbonate, the chloroform solution is evaporated and the residue is crystallized from chloroform-pentane. This gives the S-oxy-S-carbmethoxyquinuclide from F; 122 ° C as colorless crystals, from which, after the cleavage of the oxy group in 3-position described in Example 1 and hydrogenation of the double bond formed, the 3-carbmethoxy-cniriuclidine hydrochloride is obtained? ■ "" r Patent claims: 1. A process for the preparation of quinuclidine-3-carboxylic acid esters and their salts, characterized in that quinuclidones _r (3) are reacted with hydrocyanic acid, the nitrile group in the cyanohydrins obtained is converted into an esterified carboxyl group in a manner known per se, the 3 -Oxy group is removed at any stage of the process by treatment with dehydrating agents, the l-azabicyclo- (2,2,2) -octen- (2) -carboxylic acid ester- (3) formed is catalytically hydrogenated and optionally obtained bases with inorganic or organic Reacts acids or i.from the salts obtained, the free bases are produced. . , 2. The method according to claim 1, characterized in that that the S-oxy-quinuclidine-S-carboxylic acid ester treated with thionyl chloride as a dehydrating agent. A priority document was displayed when the registration was announced. 707/330 12:59