DE1670626A1 - Process for the preparation of new esters containing dimethyltropane skeleton - Google Patents

Description

VBaFAHREIi FOR THE PRODUCTION OF DIMETHTROPANE SKELETON INCLUDES 'NEW ESTEBN

Priority: April 21, 1966 / Hungary
Applicants?.: EE-1240

The invention relates to a method of manufacture Yoa new esters of the general formula I

-C-B-0

• shark

where R is a direct bond,) _{OH OH or / CHOH 2} OH groups, the ester group stent in relation to the tropane skelefct in cis or trana position, and Hal a halogen atom, preferably chlorine atom, and their acid addition salts and tertiary and quaternary Ammonium derivatives. 62/840 009887/1941 ..

They new trephine derivatives of the general formula I. can expediently be prepared in such a way that 1,5-dimethyltroplnone is reduced with the aid of sodium metal or by catalytic hydrogenation, after which the obtained Connection optionally in a manner known per se in a tertiary ammonium compound, expediently converted into a Hydrochlorld, and the compound obtained with benzoic acid halide, acetylmandelic acid halide or acetyltropic acid halide, expediently chloride, is reacted, whereupon the Compound obtained - if acetylmandelic acid halide or acetyltropic acid halide is used for the last-mentioned reaction is used - deacetylated and the compound obtained if necessary converted into an acid addition salt or into a quaternary derivative »

The 1,5-D! Methyl tropinone used as the starting material is a new compound that has not yet been described in the literature.We prepared this compound essentially in accordance with the processes described for the preparation of the unaunted tropinone ( Ann, 518 , 1935t JA, G "S. 68, 1946, 8" 1679 | Acta ChIm * Hung. 6, 365/1955 /) "with the difference that" acheive the achievement of an optimal yield of the pH of the reaction mixture. was held exactly at 9 ·. A corresponding starting compound is also known from the literature (Jriedl. 14, 1300)

The new compounds of the general formula I have * basic properties, and form *, acid · 8 al se with inorganic orgaaic acids, such as chlorohydrate,

009887/1942

Hydrobromic acid, maleic acid, fumaric acid, ethanesulpho-acid, X, 1 ^l -MetJiylen-bie (2-iiapiit; Jiol-3) -3carbonaäure _i sulfuric acid, phosphoric acid, acetic acid, citric acid and other pharmacologically acceptable acids,

The salts can by reacting the free base with the corresponding acid, advantageously in the presence of a appropriate solvent, since the isolation of the salt enables it to be produced «

The compounds of the general formula I can be converted into the quaternary derivatives, such as the quaternary methyl * or Ethyl derivatives are converted,

, The luaternary derivatives can, by implementing the free base old of a haloalkyl compound, expediently in the presence of an inert solvent.

if you want to convert the acid salts or the quaternary ea derivative is the free base, it is useful that To dissolve the salt in an appropriate solvent, to neutralize the solution with a basic substance such as sodium hydroxide, and to separate the desired base by extraction or a similar method «

The invention relates to all stereoisomers of the compounds of the general. Formula I and the mixtures of stereoisomers, not only in torrn of the free bar, but also of acid salts and quaternary derivatives

As a result of the close relationships between the new compounds JLa free form and in the form of their salts or quaternary derivatives are in the preceding and below below

009887/1942

the free bases meaningfully and appropriately also the corresponding ones Understanding saIse and quaternary derivatives

The new compounds prepared according to the invention have valuable pharmacological properties,

The ly5 -]) imethyltrGpakokain is a good local anesthetic. The intensity of the effect is 3.3% higher than that of procaine, the effect of lidocaine, also used in medical practice, being only 1.16 times higher than that of procaine. Its therapeutic index is 2.18 and that of lidocaine is only 0.23, if that of procaine is taken as the sin unit «Its toxicity is 3» more advantageous than that of lidocaine,

The 1,5-diethylhoaatropin is a selective parasympatholytic ganglion-blocking active ingredient, which in test animals by inhibiting gastric ulcer formation is proven.

Finally, 1,5-Diaethylatropin has atroactive effects,

The process according to the invention is explained in more detail using the following examples,

example 1

300 ml of water, 216 g of acetonylacetone and 280 g of acetone dicarboxylic acid fed in. · After the stirrer has been started, the flask is cooled in brewing water and the pH value of the The reaction mixture is made up by adding 30% strength potassium hydroxide solution 7 set. 1000 ml of a 15% sodium acetate solution and then 130 g of crystalline methylamine hydrochloride are used

009887/1942

Reaction mixture added »Finally, the pH of the obtained in this way. Mixture adjusted to a value of 9 with the aid of a 30% strength KOH solution. The solution is stirred for three days at room temperature.Then the reaction mixture is saturated with potassium carbonate while cooling and then extracted with ether or benzene. The ether or benzene-containing solution obtained is dried with calcined KgCO2, filtered and the product that remains after the solvent has evaporated is fractionated * The ^{distillate obtained between 125 °} C. and 145 * 0 under a bridge of 20 mm is a light yellow oil that changes into a crystalline substance. Melting point: 38-42 ⁰ C. Yield about

70 g. calculated, % C. "8th H , 06 N .38 Analysis: found, % 71 .63 10 .99 θ , 40 71 9 8th t

Melting point of the product sublimed for analysis t

16.2 g of the 1.5 dimethyltroplnons obtained in this way are, in a mixture of 16.2 ml abs. Toluene and 24.15 ml isobutanol dissolved. This solution is added dropwise to the mixture of 16.2 ml of toluene and 5.27% of sodium metal in one hour at room temperature while stirring vigorously. The stirring * is continued for two more hours. The sodium that may have remained undissolved is brought into solution by adding ethanol, poured into 100 ml bis-water, brought to a pH value of 3 with 10 IT HCl solution and extracted with 3x30 ml ether. Bit acidic aqueous solution is _{saturated with I 2} ⁰ S "ad daaa extracted with 3 × 30 ml of chloroform. The united. Solutions containing oil reform are made from latrium sulphate

dried; and evaporated. Approximately 7 * 6 g of a brown crystalline substance are obtained, which is dissolved in 20% abs, alcohol, neutralized in 10% abs * alcoholic hydrochloric acid solution, and by adding tos. Petroleum ether is crystallized »compartment filtration are obtained 6 ε lt ^ -SiBetJbyl-peeudotropin hydrochloride _f with a melting point rom 510 ^e C» analysis: CH

calculated, % 38.38 9 »80

found, % 58, C3 9.70

The 6 g of 1,5-D! Methyl-pseudotropine hydrochloride obtained in this way is boiled with 22 ml of benzoyl chloride for 80 minutes in a solvent equipped with an eeflux condenser. After cooling to room temperature the reaction mixture with 50 ml of chloroform "is the non-soluble in chloroform portion was dissolved in 200 ml of water, clarified with X ₂ ⁰ S opal and extracted with chloroform" The solution containing Chloreform is dried with Satriumsulphat and Chloreform removed in vacuo The remaining crystalline office residue is dissolved in 10 ml of absolute ethanol and neutralized with a 10% absolute ethanolic hydrochloric acid solution. Petroleum ether is diluted and then it is drained out. The precipitated crystals are filtered. Yields 7.05 g. Melting point: 220 ⁰ C.

Analysis of the 1,5-Dlmethyl-tropakekalns (l ^ -Dlmethyl-peeudotropin-benaoeeäureester-hyarechlorid) obtained in this way

0 H H 01

calculated, % 60.85 7.53 4.52 11.45 found, % 60.58 7.65 4.68 '11.17 »

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Example 2

17 g of the 1,5-dimethyltropinone prepared according to Example 1 are dissolved in 300 ml of abs. Dissolved ethanol and, in a copper autoclave, in the presence of 20 g of Raney-Hickel catalyst at room temperature, hydrogenated under a pressure of 50 atm for 40 hours. The catalyst is filtered and, after clarification, the solvent is distilled off under reduced pressure (20 mm) on a water bath. The almost colorless, crystalline substance obtained is recrystallized from η-hexane. The yield of 1,5-dimethyltropine • is almost quantitative. Melting point: 125 ⁰ O.

Analysis: * calculated, i » C. , 00 H 24 Ή , 28 found, ί> 71 , 84 11 25th 8th , 14 70 11 9

10 g of 1,5-dimethyltropine are in 25 ml of abs. Dissolved ethanol and with the help of a 10 # strength abs. alcoholic HGl solution neutralized. The solution obtained is with abs. Acetone diluted. The precipitated salt is filtered after a few hours and then dried. The thus obtained Dimethyltropin hydrochloride (10 g) is mixed with 31 »g of 5-acetyl mandelic acid chloride thoroughly mixed and then kept for 50 hours at a temperature of 95 mm ⁰ O, under a pressure of 20th Thereafter, the reaction mixture is dissolved in 1000 ml of hot water, allowed to ^{cool down to 60-70 0} C and after adding 1 ml of cc. HCl held at this temperature for an additional 50 hours. The solution is then cooled to room temperature and the light yellow solution is extracted with 3 × 250 ml of ether. the

009887/1942

Solution is cooled to 5 ⁰ C and while further cooling the pH with X-Flo is set to a value of. 9 The alkaline mixture is extracted with 5 × 200 ml of chloroform. The combined chloroform-containing solutions are with NagSO. dried and evaporated to dryness, the remainder is abs in 50 ml. Ethanol, treated with a 10 $> - HCl solution neutralized while cooling strength alcoholic and clarified. The solution obtained is warmed to almost boiling point and ether is added until it becomes cloudy. The precipitated crystalline substance is filtered, washed with ether and dried in a vacuum Esaikkator. In this way 8.6 g of 1,5-Dimethylhomatropin (1,5-Dir methyltropin-mandelsäureester hydrochloride) are obtained with a melting point of 223-225 ⁰ C.
Analyzes

calculated, j4

found, i »

Example 3

10 g to that described in Example 1. way produced 1,5-dimethyltropine base are abs in 25 ml. Dissolved ethanol and the solution is with a 10 # alcoholic HCl solution neutralized. The solution obtained is with abs. Acetone diluted. The precipitated salt is filtered and dried after a few hours. That on 1,5-dimethyltropine hydrochloride obtained in this way Thoroughly mixed with 31 g of Acetyltropanaäurechlorid and the reaction mixture obtained is worked up in the manner described in Example 2. Be that way 5 g 1,5-dimethylatropine (1,5-dimethyltropine-tropaniic acid-

009887/1942

C. H 65 N 12th Cl 45 63 , 65 7, 71 4, 36 10, 99 63 , 30 7, 4, 9,

ester hydrochloride), with a melting range of 162-163 ° C.

Analyzes O H N Cl

■ calculated, φ 64.45 7.93 3.96 10.05 found, i> 64.28 7.97 4.26 9.82.

009887/1942

Claims (1)

Patent claim Process for the preparation of new, therapeutically active esters of the general formula I. CH, H ₂ C H-N-CH H ₂ C σι CH, fa CH-O CH _n C-E . Shark wherein R is a direct bond or a CHOH or CHCH ₂ OH group; the ester group is in the cis or trans position in relation to the tropane skeleton, and Hai is a halogen atom, preferably a chlorine atom, and the tertiary and quaternary ammonium derivatives and acidic additives thereof are based on the fact that 1 , 5-Dimethyltropine reduced with the help of sodium metal or by catalytic hydrogenation, the compound obtained, if necessary in a manner known in the art, in a tertiary juaoniom charge, iweolwäealg in a hydreohlori, converted the compound obtained with B · η · ο · Λιιτ «halide, Ac rfcylmandelaaure-halid ο dar Aorfcyltropanaäure-halide, iwtckaäaaig chloride, o» gea «tst, whataaf dl · ernalten * V. bathing - case · for di ·! • trtgMuuuKt «Tylmand * leäurehalog« nid ο dar I tiIjI "Yrnf —Mnrihil ifn11 ▼ • rwaad · '!« Αχ4 · - 4 * aac * tyliert uA a «hli» e * lioh 4 ·· · Λ · 1 ^ · η · Ireiakt β · β ··· η · Αΐall · in the known INI ·· in * in 8äureadditio »aaal · or in · 1η quaternary ·· Aeaonium derifat ttb * rg«. 009887 "/ 1 ° 9A2