CH629205A5 - Process for the preparation of novel 6-substituted tropinones - Google Patents

Description

629 205

2nd

PATENT CLAIM Process for the production of new tropinones of formula I substituted in 6-position

(I),

r-chg-ch-

where R1 is an aliphatic radical, R2 is -OR3,

/ R4

the rest the rest

N <

-R4

O

-NH-C-R3 O

or the rest -NH-C-N <

'R4

• R4

denotes, the individual radicals R3 and R4 may be the same or different and each represent a hydrogen atom, an aliphatic, araliphatic or aromatic radical, moreover two radicals R4 together with the adjacent nitrogen atom can also mean members of a heterocyclic ring, characterized that 2,5-dialkoxytetrahydrofurans of the formula II

h h-c-

H

-C-CHg-R2

r50-c

(ii),

h c-or-

x X

xr «

H

It has now been found that new tropinones of the formula I substituted in the 6-position

h2c

-ch

1 1

No !

r -chg-ch — ch-

-ch0

I d.

C = 0 I

-ch2

(I),

where R1 is an aliphatic radical, R2 is -OR3,

io the rest

-N <

IS

the rest

-R4

\ R4

O

II

-NH-C-R3 O

20th

or the rest -NH-C-NC

"R4

-R4

denotes, the individual radicals R3 and R4 may be the same or different and each stand for a hydrogen atom, an aliphatic, araliphatic or aromatic radical 2s, in addition two radicals R4 together with the adjacent nitrogen atom can also mean members of a heterocyclic ring, advantageously contains when 2.5 dialkoxytetrahydrofurans of the formula III

30th

h h-c-

H

s

• c »ch2» r r5o-ö

(ii),

35

c-or "

h /% v0 '/ Xh in which the individual radicals R5 can be the same or different and each denote an aliphatic radical, treated in a first step with water at a pH of 0 to 3 and the treatment mixture obtained in this way in a second step with a primary one Amine of formula III

R'-NH2 (III)

and reacting acetone dicarboxylic acid at a pH of 4 to 6.

wherein the individual radicals R5 may be the same or different and each denote an aliphatic radical, treated in a first step with water at a pH of 0 to 3 40 and the treatment mixture thus obtained in a second step with a primary amine of formula III

R! -NH2

(III)

45

50

and acetone dicarboxylic acid at a pH of 4 to 6.

Furthermore, the new tropinones of the formula I substituted in the 6-position

ch,

k2g

-ch

'1 n-r

!

r -ch2-ch — ch-

, 2 C = 0

-CH ^

(I),

The invention relates to a process for the preparation of new tropinones substituted in the 6-position by reacting 2,5-dialkoxytetrahydrofurans with primary amines and acetone dicarboxylic acid.

It is known from British patent specification 791 770 that succinic dialdehyde can be reacted with acetone dicarboxylic acid and methylamine to give tropinone. The reaction is carried out at 55 to 60 ° C. Instead of the pure succinic dialdehyde, the reaction mixture for its preparation is used by hydrolysis of 2,5-dimethoxytetrahydrofuran in dilute hydrochloric acid. A pH of the reaction of 5 to 5.4 and a ratio of the 3 starting materials of 1.25 mol of acetone dicarboxylic acid to 1.25 mol of methylamine to 1 mol of 2,5-dimethoxytetrahydrofuran are preferred.

rest

6®

55 wherein R1 is an aliphatic radical, R2 is -OR3,

^ -R4 -N <

\ r4

O

II

-NH-C-R4 O

II / R4

-NH-C-N ^

\ R4

the rest

65

or the rest

629 205

referred to, the individual radicals R3 and R4 may be the same or different and each represent a hydrogen atom, an aliphatic, araliphatic or aromatic radical, moreover two radicals R4 together with the ring can be found.

If methylamine, 2,5-dimethoxy-3 (dimethylaminomethyl) tetrahydrofuran is used, the reaction can also be members of a heteroeyelite represented by the following formulas:

h3 ° \

H ^ C-N -CH2, CC-H

h-jco-hc

H00C

t

C00H

t

+ ch3nh2 + ch2-c-ch2

-och,

-2C0,

-h2o

-2CH ^ 0H

H0C-CH

à. I t h

—CH0

1 teaspoon

I N-CH, C = 0 I t j t

HC-CH CHp

»C-

ch2 C-N-CH,

In view of the prior art, the process according to the invention provides the new tropinones substituted in the 6- and 8-positions in a simple and economical manner in better yield and purity. All of these advantages of the method according to the invention are surprising, taking into account the prior art. W. Hückel, Theoretical Foundations of Organic Chemistry, 8th Edition, Volume 2, page 758 (Akad. Verlagsgesellschaft Geest & Portig KG, Leipzig 1957) teaches the influence of chain branches on a ring closure reaction. On page 764, Table 4, he shows that β, 5,8-trimethylvalerolactone tends to form a ring much more than y, 8, S-trimethylvalero-lactone and even more strongly than S-methyl-ö-ethylvalerolactone. One would have had to suspect that the starting materials II substituted in the 3-position cannot be split or can only be split insignificantly and therefore no conversion takes place. At a pH of the reaction solution, the amino group of the corresponding starting materials II is at least partially in salt form. It is now known that amine salts catalyze condensations of carbonyl groups with active methylene groups (Org. Synth., Coli. Vol. 4, pages 234, 408 and 463 (1968) Tetrahydrofuran molecules and condensation of the split tetra-hydrofuran molecules with each other, and overall a strong reduction in the yield and the formation of heterogeneous mixtures of numerous components of the secondary products of the aforementioned side reactions were therefore to be expected.

The starting materials can be reacted with one another in a stoichiometric amount or each in excess, preferably in a ratio of 1 to 5, in particular 1.1 to 3, moles of starting material III, based on 1 mole of starting material II, and in a ratio of 1 to 5, in particular from 1.1 to 3 moles of acetone dicarboxylic acid, based on 1 mole of starting material II. Preferred starting materials II and III and correspondingly preferred end products i are those in the formulas R] of which is an alkyl radical having 1 to 6 carbon atoms, R- the rest -OR3,

or the rest

O

ii

-NH-C-N <

the rest the rest

_N <

-R4

-R4

-R4 -R4

-NH-C-R3 O

25th

referred to, the individual radicals R3 and R4 may be the same or different and each stand for a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, a phenyl radical 30, in addition two radicals R4 together with the neighboring nitrogen atom can also mean members of a 5- or 6-membered heterocyclic ring which, in addition to the nitrogen atom, can also contain a further nitrogen atom or an oxygen atom. The abovementioned radicals and rings can also be replaced by groups and / or atoms which are inert under the reaction conditions, e.g. Alkyl groups with 1 to 4 carbon atoms, chlorine atoms, may be substituted.

The following are suitable as starting materials II: 3-hydroxy-40 methyl-, 3- (methoxymethyl) -, 3- (ethoxymethyl) -, 3- (propoxymethyl) -, 3- (isopropoxymethyl) -, 3- (butoxymethyl ) -, 3- (sec-butoxymethyl) -, 3- (isobutoxymethyl) -, 3- (tert-butoxymethyl) -, 3- (benzoxymethyl) -, 3- (phenoxymethyl) -2,5-dime -thoxy-tetrahydrofuran; 3- (aminomethyl) -, 3- (N-methylamino-4S nomethyl) -, 3- (N-ethylaminomethyl) -, 3- (N-propylamino-methyl) -, 3- (N-isopropylaminomethyl) -, 3- (N-butylamino-methyl) -, 3- (sec-butylaminomethyl) -, 3- (N-butylaminomethyl) -, 3- (N-tert-butylaminomethyl) -, 3- (N-benzylaminomethyl) ) -, 3- (N-phenylaminomethyl) -, 3- (N, N-dimethylamino-50 methyl) -, 3- (N, N-diethylaminomethyl) -, 3- (N, N-dipropyl-aminomethyl) -, 3- (N, N-diisopropylaminomethyl) -, 3- (N, N-dibutylaminomethyl) -, 3- (N, N-di-sec-butylamino-methyl) -, 3- (N, N-diisobutylaminomethyl) - , 3- (N, N-di-t-butylaminomethyl) -, 3- (N, N-dibenzylaminomethyl) -, S5 3- (N, N-diphenylaminomethyl) -, 3- (methylcarbonamidomethyl) -, 3rd - (ethyl carbonamidomethyl) -, 3- (propylcarbonamido-domethyl) -, 3- (isopropylcarbonamidomethyl) -, 3- (butylcarbonomamidomethyl) -, 3- (isobutylcarbonamidomethyl) -, 3- (sec-butylcarbonamidomethyl) -, 3- ( tert-Butylcarbonami-60 domethyl) -, 3- (Benzylcarbonamidomethyl) -, 3- (Phenylcarbo-namidomethyl) -, 3- (N-Methylureidomethyl) -, 3- (N-Ethylu-reidomethyl) -, 3- (N -Propylu reidomethyl) -, 3- (N-isopropylu-reidomethyl) -, 3- (N-butylureidomethyl) -, 3- (N-isobutylureidomethyl) -, 3- (N-sec-butylureidomethyl) -, 3- ( N-tert-buty-65 lureidomethyl) -, 3- (N-benzylureidomethyl) -, 3- (N-phenyluridomethyl) -, 3- (N, N-dimethylureidomethyl) -, 3- (N, N- Diethylureidomethyl) -, 3- (N, N-dipropylureidomethyl) -, 3- (N, N-diisopropylureidomethyl) -, 3- (N, N-dibutylu

629205

reidomethyl) -, 3- (N, N-diisobutylureidomethyl) -, 3- (N, N-di-sec-butylureidomethyl) -, 3- (N, N-di-tert-butylu-reidomethyl) -, 3rd - (N, N-Dibenzylureidomethyl) -, 3- (N, N-Diphenylureidomethyl) -2,5-dimethoxy-tetrahydro-furan; correspondingly differently substituted with the aforementioned substituents on the nitrogen atom 3- (aminomethyl) and 3- (ureidomethyl) -2,5-dimethoxy-tetrahydrofurane; 3- (piperidinyl- (N) -methyl) -, 3- (piperidinyl- (N) -carbonamido-methyl), 3- (morpholinyl- (N) -methyl) -, 3- (piperazinyl- (N ) -methyl) -, 3- (morpholinyl- (N) -carbonamidome-thylj-, 3- (piperazinyl- (N) -carbonamidomethyl) -2,5-dime-thoxy-tetrahydrofuran; appropriately substituted 2,5-di- ethoxy-, 2,5-dipropoxy-, 2,5-diisopropoxy-, 2,5-dibutoxy-, 2,5-di-sec-butoxy-, 2,5-di-tert-butoxy-, 2, 5-diisobutoxyte trahydrofurane.

Possible starting materials III are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butylamine.

The reaction is generally carried out continuously or batchwise at from 20 to 110 ° C., preferably from 70 to 105 ° C. in the first step and from 25 to 70 ° C. in the second step, without pressure or under pressure. In the first step, water is used as the reactant, advantageously in an amount of 25 to 250, preferably 50 to 60, moles per mole of starting material II. In general, water serves simultaneously as the solution medium for both steps. If appropriate, organic solvents which are inert under the reaction conditions, such as dioxane, tetrahydrofuran, glycol, methanol, ethanol, isopropanol; or corresponding mixtures with one another or with water can be used. The organic solvent or mixtures of the organic solvent with water are used in an amount of 10 to 500, preferably 100 to 200 percent by weight of solvent or solvent mixture, based on starting material II.

In the first step, a pH of 0 to 3, preferably 0.5 to 2.5, is maintained. Appropriate proportions of acid are added to adjust the pH. Inorganic and organic acids can be used. Instead of monobasic acids, equivalent amounts of polybasic acids can also be used. For example, the following acids are suitable: benzenesulfonic acid, toluenesulfonic acids, formic acid, acetic acid, propionic acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, perchloric acid, sulfuric acid, nitrous acid, phosphoric acid, nitric acid. Sulfuric acid and in particular hydrochloric acid are preferred.

In the second step, a pH of 4 to 6, preferably 5.0 to 5.5, is maintained. Basic connections are used for setting. Preferred basic compounds are tertiary amines, alkaline earth metal, ammonium and in particular alkali metal compounds and corresponding mixtures. Advantageous alkali and alkaline earth compounds are the hydroxides, oxides, carbonates, bicarbonates, salts of weak or polybasic acids of calcium, barium, magnesium, lithium and especially sodium and potassium. For example, as basic compounds in question: potassium hydroxide,

Sodium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, I potassium bicarbonate, calcium hydroxide, barium oxide, magnesium hydroxide, calcium carbonate, sodium acetate. Potassium hydroxide solution and sodium hydroxide solution are particularly preferred. You can also add the primary amine III as a salt or as a free base, if necessary in excess, and thus adjust the pH together with one of the above-mentioned basic compounds.

The reaction can be carried out as follows: A mixture of starting material II, acid and water is kept at the reaction temperature and the pH of the first step for 0.1 to 5, preferably 0.25 to 2 hours. Then the pH of the second step is adjusted with base, starting material III and acetone dicarboxylic acid are added and the mixture is kept at the reaction temperature and at the pH of the second step for 0.5 to 10, preferably 1 to 6 hours. The end product is then removed from the mixture in a conventional manner, e.g. by adjusting the mixture to pH 8 to 12 with base, extraction e.g. with ether, and fractional distillation of the extract, separated.

The new tropinones which are substituted in the 6-position and are obtainable by the process of the invention are interesting starting materials for the production of dyes, crop protection agents and in particular of pharmaceuticals, e.g. with spasmolytic effect. By reduction with hydrogen in the presence of nickel catalysts, e.g. by the method of U.S. Patent 2,366,760, 6-substituted tropines are obtained which can be obtained by esterification with acetyltropic acid chloride, e.g. can be converted into 6-substituted atropines by the method of the chemical reports, volume 41, pages 730 to 732 (1908). Atropine and its derivatives are important antispasmodics (Kuschinsky and H. Lüllmann, short textbook on pharmacology, 6th edition, Stuttgart 1974, pages 11 and 13).

The parts listed in the following example mean parts by weight. They relate to parts by volume like kilograms to liters.

example

81 parts of 2,5-dimethoxy-3- (dimethylamino-methyl) -tetrahydrofuran are added to 427 parts by volume of 1-N-HC1 and 342 parts by volume of water. The solution is heated to 100 ° C. under reflux and the pH is adjusted to 1.5 with 1N HCl. The mixture is refluxed for one hour at pH 1.5 and adjusted to pH = 6 with 1N sodium hydroxide solution. This solution is added over 30 minutes to a mixture of 148 parts of acetone dicarboxylic acid, 68 parts of methylamine hydrochloride, 171 parts of sodium acetate and 570 parts of water. The mixture is stirred at pH 5 for 4 hours at 25 ° C and 2 hours at 60 ° C. After cooling to room temperature, 125 parts of potassium carbonate and 171 parts of sodium chloride are added. The mixture is extracted with ether. The combined ether solutions are dried and evaporated. The residue is distilled. 74 parts of 6-dimethylamino-8-methyl-tropinone with a bp 150 to 160 ° C./2 mbar are obtained (89% of theory).

4th

s

10th

15

20th

25th

30th

35

40

45

50

55

B