NO140185B - PROCEDURE FOR PREPARING CONTENT DERIVATIVES - Google Patents

Description

The present invention relates to a new chemical

unique method for the production of products that can be used for the synthesis of antiphlogistically active compounds of the general formula

in which R stands for hydrogen or a -CI^-COOH group, and X is hydrogen or one or more halogen atoms or functional groups such as methoxy, nitro or trifluoromethyl groups. In particular, it concerns the compounds 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indole-acetic acid and 2-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3- indole]acetoxy-acetic acid The intermediates produced by the process according to the invention are compounds with the general formula where R means a benzyl residue or the residue and X has the same meaning as above; of which particular mention is made of the compounds 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indole-acetic acid benzyl ester and 2-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indole]- acetoxy-acetic acid benzyl ester

It is already known that the compounds of the general formula I, especially compound II, can be prepared by condensation of p-methoxyphenylhydrazine with levulinic acid to 5-methoxy-2-methyl-3-indoleacetic acid and subsequent acylation with the halides, azide or anhydride of p- chlorobenzoic acid in the presence of sodium hydride (cf. German specification 1 620 030). The synthesis takes place according to the following reaction nucleus

However, the acylation of the indole compound has proven to be difficult (cf. German Offenlegungsschrift 1 670 001, page 2, second paragraph), is very laborious and usually gives poor yields (cf. German Offenlegungsschrift 1 770 157, page 2, first paragraph ). The use of the free acids or normal esters, such as e.g. the methyl ester, prohibits itself, as in the first case a transformation of the free acid into an anhydride is obtained, by whose cleavage the N-acylation is abolished, and in the latter case the methyl ester must be hydrolysed, so that N-deacylation also occurs. The tertiary butyl ester has therefore been proposed as an easily cleavable ester group. However, as stated in the German Offenlegungsschrift 1 770 157 (page 2, last paragraph, and page 3), the preparation of this ester is extremely cumbersome and unsuitable as part of a technical synthesis. As a solution, it was therefore proposed in the German Offenlegungsschrift 1 793 678 that the p-methoxyphenolhydrazine used as starting compound is first acylated at N^j, after which the condensation with levulinic acid is carried out. This method leads to satisfactory yields, but is cumbersome insofar as one must protect the N(2)~ group before the acylation and later remove the protecting group after the acylation. The synthesis takes place according to the following scheme: Attempts have also been made to carry out the acylation of the indole compound with particularly reactive acylating agents. Proposed was e.g. p-chlorobenzoyl cyanide in the presence of amines as catalyst. This compound is used on a technical scale only when expensive safety measures are taken at the same time, as the compound in the presence of traces of moisture already decomposes at room temperature into benzoic acid and hydrogen cyanide. First by using easily cleavable and highly reactive mixed anhydrides, for example the anhydride of p-chlorobenzoic acid and carbonic acid monoethyl ester

(cf. German patent 1 693 001), better yields of acylated indoles are obtained in the presence of catalytic amounts of amines, for example triethylamine. However, this method has certain disadvantages. Firstly, highly contaminated products often arise that can only be purified chromatographically, i.e. a method that can only be carried out on a technical scale with difficulty. Secondly, the compound class is not very stable, and significant cleavages often occur at temperatures at which appreciable N-acylation does not yet take place. As cleavage products, benzoic acid ethyl ester, which is not suitable for acylation, and benzene anhydride were obtained (cf. J. Org. Chem. 24_ (1959), page 775, the reaction equation). The latter, however, is not unconditionally suitable as an acylating agent in this case, as it is known from the German Offenlegungsschrift 1 695 484 that in the acylation of indole compounds with p-chlorobenzene anhydride in the presence of catalytic amounts of camphorsulfonic acid, an acylation with

bart 55> (cf. page 6) dividend. Own attempts to achieve a better yield using acid catalysts, such as e.g. hydrogen bromide, trifluoromethylsulfonic acid, aluminum chloride or boron trifluoride, failed.

The invention is based on the surprising discovery that one can achieve an immediate N-acylation of indole compounds with high yield and better than average purity when the readily available corresponding benzoyl chloride is heated in an inert solvent together with the indole compound containing the -NH group to higher temperatures. This turnover proceeds particularly advantageously when it takes place without access to oxygen. More specifically, it was now not to be expected that the hydrochloric acid gas released by the reaction should not attack the indole compounds at temperatures up to and also above 200°C, as is the case, for example, with all the other above-mentioned acid catalysts.

The object of the invention is therefore a new and chemically unique process for the preparation of compounds of the general formula IV, in particular with formulas V and VI, which process is characterized in that compounds of the general formula VII

in which R is a benzyl residue or is condensed with compounds of the general formula VIII

in which X is hydrogen or represents one or more halogen atoms or functional groups such as methoxy, nitro or trifluoromethyl groups, at temperatures of at least 100°C in inert solvents with the formation of free HC1.

The compounds with the general formula VTI used as starting materials are known substances. As starting materials with general formula VIII, benzoyl chloride, p-chlorobenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride and 4-chloro-3-nitrobenzoyl chloride are mentioned in particular.

Inert solvents are such solvents which boil at temperatures above 100°C and which at these temperatures do not react with the reaction components, especially the compounds of general formula VII. These include aromatic hydrocarbons such as toluene, ethylbenzene, isopropylbenzene, butylbenzene, diethylbenzene, xylene, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene, 1,2,3,4-tetrahydronaphthalene, l-methyl-4- isopropylbenzene and decalin. Aliphatic hydrocarbons such as nonane, decane, decalin, undecane, dodecane and bicyclohexyl can also be mentioned. Particularly suitable are hydrocarbon mixtures such as kerosene, paraffin oil, isoparaffins, especially the so-called test petrols (b.p. 180-21p°C) and petrol special (b.p. 180-220°C). Also very suitable for the reaction are a number of chlorinated hydrocarbons such as chlorobenzene, 1,2-dichloro- and 1,3-dichloro-benzene, 1,1,2,2-tetrachloroethane, 2-chloro-, 2,4-dichloro -

and 3,4-dichlorotoluene. Also suitable for the reaction are aliphatic and aromatic ethers such as deglyme, diethylene glycol ether,

anisole, fenetol, diphenyl ether and veratrol. Finally, other hydrocarbons with oxygen functions, for example diisobutyl ketone, can also be used as a solvent. Solvents which boil between 170 and 220°C, preferably between 180 and 205°C, are most preferably preferred.

The method according to the invention proceeds according to the following reaction scheme

The hydrogen chloride released by the reaction can be determined titrimetrically and taken as a measure of the course of the reaction.

The reaction takes place preferably at temperatures between 100 and 220°C, especially between 170 and 210°C. The reaction duration depends on the nature of the solvent, its boiling point and the concentration of the solution and is usually between 3 and 24 hours. Low-boiling solvents require a longer reaction time than higher-boiling solvents. With increasing concentration of the solution, the reaction time will decrease.

The final products obtained with the general formula IV

are particularly clean and are obtained in particularly high yields when the method according to the invention is used with the exclusion of oxygen, i.e. without access to air.

In order to ensure that free oxygen, more particularly atmospheric oxygen, is excluded, it is preferred to carry out the process in an inert atmosphere, i.e. in gases which themselves will not participate chemically in the reaction. Examples of such gases are oxygen-free nitrogen and noble gases, for example helium'. According to the invention, it may be particularly preferable to direct the flow of such an inert gas through the heated reaction mixture. In particular, it may also be preferred that the reactants to be reacted with each other and/or the inert solvents used in the method are flushed with such a stream of inert gas before the start of the reaction, whereby it is already ensured from the start that any trace of oxygen is removed.

The passage of the inert gas flow through the heated reaction mixture entails the further advantage that the removal of the free halogenated hydrogen acid produced by the condensation reaction, especially HC1, from the reaction mixture is facilitated and accelerated. It has been shown that the yield and purity of the desired end product can be affected in a favorable direction. In and of itself, the reaction mixture and thus especially the indole starting compound is surprisingly stable against dry oxygen-free HC1, also at the aforementioned high reaction temperatures. Thus, it has been established by experiment that even several hours of passing gaseous dry HCl does not result in any significant resin formation of the indole compound when suitable solvents are used and this treatment takes place in the absence of the acylating acid chloride. The dry gaseous HCl that is released in the condensation reaction according to the invention by the reaction of the acid chloride thus leads to a surprisingly small degree of unwanted side reactions. This was all the more surprising as the addition of any other strong acid immediately led to rapid resin formation of significant amounts of the reaction mixture. The same applies to the addition of acidic catalysts of the type Lewis acids. Even the use of the chemically related acid bromide as an acylating agent instead of the acid chloride during HBr formation gives clearly worse results than the use of the acid chloride.

From this follows the particularly preferred use of the acid chlorides as reaction component. It is obviously a special property of the gaseous hydrochloric acid that under the stated conditions according to the invention it is essentially inert towards the reactants. Interestingly, this property is only associated with the free gaseous hydrochloric acid. If you try to capture the hydrochloric acid in the reaction mixture and render it harmless, especially during salt formation, you even then immediately get extensive side reactions during resin formation, for example when you try to react and immediately precipitate the hydrochloric acid that is formed with carbonic acid salts. Surprisingly, compared to the free gaseous hydrochloric acid, the reaction system according to the invention is stable.

However, it is preferred to keep the HCl concentration in the reactant mixture low. This is achieved or facilitated by the reactant mixture being flushed with the inert gas stream.

According to the invention, it is further preferable

that moisture is excluded from the reaction mixture. Correspondingly, the inert gas flow is also preferably pre-dried. Moisture in the reaction mixture leads to an unwanted reaction of the acid chloride and thus a reduction in yield. In some cases, it may also be preferable to exclude light from the reaction mixture. Admittedly, this precaution will only have greater significance in special cases.

The purity of the end products obtained is a particular advantage of the present method, as this gives end products which, after only one crystallization, have a purity of

, over 98%, predominantly even over 99%. In principle, the reaction can also be carried out in the presence of air, even in the absence of solvents, with usable yield. However, you usually get end products that are contaminated. These contaminants can only be removed from the reaction products with great difficulty, if at all. A technical application of the method is therefore greatly hampered under these conditions.

Appropriately, when carrying out the present method, 1-5 mol of the compounds of general formula VIII per moles of the compounds of general formula VII. The processing of the final products is very simple. It occurs, for example, by evaporating the diluent in a vacuum, whereby all

depending on the nature of the solvent either immediately obtains a crystal slurry,

or the residue is brought to crystallization by adding e.g. diethyl ether, or the reaction solution is diluted with, for example, diethyl ether, whereby the final products are obtained in a crystalline state. These crystalline end products are then re-crystallized.

In the method according to the invention, it is further preferred to work with a multiple amount of solvent in relation to the weight of the reactants. Although the reaction can in principle even be carried out in the absence of solvents, it is however appropriate to use at least about the same amount by weight of solvent as that used of reactants, preferably at least twice the amount. The use of 4-15 fold amounts of solvent, based on reactant weight, can be particularly advantageous.

Example 1

a) 309.37 g (1 mol) of 5-methoxy-2-methyl-3-indoleacetic acid benzyl ester are dissolved in 4,000 ml of absolute 1,2-dichlorobenzene and heated to 160°C under the passage of oxygen-free nitrogen and the exclusion of light and moisture . Within 15-20 minutes to-

350 g (2 mol) p-chlorobenzoyl chloride are now added dropwise, and the reaction mixture is heated to boiling (internal temperature 180-183°C). The hydrogen chloride that is released during the reaction is driven off with the help of

of the nitrogen flow and is determined quantitatively for turnover

control by titration with caustic soda. After 17 hours of boiling, the solvent and excess acid chloride are distilled off at 50°C

and 0.1 Torr, the brown oily residue is taken up in 1000 ml of diethyl ether and stored for 6 hours at -10 to 0°C. The solution solidified to a crystalline mass is suctioned off, and the residue is washed with isopropyl ether.

The thus obtained 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indole-acetic acid benzyl ester is obtained in a yield of 365.9 g (m.p. 93-94°C).

A further 27.3 g of this compound crystallizes from the ether solution (m.p. 89-90°C), so that the total yield amounts to 393.2 g (= 88% of the theoretical). After a single recrystallization from acetic acid ethyl ester/isopropyl ether, a highly pure product with a melting point of 95-96°C is obtained in a total yield of 83% of the theoretical.

b) In 2000 ml of test petrol (redistilled "Kristall6l-60n

from Shell AG with a boiling range of 190-220°C) is suspended below

passage of oxygen-free nitrogen and without access to light and moisture 300 g (0.972 mol) 5-methoxy-2-methyl-3-indole-acetic acid benzyl ester, the mixture is heated to 160°C (internal temperature, during which a clear solution is obtained between 90 and 100 °C)

and 340 g (1.944 mol) of p-chlorobenzoyl chloride are added over 15 minutes. The temperature is then raised until the solution boils

(internal temperature 193-196°C; the development of hydrogen chloride is controlled as described under a). After 8 hours of reaction, the yellow-brown solution is allowed to cool to 70°C and at this temperature 125 ml of acetic acid ethyl ester are added. After slow cooling and standing for a longer time at 0°C, the crystal slurry formed is suctioned off and washed with 1000 ml of isopropyl ether. The crude yield of 1-(p-chloro-benzoyl)-5-methoxy-2-methyl-3-indoleacetic acid benzyl ester amounts to 396.6 g (91% of the theoretical), and after recrystallization as described under a) a net yield of 348, 3 g (= 80% of the theoretical).

c) 300 g of 5-methoxy-2-methyl-3-indoleacetic acid benzyl ester are dissolved in 2 liters of "Petrol Spezial" from the company Fluka while heating, 350 g of p-chlorobenzoyl chloride are added as indicated in example la), and boiled under the introduction of argon gas for 4 hours at 195-198°C. After cooling to 60°C, 2 liters of ether are added, and the solution is left in the cold. The compound is worked up as in the previous examples and is obtained in a crude yield of 350 g (80% of the theoretical, m.p. 95-96°C) and in a net yield after purification of 320 g (74% of the theoretical, sm. p. 96°C). d) 200 g (0.647 mol) 5-methoxy-2-methyl-3-indoleacetic acid benzyl ester in 1330 ml absolute 2,4-dichlorotoluene yields with 226 g (1.29 mol) p-chlorobenzoyl chloride after 4 hours of boiling at 204° C and work-up as described, 232 g (80% of the theoretical), respectively 209 g (72% of the theoretical) 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid benzyl ester. Example 2 a) 300 g (0.82 mol) (5-methoxy-2-methyl-3-indoleacetoxy)acetic acid benzyl ester is dissolved in 4000 ml of absolute 1,2-dichlorobenzene, an oxygen-free nitrogen stream is passed through the solution and heated to 160 °C internal temperature. Over the course of 20-30 minutes, 286 g (1.63 mol) of p-chlorobenzoyl chloride are added dropwise, and the solution is boiled for 23 hours at an internal temperature of 180-183°C. The degree of conversion is determined by introducing the released hydrogen chloride into a calculated amount of sodium hydroxide solution and determining it titrimetrically. After cooling the solution, the solvent and excess acid chloride are distilled off at 50°C/0.1 Torr, and the oily residue is dissolved in 1500 ml of diethyl ether. The solution is cooled to -15°C and the formed [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-acetic acid benzyl ester crystallizes in the form of pale yellow small needles, which are treated in 1000 ml of diisopropyl ether for removal of attached acid chloride. The crude yield was 358 g (87% of the theoretical; m.p. 89-S1 C) and after recrystallization from acetic acid ethyl ester/diisopropyl ether 322 g (78% of the theoretical) with a melting point of 94-95°C. b) 6 g (0.0164 mol) (5-methoxy-2-methyl-3-indoleacetoxy)-acetic acid benzyl ester is poured over with distilled test gasoline ("Kristallol 60" from Shell, boiling range 194-220°C), heated to boiling (inner temperature 194°C) while passing oxygen-free nitrogen and stirring, and 4.28 g (0.0246 mol) of p-chlorobenzoyl chloride are added over 10 minutes. After boiling for 9.75 hours, the mixture is slowly cooled under nitrogen and with stirring, and at approx. At 130°C, an oil then begins to separate. Diethyl ether is added to the cooled mixture and stirred until crystallization occurs. The yield of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]acetic acid benzyl ester after recrystallization as described under a) is 6.2 g (75% of the theoretical). c) Under the conditions described in example 2a), 183.7 g (0.5 mol) of (5-methoxy-2-methyl-3-indoleacetoxy)acetic acid benzyl ester is obtained in 2000 ml of absolute 2,4-dichlorotoluene and 175 g (1.0 mol) p-chlorobenzoyl chloride after boiling for 10 hours (internal temperature 198-200°C) 190 g (75% of the theoretical) [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3 -indoleacetoxy]acetic acid benzyl ester with a melting point of 95°C.

Example 3

Analogous to the conditions used in examples 1 and 2, 10.0 g (0.0274 mol) (5-methoxy-2-methyl-3-indoleacetoxy)acetic acid benzyl ester and 7.7 g (0.0548 mol) benzoyl chloride are obtained after boiling for 25 hours under a nitrogen atmosphere in 130 ml of 1,2-dichlorobenzene and working up as described, 7.35 g (57% of theory)

(1-benzoyl-5-methoxy-2-methyl-3-indoleacetoxy)acetic acid benzyl ester, which melts at 95°C.

Example 4

Analogous to the conditions described under examples 1 and 2, 10 g (0.0274 mol) of (5-methoxy-2-methyl-3-indoleacetoxy)acetic acid benzyl ester and 12.6 g (0.0548 mol) 3,4 ,5-trimethoxy-benzoyl chloride by boiling for 13 hours in 130 ml of 1,2-dichlorobenzene and working up 8.3 g (54% of theory) [5-methoxy-2-methyl-1-(3,4,5- tri-methoxybenzoyl)-3-indoleacetoxy]acetic acid benzyl ester, which melts at 117-118°C.

Example 5

Under the conditions described in examples 1 and 2, 6.0 g (0.0194 mol) of 5-methoxy-2-methyl-3-indole-acetic acid benzyl ester and 6.18 g (0.0291 mol) of 4-chloro- 3-nitrobenzoyl chloride by boiling for 2 hours in 400 ml of test petrol (b.p. 190-220°C), subsequent purification from chloroform on silica gel and elution with cyclohexane/ethyl acetate (3:1) 4.6 g (48% of the theoretical) l -(4-chloro-3-nitrobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid benzyl ester with melting point 85-87°C.

Claims (2)

1- Process for the preparation of therapeutically active α-(3-indolyl)-alkanoic acid compounds with the general formula where R is a benzyl residue or the residue and X is hydrogen or one or more halogen atoms, methoxy, nitro or trifluoromethyl groups, characterized in that compounds with the general formula is condensed with compounds of the general formula where R and X have the same meaning as above, at temperatures of 100-220°C, preferably 170-210°C, in inert solvents, in the absence of oxygen and moisture, during the separation of dry HCl by passing through a stream of oxygen-free nitrogen . 2. Method according to claim 1, characterized in that the influence of light is also excluded during the reaction.