FI56832C - FOERFARANDE FOER FRAMSTAELLNING AV INDOLAETTIKSSYRAESTRAR - Google Patents

Description

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Sag c (45) - ° 4 - -3 ^ (51) Kv.lk. '/ Int.CI. * C 07 D 209/26 o / f η η I γο SU OMI — FI N LAND (21) P * t * nttlh »k * mu» - Pat «ntMw6kning (22) Hakamlipltvt - Amttknlngidag 23.11.73 '' (23) Alkuptlvi - Glltlghaudag 23 · 11 · 73 (41) Become Public - Bllvlt offsntlig 26.05 · 7 * +

Patent and Registration Office .... .... ... . . ,,, b,. . (44) Date of Nihtlvlkilpmon and other hearings. - οη το 70

- Patent ech registerstyrelsen '' And> k »n utlagd och utl.tkrlfun publkerad IV

(32) (33) (31) Privilege requested — Begird priority 25 · 11 · 72

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2257867-2 (71) Troponwerke Dinklage & Co., Berliner Strasse 220-232, Cologne 80 (Miilheim),

Federal Republic of Germany-Föbundsrepubliken Tyskland (DE) (72) Karl-Heinz Boltze, Bensberg-Kippekausen, Otffied Brendler, Cologne,

Peter-Rudolf Seidel, Porz-Wahnheide, Federal Republic of Germany-Förbunds- republiken Tyskland (DE) (7 * 0 Antti Impola (5 * 0 Method for the preparation of indoleacetic acid esters - Förfarande för framställning av indolättikssyraestrar

The present invention relates to a new, chemically unique process for the preparation of products (which can be used for the synthesis of anti-inflammatory compounds. Said anti-inflammatory compounds have the general formula q H, CO-CH-C-O-R 1 5 \ Xx o,

* ^ I

c -o 0-- Λ wherein R is a hydrogen atom or a -CB 2 -COOH group and X is hydrogen or one or more halogen atoms or a functional group such as a methoxy, nitro or trifluoromethyl group. In particular, the compounds 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indole acetic acid

and CO - r-CH 2 -C-OH

1 ^ C-0 $ 2 $ 6832

And 2- [5- (p-chlorobenzoyl) -5-ethoxy-2-methyl-3-indole] acetoxyacetic acid

Il II

-p CH2-C-O-CH2-C-OH

VS '*' CHj

C = 0 III

Φ

The intermediates prepared according to the process of the invention are compounds of general formula 0

HÄCO-r ^ S-π CHo-C-O-R

3 VOH

<5 = 0 IV

0b-x «wherein R is a benzyl residue or a residue -CH 2 -C 20 CH 2 O 2 and X is as defined above, and in particular 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indole-acetic acid benzyl ester

.5 V

c = o $

and 2-7: T- (p-Chloro-benzoyl) -5-methoxy-2-methyl-3-indole-7-acetoxy-acetic acid benzyl ester O O

H5 °° jj [CH2-C-O-CH2-C-O-CH2

c = o VI

o

Cl 5 56832

It is previously known to prepare compounds of general formula I, in particular a compound of formula II, by condensing p-methoxyphenylhydrazine with levulinic acid to form 5-methoxy-2-methyl-3-indoleacetic acid and then carrying out the acylation with p-chlorohenzoic anhydride, azides and acid halides, in the presence of (German advertisement 1 620 030). The synthesis takes place according to the following reaction scheme: Η3 °° Um2 + ch3coch2ch2cooch2 --μ o "» a t

B

g 0 ^ CO ^ - ^ - C-O-CH ^ _> H? CO -0 — J ^ 2-0-0- ^ 2 ^ * 3 i.Γ3, «^ ϊ o

- = 2 · * HjCO VXN-jrCH2-C-OH T

kAi,> CH3 01

O

Cl

However, acylation of the indole backbone has proved difficult (German Application 1 670 001, page 2, paragraph 2), is very complex and usually results in poor yields (see German Application 1 770 158, page 2, paragraph 2). The free acid or a normal ester, such as methyl ester, cannot be used because in the former case the free acid is converted to an anhydride which cleaves to prevent N-acylation, and in the latter case the methyl ester must be hydrolyzed, whereby N-deacylation also occurs. Therefore, a tertiary hutyl ester has been proposed as a more easily cleavable ester group. But as disclosed in German Application No. 1,770,157 (page 2, last paragraph, and 4 SÖ832 page 3), the preparation of this ester is very difficult and is not suitable for technical synthesis. Therefore, German Patent Application 1,793,678 proposes that the starting compound p-methoxyphenolhydrazine be first acylated at the β-position and then condensed with levulinic acid. Although this method gives satisfactory yields, it is complicated in that it must be protected before acylation and then deprotected after acylation. The synthesis proceeds according to the following reaction scheme

H ^ CO ΝΗ-Μϊ2 + O-C-R2 - * HjCO O · NH-N = C-R2 -V

R2 R

Kjc ° - {~) -K-ir = 0-E2 _p. HjCO

c = o c = o 0 0

Cl Cl

In addition, attempts have been made to acylate the indole backbone with particularly reactive acylating agents. For example, p-chlorobenzoyl cyanide in the presence of an amine catalyst has been proposed. However, on a technical scale, said compound can only be used by carrying out expensive precautions, since it decomposes into benzoic acid and hydrogen cyanide even at room temperature in the presence of a very small amount of moisture. Only with the use of readily degradable highly reactive mixed anhydrides, e.g. mixed anhydride of p-chlorobenzoic acid and carbonic acid monoethyl ester 0 0 01 V ^ 7 coco-c2h5 (see German patent 1,693,001), catalytic amounts of amines, e.g. triethylamine, are obtained. in the presence of better yields of acylated indoles. However, this method has some drawbacks. Firstly, very impure products are often formed which can only be purified by chromatography, which is difficult on a technical scale. Second, the class of compounds is poorly stable and already shows significant degradations at temperatures where no significant N-acylation has yet occurred. The decomposition products are benzoic acid ethyl ester, which can no longer be used for acylation, and benzoic anhydride (see J. Org. Chem. 24 (1959), 5 56832 page 775 »reaction equation). The latter is only of limited use as an acylating agent in this case, since it is known from German application 1 695 4-84- that acylation of an indole backbone with p-chlorobenzenic anhydride in the presence of catalytic amounts of camphorsulfonic acid gives only a maximum yield of 5% (see page 6). Attempts to obtain better yields using acid catalysts such as hydrogen chromium, trifluoromethylsulfonic acid, aluminum chloride or chlorotrifluoride have failed.

The present invention is based on the surprising finding that immediate N-acylation of the indole backbone can be performed in high yield and with better than average product purity if the readily available corresponding benzoyl chloride is heated to a high temperature with an -NH-containing indole backbone in an inert solvent. Particularly preferably, the reaction is carried out in the absence of oxygen. In this case, it was not to be expected that the hydrogen chloride released in the reaction would not affect the indole compounds even at temperatures up to 200 ° C and above, as is the case with all the other known acid catalysts mentioned above.

The invention therefore relates to a new and chemically unique process for the preparation of compounds of general formula IV, in particular for the preparation of compounds of formula V and VI, which process is characterized in that the compounds of general formula VII 2 E3CO-f frCH2'C "°" R vn H 5 wherein R is a benzyl residue or a residue -CE 2 -COOCH 9 -? are condensed with compounds of general formula

C0C1 VIII

wherein X is hydrogen or also one or more halogen atoms or a functional group, such as a methoxy, nitro or trifluoromethyl group, at a temperature of 100 to 220 ° C protected from oxygen, preferably in an oxygen-free i-inert gas stream and optionally protected from moisture and light, in an inert solvent in the formation of free HCl.

The compounds of general formula VII used as starting materials are known. Of the starting materials of the general formula VIII, mention may be made in particular of benzoyl chloride, p-chlorobenzoyl chloride, 3 ', 5-trimethoxybenzoyl chloride and 4-chloro-3-nitrobenzoyl chloride.

6 56832

Inert solvents are those which boil above 100 ° C and do not react in this temperature range with the reaction components, in particular the compounds of the general formula VII. Such solvents include aromatic hydrocarbons such as toluene, ethylbenzene, xylene, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene, 1,2,3,4-tetrahydronaphthalene, 1-methyl-4-iso -propylbenzene and decalin. Mention may also be made of aliphatic hydrocarbons such as nonane, decane, decalin, undecane, dodecane and bicyclohexyl. Particularly suitable are hydrocarbon mixtures, such as kerosenes, paraffin oil, isoparaffins, in particular the so-called reagent benzenes (b.p. 180-210 ° C) and "Petrolspezial" (b.p. 180-220 ° C). Chlorinated hydrocarbons, such as chlorobenzene, 1,2-dichloro, 1,3-dichlorobenzene, 1,1,2,2-tetrachloroethane, 2-chloro, 2,4-dichloro and 3>, are also particularly suitable for the reaction. 4-dichlorotoluene. Further suitable for the reaction are aliphatic and aromatic ethers such as diglyme, diethylene glycol ether, anisole, phenethol, diphenyl ether and veratrol. Finally, other hydrocarbons having acid groups, such as diisobutyl ketone, can be used as the solvent. Particularly preferred are solvents boiling at 170-220 ° C, preferably 180-205 ° C.

The process according to the invention takes place according to the following reaction scheme: 0 X

H * C0 -rr CHp-C-O-R / = L · 3 ♦ ö · 0001 - *

B

0

H, C0 -p CHo-C-O-R

3 c = o

The hydrogen chloride released in the reaction can be determined by titration and thus used as a measure to monitor the progress of the reaction.

The reaction is preferably carried out at a temperature of 100 to 220 ° C, especially 170 to 210 ° C. The reaction time depends on the solvent, the boiling point and the concentration of the solution, and usually takes 3 to 24 hours. Low boiling point solvents require a longer reaction time than high boiling point solvents. As the concentration of the solution increases, the reaction time decreases.

7 56832

The final products of the general formula TV obtained are very pure and are obtained in a particularly high yield when carrying out the process according to the invention with oxygen, i. especially when air is excluded.

In order to free oxygen, especially without oxygen, the reaction can be carried out under an inert gas atmosphere, i. in gases which do not themselves take part in the reaction. Examples of these are oxygen-free nitrogen or noble gases such as helium. According to the invention, it is then particularly advantageous to pass a stream of such an inert gas through the heated reaction mixture. It may also be advantageous to purge the reactants and / or the inert solvent used in the reaction with such a stream of inert gas before the start of the reaction, in order to ensure from the outset that no traces of oxygen are present.

By passing a stream of inert gas through the heated reaction mixture, the additional advantage is obtained that the free hydrohalic acid formed in the condensation reaction, in particular HCl, is removed more rapidly and easily from the reaction mixture. It has also been shown to have a beneficial effect on the yield and purity of the desired end product. The reaction mixture, and in particular also the indole starting compound, is in itself surprisingly stable against dry oxygen-free HCl, even at the said high reaction temperatures. Thus, it has been found experimentally that even in suitable solvents, even after passing several hours of gaseous dry HCl through the reaction charge, the indole compound does not become resinous in a significant amount when treated in the absence of acylating acid chloride. In addition, in the condensation reaction according to the invention, the dry gaseous HCl liberated as a result of the reaction with the acid chloride leads to a surprisingly small amount of undesired side reactions. This was all the more surprising since the immediate addition of any other strong acid immediately results in rapid resinization of substantial amounts of the reaction mixture. The same applies to the use of levic acids as acid catalysts. Moreover, the use of chemically close acid bromide as an acylating agent instead of the acid chloride, which results in the formation of HBr, gives clearly worse results than the use of acid chloride. This makes it possible to decide on a particularly advantageous use of the acid chloride as a reaction component. It is apparently a specific property of gaseous hydrochloric acid that, under the given conditions of the process of the invention, it is substantially inert to the reaction components. This interesting property occurs only with free gaseous hydrochloric acid. Attempts to isolate hydrochloric acid in the reaction mixture, and in particular by isolating it as a salt, then immediately result in numerous side reactions with the same resin support in the reaction mixture, if e.g. an attempt is made to react the formed HCl with carbon dioxide salts and precipitate immediately. Surprisingly, it is the free gaseous hydrochloric acid for which the reaction system of the invention is stable.

It is also preferred to keep the HCl concentration in the reaction mixture low. This is achieved by passing an inert gas through the reaction mixture.

According to the invention, it is also advantageous to protect the reaction mixture from moisture. For this reason, the inert gas stream is preferably pre-dried. Moisture in the reaction mixture results in an undesired reaction of the acid chloride and thus an increase in yield. In individual cases, it may also be advantageous to work with the reaction mixture protected from light. However, this measure is only relevant in special cases.

The purity of the final products obtained is a particular advantage of the process according to the invention, since according to the invention final products are obtained which, after a single crystallization, have a purity of more than 98%, in most cases more than 99%. However, the reaction can in principle be carried out in the presence of air in satisfactory yields. In this case, however, end products that are impure are usually obtained. These impurities can only be removed very difficultly, if at all, from the reaction products. The technical performance of the method is thus greatly hampered in the latter circumstances.

In the process according to the invention, 1 to 5 moles of the compound of the general formula VIII are expediently used per 1 mole of the compound of the general formula VII. The handling of the end products is very simple. This is done, for example, by evaporating the diluent in vacuo, whereby depending on the solvent, either crystalline porridge is obtained or the residue can be crystallized by adding e.g. diethyl ether, or the reaction solution can be diluted with e.g. diethyl ether, whereupon the final products precipitate crystalline. These crystalline end products are then recrystallized.

The process according to the invention preferably uses an excess of solvent based on the weight of the reaction components. Although the reaction can in principle be carried out even in the absence of a solvent, it is nevertheless expedient to use at least an equal amount, preferably at least twice the amount of the solvent, based on the weight of the reaction components. It may be particularly advantageous to use 4 to 15 times the amount of solvent based on the weight of the reaction mixture.

Example 1 H3 °° N CH3 C = 0

O

Cl a) 309-37 moles) 5-Methoxy-2-methyl-3-indoleacetic acid benzyl ester is dissolved in 4,000 ml of absolute 1,2-dichlorobenzene and heated at 150 ° C while removing oxygen-free nitrogen from light and protected from moisture. 350 g (2 moles) of p-chlorobenzoyl chloride are then added dropwise over 15 to 20 minutes and the reaction mixture is heated to reflux (reaction mixture temperature 180-183 ° C). The hydrogen chloride released during the reaction is removed with a stream of nitrogen and titrated quantitatively with sodium hydroxide to control the reaction. After boiling for 17 hours, the solvent and excess acid chloride are distilled off at 50 ° C / 0.1 tower, the brown oily residue is taken up in 1000 ml of diethyl ether and kept at -10 to -10 ° C for 6 hours. The solidified solution is filtered off with suction and the residue is washed with isopropyl ether. The yield of 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid benzyl ester thus obtained is 365-9 g (melting point 93-94 ° C). From the ether solution, 2.3 g of this compound are obtained by crystallization (melting point 89-90 [deg.] C.), so that the total yield is 393 → 2 g (88% of theory). Recrystallization once from ethyl acetate / isopropyl ether gives a very pure product, m.p. 95-96 ° C, with a total yield of 83% of theory.

b) 2000 ml of reagent benzene (redistilled "Kris-tall oil-60", manufactured by SHELL AG, boiling range 190-220 ° C) are suspended under oxygen-free nitrogen, protected from light and moisture, 300 g (0.972 moles) of 5-nie ' coke-2-methyl-3-indoleacetic acid benzyl ester, the mixture is heated to 160 ° C (a clear solution forms at 90-100 ° C) and 340 g (1.944 moles) of p-chlorobenzoyl chloride are added over 15 minutes. The temperature is then raised to the boiling point of the solution (193-196 ° C; the evolution of hydrogen chloride is controlled according to 10 56832 (a)). After 8 hours of reaction, the tan solution is allowed to cool to 70 [deg.] C. and 125 ml of ethyl acetate are added at this temperature. After slowly cooling and allowing to stand for a longer time at 0 [deg.] C., the crystalline porridge formed is filtered off with suction and washed with 1000 ml of isopropyl ether. The yield of 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid benzyl ester is 396.1 g g (91% of theory), and after recrystallization according to a) the yield is pure 34-8.3 g (80%). % of theoretical value).

c) 300 g of 5-methoxy-2-methyl-3-indoleacetic acid benzyl ester are dissolved in 2 liters of "Petrolspezial", manufactured by Fluka, under warm conditions, 350 g of p-chlorobenzoyl chloride are added according to Example 1a and boiled under argon for 4 hours 195-198 ° C.

After cooling to 60 ° C, 2 liters of ether are added and the solution is kept cold. Further processed as in the above examples, the yield of the crude compound is 350 g (80% of theory, melting point 95-96 ° C) and the yield of pure compound is 320 g (74% of theory, melting point 96 ° C). .

d) To 200 g (0.647 moles) of 5-methoxy-2-methyl-3-indoleacetic acid benzyl ester in 1330 ml of absolute 2,4-dichlorotoluene are added 226 g (1.29 moles) of o-chlorobenzoyl chloride and boiled for 4 hours. ° C and further worked up to give 232 g (80% of theory) of 209 S (72% of theory) of 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid, respectively. -pob ent warts est different ä.

Example 2 0 0 h3CO -n-GH2-C-O-CH2-C-O-CH2 ^ ^ I 5 C = 0 0

Cl a) 300 g (0.82 mol) of (5-methoxy-2-methyl-3-methyl-acetoxy) -acetic acid benzyl ester are dissolved in 400 ml of absolute 1,2-dichlorobenzene, an oxygen-free stream of nitrogen is passed through the solution and heated to 160 ° C. . 286 g (1.63 mol) of p-chlorobenzoyl chloride are then added dropwise to the solution over a period of 20-30 minutes and the mixture is boiled for 23 hours at 180-183 ° C. The degree of reaction is monitored by titration by passing the liberated hydrogen chloride into a calculated amount of ιι 56832 sodium hydroxide. 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. From a solution cooled to -15 ° C, the formed N- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetoxy7-acetic acid benzyl ester crystallizes out as pale yellow needles which are liberated from the acid chloride by stirring with 1000 ml of diisopropyl ether. The yield of the crude compound is 358 g (8% of theory; melting point 89-91 ° C) and after recrystallization from acetic acid ethyl ester / diisopropyl ether, the yield is 322 g (78% of theory), m.p. 94-95 ° C.

b) 6 g (0.0164 mol) of (5-methoxy-2-methyl-3-indole-acetoxy) -acetic acid benzyl ester are covered with distilled reagent benzene ("Kristallöl 60", manufactured by SHELL, boiling range 194-220 ° C), heated to reflux (194 ° C) while introducing oxygen-free nitrogen and stirring and adding 4.28 g (0.0246 moles) of p-chlorobenzoyl chloride over 10 minutes. After boiling for 9 3/4 hours with stirring, the charge is slowly cooled under a nitrogen atmosphere, at which point an oil begins to separate at about 130 ° C. Diethyl ether is added to the cooled charge and stirred until crystallization begins. There is thus obtained N- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetoxyacetic acid benzyl ester, which, after recrystallization according to a), gives a yield of 6.2 g (75% of theory).

c) Under the conditions described in Example 2a), 183-17 g (0.5 moles) of (§-methoxy-2-methyl-3-indoleacetoxy) -acetic acid benzyl ester in 2000 ml of absolute 2,4-dichlorotoluene and 175 g of (1.0 mol) of p-chlorobenzoyl chloride by boiling for 10 hours (198-200 ° C) 190 g (75% of theory) of N- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indoleacetoxy] acetic acid benzyl ester, mp. 95 ° C.

Example 3 0 0 H ^ CO -jr CH2-C-O-CH2-C-O-CH2 r ^ ^ 1 5 ö

In analogy to the conditions used in Examples 1 and 2, 10 56 g (0.0274 mol) of (5-methoxy-2-methyl-3-indoleacetoxy) 12,56832 acetic acid benzyl ester and 7.7 g (0.054-8 mol) of benzoyl are obtained. chloride by boiling for 25 hours under nitrogen in 130 ml of 1,2-dichlorobenzene and further treating 7.35 6 (57% of theory) of (1-benzoyl-5-methoxy-3-methyl-3-indoleacetoxy) acetic acid benzyl ester melting at 95 ° C.

Example 4-

0 O

H-, CO -r CH0-C-O-OH - C-O-OHo / ~ \ i *

Analogously to the conditions described in Examples 1 and 2, 10 g (0.0274 mol) of (5-methoxy-2-methyl-3-indoleacetoxy) acetic acid benzyl ester and 12.6 g (0.054-8 mol) of 3.4 are obtained. 5-Tri-methoxy-benzoyl chloride by boiling for 13 hours in 130 ml of 1,2-dichlorobenzene and further treating 8.3 g (54% of theory) of β-methoxy-2-methyl-1- (3 (4,5-Trimethoxy-benzoyl) -3-indole-acetoxy-7-acetic acid benzyl ester, melting at 117-118 ° C.

Example 5 -0

h3 °° 0HrJ- ° - ° ^ O

CH 2 Cl 2 O 2 NO 2

Cl

Under the conditions described in Examples 1 and 2, 6.0 g (0.194 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 are obtained. by boiling for 2 hours in 400 ml of reagent benzene (b.p. 190-220 ° C), then purifying from chloroform on silica gel and eluting with cyclohexane / ethyl acetate (3: 1) 4.6 g (48% of theory) of 1- ( 4-Chloro-3 - ((benzoybenzoyl) -5-methoxy-2-) methyl-3-indoleacetic acid benzyl ester, m.p. 85-87 ° C.

Claims (3)

15 56832 CLAIMS Process for the preparation of indoleacetic acid esters of general formula 0 II H, CO CH 2 -C-O-E 'Cti Ao 3 0- wherein E is a benzyl residue or a residue -CHg-COOCHg O and X is hydrogen or also one or more halogen atoms or a functional group such as a methoxy, nitro or trifluoromethyl group, characterized in that the compounds of general formula 0 II H, CO -r CHo-C-O-B 3 WljtoH • 5 H is condensed with compounds of general formula V Cp-COCl VIII X in which formulas E and X have the same meaning Imin above, at a temperature of 100 to 220 ° C protected from oxygen, preferably in a stream of oxygen-free inert gas and possibly from moisture and light protected in an inert solvent to form free HCl.