DE1795659C3 - Process for the preparation of 1-acyl-3-indolylcarboxylic acid compounds - Google Patents

Description

N-NH,

(H)

33

or

N == B (III) 40 N -
I. CO
R ¹ 43

The connections that can be made are partly known from US Pat. No. 3,161,654, partly new connections.

According to E. Fischer, indole homologues can be produced by heating the phenyhydrazones of aldehydes or ketones with zinc chloride, copper (I) chloride or copper (I) bromide (cf. P. Karrer. Textbook of Organic Chemistry, Georg Thieme-Verlag, Stuttgart , 10th edition, 1948, p. 823). The preparation of acyl derivatives of indole is described in a review by WC Sumpter and FMMiller in the book “Heterocyclic Compounds with Indole and Carbazole System, Interscience Publishers. Inc., New York, 1954, pp. 44 to 47. 1-Acetylindole is saponified to indole with a dilute alkali at high temperature. When boiled with water or dilute alkali, 1,3-diacetylindole is converted into 3-acetylindole. The acyl radical in the 1-position of the indole can be split off hydrolytically with acid or alkali so easily that it was considered impossible to prepare 1-acylindoles directly from the corresponding N'-acylphenylhydrazones according to Fischer.

From US Pat. No. 2,701,250 it is known to use indolylacetic acid compounds of the general formula

R ⁶

in dsr R ¹ and R ^{6 have} the above meaning and B is the radical of an aldehyde or ketone, with a ketocarboxylic acid compound of the general formula IV

R ³

R ⁴

R ² COCH, - CH _m - (CH ₂ ) "- CHL-COR ⁵

(IV)

in which R ² , R ³ , R ⁴ , R ⁵ , m, η and ρ have the meaning given above, optionally in the presence of a condensing agent and optionally in the presence of a solvent.

The invention relates to a new process for the preparation of l-acyl-S-indolylcarboxylic acid compounds. Among those according to the invention, R 'denotes a hydrogen or halogen atom or an alkyl group and R ² denotes a hydrogen atom, an alkyl group or a phenyl group, by reacting levulinic acid with the corresponding phenylhydrazine or its hydrochloride in a lower one

S3 to produce aliphatic alcohol as a solvent and in the presence of a mineral acid. The implementation is carried out by heating the mixture for several hours. The initially formed indolylacetic acid ester after cleaning in

$ 0 saponified to free acid in a known manner.

1 - Acyl-3-indolylacetic acid compounds can prepared according to the process described in US Pat. No. 3,161,654 as follows: First, a phenylhydrazine is mixed with a levulinic acid ester or amide in a lower aliphatic Alcohol as a solvent and in the presence of a mineral acid or Lewis acid as a catalyst brought to reaction at elevated temperature.

The corresponding 3-idolylacetic acid compound is formed from the intermediate phenylhydrazone. Dw ^ w * " ^{1 converted into the} 3-indolylacetic acid benzyl ester, which is also formed directly when using levulinic acid benzyl ester. The benzyl ester is acylated in the 1-position of the indole and the benzyl group is split off by catalytic hydrogenation.

Another possibility for producing J-acyl-3-indolylacetic acid compounds, which is described in US Pat. No. 3161654, is to produce the corresponding anhydride from the free 3-indolylacetic acid by reacting it with dicyclohexylcarbodiimide, this by reacting it with tert-butanol to esterify in the presence of molten zinc chloride to give S-indolylacetic acid terL-butyl ester, to convert this with sodium hydride in dimethylformamide at low temperatures into the corresponding sodium derivative and then to acylate it with a carboxylic acid halide. Then the obtained l-acyl-3-indolylacetic acid tert-butyl ester is decomposed by heating at 210 ⁰ C in the presence of porous clay shards to the free acid.

One of the most valuable compounds described in U.S. Patent 3161654, the l-p-CMorberizoyl-l-methyl-S-methoxy - ^ - indolylacetic acid (Indomethacin), starting from p-methoxyphenylhydrazine and levulinic acid in a total yield of about 9 percent of theory according to the following reaction scheme:

CH ₃ O,

CH ₃ O

1. Dicyclohexyl-CH ₃ O
carbodiimide

CH ₂ -CH ₂ -COOH CO
NH-NH ₂ HCl ⁺ CH ₃

CH ₂ -COO-ICrL-C ₄ H ₉ CH ₃ O

79%

CH ₂ COOH

2. tert-butanol
65%

CH ₃ O,

CH ₇ COOH

CH ₂ -COO-ICrL-C ₄ H ₉

Suvorov et al., J. Gen. Chem. USSR, Vol. 28 (1958), p. 1090, are of the opinion that an important precondition for the formation of indoles according to Fischer from the corresponding phenylhydrazone when converted into acetic anhydride is the cleavage of the N'-acyl radical from the N ¹ -acylphenylhydrazone formed as an intermediate.

The present invention is based on the surprising finding that 1-acylindole can be used directly by reacting N'-acylphenylhydrazines or N'-acylphenylhydrazones with carbonyl compounds receives.

The object of the invention is therefore to provide a new process for the preparation of l-acyl-3-indolylcarboxylic acid compounds to make available that is economically advantageous, gives high yields and can be carried out on an industrial scale. This object is achieved by the invention solved.

The invention relates to a process for the preparation of l-AcyW-indolylcarboxylic acid compounds of the general formula I.

55

60

"- (CH ₂ J _n -

R * CH

, - COR ⁵

CO

R ¹

in which R ^{1 is} an alkyl, haloalkyl or alkenyl radical with up to 10 carbon atoms, R ² and R ^{3 are} hydrogen atoms or lower alkyl radicals with up to 3 carbon atoms, R ^{4 is} a hydrogen atom, a

Carboxyl group or an alkoxycarbonyl group with up to 4 carbon atoms, R ^s an alkoxy group with a maximum of 4 carbon atoms, a benzyloxy, Tetrah.ydiqpyranyloxy-, hydroxyl or amino group, R ⁶ an alkyl radical with up to 4 carbon atoms, an alkoxy or alkylmeiCiptorest with up to 3 carbon atoms, a halogen or hydrogen atom, m and ρ de ρ value 0 or 1 and η have the value 0, 1, 2 or 3. The process is characterized in that either an N'-acylphenylhydrazine or its salt of the general formula II or an N ^ acylphenylhydrazone of the general formula III

(H)

R ⁶

CO
R ¹

20th

(HD

in which R ¹ and R ^{6 have} the above meaning and B is the radical of an aldehyde or ketone, with a ketocarboxylic acid compound of the general formula IV

R ² COCH,

CH

\ I

- (CH ₂ ), -

CH) -COR ⁵

35

(IV)

in which R ² , R ³ , R ⁴ , R ⁵ , m, η and ρ are as defined above, optionally in the presence of a condensing agent and optionally in the presence of a solvent.

The process of the present invention works smoothly even in the absence of a solvent, but in some cases the use of solvents is preferred. For example, organic acids such as acetic acid, formic acid, propionic acid, lactic acid or butyric acid, non-polar organic solvents such as cyclohexane, η-hexane, benzene and toluene, or polar solvents such as dioxane and Dimethylformamide. In the condensation of aliphatic carboxylic acid alkyl esters, alcohols are also preferably used in addition to the solvents mentioned. The reaction proceeds at a temperature in the range of about 50 to about 200 ⁰ C. The preferred temperature range is between 65 and 90 ° C. A condensation agent is not always necessary, but the use of leads inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, in generally favorable results. The abovementioned solvents, reaction temperatures and condensing agents are to be understood as illustrative only, and the invention is not restricted thereto

The S-indolylcarboxylic acid compounds which can be prepared by the process according to the invention are Drug; they have anti-inflammatory. analgesic and antipyretic effects and lower the Serum cholesterol levels.

If the substituent R ⁶ in the N ¹ -acylphenylhydrazine of the general formula II is in the p-position, a single compound is obtained as the indole compound of the general formula I. If, on the other hand, the substituent R ^{6 is} in the m-position, two isomers are generally formed in the process according to the invention which can be separated from one another by chromatography.

When a ketocarboxylic acid compound of the general formula IV, in which R ^{4 is} a carboxyl group, is reacted with the N'-acylphenylhydrazine or its salt, the S-indolylcarboxylic acid compound of the general formula I obtained is decarboxylated in some cases. This reaction takes place according to the following reaction scheme:

+ R ² COCH ₂ -R ³
CH

COOH

N - NH ₂

CO

R ¹

COOH

- (CH ₂ J _n - CH ₂ COOH

The working temperature in this case is between 60 and 200 ⁰ C, preferably between 80 and 14O ⁰ C. The solvents used are organic acids such as acetic acid, propionic acid and lactic acid, nonpolar solvents such as benzene and toluene, or polar organic solvents such as acetonitrile and ButanoK

used. Inorganic acids such as hydrochloric acid and sulfuric acid or Lewis acids such as zinc chloride or boron fluoride are used.

The l-acyl-S-indolylcarboxylic acid compounds of general formula I can also be obtained by reacting N'-acylphenylhydrazones of the general formula III

-N-N = B (III)

CO
R ¹

in which R ¹ and R ^{6 have} the above meaning and B is a ketone or aldehyde radical, with the ketocarbon

acid compound of the general formula IV prepared will.

Organic acids such as formic acid, propionic acid, lactic acid or butyric acid, non-polar organic solvents such as cyclohexane, η-hexane, benzene and toluene, or polar organic solvents such as alcohols are used as solvents. The reaction proceeds at a temperature in the range of 50 to 200 ⁰ C. A temperature range of 65 to 95 ° C is preferred. Inorganic acids such as hydrochloric acid and sulfuric acid, Lewis acids, for example metal halides such as zinc chloride and copper chloride, heavy metal powder, boron fluorides or polyphosphoric acids can be used as condensing agents.

The N'-acylphenylhydrazones used according to the process can be prepared according to the following reaction scheme:

O = B

R ⁶

NH-NH ₂
(V)

NH-N = B

(VI)

A phenylhydrazine of the general formula V is reacted in a suitable solvent, for example an alcohol, with a ketone or aldehyde of the general formula O = B to give the corresponding phenylhydrazone of the general formula VI. This is then acylated with a carboxylic acid chloride of the general formula R ¹ COCl in pyridine as the solvent or an acid anhydride.

The N ^l -acylphenylhydrazones of the general form! III are derived from a wide variety of ketones or aldehydes, such as diethyl ketone, phenyl ethyl ketone, ethyl butyl ketone, methoxyacetone, benzaldehyde, acetaldehyde, chloral. Levulinic acid methyl ester and γ-methoxybiiityraldehyde. In the above case, it is desirable to use a compound which contains Cl

I. co

R ¹

€, V

J6

N-N

CO

R ¹

(HI)

can be easily cleaved after the reaction has ended and no side reaction which reduces the yield and which is readily available. In this regard acetaldehyde is particularly suitable as a carbonyl compound.

The radical B can be derived from the ketocarboxylic acid compound of the general formula IV, but it preferably does not take part in the ring closure reaction. Suitable groups B are, for example, CH ₃ CH =, C _? H ₅ CH = .C ₆ H ₅ -CH = or CCl ₃ CH =. The N = C bond of the N ¹ acylphenyl hydrazone is quite unstable in acid. In a solvent in the presence of an acid, the ketocarboxylic acid compound of the general formula IV is reacted according to the following reaction scheme.

Kk

NN = B
CO

R ¹
(IH)

N-NH ₂

CO

R ¹

/ r ³ \ U *

H ₁ C | CH |. · (CH ₂ ). (cH] ,, · COR ^5
V R ²

509618/89

ίο

CH, "· (CH ₂ J _n -R ⁴

COR ⁵

The N ¹ -acylphenylhydrazines of the general formula II and their salts are generally obtained in high yield by cleaving the N'-acylphenylhydrazones of the general formula III in the presence of acid.

The preferred solvents for cleaving the N'-acylphenylhydrazones are the alcohols. if however, if more than one equivalent of alcohol is used, an ordinary inert one can also be used Use solvents such as ether, benzene, or toluene.

Inorganic acids are generally used to cleave the N'-acylphenylhydrazones, in some cases also uses organic acids. However, organic acids are not preferred in most cases, because when they are used, the yield is no longer lower, but side reactions also take place can. The preferred inorganic acids are hydrochloric acid, sulfuric acid and phosphoric acid. In this In this case, the less water the acids contain, the more favorable results can be obtained.

The reaction is completed in a short time even at a low temperature, and the yield is surprising high. Furthermore, the N'-acylphenyl

When levulinic acid is reacted with N'-acetyl-N'-ip-methoxyphenyO-hydrazine hydrochloride or N '- (2,4-hexadienoyl) -N' - (p-methoxyphenyl) hydrazine hydrochloride, the l -acetyl-2-methyl-5-methoxy-3-indolylacetic acid, melting at 163 to 164.5 ⁰ C in a yield of 55%. Th or the 1 -.. (2 ', 4 -Hexadienoyl ^ -methyl-S-methoxy ^ -indolylessigsäure mp 157 to 16O ⁰ C in a yield of 76% of theory.

Example 2

4.8 g of N'-acetyl-N '- (p-methoxyphenyl) hydrazine hydrochloride and 2.5 g of levulinic acid are added to 20 ml of acetic acid, and the mixture is heated to 76 ° C. for 2 hours while stirring. About 60 ml of water are then added to the reaction mixture, and the precipitated crystals are filtered off and dried. 4.2 g (38% of theory) of crude 1-acetyl-2-methyl-5-methoxy-3-indolylacetic acid are obtained, which is recrystallized from acetone; F. 163 to 164.5 ⁰ C.

The reaction can also be carried out in formic acid. Propionic acid, lactic acid, butyric acid, cyclohexane, n-hexane or dioxane can be carried out.

hydrazine obtained in the form of the salts, which are easily in crystalline form either by concentration of the Solvent or can be obtained by cooling the solution. When these salts with bases are treated, the free N'-acylphenylhydrazines are obtained in quantitative yield.

All of the l-acyl-3-indolylcarboxylic acid compounds mentioned are new compounds. Some of the esters. For example, the tert-butyl esters, benzyl esters and tetrahydropyranyl esters can be converted into the corresponding 1-acyl-3-indolyl carboxylic acids under suitable conditions.

The invention is illustrated by the examples.

Bet game 1

2.8 g of N'-chloroacetyl-N'-ip-methoxyphenylJ-hydrazine hydrochloride and 9.3 g of levulinic acid are heated to 75 ° C. for 1 hour and 45 minutes while stirring. After cooling, the liquid reaction mixture is poured into cold water, the precipitated crystals are filtered off and dried. 2.2 g (67% of theory) of crude 1-chloroacetyl-te 2-methyl-5-methoxy-3-indolylacetic acid are obtained. After recrystallization from ethanol, the pure compound melts at 155 to 156 ° C.

According to the procedure of Example! i becomes the hydrochloride of the corresponding N'-acylphenyihydrazine with the corresponding ketocarboxylic acid compound 90 minutes to 2.5 hours with stirring to 75 to 80 C heated.

Example 3

The procedure of Example 2 is repeated with methanol as the solvent. 1-Acetyl-2-methyl-5-methoxy-3-indolylacetic acid methyl ester is obtained as a pale yellow oil. Yield 50% of theory Th. IR absorption spectrum A ₁ ^ ₁ 5.76 and 5.99 μ.

Example 4

2.7 g of N'-chloroacetyl-N'-tp-methoxyphenyD-hydrazine and 1.6 g of levulinic acid are added to 30 ml of glacial acetic acid . About 2 ml of concentrated hydrochloric acid are added to the mixture and the mixture is warmed to 75 ° C. for 2 hours while resting. When the reaction has ended, the crystals which have separated out are filtered off and dried. 2.3 g (41% of theory) of crude 1-chloroacetyl - 2 - methyl - 5 - methoxy - 3 - indole acetic acid are obtained, which, after reconnection, melts at 155 to 157 (.

Example 5

2OgN ¹ -Crotonoyl-N '- (p-methoxyphenyl) hydrazine hydrochloride are introduced into 40 g of levulinic acid and the mixture is heated to 78 ° C. for 2.5 hours while stirring. When the reaction has ended, the liquid reaction mixture is poured into 200 ml of cold water, and the crystals obtained are filtered off. extracted with ether, and then the ether is distilled. What remains is crude crystalline 1 -Crotonoy 2-methyl-5-methoxy-3-indolylacetic acid. the one from e

a 85:15 mixture of ether and alcohol is recrystallized. Yield 7.5 g (44% of theory) of pure compound with a temperature of 130 to 131 ^° C.

According to Example 5, l-decanoyl ^ -methyl-S-methoxy-3-indolylacetic acid is prepared; F. 126 ⁰ C after recrystallization from acetone. Yield 40% of theory

Example 6

20 g of N'-Caproyl-N'-Cp-methoxyphenyO-hydrazine hydrochloride are added to 40 g of levulinic acid, and the mixture is stirred for 2 hours Heated to 75 ° C. Then the liquid reaction mixture is poured into 100 ml of cold water, and the obtained crystals are filtered off and dried. 13.0 g of crude 1-CaproyW-methyl-S-methoxy-3-indolylacetic acid are obtained obtained, which after recrystallization from a mixture of acetone and water 8.7 g (37% of theory) pure compound with a melting point of 140 to 141 ° C. ao

Example 7

17 g of N'-U '^' - HexadienoylJ-N'Kp-methoxyphenyl) -Iiydrazin hydrochloride and 10 g of 6-Acetylvaleriansäure are introduced into 35 ml of acetic acid, and the mixture is heated for 2 hours with stirring at 70 to 8O ⁰ C. . The liquid reaction mixture is then poured into 150 ml of cold water, and the crystalline precipitate obtained is filtered off and dried. 10 g of crude y- [l- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-3-indolyl] butyric acid are obtained which, after recrystallization from a mixture of acetone and water, 4.6 g of pure product from M.p. 127 to 129 ° C.

Following the procedure of Example 7, the following 3s Connections made:

0- [1- (2 ', 4'-hexadienoyl) -2-methyl-5-methoxy-3-indolyl] propionic acid, F. 166 to 167 ° C after recrystallization from aqueous acetone. Yield 34% d. Th.

1- (4-methylpentanoyl) -2-methyl-5-methox-y-3-indolylacetic acid. Mp 135 ° C after recrystallization from aqueous acetone. Yield 32% of theory Th.

1- (4-chlorobutyroyl) -2-methyl-5-methoxy-3-indolylacetic acid. F. 149 to 150 ⁰ C after recrystallization from acetone. Yield 45% of theory Th.

Example 8

10 g of NMn-pecanoyD-N'-ip-mctboxgyptyi) hydrazine hydrochloride and 9 g of levulinic acid benzyl ester "" heated in 30 ml of dioxane while resting. The crystals obtained are filtered off, the filtrate is evaporated under reduced pressure and the concentrate is washed with cold water. Here an oil separates itself. The oil is rubbed with a mixture of acetone and water, the l-De (aiKjyl-2-methvl-5-ynethoxy-3-indorylacetic acid benzyl ester of 83 to 85 ° C. Yield 30% of theory «,

Example 9

To g of N'-tn-Octanoy'.i-rn-tolvlbydrazm hydrochloride and 10 g of levulinic acid are heated to 75 to 77 ° C for 4 hours. After the reaction mixture has cooled, it is diluted with 30 ml of acetone. and insoluble substances are filtered off. The filtrate is poured into 30 ml of water and the liquid is left to stand in the refrigerator overnight. The precipitated crystals are filtered off and dried. 6.8 g of a mixture of 1- (n-octanoyl) -2,4-dimethyl-3-indolyl acetic acid and 1- (n-octanoyl) -2,6-dimethyl-3-indolylacetic acid with a melting point of 108 to 111 are obtained ⁰ C.

Example 10

3.6 gN ^l - (2'.4'-hexadienoyl) -N ¹ - (p-methoxyphenyl) hydrazine hydrochloride and 2.4 g acetonylmalonic acid are heated to 85 ° C. for 4 hours in 10 ml acetic acid while stirring. After cooling, the reaction mixture is poured into cold water. The precipitated crystals are filtered off and dried. 3.0 g (37% of theory) of crude (2 \ 4'-hexadienoyl) -2-methyl-5-methoxy-3-indolylacetic acid are obtained, which after recrystallization from aqueous acetone in yellow needles from a mp 162 to 163 Crystallize ° C.

According to example 10, the following connections are made:

l-hexanoyl ^ -methyl-S-methoxy-S-indolylacetic acid, Mp 140 to 141 ° C; Yield 26% of theory Th.

l-chloroacetyl ^ -methyl-S-methoxy-S-indolylacetic acid, M.p. 156-157 ° C; Yield 40% of theory Th.

Example 11

7.5 g acetaldehyde-N'-chloroacetyl-N'-ip-methoxyphenyl) hydrazone 50 g of levulinic acid are added and 1.45 g of dry acid are obtained while cooling with ice Hydrogen chloride gas initiated. After that, the temperature of the reaction mixture is gradually increased, and finally the mixture is heated to 80 ° C. for 3 hours. The mixture is left to stand overnight and then poured into a large amount of water. The amorphous one that fails here Product is repeatedly recrystallized from alcohol and acetone together with a little activated charcoal to decolorize. The l-chloroacetyl ^ -methyl-S-methoxy-3-indolylacetic acid obtained melts at 156-157 ° C; Yield 31% of theory Th.

According to Example 11, the following compounds manufactured:

l- (n-hexanoyl) -2-methyl-5-methoxy-3-indolylacetic acid, F. 138 to 140 ⁰ C; Yield 22% of theory

1-acetyl-2-methyl-5-methoxy-3-indolylacetic acid. M.p. 167 to 168 ° C; Yield 25% of theory Th.

0-11 - < 2 ' .4 ' -hexadienoyl) -2-methyl-5-methoxy-3-indolyl] propionic acid, mp 166 to 167 ° C; Yield «40% of theory

y- [1- (2'.4'-Hexadienoy!) -2-methyl-5-ineutoxy-3-yne dolylHnmeric acid. M.p. 127 to 129 ° C; Exploitation " 36% of the total

Example 12

2.5 g of p-mettioxyphenylhydrazone des levulinic acid methylesiers are added to 50 ml of glacial acetic acid. As mixture is added dropwise 0.9 g Acetylchloii and then 3 Standen to 8O ⁰ C HEATER) Then, an the mixture was stirred m 50 ml of cold water. An oil separates out. that is extracted with ether. Maa receives the 1-acolyl-2-ynethyl-5-ynethoxy-3-rödolvlesägsäTin methyl ester in a 29 percent dent. IR absorption spectrum A ^ _x 5.76 00 5.99 µ.

Claims (1)

Claim: Process for the preparation of l-acyl-S-indolylcarboxylic acid compounds of the general formula I. - (CH ₂ ), CH J _p - COR ⁵ in which R ^{1 is} an alkyl, haloalkyl or alkenyl radical with up to 10 carbon atoms, R ² and R ^{3 are} hydrogen atoms or lower alkyl radicals with up to 3 carbon atoms, R ^{4 is} a hydrogen atom, a carboxyl group or an alkoxycarbonyl group with up to 4 carbon atoms, R ⁵ an alkoxy group with a maximum of 4 carbon atoms, a benzyloxy, tetrahydropyranyloxy, hydroxyl or amino group and R an alkyl radical with up to 4 carbon atoms, an alkoxy or alkyl mercapto radical with up to 3 carbon atoms, a hydrogen or halogen atom, m and ρ denote The value 0 or 1 and η the value 0, 1, 2 or 3, characterized in that either an N ¹ -acylphenylhydrazine or its salt of the general formula II or an N'-acylphenylhydrazone of the general formula IH