DE1232966B - Process for the preparation of (+) - enantiomorphs of indole compounds - Google Patents

Description

German WtmWp patent office

EDITORIAL

German class: 12p-2

Number: 1232 966

File number: M 52100IV d / 12 ρ

1 232 966 Filing date: March 12, 1962

Opened on: January 26, 1967

The invention relates to a process for the preparation of (+) - enantiomorphs of indole compounds the general formula

R "-

COOH

in which R is a halogen atom or a lower alkoxy, mercapto, alkylthio, arylthio or aralkylthio radical, R 'denotes lower alkyl and R "denotes lower alkyl or alkoxy, which therein consists that in a known manner, the racemic mixtures of these indole compounds with (-i -) - a-Phenylethylamine in the presence of lower alkanols and the resulting crystalline (+) - a-Phenylethylamine salts of the (+) - enantiomorphs of indole compounds with inorganic acids treated.

The racemates of the above structural formula obtained in the chemical synthesis are known to have excellent anti-inflammatory activity and are used as agents for inhibition or Effectively prevents the formation of granulation tissue. They will therefore be used in the treatment of arthritic diseases, skin diseases, and other diseases that relate to anti-inflammatory Agents, such as the adrenal cortex hormones, are used.

It has now been found that practically all of the activity is attributable to the (+) - enantiomorph. According to the invention the breakdown into the optically active (+) - and (-) - enantiomorphs takes place with the help of of (+) - a-phenylethylamine. When implementing a solution of the racemate in a lower Alkanol with (+) - a-phenylethylamine forms a mixture of two diastereoisomeric salts, which is broken down into its components by fractional crystallization. The (-f) -a-phenylethylamine salt of the (+) - enantiomorph of the indole compound is then treated with an inorganic Acid converted into the free acid.

Process for the preparation of (-r) -enantiomorphs of indole compounds

Applicant:

Merck & Co., Incorporated, Rahway, N.J. (V. St. A.)

Representative:

Dr.-Ing. W. Abitz and Dr. D. Morf, Patent Attorneys ,. Munich 27, Pienzenauer Str. 28

Named as inventor:

Andrew Napier Wilson, Colonia, N. J. (V. St. A.) Claimed Priority:

V. St. v. America March 14, 1961 (95 480) -

The use of lower alkanols as solvents has the particular advantage that the (+) -a-Phenylethylamine salt of the (+) - form of the indole compound is the less soluble of the two diastereoisomers is and therefore crystallized out of the reaction mixture first. This salt can easily . for example, by filtration or centrifugation, obtained and treated with an inorganic one Acid can be converted into the free acid.

Typical examples of indole compounds that are easily obtainable in this way are the (+) - enantiomorphs of a- (lp-methylthiobenzyl-2-methyl-5 - methoxy - 3 - indolyl) propionic acid, α - (1 - ρ - Chlorobenzyl-2-methyl-5-methoxy-3-indolyl) propionic acid, α - (1 - ρ - methoxybenzyl - 2,5 - dimethyl - 3 - indolyl) propionic acid, a - (1 - ρ - fluorobenzyl - 2 - methyl - 5 - ethoxy - 3 - indolyl) butyric acid, a - (1 - ρ - phenylthiobenzyl-2-methyl-5-methoxy-3-indolyl) propionic acid and a- (lp-mercaptobenzyl-2-methyl-5 methoxy-3-indolyl) propionic acid.

Of the lower alkanols, ethanol and isopropanol are preferred as solvents, but Methanol, propanol, butanol and similar alcohols and mixtures thereof can also be used will. It is advisable to warm the indole compound and the (+) - a-phenylethylamine or hot alkanol and add the solution

609 759/396

Let it cool down to around room temperature. Under these conditions the less soluble crystallizes Diastereoisomers and can be obtained in practically pure form.

The superior therapeutic effectiveness of the (+) - enantiomorphs produced according to the invention Compared to the racemates and the corresponding (-) - enantiomorphs, the following Experiments proven:

1. Granuloma inhibition

The granuloma inhibition was carried out according to the method of Winter and Porter in »Am. Pharm. Assoc., Sci. Ed. ”, Vol. 46, 1957, p. 515. Results:

1-p-Chlorobenzyl-2-methyl-5-methoxy-3-indolylacetic acid

link dose
mg / kg Grar
Attempt 1 lulomhemmunj
Attempt 2 l, ⁰ Io
Average Racemate 10 29 16 23 Racemate 30th 38 20th 29 Racemate 90 37 28 32 10 26th 28 27 30th 44 22nd 33 90 42 35 38 10 7th 21 14th 30th 15th 13th 14th 90 26th 10 18th

From this the following relative potency can be calculated:

Racemate 1.0

(+) 3.8

(-) 0.4

1-p-Methylthiobenzyl-2-methyl-5-methoxy-3-indolylpropionic acid

In a first experiment, the activity of the (-i -) - form was compared with that of the racemate:

link Dose, mg / kg Granuloma inhibition,% Racemate 3.33 29 Racemate 10 36 Racemate 30th 44 (+) 1.67 34 (-) 5 33 (-) 15th 48

From this, a ratio of the potency of the (+) - form to that of the racemate is calculated 2.7. If one takes into account the possible deviations caused by the error limit, then in any case it can be said with certainty that the potency of the (+) - form is about twice as great is like that of the racemate.

In a second experiment, two samples of the (-) - form were compared with the racemate.

link Dose, mg / kg Granuloma inhibition, "'» Racemate 3.33 16 Racemate 10 28 Racemate 30th 38 (-) (1) 3.33 0 (-) (i) 10 16 (-) (I) 30th 17th (-) (2) 3.33 0 (-) (2) 10 0 (-) (2) 30th 0

2. Antipyretic effect

The antipyretic effect was demonstrated by subcutaneous injection of the compound in question Rabbits determined at a dose of 18 mg / kg. 30 minutes after the subcutaneous injection, the Rabbits are injected intravenously with a febrile agent. The temperature measurements were taken rectally in 30 minute intervals over a 5 hour period.

1-p-Chlorobenzyl-2-methyl-5-methoxy-3-indolylacetic acid

In this case, the temperature increases in ⁰ C were determined as mean values of five test animals each. The control values are the temperature increases that occurred without administration of the compounds tested.

treatment Controls (τ) (-) 0.5 hours 0.24 0.16 0.34 1.0 hour 1.06 0.58 0.82 1.5 hours 1.24 0.38 1.08 2.0 hours 1.52 0.24 1.04 2.5 hours 1.90 0.20 1.56 3.0 hours 2.14 0.14 1.88 3.5 hours 2.16 0.08 2.04 4.0 hours 2.26 0.04 2.02 4.5 hours 2.12 0.00 1.90 5.0 hours 2.02 -0.02 1.70

1-p-Methylthiobenzyl-2-methyl-5-methoxy-3-indolylpropionic acid

In this case the so-called "temperature index" was determined, which is the sum of all according to the Administration of the compound to be tested, determined temperature readings, in each case reduced around the temperature measured prior to administration of the feverish agent. These values are mean values of four test animals each.

Claims (3)

1 Temperature index Attempt 1 Attempt 2 Racemate 1.84 3.48 (+) 2.48 1.14 (-) 10.76 12.13 Controls 15.43 16.37 3. Toxicity For the toxicities of l-p-methylthiobenzyl-2-methyl-5-methoxy-3-indolylpropionic acid the following values were determined when administered intravenously and orally to mice: LD ₀ LD00 LD _iw Intravenously Racemate 182 322 500 (+) 130 265 500 (-) 130 357 500 Orally Racemate 392 929 1515 (+) 280 740 1080 (-) 770 1045 1515 example 1 A mixture of 10 g of racemic a- (lp-chlorobenzyl-2-methyl-5-methoxy-3-indolyl) propionic acid with 4 g of (+) - ci- phenylethylamine is dissolved in 100 ml of hot isopropanol. The solution is allowed to cool slowly, whereupon 2.5 g of (+) - a-phenylethylamine salt of (+) - a- (lp-chlorobenzyl-2-methyl-5-methoxy-3-indolyl) propionic acid crystallize out. This salt is filtered off, washed with isopropanol and with ether and dried. On further cooling of the filtrate, a further 3.0 g of salt crystallize out. After recrystallization from isopropanol, the salt has a melting point of 148 to 149 ^: C, [a] l ² = + 43 ° (c = 1, methanol). An excess of dilute hydrochloric acid is added to a suspension of this salt in a mixture of water and ethyl ether. The acidified mixture (pH 2) is shaken and the solvent layers are allowed to separate. The ether phase is removed, washed with water and dried over sodium sulfate and magnesium sulfate. The ether is then removed by evaporation in vacuo and the residue is recrystallized from aqueous ethanol, giving (+) - a- (lp-chlorobenzyl-2-methyl-5-methoxy-3-indolyl) propionic acid. After recrystallization from benzene-petroleum ether (1: 1) the product has a melting point of 156 to 157 ° C, [a]% = + 60 ° (c = 1, ethanol). B e i s ρ i e 1 2 24.9 g of racemic a- (1-p-methylthiobenzyl-2-methyl-5-methoxy-3-indolyl) propionic acid and 9.5 g 966 (+) -Gi -Phenyläthylamin are dissolved in 350 ml of boiling ethanol. The solution is then cooled to 20 to 25 ^° C. and allowed to stand for 90 minutes. The crystalline material is filtered off and washed with cold ethanol and with ether. It is recrystallized from ethanol, practically pure (+) - a-phenylethylamine salt of (+) - «- (1-p-methylthiobenzyl-2-methyl-5-methoxy-3-indolyl) propionic acid having a melting point of 170 up to 172 ° C and [a] ?? = +38.5 (c = 1, methanol) is obtained. This product is added to a mixture of 100 ml of ether, 50 ml of water and 2.5 ml of concentrated hydrochloric acid at room temperature. After a few minutes, the ether layer is separated off and the aqueous acidic solution is extracted twice with 75 ml of ether each time. The combined ether extracts are concentrated to dryness in vacuo. The residue obtained in this way is recrystallized from 20 ml of ether and 12 ml of benzene, practically pure (+) - «- (lp-methylthiobenzyl-2-methyl-5-methoxy-3-indolyl) propionic acid having a melting point of 118 ° C and [a] o = +62.4 (c = 0.94, ethanol). Claim: Process for the preparation of (+) - enantiomorphs of indole compounds of the general formula R ' -COOH in which R is a halogen atom or a lower alkoxy, mercapto, alkylthio, arylthio or aralkylthio radical, R 'is a lower alkyl radical and R "is a lower alkyl or alkoxy radical, characterized in that the racemic radicals are known in a manner known per se Mixtures of these indole compounds are reacted with (+) - «- phenylethylamine in the presence of lower alkanols and the resulting crystalline (+) -« - phenylethylamine salts of the ( -1- ) -u-enantiomorphs of the indole compounds are treated with inorganic acids. Considered publications:
The Journal of Biological Chemistry, 96: 511-517 (1932); published documents of Belgian patent No. 594 596.