DD151448A5 - PROCESS FOR THE PREPARATION OF BENZOTHIAZOL DERIVATIVES - Google Patents

Abstract

The invention relates to a process for preparing the compound of formula I, its two enantiomers and the racemate, their salts with the physiologically acceptable bases, inorganic cations and amines, and their salts with physiologically acceptable mineral or organic acids and their alkyl esters, characterized that the benzoic acid or a reactive equivalent, eg Acid chloride, a corresponding ester or a corresponding aldehyde, is reacted with a compound of formula II or an equivalent of this compound as the corresponding disulfide and dasz the acid obtained is converted into a salt or an ester.

Description

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Process for the preparation of benzothiazole derivatives Field of application of the invention

The invention relates to a process for preparing two steroid isomers and the eacemate of (phenyl-2-benzothiazo-6) -2-propionic acid.

Characteristic of the known technical solutions

Certain technical solutions are already known from FIKPS »n A 2 198 757 and A 2 106 462.

Aim of the invention

It is an object of the invention to enrich the state of the art,

Explanation of the essence of the invention;

The invention has for its object to develop a process for the preparation of Benzothiazolderivaten.

Two stereoisomers and the bacemate of (phenyl-2-benzothiazolyl-6) -2-propionic acid of the formula are prepared according to the invention

HOOC-CH-UfJ Nr-, (i)

and their salts with the physiologically compatible bases, alkaline cations, alkaline earth cations and amines, their salts with the physiologically tolerated mineral or organic acids, and their alkyl esters _e

- la - 2 2 O 1 7 7. 56 216 12

The racemic acids of formula I are prepared by reacting the aminothiol of formula II or one equivalent of the bisulfide corresponding to formula III

(ID

HOOC-CH

CH-COOH

(HD

with the benzoic acid or a derivative such as the benzotrichloride, a benzoyl ester or the benzaldehyde, whereby the reaction with benzoyl chloride leads to the best yield c

During the action of the acid chloride on the aminothiol of the formula II, which preferably takes place in the presence of a mineral or organic acid, there arise, in particular, the radicals IV and V

HOOC-GH CH

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(IV)

(V)

These compounds of formulas IV and V are not purified, but their mixture is cyclized either by the action of heat or by the action of acids or bases

Upon the action of benzaldehyde on the aminothiol of formula II, which takes place either in an inert solvent such as i-nitrobenzene, benzene, ... or in a basic solvent such as pyridine, quinoline, a benzothiazine of formula VI may form as intermediate

(TI)

which by oxidation, for example by I ¹ ECL, or Dime thyIsulf oxide results in the desired benzothiazole.

The two enantiomers of the acid of formula I can be separated by using a salt of the corresponding acid with a chiral amine, and more particularly each of the two enantiomers of phenyl-2-ethylamine. By a method known per se, these salts are recrystallized to separate the two diastereoisomers.

The salts of the acids of the formula I can be obtained by the action of a stoichiometric amount of the chosen acid or

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Base on the acids of the formula I which are dissolved in an alcohol, a ketone or an aliphatic ether. The esters of the acids of the formula I can be prepared by the action of an alcohol or a haloalkane on the acids of the formula I or one of their reacting Derivatives are prepared according to the methods known per se *

The aminothiols of the formula II can be prepared by degradation of a compound of the formula

(VII)

in basic, medium, in the presence or absence of a reducing agent *

These amino acids are novel chemical products produced by the action of bromine or ammonium thioeyaiiate on a compound of formula

HOOC-CH - ^ = ^^ (VIII)

CH,

which is dissolved in acetic acid, are prepared ·

The following examples illustrate the preparation of the compounds of the invention.

Example I

a) Preparation of the (Amino.o ~ 2-benzothiazalyl-6 ~) -2-propion

acid "24 _S 7 g (aminp-4-phenyl) -2-propionic acid are added.

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for example as in Org. Prep. Proc. Int. Pp. 303-307

(1977), in 3OO ml of acetic acid, then 22.8 g

0 ammonium thiocyanate dissolved. At 15 ° C., 24 g of bromine dissolved in 60 ml of acetic acid are added dropwise to this solution, then the mixture is allowed to reach room temperature again with stirring for several hours. Now, the solvent is separated under reduced pressure, and the residual oil is suspended in an acidic aqueous solution; the precipitate is separated and the aqueous phase is brought to pH 4.5 by addition of a sodium hydroxide solution. The resulting precipitate is separated by filtration and recrystallized in methanol or ethanol to yield 26 g of pure (amino-2-benzothiazolyl-6) -2-propionic acid having a melting point of 234 ⁰ G.

b) Preparation of (phenyl-2-benzothiazolyl-6) -2-propionic acid using benzoyl chloride

A solution of 45 g (amino-2-benzothiazolyl-6) -2-propionic acid in 200 ml of aqueous, 4C% sodium hydroxide solution containing or not containing 40 g of sodium sulfate, nonahydrate is refluxed until no more ammonia There are about 5OO ¹ ^ l of water in the solution, and at the temperature of 10 ⁰ G of this aqueous solution with vigorous stirring 70 g of benzoyl chloride in a 10% solution of a water-immiscible solvent, z. As benzene, added. After completion of the addition, the reaction mixture is allowed to reach room temperature again and stirred for a few hours before the organic phase is separated and the aqueous phase is acidified by the addition of hydrochloric acid in concentrated aqueous solution to a pH of 4. The resulting precipitate contains benzoic acid, the non-cyclized Type IV and V derivatives, and sometimes even the final

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benzothiazole.

The cyclization is carried out on this mixture, for example, by heating the rubbery solid for several hours at 120 ⁰ C or even in an acidic medium as follows?

The pesticide is dissolved in one liter of water containing 70 ml of 40% aqueous sodium hydroxide solution; the solution is filtered through decolorization black, then poured dropwise into an aqueous 2N hydrochloric acid solution maintained at 50 ^° C; the resulting precipitate is separated by filtration at this temperature.

The spent acid obtained in an amount of 45 g in this manner is in aqueous isopropanol (2ϊ1) or in a butanone (2) / cyclohexane mixture (1: 2) to give 36 g of pure, at 160 ⁰ C to give melting product. Depending on the recrystallization solvents and the rate of precipitation, the acid will emerge in different crystalline forms with sometimes very close melting points, but their infrared spectra can not be superimposed in the solid phase.

The cyclization can also be carried out in basic medium: The recovered, washed abundantly with water solid is dissolved in 350 ml of a 95% aqueous solution of ethanol containing 25 g of potassium hydroxide, then acidified after a few hours of heating, the ethanol eliminated and the whole poured into about 1 liter of water. The precipitate of the final acid that results is separated and recrystallized as described above.

Example 2

Preparation of (phenyl-2-bensothiazolyl-6-) -2-propion

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20. 10. 1980 57 216/12/36

acid using the benzaldehyde 22 g (amino-2-benzothiazolyl-6 -) - 2-propionic acid are dissolved in 100 ml of a concentrated sodium hydroxide solution and the mixture is refluxed for 1 hour (end of ammonia evolution). At room temperature, the solution is brought to a pH of 4.5 by addition of a solution of hydrochloric acid, and the resulting precipitate is precipitated. Thus, 16 g of precipitate with a melting point of about 154 ⁰ C are isolated. This solid and 8 g of benzaldehyde are dissolved in 100 ml of pyridine and the mixture is refluxed for 5 hours. Now the solvent is removed under reduced pressure. The residue is dissolved in 100 ml of ethanol, 200 mg of ferric chloride are added and the solution is kept at reflux for 2 hours. The precipitate formed during the cooling is purified by dissolution in a basic aqueous solution before being recrystallised in a butanone (2) / cyclohexane mixture (1: 2). The pure end product is obtained with a yield of 40%.

Example 3

The sodium salt of the hygroscopic (phenyl-2-benzothiazolyl-6) -2-propionic acid is prepared by the action of 0.55 g of sodium hydroxide to 3.7 g of acid dissolved in 100 ml of methanol. F = 270 ^° C. This salt is water-soluble.

Example 4

The pyrrolidine salt of (phenyl-2-benzothiazolyl-6) -2-propionic acid is prepared by the action of 1 g of amine on 4 g of acid dissolved in methanol. It melts at 142 ^° C. This salt is water-soluble.

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Example 5

The methanesulfonate of (phenyl-2-benzothiazolyl-6) -2-propionic acid is prepared by the action of 0.1 mol of sulfonic acid on 0.1 mol of acid dissolved in 500 ml of acetone. F = 182 ⁰ C

Example 6

The hydrochloride of (phenyl-2-benzothiazolyl-6) -2-propionic acid is prepared by the action of gaseous hydrochloric acid on the acid dissolved in benzene. It melts at 150 ⁰ C with decay.

Preparation of methyl (phenyl-2-benzothiazolyl-6) -2-propionate.

6 g of (phenyl-2-henzothiazolyl-6) -2-propionic acid are dissolved in 100 ml of anhydrous methanol and, after addition of a few drops of concentrated sulfuric acid, refluxed for 6 hours. The solution is concentrated by half and the ester is precipitated by the addition of one part by volume of ice water. This gives 5 g of ester, which melts at 8S ⁰ C.

Example 8.

separation of the 2 enantiomers of (phenyl-2-benzothiazolyl-6) -2-propionic acid, starting from their racemic mixture. a) dextrorotatory Enaatiomer (dissolved in dimethylformamide) is the salt of the acid with the levorotatory c £ - phenyl-äthylarain in butanone prepared ~ (2). Add 19 g of amine dissolved in 50 ml of butanone- (2) into a solution of 50 g of acid in 500 ml of butanone- (2)

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51 g of salt · This is recrystallized six times in the minimum amount of Batanone (2) to give 10 g of salt with a specific rotatory power of (<£) p = -22.5 in methanol (C = 2 g / 100 ml).

The acid is liberated by adding hydrochloric acid to the aqueous solution of this amine salt. The resulting precipitate is recrystallized several times in isopropanol / water-G-emischen (2ii) to give 35% yield the dextrorotatory enantiomer. P = 179 ^ C

b) Left-handed enantiomer (dissolved in dimethylformamide) The recrystallization solvents of the chiral salt obtained according to (I) are evaporated off and the acid, which is slightly enriched in levorotatory enantiomer, is liberated from its salt. 25 g of acid are thus obtained from which 28 g of salt are prepared by the action of 10.3 g of dextrorotatory eC-phenylethylamine on the acid dissolved in 540 ml of butanone (2).

After three recrystallizations in butanone (2) has the

OO λ

isolated salt has a rotatory power of (cD _D = 23 (C = 2 g / 100 ml in methanol).

The acid is now freed from its salt and recrystallized several times in succession in isopropanol / water mixtures (2: 1) and butanone (2) / cyclohexane mixtures (1ϊ2) to 25% yield, the levorotatory isomer with an optical E unit of to give close to 98%, (eC) i: = -81 ° in dimethylformamide (C s 0.1 g / ml) and melting point of 179 ⁰ C.

The compounds of the formula I and their derivatives are inhibitors of the biosynthesis of the prostaglandins and have analgesic properties in inhibiting doses.

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They also have antiplatelet activity and protect against the cardiovascular effects of endotoxin shock.

Its toxicity is low (DL ™ in mouse administered orally greater than 1000 mg / kg) * As the efficacy doses measured in the various experiments are clearly lower, the therapeutic index of these compounds is excellent because of their use in human therapy is.

The anaetic activity of the compounds of the formula I was demonstrated in torsion experiments with phenylbenzoquinone in the mouse. Thus, the acid of formula I (racemic) in this test has a DE ₁ -Q (effective dose) of 3 to 6 mg / kg P, 0. This analgesic effect is sustained over time as a dose of 12.5 mg / kg of this 24 hours after the administration results in a 42% analgie.

In addition, the compounds of formula I reduce platelet aggregation induced in vitro by ADP on platelet-enriched rat plasma; Thus, the sodium (phenyl-2-benzo'thiazolyl-6) -2 propionate is ten times lower in concentration than the acetylsalicylic acid.

The effect of the compounds of the formula I on the biosynthesis of the prostaglandins manifests itself in a protective action against the toxicity of the arachidonic acid which is a precursor of this biosynthesis. Thus, the compounds of the formula I which are administered in a dose of 0.5 mg / kg administered orally, a reduction in mortality of mice receiving a lethal dose of arachidonic acid.

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When administered intravenously, the soluble salts of the compounds of formula I, and especially the sodium salt, are effective in the same doses. The dextrorotatory enantiomer of the acid (Example 8) has an efficacy comparable to that of the racemate (Example 1) and higher than that of its levorotatory homolog.

Finally, the compounds of formula I administered intravenously at a dose of 1 mg / kg exert a protective effect on the anesthetized dog against the cardiovascular effects of the endotoxin shock of Escherichia coli. out.

The compounds of formula I may be administered to the human subject in various forms orally, rectally or parenterally in effective doses and non-toxic doses for the control of pain, treatment of hyperthermia, dysmenorrhea, shock states or even diseases in which the reduction of platelet aggregation is an important factor ,

The single dose will depend on the formula of administration and the compound chosen as the active ingredient of the drug. The solutions for parenteral or intravenous administration are preferably prepared with aqueous diluents, wherein the active ingredient may be in a soluble form in this medium and for example in the form of an alkaline cation salt. For the purpose of oral administration, the compounds of the invention may be added to jelly capsules or mixtures with the usual excipients to prepare pills, lozenges and tablets thereof which will immediately release the active or enteric components.

• The adult daily dose is between 20 mg and 1 g in one or more doses except in special cases.

Claims (1)

invention claim 1) Process for the preparation of the compound of the formula JT
HOOC-CH their two enantiomers and the racemate, their salts with the physiologically acceptable bases, mineral cations and amines and their salts with the mineral or organic physiologically acceptable acids and their alkyl esters, characterized in that the benzoic acid or a reactive equivalent, such as acid chloride , a corresponding ester or aldehyde, with a compound of the formula NH ₂ * " HOOC-CH ^ 'SH or one equivalent of this compound, such as the corresponding disulfide, and that the recovered acid is optionally converted to a salt or an ester, and that separation of the enantiomers is accomplished by recrystallization of the diastereoisomeric salts prepared by reaction of the racemate with a chiral amine , he follows..