DE1668964A1 - Novel trimethylhydroquinone derivatives and processes for making same - Google Patents

Description

31 December 1967

My files: 1395 Dr.J./Hl.

SPOPA, United Pharmaceutical Works, Praha

"New Trimethylhydroquinone Derivatives and Processes for

Manufacture of the same "

The invention relates to new trimethylhydroquinone derivatives of the general formula I.

OCHjCHCH ₄ NHR OH

v / orin X is a hydrogen atom or the remainder of an aliphatic or aromatic monocarboxylic acid having 2-18 carbon atoms and R is a hydrogen atom or a Means alkyl or aralkyl radical with 1-13 carbon atoms and their addition salts with inorganic and organic Acids, as well as a process for their preparation

the same·

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These derivatives have valuable pharmacodynamic properties. Some of them block the beta-adrenergic receptors to a remarkable degree, so they act as so-called beta-Iytica. Based on previous experience, you can such effective substances, which represent a relatively new pharmacodynamic group, therapeutically for Treatment of cardiac arrhythmias and some other disorders of cardiac activity, the development of which is adrenergic S ^ em is involved, can be used such as the well-known l- (l-naphthoxy) -3-isopropylamino-2-propanol (hereinafter referred to as Prcp & nolol or PP). These Compound has been used as the standard in the pharmacological study of l- (2,3,5-trimethyl-4 ~ hydroxyphenoxy) -3- -isopropylamino-2-prppanol (hereinafter referred to as trimepranol or TMP), which has been found to be one of the most interesting substances according to the invention. Hereinafter the results of the individual pharmacological tests are listed.

Animal species i.v. TMP P.O. iv
I. PP • P- ,. mouse
rat 48
51 350
2300 40
25th 35Q
440

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The results show that trimepranol, especially at Rats, is less toxic than Prtop & nolol. Since the MoIe * - The weight of both compounds is almost the same (509.4 and 295.8, respectively), this difference is significant.

The influence of anesthesia was also examined in orientation experiments on the toxicity of the two substances and it was found that they were in the anesthetized Animals (rats, cats) is increased.

Chronic_Toxicity

TMP and PP became dogs (strain Bea ^ le, weight 6.6-12kg) given in a dose of 25 mg / kg per os, namely 12 For weeks. At the end of the experiment, the animals were sacrificed with thiopental (100 mg / kg given intravenously). At all The following organs were examined: heart, lungs, liver, spleen and kidneys. They weren't pathological Changes in these organs were found, which indicate some harmful effects of the substances could. Neither biochemical (blood serum, urine) nor hematological determinations showed significant deviations from normal values.

Proof of the beta-table effect

On the isolated calf strachea (in vitro), trimepranol blocks those caused by isopropyl noradrenaline (the most effective

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beta-Mimeticum) triggered contractions even in a dose of 1.10 "^ M / ml. Propranolol shows this effect in same gift.

Trimepranol and propranolol block the protective effect of isopropyl noradrenaline versus histamine-induced bronchospasm in guinea pigs in one Administration of 2.10 M / kg after intraperitoneal administration. The effects of TMP last about $ 20 longer than the same from PP. This finding proves the significant difference between the two substances.

In cats anesthetized with chloralose and phenobarbital, both substances block the lowering of blood pressure, which was triggered by administration of 0.1 mg / kg isopropylnoradrenaline intravenously in doses of 1.10 "Γί / kg iv and TMP also in a dose of 3« 10 'M / kg after oral administration per- both materials have a reliable effect in a dose of 2.10 "." -. ^ M / kg the duration of the blockade of the reaction after Isopropylnoradrenalin or reverse this reaction in hypertensive effect is to TMP at about 20 $ longer than after PP. TMP is still in one oral mode

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A dose of 5.10 M / kg was effective, while PP no longer had any effect in this dose.

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Antiarrhythmic effect

After rapid intravenous administration of 200 pg / kg Numerous ventricular extrasystoles occur in rats with adrenaline. The substances TMP and PP block this arrhythmic one The effect of this high adrenaline dose is about the same. A dose of 1.10 "* ^ M / kg TMP 10 minutes before adrenaline prevents the development of extrasystoles in 90 # of cases after adrenaline, PP has the protective effect mentioned after similar administration of the same dose with the same pro - percentage of animals.

In cats, adrenaline dissolves intravenously at 8 µg / kg also a pronounced arrhythmia characterized by ectopic contractions. TMP sets the occurrence these ectopic contractions compared to control values to Q to $ 50 in 10 minutes after administration of a dose from 1.10 "* M / kg intravenously down ·; This effect lasts at the majority of the animals for 2 hours after administration. PP unfolds 10 minutes after the administration of the same Give the same protective effect, but 2 hours after application this effect is no longer detectable and the number of ectopic contractions is not significantly different from the control values before the administration of the beta-Iörbicum.

-6-ORiQiNAt INSPECTED

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Propranolol antagonizes the contractions of the ductus deferens of the rat in vitro after adrenaline still in one

0 '

Concentration of 5 x 10 'N (AiI, which means that this Substance has 'an alpha-lytic' effect, albeit lower Gradea. as characteristic alpha-lytica, v / ie e.g. phentolamine. Trimepranol also in 10 and 20 times higher Concentration shows no effect on the contractions of the ductus deferens after adrenaline, so it is not alpha-lytically effective.

Influence on_des_Zentralnervensyj> tem

Trimepranol, which was administered to the mice in a dose of 12 mg / kg iv (corresponds to about 25% of the LD 50), shows no effect on this in the usual tests (rotating rod, prolongation of thiopental anesthesia, interaction with the central action of amphetamine) Central nervous system of experimental animals,

From the test results it can be seen that Trimepranol has about the same level of effectiveness as propranolol but is longer lasting. This finding is significant. The substance is about 1/3 less after both intravenous and even percralsr administration

ger toxic

ha-lytic properties. ORIGINAL INSPECTED -7 "

"According to the invention, the trimethylhydroquinone derivatives are produced of the general formula I in such a way that a compound of the general formula II

OX

^H i ^c - i rl CHCH ₂ -H H ₃ C- y ·· ' T
OCH _x

where X is the same as in formula I, Y is a hydroxyl group and Z is a Haiagenatom, in particular chlorine, bromine or iodine, or Y and Z linked together form an oxide bridge -O- with an amino compound of the general formula III '

NH ₂ R

III

where R is the same as in formula I, or with a compound which is capable, by hydrolysis, of the amino compound of the formula III, in which R is a hydrogen atom, to provide, for example phthalimide, or its ketal derivative, such as phthalimide potassium, furthermore succinimide or Hexamethylenetetramine, after which the triraethylhydroquinone derivative obtained, optionally after desacyliejr ;, by neutralization with an inorganic or or- ^ cen acid, is converted into the corresponding ftdditionalfc, 209816/1655 iAD GRJGINAL -8-

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The reaction of the compound of general formula II, in which X, Y and Z are the same as in formula I, with the amino compound of general formula III, in which R is the same as in formula I, used in an equivalent or excess amount, can be carried out in water, in an aqueous or anhydrous alkanol having 1-3 carbon atoms, at temperatures of 0 -80 ⁰ C, advantageously at temperatures from 20 to 70 ⁰ C perform.

The reaction of the compound of the general formula II in which X is the same as in formula I and Y and Z together linked to form an oxide bridge, with "phthalimide or succinimide, one can in an alkanol with 1-3 carbon atoms, perform at the boiling point of the reaction mixture.

Finally, the compound of the general formula II, wherein X is a hydroxy group and Z represents a halogen atom, with Phtalimidkalium at 170-200 ⁰ C, preferably at 180 C, to implement.

The compounds of general formula II, i. H. the corresponding Glycid ethers or halohydrins, which are also new, can be separated by a general condensation method from epichlorohydrin and trimethylhydroquinone or its 1-monoacetyl derivative, either in the presence an equivalent amount of an alkali odexv with advantage unter Latal '.' fresh l / ir'-unr: an A ';. ins, beiupielin / oioo

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IAD ORIGINAL

Piperidine, manufacture I

The possible transfer of the halohydrine (formula II,

Y = hydroxyl, Z «halogen) in the glycidyl ether (formula II,!

Y and Z form an oxide bridge - O -), or vice versa, the Conversion of the glycidyl ether into the halohydrin can also be carried out in a known manner, ie. in the first case by the action of alkali metal hydroxides the Halagenhydrin or in the second case by the action of Hydrogen halides on the glycidic ether.

When implementing the compound of the general formula II, | it being the same whether it is in the form of the halohydrine, j Glycidäthers or a mixture of these derivatives is present, the amino compound of the general formula is used III, as already mentioned, either in an equivalent amount oda? in excess, which can have certain advantages in terms of quality and yield of the end product · As amino compounds of the general formula III come, for example, ammonia, methylamine, isopropylamine, butylamine, 6-methyl-2-aminoheptane, 1- or 2-aminotridecan, phenyl -arninopropane, phenyl-tert-butylamine, etc. in question,

If the reaction is carried out at an elevated temperature, for example at 60-80 ^° C., and with excess amine, or if the amine used has a more basic character, depending on the reaction conditions, it is also possible

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at the same time the hydrolysis of the acyl group in the compound of the general formula II takes place (X »an acyl radical with 2-18 carbon atoms) This hydrolysis in the final product of the general formula I can, if desired, be carried out as an independent operation, in fact in and of itself known way by the action of alkaline or acidic agents, for example by boiling with an alcoholic Alkali metal hydroxide solution

Is a trimethylhydroquinone derivative of the general formula I. with an unsubstituted amino group (R = H) is desired, such a compound can be used, except for the above described method, by reaction of the compound of general formula II in any form with a dicarboximide, such as phthalimide or succinimide and by hydrolysis of the condensation product formed with known ones Preparing agents such as hydrazine or acids. The same result can also be achieved when using it a metal salt of the dicarboximide, for example Phthalimide potassium, which is expediently reacted with the compound of the general formula II in the form of the halohydrin leaves. An analogous procedure is used with hexamethylenetetramine. In both cases the obtained hydrolyses. ten condensation products using one of the known methods.

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The end products of the general formula I are converted, if desired, into addition salts with either inorganic salts Acids, for example hydrochloric, hydrobromic, phosphoric or sulfuric acid or with organic acids, for example Vinegar, oxal, wine, fumar, maleic or camphor sulf onic acid. As a rule, these salts are very soluble in water and are used in the manufacture of pharmaceuticals suitable for riding.

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Examples

1. To a mixture of 7.8 g of 3- (2,3,5-trimethyl ~ 4- acetoxyphenoxy) -1,2-propylene oxide and 6.6 g of phthalimide in 70 ml of ethanol are added 3 drops of lyridine and heated this mixture to the boil for 6 hours. After cooling, the product which has crystallized out is filtered off with suction. This gives 8.1 g of the Phtalimidoderivates, which after recrystallization from ethanol at 155 -, wherein between 120,156 ⁰ O'schmilzt - 130 ⁰ C a change in the crystal form is carried · The whole amount of the Phtalimidoderivats is mixed with 4.5 g of 50 # igen hydrazine hydrate in 25 ml of ethanol and boil the mixture for 30 minutes. Then add 60 ml of an ethanolic hydrogen chloride solution to the reaction mixture and boil it for 1 hour. After cooling, the product which has crystallized out, which is a mixture of the desired substance in the form of the hydrochloride with phthalylhydrazide, is filtered off with suction, washed with ethanol and suspended in 110 ml of water. The suspension was heated to 50 ⁰ C and after cooling is filtered off the undissolved Phtalylhydrazid and washed with water. The aqueous filtrate is combined with the ethanolic components after the hydrochloride-phthalylhydrazide mixture has been filtered off with suction and evaporated in vacuo under nitrogen at 4-0-50 ° G (bath temperature). ^ Concentration to about 30 ml allows the residue to crystallize at 0 - 5 ° C, the precipitated

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_ ₁₃ - 1668364

The product is filtered off with suction, washed with acetone and dried over sodium hydroxide. Yield 4- g l- (2,3,5-trimethyl-4-hydroxyphenoxy) -3-amino-2-propanol hydrochloride with F. 236-238 ⁰ C (in vacuo), after recrystallization from water with the addition of concentrated hydrochloric acid.

2ο A mixture of 82 g of 2,3,5-trimethyl-4-acetoxyphenol (F, 105 to 107 ⁰ G), 125 g of epichlorohydrin and 0.9 ml piperidine is heated for 6 hours at 95-100 ⁰ C. After one destilüaA the excess of epichlorohydrin at 100 ⁰ C (bath temperature). 129 g of a distillation residue are obtained, v / which a crude mixture of halohydrin (formula II, X = -COCH-, Y = OH, Z = Cl) and glycidyl ether (formula 11, X = -COCH- ,, Y and Z form one Oxide bridge -0-). This mixture is dissolved in 700 ml of absolute benzene and the resultant solution is added with stirring 63 g of powdered sodium hydroxide, maintaining the temperature of the reaction mixture by cooling at ⁰ C 3Q. After stirring for 30 minutes, a further 63 g of powdered sodium hydroxide are added and, after 40 minutes, the mixture is stirred at room temperature *. The reaction mixture is then poured into 100 ml of a Wasfier ice mixture, the benzene layer is separated off and the aqueous layer is shaken out with benzene. After washing neutral with water, the combined benzene extracts are dried over anhydrous magnesium sulfate and then evaporated under reduced pressure at the end

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boiling water bath. 80 g of crude glycidyl ether are obtained, which are purified by vacuum distillation. Bp _Q ^ 117-120 ⁰ C, m.p. 94-97 ° C (ethanol).

68 ml of an ethanolic methylamine solution (containing 0.25 g of methylamine in 1 ml) are added to a solution of 7.1 g of the above glycid ether in 70 ml of ethanol, and the reaction mixture is heated to 70 ° C. in a closed vessel for 3 hours. Then ethanol and the excess methylamine are evaporated in vacuo, finally from a boiling water bath, the residue (8.6 g) is dissolved in 30 ml of ethanol and this solution is saturated with dry hydrogen chloride gas in the cold. After cooling to ⁰ ° C., the precipitated product is filtered off with suction and washed with 6 ml each of ethanol and ether. Mar wins 6.5 g of 1 - ^ (2,3,5-1 ¹ 2? Imethyl- -4-hydroxyphenoxy) -3-methylamino-2-propanol with a melting point of 225-229 C · After recrystallization from a methanol-ethyl acetate mixture the product melts at 228 - 23i ° C _e

3. A solution of 6 g Glycidäther from Example 2 and 6.5 g isopropylamino in 25 ml ethanol is heated for 3 hours at 70 ⁰ C. then distilled from the reaction mixture of ethanol and the excess isopropylamine in vacuo. The oily residue (7.6 g) is dissolved in 50 ml of 1M hydrochloric acid, 50 ml of water are added, and the solution is shaken out with ether. The. aqueous layer one with ammonia and the excreted

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Benzene on. The benzene solution is washed with water, dried over anhydrous magnesium sulfate, and attenuates it to the circuit in the vacuum at 80 ⁰ C bath temperature. The crystalline solidified residue (6 g) represents the crude 1- (2,5,5- trimethyl-4-acetoxyphenoxy) -5-isc »propylamino-2-propanol with a melting point of 97-107 ° C one can either product by suspension in ether and suction (F. 104-107 ⁰ C) - melts at 160 reinigen.Das oxalate - 162 ⁰ G (ethanol-ether), or by recrystallization from cyclohexane (107 ⁰ C F. 105).

4 are added to a solution of 6.25 E Glycidäther from Example 2 in 25 ml of ethanol, 15 g of phenyl-t-butylamine to and will warn the Re al: ti ons mixture 5.5 hours 70 ° C. The volatile components are then distilled off in vacuo at 10 torr, and finally at 150 ° C. bath temperature. The distillation residue (10 g) is dissolved in 50 ml of ethanol and a solution of 1.4 g of oxalic acid in 15 ml of ethanol is added to this still poor solution. After cooling, the precipitated oxalate is filtered off with suction, washed with ethanol, suspended in 50 ml of water and 100 ml of ether and made alkaline with 25 ml of 1 M NaOH. This mixture is then shaken until the suspension is completely dissolved, the ethereal sizing is separated off and the aqueous sizing is extracted with ether. The combined ether extracts are washed with water and, after drying, ether is distilled off. Man, G'jj.iuit ο g 1- (2,5 j 5-trimethyl-4-ace toxyphenoxy) -5-phenyl-

iii Ii ¹ OxT. eino; j "elblicLen _-i6"

J-propa

8T6 / 1

pp

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viscous oil, which after some time turns into a waxy Mass solidifies. The fabric can be cleaned by vacuum distillation, for example at 181 - 183 ° C / lo * "* Torr»

5 · Sas hydrogen tartarate of the base obtained according to Example 4 so that a solution of 0.3 g of tartaric acid in loo κΐ ' A solution of 0.4 g of base in 2oo ml of ether is added to ether. Immediately after the two solutions are poured together, they separate Crystals of the salt in the form of a hemihydrate are extracted * They are sucked off and washed with ether. F 75 - loo ° C with decomposition The oxalate produced in an analogous way melts at 225 23o C with decomposition (ethanol)

6 «A solution of 5 g of glycidyl ether from Examples 2 and 7» 7 g 2-Aminotridekan in 20 ml of ethanol is warmed to 70 ° C. for 3 hours. The volatile components are then distilled off in vacuo, finally at a bath temperature of 15 ° C. and 0.1 Torr in one yield from 8.6 g crude 1- (2,3 »5-tri» ethyl-4-aoeto: xyphenoxy is obtained (-3-) 2-tridecylamino) -2-propanol, which can be obtained by chromatography of aluminum oxide (activity II) with the aid of an ether-methanol mixture see s (8 s 2) as an eluent or by crystallization can clean from petroleum ether. The pure substance melts at 55 - 57 ° C.

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7 · A solution of 2 g of 1- (2,3,5-trinethyl-4-acetoxy-phenoxy) -3-isopropylamino-2-propanol in 13 ml of methanolic 1 M KOH solution is heated to the boil for 45 minutes under nitrogen . Then methanol is evaporated off under reduced pressure, the distillation residue is diluted with 20 ml of water and neutralized with carbon dioxide. The precipitated product is taken up in 150 ml of ether, the ethereal solution is washed with a saturated NaCl solution and dried over sodium sulfate. After distilling off the ether, finally in vacuo, the distillation residue (1.8 g) is dissolved in 15 ml of ethyl acetate, the solution is acidified with 1.5 ml of an ethanolic HC & solution and allowed to crystallize at 0-5 ° C. After the crystallized product has been filtered off with suction and washed with ethyl acetate, 1.9 g of 1- (2,3,5-trimethyl-4-hydroxyphenoxy) -I-isopropylamino-2-propanol with a mp of 194-195.5 ° C. are obtained. After recrystallization from methanol-ethyl acetate (1: 5), the pure substance melts at 194-195.5 ° G. The fumarate melts at 232-236 ⁰ C with decomposition (ethanol), the hydrobromide at 158 - 16O ° C (methanol-ethyl acetate).

8. A mixture of 6.2 g Glycidäther (Formula II, X = - ₆ with F. 130-138 ⁰ C (the pure substance melts at 145-146 ⁰ C), 4 g of isopropylamine and 20 ml ethanol is heated for 3 hours to 70 ° C. The volatile components are then distilled off in vacuo and the residue (7.4 g) is dissolved in 15Ο ml of benzene

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dry hydrogen chloride gas and allowed to crystallize at 0-5 ° C. The precipitated product is suctioned off, washed with ether and dried. Yield 5.2 g of 1 - (2,3,5-trimethyl-4-benzoyloxyphenoxy) -3-isopropylaraino-2-propanol hydrochloride with a melting point of 185-189 ° C. After recrystallization from a Hethanol-Äthylacetatgemisch the pure substance melts at 189 to 191 ⁰ C.

9 · A mixture of 3> 7 g of phthalimide potassium and 6.5 g of the compound of the formula II (X = -COCH ₅ , Y = OH, Z = Br) in the form of the bromohydrin (produced by the action of 35% hydrobromic acid on the corresponding glycidyl ether at room temperature) is heated to 180 ° C. for 1.5 hours. The cooled melt is dissolved in 150 ml of benzene, the solution is washed neutral with water, dried over magnesium sulfate and evaporated, finally in vacuo. The residue (7 g) is dissolved in 25 ml of ethanol and allowed to crystallize. The product obtained (2.7 g) is purified by further Unkx'istallisierung from ethanol and it is then melted at 152-157 ° C. It is identical to the phthalimide derivative prepared according to Example 1. Its hydrolysis to the amino derivative of the general formula I (X = H, R = H) is carried out in the same way as in the example given.

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BATH ORIGINAL

10. A solution of 2.5 S l- (2,3,5-trimethyl-4-palmi toyloxyphenoxy) -2,3-epoxypropane (P. 62-65 C) and 2 g of isopropylamine in 15 ml of ethanol is heated to 50 ⁰ C for 3 hours. Then ethanol and excess isopropylamine are distilled off under reduced pressure, sum at 90 ° C (bath temperature). The residue (2.6 g) is crude 1- (2,3,5-trimethyl ~ 4-palmitoyloxyphenoxy) -3-isopropylamino-2-propanol, which solidifies in crystalline form after cooling and melts at 80. After recrystallization from methanol, the substance melts at 80-83 ^° C.

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Claims (1)

Patent to proverbs: 1. Trimethylhydroquinone derivatives of the general formula I OCH _A CHCH _A NHR OH wherein X is a hydrogen atom or the residue of an aliphatic or aromatic monocarboxylic acid with 2-18 carbon atoms and R is a hydrogen atom or an alkyl or aralkyl radical with 1-13 carbon atoms and their addition salts with inorganic or organic Acids, 2. 1- (2,3, ^ - trimethyl - ^ - hydroxyphenoxy) -3-amino-2-propanol and its hydrochloride, 3. 1- (2.3> 5 - ^z i-hydroxyphenoxy) -3-kiethylamino -2-propanol and its hydrochloride l- (2,3,5- ^r frimethyl-4-acetoxyphenoxy) -3-isopropylamino-2-propanol and its hydrogen oxalate -21- 209818/1655 5, i- (2,3> 5-T ^ iroethyl-4-acetoxyphenoxy) -3-phenyl-tert. butylamino-2-propanol, its hydrogen tartarate and oxalate. 6. l- (2,3,5-trimethyl-4-hydroxyphenoxy) -3-isopropylamino-2-propanol, its hydrochloride, hydrobromide and fumarate, 7. l- (2, 3i 5-trimethyl-4-acetoxyphenoxy) -3- (2-tride cyl amino) -2-propanol. 8. l- (2.3> 5 amino-2-propanol and its hydrochloride. 9 · l- (2.3 »5""T3? Ii ⁿ ethyl-4-palraitoyloxyphenoxy) -3-isopropylamino-2-propanol. 10. Process for the preparation of new trimethylhydroquinone derivatives of the general formula I, characterized in that
that a compound of the general formula II H.C-J 209816/1655 wherein X is the same as in formula I, Y is a hydroxyl group and Z denotes a halogen atom, in particular chlorine, bromine or iodine, or Y and Z together link one Form oxide bridge -0-, with an amino compound of the general formula III NH ₂ R, CHI) wherein R is the same as in formula I, or with a compound which is capable of hydrolysis the amino compound of the general formula III, where R stands for a V / water atom, to be supplied, for example phthalimide, or its metal derivative, such as phthalimide potassium, also succinimide or hexamethylenetetramine, converts, after which nan the obtained Trimethylhydroquinone derivative, optionally after Deacylation, by neutralizing with an inorganic or organic acid in the corresponding Transferred addition salt. 11. The method according to claim 10,
characterized, that the reaction of the compound of general formula II in which X, Y and Z are the same as in formula means with the amino compound used in an equivalent or excess amount of the general -23- 209816/1655 Formula III, wherein E is the same as in formula I, in water, in an aqueous or anhydrous alkanol having 1-3 carbon atoms, at temperatures of 0-80 ⁰ C, preferably at temperatures from 20 to 70 ⁰ C, is carried out. 12. The method according to claim 10,
characterized, that the reaction of the compound of the general formula II in which X is the same as in formula I. and Y and Z linked together form an oxide bridge, with Fhtalimid or Succinimid in an alkanol with 1-3 carbon atoms, at the boiling point of the reaction tion mixture, performs. 15 «method according to claim 10,
characterized, that in formula I, Y is a hydroxyl group and Z represents the compound of general formula II, wherein X is the same halogen atom, with potassium Phtalirnid- at 1 0 - 200 ⁰ C, preferably at 180 ⁰ C, is reacted. 209816/1655