DE2113254C3 - Process for the preparation of γ-piperidinoburyrophenone derivatives - Google Patents

Description

CH ₂ CH ₂ CH ₂ Z

r L

N
H

(III)

in which R ² and Z uie have the aforementioned meaning, the compound of the general formula III thus obtained is reduced to an acetylamino-1-piperidinobutyrophenone derivative of the general formula I a

COCH ₂ CH ₂ CH ₂ -Z

(Ib)

NH,

in which R ² and Z have the above meanings, hydrolyzed, if desired the compound of the general formula I b is diazotized and the diazonium salt thus obtained is converted into a compound of the general formula I in which R ^{1 is} a hydrogen or halogen atom, and if desired the compound thus obtained is converted into a salt with an acid.

2. The method according to claim 1, characterized in that for the reduction of the 1 - [// - (3-indolyl) propionyl] piperidine derivative of the general formula II a complex metal hydride is used.

3. The method according to claim 1, characterized in that one door the oxidation of the 3-y-Pipcridinopropylindolderivals of the general formula III chromic acid or ozone is used.

4. The method according to claim I, characterized in that one carries out the reaction of the diazonium salt of the amino-j-pcperidinobulyrophenone derivative of the general formula Ib, in the presence of ethanol, hypophosphorous acid, alkaline Formaldehyde or sodium stannite.

5. The method according to claim I, characterized in that the implementation of the diazonium salts * of the amino-y-pipcridinobutyrophenone derivative of the general formula Ib in the presence of a copper (I) halide, mercury (II) halide, Potassium halide, copper powder or fluoroboric acid.

COCH ₇ CH ₁ CH, Z

STILL,
Il

(Ia)

in which R ² and Z have the aforementioned meaning. The invention relates to the subject matter characterized in the claims.

The most important feature of the process lies in the preparation of the γ'-piperidinobutyrophenone derivatives of the general formula Ia which are N-aectylamino-substituted in the o-position by oxidation of the 3-j'-piperidinopropylindole derivatives of the general formula III. Starting from the compounds of the general formula Ia, if desired, y-piperidinobutyrophenone derivatives of the general formula I in which R ^{1 is} an amino group or a hydrogen or halogen atom can be prepared by hydrolysis and further by diazotization and decomposition of the diazonium salts.

Organic and inorganic acids such as chlorine, Hydrobromic or rhodanic acid. Sulfur, phosphorus, nitric, Ivssig, propion, oxal, lemon,

i> 5 apples, wine, l-'umar-. Malein-. Amber, Cilycol, Benzoin. Tin, p-amino salicylic, salicylic, methanesulphone, p-Toliolsulfonic, ascorbic, lactic or mandelic acid in I'raec.

Examples of halogen atoms in the compounds of the general formula I are fluorine, chlorine, bromine or iodine atoms.

For the oxidative cleavage of the 3-i-piperidinopropylindole derivatives of the general formula III or their salts are preferably ozone, hydrogen peroxide, performic acid, peracetic acid, perbenzocic acid. Chromic acid or potassium permanganate, especially chromic acid and ozone, are used. The Oxidizing agent is used in stoichiometric amounts or in excess. In general the oxidation proceeds rapidly at room temperature; to better control the reaction you can however, higher or lower temperatures may be used. The oxidation will preferably in the presence of a solvent such as water, acetone, carbon tetrachloride. acetic acid or sulfuric acid. The choice of solvent and the reaction temperature is particular depends on the type of oxidizing agent used. When using chromic acid as an oxidizing agent in the presence of acetic acid, the oxidation is preferably with the two to carried out three times the stoichiometric amount of chromic acid at room temperature. Here is a Solution or a suspension of the 3 -) - pipcridinopropylindole derivative of the general formula III under Stir mixed with the oxidizing agent. Generally, the oxidation is within about 24 hours completed.

Even if ozone is used as the oxidizing agent, the reaction is preferably carried out at room temperature. Here, the ozone is stirred into the solution or suspension of the .Vj'-piperidinopropylindole derivative, z. B. in formic acid, acetic acid or carbon tetrachloride, initiated.

The oxidation of the 3 -}> - pipcridinopropylindoles to the corresponding acetylamino-y-piperidinobutyrophenones is a chemically peculiar and technically advanced process. It is known that ' one can oxidatively split indoles at the double bond of the pyrole ring. The oxidative cleavage of Indole compounds which have a tertiary amino group in the 3-position in the alkyl side chain, e.g. B. a piperidino group, included, but has not yet been described in the literature. In case of Oxidation of N-substituted tetrahydro-// -earbolines, as shown in the reaction scheme on page I '! 4 of the book "The Chemistry of Indoles" by R. J. S u η d b e r g, Academic Press, New York London 1970, the yield is so low that that the formation of the oxidation product can hardly be confirmed. It is therefore practically impossible to transfer this implementation to a technical process.

As from the book by R. L. Au g u s I i η e "Oxidation", Techniques and Applications in Organic Synthesis, Marcel Dekkcr, Inc., New York, 1969, Vol. I, ropes 92 to 118, amines are generally very unstable to oxidizing agents and are subject to a wide variety of oxydalionic reactions.

The acelylamino-γ-piperidinobutyrophonic derivative of the general formula la is obtained from the reaction mixture, optionally after previous neutralization of the reaction mixture and isolated by evaporating the extraction medium. The The crude product is optionally obtained by recrystallization

size from a suitable solvent such as ethanol or isopropanol. cleaned in the usual way. The hydrolysis of the acctylamino-y-piperidinobutyrophenone derivatives of the general formula I a to the corresponding amino-j'-piperidinobutyrophcnone derivatives of the general formula 1b takes place in a manner known per se under acidic or alkaline conditions.

The diazolation of the amino - ^ - piperidinobutyrophenone derivatives of the general formula Ib takes place in a conventional manner. By treating the diazonium salts with copper powder. Hydrofluoric acid or a metal salt such as copper (I) chloride or bromide. Potassium iodide or mercury {II! Halide, the y-piperidinobutyrophenone derivatives of the general formula 1 are obtained in which R ^{1 is} a halo analog.

By treating the diazonium salts with a reducing agent such as ethanol, phosphorus acid, alkaline formaldehyde or sodium lannil, the compounds of the general formula I in which R ^{1 represents} a hydrogen atom are obtained.

The reduction of the l - [// - (3-indolyl) propionyl] piperidine rivals of the general formula II / u the .Vj.-Pipcridinopropylindoldcrivaten of the general Formula III is preferably carried out with reducing agents, such as alkali metals in alcoholic solvents, Metal hydrides, by kaialytic hydrogenation with hydrogen or by electronic Reduction.

Preferably the reduction is carried out with a complex metal hydride such as lithium aluminum hydride. Diisobutyl aluminum hydride, triisupropy aluminum hydride or borohydride, in an inert solvent such as ether, tetrahydrofuran, dioxane or N-ethylmorpholine, performed.

After completion of the reaction, the excess of complex metal hydride z. B. with water, decomposed by alcohol or ethyl acetate. The compound of the general formula III is isolated and possibly z. B. purified by recrystallization.

The compounds of the general formula I in which R ^{1 represents} a halo atom, an amino or acctylamino group and R ^{2 has} the above meaning are new compounds. These compounds and their salts are potent psychotropic drugs that can be prepared in a manner similar to chlorpromazine, e.g. B. for the treatment of restlessness, anxiety and psychotic states for cramp or pain relief, can be used. Some of these compounds are more potent than chlorpromazine in rats. In addition, these compounds have a stronger anti-apomorphine and anti-methamphetamine effect than chlorpromazine. In spite of their high pharmacological activity, however, the compounds have hardly any toxic effects.

This is evident from the following comparison tests.

The following compounds of the invention, namely j- - [4 '- (2 "- Oxo - I" - benzimidazolinyl) - piperidino] -2-acetamino-4-fluorobutyrophenone (Compound A),) '- [4' - (p-Chlorobenzyl) -4'-hydroxypiperidino] -2-acetamino-4-fluorobutyrophenone hydrochloride (Compound B) and 7- [4 '- (p-Chlorbcnzyl) -4'-hydroxypipcridino] - 2 - amino - 4 - fluorobulyrophenone hydrochloride (compound C) are combined with chlorproma / in (Compound D) on rats with regard to their antiapomorphin activity as well as with regard to the suppression of the conditional curse reduction in the jumping box

examined. The acute toxicity was determined in mice.

The test animals were male rats weighing 190 to 230 g and males, respectively Mice weighing 19 to 23 g were used. Each experimental group consisted of 10 animals.

The experimental methodology for the antiapomorphintesl is by P. A. J. J a η s s e η et al., Drug Research, Vol. 10 (1960), pages 1003 to 1005. and for the spring box test by P.A.J. Jansscn et al .. Arzneimittelforforschung, Vol. II (1961), ropes 1037 to 1043. The results are summarized in the following tables:

a) Antiapomorphin test (Rallen)

b) Springkastcn-Tcst

connection UV I IV Relative ratio (A) 109 (K) 64 (B) 32 (K) 19th (C) 3 (KK) 18th (D) 170 I.

connection Ims kg) Relative
Effectiveness (A)
(B)
(C) 0.37
1.3
1.2 May 14th
4.0
4.3 (D) 5.2 1

b) Spring box Tesl (rats)

connection 1 IV (see ll
(mi! kg) Relative
Grant of effect (A) 0.11 5.5 (B) 0.25 2.4 (C) 0.20 3.0 (D) 0.60 1

c) Acute Toxiziläl (mice)

connection 1.1V (be
Img kg) Relative
Toxicity ratio (A)
(B)
(C) 1200
800
600 0.083
0.125
0.167 (D) K) O I.

The therapeutic index results from the above values as follows:

a) antiapomorphin test

connection \ l \, ID ₅₁₁ Relative discount (A) 3240 160 (B) 610 30th (C ") 500 25th (Dl 20th I.

The examples illustrate the invention.

is B c i s ρ i c 1 1

A. Establishing a connection
of the general formula II

A solution of 5.0 g / M2-methyl-3-indolyl) propionic acid and 2.5 g triethylamine in KK) ml chloroform is added dropwise with 2.7 g chloroformic acid methyl ester at a temperature below 0 C with stirring. After stirring for 15 minutes, 4.7 g of 4-benzyl-4-hydroxypiperidine are added in several portions. After stirring for 4 hours at room temperature and standing for 15 hours, the reaction product is washed thoroughly with water and concentrated to dryness. After recrystallization from ethanol, the r - [/ i- (2-methyl-3-indolyl) - \ o propionyl] -4'-benzyl-4'-hydroxypipcridine of melting point 117 to 119 ° C is obtained; Yield 75.5% of theory.

B. Establishing a connection
of the general formula III

A mixture of 2.0 g of lithium aluminum hydride and 50 ml of ether is stirred and gently Reflux dropwise over 30 minutes with a solution of 4.6 g 1 '- [// - (2 - methyl-3-indolyl) - propionyl] -4' - benzyl-4'-hydroxypiperidine added in 80 ml of tetrahydrofuran. When the addition is complete, the reaction mixture becomes heated under reflux with stirring for 4 hours and then gradually with 10 ml cold water mixed with ice while cooling. the

The precipitate obtained for 4s is filtered off, and the filtrate is concentrated to dryness. After recrystallization of the residue from benzene, 2-methyl-3 - [γ - (4 '- benzyl - 4' - hydroxypiperidino) propyl] indole with a melting point of 132 ° to 134 ° C. is obtained; Yield 89.7% of theory

C. Establishing a connection
of the general formula I a and I b

In a solution of 3.0 g of 2-methyl-3- [y- (4'-benzyl-4'-hydroxypiperidino) propyl] indole a stream of oxygen with about 3% ozone content is introduced into 50 ml of acetic acid over a period of 30 minutes, the temperature being kept at 15 to 20 "C. The solution thus obtained is diluted with 200 ml of water ho and slowly with sodium hydroxide solution up to alkaline reaction. This creates an oily layer that is extracted with chloroform. the The extract is washed with water and then dried. After concentration, one obtains the j '- (4'-Bcn-6s zy'i ■ 4'-hydroxypipcridino) -2-acctaminobulyrophenone as a viscous liquid with IR absorption maxima 3430, 3250, 1680, 1650, 1520 and 13 (K) cm '. yield (raw) 83.0% of theory.

The y- (4'-Benzyl-4'-hydroxypiperidino) -2-acetaminobutyrephenone is dissolved in 50 ml of ethanol and, after addition of 6 ml of concentrated hydrochloric acid, heated under reflux for 2 hours. After cooling, the reaction mixture is diluted with 100 ml of water, slowly mixed with sodium hydroxide solution until an alkaline reaction is achieved and then extracted with ethyl acetate. The organic layer is washed with water and concentrated to dryness. When the residue is recrystallized from ethanol, the>'-(4'-Benzyl-4'-hydroxypiperidino) -2-aminobutyrophenone of melting point 123 to 124 ^° C. is obtained; Yield 80.0 of theory.

D. Establishing a connection
of the general formula I.

A cooled solution of 3.6 g of y- (4'-Benzyi-4'-hydroxypiperidino) -2-aminobutyrophenone in 35 ml of 2N hydrochloric acid is added dropwise to a solution of 0.74 at a temperature below 0 ° C. while stirring g of sodium nitrite in 5 ml of water are added. The diazonium salt solution thus obtained is added in one pour, with vigorous stirring, to a cold suspension of 1.5 g of copper (I) chloride in 5 ml of concentrated hydrochloric acid. Then the mixture is for 30 minutes under ice-cooling, followed by stirring for further 2 hours at room temperature and then 1 hour at 55 to 60 ⁰ C. After cooling, the reaction mixture is mixed with a base until it has an alkaline reaction and then extracted with chloroform. The extract is washed with water, dried and concentrated. Treatment of the residue with methanolic hydrochloric acid and subsequent recrystallization of the solid residue from isopropanol gives y- (4'-Benzyi-4'-hydroxypiperidino) -2-chlorobutyrophenone hydrochloride with a melting point of 170 ° to 175 ° C .; Yield 68.5% of theory.

The following connections were made according to the above procedures:

} - [4 '- (2 "-oxo-1" -benzimidazolinyl) -piperidino] -2-acetamino-4-fluorobutyrophenone, m.p. 205 to 207.5 ⁼ C; Yield 69.3% of theory;
'/' - [4 '- (2 "-oxo-1" -benzimidazolinyl) -piperidino] -2-amino-4-fluorobutyrophenone, m.p. 231.5 to 234'C; Yield 76.8% of theory;
7- [4 '- (2 "-oxo-1" -benzimidazolinyl) -piperidino] -2-chloro-4-fluorobutyrophenone, m.p. 215-223 ° C; Yield 63.5% of theory;
- / - (4 '- Benzyl - 4' - hydroxypiperidino) - 2 - acetamino-4-fluorobutyrophenone, IR absorption at 1680, 1650, 1600 and 1525 cm " ¹ (caramel-like substance); yield (raw) 93.0% of the Theory;

-, - (4 '- benzyl - 4' - hydroxypiperidino) - 2 - amino-4-fluorobutyrophenone hydrochloride, m.p. 145 to 150 ⁰ C (dec.);. Yield 83.8% of theory; γ - (4 '- Benzyl - 4' - hydroxypiperidino) - 2 - chloro-4-fluorobutyrophenone hydrochloride, m.p. 160 to 165 ° C {dec.); Yield 70.5% of theory.

Example 2

A. Establishing a connection
of the general formula Ib

A solution of 2.0 g of 2-methyl-3- [y- (4'-p -chlorobenzyl - 4 '- hydroxypiperidino) - propyl] - 6 - fluoroindole (prepared according to example 1A and 1B) in 20 ml Acetic acid is used at a temperature below 15 "C A solution of 1.7 g of chromic anhydride in 3 ml of water is added dropwise with stirring. To After stirring for 15 hours at room temperature, the reaction mixture is poured into 120 ml of water. The The mixture obtained in this way is mixed with sodium hydroxide solution until an alkaline reaction occurs. The precipitation will

ίο Sucked off through a Buchner funnel and washed 3 times with 40 ml of warm chloroform each time. The collected filtrate is washed with water and concentrated to dryness. When the residue is recrystallized from aqueous acetone, the) '- [4' - (p-chlorobenzyl) -4'-hydroxypiperidino] -2-acetamino-4-fluorobutyrophenone is obtained in a yield of 95.0% of theory. The hydrochloride melts at 105 to 108 ^r'C . This compound is hydrolyzed according to Example 1C to the y- [4 '- (p-chlorobenzyl) -4'-hydroxypiperidino] -2-amino-4-fluorobutyrophenone; Yield 86.5% of theory. The hydrochloride melts at 155 to 160 ⁰ C.

B. Establishing a connection
₂ . of the general formula I.

A solution of 3.5 g of y- [4 '- (p-chlorobenzyl) -4'-hydroxypiperidino] - 2 - amino - 4 - fluorobutyrophenone in 100 ml of 1 η-hydrochloric acid is added dropwise at a temperature below OC while stirring with a A solution of 0.7 g of sodium nitrite in 5 ml of water is added. The diazonium salt solution thus obtained is poured into 40 ml of cold 50 percent aqueous hypophosphorous acid with vigorous stirring. After stirring for a further 2 hours while cooling with ice, the reaction mixture obtained is stored in a refrigerator for 15 hours. The cold reaction mixture is mixed with sodium hydroxide solution until it has an alkaline reaction and then extracted with chloroform. The extract is washed with water and concentrated to dryness. When the crystalline residue is recrystallized from aqueous acetone, the γ- [4'- (p-chlorobenzyl) -4'-hydroxypiperidino] -4-fluorobutyrophenone is obtained in a yield of 78.0% of theory. The hydrochloride melts at 194 bis

45 200 ° C. According to the aforementioned procedures 2A and 2B the following connections were established:

y- [4 '- (2 "-oxo-1" -benzimidazolinyl) -piperidino] -2-acetamino-5-fluorobutyrophenone; The compound crystallizes in the recrystallization from ethanol with 1 mole of ethanol, mp 102 to 104.5 ⁰ C. (dec.); Yield 70.5% of theory;
γ - [A ' - (2 "- Oxo - 1" - benzimidazolinyl) - piperidino] -2-amino-5-fluorobutyrophenone, mp 183-183.5 ° C; Yield 85.0% of theory;
y - [4 '- (2 "- Oxo -V- benzimidazolinyl) -piperidino] -3-fluorobutyrophenone, melting point 163.5 to 164.5 ° C.; yield 70.0% of theory;
γ - [4 '- hydroxy-4' - (p - methylbenzyl) - piperidino] -4-fluorobutyrophenone, mp 90 ⁰ C;. Yield 80.0% of theory;

γ - [4 '- hydroxy - 4' - (ρ - methoxybenzyl) - piperidino] -4-fluorobutyrophenone hydrochloride, m.p. 175 ° C; Yield 70.0% of theory.

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60

Claims (1)

Patent claims: 1. Process for the preparation of γ-piperidinobutyrophenone derivatives of the general formula I. CO-CH ₁ -CH ₁ -CH ₇ -Z (D in which R ^{1 is} a hydrogen or halogen atom, an amino or acetylamino group, R is a hydrogen or halogen atom and Z is a group of the general formula - N in which R "is a hydrogen or halogen atom, an alkyl or alkoxy radical having 1 to 4 hydrocarbon atoms represents, or a group of the formula. >> -N > —N NII means, and their salts with acids, characterized in that a l - [/> - (3-indolyl) -propionyij-piperidine derivative of the general formula II CH ₁ CH ₂ COZ cn, (II) in which R ² and Z have the above meaning, to a .Vj-piperidinopropylindole derivative of the general formula III oxidized, if desired, the compound thus obtained of the general formula I a to an amino-y-piperidinobutyrophenone derivative of the general Formula Ib