CS268485B1 - Method of 2-(4-piperidylamino)-benzimidazoles preparation - Google Patents

Abstract

The solution relates to a method of preparation Common 2- (4-piperidylamino) -benzimidazoles of formula I is a fluorobenzyl substituent of R is the benzyl group is 4-methoxyphenethyl or 4-mothoxyphenylthio, with that these compounds belong to the group of substances blocking peripheral H 1 receptors and they are therefore used in allergic therapy disease. Their synthesis lies in the condensation of 2-methylsulphonyl- of the benzimidazoles of the formula III are obtained 4-aminopiperidines of general formula IV, carried out at temperatures of 100 to 170 ° C either by direct heating of both components or from the addition of alkali or organic methyΙου neutralizing bases phon group, being isolated the bass of formula I can then be converted to the hydrochloride ncutralisace their alcoholic solutions with hydrogen chloride.

Description

The invention relates to a process for the preparation of 2- (4-piperidylamino) -benzimidazoles of the general formula I

O- » ²

L (i),

R ¹

2 in which R. represents a hydrogen atom or a 4-fluorobenzyl group and R represents a benzyl, 4-methoxyphenethyl or 4-methoxyphenylacetyl group. Substances of this type belong to the group of compounds blocking peripheral H 1 -receptors and therefore used in the treatment of allergic diseases, as evidenced by the example of 1- (4-fluorobenzyl) -2 - [[1- (4-methoxyphenethyl) -4-piperidyl]. / -amino] -benzimidazole (Astemizole ^x ) of formula II (F. Janssens et al., J. Med. Chem. 23, 1934 (1985))

A new process for the preparation of the compounds of formula I consists in that the 2-methylsulfonylbenzimidazoles of formula IIIa and 111b

they condense with 1-substituted 4-aminopiperidines of formulas IVa, IVb or IVc

IVa, FT = CII_C, H, Z o>

to the compounds of the formula I, whereby the methanesulfone group is eliminated and the amine residue IV is bound in position 2 of the benzimidazole system.

It is known from the literature that the methylsulfonyl derivative IIIa can be condensed with 2-dimethylaminoethylamine (E. Hoggarth, J. Chem. Soc. 1949, 3311) or with 4-isopropylaminoaniline (Y. Yamamoto et al., Jap. Kokai Tokkyo Koho 79 81,271 ( 1979), Chem Abstr 92, 111007b (1980) on the corresponding 2-aminobenzimidazoles Va and Vb, respectively.

Va, X = -CH ₂ CH ₂ N (CH ₃ ) ₂

CS 268485 81

According to the literature, these condensations were performed either by direct heating of both reaction components or the reaction was carried out in the presence of toluene, the yields being around 60

It has now been found that condensation of not only the N-unsubstituted methanesulfone derivative IIIa but also its 1-4-fluorobenzyl derivative IIIb can be carried out using suitable modifications of this methodology, both of which give the desired 2 by condensation with 1-substituted 4-aminopiperidines of formulas IVa-IVc. -piperidylaminobenzimidazoles of formula I.

The preparation of 2-methylsulfonybenzimidazole IIIa has been described in the literature (8. Hoggarth, J. Chem. Soc. 1949, 3311: Bednyagina National Park, I. Ya. Postovskii, Nauch. Documents of Vys. 333, etc.). The preparation of its as yet undescribed 1- (4-fluorobenzyl) derivative IIIb was carried out according to the following scheme:

4-Aminopiperidines IVa and IVc are known in the literature, e.g. IVa (F. Brookes, R. J. Terry, J. Walker, J. Chem. Soc. 1957, 3165: NJ Harper, CF Chignell, J. Hed. Chem. 2 , 729 (1964), and IVc (A. Abad et al., ES 555.340 (1986), Chem. Abst. 108, 6017f (1988). The preparation of the 4-ominopiperidine derivative JVb is based on 1.4 dioxo-8-azaspiro [4,5] -decane (K. Šindelář et al., Collection 30, 3879 (1973)), which is alkylated with 4-methoxyphenethol methanesulfoester to its 8- (4-methoxyphenethyl) -deridine. This is cleaved by acid hydrolysis to 1- (4-methoxyphenyl) -4-piperidine (E. Schenl-en, Swiss Pat. No. 528,507 (1972)), the oxime of which gives the desired 4-amino-1- (4- Methoxyphenethyl) -piperidine IVb Since the detailed conditions of the above reactions and some constants of the required intermediates of the above syntheses have not been described in the literature, they are also given in the examples.

As has now been found, a mixture of the starting components of formulas III and IV must be heated to temperatures of 100 to 170 ° C to prepare the desired end compounds of formula I. This heating can also be performed in the presence of substances which bind the cleaved methanesulfonic acid. Not suitable is the addition of alkali carbonates, high-boiling organic bases such as N-methylpyrrolidine bottom. The reaction can be carried out without medium or in the presence of high-boiling organic solvents, for example dimethylformamide. Residues of optionally unreacted methanesulfonic compound III can be easily removed from the reaction mixture by shaking it into dilute alkaline alkalis.

The methods of carrying out the reaction and working up the reaction mixture described in the examples merely document the invention and are not intended to describe all its possibilities in an exhaustive manner.

A. Preparation of starting materials

Example 1

To a mixture of 35 g of 2-nitraniline, 150 ml of toluene, 4 g of tetraethylbutylammonium chloride (TEBA) and a solution of 51 g of sodium hydroxide in 50 ml of water was added 51.3 g of 4-fluorobenzyl bromide, and the mixture was heated under reflux with stirring for 6 hours. then a further 2 g of TEBA are added and the same is heated for a further 6 hours. After cooling to 50 DEG C., 100 ml of water are added, the toluene portion is separated from the resulting suspension and, after filtration, the solvent is distilled off. A mixture of 22 ml of ethanol and 53 ml of hexane is added to the residue, and the precipitate is filtered off with suction and washed with the same mixture. 48.6 g of 2- (4-fluorobenzylamino) nitrobenzene VI are thus obtained, melting at 76-77 DEG C. (from ethanol). For ( ^2Afi > ^{2: 5)} calculated: 63.40 SC, 4.50 SH, 11.38% N, 7.72 SF;

Found: 63.12 X C, 4.49% H, 11.15 S N, 7.81% F.

Example 2

To a solution of 50 g of 2- (4-fluorobenzylamino) nitrobenzene VI in 370 ml of ethanol at 60 DEG C. are added 3.6 g of carborafin and a solution of 1 g of ferric chloride in 4 ml of ethanol over 30 minutes. at 60-65 ⁰ was added dropwise 40 ml of hydrazine hydrate 100Kního. The mixture is then further heated to the indicated temperature until decolorization, i.e. 4 to 5 hours, the suspension is filtered off with suction at 5 DEG C. and all ethanol and part of the excess hydrazine hydrate are filtered off from the filtrate. The residue is diluted with 50 ml of water, cooled below 15 [deg.] C., the precipitated product is filtered off with suction and washed with water. 42 g of 2- (4-fluorobenzylamino) -aniline VII are thus obtained, melting at 84 DEG C. (from ethanol).

For ^C 13 ^H ₁ 3 ^FN 2 (216.25) calculated: 72.20 XC 6.06 X ||, 12.4 $ N, 8.79% F; found: 72.35% C, 5.98 XH, 12.99 XN, 8.95 S F.

Example 3

A mixture of 21.6 g of 2- (4-fluorobenzyminin) -nionic acid, 18 g of potassium xanthate, 17 ml of water and 100 ml of ethanol is heated to reflux for 3 hours. Then 3 g of carborafin are added, after 15 min. After stirring, the mixture is filtered off with suction while hot and the filtrate, heated to 70 DEG C., is first diluted with 110 ml of water at 70 DEG C. and then acidified with 35 ml of SOS acetic acid. After cooling, the precipitated product is isolated by suction. 21.2 g of 1- (4-fluorohenzyl) -benzimidazole-2-thiol VIII are thus obtained, melting at 192 DEG-193 DEG C. (from benzene).

For C ₁₄ H ₁₁ FN ₂ S (258.30) calculated: 65.09 SC, 4.29% H. 10.85 XN, 7.36% F, 12.41 XS; found: 65.12 X 0.44.2H, 10.95 XN, 7.61 XF, 12.57 X S.

Example 4

A mixture of 19.6 g of 1- (4-fluorobenzyl) -benzimidazole-2-thiol (VIII), a solution of 3.3 g of sodium hydroxide in 75 ml of water and 40 ml of ethanol was stirred for 30 minutes. stir vigorously and then filter. The filtrate was stirred for 10 minutes. 18.2 g of methyl iodide are added dropwise, the suspension is stirred for 3 hours, the ethanol and the excess methyl iodide are distilled off in vacuo and the distillation residue is stirred with 200 ml of benzene. The separated benzene portion is purified by adding 2 g of carborafin, filtered and the filtrate is evaporated. The residue is stirred with 40 ml of hexane, the precipitated product is filtered off with suction and washed with hexane. 17.1 g of 1- (4-fluorobenzyl) -2-methylthiobenzenimidazole IX are thus obtained, melting at 102-103 DEG C. (from benzene and hexane).

For C ₁₅ H ₁₃ FN ₂ S (272.33) calculated: 66.15% C, 4.81 SH, 10.29 SN, 6.98 SF, 11.77 XS; Found: 66.18 XC, 4.70 i; II, 10.16 5 N, 7.24 XF, 11.73 X 5.

Example 5

To a solution of 15.0 g of 1- (4-fluorobenzyl) -2-methylthiobenzimidazole IX in 120 ml of acetic acid was stirred for 75 minutes. A solution of 12 g of potassium permanganate in 220 ml of water is added dropwise and the mixture is stirred for a further 1 hour. By adding a solution of 10 g of potassium pyrosulphite in 50 ml of water

The sags are decolorized, diluted with 500 ml of water and, after stirring for 4 hours, the precipitated product is filtered off with suction and washed with water. 13.6 g of 1- (4-fluorobenzyl) -2-methylsulphonylbenzimidazole IIIb are thus obtained, melting at 102-103 DEG C. (ethanol).

For C ₁₅ H ₁₃ FN ₂ 0 ₂ S (304.33) calculated: 59.20 8 C, 4.31 8 H, 9.21 8 N, 6.24% F, 10.53 5 S; found: 59.21 8 C, 4.25 8 H, 9.08 8 N, 6.40 8 F, 10.83 8 S.

Example 6

To a mixture of 12.7 g of 1,4-dioxo-8-azaspiro [4,5] decine. 15 g of anhydrous potassium carbonate and 80 ml of dimethylformamide, heated to 60-65 ° C, are heated for 90 minutes. A solution of 20.5 g of 4-mothoxyphenethol methanesulfoester (S.luegi et al., J. Med. Chem. 26, 42 (1983)) in 50 ml of dimethylformamide is added dropwise and the mixture is heated to 60-65 [deg.] C. for 12 hours. of the inorganic salts, the solvent is distilled off from the filtrate in vacuo, the residue is taken up in water and 100 ml of chloroform and the separated organic phase is evaporated off. 22.1 g of 8- (4-methoxyphenethyl) -1,4-dioxo-8-azaspiro [4.5] decane in the form of a colorless oil. , 8.36 δ H, 5.05 δ N;

O 4 J J Found: 68.95 8 C, 8.31 8 H, 4.99% n.

Example 7

A mixture of 22.0 g of the azaspico compound prepared according to the example, 240 ml of water and 48 ml of concentrated hydrochloric acid is heated to reflux for 16 hours. The cooled solution is then basified with 308 l of sodium hydroxide solution, shaken 3 times with 100 ml of chloroform, the combined separated extracts are dried over sodium sulfate and the chloroform is distilled off. 18.0 g of 1- (4-methoxyphenethyl) -4-piperidone are obtained, which is directly further converted into the oxime as described in Example 8. Example 8. ''

A mixture of 23.3 g of 1- (4-methoxyphenyl) -4-piperidone, 60 ml of pyridine and 8 g of hydroxylamine hydrochloride is heated at 100 DEG C. for 3 hours. The excess pyridine is then distilled off in vacuo, the residue is taken up in 50 ml of ethanol, the product is filtered off and washed with a mixture of ethane and ether (3: 2). 20.0 g of 1- (4-methoxyphenethyl) -4-piperidone oxime hydrochloride are thus obtained, melting at 224-226 ° C. .

For C 11 H 11 N 2 O 2 (284.78) calculated: 59.04 8 C, 7.43 8 H, 9.84 8 N, 12.45 8 Cl;

Z1 Z Z found: 58.84 8 C, 7.47 8 H, 9.90 8 N, 12.40 8 Cl. The oxime base ae is prepared by adding to a suspension of 4.5 g of this hydrochloride in 150 ml of ethanol a solution of 0.4 g of sodium in 15 ml of ethanol at 75 DEG C. and stirring the suspension for 1 hour. After cooling, the precipitated sodium chloride is filtered off with suction and the filtrate is evaporated to dryness in vacuo. 3.8 g of 1- (4-methoxyphenethyl) -4-piperidone oxime, m.p. 141 DEG-142 DEG C. (from chloroform and hexane), are thus obtained.

Calcd for C 18 H 20 N 2 ^{O 2 (248} > ³²⁾ : 67.71 δ C, 8.13 δ H, 11.28% N; Found: 67.48 8 C, 8.31 8 II, 10.97% N.

Example 9

To 35 g of sodium was added in 20 min. A warm solution (60-65 ° C) of 37 g of 1- (4-methoxyphenethyl) -4-piperidone oxime in 400 ml of ethanol is added dropwise and the mixture is heated to reflux until the sodium has dissolved, which takes 3 to 4 hours. 130 ml of water are added dropwise while cooling, and ethanol and a portion of the water are distilled off in vacuo. The cooled residue is stirred twice with 120 ml of ether, the solution is dried over anhydrous sodium sulfate and, after filtration, the ether is evaporated. The residual liquid (34 g) was distilled and the fractions were collected at 157 ° C / 13.3 Pa. 29.8 g of 4-amino-1- (4-methoxyphenethyl) -piperidine IVb are thus obtained in the form of a colorless liquid which solidifies on cooling and melts at 30 DEG to 32 ^DEG C.

For C ₁₄ H ₂₂ N ₂ O (234.33) calculated: 71.75 8 C, 9.47 8 H, 11.95% N found: 70.66 8 C, 9.68 8 H, 11.74 8 The dihydrochloride hemihydrate is obtained by neutralizing an isopropanol solution of the base with hydrogen chloride and melting at 275 DEG-277 DEG C. (from ethanol). *

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For ^c ₁₄ ^H 25 ^N 2 ^Cl 2 ° 0 5 m ^{6 '25} ) calculated: 53.16 SC, 7.96 SH, 8.86 KN, found: 53.36 SC, 8.04% H, 8.78 XN,

22.44 S Cl

22.84 5 Cl

8. Preparation of final substances

Example 10

A mixture of 3.9 g of 2-methylsulfonylhenzimidazole IIIa and 7.8 g of 4-amino-1-benzylpiperidine IVa is heated with stirring at 160 DEG-170 DEG C. for 3.5 hours. 50 ml of 10N acetic acid are added to the lukewarm melt and stirred until melting. The solution is filtered from a small quantity of the starting sulfoderivative (below 0.1 g), the filtrate is washed with sodium hydroxide, the precipitated product is filtered off with suction, washed with water and crystallized from methyl isobutyl ketone. To give 4.90 g (80%) of 2- (1-benzyl-4-piperidyl) aminobenzimidazole I (R = H, R₁ = Target-CJI ,.) 2 ⁶ melting at 220-221 C. .

For C ₁₉ H ₂₂ N ₄ (306.4) calculated: 74.47 SC, 7.24% H, 18.29% N; Found: 74.28 5 C, 7.46 KH, 17.96 S M.

Example 11

A mixture of 3.9 g of 2-methylsulphonylhenzimidazole IIIa, 4.8 g of 4-amino-1- (4-methoxyphenethyl) piperidine IVb, 3 g of anhydrous sodium carbonate and 5 ml of n-methylpyrrolidine is heated for 10 hours at 140-150. ° C. The melt was partitioned between water and chloroform, the organic layer was separated and extracted twice with 10% acetic acid. The combined aqueous-acidic extracts are filtered off, basified with ammonia, the precipitated product is filtered off with suction and washed with water. 5.7 g of (82 S) 2- [71- (4-methoxyphenethyl) -4-piperidyl] amine] benzimidazole (1, R 2 = H, R 2 = CH 2 CH 2 C 4 H, OCH 3) are thus obtained. , melting at 184-185 ° C (from benzene and acetone). 4 4 0 4 2

For C 1 H 2 N 2 O (350.45) calculated: 71.97 S C, 7.48 r, H, 15.99% Ni 2

40.4 found: 72.20 SC, 7.70 T. H, 15.87% N. The dihydrochloride hemihydrate was prepared by neutralizing an isopropanol solution of the above base with hydrogen chloride and crystallizing from ethanol and ether, mp 262-264 ° C. For C ₂₁ H ₂₉ Cl ₂ N ₄ O _{o> 5} (432.39) calculated: 58.32% C, 6.76 1H, 12.97 KN, 16.40; Found: 58.42 SC, 6.71% H, 13.03% N, 16.11% Cl.

Example 12

A mixture of 3.0 g of 1- (4-fluorobenzyl) -2-methylsulphonylbenzimidazole TITb, 3.5 g of 4-amino-1- (4-methoxyphenethyl) -piperidine IVb and 25 ml of dimethylformamide is heated at 160 DEG-170 DEG C. for 6 hours. . The solvent is then distilled off in vacuo, the residue is taken up in toluene and 10 ml of acetic acid, the aqueous-acidic phase is separated off, filtered and recrystallized from dilute ammonia and the precipitated base is taken up in chloroform. The separated chloroform extract was dried over anhydrous sodium sulfate, filtered, and the chloroform was evaporated. Crystallization of the residue from 70% ethanol gave 3.4 g of (76) 1- (4-fluorobenzyl) -2- [71- (4-methoxyphenethyl) -4-piperidyl] amino] benzimidazole (I, R ¹ = CH-CHF, = CH, CH, CH, OCH 3), melting at 173-174 ° C.

For C ,, H _of N.F0 (458.56) calculated: C 73.33 15 6.81 $ H, 12.22% N, 4.14 to 5 F;

found: 73.33 S C, 6.85 ° H, 12.52 S N, 4.06% F. The dihydrochloride monohydrate is obtained by neutralizing the ethanolic base solution with hydrogen chloride and crystallizing from aqueous isopropanol, m.p. 245-247 ° C.

For C__H ,, N. Cl-FO- (549.50) calculated: 61.21 S C, 6.42 Μ II. 10.20 15 N, 12.90 V, Cl, 40 PP 4 4 4

3.45 3 F;

found: 61.68% C, 6.31% H. 10.14% N, 13.04 S Cl,

3.60% F.

Example 13

A mixture of 9.0 g of 1- (4-fluorobenzyl) -2-methylsulfonylhenzimidazole ITIb and 14.0 g of 4-amino-1- (4-methoxyphenethyl) -piperidine IVb is heated with stirring at 160-165 ° C for 6 hours. . The cooled melt is dissolved hot in 80 ml of toluene, the solution is shaken with 20 ml of sodium hydroxide and 150 ml of 10 ml of acetic acid. The aqueous-acid extract was basified with ammonia, the precipitate was shaken in chloroform and the separated solvent was evaporated. The residue is stirred with ether, the substance is filtered off with suction and washed with ether.

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12.5 g (92.6%) of material are thus obtained, which melts at 173 DEG-174 DEG C. after crystallization from dilute ethanol and is identical to the product obtained according to Example 12.

Example 14

A mixture of 6.0 g of 1- (4-fluorobenzyl) -2-methylsulfonylbenzimidazole IIIb, 5.0 g of 4-amino-1- (4-methoxyphenylacetyl) -piperidine IVc and 10 ml of N-methylpyrrolidine was heated at 150 DEG-160 DEG C. for 12 hours. C. After cooling, the melt is stirred between benzene and 10% sodium hydroxide, the separated benzene is washed 3 times with water, dried over anhydrous sodium sulfate and, after filtration, the henzene is evaporated. The residue is stirred with 30 ml of ether and the precipitate is filtered off with suction. 6.6 g (71%) of 1- (4-fluorobenzyl) -2- [1- (4-methoxyphenylacetyl) -4-piperid] are thus obtained.

ridyl / amino / benzimidazole (I, R =, R = COCH 2 Cl 2 H 2 OCH 2), melting at 178 to

179 ° C (from benzene-methanol-ether).

For ^r -2j ^ll 29N ₄ F0 ₂ (472.54) calculated: 71.16% C, 6.19% I !, 11.36 5 N, 4.02 X Γ;

Found: 71.14 S C, 6.23 S H, 11.00! N, 3.93 S Γ.

Claims (1)

OBJECT OF THE INVENTION !! Process for the preparation of 2- (4-piperidylamino-benzimidines of the general formula T) in which the hydrogen atom or the 4-fluorobenzyl substituent is 4-methoxyphenethyl or 4-methoxyphenylacetyl, and their hydroxyhydrochloride group, characterized in that the 2-methylsulphonylbenzimidoles of the general formula III R ¹¹ in which R has the same meaning as in formula I is reacted with 4-aminopiperidines of formula IV in which it has the same meaning as in formula 1, at temperatures of 100 to 170 ° C, after which the isolated bases of general formula I are optionally converted into their hydrochlorides by neutralizing their alcoholic solutions with hydrogen chloride.