SU683621A3 - Method of the preparation of piperazine or piperidine derivatives or their salts - Google Patents

Description

one

The invention relates to a process for the preparation of novel piperazine or piperidine derivatives or their salts, which can be used in medicine.

The reaction of alkylation of piperazine derivatives is known. Haloalkyl or p-toluenesulfonyl derivatives to form N-substituted piperazine derivatives 1.

The purpose of the invention is a method for producing novel piperazine or piperidine derivatives with potent pharmacological properties.

The goal is achieved by the method of obtaining piperazine or piperidine derivatives of general formula I

B-CpHjn-K A- (o) p, -sn-Ar

where Ar1 and Ar2 - independently of each other pyridinyl, unsubstituted phenyl or phenyl, substituted with 1-2 substituents from among halogen, alkyl or alkoxy, in which alkyl with 1-6 carbon atoms, nitro, trifluoromethyl;

A is a group of N- or CH-, under the condition that A is a group of N-, then t is O, and when A is a group -CH-, then t is 1. p-2-6 provided that CnHzn is branched chain alkylene , then at least 2 carbon atoms are in a linear chain linking B to the piperazine or piperidine ring;

B is a radical of the formula

I15

where RI and Rs are independently of each other, hydrogen, halogen, alkyl with 1-5 carbon atoms, trifluoromethyl;

Y is oxygen, sulfur or N-L group, where L is hydrogen, alkyl with 1-6 carbon atoms, alkylcarbonyl, alkyloxycarbonylalkyl or carboxyalkyl, in each of

which alkyl contains 1-6 carbon atoms, phenyl, phenylmethyl, alkylaminocarbonyl, where alkyl with 1--6 carbon atoms

hydroxymethyl or alkenyl with 2-6 carbon atoms; or radical of formula

T1N.- COO (lower akyl) I-COO {lower alkyl) N

where RI and Ra are as defined above, and M is hydrogen, alkyl with 1-6 carbon atoms, phenyl, phenylmethyl, mercapto, alkythio, alkylcarboxylamino or alkoxycarboxylamino, in which alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms or their salts.

The method consists in the fact that the compound of the general formula II

In -CnH2n-W, II

where B and "have the above mentioned zeros, and W - chlorine, fluorine, bromine, iodine, alkylsulfonyl group with 1-6 carbon atoms or 4-methylbenzylsulfonyl group,

subjected to interaction with the compound of General formula III

- (o) m-CH-Ari "At-,

where A, t, Ari and Aha are as defined above,

when heated in an inert organic solvent in the presence of a base, followed by isolation of the desired product as a base or salt.

As an inert organic solvent in this reaction, for example, lower alkanol, methanol, ethanol, propanol, butanol, an aromatic hydrocarbon, for example benzene, methylbenzene, dimethylbenzene, etc. can be used; an ether, for example, 1,4-dioxane, 1, G-hydroxybispropane, etc.; ketone, for example, 4-methyl-2pentanone; | N, N-dimethylformamide; nitrobenzene, etc. An alkali or alkaline earth metal carbonate or bicarbonate can be used, for example, to bind the acid formed during the reaction. To speed up the reaction, a small amount of an iodide of the corresponding metal, for example, sodium or potassium iodide, can be added.

It should be noted that if the B group in the compounds of the formula I or in the intermediate compounds is a radical, such as 2- (lower alkyloxycarbonylamino) -1H-benzimidazol-1-yl or 2- (lower alkylcarbonylamino) -1H-benzimIdazole -1il, then these radicals can exist in tautomeric forms, as shown below.

NH - CO {i-uK j a ;; t: L ::: j i: - CO lower alkyl)

/ H

I- Hw: and

//

Tt;:

The compounds of formula I can be converted into their salts by treatment with an appropriate acid, for example, an inorganic acid, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, etc., or an organic acid, for example, acetic, butyric, oxyacetic, 2- oxybuty, 2-oxobutyric, dibasic propane, dibasic butane, dibasic (2) -2-butene, dibasic (E) -2-butene, dibasic 2-oxybutyl, dibasic 2,3-dioxybutane, 2-hydroxy-1, 2,3-propantricarboxylic, benzoic, 3-phenyl-2-propenoic, a-ca ibenzouksusnoy, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-metilbenzolsulfonovoy, tsiklogeksansulfonovoy, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acids. Alternatively, the salts can be converted to the free bases by treatment with alkalis.

The following examples illustrate the invention, but do not limit its scope. In all examples, parts are by weight.

Example 1. Getting source 2H-benzimidazolone-2-s.

To a stirred mixture of 54 parts of 1,3-dihydro-G-phenylmethyl-2H-benzimidazol-2., 47.25 parts of 1-bromo-3-chloropropane and 6 parts of chloride S, S, M-triethylbenzenemethanamine are added dropwise 450 parts 60% solution of caustic soda at 60 ° C. After the addition is complete, stirring is continued for 6 hours at 60 ° C. The reaction mixture is cooled and poured into water. The oily product is extracted with chloroform. The extract is dried, filtered and evaporated. The residue is crystallized from

2,2-oxybispropane and after drying

42 parts (58%) of 1- (3-chloropropyl) -1,3-dihydro-3-phenylmethyl-2H-benzimidazol-2-one are obtained.

In a similar way receive the substances given in tab. one.

Table 1

Example 2. According to the method described in example 1, using equivalent

M

CH,

C2Hs

n

Cehs snake

Example 3. A mixture of 20 parts of 3- (2-amino-4-chlorophenyl) amino-1-propanol, 150 parts of a 4N hydrochloric acid solution and 50 parts of acetic acid was heated under reflux with stirring overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in water and the solution is made alkaline with ammonium hydroxide. The product is extracted with chloroform. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2-oxybispropane and 6.5 parts (28%) of 5-chloro-2-hydroxymethamide of the corresponding 1H-benzimidazole are obtained as starting material for the compounds given in table. 2

table 2

1 1-Cr, Ngp-C1.

Cnhj

(CH2) s

(CH2) s

(CH) e CHa-CH-CHg

SNS

(CH2) s

(CHj),

Tyl-1H-benzimidazole-1-propanol.

In a similar way, 5-chloro-2-ethyl-1H-benzimidazole-1-propanol is obtained from

3- (2-amino-4-chlorophenyl) -amino -1-propanol and propionic acid.

Example 4. To a stirred and heated under reflux and water separator mixture of 30 parts of 3- (2-amino-4-chlorophenylamino-1-propanol and 0.1 part of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene is added dropwise a solution

34 parts cyclohexanecarboxaldehyde in 45 parts methylbenzene. After the addition is complete, stirring is continued for 1 h under reflux with a water separator. Methylbenzene is removed by vacuum distillation, and the residue is triturated in 2,2-oxybispropane. The product is filtered and dried; 16.5 parts (38%) of 5-chloro-2-cyclohexyl-1H-benzimidazole-2-propanol are obtained; m.p. 95 ° C.

Example 5. A mixture of 30 parts of 3- (2-amino-4-chlorophenyl) amino-1-propanol, 44.8 parts of da-hydroxybenzene sodium sulfate and 120 parts of ethanol was stirred at reflux for 30 minutes. The reaction mixture was evaporated and the residue was dissolved in water. The crude product is extracted with chloroform. The extract is dried, filtered and evaporated to give 45 parts (100%) of 5-chloro-2-phenylmethyl-1H-benzimidazole-1-propanol as a residue.

In a similar way, 6-chloro-2-cyclohexyl-1H-benzimidazol-1-propanol is obtained; m.p. 120.1 ° C from 3- (2-amino-5-chlorophenyl) amino-propanol and a-hydroxycyclohexane methane sulfonate sodium.

Example 6 To a stirred mixture of 93 parts of 3- (2-aminophenyl) amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of an 85% ethanol solution was added dropwise 69.8 parts of carbon disulfide. Once the addition is complete, stirring is continued and refluxing for 6 hours. The reaction mixture is evaporated and the residue is dissolved in 1500 parts of water, filtered and the filtrate is acidified with acetic acid. The oily product hardens when rubbed. It is filtered, washed with water and dried, yielding 92 parts (78.9%) of 2-mercapto-1H-benzimidazole-1-propanol; m.p. 110 ° C.

A mixture of 20.8 parts of 2-mercapto-1H-benzimidazole-1-propanol, 15.62 parts of iodomethane and 120 parts of methanol is stirred overnight at room temperature. The reaction mixture was evaporated and the residue was dissolved in 500 parts of water. The solution is filtered and the filtrate is alkalized with solid potassium hydroxide. The oily product is extracted with chloroform. The extract is dried, filtered and evaporated to give 19 parts (85.5%) of 2-methylthio-1H-benzimidazole-1-propanol.

To a stirred mixture of 19 parts of 2-methylthio-1H-benzimidazole-1-propanol, 15.2 parts of M, N-diethylethylamine and 195 parts of methylene chloride are added dropwise 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued at reflux for 1 hour. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated to give 19 parts of 3- (2-methylthio-1H-benzimidazole-1-yl) propyl methanesulfonate as an oily residue.

Example 7. A mixture of 30 parts of benzimidazole, 49 parts of 2- (4-chlorobutoxy) -tetrahydro-2H-pyrap, 21 parts of potassium hydroxide and 200 parts of ethanol was stirred at reflux overnight. The reaction mixture is cooled to room temperature, filtered and the filtrate is evaporated. The residue is stirred in water, acidified with a dilute hydrochloric acid solution. The whole volume is stirred and heated in a water bath for 30 minutes. After cooling to room temperature, the product is extracted with methyl benzene. The aqueous phase is separated and acidified with ammonium hydroxide. The product is extracted with methylene chloride. The extract is dried, filtered and evaporated to give 50 parts of 1H-benzimidazole-1-butanol as an oily residue.

Example 8. To a stirred mixture of 5 parts of 4-chloro-l, 3-dihydro-3- (3-oxyclopyl) -2P-benzimidazol-2-ona and 75 parts of chloroform are added dropwise 8 parts of thionyl chloride. After the addition is complete, stirring is continued for 3 hours under reflux. The reaction mixture is cooled and evaporated. The residue is stirred with a small amount of 4-methyl-2-pentanone. The product is filtered and dried to give 3.5 parts of 4-chloro-3 - (3 - chloropropyl) -1,3-dihydro-2Pbenzimidazol-2-one.

In a similar way, 1- (chloroalkyl) -1H-benzimidazoles are obtained, given in Table 3.

Example 9. A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1 propanol, 0.2 parts of potassium iodide and 200 parts of butanol was stirred at reflux overnight. Butanol is distilled off in vacuo and water is added to the residue. The product is extracted with 4-methyl-2-pentanop. The extract is washed several times with water, dried, filtered and evaporated. The oily residue was purified by silica gel column chromatography using chloroform containing 5% methanol as eluent. Pure fractions are collected and the eluent is evaporated. The residue is triturated with 2,2-oxybispropane. The product is filtered and crystallized from a mixture of 2,2-oxybispropane and 2-propanol, to obtain 31.7 parts of 3- (4,5-dichloro-2-nitrophenyl) -amino - -propanol; m.p. 97 ° C.

In a similar way receive:

3- (2-nitro-4-trifluoromethylphenyl) amino-propanol;

2- (2-nitro-4-trifluoromethylphenyl) -amino ethanol; m.p. 74.9 °.

Example 10 To a stirred mixture of 39.2 parts of 3- (2-nitrophenyl) amino-1-propanol and 225 parts of chloroform were added dropwise 35.7 parts of thionyl chloride (exo 683621

ten

Table 3

thermal reaction, temperature rises to 45 ° C). After the addition is complete, stirring is continued for 6 hours under reflux. The reaction mixture was evaporated and 43 parts (100%) of M- (3-chloropropyl) -2-nitrophenylamine were obtained.

In a similar way obtained:

N-3-chloropropyl -2-nitro-4-trifluoromethylphenylamine;

4,5-dichloro-M-3-chloropropyl-2-nitrophenylamine; m.p. 78 ° C;

N-2-chloroethyl -2-nitro-4- (trifluoromethyl) phenylamine.

Example 11. A mixture of 21.5 parts of N- (3-chloropronyl) -2-nitrophenylamine, 22.68 parts of 1- (diphenylmethyl) -piperazine, 20 parts of H, M-diethylethylamine and 189 parts of N, N-dimethylacetamide is stirred under heating to 100 ° C for 6 hours. The reaction mixture was evaporated and the residue was dissolved in water. The oily product is extracted with chloroform. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol, ethanol and 2,2-oxybispropane. The product is filtered and dried; 15.5 parts (36.9%) of hydrochloric 4-diphenylmethyl-N- (2-nitrophenyl) -1-piperazine propylamine are obtained; m.p. 228 ° C.

A similar method was used to obtain: N- (4,5-dichloro-2-nitrophenyl) -4- (diphenylmethyl) -1-piperazine propylamine;

4-diphenylmethyl - - nitro-4- (trifluoromethyl) -phenyl -1-piperazine propylamine; m.p. 113.7 ° C;

4-diphenylmethyl-N-2-nitro-4- (trifluoromethyl) -phenyl -1-piperazine ethyl amine; m.p. 152.1 ° C.

Example 12. A mixture of 15 parts of hydrochloric 4-diphenylmethyl-N- (2-nitrophenyl) -1-piperazinenopylamine in 160 parts of methanol was hydrogenated at normal pressure and room temperature in the presence of 5 parts of Rene nickel. After having absorbed the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The solid residue is crystallized from a mixture of 2-propanol and 2,2-oxybispropane. The product is filtered and dried; 12 parts (78.9%) of hydrochloric N- (2-aminophenyl) -4- (diphenylmethyl) -1-piperazinepronylamine are obtained; m.p. 223.1 ° C; In a similar way, 4,5-dichloro-3- {3-4- (diphenylmethyl) -1-piperazinyl-propyl} -1,2, 2-phenyldiamine in the form of an oily residue;

L- {3- 4- (diphenylmethyl) -1-piperazinyl propyl} -4- (trifluoromethyl) -1,2-phenyldiamine;

N- {2- 4- (diphenylmethyl) -1-piperazinyl ethyl} -4- (t eifluoromethyl) - 1,2-phenyldiamine as an oily residue.

Example 13. The preparation of compounds of formula I.

A mixture of 60.5 parts of 1- (3-chloropropyl) -1,3-di1-idro-3- (1-methylethenyl) -2H-benzimilazol-2, 31.68 parts of 1- (phenylmethyl) piperazine, 21.2 portions of sodium carbonate and 400 parts of 4-methyl-2-pentanone are stirred for 20 hours. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered, evaporated, get 70 parts (100%) 1,3-dihydro - 1- (1-methylethenyl) -3- {3- 4- (phenylmethyl) - 1 - piperazinyl-propyl} -2H-bevimidazole -2-it is in the form of an oily residue. In a similar manner, 1,3-dihydro-1- {2-4- (phenylmethyl) -1-piperazinyl-ethyl} -2H-benzimidazol-2-one is obtained; m.p. 136.5 ° C. Example 14. 63 Parts of 1,3-dihydro-1- {3 4- (phenylmethyl) -1-piperazinyl-propyl} 2H-benzimidazol-2-one in 400 parts of methanol is hydrogenated at normal pressure and room temperature in the presence of 10% palladium on coal. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. The product was filtered and dried; 29.5 parts (63%) of 1,3-dihydro (1-piperazinyl) propyl -2H-benzimidazol-2-one were obtained; m.p. 157.5 ° C. In a similar way, receive: 1,3-dihydro-C 2- (1 - piperazinyl) -ethyl; 2H-benzimidazol-2-one; m.p. 122.6 ° C. Example 15 To a stirred mixture of 20 parts of aluminum chloride and 100 parts of fluorobenzene was added dropwise 20.5 parts of 2,4-dichlorobenzoyl chloride. After the addition is complete, the mixture is heated under reflux and stirred at reflux for 5 minutes. The reaction mixture is poured onto crushed ice and the product is extracted with 1,1-oxybisethane. The extract is dried and evaporated to give 30 parts of (2,4-dichlorophenyl) - (4-fluorophenyl) -methaion in the form of an oily residue. In a similar way, receive: (4-fluorophenyl) - (4-pyridinyl) -methanone; m.p. 85.5 ° C. Example 16 To a mixture of 23.4 parts of (4-chlorophenyl) - (2-fluorophenyl) methanone and 280 parts of 2-propanol stirred under reflux in 280 parts of 2-propanol, was added portionwise 3.7 parts of sodium borohydride. Upon completion, stirring is continued and refluxing (+ 80 ° C) for 2 hours. The reaction mixture is cooled and diluted by adding water. 2-Proaanol is distilled off and the residue is extracted with chloroform. The extract is dried, filtered and evaporated to give 23.6 parts of 4-chloro-a- (2-fluorophenyl) -phenylmethanol. A 1 in a logical way they crawl: 2,4-dichloro- (4-fluorophenyl) - foni; methanol; 5 10 15 20 25 30 35 40 15 50 55 60 65 a- (4-fluorophenyl) -4-pyridine methanol; m.p. 138.2 ° C; hydrochloric O} - (4-fluorophenyl) -3 pyridine methanol; m.p. 158.3 ° C; and 4-metoxy-a-3- (tripto-methyl) -phenyl phenylmethanol. Example 17. A mixture of 22 parts of 2,4-dichloro - a - (4-fluorophenyl) - phenylmethanol and 240 parts of 12 n. The hydrochloric acid solution is stirred for 40 hours at room temperature. The reaction mixture is poured into ice-water and the product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The residue was distilled and 13.2 parts of 2,4-dichloro-1- (4-fluorophenyl) chloromethyl benzene were obtained; m.p. 146 ° C (0.15 mm Hg. Art.). In a similar way, the following is obtained: 1 - {a-chloro-CHss- (4-methoxyphenyl) -metnl-3 (trifluoromethyl) -benzene; 1-a-chloro- (4-methylphenyl) methyl-4-fluorobenzene. Example 18 To a stirred mixture of 23.6 parts of 4-chloro-a- (2-fluorophenyl) phenylmethanol in 108 parts of benzene was added dropwise 24 parts of thionyl chloride. At the end of the addition, the entire volume is refluxed for 5 hours and then stirred overnight at room temperature. The benzene is evaporated and the residue is distilled to obtain 16.5 parts of 1 - chlorine-44 a-chloro-a- (2-fluorophenyl) methyl benzene; m.p. 122-125 ° C (0.1 mm Hg. Art.). In a similar way, 3-a-chloro-a- (4-fluorophenyl) -methyl-pyridine hydrochloride is obtained in the form of an oily residue; hydrochloric 3-wasp-chloro-a- (4-chlorophenyl) -methyl-pyridine as an oily residue; hydrochloric 4- a-chloro-a- (4-fluorophenyl) -methyl-pyridine; m.p. 198-200 0; 1- (chlorophenylmethyl) -2,3-dimethylbenzene; m.p. 137 ° C (0.7 mmHg); 1 - (chlorophenylmethyl) -2,4-dimethylbenzene; m.p. 137 ° C (0.7 mmHg); 2- (chlorophenylmethyl) -1,4-dimethylbenzene; m.p. 136 ° C (0.7 mmHg); 1- (chlorophenylmethyl) -2-fluorobenzene; m.p. 108-109 ° С (0.4 mmHg); Example 19. A mixture of 5.3 parts of 1- (3-chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 1 - (diphenylmethyl) - piperazine, 6.4 parts of sodium carbonate and 200 parts 4 -methyl-2-pentanone with stirring and refluxing with a water separator overnight. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone phase is dried, filtered and evaporated. The residue was purified by silica gel column chromatography using chloroform with 5% methanol as eluent. The numbers; ys fractions are collected and the eluent is evaporated. The oily residue is crystallized from

about II

L - N 11-SpNg „-1G TT-Sn

M -.

Table 4

/ Ag,

mixtures of 2,2-oxybispropane and a small amount of 2-propanol. The product is filtered off, dried, and 2 parts (23%) of 1- {3- 4- (diphenylmethyl) -1-piperazinyl propyl} -1, 3-dihydro-2H-benzimidazole-2one are obtained; m.p. 153.6 ° C.

In a similar way, compounds were obtained in the form of a base or a salt after treating the base with an appropriate acid; four.

Example 20. In a manner similar to that described in example 19, receive:

C 3- {4-1 | bis- (4-fluorophenyl) -methyl -1-pi-perazinyl} -propyl-1, 3-dihydro-2H-benzimidazole -2-one; m.p. 197.3 ° C from 1,3-dihydro-1 (3-hydroxypropyl) -2H-benzimidazol-2-one methanesulfonate and (4-fluorophenyl) methyl piperazine;

hydrate dichloride 1- {3-4 (diphenylmethyl) - 1 - piperazinyl-propyl} 1, 3-dihydro - 3 - methyl-2H-benzimidazol-2on; m.p. 201.8 ° C from 1,3-dihydro-1- (3-iodopropyl) -3-methyl-2H-benzimidazol-2-one and 1 - (diphenylmethyl) piperazine;

hemihydrate two chloride

3- {3-f 4- (diphenylmethyl) -1-piperazinyl propyl} -2 (3N) -benzothiazolone; m.p. 186, HS from 3- (3-bromopropyl) -2- (ЗН). Ag

SOUTH U- (CH,), - K-CH

 hl.

Example 22. A mixture of 4.9 parts of 1- (3-chloropropyl) -1H-benzimidazole, 5.76 parts of (4-fluorophenyl) methyl piperazine, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone are heated under reflux with a water separator with stirring for 20 hours. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-2-oxybispropane. The product is filtered, dried.

benzothiazolone and I- (diphenylmethyl) -piperazine;

hydrochloride 3- (diphenylmethyl) - -piperazinyl-propyl} -2 (ZN) 5 benzoxazolone; m.p. 212.4 ° C from 3- (3-chloropropyl) -2 (ZN) -benzoxazolone and 1- (diphenylmethyl) -piperazine.

Example 21. A mixture of 6.95 parts of 1- (5-chloropentyl) -1,3 - dihydro-3- (1-methylethyl) -2H0 benzimidazol-2-one, 5.15 parts of 1- (diphenylmethyl) piperazine, 5 , 30 parts of sodium carbonate, 0.1 parts of potassium iodide and 100 parts of 4-methyl-2-pentanone are heated under reflux with stirring.

5 water separator overnight. The reaction mixture is cooled to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The rest in 12 parts of solution

Hydrochloric acid and 40 parts of ethanol are heated under reflux with stirring for 30 minutes. The mixture is evaporated, the residue is crystallized from ethanol and 5 parts (46%) of 1-hydrochloride hydrochloride 1- (diphenylmethyl) -1-piperazinyl-pentyl} -1,3-dihydro2H-benzimidazol-2-one are obtained; m.p. 215.3 ° C.

In a similar way, the compounds given in Table 1 are obtained. five.

Table 5

and 5.5 parts (59.3%) of 1- {2 4- (bis- (4-fluorophenyl) methyl -1 -1-piperazinyl} -propyl-1H-benzimidazole) hydrate are obtained; mp 108.4 ° C In a similar manner, the compounds shown in Table 6 are prepared.

Example 23. A mixture of 13 parts of 1,3-dihydro-L 3- (1-piperazinyl) - propyl -2H-benzimidazol-2-one, 12.4 parts of 1,1- (bromomethylene) -bisbenzene, 6.6 parts of carbonate sodium and 200 parts of 4-methyl-2-pentanone when stirpshwapip is refluxed with a water separator for

BUT

 .V

Table 6

.

chi After cooling to room temperature, water is added and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2-oxybispropane and a small amount of 2-propanol to give 1- {3- 4- (diphenylmethyl) -1-piperazinyl propyl-1, 3-dihydro -2H-benzimidazol-2-one; m.p. 153 ° C.

Example 24. According to the method described in Example 23, using the equivalent amounts of the corresponding starting materials, the following compounds were prepared:

(4-bis- (1-fluorophenyl) methyl - - piperazinyl} -ethyl -1,3-dihydro2H-benzimidazol-2-one) hemihydrate; mp 131.5 ° C;

1- {2- 4- (diphenylmethyl) - - piperazinyl ethyl} -1, 3-dihydro-2H-benzimidazol-2-one; m.p.

B- (CH,) p-1T

1- 3- {4-Gbis - (4-fluorophenyl) -methyl -1-piperazinyl) -propyl -1.3-dihydro-2H-benzimidazol-2-one; m.p. 98 ° C. Example 25. A mixture of 4.8 parts of - (3-chloropropyl) -, 3-dihydro-2H-benzimidazol-2one, 6.1 parts of hydrochloric (diphenylmethoxy) -piperidine, 7.5 parts of sodium carbonate and 200 parts of 4-methyl -2-petanone with stirring boil with reverse

fridge with water separator during the first night. The reaction mixture is cooled and water is added. The layers are separated and the 4-methyl 2-peitanone phase is dried, filtered and evaporated. Oily residue

Purified by silica gel column chromatography using chloroform with 5% methanol as eluent.

Table 7

/ AG1

1G-0-CH /

Ag,

21

The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl2-pentanone and 4.2 parts (48%) of 1- | (diphenylmethoxy) -1-piperidinyl propyl} -1.3-dihydro-2H-benzimidazole-2one are obtained; m.p. 149.2 ° C.

In a similar way, the compounds given in Table 1 are obtained. 7

Claims (1)

1. US patent No. 3956328, cl. 260-268, publ. 05/11/76.