SU464997A3 - Method for preparing -aryl-4-substituted piperidino-alkanol derivatives - Google Patents

Description

This invention relates to a process for the preparation of new compounds that can be used in medicine. Using the well-known methods for reducing the carbonyl group, a number of new compounds with useful biological activity have been obtained. The described method for the production of a-aryl-4-substituted piperidino-alkanol derivatives of the general formula OH CH2) No. -2 where R is hydrogen or hydroxyl; R is hydrogen, or R and R, taken together, form a double bond between the carbon atoms attached to R and R; n is an integer from 1 to 3; Z is thienyl, phenyl or substituted phenyl, where the substituent may be attached at the ortho, meta or para position of the phenyl ring, and is halogen, straight or branched lower alkyl with 1-4 carbon atoms, lower alkoxy with 1-4 carbon atoms, a di (lower) alkylamino group or a saturated monocyclic heterocyclic group selected from the group consisting of pyrrolidine, lipidin, morpholine or N- (lower) alkylpiperazine, or their salts, is that in aryl - 4- substituted piperidino-alkylketone general The formulas (where R, R, and Z have the indicated meanings are subjected to the reduction of the keto group. Sodium borohydride such as sodium borohydride may be used as a reducing agent. The reaction is carried out in a solvent, for example, in methanol, isopropyl dross, tert-butanol, at a temperature of, for example, from 0 ° C to the boiling point of the solvent. The reaction time is usually from 30 minutes to 8 hours. Other reducing agents can be used, for example lithium aluminum hydride and diborane, in an environment such as diethyl ether ir The reaction can also be carried out by catalytic reduction with Raney nickel, a palladium, platinum or rhodium catalyst in an environment of lower alcohols, acetic acid or in their aqueous solutions, or using aluminum isopropylate in isopropanol. Salts of the desired products can be obtained via neorgapicheskih and organic acids such as hydrochloric, hydrobromic, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, oksimaleinova and day-oksimaleimova, and benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, aitranilova, cinnamic, salicylic, 4-s) Osalitsilova, fenoksibenzoypa-2, 2-atsetoksibepzoyna, mandelic acid, sulfonic acids such as methanesulfonic , ethanesulphonic acid, p-hydroxyethanol). Example 1. a- (l-treg-butylphenyl) -4- (aoxy-o-phenyl-benzyl) -1-niperidinobutanol. To 60 g (0.12 mol) of hydrochloric 4-Greg-butyl-4-4- (a-hydroxy-a-phenylbenzyl) piperidino-butyrophenone, dissolved in 1200 ml of methanol, methanol potassium hydroxide is added until the solution will not become alkaline. The solution is then cooled in ice (ice bath) with stirring and 5 g (0.13 mol) of sodium borohydride is added dropwise. The mixture is stirred for half an hour and allowed to warm to room temperature, then heated on the steam bath for 30 minutes. The solvent is removed under reduced pressure, the residue is washed with water and recrystallized from acetone to obtain the desired product with a m.p. 146.5-148.5 ° C. The compound can also be obtained by reducing the pressure of. M under a hydrogen pressure of 2 atm in the presence of a rhodium catalyst on charcoal for about 3 hours of the corresponding butyrophenone derivative dissolved in methanol. After the reduction reaction, the catalyst is removed by filtration. The remaining material is concentrated to a solid, which is purified by recrystallization to obtain the desired product. Example 2. 4- (Diphenylmethylene) - a - (/ gfluorophenyl) - - (piperidinobutanol) - hydrogen chloride (hydrochloride, hydrochloride). To 12 g (0.029 mol) of 4-fluoro-4- (4-diphenylmethylene piperidino) -butyrophenone, dissolved in 1000 ml of isopropyl alcohol, 1 g (0.027 mol) of sodium borohydride is added. The compound is left to stand for 45 minutes, after which it is brought to a boil. The solvent is removed and the residue is triturated in water, then with petroleum ether and filtered off. The residue is recrystallized from a mixture of ether and petroleum ether to obtain 4- (diphenylmethylene) -a - (/ g-fluorophenyl) -1-piperidinobutanol, which is then converted to the hydrochloride salt with mp. 193-. Example 3. 4- (a-hydroxy-a-phenylbenzyl) a- (fluorine phenyl) -1-pineridinobutatsol. To 43.14 g (0.1 mol) of 4-fluoro-4- 4- (a-hydroxy-aghenylbenzyl) -piperidino-butyrophenoia, pacTBOpeHHOio in 3 l of methanol, add 3.78 g (0 , 1 mole) sodium borohydride. The mixture was left to stand at room temperature for 1 hour, after which the solvent was removed under reduced pressure, while the mixture was heated in a new bath. The residue is dissolved in ether - water and separated. The ether layer is washed with water, dried over anhydrous magnesium sulfate and filtered. The ether is evaporated and petroleum ether is added. The resulting precipitate is recrystallized from ether and the required product is obtained with t. 114.5 - 16.6 ° C. Example 4. 4-a- (hydroxy-a-Fepilbepzil) -a (2-thienyl) -1-piperidinobutanol. To 15.1 g (0.03 mol) -chloride (a-hydroxy-a-phenylbenzyl) -niperidino 1- (2-thienyl) -butanol-1-one, dissolved in 600 ml of methanol, add potassium hydroxide to as long as the solution is not alkaline. 4 g (0.11 mol) of sodium borohydride is added portionwise to this solution, and the mixture is left to stand overnight. The solvent is removed by a steam bath and 150 ml of water is added to the residue, which then solidifies. The solid is filtered off, washed with water and recrystallized from a: cetone and hexane to obtain the desired product with m.p. 134-136 ° C. Example 5. Sat- (p-Bromophenyl) -4- (a-hydroxy-athenylbenzyl) -1-piperidinobutanol. To 23 g (0.044 mol) of 4-bromo-4-4 - (-, a - hydroxy-a - phenylbenzyl) -piperidino-butyrophenone hydrochloride dissolved in 900 ml of methanol, which is pretreated with an excess of an alcohol solution of CPC and cooled to 0 ° C , 4 g (0.11 mol) of sodium borohydride was added. The mixture is stirred for 15 minutes. The reaction temperature is about

0 ° C and then slowly brought to room temperature. The solvent is removed and water is added. The resulting oil is extracted into toluene, dried over magnesium sulfate, and filtered. The filtrate is concentrated to 100 ml volume and then 250 ml 75-90-hail petroleum ether is added, and the material is cooled. The precipitate is recrystallized from 75-90-hail petroleum ether and acetone to obtain the desired product with so pl. 134-137 ° C.

Example 6. Hydrochloride a- (p-bromophenyl) -4- (diphenylmethylene) -1 - piperidinobutanol.

To 7.3 g (0.019 mol) of 4-bromo-4- (4-diphenylmethylene piperidino) -butyrophenone hydrochloride dissolved in 1500 ml of methanol, methanol KOH is added until the solution is alkaline, after which 2 g (0.053 mole) sodium borohydride.

The mixture is left for 3 hours, then the methanol is removed by heating under reduced pressure. Water was added to the residue, and the resulting solid was collected by filtration and dissolved in ether. The ether solution is dried over anhydrous magnesium sulphate and filtered. The filtrate is treated with ethereal HCl, and the resulting precipitate is recrystallized from a mixture of methanol and ethyl acetate to obtain the desired product with m.p. 215-217 ° C.

Example 7. 4- (Diphenylmethyl) -a-phenyl-1-piperidinobutanol.

Raw material

Example

(a-hydroxy-a-phen. 1Lbenz11L) piperidino-butyrofenone hydrochloride with m. pl. 193.5-195 ° G

(-Oxy-21-phenylbenzyl) p. 1 peridino-4-methyl-butyrophenone hydrochloride with m.p. 236-237 0

4-Fluoro-4- 4- (-oxy-athenylbenznl) -nnperid1she butyrophenone hydrochloride with m. Pl. 171-174 0 Analogously to example 2, but only by replacing 4-fluoro-4 - (4 - diphenylmethylene niperidino) - 35 butyrophenone with an appropriate amount

Example

Source material

4-Fluoro-3- 4- (a-oxn (-phenylbenzyl) -piperidino propiophenone with mp 250 ° C

(a-hydroxy-a-phenylbenzyl) piperidino-4-piperidinobut-11-phenenone with m. pl. 137.5-139С

A mixture of 39.76 g (0.1 mol) of 4- (4-diphenylmethylpiperidiio) -butyrophenone, 3 liters of isopropyl alcohol, 500 microns of methanol and 8 g (0.21 mol) of sodium borohydride is left

stand at room temperature for 63 hours. The solvent is removed under reduced pressure, after which 1 l of water is added. The resulting solid is filtered and recrystallized from petroleum ether to give the desired product with mp. 122.5-124.5 ° C.

Example 8. 4- (Diphenylmethyl) -a- (l-fluorophenyl) -1-piperidinobutanol.

To a mixture of 45.2 g (0.1 mol), hydrochloride

4-fluoro-4- (4-diphenyl-methylpiperidino) -butyrofenone, 2500 ml of thermal isopropyl alcohol and 5.6 g of KOH are added 4 g (0.105 mol) of sodium borohydride. The mixture is left to stand for 30 minutes, after which the

4 g (0.105 mole) of sodium borohydride. All are left to stand for 1 hour and then heated to boiling. The solvent is removed in vacuo and water is added to the solid residue. The solid is collected on a filter, washed with water and recrystallized from 75-90-degree petroleum ether to obtain the desired product with m.p. 129-131 ° C. Analogously to example 1, but only replacing 4-greg-butyl-4-4-a - hydroxy-a-phenylbenzyl) -piperidino butyrophenone hydrochloride with the corresponding amount of one of the starting materials listed in table. 1, receive the products listed there.

T a b l II c a 1

Product

4- (a-hydroxy-phenylbenzyl) cc-phenyl-1-piperid1. Nebutanol

4- (cc-hydroxy-g-phenylbenzyl) a- (l-methylphenyl) -1-piperidine Jb tanol

a- (l.fluorophen: 1l) -4- (-ox11-a-phen, 1lbenzyl) -1-piperid11Nebutan,) l

Product

a; - (/ g-fluorophenyl) -4- (1-ox11-2-phenylbenzyl) -1-piperidinopropanol

4- (o-oxy-a-phenylbenzyl) -a (p-piperidinophenyl-1-piperid1ShEbutanol of one of the starting materials listed in Table 2 gives the products listed there. Table 2

The subject of the invention 1. The method of obtaining

.., a-aryl-4-substituted

piperidino-alkanol derivatives of total

FIDI

formulas

OH (CH2) l-CH-2

where R is hydrogen or hydroxyl; R is hydrogen or R and R, taken together, form a double bond between carbon atoms, attached to R and R;

n is an integer from 1 to 3;

Z is thienyl, phenyl or substituted phenyl, where the substituent may be attached at the ortho, meta or para position of the phenyl ring, and is a halogen, straight or branched lower alkyl

with 1-4 carbon atoms, lower alkos 1-4 carbon atoms.

xygroup., ,,

di (lower) alkylamino or saturated monocyclic heterocyclic group selected from the group

containing morpholine or pyrrolidine, piperidine, N- (lower) alkylpiperazine,

or salts thereof, characterized in that in the aryl-4-substituted piperidinoalkyl ketone of the general formula

(

where R, R p and Z are as defined above,

subjected to reduction of the keto group in the solvent, followed by isolation of the α-target product by a known method.