SU1109390A1 - Process for preparing 4-phenyl-4-piperidinol - Google Patents

Abstract

A method for producing 4-Fensh1-4Piperidinol, characterized in that, in order to simplify the process and increase the yield, 1-methyl4-piperidone is reacted with an equimolar amount of ethyl chloroformic acid in boiling benzene solution, to form 1-carboethoxy-4 Piperidone acts with a double amount of phenylmagnesium bromide in dibutyl ether in a stream of inert gas at room temperature followed by V-decarboethoxylation of 1-carboethoxy-4-phenyl-4-piperidinol obtained with an alcoholic solution of potassium. ; About 10 UD

Description

This invention relates to a process for the preparation of 4-phenyl-4-piperidinol, which is an intermediate in the synthesis of pharmaceutical and other biologically active preparations.

A known method for the preparation of 4-phenyl-4-piperidinol involves the condensation of 0-methylstyrene, formaldehyde, and ammonium chloride. The resulting 6-methyl-6-phenyltetrahydro-1, 3-oxazine is heated with an excess of hydrochloric acid to obtain D-phenyl-1,2,3,6-tetrahydropyridine, the latter being hydrobromized, the resulting 4-phenyl-4-bromo-piperidine hydrobromide by hydration t to 4-phenyl-4-1iperidine. The yield of 4-phenyl-4-piperidinol is 22.5% on e / methyl tyr ol Sz 3.

The disadvantage of the known method of producing 4-phenyl-4-piperidinol is multistage, the use of lightly polymerizable o-methyl O

CgHsMgBrp SL.R-R

ClCOOCgHg

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СООед COOCjHs

sns

sh

P

Example. Getting 4-phenyl-4-piperidine.

In a three-necked round-bottomed flask equipped with a reflux condenser, mechanical stirrer, and a dropping funnel, 109 g (1.0 mol) of freshly distilled chloroformic acid ethyl ester in 300 ml of dry benzene and 113.2 g (1, 0 mol) 1-methylpiperidone-4 (II). The mixture was boiled for 5 hours and left for 16 hours. The benzene was distilled off and the residue was distilled in vacuo. Obtain 128.36 g (75% of theoretical) 1-carbethoxy4-piperidone (111) with so kip. 138140 with 12 mm, 1.4716. Literature. Data: bp.149-151 ° C / 24 mm C4J

In a three-necked round-bottomed flask, equipped with a reflux condenser with a chlor-calcium tube, a mechanical stirrer and an addition funnel, A9 g (0.27 mol) of freshly prepared phenylmagnesium bromide is placed

styrene, aggressive hydrogen bromide and a low yield of the target product (22.5%).

The aim of the invention is to simplify the process and increase the yield.

This goal is achieved in that according to the method for preparing 4-phenyl-4-piperidinol (1) by reacting 1-methyl-4-piperidone (P) with ethyl chloroformate in a boiling solution of benzene to form 1-carbethoxy-4-piperidone (111) act as double amount of phenylmagnesium bromide in dibutyl ether in a stream of inert gas at room temperature followed by N-decarbethoxylation of the obtained 1-carbethoxy-4-phenyl4-piperidinol (IV) with an alcohol solution of potassium hydroxide to 4-phenyl-4-piperidinol (1)

but Sat1%

but sbnz but

b

L. J con

N

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well

in 200 ml of dibutyl ether and in a stream of argon, 25.13 g (0.14 mol) of 1-carbethoxy-4-piperidone (111) are added dropwise with stirring over 40 minutes. The reaction mixture was stirred for 5 hours at room temperature and left for 16 hours. Then, with external cooling for one hour, 200 ml of a saturated aqueous solution of ammonium chloride was added to the reaction mixture, the ether layer was separated and dissolved over magnesium sulfate. Dibutyl ether is distilled off, the product is crystallized from ethanol, 23.8 g (68.2% of theory) of 1-carbethoxy-4phenyl-4-piperidinol (IV) are obtained with mp, 154155 ° C, R {0.36 ( eluent sulfur ether: petroleum ether 2: 1) (1 11 degrees of activity). Literary data (1U) so pl. 154 5.

In a round bottom flask equipped with a reflux condenser and a mechanical solvent, place the reaction mixture of 4.8 g (0.086 mol) of caustic 111093 potassium in 40 ml of ethanol and 7.5 g (0.03 mol) of 1-carbethoxy-A-phenyl-4-piperndinol ( 1U) with m.p. ISA-ISS C and boil with stirring for 5 hours. The progress of the reaction is monitored by those and GLC. The alkaline solution is diluted with 50 MP of water, extracted with chloroform, the extract is dried with anhydrous potash, chloroform is distilled off and 3.8 g (71.4% of theory) of 4-phenyl-4-piperidinol are obtained (O with mp 158-16 C. The total yield (IV) on the basis of (II) is 36.5%. Received 4-fenst-4-piperidinol (O does not show a melting point depression in the mixing sample with the sample obtained in a known manner Compared with the known method C3J, the proposed The method has the following advantages: a higher yield of 4-phenyl-4-sh1peridinol (1) is 36.5% versus 22.5%, contains fewer stages and d Its implementation does not use easily polymerized o-methylstyrene and aggressive hydrogen bromide as a raw material for the synthesis is available commercial product 1-methyl-4-piperidone (P) 6.

Claims (1)

METHOD FOR PRODUCING 4-PHENYL-4PIPERIDINOL, characterized in that, in order to simplify the process and increase yield, 1-methyl4-piperidone is reacted with an equimolar amount of chloroformic acid ethyl ester in a boiling benzene solution to form 1-carboethoxy-4-piperium act with a double amount of phenylmagnesium bromide in dibutyl ether in an inert gas stream at room temperature followed by / V-decarboethoxylation of the obtained 1-carboethoxy-4-phenyl-4-piperidinol with an alcoholic solution of potassium hydroxide. £ 1 109390