SU508502A1 - The method of obtaining derivatives of-cinnamyl-4-phenylpiperidine or their salts - Google Patents

Description

(54) METHOD OF OBTAINING DERIVATIVES OF M-TSINNAMIL-4-PHENYLPIPERIDINE OR THEIR SALTS

one

This invention relates to an improved process for the preparation of piperidine N-cinnamyl derivatives, which can be used in pharmaceutical industry.

A known method for the preparation of N-cinnamyl-4-phenyl-4-acyloxypiperidines is that the primary amine is condensed with 2 moles of acrylic acid methyl ester, the resulting diester is subjected to Dicman cyclization followed by hydroxy, and decarboxylation, the resulting polymeric 4-in in interaction with phenyllithium and then acylated with the corresponding anhydride and the desired product is isolated as a salt.

CHoCH CHCeHs

where R is hydrogen or lower acyl;

RI and R2 are hydrogen or lower alkyl, or their salts, consisting in that a compound of the general formula

However, the known method is characterized by a low yield of the target product (below 20%), a multistage process and low availability of intermediate N-substituted piperidones 4.

In order to increase the yield of the target product and simplify the process, a method for producing N-cinnamyl-4-phenyl-piperidine derivatives of the general formula is proposed.

SNGS5S-SbN5

where R, RI, R2 are the indicated values, subjected to selective catalytic hydrogenation in the presence of 5% palladium catalyst on calcium carbonate, followed by separation of the target product as a base or salt.

The yield of the target product by the proposed method is usually not lower than 90% of theoretical.

The individuality of the products obtained is confirmed by the data of TLC of elemental analysis and IR spectroscopy.

The advantage of the proposed method is also the possibility of easily obtaining non-5 compounds described in the literature.

Example 1. N-cinnamyl-4-phenyl-4-propionyloxypiperidine hydrochloride.

A solution of 2.0 g of hydrochloride 1 - (phenylpropargyl) - 4 - fesch - 4 - g of propioxycholipiperidine (mp 132-133 ° C, Rf 0.45) in 80 ml of absolute ethanol is introduced into the duck for hydrogenation, where 0.2 g of palladium catalyst, which is supported on calcium carbonate with the content of active metal in 50 ml of 15 absolute ethanol, is saturated with hydrogen and hydrogenated at 20 ° C and atmospheric pressure with vigorous shaking. After absorption of 1 mol of hydrogen (14) ml, the hydrogenation is terminated, the catalyst is filtered off, and washed several times with 2-ethanol. The alcoholic solution is evaporated and the residue is crystallized from a mixture of ethanol and ether to obtain 1.9 g (94.6%) of N-treshamyl- hydrochloride. 4 phenyl - 4 - propionyloxypiperidine with m. Pl. 168-169 ° C; Rf 0.52 (, 11 degree of activity, eluent - ether; petroleum ether 2: 1).

Found,%: C 71.44; 71.74; H 7.60; 7.80; N3.45; 3.58; C19.45; 9.28.

C23H28CINO2.

Calculated,%: 71,58; H 7.31; N 3.63; C1 9.19. zo

PRI mme R 2. Hydrochlori / t N - di1 shamyl - 2, 3 and methyl - 4 - feshl - 4 - propionylox1 shiperidia.

A mixture of 4.0 g of M-7-phenylpropargyl-2, 3 dimethyl-4-phenyl-4-oxi-piperidine, 28.2 ml of propionic anhydride and 8 ml of propionic acid 35 is heated at 110-120 ° C for 25 hours. After oh; (the reaction mixture is diluted with water, neutralized with aqueous ammonia solution, extracted several times with ether, dried, the solvent is removed and propionic sufir is obtained in the form of a 40 yellow oil, which is not allowed to crystallize.

The hydrochloride is obtained in a yield of 45.6% of theoretical by treating the base with an ethereal solution of hydrogen chloride; 45 small colorless crisgalls with so-called. 152-154 C (from ethyl acetate), Rf 0.62 (A12Oz, III degree of activity, eluent - ether: petroleum ether 1: 1).

Found,%: C 72,16; 72.42; H7.75; 7.88; N 3.10; 3.19; C18.02; 8.48. 50

C sHjoCINDz.

Implanted,%: C, 72.88; H7.34; N 3.39; C1 8.60.

A solution of 0.9 g of hydrochloride salt N-7-phenylpropargyl 2, 3-dimethyl-4-phenyl-4-propionyloxy-55 peridine in 5p ml of absolute alcohol is added to the duck for hydrogenation, where it is pre-saturated with hydrogen in 10 ml of alcohol 0.12 g of palladium catalyst supported on calcium carbonate containing 5% palladium and hydrogenated at 2 (f C and atmospheric pressure 60

Lesh with vigorous stirring. After absorbing the theoretically calculated amount of hydrogen, 72 ml of hydrogenation is terminated, the catalyst is filtered off and washed several times with hot ethanol (5 ml each). The alcoholic solution is evaporated and the crystallization of the residue from ethyl acetate yields 0.76 g (80.0%) of N-cinnamyl-2, 3-dimethyl-4-phenyl-4 propionyloxypiperidine hydrochloride with m.p. 184-18 C; Rf 0.52 (ether: petroleum ether 1: 1).

Found,%: C 72.86; 72.52; H7.97; 8.03; N3.41; 3.73; C1 8.68; 8.56.

QisHaaCINOz.

Calculated,%: C72,53; H7.79; N3.38; C1 8.56.

Example 3. Getting N - cinnamyl - 2, 3 dimethyl - 4 - phenyl - 4 - hydroxypiperidine.

To the etrioma, phenyllithium, prepared according to the usual procedure from 2.6 g of lithium wire and 29.27 g of bromobenzene in 350 ml of absolute ether, is added over 1.5 hours while cooling (-10 ° C) and moving in a stream of dry argon a solution of 30 g of N - u-phenylpropargyl-2, 3 - dimethylpiperidone - 4 (mp. 57-58 ° C) in 200 ml of absolute ether. Then the reaction mass is stirred for 3 hours at the boiling point of ether, cooled at -l (f C and hydrolyzed with 100 ml of water. The ether layer is separated, the aqueous layer is extracted with ether, the ether extracts are combined, magnesium sulfate and evaporated. Completely crystallized the residue (37.7 g, 94.9%) upon chromatography in a thin layer of alumina shows the presence of one spot with Rf 0.45 (eluent: ether: petroleum ether 1: 1). By recrystallization of the residue from benzene, 30.18 g are obtained (76%) N - 7 - phenylpropargyl - 2, 3 dimethyl - 4 - phenyl - 4 - hydroxypiperidine; with t. Pl. 141-141, S.

Found,%: C 83.00; 83.09; H8.12; 7.93; N4.15; 4.40.

QjzHjsNO.

Calculated,%: C 82.72; H 7.89; N 4.38.

Hydrochloride is obtained in quantitative yield by treating the base with an ethereal solution of hydrogen chloride; small colorless crystals with m. pl. 205-20 C (from a mixture of alcohol and ether).

Found,%: C 74.55; 74.33; H7.46; 7.30; N4.00; 3.91.

C22H2sNO “HCI.

Calculated, -: C 74,24; H 7.36; N 3.90.

Claims (1)

A solution of 6.0 g of N-7-phenylpropargyl-2, 3-dimethyl-4-phenyl-4-hydroxypiperidine in 150 ml of absolute ethanol is introduced into the duck for hydrogenation, where it was pre-saturated with 0.3 g of hydrogen with a 5% palladium catalyst per calcium carbonate in 50 MF1 absolute ethanol and hydrogenated at room temperature and atmospheric pressure with vigorous shaking. After uptake of one mole of hydrogen, the catalyst is filtered off and the alcoholic solution is evaporated. Lromatography on a thin layer of alumina oily residue (5.94 g, 98.5%) shows the presence of only one product with Rf 0.25 (petroleum ether: ether 1: 1), when recrystallization of which is obtained from petroleum ether analytically pure sample N - cinnamyl - 2, 3 dimethyl - 4 - phenyl - 4 - oxaxperidine with m. GO1. 82-8 C. Found,%: C 82.62; 82.30; H8.79; 8.87; N4.20; 4.39; SagNgTMO. Calculated,%: G N 8,46; N 4.35. Hydrochloride - colorless crystals with so pl. 49-50 ° C (from a mixture of ethyl acetate and ether). Claims 1. Method for producing N-cinnamyl-4-phenylpiperidazn derivatives of the general formula CHiCHCHCeHs where R is hydrogen or lower acyl; RI and RZ are hydrogen or lower alkyl, or their salts, characterized in that, in order to increase the yield of the target product and simplify the process, the compound of the general formula CftHs OR X ШгСнС-СБН5 where R, RI, Ra have these values, is selectively catalytic hydrogenation in the presence of 5% palladium catalyst on calcium carbonate, followed by isolation of the target product as a base or salt.