FI87561C - Process for the preparation of phenylpiperidinecarbinols and process useful new intermediates - Google Patents

Description

1 37561

Process for the preparation of phenylpiperidine carbinols and new intermediates used in the process

The invention relates to a chemical process for the preparation of phenylpiperidine carbinols and to novel intermediates used in the process.

GB Patent 1,422,263 and U.S. Patent 4,007,196 cover compounds of formula A * <70.

I X A

wherein R 1 is hydrogen, trifluoro- (C 1-4) alkyl, alkyl or alkynyl, R 2 is alkyl or an alkynyl group having 1 to 4 carbon atoms, or a phenyl group substituted with C 1-4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy or then tetrahydronaphthyl and X is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkyloxy.

The pharmacological properties of the compounds of formula A are such that the compounds are well suited for use in antidepressant drugs.

One compound found to be remarkably useful is paroxetine in its [R1 = H, R2 = 5- (1,3-benzodioxyl), X = 4-F] (-) - trans form.

In the aforementioned patents, compounds of formula A are prepared using intermediate of formula B 2 87561 '-QO,.

ch2oh where R1 and X are the same as above.

Piperidine carbinols of formula B are prepared by reduction of the ester of formula C '-QQ. c cooch3 with a complex metal hydride reducing agent.

The compound of formula C is obtained by reacting an arecoline (when R 1 = methyl) or an arecoline homologue with phenyl (or substituted phenyl) magnesium bromide.

The disadvantage of this method is that arecoline is highly irritating and that the ester of formula C is obtained as a mixture of its cis and trans forms.

We have now invented a new process for the preparation of piperidine carbinols which has the advantage of not using arecoline and of selectively obtaining the trans isomer in good overall yield.

According to the invention there is thus provided a process for the preparation of a compound of formula I: 3 37561

F

u | wherein R 3 is hydrogen or methyl, which process is characterized in that a compound of formula II is reduced:

II

✓ n. * COoR4 II 'R3 wherein R3 is as defined in formula I and R4 is alkyl. In formula II, R 4 is preferably ethyl.

The reduction can be carried out in a general manner using a metal hydride, for example, using lithium aluminum hydride or aluminum hydride in an inert solvent such as tetrahydrofuran or a mixture of tetrahydrofuran and toluene.

The compounds of formula I are obtained in their trans form but as a mixture of enantiomers. The compounds may be separated into their enantiomeric forms by any of the methods well known in the art, for example, using an optically active acid such as (+) - 2'-nitrovinianiline acid or (-) - di-p-toluoyltartaric acid.

Compounds of formula I may be used as intermediates in the preparation of compounds of formula A utilizing the methods set forth in GB Patent 1,422,263 or U.S. Patent 4,007,196.

For example, to prepare paroxetine, a compound of formula I wherein R 3 is preferably methyl to protect the nitrogen atom in its (-) - trans form may be reacted first with thionyl chloride or benzenesulfonyl and then with sodium 3,4-methylenedioxyphenoxide. The N-methyl group is then replaced by reaction with phenyl chloroformate, followed by deacylation with KOH to give R3 H.

The invention also relates to novel intermediates of formula II which are (±) -trans-3-ethoxycarbonyl-4- (4'-fluorophenyl) -piperidine-2,6-dione, (±) -trans-3-ethoxycarbonyl -4- (4'-fluorophenyl) -N-methylpiperidine-2,6-dione and (±) -trans-3-methoxycarbonyl-4- (4'-fluorophenyl) piperidine-2,6-dione.

Compounds of formula II may be prepared by reacting a suitable cinnamic acid ester such as an alkyl or aryl ester with an alkyl amidomalonate of formula III wherein R 3 and R 4 are as defined above.

C0, R4 and CH- I 3

CONHR3 III

The reaction can be carried out by condensation in a base / solvent environment such as sodium hydride / dimethyl sulfoxide, cat-tert-butoxide / ethanol or tetrahydrofuran or sodium methoxide or ethoxide / ethyl acetate.

Compounds of formula II may preferably be prepared in a "single pot" reaction by forming an in situ cinnamate from the appropriate benzaldehyde. For example, a suitable alkyl amidomalonate can be added to a mixture of benzaldehyde and sodium methoxide in ethyl acetate.

Compounds of formula II in which R 3 is methyl may also be prepared by conventional methylation of compounds of formula II in which R 3 = H. For example, ester imides of formula II in which R 3 = H may be reacted with a methyl halide in the presence of a dilute base such as potassium carbonate.

The terms "alkyl" mean straight-chain or branched alkyls containing 1 to 6 carbon atoms, especially 1 to 4 carbon atoms.

The following examples illustrate the preparation of the novel intermediates of the invention (Examples 1-4) and the novel process of the invention (Examples 5-9). Temperatures are in degrees Celsius, ° C.

Example 1 (+) - Trans-3-ethoxycarbonyl-4- (4 * -fluorophenyl) piperidine-2,6-dione (E1)

Potassium t-butoxide (1.01 g) was added to a solution of ethyl amidomalonate (1.38 g) in tetrahydrofuran (38 ml), temperature 33 °. After the temperature dropped to 25 °, ethyl 4-fluorocinnamate (1.50 g) was added and the mixture was stirred overnight at room temperature. Brine was added, the mixture was extracted with ethyl acetate (3 x 60 ml) and the organic solution was dried and evaporated to give a crude substance. It was chromatographed on silica gel using dry ether as solvent 6 H 7 561 to give the title compound (0.92 g, 43%), mp 97-99 °.

1 H-N.m.r. (CDCl 3) δ = 1.07 (t, J = 8Hz, 3H) 2.67-3.90 (m, 2H) 3.50-3.84 (m, 2H) 4.00 (q, J = 8Hz) (2H) 6.70 - 7.27 (m, 4H) 8.90 (br.s, 1H)

Example 2 (+) - Trans-3-ethoxycarbonyl-4- (4'-fluorophenyl) -N-methyl-piperidine-2,6-dione (E2) (a) Sodium hydride (80%, 2.6 g) was added slowly to stirred ethyl To -N-methylamidomalonate (11.9 g) in dimethyl sulfoxide (50 mL) under nitrogen. After the evolution of hydrogen ceased and the dark solution was cooled to room temperature, 4-fluorocinnamate (15.3 g) was added in one portion again in dimethyl sulfoxide (10 ml) and the whole was stirred for 19 hours. at room temperature. After extraction with petroleum ether (3 x 16 ml) ... the mixture was stirred and neutralized by the addition of glacial acetic acid (4.9 ml), followed by the addition of ethyl acetate (75 ml) and water (35 ml). The organic solution was separated, washed with brine (30 mL), sodium bicarbonate solution (22 mL) and brine, and finally dried over anhydrous sodium sulfate. Evaporation gave an off-white crystalline solid (22.7 g) which was triturated with isopropyl ether before filtration and drying to give the title compound as a white solid (20.0 g, 86%), mp 91-96 °.

7 · i 7 5 o 1 1H-n.m.r. (CDCl 3) δ = 1.10 (t, J = 8Hz, 3H) 2.75-3.00 (m, 2H) 3.18 (S, 3H) 3.50-3.90 (m, 2H) 4 , 10 (q, J = 8 Hz, 2H) 6.80-7.30 (m, 4H) (b) (±) -Trans-3-ethoxycarbonyl-4- (4-fluorophenyl) piperidine-2 according to E1, 6-Dione (1.0 g) in anhydrous dimethylformamide was stirred and cooled to about 0 ° and methyl iodide (0.67 g) and anhydrous potassium carbonate (0.5 g) were added. The mixture was stirred at 0-2 ° for 7.5 hours, then diluted with water and extracted with ethyl acetate (100 ml). The extract was washed with water, brine and dried over anhydrous sodium sulfate. After evaporation, the title compound was obtained as a pale yellow oil, approximately 90% pure by NMR spectral analysis.

Example 3 (+) - Trans-3-ethoxycarbonyl-4- (4'-fluorophenyl) piperidine-2,6-dione (E3)

A solution of ethylamidomalonate (17.5 g, 1.0 eq. In 70%) in ethyl acetate (50 mL) was added to a solution of ethyl cinnamate (21.6 g, 0.1 M in 90%) in ethyl acetate containing sodium methoxide (7.6 g). (200 ml) for half an hour at 20 ° C. The slurry was stirred for 8 hours at 20 ° and 72 hours at 5 °. The slurry was then added to a mixture of water (200 mL) and acetic acid (2.5 eq.).

After separation of the enriched ethyl acetate, the solution was evaporated under reduced pressure and the product was isolated by crystallization from propan-2-ol with the addition of heptane.

Yield = 5.2 g

8 · 3 7 5 M

The product was a mixture of methyl (20%) and ethyl esters (80%).

The structure was confirmed using NMR and HPLC comparison with the N-methyl equivalent (E2).

Example 4 A solution of (± j-trans-3-ethoxycarbonyl-4- (4'-fluorophenyl) -N-methylpiperidine-2,6-dione (E4) p-fluorobenzaldehyde (100 g) in ethyl acetate (100 ml) was slowly added to the sodium methoxide mixture. (105 g) in ethyl acetate (900 ml) and the temperature was maintained at 10-20 ° C, then stirred for a further 30 minutes at 15-25 ° C. A solution of dried ethyl N-methylamidomalonate (139 g) in ethyl acetate (200 ml) was added. ) Over 1 hour, maintained at 15-25 ° C and stirred for a further 1-2 hours, the resulting mixture was added to acetic acid (120 g) in water (475 ml) and stirred for 15 minutes, the lower aqueous layer was separated and removed. The rich solution was washed with brine (250 mL), the solvent was removed by vacuum distillation and replaced with propan-2-ol and cooled to give the title compound as crystals, water was added (600 mL) over 30 minutes and the mixture was stirred for 1-2 hours. ° C. The product was filtered and washed with water and then isopropyl. It was dried and finally dried.

Yield = 80-90%; Example 5 (i) -Trans-4- (4'-fluorophenyl) -3-hydroxymethyl-N-methyl-: piperidine (E51

Compound E2, (+) - trans-3-ethoxycarbonyl-4- (4'-fluorophenyl) -N-methylpiperidine-2,6-dione (18.0 g) in tetrahydrofuran (80 ml) was added slowly with lithium aluminum hydride. solution (6.0 g) in tetrahydrofuran (40 ml) under nitrogen at a temperature below 40 ° C. After the addition, the reaction mixture was stirred at room temperature overnight, then warmed to 50 ° for about 7 hours and finally stirred at room temperature overnight.

Decomposition was achieved by careful addition of water (30 ml) followed by 10% aqueous sodium hydroxide solution (6.0 ml). The hydrolyzed mixture was stirred for 1.5 hours and then the precipitated salts were filtered off by washing with ethyl acetate (50 ml). The filtrate was dried over anhydrous sodium sulfate and evaporated to give a solid which was triturated with ether, filtered and dried. The title compound was obtained (9.0 g, 65%), mp 122-126 °.

1 H-nmr (DMSO-d 6) δ = 1.56-1.92 (m, 5H) 2.15-2.29 (m, 4H) 2.77-2.85 (d, 1H) 2.88- 2.99 (m, 1H) 3.02-3.14 (m, 2H) 3.38 (s, 1H) 7.06-7.29 (m, 4H);

The title compound E5 (8.6 g) and (+) - 2'-nitrotartranilic acid (10.4 g) were dissolved in warm acetone (70 ml) and then water (1.9 ml) was added. The solution was allowed to cool and stand for two days at 5 ° C, after which the crystallized salt was filtered, washed with acetone and dried in vacuo (7.7 g, 39%).

The salt (7.6 g) was dissolved in water as a suspension, and a slightly larger amount of dilute hydrochloric acid was added to precipitate tartaric acid, which was then filtered and washed with water. The filtrate was basified with sodium carbonate solution and extracted with ethyl acetate (60 ml in total), and the extracts were washed first with sodium carbonate solution, then with water and finally dried over anhydrous sodium sulfate. After evaporation, (-) - trans-4- (4'-fluorophenyl) -3-hydroxymethyl-N-methylpiperidine was obtained as a crystalline substance which was triturated with ether / Petro ether (b.p. 60-80 °), filtered and dried (3 , 1 g, 95%), m.p. 102-103 ° C.

Example 6 (+) - Trans-4- (4'-fluorophenyl) -3-hydroxymethylpiperidine

E1, (±) -trans-ethoxycarbonyl-4- (4'-fluorophenyl) piperidine-2,6-dione (2.0 g) was reduced with lithium aluminum hydride (0.58 g) by refluxing in tetrahydrofuran 4 hours. Following the procedure of Example 5, the title compound was obtained as a solid (0.28 g, 22%).

Example 7 (+) - Trans-4- (4'-fluorophenyl) -3-hydroxymethyl-N-methyl-piperidine (E7)

Compound E4 (3.4 g) in toluene (150 ml) was slowly added to a slurry of lithium aluminum hydride (10 g) in a mixture of tetrahydrofuran-1 (50 ml) / toluene (150 ml) under nitrogen at room temperature. at 0-5 °. (Commercially available ready-made solutions of lithium aluminum hydride in tetrahydrofuran / toluene have also been used successfully). The mixture was stirred for an additional 1-5 hours and then allowed to warm to 15-25 ° C overnight. Excess lithium aluminum hydride was removed by • careful addition of water (10 mL), the mixture was diluted to 15% with sodium hydroxide (10 mL) and water (30 mL). The solids were then removed by filtration and reslurried in toluene (100 mL). The combined rich toluene layers were concentrated (75 mL) and poured into petroleum ether [100-1200] (25 mL). After stirring for 8-24 hours, the product was isolated by filtration, washed with Petro-ether (10 ml) and dried.

Yield = 65-75%.

Example 8 (-) - Trans-4- (4'-fluorophenyl) -3-hydroxymethyl-N-methylpiperidine

Compound E7 (5 g) was dissolved in acetone (50 ml) and added to a solution of (-) - di-p-toluoyl tartaric acid (11.25 g) in acetone (50 ml) at 15-25 ° C. The mixture was stirred for 1 hour at 15-25 ° C and then for another 1 hour at 0-10 ° C. The crystalline salt was filtered, washed with acetone and dried.

Yield = 40-45%.

The salt (6 g) was suspended in water and methylene chloride (MDC). (-) - Trans-4- (4'-fluorophenyl) -3-hydroxymethyl-N-methylpiperidine was extracted into MDC using sodium hydroxide. Evaporation of the rich MDC gave an oily substance which was redissolved in toluene. The toluene was removed by evaporation to give an oil.

After addition of heptane and trituration, a crystalline solid was obtained which was filtered and dried.

26

Yield = 85-89% [α] = 35 ° (c = 1% in methanol)

D

Example 9 (+) - Trans-4- (4'-fluorophenyl) -3-hydroxymethyl-N-methyl-piperidine (E9)

Lithium aluminum hydride (3.24 g; 0.085 mol) was added with stirring to dry tetrahydrofuran (200 ml) at 0 ° C under nitrogen. Concentrated sulfuric acid (2.16 ml) was added dropwise and the mixture was stirred at 0 ° C for 1 hour to give an aluminum nihydride solution. The imide (E2, 10.0 g; 0.034 mol) was added as a solution in dry tetrahydrofuran (199 ml) and the mixture was stirred for 4-5 hours at 0-5 ° C, then overnight at room temperature. Sodium hydroxide (16.2 ml of 40% aqueous solution) was added and the resulting precipitate was filtered and washed. Filtration was performed several times to remove turbidity and then the filtrate and washed precipitate were evaporated in vacuo to give an orange oily substance (6.9 g, 92%) which could be crystallized from ether, mp 122-123 ° C.

Claims (3)

13 97 561 A process for the preparation of a compound of the formula I: F jossa 1 .CH 2 OH (7 r 3 with hydrogen or methyl, characterized in that a compound of the formula II is reduced: F ό II, co 2 r 4 XI «3 in which R 1 has the same meaning as in the formula I and R4 are alkyl. Process according to Claim 1, characterized in that the reduction is carried out with a metal hydride reducing agent. A compound which is (±) -trans-3-ethoxycarbonyl-4- (4'-fluorophenyl) -piperidine-2,6-dione, (±) -trans-3-ethoxycarbonyl-4- (4'-fluorophenyl) ) -N-methyl-piperidine-2,6-dione, or (±) -trans-3-methoxycarbonyl-4- (4'-fluorophenyl) -piperidine-2,6-dione. 14 87 561