NO174294B - Methods and intermediates for the production of piperidinecarbinols - Google Patents

Description

The invention relates to a new chemical process for the production of aryl piperidine carbinols as well as new intermediate products used in this process.

British Patent No. 1,422,263 and US Patent No. 4,007,196 disclose compounds of formula A:

where R<1> represents hydrogen, trifluoro(C1.4)-alkyl, alkyl or alkynyl, R<2> represents an alkyl or alkynyl group with 1-4 carbon atoms, or a phenyl group optionally substituted with C1.4-alkyl .

The compounds of formula A are said to have pharmacological properties that make them useful as anti-depressants.

One compound that has proved particularly valuable is paroxetine [R<1> = H, R<2> = 5-(1,3-benzdioxylyl), X = 4-F] which is in

(-)-trans configuration on.

In the above-mentioned patents, the compounds of formula A are prepared using an intermediate of formula B:

where R1 and X are as defined above.

The piperidine carbinols of formula B are prepared by reduction of an ester of formula C:

with a complex metal hydride reducing agent.

The compound of formula C is obtained by reacting arecoline (if R<1> = methyl) or arecoline homologues with phenyl (or substituted phenyl) magnesium bromide.

This method has the disadvantage that arecoline is a strong irritant and that the ester of formula C is obtained as a mixture of cis- and trans-configuration compounds.

We have now discovered a new process for the preparation of piperidine carbinols which advantageously avoids the use of arecoline and selectively produces the trans isomer in good overall yield.

Accordingly, the present invention provides a process for the preparation of a compound of formula (I).

where R 3 is hydrogen or methyl,

and the method is characterized in that a compound of

formula (II)

wherein R3 is as defined with respect to formula (I), and R<4> is alkyl, is reduced with a metal hydride.

The reduction is carried out e.g. by using lithium aluminum hydride or aluminum hydride in an inert solvent, e.g. tetrahydrofuran, or in a tetrahydrofuran/toluene mixture.

The compounds of formula I are obtained in the trans configuration, but as a mixture of enantiomers. The compounds can be resolved in their enantiomeric forms by conventional methods, e.g. by using an optically active acid, e.g. (+)-2<1->nitrotartranilic acid or (-)-di-p-toluoyltartaric acid.

The compounds of formula I can be used as intermediates in the preparation of compounds of formula A by methods which appear in GB patent no. 1422263 or US patent no. 4007196.

For example, to prepare paroxetine, the compound of formula I in the (-)-trans configuration is reacted with thionyl chloride or benzenesulfonyl chloride and then with sodium 3,4-methylenedioxyphenoxide. Afterwards, the N-methyl group is replaced by reaction with phenylchloroformate followed by deacylation with KOH to obtain R<3> = H.

The intermediate products according to the invention are specified in claims 2-4.

The compounds of formula II can be prepared by reacting suitable cinnamic acid esters, e.g. alkyl and aryl esters, and alkyl amido malonates of formula III where R<3> and R<4> are as defined previously.

The reaction can be carried out as a condensation reaction in a base/solvent system, e.g. sodium hydride/dimethyl sulfoxide; potassium tert-butoxide in ethanol or tetrahydrofuran; or sodium methoxide or ethoxide in ethyl acetate.

Compounds of formula II are advantageously prepared as a one-pot reaction which forms the cinnamate in situ from the appropriate benzaldehyde. For example, the appropriate alkyl amidomalonate is added to a mixture of benzaldehyde and sodium methoxide in ethyl acetate.

Compounds of formula II where R<3> = methyl can also be prepared by conventional methylation of compounds of formula II where R3 -= H. For example, ester-imides of formula II where R<3> = H can be reacted with methyl halide in the presence of mild bases, e.g. potassium carbonate.

The following examples illustrate the production of intermediate products according to the invention (examples 1-4) and the new method according to the invention (examples 5-9). Temperatures are in "C.

Example 1

( ±)- trans- 3- ethoxycarbonyl- 4-( 4'- fluorophenyl)

piperidine-2,6-dione (El) (intermediate)

1.01 g of potassium t-butoxide was added to a solution of 1.38 g of ethyl amidomalonate in 38 ml of tetrahydrofuran, maintained at 33°. After cooling to 25°, 1.50 g of ethyl 4-fluorocinnamate was added and the mixture stirred overnight at room temperature. Brine was added and the mixture extracted with ethyl acetate (3 x 60 ml) and the organic solution dried and evaporated to give the crude product. This was chromatographed on silica gel, with dry ether as eluent, to give the title compound (0.92 g, 43%), m.p. 97-99°.

^- n. m. r. ( CDC1,)

6 = 1.07 (t, J=8Hz, 3H)

2.67-2.90 (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 ) ( intermediate) (a) Sodium hydride (80%, 2.6 g) was added slowly to a stirred solution of 11.9 g of ethyl N-methylamidomalonate in 50 ml of dimethylsulfoxide under nitrogen. After hydrogen evolution had ceased and the dark solution cooled to room temperature, 15.3 g of ethyl 4-fluorocinnamate was added in one portion together with a further 10 ml of dimethylsulfoxide and the whole was stirred at room temperature for 19 hours.

After extraction with petroleum ether (3 x 16 ml), the mixture was stirred and neutralized by the addition of 4.9 ml of glacial acetic acid, followed by the addition of 75 ml of ethyl acetate and 35 ml of water. The organic solution was separated, washed with 30 ml of brine, 22 ml of sodium bicarbonate solution 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 crystalline solid (20.0 g, 86%), m.p. 91-96°.

tøn- n. m. r. ( CDC1,)

S = 1.10 (t, J=8Hz, 3H)

2.75-3.00 (m, 2H)

3.18 (p, 3H)

3.50-3.90 (m, 2H)

4.10 (q, J=8Hz, 2H)

6.80-7.30 (m, 4H) (b) A solution of 1.0 g of the compound E1 (±)-trans-3-ethoxycarbonyl-4-(4'fluorophenyl)piperidine-2,6-dione in anhydrous dimethylformamide was stirred and cooled to approx. 0°, and 0.67 g of methyl iodide and 0.51 g of anhydrous potassium carbonate were added. The mixture was stirred at 0-2° for 7.5 hours, after which it was diluted with water and extracted with 100 ml of ethyl acetate. The extract was washed with water, brine and dried over anhydrous sodium sulfate. Evaporation gave the title compound as a pale yellow oil, approx. 90% pure by n.m.r. spectroscopy,

Example 3

( ± )- trans- 3- ethoxycarbonyl- 4-( 4'- fluorophenyl)-

piperidine-2.6-dione (E3) (intermediate)

A solution of ethylamidomalonate (17.5 g, 1.0 eq. at 70%) in 50 ml ethyl acetate was added to a solution of ethyl cinnamate (21.6 g, 0.1 ml at 90%) in 200 ml ethyl acetate containing 7 .6 g of sodium methoxide during 0.5 hour at 20°C. The slurry was stirred for 8 hours at 20°C and 72 hours at 5°C. The slurry was then set

to a mixture of 200 ml of water and 2.5 eq. acetic acid.

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

Yield = 5.2 g

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

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

Example 4

( ±)- trans- 3- ethoxycarbonyl- 4-( 4'- fluorophenyl)- N- methyl- piperidine- 2. 6- dione fE4) (intermediate)

A solution of 100 g of p-fluorobenzaldehyde in 100 ml of ethyl acetate was added slowly to a mixture of 105 g of sodium methoxide in 900 ml of ethyl acetate, the temperature was maintained at 10-20°C and stirring was carried out for a further 30 minutes at 15- 25°C. Then a solution of 139 g of dried ethyl N-methylamidomalonate in 200 ml of ethyl acetate was added over 1 hour while maintaining the temperature at 15-25°C and stirring for a further 1-2 hours. The resulting mixture was added to a solution of 120 g of acetic acid in 475 ml of water and stirred for 15 minutes. The lower aqueous layer was then separated and decanted. The rich solvent was washed with 250 ml of saturated brine. The solvent was removed by vacuum distillation and replaced with propan-2-ol and then cooled with stirring to obtain the crystalline title compound. 600 mL of water was added over 30 minutes and the mixture stirred for 1-2 hours at 15-25°C. The product was filtered and washed with water and then isopropyl ether for drying.

Yield = 80-90%

Example 5

( ±)- trans- 4-( 4'- fluorophenyl)- 3- hydroxymethyl- N- methyl- piperidine ( E5)

18.0 g of the compound E2 (±)-trans-3-ethoxycarbonyl-4-(4'-fluorophenyl)-N-methylpiperidine-2,6-dione in 80 ml of tetrahydrofuran was slowly added to a solution of 6.0 g lithium aluminum hydride in 40 ml of tetrahydrofuran under nitrogen, keeping the temperature below 40°. When the addition was complete, the reaction mixture was stirred at room temperature overnight, then heated to 50° for approx. 7 hours and finally stirred overnight at room temperature.

Cleavage was performed by careful addition of 30 ml of water followed by 6.0 ml of 10% aqueous sodium hydroxide solution. The hydrolyzed mixture was stirred for 1.5 hours before filtering off the precipitated salts which were washed with 50 ml of ethyl acetate. The filtrate was dried over anhydrous sodium sulfate and evaporated to give a solid product which was triturated with ether, filtered and dried to give the title compound (9.0 g, 65%).

m.p. 122-126°.

^- n. m. r. fDMSO- d.')

S = 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 (p, 1H)

7.03-7.29 (m, 4H)

Resolution

The title compound E5 (8.6 g) and 10.4 g of (±)-2'-nitrotartranilic acid were dissolved in 70 ml of hot acetone, and 1.9 ml of water was added. After cooling and standing at 5° for 2 days, the crystalline salt was filtered off, washed with acetone and dried in vacuo (7.7 g, 39%).

The salt (7.6 g) was suspended in water and a small excess of dilute hydrochloric acid was added to precipitate the tartranilic acid, which was filtered off and washed with water. The filtrate was basified with sodium carbonate solution and extracted with ethyl acetate (total 60 ml) and the extracts washed with sodium carbonate solution, water and dried over anhydrous sodium sulfate. Evaporation gave (-)-trans-4-(4'-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine as a crystalline solid, which was triturated with ether/petroleum ether (b.p. 60-80°), filtered and dried (3.1 g, 95% recovery), m.p. 102-103°, [α]D26 (c=5 in acetone) -37°.

Example 6

(±)-trans-4-(4'-fluorophenyl)-3-hydroxymethylpiperidine

2.0 g of the compound E1 (±)-trans-3-ethoxycarbonyl-4-(4'-fluorophenyl)piperidine-2,6-dione was reduced with 0.58 g of lithium aluminum hydride in 50 ml of refluxing tetrahydrofuran for 4 hours. Processing as described in ex. 5 gave the title compound as a solid (0.28 g, 22%).

Example 7

f±)- trans- 4-( 4'- fluorophenyl)- 3- hydroxymethyl- N- methyl-

py<p>eridine ( E7)

34 g of compound E4 in 150 ml of toluene was added slowly to a slurry of 10 g of lithium aluminum hydride in a tetrahydrofuran (50 ml)/toluene (150 ml) mixture, keeping the temperature at 0-5°C under nitrogen. (Commercially available 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. The excess lithium aluminum hydride was destroyed by the careful, controlled addition of 10 ml of water, 10 ml of dilute 15% sodium hydroxide and 30 ml of water. The solid was then removed by filtration and resuspended in 100 ml of toluene. The combined rich toluene layers were concentrated to small volume (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 10 ml of petroleum ether and dried.

Yield = 65-75%

Example 8

(-)- trans- 4-( 4'- fluorophenyl)- 3- hydroxymethyl- N- methyl-

piperidine

5 g of the compound E7 was dissolved in 50 ml of acetone and added to a solution of 11.15 g of (-)-di-p-toluoyltartaric acid in 50 ml of acetone at 15-25"C. The mixture was stirred for 1 hour at 15- 25° C., and then 1 hour more at 0-10° C. The crystalline salt was filtered off, washed with acetone and dried.

Yield = 40-45%

The salt (6 g) was suspended in water and methylene dichloride (MDC). (-)-trans-4-(4'-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine was extracted into MDC using sodium hydroxide. Evaporation of the rich MDC gave an oil which was redissolved in toluene. The toluene was removed by evaporation to give an oil. Addition of heptane and trituration gave a crystalline solid which was filtered off and dried.

26

Yield = 85-89% [a] = -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 200 ml of dry tetrahydrofuran at 0°C under an atmosphere of nitrogen. 2.16 ml of concentrated sulfuric acid was then added dropwise, and the mixture was stirred at 0°C for 1 hour to give a solution of aluminum hydride. The imide (E2, 10.0 g; 0.034 mol) was added as a solution in 199 mL of dry tetrahydrofuran, and the mixture was stirred at 0-5°C for 4-5 hours, then at room temperature overnight. Sodium hydroxide (16.2 mL of a 40% aqueous solution) was added and the resulting precipitate was filtered and washed. Filtration was repeated several times to remove cloudiness, and then the filtrate and washing water were evaporated in vacuo, so that the product was obtained in the form of an orange colored oil (6.9 g, 91%), which could be crystallized from ether, m.p. 122-123°C.

Claims (4)

1. Process for preparing a compound of formula (I): where R<3> is hydrogen or methyl, characterized by reducing a compound of formula (II): where R<3> is as defined with respect to formula (I), and R<4> is alkyl, with a metal hydride. 2. Intermediate for the preparation of a compound of formula (I) as stated in claim 1, characterized in that it is (—)-trans-3-ethoxycarbonyl-4-(4<1->fluorophenyl)-piperidine-2,6 -dion. 3. Intermediate for the preparation of a compound of formula (I) as stated in claim 1, characterized in that they are (—)-trans-3-ethoxycarbonyl-4-(4'-fluorophenyl)-N-methyl-piperidine -2,6-dione. 4.. Intermediate for the preparation of a compound of formula (I) as stated in claim 1, characterized in that it is (—)-tris-3-methoxycarbonyl-4-(4'-fluorophenyl)-piperidine-2,6- dion.