4-HETEROARYL PIPERIDINE INTERMEDIATES AND THEIR PREPARATION

Abstract: This invention relates to new compounds of formulae (I, II) in which X is O, S, or NR where R is H or C1-4-alkyl, Z is hydrogen, halogen, trifluoromethyl, C1-8-alkoxy, C1-8-alkyl straight or branched, nitro, C2-8-alkenyl, or a C1-4-alkyl mono- or disubstituted amino group, R<1> is H or straight or branched C1-8-alkyl. The invention also relates to a method of preparing a compound of formulae (I and II).

Description: 4-HETEROARYL PIPERIDINE INTERMEDIATES AND THEIR PREPARATION This invention relates to a novel chemical process for preparing new heteroaryl piperidine carbinols and to novel intermediates used in that process. The novel compounds are useful as intermediates in processes leading to pharmacological active substances. This invention relates to new compounds of formula I in which X is 0, S, or NR where R is H or C. .-alkyl, Z is hydrogen, halogen, trifluoromethyl, C. _ R -alkoxy, C, β - alkyl straight or branched, nitro, C 2 _ R -alkenyl, or a C. ,-alkyl mono- or disubstituted amino group, R is H or straight or branched C, „-alkyl. The invention also relates to a method of preparing a compound of formula I. This method which uses easily accessible commercially available starting materials comprises: a) preparation of a compound of formula II wherein X, Z, R and R have the meaning defined 2 above and R is C,_ 2 -alkyl, by reacting a compound of formula IV R 3 0CCH 2 C00R 2 IV with a compound of the formula V under basic conditions eg. using alkoxide in ethanol, wherein X, Z, R, R 1 and R2 have the meaning defined above and R 3 being C. -alkoxy when R4 is NHR1 or b) reduction of a compound of formula II wherein X, Z, R, R 1 and R2 have the meaning defined above, with metal hydride eg. LiAlH, or A1H„ in ether or THF giving a compound of formula I wherein X, Z, R and R have the meaning defined above, c) reduction of a compound of formula III wherein X, Z, R, R 1 and R2 have the meaning defined above with a metal hydride eg. LiAlH. or A1H„ giv¬ ing a compound of formula I wherein X, Z, R and R have the meaning defined above; compounds of formula III can be prepared convenient¬ ly from Arecoline-type derivatives and metal organic derivatives of heterbaromates using well known pro¬ cedures, d) compounds of formula I may also be prepared by react¬ ing compounds of formula I wherein Z is H, with rea¬ gents causing heteroaromatic substitution using well known procedures, e) compounds of formula I may be prepared by metal hydride reduction of a compound of formula VI wherein X, Z, R, R 1 and R2 have the meaning defined above, f) compounds of formula II may be prepared in a one pot reaction using a compound of formula VII where¬ in X, Z and R have the meaning defined above as starting material. The reaction is carried out using ethyl acetate as solvent and ethoxide or ethoxide as base. After initial reaction between VII and solvent a compound of formula VIII wherein R 2 and R have the meaning defined above, R 2 OOCCH 2 CONHR 1 VIII is added resulting in the formation of compounds of ffoorrmmuullaa IIII wwhheerreeiinn X, Z, R, R 1 and R2 have the mean- ing defined above. The invention will now be described in further detail with reference to the following examples. EXAMPLE 1 3-hydroxymethyl-l-methyl-4-(2-thienyl)-piperidine (1) 3-methoxycarbony1-1-meth l-4-(2-thieny1)-piperidine (2) was prepared from Arecoline, HBr (52 g), 2-bromo- thiophene (41 ml) and Mg-turnings (9.9 g) as described by Plati et. al. (J. Org. Chem. 22 (1957) 261). The resulting proudct was purified by distillation giving 15 g cis/trans mixture b.p. 50-120 C / 1.1 mm Hg. 30 g of this product was reduced with LiAlH. (5 g) in dry ether (200 ml) by reflux for 30 min. in N_-atmos¬ phere. The well known rinse up procedure gave a hard oil (21 g) identified as 3-hydroxyme hyl-1-methyl-4- (2-thienyl )-piperidine( 1 ) by 1 H NMR (CDClg), : 6.7 - 7.3 (3H,m); 3.8- 4.5 (1H,broad) 3.5-3.7 (2H,m); 2.8- 3.5 (3H,m); 2.2 (3H,s); 1.8-2.8 (5H,m) EXAMPLE 2 3-(2-thienyl)-propenoyl chloride (3) was prepared by dropwise addition of thionyl chloride (50 ml) to 3- (2-thienyl)-propenoic acid (25 g) and subsequent heat¬ ing to 60 C for 2 hours. Excess of S0C1 ? was evaporated in vacuo, CH^Cl^ was added and the reaction mixture was evaporated to dryness yielding 28 g of (3). N-pentyl-3-( 2-thienyl )-propenoic amide (4) was prepared from (3) (28 g) dissolved in dry toluene (200 ml) pen- tyl amine (25 ml) and triethyl amine (70 ml) was added under cooling (ice bath). Stirring for 1 hour. The pre¬ cipitate of triethylammonium chloride was removed by filtration, the filtrate was evaporated to dryness and the resulting mass treated with ether giving (4) as colourless crystals (22.8 g). 1 H NMR (CDC1„), : 0.7- 1.1 (3H,m); 1.1-1.7( 6H,m) ; 3.0-3.4 (2H, dist.q), 6.2- 8.2 (6H,m). 3-ethoxycarbonyl-l-pentyl-4-(2-thienyl)-piperidine 2,6-dione (5) Sodium (3 g) was dissolved in abs. ethanol (60 ml), diethyl malonate (20 ml) dissolved in abs. ethanol (30 ml) was . added followed by a slurry of (4) (22.8 g) in abs. ethanol (50 ml). Reflux for 4 hours, the ethanol was evaporated, toluene added (100 ml), and the reflux continued overnight. After cooling the formed preci¬ pitate was isolated, dissolved in 1M HCI and extracted several times with ether. The combined ether phases were evaporated giving an oil which was purified on silica gel using CH 2 C1 9 /CH 3 0H 9/1 as eluent. Yield : 0.7-0.95 (3H,m); 1.0-1.5 (9H,rn); 2.9-3.2 (2H,m) 4.15 (2H,q); 3.6-4.15 (4H,m); 6.8-7.2 (3H,m). 3-hydroxymethyl-l-pentyl-4-(2-thienyl )-piperidine (6) was prepared from (5) (22.6 g) by reduction with LiAlH. (13 g) in dry THF. Reflux for 3 hours under N ? . Using the well known work up procedure gave a hard oil (4 g) identified by 1 H NMR (CDClg), : 0.7-1.1 (3H,m); 1.1-1.7 (6H,m); 1.7-2.1 (4H,m); 2.1-3.9 (9H,m); 6.8-7.2 (3H,m). EXAMPLE 3 N-pentyl-3-(3-thienyl )-propenoic amide (7) was prepared as described for (4) .^Ή NMR (CDClg), : 0.7-1.1 (3H,m); 1.1-1.7 (6H,m); 3.2-3.6 (2H, dist. q); 6.1-7.8 (6H,m). 3-ethoxycarbonyl-l-pentyl-4-(3-thienyl )-piperidine- 2,6-dione (8) was prepared as described for ( 5 ) . 32 g (7) gave 41 g of crude (8) which was used without further purification. Reduction and work up as describ¬ ed for the preparation of (6) gave 7.7 g of crystalline 3-hydroxymethyl-l-pentyl-4-(3-thienyl)-piperidine (9 ) . M.p. 96.5-97.5°C. EXAMPLE 4 ( -l-butyl-3-ethoxycarbonyl-4-(2-thienyl)-2, 6-piperi- dinedione (10) A solution of 2-thiophenecarbaldehyde (22.4 g) in ethyl acetate (20 ml) was added to a slurry of sodium ethanol- ate (32.6 g) in ethyl acetate (200 ml). The temperature was kept at 10 C and the mixture stirred for one hour. A solution of ethyl N-butylamidomalonate (41.2 g) in ethyl acetate (40 ml ) was slowly added to the mixture whilst keeping the temperature below 5 C. The mixture was stirred for 18 hours at 20 C and neutralized with 25% acetic acid (130 ml). The water phase was dis- charged and the organic phase extracted twice with sa¬ turated sodium chloride solution (2x50 ml) . The organic phase was evaporated, the residue dissolved in toluene (200 ml), dried with potassium carbonate and evaporated to give the crude product. Yield 72 g of an oil identi- fied by 1 H NMR (CDClg), : 0.7-1.4 (10H,m); 2.7-4.2 (8H,m); 6.7-7.3 (3H,m). ( +_)-l-butyl-3-hydroxymethyl-4-( 2-thienyl )-piperidine (11) A solution of crude ( +_)-l-butyl-3-ethoxycarbonyl-4-(2- thienyl)-2, 6-piperidindione (72 g) in toluene (100 ml) was added to a slurry of LiAlH 4 (15.2 g) in THF (100 ml) and toluene (50 ml). The temperature was kept below 10 C during the addition. The reaction mixture was stirred for 18 hours and decomposed by careful addition of water (75 ml) keeping the temperature below 10 C. The hydrolyzed mixture was stirred for 1 hour before the precipitated salts was filtered off. The filtrate was evaporated to give an oil (33 g) which was recry- stallized from ethyl acetate (50 ml ) , filtered off and dried to give the title compound (17 g), m.p. 89.7- 90.1°C. EXAMPLE 5 (+-)-l-butyl-3-ethoxycarbonyl-4-( 5-methyl-2-furanyl )- 2, 6-piperidinedione ( 12 ) was prepared from 5-methyl- 2-furancarbaldehyde (22 g) as described for compound (10). Yield 59.5 g of an oil (80% pure by HPLC). Identified by " " " H NMR (CDClg) : 0.7-1.6 (10H, m), 2.2 - 2.4 (3H, d); 2.8 - 4.5 (8H, m); 5 . 8-7 . 5 ( 2H , m ) . (+- )-l-butyl-3-hydroxymethyl-4-( 5-methyl-2-furanyl)- piperidine (13) was prepared from crude (12) (59 g) by reduction with LiAlH., as described for (11). Yield 22 g of (13). M.p. 83.5°C. EXAMPLE 6 (+- )-l-butyl-3-ethoxycarbonyl-4-( l-methyl-2-pyrrolyl )- 2, 6-piperidinedione ( 14) was prepared from l-methyl-2-pyrrolecarbaldehyde (10.2 g) and ethyl N-butylamidomalonate (15.4 g) in ethyl acetate as described for compound (10). The crude pro¬ duct (27 g) was subsequently reduced without further purification as described for compound (11). Yield 14 g of (+-)-l-butyl-3-hydroxymethyl-4-( 1-methyl-2-pyrrolyl)- piperidine (15) precipitated as the oxalate. H NMR (CDClg) : 0.7-1.1 (3H, m); 1.1 - 2.2 (6H, m); 2.5 - 3.. (10H, m), 3.5 (3H, s), 5.7 - 6.0 (2 H, m); 6.1 - 6.7 (1H, m). EXAMPLE 7 3-Ethoxycarbonyl-l-(2-methylbutyl)-4-(3-thienyl )-2, 6- piperidinedione (16) was prepared from 3-thiophenecarbaldehyde (20 g) and ethyl N-(2-methylbutylamidomalonate) (35 g) in ethyl acetate as described for compound ( 10) . The crude product (60 g oil ) was reduced in THF by means of LiAlH. as described for compound (11) giving 3-hydroxymethyl-l-(2-methylbutyl)-4-(3-thienyl)- piperidine ( 17) The crude product (23 g) was purified on silica gel using ethyl acetate as eluent. Mass spectrum (M : 267) degradation in accordance with proposed structure, m.p. 88.8-90.2 C. EXAMPLE 8 The following compounds were prepared exactly as described for (17) using the appropriate substituted thiophenecarbaldehyde and ethyl amidomalonate. The dione intermediate was used without purification. 3-hydroxymethyl-l-pentyl-4-(2-thienyl )piperidine ( 18 ) Yield 17.6%; m.p. 107.6°C. l-butyl-3-hydroxymethyl-4-(2-thienyl)piperidine ( 19) Yield 27.2%; m.p. 90.9°C. l-butyl-3-hydroxymethyl-4-(3-thienyl )piperidine (20) Yield 27.9%; m.p. 81.7°C. 3-hydroxymethyl-l-pentyl-4-(3-thienyl )piperidine (21 ) Yield 2 . 7.5%; m.p. 93.9°C.

Claims: CLAIMS 1) A process for the preparation of a compound of formula I wherein X is O, S or NR, R is H or C- .-alkyl, Z is hydrogen, halogen, trifluoromethyl, C 1 _ R -alkoxy, straight or branched C 1 _n-alkyl, nitro, C 2 R -alkenyl, or a C- .-alkyl mono- or disubstituted amino group, R is H, straight or branched C, g -alkyl; the process comprises a preparation and reduction of a compound of formula II with a metal hydride eg. LiAlH. wherein X, Z, R and R 1 is defined above and R2 is C. 2 -alkyl and the preparation and reduction of a compound of formula III by means of metal hydride eg. LiAlH 4 wherein X, Z, R, R 1 and R2 have the meaning defined above 2) a compound of formula II wherein X, Z, R, R 1, and R2 have the meaning defined above 3) a process for the preparation of a compound of for¬ d above, which comprises reacting a compound of formula IV R 3 OCCH 2 COOR 2 IV with a compound of formula V V & - CH=CH-COR 4 under basic conditions, wherein X, Z, R, R 1 and R2 have the meaning defined above, R3 being C. -alkoxy when R 4 is NHR1 or R3 being NHR1 when R 4 is C.—„-alkoxy. 4) a process for the preparation of a compound of formula II wherein X, Z, R, R 1 and R2 have the meaning defined above, which comprises reacting of a compound of for- mula VII wherein X, Z and R have the meaning defined above, with a compound of formula VIII R 2 OOCCH 2 CONHR 1 VIII wherein R 1 and R2 have the meaning defined above, in ethyl acetate using ethoxide or methoxide as base. 5) a compound which is 3-ethoxycarbonyl-l-pentyl-4-(2- thienyl)-piperidine-2,6-dione. 6) a compound which is 3-hydroxymethyl-l-methyl-4-(2- thienyl)-piperidine. 7) a compound which is 3-hydroxymethyl-l-pentyl-4-(3- thienyl)-piperidine. 8) a compound which is 3-ethoxycarbonyl-l-pentyl-4-(3- thienyl)-piperidine-2, 6-dione. 9) a compound which is 3-methoxycarbonyl-l-methyl-4-(2- thienyl)-piperidine. 10) a compound which is 3-hydroxymethyl-l-pentyl-4-(2- thienyl )piperidine 11) a compound which is l-butyl-3-hydroxymethyl-4-(2- thienyl)piperidine 12) a compound which is l-butyl-3-hydroxymethyl-4-( 5- methyl-2-furanyl )piperidine 13) a compound which is l-butyl-3-hydroxymethyl-4-(3- thienyl)piperidine 14) a compound which is 3-hydroxymethyl-l-(2-methyl- butyl)-4-(3-thienyl )piperidine 15) a compound which is l-butyl-3-hydroxymethyl-4-(1- methyl-2-pyrrolyl )piperidine.

Inventors: JAKOBSEN PALLE, SONNEWALD URSULA, TREPPENDAHL SVEND, JAKOBSEN, PALLE, SONNEWALD, URSULA, TREPPENDAHL, SVEND
Applicants: NOVONORDISK AS, NOVO NORDISK A/S
Application year: 1990
Main classification: C07D405
IPC codes: C07D401, C07D405, C07D409