PROCESS FOR PRODUCING 9-CARBAMOYL FLUORENE DERIVATIVES

Abstract: Processes are described for preparing pharmaceutical 9-­ carbamoyl-9-aminoalkylfluorenes of the formula wherein R⁴ is C₁-C₆ alkyl; or a salt thereof; which comprises react­ ing a compound of the formula wherein either R⁵ is -CONH₂ and R⁶ is -(CH₂)₂CHO; or R⁵ and R⁶ together, form the ring with an amine of the formula R⁴NH₂ and a reducing agent; or isolating from reaction of the compound of formula (II) with amine, an intermediate of formula: where R⁷ is -CH(OH)NHR⁴ or -CH=NR⁴ and reducing the said intermediate, and certain intermediates in their preparation.

Description: PROCESS FOR PRODUCING 9-CARBAMOYL FLUORENE DERIVATIVES A group of 9-disubstituted fluorenes recently has been discovered to have potent antiarrhythmic activity; see U.S. Patent Nos. 4,197,313 and 4,382,093. The 9-carbamoyl-9-aminoalkylfluorenes are among the most active compounds, and one compound within this group, namely 9-(3-isopropylaminopropyl)-9-carbamoylfluorene hydrochloride, is now known generically as indecainide. The reported synthesis of the 9-carbamoyl9-aminoalkylfluorenes have included acid hydrolysis of a 9-cyano-9-aminoalkylfluorene, and more recently reductive alkylation of a 9-carbamoyl-9-cyanoalkylfluorene, see U.S. Patent No. 4,282,170. The invention provides a process for producing a compound of the formula EMI1.1 wherein R4 is C1-C6 alkyl; or a salt thereof; which comprises reacting a compound of the formula EMI2.1 wherein either 5 -CONH2 and R6 is -(CH2)2CHO; or 5 and R6, together, form the ring EMI2.2 with an amine of the formula R4NH2 and a reducing agent; or isolating an intermediate of the following formula from reaction of the compound of formula (II) with amine: EMI3.1 where R7 is -CH(OH)NHR4 or -CH=NR4 and reducing the said intermediate. The compounds of formula (II) are of two types: EMI3.2 Such compounds are in fact interchangeable since reaction of base on compound (V) readily yields the aldehyde of formula (IV). In most systems an equilibrium between the two forms exists and the reactive species in the above process of the invention is probably always of formula (IV). Notwithstanding this both species can be employed in the reaction. Amine (R4NH2) and reducing agent can be added simultaneously or the reducing agent added after reaction with amine. The compounds of formula (III) are products of the reaction of amine with the compound of formula (II) and can be isolated and subsequently reacted with reducing agent. Often, however, it is preferable to avoid the extra step of isolating the intermediate product and to carry out the reaction in situ as described above. The compounds of formula (II) and (III) are novel and are provided in one aspect of the invention. The compounds of formulae (II) can be prepared by a process which comprises reacting a compound of the formula EMI4.1 with acrolein (CH2=CHCHO) under basic conditions. Thus the invention also provides a process for preparing a compound of formula (I) as defined above, which comprises (a) reacting a compound of the formula EMI5.1 with acrolein under basic conditions to provide a compound of formula: EMI5.2 wherein R5 and R6 are as defined above, and (b) reacting the compound of formula (II) with an amine of the formula R4NHi and a reducing agent. In the above formulae R is C1-C6 alkyl. The term ''C1-C6 alkyl" carries its art recognized meaning and includes methyl, isopropyl, tert.-butyl and l,l-dimethylbutyl. A particularly preferred R4 alkyl group is isopropyl. The reaction of amine with the compound of formula (II) above, is one of amination and, in the case where an intermediate is not isolated, the reaction is one of reductive amination. It is preferably carried out with approximately equimolar quantities of the reactants or with an excess of the amine, at a pH within the range of 6 to 10, such as for example 8 to 9, and at a temperature of from -200C to 1000C, such as for example from 250C to 800C. It is preferred to perform the reaction under basic conditions which may be ensured by the use of a molar excess of the amine reactant. The subsequent reduction in the case where an intermediate is isolated is carried out under similar conditions. Suitable reducing agents for use in the above process can be catalytic or chemical. Examples of the former kind include hydrogenation with palladium and charcoal, hydrogen and Adams catalyst (PtO2), and platinum on charcoal. Such catalytic methods of hydrogenation are discussed for instance in "Practical Catalytic Hydrogenation" by M. Freifelder, Wiley Interscience, 1971, and in "Catalytic Hydrogenation in Organic Synthesis" by P.N. Rylander, Academic Press, 1979. Chemical reagents which may preferably be used include, for example, sodium cyanoborohydride, lithium cyanoborohydride, tetrabutylammonium cyanoborohydride. The first named reagent, which is the most preferred for use in the process of the invention, is reviewed, for example, in the paper by C.F. Lane, Aldrichimica Acta 1975, 8, 3. Reducing agents with too strong an effect should be avoided. The reaction is generally carried out in an inert organic solvent and we have found that acetonitrile, dichloromethane and ethyl acetate are particularly useful for this purpose but other solvents can be employed such as for example tetrahydrofuran and aromatic and halogenated hydrocarbons, or if desired the amine reactant can be employed in sufficient quantity to serve both as reactant and solvent. The product can be extracted by routine procedures. As noted above compounds of formula (II) can be prepared by a novel process which comprises reaction with acrolein according to the following scheme EMI7.1 The reaction is carried out by combining the 9-carbamoylfluorene with acrolein in approximately equimolar quantities in the presence of a base. The particular base employed and the quantity are not critical, and an equimolar quantity or excess generally is used. Typical bases that can be employed include organic bases such as benzyltrimethylammonium hydroxide (Triton B), triethylamine, as well as alkali metal hydrides such as sodium hydride. The reaction is preferably conducted in an organic solvent, and typical solvents include ethers such as diethyl ether and tetrahydrofuran, and aromatics such as benzene and toluene. The reaction typically is carried out at a temperature of about 0 to 100 C, and at such temperature is usually complete within about one to about eight hours. The product of the reaction, a tautomeric mixture of an aldehyde and a cyclic carbinol, is readily isolated by removing the reaction solvent or when a water-miscible solvent has been employed, by dilution of the reaction mixture with water. The product can be crystallized from common solvents such as for example ethyl acetate or ether, when it is obtained predominantly in the carbinol form (formula (V)) which as such can be readily isolated. The following detailed Examples further illustrate this invention. Example 1 6'-Hydroxyspiro(9H-fluorene-9,3'-piperidine)- 2'-one A solution of 10.0 g (48 mM) of 9-carbamoylfluorene in 100 ml of tetrahydrofuran was heated to 450C and stirred under a nitrogen blanket while 2 ml of N-benzyltrimethyl ammonium hydroxide (Triton B) were added in one portion. The reaction mixture was stirred for fifteen minutes at 450C, and then 2.8 g (50 mM) of acrolein were added dropwise over ten minutes. The reaction mixture was heated at reflux for three hours following the addition. The reaction mixture was cooled to room temperature and concentrated to an oil by evaporation of the solvent under reduced pressure. The oil was dissolved in 100 ml of ethyl acetate and washed with water. The organic layer was dried and the solvent was removed by evaporation to provide a solid. The solid was crystallized from ethyl acetate and petroleum ether to give 4.0 g of solid product. The product was purified further by high pressure liquid chromatography over silica gel, eluting with chloroform containing 5% (v/v) methanol. The appropriate fractions were combined and concentrated to dryness to afford 500 mg of 6'-hydroxyspiro-(9H-fluorene-9,3'piperidine)-2'-one melting at 210-2120C. Analysis calculated for C17H15NO2 (after drying at 1200C): Theory: C, 76.96; H, 5.70; N, 5.28; 0, 12.06 Found: C, 76.66; H, 5.99; N, 5.21; 0, 12.27. Mass Spec. M+ Theory 265, Found 265. NMR (DMSOd6): 6 1.6-2.5 (m, 4H); 5.32 (broad 1H): 6.12 (d, lH); 7.3-8.1 (m, 8H); 8.32 (d, 1H). IR (KBr): 1642 cm 1 (amide) Example 2 6'-Hydroxyspiro(9H-fluorene-9,3'-piperidine}- 2' one Following the general procedure of Example 1, 20.9 g (0.1 mole) of 9-carbamoylfluorene were added to 300 ml of tetrahydrofuran. The solution was heated to 500C and stirred while 6 ml of benzyltrimethylammonium hydroxide were added in one portion. After stirring the reaction mixture at 50 C for thirty minutes, 6.2 g (0.11 mole) of acrolein were added and the mixture was then heated at reflux for four hours. The reaction mixture was cooled to 250C and the solvent was removed by evaporation under reduced pressure to provide 29.9 g of 6' -hydroxyspiro(9H-fluorene-9,3 '-piperidine)-2 '-one and its tautomeric isomer 9-carbamoyl-9-(3-oxo-propyl)fluorene, m.p. 199-2010C, Analysis calculated for C16H15NO2 (after drying at 1200C for one minute) Theory: C, 76.96; H, 5.70; N, 5.28 Found: C, 76.71; H, 5.88; N, 5.23. Mass Spec. M+ Theory 265; Found 265. NMR (CDCl3 + DMSOd6): 6 1.7-2.6 (m, 4H); 5.3 (broad s, lH); 5.9 (d, lH); 7.2-7.9 (m, 9H). IR (KBr): 1639 cm 1 (amide) Example 3 9-Carbamoyl-9- (3-isopropylaminopropyl ) fluorene hydrochloride A solution of isopropylamine (45.0 ml) in acetonitrile (250 ml) was cooled to 100C and hydrogen chloride gas introduced into the solution keeping the temperature below 150C to pH 8.5 i 0.3. The resultant slurry was allowed to warm to room temperature and sodium cyanoborohydride (12.0 g) added in one portion and the pH readjusted to 8.5 if necessary. 6'-Hydroxyspiro (9H-fluorene-9,3'-piperidine)-2'-one (30.0 g) was then added and the reaction mixture heated to reflux for 2 hours. The mixture was allowed to cool to room temperature and dilute hydrochloric acid added to pH 1-2 to destroy any excess cyanoborohydride. The acetonitrile was removed under reduced pressure and the residue basified with sodium hydroxide solution (pH 11) and extracted with dichloromethane (3 x 100 ml) and the combined organic layers washed with sodium hydroxide solution, dried with anhydrous sodium sulphate and evaporated to give the crystalline free amine. This amine was dissolved in acetone (120 ml) and cooled to 150C. Dry hydrogen chloride gas was passed through the solution until a pH of 7 was obtained. The resultant mixture was cooled slowly to -300C, and the product isolated by filtration, washed with cold acetone, and dried in vacuo at 400C overnight to give the title compound, yield 25.4 g, 65%. NMR (DMSOd6): 6 1.08 (s, 3H); 1.19 (s, 3H); 2.2-2.9 (m, 6H); 6.28 (s, lH); 7.0 (s, lH); 7.3-8.1 (m, 9H); 8.8 (broad s, 2H). Example 4 9-Carbamoyl-9- (3-isopropylaminopropyl ) fluorene 6'-Hydroxyspiro-(9H-fluorene-9,3'-piperidine)- 2'-one (2.7 g) was dissolved in isopropylamine (350 ml) and 10% palladium on charcoal (0.3 g) was added and the vessel presurized to 90 p.s.i. with hydrogen. The reaction mixture was then heated at 400C for 16 hours and then allowed to cool to room temperature. The catalyst was removed by filtration and the isopropylamine evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (20 ml) washed with water (2 x 50 ml), dried with anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue was triturated with hexane to give the title compound as white crystals, yield 2.0 g, 64%, the identity of which was confirmed by thin layer chromatographic comparison with an authentic sample (silica gel, ethylacetate:methanol 80:20 v/v). Example 5 9-Carbamoyl-9- (3-isopropyliminopropyl ) fluorene A mixture of 5.9 g (0.1 mole) of isopropylamine and 2.5 g (0.009 mole) of the tautomeric mixture from Example 2 was stirred at 250C under a nitrogen blanket for sixteen hours. Excess isopropylamine was removed by evaporation under reduced pressure to provide, following crystallization from ethyl acetate and petroleum ether, 0.7 g of a solid identified as 9-carbamoyl-9 (3-isopropyliminopropyl)fluorene, m.p. 149-1550C. M+ theory 306; found 306. NMR (CDC13): signals at 6 1.0 (two s, 6H); 1.62 (M, 2H); 2.65 (M, 2H); 3.06 (M, lH); 5.05 (Broad s, 2H, signal removed with D20 shake); 7.28-7.79 (M, 9H). Example 6 9-Carbamoyl-9- (3-isopropylaminopropyl ) fluorene hydrochloride 9-Carbamoyl-9- ( 3-isopropyliminopropyl ) fluorene prepared as described in Example 5, was dissolved in 200 ml of ethanol containing 3.0 g of 5% palladium on carbon. The reaction mixture was shaken in a hydrogen atmosphere at 250C for six hours. The actual hydrogen uptake was 19.5 lbs; theoretical uptake was 19.7 lbs. The reaction mixture was filtered to remove the hydrogenation catalyst and the filtrate was concentrated to dryness by evaporation under reduced pressure. The solid that was formed was dissolved in 100 ml of diethyl ether containing 100 ml of ethyl acetate. The product was extracted into 6N hydrochloric acid and the acid extracts were combined, cooled to 100C and made alkaline to pH 10.0 by addition of 10% (w/v) aqueous sodium hydroxide. The alkaline solution was extracted several times with fresh diethyl ether, and the ethereal extracts were combined, washed with water, dried, and then saturated with gaseous hydrogen chloride. The precipitate which formed was collected by filtration and recrystallized from ethanol and diethyl ether to give 2.1 g of 9-carbamoyl-9-(3-isopropylaminopropyl)fluorene hydrochloride (indecainide hydrochloride), m.p. 206-207.50C. Analysis calculated for C20H25C1N2O Theory: C, 69.65; H, 7.31; H, 8.12 Found: C, 69.55; H, 7.18; N, 7.99. IR (KBr): 1680, 1665 cm 1 NMR (DMSOd6): 6 1.08 (s, 3H); 1.19 (s, 3H); 2.2-2.9 (m, 6H); 6.28 (s, lH); 7.0 (s, lH); 7.3-8.1 (m, 9H); 8.8 (broad s, 2H). Titration (66% v/v N,N-dimethylformamidewater) pKa = 10.2.

Claims: CLAIMS 1. A process for producing a compound of the formula EMI15.1 wherein R4 is C1-C6 alkyl; or a salt thereof; which comprises reacting a compound of the formula EMI15.2 wherein either R5 is -CONH2 and R6 is -(CH2)2CHO or R5 and R6, together, form the ring EMI16.1 with an amine of the formula R4NH2 and a reducing agent; or isolating from reaction of the compound of formula (II) with amine, an intermediate of formula: EMI16.2 where R7 is -CH(OH)NHR4 or -CH=NR4 and reducing the said intermediate. 2. A process according to claim 1 for preparing a compound of formula (I) in which R4 is isopropyl. 3. A process for producing a compound of formula (II) EMI17.1 wherein either R5 is -CONH and R6 is -(CH2)2CHO; or R5 6 2 22 or R5 and R6, together, form the ring EMI17.2 which comprises reacting a compound of the formula EMI18.1 with acrolein under basic conditions. 4. A compound of formula (III): EMI18.2 where R7 is -CH(OH)NHR4 or -CH=NR4 where R4 is C16 alkyl. 5. A compound of formula (III) as claimed in claim 4, wherein R7 is -CH=NR4, where R4 is isopropyl. 6. A compound of formula (II): EMI19.1 wherein either R5 is CONH2 and R6 is -(CH2)2CHO; or R5 and R6, together, form the ring: EMI19.2

Inventors: JOHNSON, DEREK, LACEFIELD, WILLIAM BRYANT, LINDSTROM, TERRY DONALD, SPREADBURY, ALAN CHARLES
Applicants: ELI LILLY AND COMPANY
Application year: 1984
Main classification: C07C103
IPC codes: C07D221, A01N45