NOVEL PROCESSES
The present invention relates to novel processes for the preparation of indolotropanes. In particular the invention relates to highly stereoselective routes to both exo- and endo- indolotropanes.
The indolopiperidine ring system (A) is well known in pharmaceutical research as a template for ligands at numerous G-protein coupled receptors (GPCR's) e.g. 5-hydroxytryptamine (5-HT) receptor subtypes and dopamine receptors [WO 9418196 (Wellcome Foundation), WO 9316073 (Wellcome Foundation), DE 2338283 (Roussel-UCLAF) and DE 2503816 (Roussel- UCLAF)]. In marked contrast, the related indolotropane analogues (B) and (C) are extremely poorly documented. Repke et al, J. Org. Chem., 1994, 59, 2164-2171 discloses 2- tropanylindoles. WO 99/65492 (Eli Lilly and Company) discloses 3-(bicyclic heteroaryl)-8- azabicyclo[3.2.1]octenes and octanes, including certain 3-indolyl-8-azabicyclo[3.2.1]octanes and their use as seratonin reuptake inhibitors in mammals. WO 00/04017 (Merck, Sharp & Dohme Ltd) discloses azabicycle-substituted phenylindole derivatives, including endo- and exo-3-(8- azabicyclo[3.2.1]oct-3-yl)-2-phenylindoles, as 5-HT2A receptor ligands. Stereoselective processes are neither disclosed nor suggested. Tetrahedron Letters, 1999, 9293-9295 (Forbes et al), published after the priority date of the present application, discloses stereoselective routes to exo- and erc o-indolotropanes.
3-Tropanylindole derivatives are of substantial interest for two reasons:
The increased steric bulk around the basic nitrogen and, secondly, the conformationally locked piperidine ring, which "freezes" the indole substituent in either the equatorial (exo isomer) or axial (endo isomer) orientation. Both of these features may impart useful affinity/selectivity advantages to the specific ligand under investigation.
Standard literature methodology for the preparation of 3-tropanyl indoles is non- stereoselective, giving a mixture of isomers which may be difficult, if not impossible to separate. We have now discovered methodology for stereoselectively preparing both e«_fo-indolotropane isomers and exo indolotropane isomers which may be useful intermediates in the synthesis of pharmacologically active compounds.
Exo Endo
According to the present invention therefore there is provided a process for preparing an e«_fo-indolotropane compound of formula (IA):
(IA) wherein
R.1 is hydrogen or (C ι_g)alkyl;
R- and RJ, which may be the same or different, are selected from the group consisting of hydrogen, halogen, cyano, (C j-g^lkyl, (C3-7)cycloalkyl, (C ι -6_alkoxy, halo(C ι-6. alkyl, hydroxy, oxo, amino, mono- or di-(C ι -6)alkylamino, acylamino, nitro, carboxy, (Cι -6)alkoxycarbonyl, (C j-g)alkenyloxycarbonyl, (Cι -6)alkoxycarbonyl(Cι -6)alkyl, carboxy(Cι-6)alkyl, (C ι -g)alkylcarbonyloxy, carboxy(Cι -g)alkyloxy,
(C j-6)alkoxycarbonyl(C i-6)alkoxy, (Cι -g)alkylthio, (C j-^alkylsulphinyl, (C j-6)alkylsulphonyl, sulphamoyl, mono- and di-(C ι -6)-alkylsulphamoyl, carbamoyl, mono- and di-(Cι-6)alkylcarbamoyl, (Cι -6)alkylsulphonamido, arylsulphonamido, aryl, aryl(Cι-6)alkyl, aryl(C ι -6)alkoxy, aryloxy and heterocyclyl; and
Nq represents optional ring nitrogen atoms in positions 4, 5, 6, and 7; wherein q is 0, 1 or 2; which process comprises re ula (II):
(II)
wherein R
1, R2, R
Jand Nq are as hereinbefore defined for compound (IA); in a condensation reaction with a compound of formula (III):
(III)
wherein R^ is hydrogen or benzyloxycarbonyl; to give an olefinic co
(IV)
wherein Rl, 2, R->, R and Νq are as hereinbefore defined; and thereafter hydrogenating the compound of formula (IV) to give a compound of formula (IA); and if required, converting to another compound of formula (IA).
A representative value for R^ is benzyloxycarbonyl.
Suitable condensation conditions are well known to those skilled in the art and include acetic acid/phosphoric acid (Tetrahedron, 1996, 10185) at about 70 - 100°C for 1 - 3 hours, e.g. 90°C for 1.5 hours.
Suitable hydrogenation procedures are well known to those skilled in the art. Suitable conditions include hydrogen in the presence of a palladium catalyst, a preferred catalyst is palladium on charcoal, e.g. 10% palladium on charcoal. Suitable solvents include alcohol esters, tetrahydrofuran and (C i ^alcohols (e.g. methanol or ethanol, especially ethanol).
An exo-compound of formula (IB) may also be prepared stereoselectively. Accordingly, in a further aspect, the present invention provides a process for preparing an e o- indolotropane compound of formula (IB):
wherein R' , R-, R
J and N„ are as hereinbefore defined for compounds of formula (IA), and Y is hydrogen, a nitrogen protecting group or an organic substituent e.g. substituted alkyl; which process comprises effecting migration of an exocyclic double bond in a compound of formula (V):
(V) wherein R , R^, R^» Nq and Y are as hereinbefore defined. Suitable conditions that effect migration of the exocyclic bond include ethanolic hydrogen chloride. Representative values for Y include hydrogen, substituted alkyl and nitrogen protecting groups, e.g. .er.-butoxycarbonyl and benzyloxycarbonyl; especially hydrogen and nitrogen protecting groups, e.g. .er.-butoxycarbonyl and benzyloxycarbonyl. A representative value for R^ and RJ is hydrogen. A representative value for q is 0. Within the present invention exists a process in which substituents R^ and R^ are other than hydrogen.
Compounds of formula (V) may be prepared by cyclising a compound of formula (VI):
wherein Rl, R2, R- Nq and Y are as hereinbefore defined, Q is iodine, bromine or triflate and P is a nitrogen protecting group or hydrogen; and thereafter removing P, if P is a nitrogen protecting group. Suitable cyclisation conditions include Heck conditions as described in, for example,
Larock et al, Tetrahedron Lett., 1988, 29, 6399-6402; and Macor et al, Tetrahedron Lett, 1996, 37, 4289-4293.
It will be appreciated by those skilled in the art that during the cyclisation process the exocyclic double bond in compounds of formula (V) may migrate spontaneously to form an indole ring.
It will also be appreciated by those skilled in the art that conditions used to effect the removal of the nitrogen protecting group P may also result in the removal of a nitrogen protecting group Y.
Compounds of formula (VI) may be prepared by reacting a compound of formula (VII):
(VII)
wherein Y is as hereinbefore defined, and L is hydroxy; a leaving group; or together with the carbon atom to which it is attached foπns a carbonyl group; in an alkylation, or reductive alkylation, reaction with a compound of formula (VIII):
wherein R^, R^, p and Nq are as hereinbefore defined; and, if required or so desired, removing the protecting group P. Suitable alkylation conditions when P is trifluoroacetyl and L is hydroxy include Mitsunobu alkylation as described in O. Mitsunobu, Synthesis, 1981, 1.
When used herein the term "amino protecting group", unless otherwise defined are those well known in the art, and which may be removed under conventional conditions and without disrupting the remainder of the molecule. A comprehensive discussion of the ways in which amino groups can be protected and methods for cleaving the resulting protected derivatives is given in for example "Protective Groups in Organic Chemistry" (T.W. Greene and P.G.M. Wuts. Wiley-Interscience, New York, 2nd edition, 1991). Particularly suitable amino protecting groups include rerr-butoxycarbonyl, benzyloxycarbonyl and trifluoroacetyl.
Representative values for Y when an amino-protecting group are tert-butoxycarbonyl and benzyloxycarbonyl . Representative values for L are chlorine, bromine or hydroxy, preferably hydroxy.
Representative values for P include hydrogen and trifluoroacetyl. When used herein, the term "alkyl" and similar terms such as "alkoxy" includes all optionally substituted straight chain and branched isomers. Representative examples thereof include methyl, ethyl, /.-propyl, wo-propyl, n-butyl, sec-butyl, wo-butyl, tert-bu y\, n-pentyl and .z-hexyl. Suitable optional substituents for alkyl groups include one or more substituents selected from aryl, heteroaryl, heterocyclyl, (C j.^alkoxy, (Ci.g.alkylthio, aryl(Cι_6)alkoxy, aryl(C ι.(5)alkylthio, amino, mono- or di-(Cι_<3)alkylamino, cycloalkyl, cycloalkenyl, carboxy and (C ι.g)alkylesters thereof, amide, ureido, guanidino, (Cj^alkylguanidino, amidino, (Ci . 5)alkylamidino, (Cι _g)acyloxy, azido, hydroxy, and halogen.
When used herein, the term "aryl" includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
Suitable substituents for an aryl group include, for example, and unless otherwise defined, halogen, cyano, (Cj^alkyl, (C3"7)cycloalkyl, (Cι -6)alkoxy, halo(Cι-g)alkyl, hydroxy, amino, mono- or di-(Cι -g)alkylamino, acylamino, nitro, carboxy, (Ci -6)alkoxycarbonyl, (C i -g)alkenyloxycarbonyl, (C i -6)alkoxycarbonyl(C 1 -6. alky l, carboxy(C i -g)alky 1, (C i -g)alkylcarbonyloxy, carboxy(C \ -6)alkyloxy, (C 1 -6)alkoxycarbonyl(C 1 -6)alkoxy, (Cι -6)alkylthio, (Cι -6)alkylsulphinyl, (Cι -g)alkylsulphonyl, sulphamoyl, mono- and di-(C ] -g)- alkylsulphamoyl, carbamoyl, mono- and di-(Cι -6)alkylcarbamoyl, (Cι -g)alkylsulphonamido, arylsulphonamido, aryl, aryl(Cι -($)alkyl, aryl(C 1 -g)alkoxy, aryloxy and heterocyclyl.
When used herein, the terms "cycloalkyl" and "cycloalkenyl" refer to groups having from three to eight ring carbon atoms and are optionally substituted as described hereinabove for alkyl and alkenyl groups.
When used herein, the term "heterocyclyl" or "heterocyclic" includes single or fused aromatic or non-aromatic rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents. Suitably the heterocyclic ring comprises from 4 to 7, preferably 5 to 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
When used herein, the term "heteroaryl" includes an aromatic heterocyclic ring or ring system, preferably with 5 or 6 ring atoms on each ring.
When substituted, a heterocyclyl group may have up to three substituents. Suitable such substituents include those previously mentioned for an aryl group as well as oxo.
When used herein, the terms "halogen" and "halo" include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively. Compounds of formula (II) are commercially available or may be prepared by standard methodology.
Compounds of formula (III) may be prepared from N-benzyltropinone by catalytic hydrogenation optionally followed by reaction with benzyl chloroformate.
Compounds of formula (VII) may be prepared from N-tert-butoxycarbonyl-nortropinone by a Wittig-Horner reaction with triethyl phosphonoacetate, followed by selective reaction at - 40°C with di-z'so-butylaluminium hydride ("Reductions in Organic Chemistry", M. Hudlicky, Ellis Horwood, Chichester, 1984).
Compounds of formula (VIII) are commercially available or may be prepared from the appropriate amine by reaction with, for example, trifluoroacetic anhydride. In a further aspect, the present invention also provides for novel intermediates.
The following is a description by way of example only of embodiments of the present invention.
EXAMPLES
Example 1 - 3-(lH-Indol-3-yl)-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid benzyl ester
(El)
A mixture of indole (0.936 g), N-benzyloxycarbonyl-tropinone (8 g) in acetic acid (24 mL) containing 2M phosphoric acid (8 mL) was heated to 90°C for 1.5 h. The mixture was then allowed to cool, and poured onto aqueous ammonia/ice with vigorous stirring. Extraction twice with ethyl acetate, followed by drying of the organic layer and evaporation afforded a yellow oil. Chromatography on silica and elution with 30-50% ethyl acetate/hexane afforded the title compound as a pale yellow oil (1.8 g). Mass spectrum MPT 359.
Example 2 - £ .rfo-3-(8-Aza-bicyclo[3.2.1]oct-3-yl)-lH-indole (E2)
A solution of El (1.7 g) in ethanol (100 mL) containing 10% palladium on charcoal (0.2 g) was hydrogenated at 50 psi for 24 h. Filtration and evaporation of the solvent afforded the title compound as a colourless oil (1.0 g) which could be used directly for further elaboration. Mass spectrum MIT 227.
Further purification and stereochemical analysis was achieved by conversion to the N- BOC derivative (see Example 3).
Example 3 - £rt_/ø-3-(lH-Indol-3-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (E3)
A solution of E2 (0 9 g) in DMF (50 mL) was cooled to 0°C under argon. Tπethylamine ( 1 5 L) was added followed by di-t-butyl-di-carbonate (1.2 g), and the mixture stirred for 18 h The reaction mixture was then poured onto brine and extracted with ethyl acetate. The organic layer was dπed and evaporated to dryness to afford a yellow oil ( 1.5 g). Chromatography on silica and elution with 20-35% ethyl acetate/hexane afforded the title compound (0 79 g). Mass spectrum MIT
" 227 (corresponds to loss of BOC group). Η NMR: δ CDC1
3 1.52 (9H, s), 1.6- 1 8 (4H, m), 2.0 (2H, m), 2.6 (2H, b s), 3.1 1 (IH, m), 4.25 (IH, b s), 4.36 (IH, b s), 6.99 (IH, d), 7.10 (IH, dd), 7.20 (IH, dd), 7.35 (IH, d), 7.60 (IH, d), 7.93 (IH, b s). The stereochemistry was assigned by examination of the coupling constants of the signal at δ 3.11, in addition to nOe studies
Example 4 - 3-(2-Hydroxy-ethylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert- butyl ester (E4)
a) A mixture of triethyl phosphonoacetate (11.6 g), potassium carbonate (17 g) and N- BOC-nortropinone (9 g) in DMF was heated at 100°C with stirring for 4 days. The reaction mixture was then allowed to cool and poured onto brine. Extraction with ethyl acetate, followed by drying of the organic layer and evaporation afforded the crude product (12 g).
Chromatography on silica and elution with 20% ethyl acetate/hexane afforded the conjugated ester which was used directly in Part b) b) The conjugated ester from Part a) (7.1 g) was dissolved in dry THF (90 mL) and cooled to -40°C under argon. DIBAL (90 mL; 1 Molar) was added slowly, and the resulting solution stirred for 1 h at that temperature. The reaction mixture was quenched with methanol, then Rochelle salt solution added (100 mL) The organic layer was separated, and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were dried and evaporated to afford the title compound as a colourless oil (6 4 g). Mass spectrum MFf 154 (corresponds to loss of BOC group)
Example 5 - 3-{2-[(2-Iodophenyl)-(2,2,2-trifluoroacetyl)amino]ethyIidene}-8-aza- bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (E5)
A mixture of diethyl azodicarboxylate (4.35 g) and triphenylphosphine (6.5 g) was stirred at 0°C under argon To this mixture was added o-iodoaniline-N-trifluoracetamide (7.25 g)
followed by the alcohol E4 (5.7 g) in THF (20 mL). The mixture was stirred at room temperature for 18 h, then evaporated to dryness. Chromatography on silica and elution with 15-20% ethyl acetate/hexane afforded the title compound as a colourless oil (7.7 g). Mass spectrum MPT 451 (corresponds to loss of BOC group).
Example 6 - 3-[l-(2,2,2-Trifluoroacety-)-l,2-dihydro-indol-3-ylidene]-8-aza- bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (E6)
A mixture of the iodo compound E5 (0.55 g), sodium carbonate (0.3 g), sodium formate (0.07 g), palladium acetate (30 mg) and tetrabutylammonium chloride (0.3 g) in degassed DMF under argon was stirred at room temperature for 18 h. The mixture was then poured onto brine and extracted three times with ethyl acetate. The organic layer was dried and evaporated to dryness. Chromatography of the residue on silica and elution with 12% ethyl acetate/hexane afforded the title compound as a yellow solid (0.23 g). Mass spectrum MH+ 323 (corresponds to loss of BOC group).
Example 7 - £xro-3-(8-Aza-bicyclo[3.2.1]oct-3-yl)-lH-indole hydrochloride (E7)
A solution of E6 (0.7 g) in ethanol saturated with HC1 was refluxed for 3 h. The solution was then cooled and evaporated to dryness to afford the title compound as a yellow solid (0.48 g) which could be used directly for further elaboration. Mass spectrum MH4" 227.
Further purification and stereochemical analysis was achieved by conversion to the N- BOC derivative (see Example 8).
Example 8 - Erø-3-(lH-Indol-3-yI)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (E8)
A solution of the amine E7 (300 mg) in isopropanol (6 mL) was cooled to 0°C and a solution of NaOH (200 mg) in water (1 mL) added, followed by di-t-butyl-di-carbonate (220 mg). The solution was stirred for 18 h then poured onto water. The aqueous layer was extracted with ethyl acetate, washed with brine, dried and evaporated. Chromatography of the residue on silica, and elution with 15% ethyl acetate/hexane afforded the title compound (200 mg) as a colourless foam. Mass spectrum MH+ 227 (corresponds to loss of BOC group). 'H NMR: δ CDCl3 1.50 (9H, s), 1.87 (5H, m), 2.00 (3H, m), 3.43 (IH, m), 4.26 (IH, b s), 4.37 (IH, bs), 6.97 (IH, d), 7.07 ( IH, dd), 7.18 ( IH, dd), 7.35 ( I H, d), 7.61 (IH, d), 7.91 (IH, s). The stereochemistry was assigned by examination of the coupling constants of the signal at δ 3.43, in addition to nOe studies.
HPLC Analysis of Isomeric Purity
Chromatographic conditions used:
Column: Spherisorb Silica, 5um, 50x4.6mm, no. 101327203 063
Eluent: 5ml methanol (HPLC grade, Romil)/100ml dichloromethane (HPLC grade, Romil)/900ml hexane (HPLC grade, Romil)/lml triethylamine (Fisher, HPLC grade); Flow rate: 1.5ml/ min; Detection: UV at 280nm; Injection: 5ul, sample dissolved in dichloromethane/hexane.
Example 9 - 3-{2-[(2-Iodo-4-nitropheny_)-(2,2-2-trifluoroacetyl)amino]ethy_idene}-8-a__a- bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (E9)
The title compound was prepared in 52% yield from the alcohol E4 and 2-iodo-4-nitro- aniline-N-trifluoroacetamide using a procedure similar to that for Example 5. Mass spectrum M T 451 (corresponds to loss of BOC group).
Example 10 - 3-(5-Nitro-l,2-dihydro-indol-3-ylidene)-8-aza-bicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (E10)
The title compound was prepared in 74% yield from E9 using a procedure similar to that for Example 6. N.B. In this case the trifluoroacetyl group was cleaved during the work-up process. Mass spectrum [M-H]" 370.
Example 11 - Exø-3-(8-Aza-bicyclo[3.2.1]oct-3-yl)-5-nitro-lH-indole hydrochloride (Ell)
The title compound was prepared in 100% yield from E10 using a procedure similar to that for Example 7. Mass spectrunrMFT 272.