Process for preparation of 2-oxo-1-piperidinyl derivatives

Abstract: The present process involves ring opening and ring closure of compounds containing a tetrahydrofuroyl group to provide facile synthesis of compounds containing a piperidin-2-one group of the formula

Description: A novel process for preparing compounds of the formula such as, is disclosed where X is hydrogen or an oxygen protecting group; R is alkyl, cycloalkyl, aryl, hydroxyalkyl, protected hydroxyalkyl or Ra and Rb are independently selected from hydrogen, X 1 is -OX or a leaving group; R 1 and R 2 are the same or different and are hydrogen, alkyl, hydroxyalkyl or protected hydroxyalkyl; R 3 and R 4 are the same or different and are hydrogen, alkyl, hydroxyalkyl or protected hydroxyalkyl. The term alkyl refers to straight or branched chain groups of one to six carbon atoms including methyl, ethyl and propyl. Hydroxyalkyl refers to such alkyl groups having one or more hydroxy moieties. Preferred hydroxyalkyl groups include Protected hydroxyalkyl refers to hydroxyalkyl which contains a protecting group instead of hydrogen in the -OH portion. Protected hydroxyalkyl groups include but are not limited to alkoxyalkyl, acyloxyalkyl, 1,3-dioxolanyl or 1,3-dioxanyl. The cited refences include Ep-A-431838 which discloses iodinated contrast agents of formula in which Y is a bond or linkers like -CH 2 -CH 2 -, -CH 2 O-, -OCH 2 -, -NCH 2 -, -CH 2 -N-CO-, -CH 2 N-, -CH 2 -, -O-, and -N-; R 1 and R 2 are the same or different and are R3 and R4 are the same or different and are H, -CH 3 or -(CH 2 ) 2 OH; R 5 and R6 are H, alkyl, -CH 2 OH, -(CH 2 ) 2 OH, or -OH; and m = 0 or 1. The document "Organic Mass Spectroscopy" 18 (1983), 60-3, discloses mass spectra of benzyl esters and thioesters. The document J. Org. Chem. 42 (1987), 1680 discloses the stereocontrolled opening of THF derivatives by the action of Lewis acids. The present process involves ring opening and ring closure of compounds containing a tetrahydrofuroyl group to provide facile synthesis of compounds containing a piperidin-2-one group of the formula Products, for example, of formula I' are useful as contrast agents and intermediates therefor. For example, such compounds are disclosed in EP 431,838 and a related copending U. S. application entitled "Nonionic Radiographic Contrast Agents", (attorney docket RA43c) filed concurrently herewith, which compounds are of the formula where R 1 and R 2 are the same or different and are hydrogen or hydroxyalkyl; R 3 and R 4 are the same or different and are hydrogen, alkyl or -CH 2 CH 2 OH. The term alkyl refers to straight or branched chain groups of one to six carbon atoms including methyl, ethyl and propyl. Hydroxyalkyl refers to such alkyl groups having one or more hydroxy moieties. Preferred hydroxyalkyl groups include Compounds of formula Ia are prepared by Scheme B. Scheme B illustrates that an intermediate containing the tetrahydrofuroyl portion can be ring-opened prior to coupling with the triiodinated phenyl nucleus. Treatment with base to provide ring-closure to a plperidin-2-one group is carried out after coupling to the triiodinated phenyl portion when utilizing Scheme B. As described above the present process begins with the treatment of tetrahydrofuroyl derivatives, such as compound VIII below, with a Lewis acid and a source of halide or leaving group. In a preferred embodiment the Lewis acid can function as the source of halide and use of a separate compound providing additional halide or leaving group is optional. An optional compound can also be added which serves as a source of oxygen protection, X, for the -OX moiety on the piperidin-2-one products. Further, compounds which serve the dual function of providing a source of halide or leaving group and a source of oxygen protection are also useful herein. Sources of halide include chlorides, bromides, iodides, carboxylic acid halides, sulfonylhalides, trialkylsilylhalides and the like. Optional compounds suitable for providing O-protection, but not a halide or leaving group, include anhydrides, e.g., acetic anhydride. Optional compounds suitable for providing a source of halide or leaving group and O-protection for the 3-hydroxy on the piperdinyl moiety include acyl halides, e.g., acetyl chloride, sulfonyl halides, e.g., methanesulfonyl chloride, silyl halides, e.g., trimethylsilyl iodide, mixed (carbonyl-sulfonyl) anhydrides, e.g., acetyl-p-toluene sulfonic anhydride, silyl sulfonates, sulfonic anhydrides and the like. The term oxygen protecting group is well known in the art and any convenient group can be used. Such known groups, include but are not limited to methyl, benzyl, methoxy- or dimethoxybenzyl, silyl, trialkylsilyl, acyl (e.g., acetyl, formyl), alkylsulfonyl, arylsulfonyl and the like. The term leaving group refers to groups which form stable anionic species, such as alkylsulfonate, arylsulfonate, halogen, e.g., Cl, Br, I and the like or -OCOalkyl, ONR 5 R 6 (where R 5 and R 6 form succinoyl or N-hydroxybenzotriazolyl and the like). Lewis acids are understood to be any compound capable of accepting an election pair and typical Lewis acids include but are not limited to BBr 3 , MgBr 2 , ZnCl 2 , (alkyl) 2 BBr, alkylBBr 2 , FeCl 3 , SnCl 4 , AlCl 3 , TiCl 3 and BF 3 . Preferred Lewis acids are those which also function as a source of halide. Most preferred is BBr 3 . Base, as that term is used herein refers to any convenient base and may include sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium t-butoxide, organic bases, e.g., diisopropylamine, triethylamine, pyridine, diazabicyclononane, Hunig's Base and the like. The present invention is further described in the Scheme B below and the explanation which follows, each of which refers to the preferred compounds of I', i.e. where R is In Scheme B the tetrahydrofuroyl ring is opened prior to coupling with the triiodinated phenyl group. Accordingly, 2-tetrahydrofuroyl chloride IV is reacted with HOX 1 , such as benzyl alcohol (where X 1 is an oxygen protecting group, e.g., benzyl) in a solvent, e.g., pyridine, to provide VIII. Intermediate VIII is thereafter treated with a Lewis acid, e.g., ZnCl 2 and XOCl (preferably where X is an oxygen protecting group), e.g., acetyl chloride, to provide the chloro-pentanoate intermediate IX. Reductive deprotection of IX by standard methods, e.g., treatment with H 2 in the presence of Pd/C, provides compound X which is conveniently activated with, for example, oxalyl chloride to provide the chloro-pentanoyl chloride XI. Reaction of XI with a preferably O-protected XII i.e., where hydroxy groups in R 1 -R 4 are preferably, for example acetyloxy, provides the benzenedicarboxamide XIII. Treatment of XIII with a base, e.g., potassium carbonate, in a solvent, e.g., N,N-dimethylacetamide, affords the pyrrolidin-2-one compound Ia'. Standard deprotection of Ia', for example, via treatment with NaOMe in a solvent, e.g., methanol, provides compounds of Ia. Example N,N'-Bis(2,3-Dihydroxypropyl)-5-(3-hydroxy-2-one-1-piperidinyl)-2,4,6-triiodo-1,3-benzenedicarboxamide A. Tetrahydrofuroyl chloride Oxalyl chloride (63.5 g, 500 mmol) was added dropwise to tetrahydrofuroic acid 23.2 g, 200 mmol) at 0°. The solution was then stirred overnight at room temperature. Removal of excess oxalyl chloride (60°, 20 mm Hg), followed by distillation of the residue provided the desired tetrahydrofuroyl chloride as a colorless liquid (23.8 g), b.p. 88-92° at 20 mm Hg. B. Benzyl tetrahydrofuroate Tetrahydrofuroyl chloride (15.0 g, 112 mmol) was added dropwise to a cold solution of benzyl alcohol (10.9 g, 101 mmol) and pyridine (20.0 g, 253 mmol) in Et 2 O (200 mL). The solution was stirred at 0° for 40 minutes, then filtered to remove the side product pyridine hydrochloride. The filtrate was washed with 0.1 M HCl (50 mL), saturated aqueous NaHCO 3 (50 mL), and brine (50 mL), and then dried over MgSO 4 . Filtration and evaporation of the solvent gave a yellow oil, which was distilled. Benzyl tetrahydrofuroate was obtained as a colorless oil (21.1 g), b.p. 118 to 120° at 0.5 mm Hg. Microanalysis calc'd for C 12 H 14 O 3 (206.2): C, 69.89; H, 6.84; O, 23.27; Found: C, 69.62; H, 6.89. C. Benzyl 2-acetyloxy-5-chloro-pentanoate To a suspension of freshly fused ZnCl 2 (35 mg, 0.25 mmol) in acetyl chloride (31 mL, 436 mmol) was added dropwise benzyl tetrahydrofuroate (15 g, 72 mmol). The mixture was heated at reflux for 17 hours, by which time it turned black. Excess CH 3 COCl was evaporated and the residue dissolved in Et 2 O (200 mL). This solution was washed twice with saturated aqueous NaHCO 3 (50 mL). The organic layer was dried over MgSO 4 , filtered and evaporated. The black residue was chromatographed over silica gel, eluting with 20:80 EtOAc-heptane. Fractions containing the desired ester were combined and evaporated to give a yellow oil. This oil was distilled to give the title C compound as a faintly yellow oil, which crystallized after several days in the refrigerator (17.6 g), b.p. 144 to 152° at 0.1 mm Hg, m.p. 40 to 41°. Microanalysis calc'd for C 14 H 17 O 4 Cl (284.7): C, 59.06; H, 6.02; Cl, 12.45; O, 22. 48; Found: C, 59.22; H, 6.04; Cl, 12.63: D. 2-Acetyloxy-5-chloro-pentanoic acid 5% Palladium on carbon (0.96 g) was suspended in a solution of the title C compound (15.3 g, 53.7 mmol) in ethyl acetate (170 mL) and HOAc (9.0 mL). The solution was shaken under an atmosphere of hydrogen (10 psi) for 1 hour, then filtered through a bed of celite. The solvent was evaporated and the residual oil was distilled to give the title D compound as a colorless oil (9.1 g), b.p. 135 to 136° at 0.03 mm Hg. Microanalysis calc'd for C 7 H 11 O 4 Cl (194.6): C, 43.20; H, 5.70; Cl, 18.22; O, 32.88; Found: C, 42.95; H, 5.80; Cl, 17.84. E. 2-Acetyloxy-5-chloro-pentanoyl chloride Oxalyl chloride (13.1 g, 103 mmol) was added to the title D compound (7.99 g, 41.1 mmol) and stirred at 25° overnight. Distillation gave unreacted oxallyl chloride followed by the title E compound (8.51 g), b.p. 76-78° at 0.5 mm Hg). F. N,N-Bis[2,3-bis(acetyloxy)propy]-5-[(2-acetyloxy-5-chloro-1-oxopentyl)-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide The title E compound (2.77 g, 13.0 mmol) was added dropwise to a cold solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (prepared as described in EP 431,838) (8.73 g, 10.0 mmol) in dry DMA (400 mL). The solution was stirred at 25° overnight. The reaction mixture was purged with N 2 for 30 minutes to remove as much HCl as possible, then dissolved in EtOAc (200 mL) and washed with H 2 O (100 mL), cold saturated aqueous NaHCO 3 (50 mL), and brine (50 mL). The organic layer was dried over MgSO 4 , filtered, and evapoated to obtain a yellow foamy solid. This solid was chromatogrpahed over silica gel and eluted with 70:30 EtOAc-heptane. Fractions containing the product were combined and evapoated to give the title F compound as a white foamy solid (8.31 g). TLC: Rf 0.48 on silica gel, EtOAc, UV. G. N,N-Bis[2,3-bis(acetyloxy)propyl]-5-(3-acetyloxy-2-oxo-1-piperdinyl)-2,4,6-triiodo-1,3-benzenedicarboxamide Powdered K 2 CO 3 (3.32 g, 24 mmol) was added to a solution of the title F compound (6.00 g, 57.1 mmol) in DMA (29 mL) and stirred at 25° overnight. The reaction mixture was filtered and evaporated. The residual yellow oil was dissolved in ethyl acetate (100 mL) and washed with H 2 O (50 mL) and brine (50 mL). The organic layer was dried over MgSO 4 , filtered, and evaporated to give a white foamy solid. This solid was chromatographed over silica gel and eluted with 80:20 ethyl acetate-heptane. Fractions containing the pure product were combined and evaporated to give the title G compound as a white foamy solid (4.56 g). This product was identified in all respects with the peutaacetate previously described in EP431,838 and in RA43c. H. N,N'-Bis(2,3-Dihydroxypropyl)-5-(3-hydroxy-2-one-1-piperidyl)-2,4,6-triiodo-1,3-benzenedicarboxamide To a solution of the title G compound (25 mg, 0.026 mmol) in anhydrous methanol (3 mL) was added a solution of sodium methoxide in methanol (0.2 mL/0.5 M solution), and the mixture stirred for 2 hours. The solution was neutralized by addition of AG 50 W-X8(H + ) resin which was filtered off and the filtrate concentrated to give 17 mg of the title product.

Claims: A process for preparing compounds of the formula where X is H or an O-protecting group; R is alkyl, cycloalkyl, aryl, hydroxyalkyl, protected hydroxyalkyl or R a and R b are independently selected from H, -COX 1 , -CONR 1 R 3 , and -CONR 2 R 4 ; X 1 is -OX or a leaving group; R 1 and R 3 , as well as R 2 and R 4 , the same or different, are H, alkyl, hydroxyalkyl, or protected hydroxyalkyl, the term alkyl referring to straight or branched C 1-6 chain groups, and hydroxyalkyl referring to said alkyls having one or more -OH; which process includes (b) treating a compound of formula VIII with a Lewis acid, a source of halide or leaving group and optionally a source of O-protection to provide a compound of formula IX reducing the compound IX to provide compound X providing compound X with halogen or leaving group to give compound XI reacting XI with an amine of formula H 2 NR to provide and thereafter treating the formed compound with a base. The process of claim 1, wherein said Lewis acid is also said source of halide. The process of claim 2, wherein said Lewis acid is selected from BBr 3 , ZnCl 2 , (alkyl) 2 BBr, alkyl-BBr 2 , FeCl 3 , SnCl 4 , AlCl 3 , TiCl 3 , and MgBr 2 . The process of claim 3, wherein said Lewis acid is BBr 3 or Me 2 BBr The process of claim 1, wherein said source of halide or leaving group is selected from chlorides, bromides, iodides, caboxylic acid halides, sulfonyl halides and trialkylsilyl halides. The process of claim 5, wherein said source of halide is AcCl, trimethylsilyl iodide, and p-toluenesulfonyl chloride. The process of claim 1, wherein said optional source of O-protection is selected from anhydrides, sulfonyl halides, silyl halides, mixed anhydrides, silyl sulfonates and sulfonic anhydrides. The process of claim 1, wherein said source of oxygen protection also function as said source of halide or leaving group and is selected from acyl halides, sulfonyl halides, silyl halides, mixed anhydrides, silyl sulfonates and sulfonic anhydrides. The process of claim 7, wherein said source of oxygen protection is acetic anhydride. The process of claim 8, wherein said source of O-protection and of halide is selected from AcCl, methanesulfonyl chloride, trimethylsilyl iodide, and acetyl-p-sulfonic anhydride. The process of claim 1, wherein the O-protecting group X is selected from methyl, benzyl, methoxybenzyl, dimethoxybenzyl, silyl, trialkylsilyl, acyl, alkylsulfonyl, and arylsulfonyl. The process of claim 11, wherein the O-protecting group X is acetyl. The process of claim 1, wherein said leaving group is selected from halogen, alkyl sulfonates, aryl sulfonates, -OCO-alkyl, and -O-NR 5 R 6 where R 5 and R 6 , together with the N atom to which they are attached, form succinoyl or N-hydroxybenzotriazolyl groups. The process of claim 13, wherein said leaving group is Cl, Br or I. The process of claim 1, wherein said base is selected from NaHCO 3 , K 2 CO 3 , NaOH, t·Bu-OK, diisopropylamine, NEt 3 , pyridine, diazabicyclononane and Hunig's base. The process of claim 1, wherein compound VIII is treated whith a Lewis acid and an acyl halide, and wherein X is acetyl, X 1 is Cl, R a is -NR 1 R 3 , and R b is -NR 2 R 4 . The process of claim 16, wherein the Lewis acid is ZnCl 2 and the acyl halide is acetyl chloride. The process of claim 1, wherein the compounds of formula I are and A compound of the formula where X is H or an O-protecting group. A compound of the formula where X is H or an O-protecting group. A compound of the formula where X is H or an O-protecting group, and halogen is Br or Cl. A compound of the formula where at least one of R 1 and R 3 and at least one of R 2 and R 4 is a protected hydroxyl, X is H or an O-protecting group and halogen is Br or Cl.

Inventors: ARUNACHALAM THANGAVEL, NATALIE KENNETH J JR, RANGANATHAN RAMACHANDRAN S, ARUNACHALAM, THANGAVEL, NATALIE, KENNETH J., JR., RANGANATHAN, RAMACHANDRAN S.
Applicants: BRACCO INT BV, BRACCO INTERNATIONAL B.V.
Application year: 1993
Main classification: C07D211
IPC codes: C07D211, C07C235, C07C237, C07D307, C07C69