Patent Application
20070249823
The present invention provides compounds, which are useful intermediates for the production of gemcitabine, processes for producing such intermediates, and processes for producing gemcitabine therewith. Exemplary compounds of the present invention include 3-substituted, alkyl 2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxolan-4-yl)-propionate derivatives of the formula 15:
wherein R1 is unsubstituted or substituted C1-C5 saturated or unsaturated alkyl, substituted phenyl, or C1-C5 saturated or unsaturated aralkyl; R2 and R3 are independently C1-C3 alkyl; and R4 is C1-C4 alkyl. Exemplary compounds of the present invention also include 3,5-disubstituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose derivatives of the formula 16 and 16A:
wherein R1 is unsubstituted or substituted C1-C5 saturated or unsaturated alkyl, substituted phenyl, or C1-C5 saturated or unsaturated aralkyl; X is O or S; and R5 is unsubstituted or substituted phenyl, unsubstituted or substituted phenylsulfonyl, or C1-C5 alkylsulfonyl.
In accordance with the present invention, R1 includes C1-C5 saturated alkyl and C1-C5 unsaturated alkyl substituents, which may be unsubstituted or substituted phenyl (e.g., 4-chlorophenyl, which, when combined with the carbonyl, forms a 4-chlorobenzoyl), or C1-C5 saturated or unsaturated aralkyl (e.g., trans-2-phenylethenyl, which, when combined with the carbonyl, forms a cinnamoyl); R2 and R3 are the same or different and each can include, e.g., C1-C3 alkyl (e.g., methyl); and R4 includes C1-C4 alkyl (e.g., ethyl); R5 includes unsubstituted or substituted phenyl (e.g., phenyl, 4-methylphenyl, 4-chlorophenyl), unsubstituted or substituted phenylsulfonyl, or C1-C5 alkylsulfonyl; and X includes O or S.
In accordance with the present invention, gemcitabine can be prepared from compounds of the formula 16A, which are readily obtainable from compounds of formula 16. The present invention also provides methods of producing compounds of the formula 16 from compounds of the formula 15.
In a preferred embodiment, the present invention provides a method of converting a compound of the formula 16A into gemcitabine, as demonstrated in Scheme 3 below. An exemplary process of the present invention includes:
reducing a compound of the formula 16A:
to produce a lactol of the formula 19:
activating the hydroxyl group, e.g., by conversion into a sulfonate, e.g., a mesylate;
reacting the activated hydroxyl (e.g., the mesylate) with a suitably protected cytosine to produce a protected nucleoside;
optionally separating the β-anomer;
deprotecting the protected nucleoside; and,
optionally separating the β-anomer,
wherein R1 is unsubstituted or substituted C1-C5 saturated or unsaturated alkyl, unsubstituted or substituted phenyl (e.g., 4-chlorophenyl), or C1-C5 saturated or unsaturated aralkyl (e.g., a trans-2-phenylethenyl, which, together with the carbonyl forms a cinnamoyl); R5 is unsubstituted or substituted phenyl, unsubstituted or substituted phenylsulfonyl, or C1-C5 alkylsulfonyl; and X is O or S.
In another embodiment, the present invention provides processes for preparing the novel diastereomeric mixtures of (D-erythro and D-threo)-3,5-disubstituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose derivatives of the formula 16, which are valuable as precursors in the synthesis of gemcitabine. In accordance with the present invention, compounds of formula 16 preferably are prepared by a process that includes hydrolyzing a mixture of erythro and threo isomers of a 3-substituted, alkyl 2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxolan-4-yl)-propionate in the presence of an acid, to produce a 3-substituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose, and reacting the product with a compound of the formula R5NCX (17), wherein X and R5 are as defined herein. Optionally, water is removed from the reaction mixture produced in the hydrolysis step, preferably by azeotropic distillation. Preferably, compound 17 is an isocyanate or an isothiocyanate.
A preferred process of the present invention includes:
hydrolyzing a mixture of erythro and threo isomers of the 3-substituted, alkyl 2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxolan-4-yl)-propionate in the presence of a water-miscible solvent, water and an acid;
heating the mixture until the hydrolysis reaction is substantially complete;
optionally reducing the solution volume by distillation;
adding a water-immiscible solvent and removing at least a portion of the water (preferably removing at least a substantial portion of the water), e.g., by azeotropic distillation;
further distilling off the solvent mixture, to obtain a 3-substituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose as a solid;
optionally treating the 3-substituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose with activated carbon in an organic solvent and removing the activated carbon;
reacting the 3-substituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose with an isocyanate or isothiocyanate, optionally in presence of a base, and mixing until the reaction is substantially complete; and
obtaining the resulting 3,5-disubstituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose product by precipitation.
Exemplary water-miscible solvents include acetonitrile, tetrahydrofuran (THE), 2-methyltetrahydrofuran, acetone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and mixtures thereof. A preferred water-miscible solvent is acetonitrile.
Exemplary acids include methanesulfonic acid, sulfuric acid, trifluoroacetic acid, and the like, and combinations thereof. A preferred acid is trifluoroacetic acid.
Exemplary mixtures of a water-miscible solvent, water and an acid preferably include mixtures of acetonitrile, water and trifluoroacetic acid. Exemplary acetonitrile:water:trifluoroacetic acid ratios include 54/1.25/0.3 v/v/v or 160/3.75/0.9 v/v/v (acetonitrile:water:trifluoroacetic acid).
Exemplary water-immiscible solvents include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, diethylbenzene, and the like, and mixtures thereof. A preferred water-immiscible solvent is toluene.
In accordance with the present invention, the isocyanates or isothiocyanates used in the reaction preferably are selected from, e.g., 2-chloroethyl isothiocyanate, 5-chloro-2-methylphenyl isothiocyanate, 2-chloro-4-nitrophenyl isothiocyanate, 2-chlorophenyl isothiocyanate, 3-chlorophenyl isothiocyanate, 4-chlorophenyl isothiocyanate, 3-acetylphenyl isothiocyanate, 4-acetylphenyl isothiocyanate, 2-(chloromethyl)phenyl isocyanate, 2-chloro-5-methyl-phenyl isocyanate, 2-chloro-6-methylphenyl isocyanate, 3-chloro-2-methylphenyl isocyanate, 3-chloro-4-methylphenyl isocyanate, 4-(chloromethyl)-phenyl isocyanate, 4-chloro-2-methylphenyl isocyanate, 5-chloro-2-methylphenyl isocyanate, 2-chloro-4-nitrophenyl isocyanate, 2-chloro-5-nitrophenyl isocyanate, 4-chloro-2-nitrophenyl isocyanate, 4-chloro-3-nitrophenyl isocyanate, 2-chloro-2-nitrophenyl isocyanate, 2-chlorophenyl isocyanate, 3-chlorophenyl isocyanate, 4-chlorophenyl isocyanate, 3-acetylphenyl isocyanate, phenyl isocyanate, N-benzenesulfonyl isocyanate, p-toluenesulfonyl isocyanate, and o-toluenesulfonyl isocyanate.
Preferably, the isocyanate or isothiocyanate includes p-toluenesulfonyl isocyanate, phenylsulfonyl isocyanate, or 4-chlorophenyl isothiocyanate.
The base that may be used in the reaction preferably includes triethyl amine, one or more lutidines, morpholine, diisopropylethylamine, pyridine, 2-(dimethylamino)-pyridine, 4-(dimethylamino)-pyridine, and the like, and combinations thereof. In a preferred embodiment, the base is 4-(dimethylamino)-pyridine.
The present invention further provides a process for selectively isolating the D-erythro-3,5-disubstituted-2-deoxy-2,2-difluoro-pentofuranose-1-oxo-D-ribose of formula 16A:
in purity of at least 95%, from a diastereomeric mixture of (D-erythro and D-threo)-3,5-disubstituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose of the formula 16, the process comprising:
mixing the diastereomeric mixture with a non-polar solvent to dissolve at least a portion of the diastereomeric mixture;
cooling the mixture sufficiently to allow crystallization and isolating at least a portion of the crystals, e.g., by filtration, and, optionally, washing and/or drying the crystals.
Exemplary non-polar solvents, which can be used for precipitating and/or for washing include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, diethylbenzene, n-pentane, n-hexane, n-heptane, n-octane, isooctane, cyclohexane, petrol ether, and the like, and mixtures thereof. A preferred solvent used for precipitating is toluene, and preferred solvents for washing include toluene and hexane or a mixture thereof. An exemplary process of the present invention is depicted in Scheme 3.
In accordance with Scheme 3, gemcitabine further can be obtained from the D-erythro-3,5-disubstituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose of the formulae 16A by carrying out the following steps:
reducing the compound 16A with a suitable reducing agent in an organic solvent to obtain the lactol intermediate of the formula 19;
reacting the lactol intermediate of the formula 19 with methanesulfonyl chloride (MsCl) in the presence of a base to obtain the sulfonate intermediate of the formula 20;
coupling the compound 20 with bis(trimethylsilyl)-N-acetylcytosine 8, preferably at ambient temperatures using a catalyst in an organic solvent to obtain a mixture of the α and β anomers of the 3,5-diprotected-N-1-trimethylsilylacetyl-2′-deoxy-2′,2′-difluorocytidine 21;
optionally precipitating the β isomer of compound 21, thus separating the two isomers and allowing the β isomer to be isolated (e.g., by filtration); and
removing the protecting groups (e.g., by hydrolysis), to obtain gemcitabine; and
optionally separating the β anomer of gemcitabine.
In accordance with the present invention, the process using one of the starting materials D-erythro-3,5-disubstituted-2-deoxy-2,2-difluoro-1-oxo-D-ribose having the general formulae 16A (e.g., 3-cinnamoyloxy-5-(N-p-toluenesulfonyl)carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose, 3-cinnamoyloxy-5-(N-benzenesulfonyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose, 3-cinnamoyloxy-5-(N-4-chlorobenzenesulfonyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose,3-cinnamoyloxy-5-(N-4-chlorophenyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose, and 3-(4-chlorobenzoyloxy)-5-(N-4-chlorophenyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose), e.g., as depicted in Scheme 3, is more advantageous over conventional processes for obtaining gemcitabine, as the present invention provides a process that requires fewer synthetic steps, and in addition the erythro isomer 16A is obtained in high purity and yield.
The reduction of the lactone 16A, e.g., as depicted in Scheme 3, can be carried out using any suitable reducing agent such as, for example, lithium aluminium hydride, diisobutyl aluminium hydride, and sodium bis-(2-methoxyethoxy)-aluminium hydride, or the like, or a combination thereof. The reduction, e.g., as illustrated in Scheme 3, is preferably carried out using lithium aluminium hydride, particularly for commercial scale production, particularly in view of its low molecular weight and relatively high reduction capacity (4 available hydrogen atoms per molecule). The reduction also can be carried out using diisobutyl aluminium hydride (e.g., as taught in U.S. Pat. No. 4,808,614 and Chou et al., Synthesis, 565-570 (1992), although diisobutyl aluminium hydride is less preferred in view of its molecular weight and the fact that it has only 1 hydrogen atom available for reduction.
The coupling reaction, e.g., as depicted in Scheme 3, can be carried out in any suitable solvent, which can include, for example, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, toluene, one or more xylenes, and the like, and mixtures thereof. In one embodiment, the coupling reaction is carried out in 1,2-dichloroethane. Optionally, the coupling reaction can be facilitated by using a suitable catalytic reagent such as, for example, trimethylsilyl triflate (Me3SiOTf).
Removal of the protecting groups, e.g., as depicted in Scheme 3, can be carried out by using any suitable conditions, which can include, for example, basic hydrolysis, e.g., ammonia in methanol.
This example illustrates the preparation of 3-cinnamoyloxy-5-(N-p-toluenesulfonyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose.
A mixture of ethyl (D-erythro and D-threo)-3-(cinnamoyloxy)-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)-propionate [having a purity of 96% (by HPLC), a ratio of D-erythro-isomer to D-threo-isomer of 4.3 to 1; 15.6 g, 0.039 mol], acetonitrile (160 ml), CF3COOH (0.9 ml) and water (3.75 ml) was heated under reflux for 5.5 hours. Then, the water/CF3COOH/acetonitrile mixture (36 ml) was distilled off and toluene (36 ml) was added. A following portion (about 40 ml) was distilled and toluene (40 ml) was added. The procedure was repeated 4 times to obtain, while the internal temperature of the reaction mixture was about 99° C. Ethyl acetate (50 ml) and activated carbon (Darco G-60, 1.5 g) were added to the solution, and the mixture was heated under reflux for 0.5 hour. The activated carbon was collected by filtration to obtain a slightly yellow filtrate. The ethyl acetate was removed under reduced pressure, and the thus obtained residual solution was cooled to ambient temperature under nitrogen. Next, p-toluenesulfonyl isocyanate (96% purity, 8.5 g, 0.0429 mol, 1.1 equiv.) was added to the solution, and the reaction mixture was stirred at ambient temperature for 3 hours after which time a precipitate was obtained, and the mixture was kept at 5° C. overnight. The colorless precipitate was collected by filtration, washed with toluene and n-hexane and dried at 60° C. overnight to obtain 8.5 g of 3-cinnamoyloxy-5-(N-p-toluenesulfonyl)-carbamoyloxy-2-deoxy-2,2-difluoro-1-oxo-D-ribose, in 44.0% yield; mp.129-131° C. 1H NMR (CDCl3): δ=2.33 (s, 3 H, C6H4CH3), 4.46 (2 AB-q, 2 H, CH2), 4.72 (m, 1 H, 4-CH), 5.50 (m, 1 H, 3-CH), 6.45 (d, 1 H, ═CH), 7.34 (d, 2 Harom, C6H4CH3), 7.47 (m, 5 Harom, C6H5), 7.79 (d, 1 H, ═CH), 7.91 (d, 2 Harom, C6H4CH3), 8.31 (s, 1 H, SO2NHCO). 13C NMR (CDCl3): δ=21.7 (C6H4CH3), 63.1 (CH2), 68.2 (C-3, JC-F=30.0, 30.0 Hz), 77.3 (C-4), 111.2 (C-2, JC-F=256, 256 Hz), 114.6 (═CH), 128.3, 128.5, 129.0, 129.8, 131.3, 133.5, 145.5 (Carom), 148.7 (CH), 149.7 (OCONHSO2), 162.1 (C-1, JC-F=30, 30 Hz), 164.8 (OCOCH═CH). 19F NMR [δ=−118.6 (2 AB-q)], indicating that one fluorine containing product is mainly present. AOCI (negative)/MS: m/z=494.24 [M−H+].
This example illustrates the preparation of 3-cinnamoyloxy-5-(N-benzenesulfonyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose.
A mixture of ethyl (D-erythro and D-threo)-3-(cinnamoyloxy)-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)-propionate [having a purity of 96% (by HPLC), a ratio of D-erythro-isomer to D-threo-isomer of 4.3 to 1; 5.2 g, 0.013 mol], acetonitrile (54 ml), CF3COOH (0.3 ml) and water (1.25 ml) was heated under reflux for 5.5 hours. Then, the water/CF3COOH/acetonitrile mixture (13 ml) was distilled off and toluene (13 ml) was added. A following portion (about 14 ml) was distilled and toluene (14 ml) was added. The procedure was repeated 4 times while the internal temperature of the reaction mixture was about 99° C. Ethyl acetate (20 ml) and activated carbon (Darco G-60, 0.3 g) were added to the solution, and the mixture was heated under reflux for 0.5 hour. The activated carbon was collected by filtration to obtain a slightly yellow filtrate. The ethyl acetate was removed under reduced pressure, and the residual solution was cooled to ambient temperature under nitrogen. Benzenesulfonyl isocyanate (95% purity, 2.6 g, 0.0135 mol, 1.04 equiv.) was then added to the solution, and the reaction mixture was stirred at ambient temperature overnight. A colorless precipitate was collected by filtration, washed with toluene and n-hexane and dried at 60° C. overnight to obtain 2.2 g of the pure 3-cinnamoyloxy-5-(N-benzenesulfonyl)-carbamoyloxy-2-deoxy-2,2-difluoro-1-oxo-D-ribose in 35.2% yield, [α]D25+51.1° (c 1, in acetonitrile); mp.145-146.5° C. 1H NMR (CDCl3): δ=4.51 (2 AB-q, 2 H, CH2), 4.76 (q, 1 H, 4-CH), 5.55 (m, 1 H, 3-CH), 6.49 (d, 1 H, ═CH), 7.47 (m, 3 Harom,), 7.60 (m, 4 Harom,), 7.71 (t, 1 Harom), 7.83 (d, 1 H, ═CH), 8.08 (d, 2 Harom), 8.30 (s, 1 H, SO2NHCO).
13C NMR (CDCl3): δ=63.4 (CH2), 68.3 (C-3, JC-F=30.0, 30.0 Hz), 77.5 (C-4),111.4 C-2, JC-F=256, 256 Hz), 114.8 (═CH), 128.4, 128.7, 129.2, 129.4, 131.5, 133.6, 134.4, 138.1 (Carom), 148.9 (═CH), 149.7 (OCONHSO2), 162.1 (C-1, JC-F=30, 30 Hz), 165.0 (OCOCH═CH). ESI (negative)/MS: m/z=480.1 [M−H+].
This example illustrates the preparation of 3-cinnamoyloxy-5-(N-4-chlorobenzenesulfonyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose.
A mixture of ethyl (D-erythro and D-threo)-3-(cinnamoyloxy)-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)-propionate [having a purity of 96% (by HPLC), a ratio of D-erythro-isomer to the D-threo-isomer of 4.3 to 1; 5.2 g, 0.013 mole], acetonitrile (54 ml), CF3COOH (0.3 ml) and water (1.25 ml) was heated under reflux for 5.5 hours. Then, the water/CF3COOH/acetonitrile mixture (13 ml) was distilled off and toluene (13 ml) was added. A following portion (about 14 ml) was distilled and toluene (14 ml) was added. The procedure was repeated 4 times, while the internal temperature of the reaction mixture was about 99° C. Ethyl acetate (20 ml) and activated carbon (Darco G-60, 0.3 g) were added to the residual solution, and the mixture was heated under reflux for 0.5 hour. The activated carbon was collected by filtration to obtain a slightly yellow filtrate. The ethyl acetate was removed under reduced pressure, and the residual solution was cooled to ambient temperature under nitrogen. 4-chlorobenzenesulfonyl isocyanate (97% purity, 3.2 g, 0.0143 mole, 1.1 equiv.) was then added to the solution, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then kept at −20° C. for 78 hours. A colorless precipitate was collected by filtration, washed with cold toluene and n-hexane and dried at 60° C. overnight to obtain 3.1 g of pure 3-cinnamoyloxy-5-(N-4-chlorobenzene-sulfonyl)-carbamoyloxy-2-deoxy-2,2-difluoro-1-oxo-D-ribose in 43.6% yield. The crude product was dissolved in toluene (3.5 ml) and the solution was kept at 5° C. overnight. The colorless crystals were collected by filtration to give a pure 3-cinnamoyloxy-5-(N-4-chlorobenzenesulfonyl)-carbamoyloxy-2-deoxy-2,2-difluoro-1-oxo-D-ribose; total yield: 2.0 g (29.9%); [α]D25+29.3° (c 1, acetonitrile); mp 145-147° C. 1H NMR (CDCl3): δ=4.49 (2 AB-q, 2 H, CH2), 4.76(q, 1 H, 4-CH), 5.57 (m, 1 H, 3-CH), 6.43 (d, 1 H, ═CH), 7.41(m, 3 Harom), 7.50 (m, 4 Harom), 7.76 (d, 1 H, ═CH), 7.95 (d, 2 Harom), 8.89 (s, 1 H, SO2NHCO). 13C NMR (CDCl3): δ=63.3 (CH2), 68.2 (C-3, JC-F=30.0, 30.0 Hz), 77.4 (C-4, JC-F=7 Hz), 111.3 (C-2, JC-F=256, 256 Hz), 114.6 (═CH), 128.6, 129.1, 129.5, 129.8, 131.4, 133.4, 136.3, 141.0 (Carom), 148.7 (═CH), 149.9 (OCONHSO2), 162.4 (C-1, JC-F=30, 30 Hz), 165.1 (OCOCH═CH). The 19F NMR spectrum indicates that one fluorine containing product is mainly present. APCI (positive)/MS: m/z=516.14 [M+H]+.
This example illustrates the reparation of 3-cinnamoyloxy-5-(N-4-chlorophenyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose.
A mixture of ethyl (D-erythro and D-threo)-3-(cinnamoyloxy)-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)-propionate [having a purity of 96% by HPLC, a ratio of D-erythro-isomer to D-threo-isomer of 4.3 to 1; 5.2 g, 0.013 mole], acetonitrile (54 ml), CF3COOH (0.3 ml) and water (1.25 ml) was heated under reflux for 5.5 hours. Then, water/CF3COOH/acetonitrile mixture (13 ml) was distilled off and toluene (13 ml) was added. A following portion (about 14 ml) was distilled and toluene (14 ml) was added. The procedure was repeated 4 times, while the internal temperature of the reaction mixture was about 99° C. Ethyl acetate (20 ml) and an activated carbon (Darco G-60, 0.3 g) were added to the residual solution, and the mixture was heated under reflux for 0.5 hour. The activated carbon was collected by filtration to obtain a slightly yellow filtrate. The ethyl acetate was removed from the filtrate under reduced pressure, and the residual solution was cooled to ambient temperature under nitrogen. 4-chlorophenyl isocyanate (98% purity, 2.48 g, 0.0143 mol, 1.1 equiv.) and 4-(dimethylamino)-pyridine (99% purity, 0.033 g, 0.0003 mole) were then added to the solution, and the reaction mixture was stirred at 80-90° C. for 6 hours, cooled to ambient temperature, and the colorless crystals of 1,3-di(4-chlorophenyl)urea were collected by filtration. Ethyl acetate (20 ml) and an activated carbon (Darco G-60, 0.3 g) were added to the filtrate and the mixture was heated under reflux for 0.5 hour. The activated carbon was collected by filtration to obtain a slightly yellow filtrate. The solvents were removed under reduced pressure from the filtrate to yield 5.64 g of crude (D-erythro and D-threo)-3-cinnamoyloxy-5-(N-4-chlorophenylcarbamoyloxy)-2-deoxo-2,2-difluoropentofuranos-1-ulose cake in 96% yield. Toluene (12 ml) was added to the cake and the mixture was heated to obtain a solution. The solution was kept at 5° C. overnight. A colorless precipitate was collected by filtration, washed with toluene and n-hexane and dried at 60° C. overnight to obtain 2.7 g of pure 3-cinnamoyloxy-5-(N-4-chlorophenyl)-carbamoyloxy-2-deoxy-2,2-difluoro-1-oxo-D-ribose in 46% yield; [α]D25+95.0° (c 1, in acetonitrile); mp. 119-121° C. 1H NMR (CDCl3): δ=4.59 (2 AB-q, 2 H, CH2), 4.88 (q, 1 H, 4-CH), 5.67 (m, 1 H, 3-CH), 6.51 (d, 1 H, ═CH), 7.14 (s, 1 H, ArNHCO), 7.32 (m, 4 Harom,), 7.51 (m, 5 Harom), 7.84 (d, 1 H, ═CH). 13C NMR (CDCl3): δ=62.3 (CH2), 68.7 (C-3, JC-F=30.0, 30.0 Hz), 78.4 (C-4, JC-F=6 Hz), 111.6 (C-2, JC-F=256, 256 Hz), 114.8 (═CH), 120.3, 128.6, 129.1, 129.2, 131.5, 133.5, 135.8 (Carom), 148.7 (═CH), 152.3 (OCONHAr), 162.8 (C-1, JC-F=30, 30 Hz), 165.0 (OCOCH═CH). The 19F NMR spectrum indicates that one fluorine containing product is mainly present. ESI (positive)/MS: m/z=451.44[M+H]+.
This example illustrates the preparation of 3-(4-chlorobenzoyloxy)-5-(N-4-chlorophenyl)-carbamoyloxy-2-deoxo-2,2-difluoro-1-oxo-D-ribose.
A mixture of ethyl (D-erythro and D-threo)-3-hydroxy-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)-propionate [having a purity of 83% (by HPLC), a ratio of the D-erythro-isomer to the D-threo-isomer of 3.4 to 1; 6.25 g, 0.02 mol], 2,6-lutidine (4.65 ml, 0.04 mol) and 4-(dimethylamino)-pyridine (1.2 g, 0.01 mol) in ethyl acetate (30 ml) was warmed to 65-70° C. Then, a solution of 4-chlorobenzoyl chloride (3.05 ml, 0.024 mol) in ethyl acetate (25 ml) was added drop-wise for 4 hours at this temperature. The mixture was cooled to 5° C. and 2,6-lutidine hydrochloride was filtered off. The ethyl acetate was removed under reduced pressure from the filtrate to obtain 7.6 g of ethyl (D-erythro and D-threo)-3-(4-chlorobenzoyloxy)-2,2-difluoro-3-(2,2-dimethyldioxolan-4-yl)-propionate as an oil in 97% yield. Acetonitrile (82 ml), CF3COOH (0.5 ml) and water (1.9 ml) were added to the oil and the mixture was heated under reflux for 5.5 hours. Then, the water/CF3COOH/acetonitrile mixture (20 ml) was distillated and toluene (20 ml) was added. A following portion (about 20 ml) was distilled and toluene (20 ml) was added. The procedure was repeated 4 times to obtain a temperature of the reaction mixture of about 99° C. Ethyl acetate (20 ml) and activated carbon (Darco G-60, 0.4 g) were added to the residual solution, and the mixture was heated under reflux for 0.5 hour. The activated carbon was collected by filtration to obtain a slightly yellow filtrate. The ethyl acetate was removed from the filtrate under reduced pressure, and the residual solution was cooled to ambient temperature under nitrogen. 4-chlorophenyl isocyanate (98% purity, 3.45 g, 0.022 mol, 1.1 eq.) and 4-(dimethylamino)-pyridine (99% purity, 0.050 g, 0.0004 mol) were then added to the solution, and the reaction mixture was stirred at 80-90° C. for 6 hours, cooled to ambient temperature, and the colorless crystals of 1,3-di(4-chlorophenyl)urea were collected by filtration. Ethyl acetate (20 ml) and activated carbon (Darco G-60, 0.4 g) were added to the filtrate and the mixture was heated under reflux for 0.5 hour. The activated carbon was collected by filtration to obtain a slightly yellow filtrate. The solvents were removed under reduced pressure and toluene (22 ml) was added to residual oil (11 g). The mixture was heated to obtain a solution. The solution was kept at 5° C. overnight. A colorless precipitate was collected by filtration, washed with toluene and n-hexane and dried at 60° C. overnight to yield 2.75 g of 3-cinnamoyloxy-5-(N-4-chlorophenyl)-carbamoyloxy-2-deoxy-2,2-difluoro-1-oxo-D-ribose in 30.4% yield; [α]D25+91.7° (c 1, in acetonitrile); mp. 136.5-138.0° C.
1H NMR (CDCl3): δ=4.58 (2 AB-q, 2 H, CH2), 4.90 (q, 1 H, 4-CH), 5.70 (m, 1 H, 3-CH), 7.00 (s, 1 H, ArNHCO), 7.28 (m, 4 Harom,), 7.45 (d, 2 Harom), 7.98 (d, 2 Harom).
13C NMR (CDCl3): δ=62.2 (CH2), 69.2 (C-3, JC-F=30.0, 30.0 Hz), 78.3 (C-4, JC-F=6 Hz), 111.4(C-2, JC-F=256, 256 Hz), 120.2, 125.7, 129.1, 129.2, 131.5, 135.6, 141.3 (Carom), 152.1 (OCONHAr), 162.5 (C-1, JC-F=30, 30 Hz), 163.9 (OCOAr). The 19F NMR spectrum indicates that one fluorine containing product is mainly present APCI (positive)/MS: m/z=459.6 [M+H]+.
All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
| Number | Date | Country | |
|---|---|---|---|
| 60793461 | Apr 2006 | US |
