WO2024075025A1 - An industrial process for the preparation of substantially pure 2,3-o-isopropylidene-d-ribofuranose - Google Patents
An industrial process for the preparation of substantially pure 2,3-o-isopropylidene-d-ribofuranose Download PDFInfo
- Publication number
- WO2024075025A1 WO2024075025A1 PCT/IB2023/059943 IB2023059943W WO2024075025A1 WO 2024075025 A1 WO2024075025 A1 WO 2024075025A1 IB 2023059943 W IB2023059943 W IB 2023059943W WO 2024075025 A1 WO2024075025 A1 WO 2024075025A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solvent
- isopropylidene
- ether
- ribofuranose
- preparation
- Prior art date
Links
- OYYTWUSIDMJZCP-RKEPMNIXSA-N (3ar,6r,6ar)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-ol Chemical compound OC1O[C@H](CO)[C@H]2OC(C)(C)O[C@H]21 OYYTWUSIDMJZCP-RKEPMNIXSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 title abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims description 37
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 239000010410 layer Substances 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003610 charcoal Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 7
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- XSSYCIGJYCVRRK-RQJHMYQMSA-N (-)-carbovir Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1C[C@H](CO)C=C1 XSSYCIGJYCVRRK-RQJHMYQMSA-N 0.000 abstract description 3
- JGUADRHIBCXAFH-XAUFSTHISA-N (2r,3s,4r,5s)-2-[(e)-2-[2-(hydroxymethyl)-3-methoxyphenyl]ethenyl]-5-methyloxolane-3,4-diol Chemical compound COC1=CC=CC(\C=C\[C@@H]2[C@H]([C@@H](O)[C@H](C)O2)O)=C1CO JGUADRHIBCXAFH-XAUFSTHISA-N 0.000 abstract description 3
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 abstract description 3
- 229960004748 abacavir Drugs 0.000 abstract description 3
- RKSUYBCOVNCALL-NTVURLEBSA-N sapropterin dihydrochloride Chemical compound Cl.Cl.N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 RKSUYBCOVNCALL-NTVURLEBSA-N 0.000 abstract description 3
- 229960004209 sapropterin dihydrochloride Drugs 0.000 abstract description 3
- JGUADRHIBCXAFH-UHFFFAOYSA-N varitriol Natural products COC1=CC=CC(C=CC2C(C(O)C(C)O2)O)=C1CO JGUADRHIBCXAFH-UHFFFAOYSA-N 0.000 abstract description 3
- LHQIJBMDNUYRAM-UHFFFAOYSA-N L-erythro-Biopterin Natural products N1=C(N)NC(=O)C2=NC(C(O)C(O)C)=CN=C21 LHQIJBMDNUYRAM-UHFFFAOYSA-N 0.000 abstract description 2
- LHQIJBMDNUYRAM-DZSWIPIPSA-N L-erythro-biopterin Chemical compound N1=C(N)NC(=O)C2=NC([C@@H](O)[C@@H](O)C)=CN=C21 LHQIJBMDNUYRAM-DZSWIPIPSA-N 0.000 abstract 1
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000011929 di(propylene glycol) methyl ether Substances 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011174 lab scale experimental method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
Definitions
- the present invention relates to an industrial process for the preparation of 2,3-0- Isopropylidene-D-ribo furanose of formula (I).
- the intermediate formula (I) is used for the preparation of Varitriol, Carbovir, Abacavir, Sapropterin dihydrochloride, and L- Biopterin.
- the process of present invention provides the 2,3-O-Isopropylidene-D- ribo furanose of formula (I) having purity at least 98%.
- the various publications such as Journal of the American Chemical Society, 2004, vol. 126(2), p. 516-528, Tetrahedron, 2012, vol. 68, no. 5, p. 1540-1546, Heterocycles, 2018, vol. 97, no. 2, p.
- One aspect of the present invention is to provide an industrial process for preparation of substantially pure 2, 3-0-Isopropylidene-D-ribo furanose of formula (I).
- the present invention provides an industrial process for preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps: a) treating D-ribofuranose with acetone in presence of p-toluenesulfonic acid; b) adding an inorganic base to the solution from step a); c) filtering the solution from step b), concentrating, adding water and saturated hydrocarbon solvent followed by separating aqueous layer; d) adding sodium chloride to aqueous layer from step c); e) extracting the solution of step d) with solvent; f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica; g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).
- the present invention provides an industrial process for preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps: a) treating D-ribofuranose with acetone in presence of p-toluenesulfonic acid; b) adding sodium carbonate to the solution from step a); c) filtering the solution from step b), concentrating, adding water and n-heptane followed by separating aqueous layer; d) adding sodium chloride to aqueous layer from step c); e) extracting the solution of step d) with solvent; f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica; g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I). DETAILED DESCRIPTION OF THE INVENTION
- solvent refers to one or more solvents.
- substantially pure used herein indicates purity not less than 98%.
- the present invention provides an industrial process for preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps: a) treating D-ribofuranose with acetone in presence of p-toluene sulfonic acid b) adding inorganic base to the solution from step a); c) filtering the solution from step b), concentrating, adding water and saturated hydrocarbon solvent followed by separating aqueous layer; d) adding sodium chloride to aqueous layer from step c); e) extracting the solution of step d) with solvent; f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica; g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).
- the solvent may be selected from the group consisting of ether solvents such as methyl-tertiary-butyl ether, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, ethyl tert-butyl ether, di-tert-butyl ether, di(propylene glycol) methyl ether, dimethoxyethane, dimethoxymethane, 1,4- dioxane alcoholic solvents such as methanol, ethanol, isopropanol; acetate solvents such as ethyl acetate, isopropyl acetate and the like or mixture of solvents thereof.
- ether solvents such as methyl-tertiary-butyl ether, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, ethyl tert-butyl ether, di-tert-
- an inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate and the like.
- the saturated hydrocarbon solvent is selected from n-hexane, n-heptane, toluene, cyclohexane, n-pentane and the like.
- a solvent used in step (e) is selected from ester solvent, ether solvent, chlorinated solvent, alcoholic solvent, and saturated hydrocarbon solvent.
- an ester solvent used in step (e) is selected from ethyl acetate, butyl acetate, methyl acetate, isopropyl acetate and the like.
- an ether solvent is selected from dimethyl ether, diethyl ether, isopropyl ether, 2-methyl tetrahydrofuran, petroleum ether, tetrahydrofuran, dioxane, methyl ter-butyl ether and the like.
- an alcoholic solvent is n- butanol.
- chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform and the like.
- step (c) to step (f) are performed at -10°C to 65°C.
- step (g) is performed at -35°C to 120°C.
- 3-O-Isopropylidene-D-ribo furanose of formula (I) involves simple work up process using water which is a cheap and eco-friendly solvent.
- crude compound may be used as such or may be purified by distillation or crystallization or by different techniques well understood by those skilled in the art.
- Example 1 Preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) using p-toluene sulfonic add and purified by using celite and charcoal.
- acetone (6-10 V) and D-ribo furanose (1.0 eq) were charged under inert atmosphere at room temperature (rt).
- the reaction mixture was cooled and p-toluene sulfonic acid (0.02 - 0.1 eq) was added and further stirred for 30 min.
- the temperature of the reaction mixture was raised to 20°C to 40°C and stirred for 4 to 6 hr.
- solid sodium carbonate (10-15 % w/w) was added and the solution was filtered.
- Example 2 Preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) using p-toluene sulfonic add and silica.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The present invention relates to an industrial process for the preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I). The intermediate of formula (I) is used for the preparation of Varitriol, Carbovir, Abacavir, Sapropterin dihydrochloride, L-Biopterin. The process of present invention provides the 2,3-O-Isopropylidene-D-ribofuranose of formula (I) having purity at least 98%.
Description
AN INDUSTRIAL PROCESS FOR THE PREPARATION OF
SUBSTANTIALLY PURE 2,3-O-ISOPROPYLIDENE-D-RIBOFURANOSE
RELATED APPLICATION
This application claims the benefit to Indian Provisional Application No. IN202221057046, filed on October 04, 2022, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to an industrial process for the preparation of 2,3-0- Isopropylidene-D-ribo furanose of formula (I). The intermediate formula (I) is used for the preparation of Varitriol, Carbovir, Abacavir, Sapropterin dihydrochloride, and L- Biopterin. The process of present invention provides the 2,3-O-Isopropylidene-D- ribo furanose of formula (I) having purity at least 98%.
BACKGROUND OF THE INVENTION
2,3-O-Isopropylidene-D-ribofuranose of formula (I), chemically known as (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d] [l,3]dioxol-4-ol, is an intermediate of various active compounds such as Varitriol, Carbovir, Abacavir, Sapropterin dihydrochloride, L-B iopterin etc.
The various publications such as Journal of the American Chemical Society, 2004, vol. 126(2), p. 516-528, Tetrahedron, 2012, vol. 68, no. 5, p. 1540-1546, Heterocycles, 2018, vol. 97, no. 2, p. 776-784, US20060241064A1, WO200975818A1, WO2017161349A1, WO200747793A1, WO2008124157A1, W02020205867A1, disclose the preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) using D-ribofuranose, p- toluenesulfonic acid or sulfuric acid & acetone, however, these processes are having one or more disadvantage(s) such as: i) more cycle time, ii) uses additional reagent such as 2,2-dimethoxypropane or imidazole, iii) more number of impurities, , iv) use of column chromatography for purification, v) less yield & purity which makes process uneconomical & unsuitable on industrial scale. Though the several prior art literatures disclosed the preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I), using acid catalyst such as p-toluenesulfonic acid, sulphuric acid, perchloric acid or hydrochloric acid, however, the maximum yield and purity is not reproducible in lab scale experiments, ultimately unsuitable on industrial scale. Therefore, there is need of an industrial and economical process for the preparation of substantially pure 2,3-0- Isopropylidene-D-ribo furanose of formula (I) with high yield using selective acid catalyst, optimized reaction conditions such as temperature, purification, and simple isolation steps.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide an industrial process for preparation of substantially pure 2, 3-0-Isopropylidene-D-ribo furanose of formula (I).
In an embodiment, the present invention provides an industrial process for preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps:
a) treating D-ribofuranose with acetone in presence of p-toluenesulfonic acid; b) adding an inorganic base to the solution from step a); c) filtering the solution from step b), concentrating, adding water and saturated hydrocarbon solvent followed by separating aqueous layer; d) adding sodium chloride to aqueous layer from step c); e) extracting the solution of step d) with solvent; f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica; g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).
In an embodiment, the present invention provides an industrial process for preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps:
a) treating D-ribofuranose with acetone in presence of p-toluenesulfonic acid; b) adding sodium carbonate to the solution from step a); c) filtering the solution from step b), concentrating, adding water and n-heptane followed by separating aqueous layer; d) adding sodium chloride to aqueous layer from step c); e) extracting the solution of step d) with solvent; f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica; g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described in more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.
The term “solvent” used herein, refers to one or more solvents.
The term “substantially pure” used herein indicates purity not less than 98%.
In one embodiment, the present invention provides an industrial process for preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps:
a) treating D-ribofuranose with acetone in presence of p-toluene sulfonic acid b) adding inorganic base to the solution from step a); c) filtering the solution from step b), concentrating, adding water and saturated hydrocarbon solvent followed by separating aqueous layer; d) adding sodium chloride to aqueous layer from step c); e) extracting the solution of step d) with solvent; f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica; g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).
The process of the present invention is illustrated in the following synthetic scheme:
D-ribofuranose (I)
In another embodiment of the present invention, wherein the solvent may be selected from the group consisting of ether solvents such as methyl-tertiary-butyl ether, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, ethyl tert-butyl ether, di-tert-butyl ether, di(propylene glycol) methyl ether, dimethoxyethane, dimethoxymethane, 1,4- dioxane alcoholic solvents such as methanol, ethanol, isopropanol; acetate solvents such as ethyl acetate, isopropyl acetate and the like or mixture of solvents thereof.
In another embodiment of the present invention, wherein the D-ribo furanose treated with acetone in presence of p-toluene sulfonic acid at -10°C to 15°C and stirred at 15°C to 40°C to achieve better conversion to product and to form less impurities.
In another embodiment of the present invention, wherein an inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate and the like.
In another embodiment of the present invention, wherein addition of inorganic base is performed at -10°C to 40°C.
In another embodiment of the present invention, wherein the saturated hydrocarbon solvent is selected from n-hexane, n-heptane, toluene, cyclohexane, n-pentane and the like.
In another embodiment of the present invention, wherein the mixture of celite and Charcoal or silica is used in a ratio of 1:1 to 1:2 w/w.
In another embodiment of the present invention, wherein the sodium chloride is added with 20 to 40% w/w.
In another embodiment of the present invention, wherein a solvent used in step (e) is selected from ester solvent, ether solvent, chlorinated solvent, alcoholic solvent, and saturated hydrocarbon solvent.
In another embodiment of the present invention, wherein an ester solvent used in step (e) is selected from ethyl acetate, butyl acetate, methyl acetate, isopropyl acetate and the like.
In another embodiment of the present invention, wherein an ether solvent is selected from dimethyl ether, diethyl ether, isopropyl ether, 2-methyl tetrahydrofuran, petroleum ether, tetrahydrofuran, dioxane, methyl ter-butyl ether and the like.
In another embodiment of the present invention, wherein an alcoholic solvent is n- butanol.
In another embodiment of the present invention, wherein chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform and the like.
In another embodiment of the present invention, wherein step (c) to step (f) are performed at -10°C to 65°C.
In another embodiment of the present invention, wherein step (g) is performed at -35°C to 120°C.
In another embodiment of the present invention, wherein an industrial process for the preparation of 2, 3-O-Isopropylidene-D-ribo furanose of formula (I) involves simple work up process using water which is a cheap and eco-friendly solvent.
In another embodiment of the present invention, wherein crude compound may be used as such or may be purified by distillation or crystallization or by different techniques well understood by those skilled in the art.
In another embodiment, 2, 3-O-Isopropylidene-D-ribo furanose of formula (I) is obtained by the process of the present invention with chemical purity at least 98%.
The preparation of the starting materials and reagents used in the present invention are well known in prior art.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
EXPERIMENTAL
Example 1: Preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) using p-toluene sulfonic add and purified by using celite and charcoal.
In RBF, acetone (6-10 V) and D-ribo furanose (1.0 eq) were charged under inert atmosphere at room temperature (rt). The reaction mixture was cooled and p-toluene sulfonic acid (0.02 - 0.1 eq) was added and further stirred for 30 min. The temperature of the reaction mixture was raised to 20°C to 40°C and stirred for 4 to 6 hr. To the reaction mixture, solid sodium carbonate (10-15 % w/w) was added and the solution was filtered. The acetone (1-2 Vol) was distilled out and n-heptane (3-5 Vol) was added to reaction mass. The n-Heptane was distilled out till minimum stirrable volume (1-2 Vol). To the reaction mass, water (1-2 V) was added while stirring. The organic and aqueous layer were separated. The aqueous layer was washed with n-Heptane. To the aqueous layer, solid sodium chloride was added. This solution was extracted with methyl tert-butyl ether (MTBE). The combined organic layer was distilled out to residual 2-4 Vol. To the reaction a mixture of celite and charcoal (1:1 to 1:2, 0.5-1 w/w) was added. The reaction mixture was stirred for 6 to 10 hrs and filtered. The solvent was distilled out to obtain yellowish viscous oil 2,3-O-Isopropylidene-D-ribofuranose of formula (I, with Chemical yield >80%, and GC purity >98%, and GC Assay > 98%).
Example 2: Preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) using p-toluene sulfonic add and silica.
In RBF, acetone (6-10 V) and D-ribo furanose (1.0 eq) were charged under inert atmosphere at room temperature (rt). The reaction mixture was cooled, p-toluene sulfonic acid (0.02 - 0.1 eq) was added and stirred for 30 min. The temperature of the reaction mixture was raised to 20°C to 40°C and stirred for 4 to 6 hr. To the reaction mixture, solid sodium carbonate (10-15 % w/w) was added and the solution was filtered. The acetone (1-2 Vol) was distilled out and n-heptane (3-5 Vol) was added to reaction mass. The n- Heptane was distilled out till minimum stirrable volume (1-2 Vol). To the reaction mass, water (1-2 V) was added, and layer was separated. The aqueous layer was washed with n-Heptane. To the aqueous layer, solid sodium chloride was added and extracted with methyl tert-butyl ether (MTBE). The combined organic layers were distilled out to residual 2-4Vol, and silica gel (0.5 to 1 w/w) was added. The reaction mixture was stirred for 6 to 10 hrs and filtered. The organic layer was distilled out to obtain yellowish viscous oil of 2, 3-O-Isopropylidene-D-ribo furanose of formula (I, with chemical yield >76%, and GC purity> 97.8%).
Claims
CLAIM:
1) A process for the preparation of preparation of substantially pure 2,3-O-Isopropylidene-D- ribo furanose of formula (I),
which comprises the steps: a) treating D-ribofuranose with acetone in presence of p-toluenesulfonic acid; b) adding an inorganic base to the solution from step a); c) filtering the solution from step b), concentrating, adding water and saturated hydrocarbon solvent followed by separating aqueous layer; d) adding sodium chloride to aqueous layer from step c); e) extracting the solution of step d) with solvent; f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica; g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).
2) The process as claimed in claim 1, where inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and cesium carbonate.
3) The process as claimed in claim 1, wherein the saturated hydrocarbon solvent is selected from n-hexane, n-heptane, toluene, cyclohexane, and n-pentane.
4) The process as claimed in claim 1, wherein solvent used in step (e) is selected from ester solvent, ether solvent, chlorinated solvent, alcoholic solvent, and saturated hydrocarbon solvent.
5) The process as claimed in claim 4, wherein an ester solvent is selected from ethyl acetate, butyl acetate, methyl acetate, isopropyl acetate; an ether solvent is selected from dimethyl ether, diethyl ether, isopropyl ether, 2-methyl tetrahydrofuran, petroleum ether, tetrahydrofuran, dioxane, methyl ter-butyl ether; an alcoholic solvent is n-butanol and chlorinated solvent is selected from dichloromethane, dichloroethane, and chloroform.
) The process as claimed in claim 1, wherein the sodium chloride is added with 20 to 40% w/w, and the mixture of celite with Charcoal or silica is used in a ratio of 1:1 to 1:2 w/w. ) The process as claimed in claim 1, wherein substantially pure 2,3-O-Isopropylidene-D- ribofuranose having purity atleast 98%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202221057046 | 2022-10-04 | ||
| IN202221057046 | 2022-10-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024075025A1 true WO2024075025A1 (en) | 2024-04-11 |
Family
ID=90607628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2023/059943 WO2024075025A1 (en) | 2022-10-04 | 2023-10-04 | An industrial process for the preparation of substantially pure 2,3-o-isopropylidene-d-ribofuranose |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2024075025A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101845066A (en) * | 2010-05-28 | 2010-09-29 | 河南省健康伟业医药科技有限公司 | Synthetic method of capecitabine intermediate 5-deoxy-D-ribofuranose |
| CN105037453A (en) * | 2015-07-14 | 2015-11-11 | 启东东岳药业有限公司 | Preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside |
| CN109369736A (en) * | 2018-10-29 | 2019-02-22 | 广安凯特制药有限公司 | A kind of preparation method of high-purity capecitabine key intermediate |
-
2023
- 2023-10-04 WO PCT/IB2023/059943 patent/WO2024075025A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101845066A (en) * | 2010-05-28 | 2010-09-29 | 河南省健康伟业医药科技有限公司 | Synthetic method of capecitabine intermediate 5-deoxy-D-ribofuranose |
| CN105037453A (en) * | 2015-07-14 | 2015-11-11 | 启东东岳药业有限公司 | Preparation method of methyl-2,3-O-isopropylidene-5-deoxy-D-ribofuranoside |
| CN109369736A (en) * | 2018-10-29 | 2019-02-22 | 广安凯特制药有限公司 | A kind of preparation method of high-purity capecitabine key intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7208640B2 (en) | Process for isolating highly pure 2-methoxypropene | |
| Pearce et al. | Synthesis and absolute configuration of multistriatin | |
| Aoki et al. | Total syntheses of natural pseurotins A, F2, and azaspirene | |
| EP2048139B1 (en) | PROCESS FOR PRODUCTION OF (±)-3a,6,6,9a TETRAMETHYLDECAHYDRONAPHTHO[2,1-b]FURAN-2(1H)-ONE | |
| CN101341139B (en) | Propylene oxide purification and recovery | |
| WO2024075025A1 (en) | An industrial process for the preparation of substantially pure 2,3-o-isopropylidene-d-ribofuranose | |
| US4659809A (en) | Process for production of sugar ketals | |
| US9745236B2 (en) | Method for recovering di-trimethylolpropane by distillation | |
| WO2009023260A2 (en) | An improved process for synthesis of pyrrole derivative, an intermediate for atorvastatin | |
| CN110724173B (en) | Sulfonic acid catalysis-based method for directionally transferring hydroxy-m-benzoyl | |
| US10836776B2 (en) | Process for preparation of eribulin and intermediates thereof | |
| DK2643326T3 (en) | A process for the preparation of (3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-ol | |
| Panek et al. | Double stereodifferentiation in the Lewis acid promoted C-glycosidation of activated glycals with chiral (E)-crotylsilanes | |
| Pasetto et al. | A Mitsunobu route to C-glycosides | |
| Davoli et al. | Lipase-catalyzed resolution and desymmetrization of 2-hydroxymethylaziridines | |
| EP2331549B1 (en) | Method for preparing 1,6:2,3-dianhydro-beta-d-mannopyranose | |
| EP0521571B1 (en) | Procedure for the preparation of bicyclo [3.2.0] hept-2-en-7-ones | |
| Claire et al. | Complex tetrahydrofurans from carbohydrate lactones: Easy access to epimeric C-glycosides of glucofuranose from d-glycero-d-gulo-heptono-1, 4-lactone | |
| JP2008510761A5 (en) | ||
| Salomon | Bis-chlorodibutyltin oxide as a new reagent for a mild, versatile and regioselective ring-opening of epoxides | |
| US6207841B1 (en) | Bisphenol derivative and its manufacturing method | |
| TAMOTO et al. | Elucidation of the racemization mechanism of the α-hydroxy ketone moiety (C9-position) of optically active anthracyclinone derivatives | |
| Bian et al. | Scalable, Stereocontrolled, Total Synthesis of Carolacton | |
| KR100375961B1 (en) | Process for the preparation of protected 3-amino-1,2-dihydroxypropane acetal and derivatives thereof | |
| Horneman et al. | Highly Functionalised Cyclopentanes by Radical Cyclisation of Unsaturated Bromolactones III. Preparation of Carbaaldohexofuranoses. Determination of the Relative Configuration at C-4/C-5 of 2, 3-Unsaturated Heptono-1, 4-lactones by Means of 1H NMR Spectroscopy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23874410 Country of ref document: EP Kind code of ref document: A1 |