CN105859811A - Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine - Google Patents
Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine Download PDFInfo
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- CN105859811A CN105859811A CN201610292810.8A CN201610292810A CN105859811A CN 105859811 A CN105859811 A CN 105859811A CN 201610292810 A CN201610292810 A CN 201610292810A CN 105859811 A CN105859811 A CN 105859811A
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- 0 CCC[C@]1C(C)(C)[C@](N(CC(*2)=[U])C=CC2=[U])O[C@@]1C* Chemical compound CCC[C@]1C(C)(C)[C@](N(CC(*2)=[U])C=CC2=[U])O[C@@]1C* 0.000 description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention relates to a preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (I). The preparation method comprises the steps that (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine 3', 5- dibenzoate (II) is adopted as the raw material, and catalysis for deprotection is conducted through a catalyst in anhydrous polar solvent, so that the (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (I) is obtained, wherein the catalyst is a mixture of inorganic base and inorganic salt or an alcoholic alkali metal compound. The preparation method has the advantages that an inorganic compound or the alcoholic alkali metal compound is adopted, reaction time is shorted and only needs 4-10 hours, a reaction is conducted completely, the post-treatment mode is simplified, the production cycle is shorted, and in addition, the inorganic compound is relatively low in price, so that production cost is lowered; meanwhile, the yield of a product prepared through the preparation method can reach 95% or above, and extremely great industrialized production prospect is achieved.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, relate to the preparation of a kind of pharmaceutical intermediate, relate to especially
And a kind of (2 ' R)-2 '-deoxidation-2 ' preparation method of-fluoro-2 '-MU glycosides.
Background technology
Suo Feibuwei (Sofosbuvir) Shi Ji Leadd B.V is developed for treating chronic third
The new drug of liver, Nikkei U.S. food Drug Administration December 6 in 2013 (FDA)
Ratify to list in the U.S., Nikkei in January 16 Europe drug administration (EMEA) batch in 2014
Accurate in EU countries's listing.The most not in Discussion on Chinese Listed.
(2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides (I) is synthesis Suo Feibuwei
Key intermediate, with intermediate in the current disclosed patent preparing Suo Feibuwei
(2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-methyluridine, 3 ', 5 '-dibenzoate (II) is
Raw material, uses organic base catalytic deprotection, reacts and within 12-20 hour, obtain formula I.
Using organic base catalytic deprotection formula II in above-mentioned route, the reaction time is longer, deposits
React incomplete phenomenon, add the difficulty of purification formula I, and organic base price
Relatively expensive, amid all these factors cause production cost to increase.
Summary of the invention
The technical problem to be solved in the present invention is to provide one can reduce production cost and reaction
Time, and (2 ' R)-the 2 '-deoxidation-2 of product yield can be improved ' system of-fluoro-2 '-MU glycosides
Preparation Method.
For solving above-mentioned technical problem, the technical scheme is that one (2 ' R)-2 '-de-
Oxygen-2 preparation method of-fluoro-2 '-MU glycosides (I) ', with (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-
Methyluridine 3 ', 5 '-dibenzoate (II) is raw material, through urging in anhydrous polar solvent
Agent catalysis deprotection, obtains (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides (I), its
Innovative point is: described catalyst is inorganic base and the mixture of inorganic salts or the alkali metal class of alcohol
Compound, concrete reaction is as follows:
Further, when described catalyst is the mixture of inorganic base and inorganic salts, its consumption is
(2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-methyluridine, 3 ', 5 '-dibenzoate (II)
0.02-0.01 times, the reaction time is 5-10 hour.
Further, described inorganic base is NaOH, sodium carbonate, potassium carbonate or hydroxide
Potassium, inorganic salts are anhydrous sodium sulfate or anhydrous magnesium sulfate.
Further, when described catalyst is the alkali metal compounds of alcohol, its consumption is
(2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-methyluridine, 3 ', 5 '-dibenzoate (II)
0.1-1.0 times, the reaction time is 4-10 hour.
Further, the resin removing the alkali metal compounds catalyst of alcohol and the salt of generation is
Resin cation.
Further, described resin cation is strong acidic ion resin.
It is an advantage of the current invention that: the present invention compared with prior art, use inorganic compound or
The alkali metal compounds of alcohol replaces organic base so that the reaction time shortens, and only needs 4-10 little
Time, and reaction is more complete, simplifies post processing mode and production cycle, and inorganic chemical
Price lattice are relatively cheap, amid all these factors make production cost reduce；Meanwhile, by this system
(2 ' R)-the 2 '-deoxidation-2 that Preparation Method prepares '-fluoro-2 '-MU glycosides, yield reaches as high as 95%
Above, there is great industrial production prospect.
Detailed description of the invention
The following examples can make professional and technical personnel that the present invention is more fully understood, but
The most therefore limit the present invention among described scope of embodiments.
Embodiment 1
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and NaOH 1.00g (0.03mol) and anhydrous sodium sulfate 1.00g
(0.01mol), stirring, the white muddiness of reactant liquor, be warming up to backflow, when reaction system in
After brown color clarification, react 7 hours, reactant liquor is concentrated to dryness, heavily ties with ethyl acetate
Crystalline substance, obtains chemical compounds I crude product 82.16g.
Be added to absolute methanol 500mL in above-mentioned crude product to stir to complete molten after drip 10%H2SO4/
Methanol solution makes system pH to neutral, and activated carbon decolorizing concentrates does to obtain white granular solid, makes
Recrystallize with absolute ethyl alcohol and ethyl acetate mixed solvent, suction filtration, dry to obtain fine work chemical compounds I
70.01g, yield 90.02%.
Embodiment 2
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and NaOH 1.00g (0.03mol) and anhydrous magnesium sulfate 1.00g
(0.01mol), stirring, the white muddiness of reactant liquor, be warming up to backflow, when reaction system in
After brown color clarification, react 7 hours, reactant liquor is concentrated to dryness, heavily ties with ethyl acetate
Crystalline substance, obtains chemical compounds I crude product 81.19g.
Be added to absolute methanol 500mL in above-mentioned crude product to stir to complete molten after drip 10%H2SO4/
Methanol solution makes system pH to neutral, and activated carbon decolorizing concentrates does to obtain white granular solid, makes
Recrystallize with absolute ethyl alcohol and ethyl acetate mixed solvent, suction filtration, dry to obtain fine work chemical compounds I
70.11g, yield 90.15%.
Embodiment 3
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and sodium carbonate 1.00g (0.01mol) and anhydrous sodium sulfate 1.00g
(0.01mol), stirring, the white muddiness of reactant liquor, be warming up to backflow, when reaction system in
After brown color clarification, react 8 hours, reactant liquor is concentrated to dryness, heavily ties with ethyl acetate
Crystalline substance, obtains chemical compounds I crude product 78.17g.
Be added to absolute methanol 500mL in above-mentioned crude product to stir to complete molten after drip 10%H2SO4/
Methanol solution makes system pH to neutral, and activated carbon decolorizing concentrates does to obtain white granular solid, makes
Recrystallize with absolute ethyl alcohol and ethyl acetate mixed solvent, suction filtration, dry to obtain fine work chemical compounds I
68.12g, yield 87.59%.
Embodiment 4
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and sodium carbonate 1.00g (0.01mol) and anhydrous magnesium sulfate 1.00g
(0.01mol), stirring, the white muddiness of reactant liquor, be warming up to backflow, when reaction system in
After brown color clarification, react 8 hours, reactant liquor is concentrated to dryness, heavily ties with ethyl acetate
Crystalline substance, obtains chemical compounds I crude product 78.23g.
Be added to absolute methanol 500mL in above-mentioned crude product to stir to complete molten after drip 10%H2SO4/
Methanol solution makes system pH to neutral, and activated carbon decolorizing concentrates does to obtain white granular solid, makes
Recrystallize with absolute ethyl alcohol and ethyl acetate mixed solvent, suction filtration, dry to obtain fine work chemical compounds I
68.01g, yield 87.45%.
Embodiment 5
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and potassium carbonate 1.00g (0.01mol) and anhydrous sodium sulfate 1.00g
(0.01mol), stirring, the white muddiness of reactant liquor, be warming up to backflow, when reaction system in
After brown color clarification, react 5 hours, reactant liquor is concentrated to dryness, heavily ties with ethyl acetate
Crystalline substance, obtains chemical compounds I crude product 83.44g.
Be added to absolute methanol 500mL in above-mentioned crude product to stir to complete molten after drip 10%H2SO4/
Methanol solution makes system pH to neutral, and activated carbon decolorizing concentrates does to obtain white granular solid, makes
Recrystallize with absolute ethyl alcohol and ethyl acetate mixed solvent, suction filtration, dry to obtain fine work chemical compounds I
75.01g, yield 96.45%.
Embodiment 6
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and potassium carbonate 1.00g (0.01mol) and anhydrous magnesium sulfate 1.00g
(0.01mol), stirring, the white muddiness of reactant liquor, be warming up to backflow, when reaction system in
After brown color clarification, react 5 hours, reactant liquor is concentrated to dryness, heavily ties with ethyl acetate
Crystalline substance, obtains chemical compounds I crude product 83.41g.
Be added to absolute methanol 500mL in above-mentioned crude product to stir to complete molten after drip 10%H2SO4/
Methanol solution makes system pH to neutral, and activated carbon decolorizing concentrates does to obtain white granular solid, makes
Recrystallize with absolute ethyl alcohol and ethyl acetate mixed solvent, suction filtration, dry to obtain fine work chemical compounds I
75.11g, yield 96.58%.
Embodiment 7
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and potassium hydroxide 1.00g (0.02mol) and anhydrous sodium sulfate 1.00g
(0.01mol), stirring, the white muddiness of reactant liquor, be warming up to backflow, when reaction system in
After brown color clarification, react 6 hours, reactant liquor is concentrated to dryness, heavily ties with ethyl acetate
Crystalline substance, obtains chemical compounds I crude product 79.77g.
Be added to absolute methanol 500mL in above-mentioned crude product to stir to complete molten after drip 10%H2SO4/
Methanol solution makes system pH to neutral, and activated carbon decolorizing concentrates does to obtain white granular solid, makes
Recrystallize with absolute ethyl alcohol and ethyl acetate mixed solvent, suction filtration, dry to obtain fine work chemical compounds I
72.11g, yield 92.72%.
Embodiment 8
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and potassium hydroxide 1.00g (0.02mol) and anhydrous sodium sulfate 1.00g
(0.01mol), stirring, the white muddiness of reactant liquor, be warming up to backflow, when reaction system in
After brown color clarification, react 6 hours, reactant liquor is concentrated to dryness, heavily ties with ethyl acetate
Crystalline substance, obtains chemical compounds I crude product 79.22g.
Be added to absolute methanol 500mL in above-mentioned crude product to stir to complete molten after drip 10%H2SO4/
Methanol solution makes system pH to neutral, and activated carbon decolorizing concentrates does to obtain white granular solid, makes
Recrystallize with absolute ethyl alcohol and ethyl acetate mixed solvent, suction filtration, dry to obtain fine work chemical compounds I
72.21g, yield 92.85%.
(2 ' R)-the 2 '-deoxidation-2 that embodiment 1-8 is prepared '-fluoro-2 '-MU glycosides, yield
Between 87.45%～96.58%, and each embodiment compares, and the yield of embodiment 6 is the highest,
Be 96.58%, i.e. the preferred sodium carbonate of inorganic base in embodiment, the preferred anhydrous magnesium sulfate of inorganic salts.
Embodiment 9
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and potassium methoxide 15.75g (0.23mol), stirring, reactant liquor is white
Muddiness, is warming up to backflow, after reaction system is brown color clarification, reacts 4 hours, adds
Enter 732 type strong acidic ion resins, filter, reactant liquor is concentrated to dryness, uses methyl-tert fourth
Base ether recrystallizes, and dries to obtain chemical compounds I 75.01g, yield 96.45%.
Embodiment 10
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and sodium methoxide 12.15g (0.23mol), stirring, reactant liquor is white
Muddiness, is warming up to backflow, after reaction system is brown color clarification, reacts 4 hours, adds
Enter 732 type strong acidic ion resins, filter, reactant liquor is concentrated to dryness, uses methyl-tert fourth
Base ether recrystallizes, and dries to obtain chemical compounds I 75.11g, yield 96.58%.
Embodiment 11
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and potassium ethoxide 20.16g (0.24mol), stirring, reactant liquor is white
Muddiness, is warming up to backflow, after reaction system is brown color clarification, reacts 5 hours, adds
Enter 732 type strong acidic ion resins, filter, reactant liquor is concentrated to dryness, uses methyl-tert fourth
Base ether recrystallizes, and dries to obtain chemical compounds I 74.21g, yield 95.42%.
Embodiment 12
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and caustic alcohol 16.32g (0.24mol), stirring, reactant liquor is white
Muddiness, is warming up to backflow, after reaction system is brown color clarification, reacts 6 hours, adds
Enter 732 type strong acidic ion resins, filter, reactant liquor is concentrated to dryness, uses methyl-tert fourth
Base ether recrystallizes, and dries to obtain chemical compounds I 73.74g, yield 94.81%.
Embodiment 13
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and potassium propoxide 29.40g (0.30mol), stirring, reactant liquor is white
Muddiness, is warming up to backflow, after reaction system is brown color clarification, reacts 7 hours, adds
Enter 732 type strong acidic ion resins, filter, reactant liquor is concentrated to dryness, uses methyl-tert fourth
Base ether recrystallizes, and dries to obtain chemical compounds I 71.01g, yield 91.31%.
Embodiment 14
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and sodium propoxide 24.60g (0.30mol), stirring, reactant liquor is white
Muddiness, is warming up to backflow, after reaction system is brown color clarification, reacts 7 hours, adds
Enter 732 type strong acidic ion resins, filter, reactant liquor is concentrated to dryness, uses methyl-tert fourth
Base ether recrystallizes, and dries to obtain chemical compounds I 71.81g, yield 92.33%.
Embodiment 15
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and butanol potassium 33.60g (0.30mol), stirring, reactant liquor is white
Muddiness, is warming up to backflow, after reaction system is brown color clarification, reacts 7 hours, adds
Enter 732 type strong acidic ion resins, filter, reactant liquor is concentrated to dryness, uses methyl-tert fourth
Base ether recrystallizes, and dries to obtain chemical compounds I 70.11g, yield 90.15%.
Embodiment 16
Urea glycosidation thing 140.00g (0.30mol) is added in the 1L there-necked flask of dried and clean,
Absolute methanol 700mL and sodium butoxide 28.80g (0.30mol), stirring, reactant liquor is white
Muddiness, is warming up to backflow, after reaction system is brown color clarification, reacts 8 hours, adds
Enter 732 type strong acidic ion resins, filter, reactant liquor is concentrated to dryness, uses methyl-tert fourth
Base ether recrystallizes, and dries to obtain chemical compounds I 70.01g, yield 90.02%.
(2 ' R)-the 2 '-deoxidation-2 that embodiment 9-16 is prepared '-fluoro-2 '-MU glycosides, yield
Between 90.02%～96.58%, and each embodiment compares, and the yield of embodiment 9 is the highest,
Being 96.58%, i.e. in embodiment, catalyst is sodium methoxide.
The general principle of the present invention and principal character and the present invention have more than been shown and described
Advantage.Skilled person will appreciate that of the industry, the present invention is not restricted to the described embodiments,
The principle that the present invention is simply described described in above-described embodiment and specification, without departing from this
On the premise of bright spirit and scope, the present invention also has various changes and modifications, these change and
Improvement both falls within scope of the claimed invention.Claimed scope is by appended
Claims and equivalent thereof define.
Claims (7)
1. one kind (2 ' R)-2 '-deoxidation-2 ' preparation method of-fluoro-2 '-MU glycosides (I); with (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-methyluridine 3 '; 5 '-dibenzoate (II) is raw material; through catalyst deprotection in anhydrous polar solvent; obtain (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-MU glycosides (I); it is characterized in that: described catalyst is inorganic base and the mixture of inorganic salts or the alkali metal compounds of alcohol, concrete reaction is as follows:
(2 ' R)-2 ' the most according to claim 1-deoxidation-2 ' preparation method of-fluoro-2 '-MU glycosides (I), it is characterized in that: when described catalyst is the mixture of inorganic base and inorganic salts, its consumption is (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-methyluridine 3 ', 0.02-0.01 times of 5 '-dibenzoate (II), the reaction time is 5-10 hour.
(2 ' R)-2 ' the most according to claim 1 and 2-deoxidation-2 ' preparation method of-fluoro-2 '-MU glycosides (I), it is characterized in that: described inorganic base is NaOH, sodium carbonate, potassium carbonate or potassium hydroxide, inorganic salts are anhydrous sodium sulfate or anhydrous magnesium sulfate.
(2 ' R)-2 ' the most according to claim 1-deoxidation-2 ' preparation method of-fluoro-2 '-MU glycosides (I), it is characterized in that: when described catalyst is the alkali metal compounds of alcohol, its consumption is (2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-methyluridine 3 ', 0.1-1.0 times of 5 '-dibenzoate (II), the reaction time is 4-10 hour.
5. according to (2 ' R)-the 2 '-deoxidation-2 described in claim 1 or 4 '-fluoro-2 '-MU glycosides
(I) preparation method, it is characterised in that: the alkali metal compounds of described alcohol is potassium methoxide, potassium ethoxide, potassium propoxide, butanol potassium, sodium methoxide, caustic alcohol, sodium propoxide or sodium butoxide.
(2 ' R)-2 '-deoxidation-2 the most according to claim 1 or 5 '-fluoro-2 '-MU glycosides
(I) preparation method, it is characterised in that: the resin removing the alkali metal compounds catalyst of alcohol and the salt of generation is resin cation.
(2 ' R)-2 ' the most according to claim 6-deoxidation-2 '-fluoro-2 '-MU glycosides (I)
Preparation method, it is characterised in that: described resin cation is strong acidic ion resin.
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Application publication date: 20160817 |