CN105085445B - The preparation of Suo Feibuwei intermediate - Google Patents
The preparation of Suo Feibuwei intermediate Download PDFInfo
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- CN105085445B CN105085445B CN201510486803.7A CN201510486803A CN105085445B CN 105085445 B CN105085445 B CN 105085445B CN 201510486803 A CN201510486803 A CN 201510486803A CN 105085445 B CN105085445 B CN 105085445B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The preparation of Suo Feibuwei intermediate, the present invention provides Suo Feibuwei key intermediate 3,5 pairsOBenzoyl 2 deoxygenates 2 fluorine 2CThe preparation method of methyl D ribonic acid gamma lactone, the method transfers above-mentioned useful intermediate to by the unwanted α configuration accessory substance obtained during preparing Suo Feibuwei, thus improves the overall yield of whole project.
Description
Technical field
The present invention relates to Suo Feibuwei key intermediate 3,5-double-O-benzoyl-2-deoxygenates the fluoro-2-of-2-C-methyl D-
The preparation of ribonic-gamma-lactone
Background technology
Suo Feibuwei (it is translated into again rope fluorine cloth Wei, English name Sofosbuvir, trade name Sovaldi, calls GS-7977,
PSI-7977) Shi Ji Leadd B.V is developed for treating the new drug of chronic hepatitis C.This medicine is first without just combining interferon
Can safely and effectively treat the medicine of some type hepatitis.Clinical testing confirms for 1 and 4 type hepatitis, this medication combined poly-second two
The overall continued viral response rate (SVR) of alcohol interferon and Ribavirin up to 90%;For 2 type hepatitis, this is medication combined
The SVR of Ribavirin is 89%-95%;For 3 type hepatitis, the SVR of this medication combined Ribavirin is 61%-63%.This medicine in
In December, 2013 through Bureau of Drugs Supervision of the U.S. approval the U.S. list, in January, 2014 through Europe drugs administration approved in EU countries
Listing.Suo Feibuwei is new role target spot, novel mechanism, the NS5B polymerization inhibitor of global first treatment hepatitis, the most still
List without identical mechanism of action medicine, be also simultaneously first just safely and effectively to treat some genotype third without combining interferon
The medicine of liver.
Suo Feibuwei chemistry entitled (S)-2-(((S)-(((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-bis-
Hydrogen pyrimidine-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyl oxolane-2-base) methoxyl group) phosphorylated phenoxy group) amino) third
Isopropyl propionate, its structural formula is as follows:
At present, existing numerous patents and document report Suo Feibuwei and the chemical synthesis of intermediate thereof.
In industrialized production use synthetic route be patent US20130324709, WO2013045419,
WO2010135569, WO2013178571, document J. Org. Chem. 2009,74,6819-6824, J. Med. Chem.
The route of the report such as 2010,53,7202-7218.This route sets out with (R)-glyceraldehyde, through Wittig reaction, dihydroxylated
It is borontrifluoride that reaction obtains sultones, sultones and triethylamine through peroxidating after obtaining glycol, glycol and thionyl chloride reaction
Hydrogen reaction is fluorinated, and product carries out closing lactone environment-development subsequently under acidic alcohol effect should obtain double hydroxy-lactone, double hydroxyls
Two hydroxyl benzoyls of lactone carry out protection and obtain key intermediate, 3,5-pairs-OIt is fluoro-that-benzoyl-2-deoxygenates-2-
2-C-methyl-D-ribono-gamma lactone.This lactone reduces subsequently under red aluminium effect, and the hemiacetal obtained is through sulphonyl
Chlorine chlorination, the N-Bz cytimidine reaction that chloro-product is protected with TMS under the acid effect of Louis, obtain the glucosides of α configuration and beta comfiguration
Change product.After the glycosylation product of the beta comfiguration required for separating and purifying, to the AcOH/MeOH process of beta comfiguration product, so
Rear use MeONa removes two benzoyl protecting groups, obtains 2-and deoxygenates-2-fluoro-2-methylcytidine.It is fluoro-that last 2-deoxygenates-2-
Methylol and the chiral phosphine ester fragment of 2-methylcytidine are condensed, and complete the preparation of Suo Feibuwei after product recrystallization.Relevant
Synthetic route is as follows.
Although the industrialized route of foregoing description has, raw material is cheap, easy and simple to handle, the more high advantage of yield, but right
The glycosylation product of α configuration and beta comfiguration can be obtained with TMS during the N-Bz cytimidine reaction that chloro-product is protected under the acid effect of Louis
Thing (beta/alpha ≈ 3.5/1), by obtaining the beta comfiguration and unwanted α configuration, the therefore yield meeting of this step that need after post processing
Because having unwanted α configuration to produce to be greatly reduced.Have for this project if therefore unwanted for this project α configuration can be transferred to
Intermediate, the overall yield of whole project will be improved greatly.
Summary of the invention
The technical problem to be solved is the unwanted formula (II) that will generate during synthesis Suo Feibuwei
α anomeric product be converted into formula (I) midbody product (lactone) of this project (it is fluoro-that the double-O-benzoyl-2-of 3,5-deoxygenates-2-
2-C-methyl-D-ribono-gamma lactone), specific as follows:
A kind of method preparing formula (I) lactone, it is characterised in that formula (II) compound in a solvent, at (NH4)2Ce
(NO3)6In the presence of, the lactone of formula (I) is prepared by illumination reaction, reaction equation is as follows:
Wherein, R1、R2Represent hydroxyl protecting group, preferably benzoyl (Bz) or acetyl group (Ac).Experiment shows, works as formula
(II) compound is (2R, 3R, 4R, 5S)-5-(4-benzamido-2-oxopyrimidin-1 (2H)-yl)-2-((benzoxy
Base) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoic acid ester or (2R, 3R, 4R, 5S)-5-(4-benzamido-2-oxygen
For pyrimidine-1 (2H)-yl)-2-((acetoxyl group) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl acetate time, this reaction can
To be smoothed out and there is higher productivity.
Reaction dissolvent is preferably the mixed solvent of acetonitrile, dioxane, water and acetonitrile or water and the mixing of dioxane
Solvent.
100-300 watt of high voltage mercury lamp radiation is preferably taked in illumination.
(NH4)2Ce(NO3)6Equivalent is used to be preferably the 0.1-1.0 equivalent of starting material formula (II) compound.
Reaction time is preferably 6 hours-48 hours.
By the invention it is possible to unwanted α configuration is converted into corresponding lactone with the yield of 30-85%.
Detailed description of the invention
Can more specifically understand the present invention by the following examples, but it illustrates rather than the restriction present invention
Scope.
Embodiment
1, reaction equation
1000mL there-necked flask, addition α configuration of compound (2R, 3R, 4R, 5S)-5-(4-benzamido-2-oxopyrimidin-
1 (2H)-yl)-2-((benzoyloxy) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoic acid ester (50g,
0.088mmol), in reaction system, then add acetonitrile 300mL, disposable addition (NH after being sufficiently stirred for4)2Ce(NO3)6
(24g, 0.044 mmol, 0.5 eq.).After addition, reaction system is sufficiently stirred for lower 100 watts of high voltage mercury lamp radiations 12
Hour, period used TLC to carry out a plate analysis every 2 hours.Reaction terminates rear system and is naturally cooling to room temperature, Rotary Evaporators
Upper removed under reduced pressure organic solvent, residue adds water (200mL) and dichloromethane (200mL), and after separating organic phase, aqueous phase is with two
Chloromethanes extraction (2*100mL), merges organic phase, and organic phase uses isopropanol to carry out being recrystallized to give interior ester products 3 after concentrating,
5-pair-O-benzoyl-2-deoxygenates the fluoro-2-of-2-C-methyl-D-ribono-gamma lactone 13.5g (41.2%).
2, reaction equation
1000mL there-necked flask, addition α configuration of compound (2R, 3R, 4R, 5S)-5-(4-benzamido-2-oxopyrimidin-
1 (2H)-yl)-2-((benzoyloxy) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoic acid ester (52g,
0.091mmol), in reaction system, then add dioxane 310mL, disposable addition (NH after being sufficiently stirred for4)2Ce
(NO3)6(36g, 0.066 mmol, 0.72 eq.).After addition, reaction system is sufficiently stirred for lower 100 watts of high-pressure sodium lamps
Irradiating 6 hours, period used TLC to carry out a plate analysis every 2 hours.Reaction terminates rear system and is naturally cooling to room temperature, rotates
Removed under reduced pressure organic solvent on evaporimeter, residue adds water (200mL) and dichloromethane (200mL), separates water after organic phase
Extracting (2*100mL) with dichloromethane, merge organic phase, organic phase uses isopropanol to carry out being recrystallized to give lactone after concentrating
Product 3,5-pair-O-benzoyl-2-deoxygenates the fluoro-2-of-2-C-methyl-D-ribono-gamma lactone 17.6g (52%).
3, reaction equation
1000mL there-necked flask, addition α configuration of compound (2R, 3R, 4R, 5S)-5-(4-benzamido-2-oxopyrimidin-
1 (2H)-yl)-2-((benzoyloxy) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoic acid ester (46g,
0.081mmol), in reaction system, then add acetonitrile 150mL and water 150mL, disposable addition after being sufficiently stirred for
(NH4)2Ce(NO3)6(10.2g, 0.019 mmol, 0.23 eq.).After addition, reaction system is sufficiently stirred for lower with 200
Watt high voltage mercury lamp radiation 12 hours, period used TLC to carry out a plate analysis every 2 hours.Reaction terminates rear system Temperature fall
To room temperature, removed under reduced pressure organic solvent on Rotary Evaporators, residue adds water (50mL) and dichloromethane (200mL), separates
After organic phase, aqueous phase dichloromethane extracts (2*100mL), merges organic phase, and organic phase uses isopropanol heavily to tie after concentrating
Crystalline substance obtain interior ester products 3,5-double-O-benzoyl-2-deoxygenates the fluoro-2-of-2-C-methyl-D-ribono-gamma lactone 10.2g
(33.9%)。
4, reaction equation
200ml there-necked flask, addition α configuration of compound (2R, 3R, 4R, 5S)-5-(4-benzamido-2-oxopyrimidin-
1 (2H)-yl)-2-((acetoxyl group) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl acetate (5.1g,
0.011mmol), in reaction system, then add acetonitrile 50mL, disposable addition (NH after being sufficiently stirred for4)2Ce(NO3)6
(3.6g, 0.0066 mmol, 0.58 eq.).After addition, reaction system is sufficiently stirred for lower 200 watts of high voltage mercury lamp radiations
8 hours, period used TLC to carry out a plate analysis every 2 hours.Reaction terminates rear system and is naturally cooling to room temperature, rotary evaporation
Removed under reduced pressure organic solvent on instrument, residue adds water (40mL) and dichloromethane (40mL), and after separating organic phase, aqueous phase is with two
Chloromethanes extraction (2*40mL), merges organic phase, and after organic phase concentrates, residue column chromatography purifies, and obtains product 3,5-pair-O-
Acetyl group-2-deoxygenates the fluoro-2-of-2-C-methyl-D-ribono-gamma lactone 2.25g (82.5%).
5, reaction equation
500mL there-necked flask, adds α configuration of compound (2R, 3R, 4R, 5S)-5-(4-benzamido-2-oxopyrimidin-1
(2H)-yl)-2-((acetoxyl group) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl acetate (17.5g,
0.039mmol), in reaction system, then add dioxane 120mL, disposable addition (NH after being sufficiently stirred for4)2Ce
(NO3)6(21.45g, 0.045 mmol, 1.0eq.).After addition, reaction system is sufficiently stirred for lower 200 watts of high-pressure mercury
Light irradiation 24 hours, period every 2 hours use TLC carry out a plate analysis.Reaction terminates rear system and is naturally cooling to room temperature, rotation
Turning removed under reduced pressure organic solvent on evaporimeter, residue adds water (100mL) and dichloromethane (100mL), after separating organic phase
Aqueous phase dichloromethane extracts (2*100mL), merges organic phase, and after organic phase concentrates, residue column chromatography purifies, and obtains product
3,5-pair-O-acetyl group-2-deoxygenates the fluoro-2-of-2-C-methyl-D-ribono-gamma lactone 8.25g (85.3%).
6, reaction equation
500mL there-necked flask, adds α configuration of compound (2R, 3R, 4R, 5S)-5-(4-benzamido-2-oxopyrimidin-1
(2H)-yl)-2-((acetoxyl group) methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl acetate (20.5g,
0.046mmol), in reaction system, then add dioxane 75mL and water 75mL, disposable addition after being sufficiently stirred for
(NH4)2Ce(NO3)6(12.6g, 0.0229 mmol, 0.5eq.).After addition, reaction system is sufficiently stirred for lower with 300
Watt high voltage mercury lamp radiation 12 hours, period used TLC to carry out a plate analysis every 3 hours.Reaction terminates rear system Temperature fall
To room temperature, removed under reduced pressure organic solvent on Rotary Evaporators, residue adds water (50mL) and dichloromethane (120mL), separates
After organic phase, aqueous phase dichloromethane extracts (2*120mL), merges organic phase, and after organic phase concentrates, residue column chromatography purifies,
Obtain product 3,5-double-O-acetyl group-2-deoxygenates the fluoro-2-of-2-C-methyl-D-ribono-gamma lactone 6.81g (59.7%).
Claims (6)
1. the method preparing formula (I) lactone, it is characterised in that formula (II) compound in a solvent, at (NH4)2Ce(NO3)6
In the presence of, the lactone of formula (I) is prepared by illumination reaction, reaction expression is as follows:
Wherein, R1、R2Represent hydroxyl protecting group.
2. the method for claim 1, wherein R1、R2It is each independently benzoyl (Bz) or acetyl group (Ac).
3. method as claimed in claim 1 or 2, wherein reaction dissolvent is the mixed solvent of acetonitrile, dioxane, water and acetonitrile
Or water and the mixed solvent of dioxane.
4. the method for claim 1, wherein 100-300 watt of high voltage mercury lamp radiation is taked in illumination.
5. the method for claim 1, wherein (NH4)2Ce(NO3)6Using equivalent is starting material formula (II) compound
0.1-1.0 equivalent.
6. the method for claim 1, wherein the reaction time is 6 hours-48 hours.
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| CN114621164A (en) * | 2020-12-11 | 2022-06-14 | 余购粮 | Method for removing impurities of sofosbuvir intermediate |
| CN114621163A (en) * | 2020-12-11 | 2022-06-14 | 余购粮 | Refining method of sofosbuvir intermediate |
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| US7838693B2 (en) * | 2006-12-18 | 2010-11-23 | Hoffmann-La Roche Inc. | Process for the preparation of 3,5-di-O-acyl-2-fluoro-2-C-methyl-D-ribono-gamma-lactone |
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Address after: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee before: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address after: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee before: WISDOM PHARMACEUTICAL Co.,Ltd. |
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