CN106366145A - 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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Abstract
The invention discloses a synthetic method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (formula I). The above compound of formula I is prepared from cheap and easily available initial raw materials through hydroxyl group protein, cyclization and fluorination.
Description
Technical field
This invention belongs to field of medicine and chemical technology.
Background technology
Hepatitis C, abbreviation hepatitis C, hepatitis C, are a kind of viral diseases being caused by hepatitis C viruss (hepatitis c virus, hcv) infection.After hcv infection, 50%-85% translates into chronic infection, if not taking rational prophylactico-therapeutic measuress, patient leads to liver cirrhosis and hepatocarcinoma, serious life-threatening safety the most at last.Hcv is mainly propagated by modes such as blood, acupuncture, drug abuse.Some data displays, the mortality rate related to global infection with hepatitis C virus in following 20 years (death that liver failure and hepatocarcinoma lead to) will continue increase, and the preventing and treating of hcv has become one of main public health problem in the world.
Sofosbuvir is a class ucleosides AG14361 of gilead company exploitation, can become people's gene 2,3 types chronic hcv infection with ribavirin combination therapy.This medicine lists for 2013 first in the U.S., and compared to traditional anti-hcv medicine, the treatment cycle of sofosbuvir is short, and cure rate is high, is the breakthrough medicine for the treatment of hcv.
(2'r) (formula i) is the important intermediate of synthesis sofosbuvir to -2'- deoxidation -2'- fluoro- 2'- MU glycosides.The synthetic method of formula i compound mainly has following several.One is to be prepared by glycosylation reaction, such as patent wo2008045419, and us2010016251 discloses the method (2'r) -2'- deoxidation -2'- fluoro- 2'- MU glycosides being synthesized for raw material through more than ten steps with (r)-propylidene glyceraldehyde.
This reaction circuit is long, and the three wastes are many, and environmental protection pressure is big, and cost of material and production cost are high.
Patent wo2005003147, cn104327138 carries out glycosylation reaction with the uracil that double trimethyl silicanes are protected for raw material.
Another kind of method is with other nucleoside as raw material, such as document journal of medicinal chemistry, 2005, voi.48, no.17,
5504 ~ 5508 report the method (scheme 3) that cytidine is changed into compound i.
Document nucleosides, nucleotides and nucleic acids, 2011, vol:30,11#, p 886 ~ 896 also report the method (scheme 4) synthesizing i in a similar fashion with uridnine.
These (2'r) -2'- deoxidation -2'- fluoro- 2'- MU glycosides (methods of formula i) with other glucosides as Material synthesis, have the advantages that circuit is shorter, but need to use the fluorination reagent dast (diethylin sulfur trifluoride) of high cost, and its selectivity and yield are bad, lead to product cost high, there is no competitive advantage.
In addition, angew. chem. int. ed., the new method (scheme 5) of the fluoro- cytidine of a kind of synthesis 2'- deoxidation -2'- etc. document report, the method is through intramolecular cyclization, then the strategy with fluoride open loop.Stereo selectivity is good, but yield has much room for improvement.
As fully visible, the method in scheme 1 and scheme 2 is classical, reliable, but synthetic line is long, high cost, and quantity of three wastes is big, and environmental protection pressure is big.Method in scheme 3 and scheme 4 is although circuit is shorter, but it is expensive to there is fluoro reagent, fluoro-reaction poor selectivity, the low shortcoming of yield.Although the method in scheme 5 solves selective problem, have the shortcomings that yield is relatively low, need to improve yield.
Content of the invention
With regard to the term mentioned in the present invention, it is explained as follows:
Ac: acetyl group
Oac: acetoxyl group
Tea: triethylamine
Dmf:n, n- dimethylformamide
Dmso: dimethyl sulfoxide
Bz: benzoyl
Obz: benzoyloxy
Oms: mesyloxy
Ots: tolysulfonyl epoxide
Tempo: tetramethyl piperidine nitrogen oxides
Cl: chlorine
Br: bromine
The present invention relates to (2'r) -2'- deoxidation -2'- fluoro- 2'- MU glycosides (preparation method of formula i),
In the presence of carbinolamine, formula iv compound deprotection,
Wherein, r is ac or bz,
Preparation accepted way of doing sth iii compound；
In the presence of diphenyl carbonate and phosphoric triamides, cyclization obtains compound ii to formula iii compound；
Compound ii is reacted with fluorination reagent and obtains compound i, fluorination reagent preferably is selected from potassium fluoride, fluohydric acid gas/tea, fluohydric acid gas/pyridine, tetrabutyl ammonium fluoride, reaction dissolvent preferably is selected from dmf, dichloromethane, chloroform, oxolane, chlorobenzene, acetonitrile, dmso, 2- methyltetrahydrofuran.
Formula iv compound can method as described below be prepared:
Wherein, r is ac or bz, and l is oac, obz, cl, br, oms, ots.Compound vii and three tertiary butyoxy aluminum lithiums or red aluminium reducing obtain compound vi.Formula vi and excess acetyl chloride, obtain compound v, and l is oac；Or compound vi is reacted with Benzenecarbonyl chloride., obtain compound v, l is obz；Or compound vi and n- chlorosuccinimide reacts, obtain compound v, l is cl, available oxalyl chloride replaces n- chlorosuccinimide；Or compound vi is reacted with mesyl chloride, obtain compound v, l is oms；Or compound vi is reacted with paratoluensulfonyl chloride, obtain compound v, l is ots；Or compound vi and nbs reacts, obtain compound v, l is br.Formula iv compound is to be occurred obtained from vorbr ü ggen glycosylation reaction with uracil by formula v.
Alternatively, formula i can use following method to prepare:
Formula iii' is reacted with fluorination reagent, wherein, r is ac or bz, fluorination reagent preferably is selected from potassium fluoride, fluohydric acid gas/tea, fluohydric acid gas/pyridine, tetrabutyl ammonium fluoride, reaction dissolvent preferably is selected from dmf, dichloromethane, chloroform, oxolane, chlorobenzene, acetonitrile, dmso, 2- methyltetrahydrofuran, prepares compound ii'.
In the presence of carbinolamine, deprotection obtains formula i compound to formula ii'.
Formula iii' compound can method as described below be prepared:
Wherein, r is ac or bz.In the presence of diphenyl carbonate and phosphoric triamides, cyclization obtains compound viii' to formula ix', then protects hydroxyl, obtains formula vii'.Formula vii', in water/organic two-phase system, obtains compound vi' with tetrabutyl ammonium bromide for Catalyzed By Phase-transfer Catalyst open loop.Formula vi' tempo be catalyst, sodium hypochlorite be oxidant under conditions of aoxidize prepare compound v'.Formula v' reacts prepare compound iv' with methyl-magnesium-chloride Grignard reagent.In the presence of diphenyl carbonate and phosphoric triamides, cyclization obtains compound iii' to formula iv'.
Alternatively, compound iii' also can be prepared in the following way:
Wherein, r is ac or bz, and in the presence of diphenyl carbonate and phosphoric triamides, heating cyclization to obtain formula iii' compound to compound iv occurs.The preparation method of formula iv compound can be prepared by the aforesaid method with viii as starting material.
Specific embodiment
The synthesis of embodiment 1 compound viii'
By 24.4g uridnine ix'(uridine), 32.1g diphenyl carbonate (1.5eq), 8.4g sodium bicarbonate, 250ml phosphoric triamides, it is added in 500ml there-necked flask.It is heated to 150 DEG C of reactions, controls in hplc to reaction completely, be cooled to room temperature, add water, with chloroform extraction, combining extraction liquid, anhydrous sodium sulfate drying, filter.Filtrate enters next step reaction.
The synthesis of embodiment 2 compound vii'b
In the chloroformic solution of the compound obtaining in embodiment 1, add triethylamine (1.2eq), be cooled to 0 ~ 5 DEG C, Deca Benzenecarbonyl chloride., after dripping, it is warming up to room temperature, control reaction in hplc, after reaction completely, add 2n hcl, stirring, separate organic layer, successively with 1n naoh, water washing, organic faciess anhydrous sodium sulfate drying, filter, filtrate concentrates, add normal heptane to wash and starch, it is filtrated to get white solid, dry, weight 32g.
The synthesis of embodiment 3 compound vi'b and v'b
Nahco by the compound obtaining in 21g embodiment 2 vii'b, 250g dichloromethane and 100ml 0.1n3, 0.1g tetrabutyl ammonium bromide (tbab) is added in there-necked flask, stirs at 50 DEG C, controls in hplc, after reaction completely, separates water layer, obtains the organic layer of vi'b.The organic layer of vi'b is proceeded in there-necked flask, is cooled to 0 ~ 10 DEG C, add tetramethyl piperidine nitrogen oxides (tempo, 0.5% eq), Deca 10% liquor natrii hypochloritises, rise again to room temperature reaction.Separate organic layer, anhydrous magnesium sulfate is dried, filter, concentrate, obtain 16g off-white powder v'b after purification.
The synthesis of embodiment 4 compound iv'b
The compound v'b that 16g is implemented to obtain in 3 is dissolved in 200 milliliters of 2- methyltetrahydrofurans, is cooled to -40 ~ -78 DEG C, Deca methyl-magnesium-chloride Grignard reagent, and insulation reaction 2 ~ 6h completes to reaction, adds saturated ammonium chloride solution that reaction is quenched.Separate organic faciess, aqueous phase methyl tertiary butyl ether(MTBE) extracts.Merge organic faciess, after concentration compound iv'b. not separated, be directly used in next step reaction.
The synthesis of embodiment 5 compound iii'b
It is added to the compound ivb' obtaining in embodiment 4, diphenyl carbonate (1.5eq), sodium bicarbonate (1.0eq) and phosphoric triamides in there-necked flask.It is heated to 150 DEG C of reactions, controls in hplc to reaction completely, be cooled to room temperature, add water, with chloroform extraction, combining extraction liquid, anhydrous sodium sulfate drying, filter.Concentrate, add normal hexane crystallize, obtain off-white powder.The sample that purity is higher than 99.5% is obtained, sample presentation carries out nmr analysis, and analysis result is consistent with structure after recrystallization.Ihnmr (d6-dmso, 400hz): δ 8.02 ~ 8.06(m, 4h), 7.55 ~ 7.67 (m, 6h) 7.36 (d,
j=7.5, 1h), 6.08(d, j=7.5, 1h), 6.00(s, 1h), 4.36(m,1h), 4.31(m,1h), 3.3~3.5(m,
2h), 1.3(s, 3h).
The synthesis of embodiment 6 compound ii'b
Embodiment 6.1 is by 2g compound iii'b, 10ml dmf(dimethylformamide), 2g potassium fluoride is added in flask, is heated to 120 DEG C of reaction 2 ~ 4h, is cooled to room temperature, adds water quenching to go out reaction.Aqueous phase is extracted with ethyl acetate, and column chromatography for separation obtains 0.7g white solid.
Embodiment 6.2, by 2.1g compound iii'b, 10ml dichloromethane, 4ml fluohydric acid gas/pyridine solution, is added in flask, is heated to back flow reaction, control reaction in hplc, after reaction terminates, is cooled to room temperature, adds water quenching to go out reaction.Aqueous phase is extracted with dichloromethane, and column chromatography for separation obtains 1.1g white solid.
Embodiment 6.3, by 1.8g compound iii'b, 10ml chloroform, 4ml fluohydric acid gas/triethylamine solution, is added in flask, is heated to back flow reaction, control reaction in hplc, after reaction terminates, is cooled to room temperature, adds water quenching to go out reaction.Aqueous phase chloroform extraction, column chromatography for separation obtains 1.2g white solid.
Embodiment 6.4 is by 2g compound iii'b, 10ml oxolane, 3g tbaf(tetrabutyl ammonium fluoride), it is added in flask, be heated to back flow reaction, control reaction in hplc, after reaction terminates, it is cooled to room temperature, add water quenching to go out reaction.Separate organic faciess, aqueous phase is extracted with dichloromethane, merge organic faciess, after concentration, obtain 1.0g white solid through column chromatography for separation again.
Embodiment 6.5 is added to 2.2g compound iii'b, 10ml chlorobenzene, 3g tbaf in flask, is heated to back flow reaction, control reaction in hplc, after reaction terminates, is cooled to room temperature, adds water quenching to go out reaction.Separate organic faciess, aqueous phase is extracted with dichloromethane, merge organic faciess, after concentration, obtain 1.3g white solid through column chromatography for separation again.
The synthesis of embodiment 7 compound i
6.8g compound ii'b is added in flask, adds 20ml methanol amine aqueous solution, 25 ~ 30 DEG C of reaction 24h.Add 0.7g activated carbon decolorizing, filter, be concentrated to give off-white powder, add 20ml ethyl acetate to wash and starch, filter, after being dried, obtain off-white powder 3.0g.
The synthesis of embodiment 8 compound vii
The synthesis of embodiment 8.1 compound viia
Compound viii is obtained for Material synthesis by glucose, sees document tetrahedron letters; vol.
48; nb. 4; (2007);P. 517 520 preparation.By compound viii, triethylamine (5eq), dmap (dimethylamino naphthyridine, 0.1eq), acetone is added in flask, Deca acetic anhydride (5eq), room temperature reaction 24h.Water quenching is added to go out reaction, ethyl acetate extracts, organic faciess anhydrous sodium sulfate drying, filtration, obtain off-white powder after concentration.
The synthesis of embodiment 8.2 compound viib
Compound viii(is pressed document tetrahedron letters; vol.
48; nb. 4; (2007);P. 517 520 preparation), pyridine (5v), it is added in flask, Deca Benzenecarbonyl chloride. (5eq), room temperature reaction 24h.Water quenching is added to go out reaction, ethyl acetate extracts, organic faciess anhydrous sodium sulfate drying, filtration, obtain off-white powder after concentration.
The preparation of embodiment 9 compound vi
The preparation of embodiment 9.1 compound via
By three tertiary butyoxy aluminum lithium (1.2eq), thf, it is added in there-necked flask, is cooled to -20 ~ -40 DEG C.The tetrahydrofuran solution of Deca viia, after completion of dropping, -20 ~ -40 DEG C of insulation is reacted 4 ~ 6 hours.After reaction completely, add ethyl acetate, add saturated ammonium chloride solution.Separate organic layer, aqueous layer with ethyl acetate extracts.Merge organic faciess, in anhydrous sodium sulfate drying, filter via EtOAc solution, be directly used in next step reaction.
The preparation of embodiment 9.2 compound vib
By three tertiary butyoxy aluminum lithium (1.2eq), thf, it is added in there-necked flask, is cooled to -20 ~ -40 DEG C.The tetrahydrofuran solution of Deca viib, after completion of dropping, -20 ~ -40 DEG C of insulation is reacted 4 ~ 6 hours.After reaction completely, add ethyl acetate, add saturated ammonium chloride solution.Separate organic layer, aqueous layer with ethyl acetate extracts.Merge organic faciess, in anhydrous sodium sulfate drying, filter vib EtOAc solution, be directly used in next step reaction.
The preparation of embodiment 9.3 compound vib
68% red aluminum toluene solution (1.5eq) is added in flask, adds toluene, stirring, it is cooled to -20 ~ -10 DEG C, Deca trifluoroethanol (1.5eq), in the toluene solution of red aluminum, after dripping, is risen again and reacted to 20 ~ 25 DEG C, obtain the red aluminum solution of modification.Viib (1eq) is added in another flask, adds dichloromethane dissolving, be cooled to -30 ~ -10 DEG C, the red aluminum solution that then Deca is modified thereto.After completion of dropping, insulation reaction 4 ~ 6h.Add 37% concentrated hydrochloric acid that reaction is quenched in reactant liquor, separate organic layer, use water, 8% sodium bicarbonate solution washing successively.Organic layer uses anhydrous sodium sulfate drying again, filters, obtains vib solution.This solution is not separated, is directly used in next step reaction.
The synthesis of embodiment 10 compound v
The synthesis of embodiment 10.1 compound vg
It is added to vib ethyl acetate solution in there-necked flask, adds triethylamine (1.5eq), gentle liquid is cooled to 0 ~ 5 DEG C, Deca chloroacetic chloride (1.3eq).After dripping, the room temperature reaction 8 ~ 12 hours of rising again.Add the reaction of 2n hydrochloric acid, separate organic layer, use 8% sodium bicarbonate, water washing successively, separate organic faciess, concentrate, and take away the ethyl acetate of remnants with chlorobenzene, add chlorobenzene to dissolve the chlorobenzene solution that residue obtains vg, this solution is directly used in next step reaction.
The synthesis of embodiment 10.2 compound vh
It is added to vib ethyl acetate solution in there-necked flask, adds triethylamine (1.5eq), gentle liquid is cooled to 0 ~ 5 DEG C, Deca Benzenecarbonyl chloride. (1.2eq).After dripping, the room temperature reaction 8 ~ 12 hours of rising again.Add the reaction of 2n hydrochloric acid, separate organic layer, use 8% sodium bicarbonate, water washing successively, separate organic faciess, concentrate, and take away the ethyl acetate of remnants with chlorobenzene, add chlorobenzene to dissolve the chlorobenzene solution that residue obtains vh, this solution is directly used in next step reaction.
The synthesis of embodiment 10.3 compound vi
By vib ethyl acetate solution concentrating under reduced pressure, residue adds dichloromethane dissolving, adds triphenylphosphine (2eq) and is cooled to 0 ~ 5 DEG C, adds n- chlorosuccinimide (3eq) in batches.After adding, the room temperature reaction 1 ~ 2 hour of rising again.Add 8% sodium bicarbonate that reaction is quenched, separate organic layer, be concentrated to dryness, add hexamethylene to wash and starch in residue, filter, after filtrate concentrates, add chlorobenzene distillation, add chlorobenzene dissolving residue, obtain the chlorobenzene solution of vi, this solution is directly used in next step reaction.
The synthesis of embodiment 10.4 compound vi
By dmf(1.08eq) it is added in flask, it is cooled to 0 ~ 5 DEG C, Deca oxalyl chloride 1.1eq, after completion of dropping, it is warming up to 20 ~ 25 DEG C of reaction 2h, obtains vilsmeier reagent.By vib ethyl acetate solution concentrating under reduced pressure, residue adds dichloromethane dissolving, is then added in the vilsmeier reagent preparing in advance.After adding, it is warming up to 35 ~ 40 DEG C and reacts 1 ~ 2 hour.Add 8% sodium bicarbonate that reaction is quenched, separate organic layer, concentrate, add chlorobenzene distillation, add chlorobenzene dissolving residue, obtain the chlorobenzene solution of vi, this solution is directly used in next step reaction.
The synthesis of embodiment 10.5 compound vk
It is added to vib ethyl acetate solution in there-necked flask, adds triethylamine (1.5eq), gentle liquid is cooled to 0 ~ 5 DEG C, Deca mesyl chloride (1.3eq).After dripping, the room temperature reaction 8 ~ 12 hours of rising again.Add the reaction of 2n hydrochloric acid, separate organic layer, use 8% sodium bicarbonate, water washing successively, separate organic faciess, concentrate, and take away the ethyl acetate of remnants with chlorobenzene, add chlorobenzene to dissolve the chlorobenzene solution that residue obtains vk, this solution is directly used in next step reaction.
The synthesis of embodiment 10.6 compound vl
It is added to vib ethyl acetate solution in there-necked flask, adds triethylamine (1.5eq), gentle liquid is cooled to 0 ~ 5 DEG C, Deca paratoluensulfonyl chloride (1.3eq).After dripping, the room temperature reaction 8 ~ 12 hours of rising again.Add the reaction of 2n hydrochloric acid, separate organic layer, use 8% sodium bicarbonate, water washing successively, separate organic faciess, concentrate, and take away the ethyl acetate of remnants with chlorobenzene, add chlorobenzene to dissolve the chlorobenzene solution that residue obtains vl, this solution is directly used in next step reaction.
The synthesis of embodiment 10.7 compound vj
By vib ethyl acetate solution concentrating under reduced pressure, residue adds dichloromethane dissolving, adds triphenylphosphine (2eq) and is cooled to 0 ~ 5 DEG C, adds n- bromo-succinimide (3eq) in batches.After adding, the room temperature reaction 1 ~ 2 hour of rising again.Add 8% sodium bicarbonate that reaction is quenched, separate organic layer, be concentrated to dryness, add hexamethylene to wash and starch in residue, filter, after filtrate concentrates, add chlorobenzene distillation, add chlorobenzene dissolving residue, obtain the chlorobenzene solution of vj, this solution is directly used in next step reaction.
The synthesis of embodiment 11 compound iv
The synthesis of embodiment 11.1 compound iva
Add the ammonium sulfate (0.5%w/w) of uracil (1.2eq) and catalytic amount; add HMDS (1.38eq); add chlorobenzene; it is warming up to 125 ~ 130 DEG C of reactions, after dissolving completely, control temperature to react 2 hours at 125 ~ 130 DEG C; it is cooled to 40 ~ 70 DEG C under nitrogen protection; vacuum distillation, adds chlorobenzene dissolving, obtains the uracil of silicon substrate activation.Add the chlorobenzene solution (1eq) of va, add anhydrous stannic chloride (2.5eq), be warming up to 60 ~ 70 DEG C of reactions, after reaction completely, it is cooled to room temperature, add sodium bicarbonate (6eq), dichloromethane and water quenching are gone out reaction, silicon bath soil drainage, 40 DEG C of filtrate, -0.08mpa concentrates, it is cooled to -10 ~ 0 DEG C of crystallize, filter and dry, obtain off-white powder iva, yield 65%.
The synthesis of embodiment 11.2 compound ivb
Add the ammonium sulfate (0.5%w/w) of uracil (1.2eq) and catalytic amount; add HMDS (1.38eq); add chlorobenzene; it is warming up to 125 ~ 130 DEG C of reactions, after dissolving completely, control temperature to react 2 hours at 125 ~ 130 DEG C; it is cooled to 40 ~ 70 DEG C under nitrogen protection; vacuum distillation, adds chlorobenzene dissolving, obtains the uracil of silicon substrate activation.Add the chlorobenzene solution (1eq) of vl, add anhydrous stannic chloride (2.5eq), be warming up to 60 ~ 70 DEG C of reactions, after reaction completely, it is cooled to room temperature, add sodium bicarbonate (6eq), dichloromethane and water quenching are gone out reaction, silicon bath soil drainage, 40 DEG C of filtrate, -0.08mpa concentrates, it is cooled to -10 ~ 0 DEG C of crystallize, filter and dry, obtain off-white powder ivb, yield 58%.
The synthesis of embodiment 11.3 compound ivb
Add the ammonium sulfate (0.5%w/w) of uracil (1.2eq) and catalytic amount; add HMDS (1.38eq); add chlorobenzene; it is warming up to 125 ~ 130 DEG C of reactions, after dissolving completely, control temperature to react 2 hours at 125 ~ 130 DEG C; it is cooled to 40 ~ 70 DEG C under nitrogen protection; vacuum distillation, adds chlorobenzene dissolving, obtains the uracil of silicon substrate activation.Add the chlorobenzene solution (1eq) of vi obtained in the previous step, add anhydrous stannic chloride (2.5eq), be warming up to 60 ~ 70 DEG C of reactions, after reaction completely, it is cooled to room temperature, add sodium bicarbonate (6eq), dichloromethane and water quenching are gone out reaction, silicon bath soil drainage, 40 DEG C of filtrate, -0.08mpa concentrates, it is cooled to -10 ~ 0 DEG C of crystallize, filter and dry, obtain off-white powder ivb, three step total recoverys 62%.
The synthesis of embodiment 12 compound iii
6.8g compound ivb is added in flask, adds 20ml methanolic ammonia solution, 25 ~ 30 DEG C of reaction 24h.Add 0.7g activated carbon decolorizing, filter, be concentrated to give off-white powder, add 20ml ethyl acetate to wash and starch, filter, after being dried, obtain compound iii, off-white powder, weight 3.0g.
The synthesis of embodiment 13 compound ii
By 2g compound iii, diphenyl carbonate (1.5eq), 0.8g sodium bicarbonate, 20ml phosphoric triamides are heated to 150 DEG C of reactions, control in hplc to reaction completely, be cooled to room temperature, add water, with chloroform extraction, combining extraction liquid, anhydrous sodium sulfate drying, filters.Compound ii, off-white powder, weight 1.5g. is obtained after filtrate distillation
The synthesis of embodiment 14 compound iii'b
5g compound ivb is added in flask, adds 20ml phosphoric triamides, 2g Anhydrous potassium carbonate, be heated to 150 DEG C of reactions.After reaction completely, it is cooled to room temperature, adds water, with chloroform extraction, combining extraction liquid, anhydrous sodium sulfate drying, filter.Compound iii'b, off-white powder, weight 3.6g. is obtained after filtrate distillation
The synthesis of embodiment 15 compound ii'
The synthesis of embodiment 15.1 compound ii'b
By 2.0g compound iii'b, 10ml dmf, 2g potassium fluoride is added in flask, is heated to 120 DEG C of reaction 2 ~ 4h, is cooled to room temperature, adds water quenching to go out reaction.Aqueous phase is extracted with ethyl acetate, and column chromatography for separation obtains 0.6g white solid.
The synthesis of embodiment 15.2 compound ii'a
By 3.0g compound iii'a, 10ml chloroform, 4ml fluohydric acid gas/triethylamine solution, it is added in flask, is heated to back flow reaction, control reaction in hplc, after reaction terminates, it is cooled to room temperature, add water quenching to go out reaction.Aqueous phase chloroform extraction, column chromatography for separation obtains 1.7g white solid.
The synthesis of embodiment 16 compound i
2g compound ii, 10ml dmf, 2g potassium fluoride are added in flask embodiment 16.1, are heated to 120 DEG C of reaction 2 ~ 4h, are cooled to room temperature, add water quenching to go out reaction.Aqueous phase is extracted with ethyl acetate, and column chromatography for separation obtains 0.7g white solid.
Embodiment 16.2, by 2.1g compound ii, 10ml dichloromethane, 4ml fluohydric acid gas/pyridine solution, is added in flask, is heated to back flow reaction, control reaction in hplc, after reaction terminates, is cooled to room temperature, adds water quenching to go out reaction.Aqueous phase is extracted with dichloromethane, and column chromatography for separation obtains 1.1g white solid.
Embodiment 16.3, by 1.8g compound ii, 10ml chloroform, 4ml fluohydric acid gas/triethylamine solution, is added in flask, is heated to back flow reaction, control reaction in hplc, after reaction terminates, is cooled to room temperature, adds water quenching to go out reaction.Aqueous phase chloroform extraction, column chromatography for separation obtains 1.2g white solid.
Embodiment 16.4 is added to 2g compound ii, 10ml oxolane, 3g tbaf in flask, is heated to back flow reaction, control reaction in hplc, after reaction terminates, is cooled to room temperature, adds water quenching to go out reaction.Separate organic faciess, aqueous phase is extracted with dichloromethane, merge organic faciess, after concentration, obtain 1.0g white solid through column chromatography for separation again.
Embodiment 16.5 is added to 2.2g compound ii, 10ml chlorobenzene, 3g tbaf in flask, is heated to back flow reaction, control reaction in hplc, after reaction terminates, is cooled to room temperature, adds water quenching to go out reaction.Separate organic faciess, aqueous phase is extracted with dichloromethane, merge organic faciess, after concentration, obtain 1.3g white solid through column chromatography for separation again.
4.0g compound ii'b is added in flask embodiment 16.6, adds 20ml methanolic ammonia solution, 25 ~ 30 DEG C of reaction 24h.Add 0.4g activated carbon decolorizing, filter, be concentrated to give off-white powder, add 20ml ethyl acetate to wash and starch, filter, after being dried, obtain compound i, off-white powder, weight 1.9g.
Finally illustrate is, above example is only in order to illustrate technical scheme and unrestricted, although being described in detail to the present invention with reference to preferred embodiment, it will be understood by those within the art that, technical scheme can be modified or equivalent, objective without deviating from technical solution of the present invention and scope, it all should be covered in the middle of scope of the presently claimed invention.
Claims (21)
1. a kind of preparation method of formula i compound,
The method includes in the presence of carbinolamine, formula iv compound deprotection,
Wherein, r is ac or bz,
Preparation accepted way of doing sth iii compound；
In the presence of diphenyl carbonate and phosphoric triamides, cyclization obtains compound ii to formula iii compound；
Compound ii and fluorination reagent react and obtain compound i.
2. preparation method according to claim 1, wherein, fluorination reagent is selected from potassium fluoride, fluohydric acid gas/tea, fluohydric acid gas/pyridine, tetrabutyl ammonium fluoride.
3. preparation method according to claim 1, wherein, by compound this step of ii prepare compound i, reaction dissolvent preferably is selected from dmf, dichloromethane, chloroform, oxolane, chlorobenzene, acetonitrile, dmso, 2- methyltetrahydrofuran.
4. preparation method according to claim 1, the method preparation as described below of formula iv compound:
Wherein, r is ac or bz, and l is oac, obz, cl, br, oms, ots.
5. preparation method according to claim 4, in the presence of three tertiary butyoxy aluminum lithiums or red aluminum, reduction obtains compound vi to compound vii.
6. preparation method according to claim 4, compound vi and excess acetyl chloride, obtain compound v, l=oac；Or compound vi is reacted with Benzenecarbonyl chloride., obtain compound v, l is obz；Or compound vi and n- chlorosuccinimide reacts, obtain compound v, l is cl, oxalyl chloride alternative n- chlorosuccinimide reacts；Or compound vi is reacted with mesyl chloride, obtain compound v, l is oms；Or compound vi is reacted with paratoluensulfonyl chloride, obtain compound v, l is ots；Or compound vi and nbs reacts, obtain compound v, l is br.
7. preparation method according to claim 4, compound v and uracil occur vorbr ü ggen glycosylation reaction to obtain formula iv compound.
8. a kind of preparation method of formula i compound,
The method includes, and formula iii' compound and fluorination reagent react,
Wherein, r is ac or bz,
Prepare compound ii'；
In the presence of carbinolamine, deprotection obtains formula i compound to formula ii' compound.
9. preparation method according to claim 8, wherein, fluorination reagent is selected from potassium fluoride, fluohydric acid gas/tea, fluohydric acid gas/pyridine, tetrabutyl ammonium fluoride.
10. preparation method according to claim 8, wherein, is this step of ii' by Formula iii' prepare compound, reaction dissolvent preferably is selected from dmf, dichloromethane, chloroform, oxolane, chlorobenzene, acetonitrile, dmso, 2- methyltetrahydrofuran.
11. preparation methoies according to claim 8, formula iii' compound can method as described below be prepared:
Wherein, r is ac or bz.
12. preparation methoies according to claim 11, in the presence of diphenyl carbonate and phosphoric triamides, cyclization obtains compound viii' to ix'.
13. preparation methoies according to claim 11, compound vii', in water/organic two-phase system, obtains compound vi' with tetrabutyl ammonium bromide for Catalyzed By Phase-transfer Catalyst open loop.
14. preparation methoies according to claim 11, compound vi' tempo be catalyst, sodium hypochlorite be oxidant under conditions of aoxidize prepare compound v'.
15. preparation methoies according to claim 11, compound v' reacts prepare compound iv' with methyl-magnesium-chloride Grignard reagent.
16. preparation methoies according to claim 11, in the presence of diphenyl carbonate and phosphoric triamides, cyclization obtains compound iii' to compound iv'.
17. preparation methoies according to claim 8, formula iii' compound also can be prepared in the following way:
Wherein, r is ac or bz, and l is oac, obz, cl, br, oms, ots.
18. preparation methoies according to claim 17, in the presence of three tertiary butyoxy aluminum lithiums or red aluminum, reduction obtains compound vi to compound vii.
19. preparation methoies according to claim 17, compound vi and excess acetyl chloride, obtain compound v, and l is oac；Or compound vi is reacted with Benzenecarbonyl chloride., obtain compound v, l is obz；Or compound vi and n- chlorosuccinimide reacts, obtain compound v, l is cl, oxalyl chloride alternative n- chlorosuccinimide；Or compound vi is reacted with mesyl chloride, obtain compound v, l is oms；Or compound vi is reacted with paratoluensulfonyl chloride, obtain compound v, l is ots；Or compound vi and nbs reacts, obtain compound v, l is br.
20. preparation methoies according to claim 17, compound v and uracil occur vorbr ü ggen glycosylation reaction to obtain formula iv compound.
21. preparation methoies according to claim 17, in the presence of diphenyl carbonate and phosphoric triamides, heating cyclization to obtain formula iii' compound to compound iv occurs.
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| CN108440613A (en) * | 2018-03-26 | 2018-08-24 | 上海仁实医药科技有限公司 | The synthesis technology of one kind fluoro- 2`- methylurea glycosides of (2`R) -2`- deoxidations -2`- |
| CN112500446A (en) * | 2020-12-11 | 2021-03-16 | 平江县吉成科技有限责任公司 | Synthetic method of 2 '-fluoro-2' -deoxyuridine |
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