CN106810515A - The midbody compound and its synthetic method of a kind of synthesis Suo Feibuwei - Google Patents
The midbody compound and its synthetic method of a kind of synthesis Suo Feibuwei Download PDFInfo
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- CN106810515A CN106810515A CN201710067409.9A CN201710067409A CN106810515A CN 106810515 A CN106810515 A CN 106810515A CN 201710067409 A CN201710067409 A CN 201710067409A CN 106810515 A CN106810515 A CN 106810515A
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses the midbody compound and its synthetic method of a kind of synthesis Suo Feibuwei, the midbody compound is 4 intermediate products and 1 target compound, wherein 4 intermediate products are respectively：((2R, 3R, 4R) the base of 35 hydroxyl of (benzoyloxy) 4 fluorine, 4 methyltetrahydrofuran 2) methyl benzoate, ((2R, 3R, 4R) the base of 35 chlorine of (benzoyloxy) 4 fluorine, 4 methyltetrahydrofuran 2) methyl benzoate, (2'R) N benzoyl 2' deoxidation 2' fluorine 2' methylcytidines 3', 5' dibenzoates and ((2R, 3R, 4R, 5R) 3 (benzoyl epoxide) 4 fluorine 5 (2, 4 dioxos 3, 4 dihydro-pyrimidin 1 (2H) bases) base of 4 methyltetrahydrofuran 2) methyl benzoic acid, final goal compound is (2'R) 2' deoxidation 2' fluorine 2' MU glycosides.The present invention is high compared to existing synthetic method target compound content, and the impurity content produced in building-up process is few.And the result stabilization that synthetic method is obtained, it is simple to operate, it is adaptable to industrial production and Technique Popularizing on a large scale.
Description
Technical field
The invention belongs to medical field, more particularly to a kind of new method of fluorinated lactones cycle compound reduction, tool
It is Suo Feibuwei intermediates, (the fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- of (2R, 3R, 4R) -3- (benzoyloxy) -4- that body is said
Base) methyl benzoate, (the chloro- 4- methyltetrahydrofurans -2- bases of the fluoro- 5- of (2R, 3R, 4R) -3- (benzoyloxy) -4-) benzoic acid
Methyl esters, fluoro- 2'- methylcytidines 3', the 5'- dibenzoates of (2'R)-N- benzoyl -2'- deoxidations -2'-, ((2R, 3R, 4R,
5R) the fluoro- 5- of -3- (benzoyl epoxide) -4- ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins -1) -4- methyl tetrahydrochysene furans
Mutter -2- bases) synthetic method of methyl benzoic acid, and the fluoro- 2'- MUs of final goal compound (2'R) -2'- deoxidations -2'-
The synthetic method of glycosides.
Background technology
Hepatitis viroid drastically influence the health of the mankind at present, and the crowd of whole world infection hepatitis about occupies 3%.By
This, lucky Leadd B.V is developed for treating the new drug of chronic hepatitis C, and Suo Feibuwei (is translated into rope fluorine cloth Wei, English name again
Sofosbuvir, trade name Sovaldi), in December 6 in 2013, food and medicine Surveillance Authority of the Nikkei U.S. (FDA) approval existed
The U.S. lists, and the Nikkei of January 16 in 2014 Europe drug administration (EMEA) approval is in EU countries's listing.Suo Feibuwei is used as one
The new drug for treating hepatitis is planted, becomes the emphasis of research, with very big market prospects.
Suo Feibuwei synthetic routes had been reported that, the first step：With lithium aluminium hydride reduction as reducing agent, but this method is reduced
The effect of agent is too strong, has open loop and pushes away the impurity of fluorine.
In the prior art, second step, this reaction has the impurity that first step impurity 01 is produced after chloro, and structure is as follows：
In the prior art, the 3rd step, the impurity structural formula that this reaction is easily generated is as follows：
In the prior art, the 4th step, the impurity structural formula that this reaction is easily generated is as follows：
This impurity is avoided in many distinct methods.
In the prior art, the 5th step, the impurity for easily generating：
Intermediate state：
The content of the invention
To solve the shortcoming and defect of prior art, the invention provides a kind of intermediate compound of synthesis Suo Feibuwei
Thing, the midbody compound is 4 intermediate products and 1 target compound, wherein 4 intermediate products are respectively：((2R,
3R, 4R) the fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- bases of -3- (benzoyloxy) -4-) methyl benzoate, ((2R, 3R, 4R) -
The chloro- 4- methyltetrahydrofurans -2- bases of the fluoro- 5- of 3- (benzoyloxy) -4-) methyl benzoate, (2'R)-N- benzoyls -2'-
Fluoro- 2'- methylcytidines 3', the 5'- dibenzoates of deoxidation -2'- are with ((2R, 3R, 4R, 5R) -3- (benzoyl epoxide) -4- is fluoro-
5- (2,4- dioxo -3,4- dihydro-pyrimidins -1 (2H)-yl) -4- methyltetrahydrofuran -2- bases) methyl benzoic acid, final goal
Compound is (2'R) -2'- deoxidations fluoro- 2'- MUs glycosides of -2'-.
Further, the invention also discloses the synthetic method of the Suo Feibuwei midbody compounds, described ((2R,
3R, 4R) the fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- bases of -3- (benzoyloxy) -4-) methyl benzoate compound (compound
2) obtained by initiation material reduction, wherein the chemical constitution of the initiation material is：
Further, the reducing agent is DIBAL, and the temperature of reaction is -20~25 DEG C, and its reaction equation is：
Further, the invention also discloses the synthetic method of the Suo Feibuwei midbody compounds, described ((2R,
3R, 4R) the chloro- 4- methyltetrahydrofurans -2- bases of the fluoro- 5- of -3- (benzoyloxy) -4-) methyl benzoate be it is described ((2R, 3R,
4R) the fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- bases of -3- (benzoyloxy) -4-) methyl benzoate obtains by NCS chloros,
Its reaction equation is：
Further, the invention also discloses the synthetic method of the Suo Feibuwei midbody compounds, (2'R)-
Fluoro- 2'- methylcytidines 3', the 5'- dibenzoates of N- benzoyl -2'- deoxidations -2'- are by ((2R, 3R, 4R) -3- (benzene first
Acyloxy) the fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methyl benzoate and silanization cytimidine process tetrachloro
Change tin does lewis acid glycosylation reaction and obtains, and its reaction equation is：
Further, the invention also discloses the synthetic method of the Suo Feibuwei midbody compounds, described ((2R,
3R, 4R, 5R) the fluoro- 5- of -3- (benzoyl epoxide) -4- ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins -1) -4- methyl four
Hydrogen furans -2- bases) methyl benzoic acid is (the 2'R)-N- benzoyl -2'- deoxidations -2'- fluoro- 2'- methylcytidines 3', 5'-
Dibenzoate flows back and takes off benzamido and obtain at high temperature through the aqueous solution of performic acid, and its reaction equation is：
Further, the invention also discloses the synthetic method of the Suo Feibuwei midbody compounds, the final mesh
Mark compound (the 2'R) -2'- deoxidations fluoro- 2'- MUs glycosides of -2'- is by ((2R, 3R, 4R, 5R) -3- (benzoyl oxygen
Base) the fluoro- 5- of -4- ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins -1) -4- methyltetrahydrofuran -2- bases) methyl benzoic acid
Take off protection group benzoyl under conditions of alkaline ammoniacal liquor to obtain, its reaction equation is：
The beneficial effects of the invention are as follows：The synthetic method of Suo Feibuwei midbody compounds of the present invention is compared to existing
Synthetic method target compound content it is high, in building-up process produce impurity content it is few.And the result stabilization that synthetic method is obtained,
It is simple to operate, it is adaptable to industrial production and Technique Popularizing on a large scale.
Specific embodiment
With reference to embodiment, the present invention will be further described, it should be understood that these embodiments are only used for illustration
Purpose, be in no way intended to limit protection scope of the present invention.
The present invention includes 4 fragments, (the fluoro- 5- hydroxy-4-methyls tetrahydrochysene furans of (2R, 3R, 4R) -3- (benzoyloxy) -4-
Mutter -2- bases) methyl benzoate, (the chloro- 4- methyltetrahydrofurans -2- bases of the fluoro- 5- of (2R, 3R, 4R) -3- (benzoyloxy) -4-)
Methyl benzoate, fluoro- 2'- methylcytidines 3', the 5'- dibenzoates of (2'R)-N- benzoyl -2'- deoxidations -2'- and ((2R,
3R, 4R, 5R) the fluoro- 5- of -3- (benzoyl epoxide) -4- ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins -1) -4- methyl four
Hydrogen furans -2- bases) methyl benzoic acid.Wherein, the fluoro- 2'- MUs glycosides of (2'R) -2'- deoxidations -2'- is main target chemical combination
Thing.Its synthesis is last deprotection to be connected with pyrimidine ring by sugared ring and is obtained.Concretely comprise the following steps：
1. (the fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- bases of (2R, 3R, 4R) -3- (benzoyloxy) -4-) benzoic acid first
Ester compounds (compound 2) are that (in the market is commercially available initial compound 1, and its No. CAS is：874638-80-9) pass through
Obtained from DIBAL reduction.It is of the invention main to have used selective reduction agent DIBAL, selectivity by compound 1
Lactone carbonyl is reduced to hydroxyl, and the fluorine on carbonyl and sugared ring on benzoyl is not reduced.The main synthesis of this step
Product (compound 2) is as follows：
The synthetic reaction formula of this step is：
The reducing agent used in this invention is DIBAL, screens other reducing agent：Lithium aluminium hydride reduction, sodium hydrogen, sodium borohydride,
Acetic acid sodium borohydride, sodium cyanoborohydride, red aluminum, three tert-butoxy aluminium lithium hydrogen etc..Solvent application dichloromethane, it is garbled molten
Agent has：Tetrahydrofuran, dichloromethane, toluene, isopropyl acetate, dioxane, dichloroethanes.The temperature of reaction：- 20~25
℃.Realize that the concrete operations of synthetic reaction formula described in this step are as follows：
A. the various solvents of this experiment and the moisture of reagent are tested first.(dichloromethane, moisture KF=0.03%).So
100g compounds 1 are added in the Jacketed bottle R1 of 2000mL afterwards, under nitrogen protection, the dichloromethane of 1000mL are added to
In R1, the interior temperature for adjusting R1 is -10~-18 DEG C.It is -10~-18 DEG C to keep temperature in R1, stirs 0.5h.DIBAL100mL is existed
Under nitrogen protection, it is added in dropping funel, controls the interior temperature of R1 to be no more than -5 DEG C, lentamente the liquid in dropping funel is added dropwise
To in R1.Temperature in R1 is kept to stir 2h at -5 DEG C.
B. after reaction raw materials are totally converted and finish, the 37% of 500mL hydrochloric acid is added in Jacketed bottle R2, adjustment R2's
Interior temperature is 0~10 DEG C, and the reaction solution in R1 is lentamente added drop-wise in R2.After being added dropwise to complete, the dichloromethane of 100mL is rinsed
Once R1, is also added drop-wise in R2.The process water of 500mL is added slowly in R2, the interior temperature for keeping R2 is 25~30 DEG C, is stirred
Mix 1h.
C. a point liquid is stood, organic phase is stayed in R2, water phase point is walked.Then the 15% of 1000mL citric acid is added to
In R2, the interior temperature of R2 is kept at 25~30 DEG C, point liquid after stirring 1h is transferred to organic phase in R1.Then again by 1000mL's
8% sodium acid carbonate is added in R1, stirs R1 half an hour, and stratification, organic phase is transferred in R2, and water phase point is walked.Will
The process water of 500mL is added in R2, and it is 20~30 DEG C of stirring 30min to control the interior temperature of R2, and stratification, organic phase is transferred to
In R1.Temperature is less than 50 DEG C, vacuum distillation to 3 times of volumes of former compound 1 in control R1.The dichloromethane of 300mL is added to
In R1, temperature is less than 50 DEG C, vacuum distillation to 3 times of volumes of former compound 1 in control R1.The purity of sampling and testing compound 2, weight
Amount content.Weight content：(1550-292) × 7.4%=93.1%, yield：94%.
2. (the chloro- 4- methyltetrahydrofurans -2- bases of the fluoro- 5- of (2R, 3R, 4R) -3- (benzoyloxy) -4-) methyl benzoate
It is to obtain the compound 3 that we want by NCS chloros by compound 2.The structural formula of compound 3 is as follows：
The synthetic reaction formula of this step is as follows：
With N- chlorosuccinimides as chlorinating agent in this step.Used cooperatively with triphenylphosphine, improve advantage
Configuration ratio.Garbled chlorinating agent：Oxalyl chloride, thionyl chloride, POCl3 etc., finally determine the synthesis of compound 3
Method.The determination of temperature range：- 10 DEG C to 40 DEG C.Realize that the concrete operations of synthetic reaction formula described in this step are as follows：
A. preparation：The moisture of material and solvent.(dichloromethane, moisture KF=0.02%).
B. 100g compounds 2 and 500ml dichloromethane are added in 2000mL there-necked flasks S1, then by the triphen of 43g
Base phosphine is added in S1, opens stirring.Under nitrogen protection by 0~10 DEG C of the interior temperature control system of S1.NCS is dividedly in some parts S1
In, it is 15 DEG C that temperature in S1 is adjusted after adding, and stirs 1h at this temperature, is controlled in sampling, when the ratio of the compound 3 of compound 2/
≤ 0.5%, reaction terminates.Washed twice to addition 300ml saturated sodium carbonate solutions in S1, then with 300ml water washings twice, control
Vacuum distillation is cooled to room temperature to without cut at heating 50 DEG C of bath temperature.500g isopropyl ethers are subsequently adding, 1h are stirred at room temperature,
- 10 DEG C of stirring 1h are cooled to again.Control temperature in -10 DEG C of filterings after stirring, with the isopropyl ether drip washing filter cake of precooling, filtrate is in control
Vacuum distillation is to without cut at heating 50 DEG C of bath temperature.Add 200g chlorobenzenes to continue to distill to without cut, be down to room temperature.Plus
After entering 900g chlorobenzene stirring and dissolvings, the next step, the yield 95% of compound 3 are carried out.
3. fluoro- 2'- methylcytidines 3', the 5'- dibenzoates of (2'R)-N- benzoyl -2'- deoxidations -2'- are by changing
Compound 2 does lewis acid glycosylation reaction and obtains the compound 5 that we want with the process butter of tin of cytimidine 4 of silanization.
The structural formula of compound 5 is as follows：
The synthetic reaction formula of this step is as follows：
Catalysis being done using ammonium sulfate and accelerating Silanization reaction speed, post processing alkali is quenched and replaces pickling in this step,
Reduce three wastes generation.Realize that the concrete operations of synthetic reaction formula described in this step are as follows：
A. preparation：Device is connected, the air-tightness of check device controls anhydrous condition.
B. 125g N4- benzoylcytosines, 0.2g ammonium sulfate, 94g hexamethyldisilazanes and 550ml chlorobenzenes are added
Enter in the there-necked flask T1 of 3000ml, be warming up to 130 DEG C of reactions, until system it is molten it is clear after, then insulation reaction 2h drops after insulation
Temperature is to 60 DEG C.Vacuum distillation below 60 DEG C of heating bath temperature of control is to without cut, 0.5~1h of switching high vacuum distillation.It is cooled to
Room temperature, obtains compound 4.To the chlorobenzene solution (1000ml) and butter of tin of the compound 2 that 90g is added in compound 4, heat up
To 75 DEG C of 8~10h of reaction, controlled in sampling, reaction terminates during 2/ 5 ratio≤5.0% of compound of compound.Room temperature is cooled to, plus
Enter 1000ml dchloromethanes.470g sodium bicarbonate solids, 150g diatomite and 1000ml dichloromethane are added to 10L's
In reaction bulb T2, stirring is opened, material in T1 is transferred to T2, the interior temperature of temperature control T2 is less than 25 DEG C, 84g water is added dropwise, after adding
Insulated and stirred 2h, is to slowly warm up to 45 DEG C and is stirred at reflux 1h, is cooled to room temperature.Filtering, filter cake is beaten with 1000ml dichloromethane
Twice.Filtrate air-distillation to interior temperature reaches 90 DEG C, stops distillation.90 DEG C of mashing 3h of temperature control, are cooled to mistake after 0 DEG C of crystallization 3h
Filter, filter cake is washed with 100ml isopropanols and obtains white solid.70 DEG C of dryings of temperature control obtain the dry product 85g of compound 5 to constant weight, receive
Rate 65%.
4. ((2R, 3R, 4R, 5R) -3- (benzoyl epoxide) -4- fluoro- 5- (2,4- dioxo -3,4- dihydro-pyrimidins -1
(2H)-yl) -4- methyltetrahydrofuran -2- bases) methyl benzoic acid be by compound 5 through performic acid the aqueous solution at high temperature
Backflow is taken off benzamido and obtains the compound 6 that we want.The structural formula of compound 6 is as follows：
The synthetic reaction formula of this step is as follows：
With aqueous formic acid as the reagent for sloughing protection group in this step.Avoid excessive side reaction benzoyl
Take off.Garbled acid：Benzoic acid, phenylacetic acid, acetic acid, formic acid, acetic anhydride, sulfuric acid, hydrochloric acid etc., a series of acid.Also there is Louis
This acid：Alchlor, zinc chloride, stannic chloride etc., effect is bad.Acid is screened with the ratio of water, and the conjunction of compound 6 is finally determined
Into method.The determination of temperature range：25 DEG C to 125 DEG C of room temperature.Realize that the concrete operations of synthetic reaction formula described in this step are as follows：
A. preparation：The content of isomer of test compound 6 is less than 0.5%.
B. 100g compounds 5 are added in 2000mL there-necked flasks U1, the formic acid of 600mL is added in U1, opened
Stirring, it is 25 DEG C to keep temperature in U1, and the process water of 300mL is added in U1, and temperature is 35 DEG C in adjustment U1, is stirred at this temperature
0.5h is mixed, the slow high-temperature that rises keeps this temperature to stir 6h to 90~100 DEG C.Controlled in sampling, the compound 6 of compound 5/≤
0.5%, reaction terminates.The slow interior temperature for reducing U1 is 25 DEG C, and 2h is stirred at 25 DEG C.Reaction solution in U1 is put to suction filtration machine
In F1, the reaction solution in vacuum filtration F1, filtrate is transferred in there-necked flask U2, the methyl alcohol of 100mL is added in F1 and is beaten
And vacuum filtration, filtrate is transferred in U2, takes filtrate test residue of mother in U2.Solid in F1 is transferred in baking oven D1,
The interior temperature for adjusting D1 is 65 DEG C of vacuum drying 20h, can there is trace nitrogen air-flow.Obtain 72g solid chemical compounds 6, yield 93%.
5. the fluoro- 2'- MUs glycosides of (2'R) -2'- deoxidations -2'- is taken off under conditions of alkaline ammoniacal liquor by compound 6
Protection group benzoyl obtains final compound 7.The structural formula of compound 7 is as follows：
The synthetic reaction formula of this step is as follows：
In this step, the reagent of benzoyl protecting groups is taken off using the ammoniacal liquor of alkalescence, condition is easily controlled, reaction ratio
It is relatively clean, ammoniacal liquor used can also recycle and reuse, accomplished environment-friendly.Screened different alkali：Solid base, such as carbon
Sour potassium, sodium carbonate, cesium carbonate, sodium acid carbonate etc..Liquid base：Such as triethylamine, ammoniacal liquor, diisopropyl ethyl amine, pyridine, etc..This
The selection of outer solvent：Such as the environment of pure water, ammonia methanol solution, dichloromethane system etc..Temperature range：0~35 DEG C.Realize this
The concrete operations of synthetic reaction formula are as follows described in step：
A. preparation：Connect device, the air-tightness of check device.
B. 1000g ammoniacal liquor is added in the there-necked flask V1 of 2000mL, opens stirring, slowly reduce temperature, control V1
Interior temperature is at 0~5 DEG C.Then the compound 6 of 100g is added in V1, the interior temperature for keeping V1 is 10~15 DEG C, stirs 20h.
C. controlled in sampling：, to 40~45 DEG C, vacuum distillation is extremely for temperature in (during 6/ compound 7≤0.5% of compound) adjustment V1
100~200mL, by the methyl alcohol addition V1 of 200g, it is 40~45 DEG C, vacuum distillation to 100~200mL to keep temperature in V1.Protect
Temperature is held in V1 for 45~50 DEG C, the toluene of 2000mL is added in R1, vacuum distillation to 1500~1600mL, then by 500mL
Toluene be added in V1, keep V1 in temperature be 45~50 DEG C, vacuum distillation to 1600~1700mL.The slow interior temperature for raising V1
It it is 80 DEG C, the interior temperature for keeping V1 is 80 DEG C, stirs 6h.The solid purity of filtering and sampling test while hot：99%.Will under the conditions of 80 DEG C
Material in V1 is transferred to vacuum filtration in suction filtration machine F1, and filtrate is transferred in V2.By in 80 DEG C of 100g of toluene addition F1
Vacuum filtration.Solid after suction filtration is put into baking oven D1, keeps warm for that at 50 DEG C, can remain under nitrogen stream, very in D1
Sky drying 20h.White solid 55g is obtained, the solid of white is compound 7, its purity is 99%, yield 98%.
Claims (7)
1. a kind of midbody compound of synthesis Suo Feibuwei, it is characterised in that the midbody compound is 4 intermediate products
With 1 target compound, 4 intermediate products are respectively：(the fluoro- 5- hydroxyls -4- first of (2R, 3R, 4R) -3- (benzoyloxy) -4-
Base tetrahydrofuran -2- bases) methyl benzoate, (the chloro- 4- methyl tetrahydrochysene furans of the fluoro- 5- of (2R, 3R, 4R) -3- (benzoyloxy) -4-
Mutter -2- bases) methyl benzoate, fluoro- 2'- methylcytidines 3', the 5'- dibenzoates of (2'R)-N- benzoyl -2'- deoxidations -2'-
(the fluoro- 5- of (2R, 3R, 4R, 5R) -3- (benzoyl epoxide) -4- ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins -1) -
4- methyltetrahydrofuran -2- bases) methyl benzoic acid, final goal compound is (2'R) -2'- deoxidations fluoro- 2'- MUs of -2'-
Glycosides.
2. the synthetic method of Suo Feibuwei midbody compounds described in claim 1, it is characterised in that described ((2R, 3R, 4R)-
The fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- bases of 3- (benzoyloxy) -4-) methyl benzoate compound (compound 2) is by
The reduction of beginning raw material is obtained, wherein the chemical constitution of the initiation material is：
3. the synthetic method of a kind of Suo Feibuwei midbody compounds according to claim 2, it is characterised in that it is described also
Former agent is DIBAL, and the temperature of reaction is -20~25 DEG C, and its reaction equation is：
4. the synthetic method of Suo Feibuwei midbody compounds described in claim 1, it is characterised in that described ((2R, 3R, 4R)-
The chloro- 4- methyltetrahydrofurans -2- bases of the fluoro- 5- of 3- (benzoyloxy) -4-) methyl benzoate is described ((2R, 3R, 4R) -3-
The fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- bases of (benzoyloxy) -4-) methyl benzoate obtains by NCS chloros, its reaction
Formula is：
5. the synthetic method of Suo Feibuwei midbody compounds described in claim 1, it is characterised in that (the 2'R)-N- benzene first
Fluoro- 2'- methylcytidines 3', the 5'- dibenzoates of acyl group -2'- deoxidations -2'- are by ((2R, 3R, 4R) -3- (benzoxies
Base) the fluoro- 5- hydroxy-4-methyls tetrahydrofuran -2- bases of -4-) methyl benzoate and silanization cytimidine process butter of tin
Do lewis acid glycosylation reaction to obtain, its reaction equation is：
6. the synthetic method of Suo Feibuwei midbody compounds described in claim 1, it is characterised in that described ((2R, 3R, 4R,
5R) the fluoro- 5- of -3- (benzoyl epoxide) -4- ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins -1) -4- methyl tetrahydrochysene furans
Mutter -2- bases) methyl benzoic acid is fluoro- 2'- methylcytidines 3', the 5'- hexichol of (the 2'R)-N- benzoyl -2'- deoxidations -2'-
Formic acid esters flows back and takes off benzamido and obtain at high temperature through the aqueous solution of performic acid, and its reaction equation is：
7. the synthetic method of Suo Feibuwei midbody compounds described in claim 1, it is characterised in that the final goal chemical combination
The fluoro- 2'- MUs glycosides of thing (2'R) -2'- deoxidations -2'- is by described ((2R, 3R, 4R, 5R) -3- (benzoyl epoxide) -4-
Fluoro- 5- ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidins -1) -4- methyltetrahydrofuran -2- bases) methyl benzoic acid is in alkalescence
Take off protection group benzoyl under conditions of ammoniacal liquor to obtain, its reaction equation is：
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