CN110615823B - Preparation method of (2 'R) -2' -deoxidized-2 '-fluoro-2' -methyluridine - Google Patents

Abstract

The application discloses a synthetic method of (2 'R) -2' -deoxidized-2 '-fluoro-2' -methyluridine (formula I). The compound of the formula I is obtained by using cheap and easily available starting materials through links such as hydroxyl protection, cyclization, fluorination and the like.

Description

Preparation method of (2 'R) -2' -deoxidized-2 '-fluoro-2' -methyluridine

The application is a divisional application of application number 201510441384.5, application date 2015, 07 and 25, and the application and creation name of the application is a preparation method of (2 'R) -2' -deoxidized-2 '-fluoro-2' -methyluridine.

Technical Field

The application belongs to the field of pharmaceutical chemical industry.

Background

Viral hepatitis c, abbreviated as hepatitis c, is a viral disease caused by infection with hepatitis c virus (Hepatitis C Virus, HCV). After HCV infection, 50% -85% will be converted into chronic infection, and if reasonable control measures are not taken, the patients will eventually lead to cirrhosis and hepatocellular carcinoma, which seriously threatens life safety. HCV is mainly transmitted by means of blood, needle sticks, drug sticks, and the like. Some data show that mortality associated with global hepatitis c virus infection (liver failure and death from hepatocellular carcinoma) will continue to increase in the next 20 years, and HCV control has become one of the major public health problems in the world.

Sofosbuvir is a class of nucleoside polymerase inhibitors developed by Gilead corporation and can be used in combination with ribavirin to treat adult gene type 2, 3 chronic HCV infection. Compared with the traditional anti-HCV drug, the drug has short treatment period and high cure rate of Sofosbuvir, and is a breakthrough drug for treating HCV.

(2 'R) -2' -deoxy-2 '-fluoro-2' -methyluridine (formula I) is an important intermediate for the synthesis of Sofosbuvir. The synthesis methods of the compounds of formula I mainly include the following. First, the method is prepared by glycosylation reaction, for example, patent WO2008045419 and US2010016251 disclose a method for synthesizing (2 'R) -2' -deoxy-2 '-fluoro-2' -methyluridine from (R) -propylidene glyceraldehyde as a raw material through more than ten steps of reaction.

The reaction line is long, the three wastes are more, the environmental protection pressure is high, and the raw material cost and the production cost are high.

Patent WO2005003147, CN104327138, uses bistrimethylsil protected uracil as a starting material for glycosylation reactions.

Another approach is to use other nucleosides as starting materials, as reported in documents Journal of Medicinal Chemistry,2005, voi.48, no.17, 5504-5508 (Scheme 3) for the conversion of cytidine to compound I.

The synthesis of I from uridine in a similar manner is reported in literature Nucleosides, nucleotides and nucleic acids,2011, vol:30, # 11, p 886-896 (Scheme 4).

These methods for synthesizing (2 'R) -2' -deoxy-2 '-fluoro-2' -methyluridine (formula I) from other glycosides have the advantage of shorter routes, but require the use of DAST (diethylaminosulfur trifluoride), a costly fluorinating reagent, which is poor in selectivity and yield, resulting in high product costs and no competitive advantage.

In addition, the angel. Chem. Int. Ed., et al, report a new method for synthesizing 2 '-deoxy-2' -fluoro-cytidine (Scheme 5), which is a strategy of intramolecular cyclization followed by fluoride ring opening. The stereoselectivity is good, but the yield is to be improved.

In summary, the methods in Scheme 1 and Scheme 2 are classical and reliable, but have long synthesis line, high cost, large three wastes and high environmental protection pressure. The methods in Scheme 3 and Scheme 4 have the disadvantages of expensive fluoro reagent, poor fluoro reaction selectivity and low yield although the line is short. Although the method in Scheme 5 solves the selectivity problem, it has a disadvantage of low yield, and it is required to increase the yield.

Disclosure of Invention

With respect to terms mentioned in the present application, the following is explained:

ac: acetyl group

OAc: acetoxy group

TEA: triethylamine

DMF: n, N-dimethylformamide

DMSO: dimethyl sulfoxide

Bz: benzoyl group

OBz: benzoyloxy group

OMs: methanesulfonyloxy group

OTs: para-toluenesulfonyloxy group

TEMPO: tetramethyl piperidine nitroxide

Cl: chlorine

Br: bromine

The application relates to a preparation method of (2 'R) -2' -deoxidized-2 '-fluoro-2' -methyluridine (formula I),

deprotection of a compound of formula IV in the presence of methanolic amine,

wherein R is Ac or Bz,

preparing a compound of formula III;

closing a ring of the compound of the formula III in the presence of diphenyl carbonate and phosphoric triamide to obtain a compound II;

the compound II is reacted with a fluorinating reagent to obtain a compound I, wherein the fluorinating reagent is preferably potassium fluoride, hydrogen fluoride/TEA, hydrogen fluoride/pyridine or tetrabutylammonium fluoride, and the reaction solvent is preferably DMF, dichloromethane, chloroform, tetrahydrofuran, chlorobenzene, acetonitrile, DMSO or 2-methyltetrahydrofuran.

The compounds of formula IV may be prepared as follows:

wherein R is Ac or Bz, and L is OAc, OBz, cl, br, OMs, OTs. The compound VII is reduced with lithium aluminum tri-tert-butoxide or red aluminum to obtain the compound VI. Reacting the formula VI with acetyl chloride to obtain a compound V, wherein L is OAc; or reacting the compound VI with benzoyl chloride to obtain a compound V, wherein L is OBz; or the compound VI reacts with N-chlorosuccinimide to obtain a compound V, wherein L is Cl, and oxalyl chloride can be used for replacing the N-chlorosuccinimide; or reacting the compound VI with methanesulfonyl chloride to obtain a compound V, wherein L is OMs; or the compound VI reacts with p-toluenesulfonyl chloride to obtain a compound V, wherein L is OTs; or reacting the compound VI with NBS to obtain a compound V, wherein L is Br. The compounds of formula IV are obtained by vorbBuggen glycosylation of formula V with uracil.

Alternatively, formula I can be prepared by the following method:

the compound II 'is prepared by reacting a fluoridation reagent of formula III' with a fluoridation reagent, wherein R is Ac or Bz, the fluoridation reagent is preferably potassium fluoride, hydrogen fluoride/TEA, hydrogen fluoride/pyridine or tetrabutylammonium fluoride, and the reaction solvent is preferably DMF, dichloromethane, chloroform, tetrahydrofuran, chlorobenzene, acetonitrile, DMSO or 2-methyltetrahydrofuran.

Deprotection of formula II' in the presence of methanolic amine affords compounds of formula I.

The compounds of formula III' may be prepared as follows:

wherein R is Ac or Bz. In the presence of diphenyl carbonate and phosphoric triamide, the ring is closed to obtain a compound VIII ', and hydroxy is protected to obtain a compound VII'. In the water/organic two-phase system, tetrabutylammonium bromide is used as a phase transfer catalyst to catalyze and open the loop to obtain a compound VI'. The compound V 'is prepared by oxidizing the formula VI' under the condition that TEMPO is used as a catalyst and sodium hypochlorite is used as an oxidant. The compound IV 'is prepared by reacting the formula V' with a methyl magnesium chloride Grignard reagent. Ring closure of formula IV 'in the presence of diphenyl carbonate and phosphoric triamide gives compound III'.

Alternatively, compound III' may be prepared as follows:

wherein R is Ac or Bz, and the compound IV is heated to carry out cyclization reaction in the presence of diphenyl carbonate and phosphoric triamide to obtain the compound shown in the formula III'. The process for the preparation of the compounds of formula IV can be carried out by the process described above starting from VIII.

Detailed Description

EXAMPLE 1 Synthesis of Compound VIII

24.4g Uridine IX' (Uridine), 32.1g diphenyl carbonate (1.5 eq), 8.4g sodium bicarbonate, 250mL phosphoric acid triamide were added to a 500mL three-necked flask. Heating to 150deg.C, performing HPLC control to complete reaction, cooling to room temperature, adding water, extracting with chloroform, mixing the extracts, drying with anhydrous sodium sulfate, and filtering. The filtrate enters the next reaction.

EXAMPLE 2 Synthesis of Compound VII' b

To the chloroform solution of the compound obtained in example 1, triethylamine (1.2 eq) was added, cooled to 0 to 5 ℃, benzoyl chloride was added dropwise, after the dropwise addition was completed, the temperature was raised to room temperature, the reaction was controlled by HPLC, after the reaction was completed, 2N HCl was added, stirring was performed, the organic layer was separated, washing with 1N NaOH and water in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, N-heptane was added for slurry washing, and white solid was obtained by filtration, and dried, and 32g was weighed.

EXAMPLE 3 Synthesis of Compounds VI 'b and V' b

21g of the compound obtained in example 2VII' b, 250g of dichloromethane and 100mL of 0.1N NaHCO ₃ 0.1g of tetrabutylammonium bromide (TBAB) was added to a three-necked flask, stirred at 50℃and subjected to HPLC chromatography, and after completion of the reaction, an aqueous layer was separated to obtain an organic layer of VI' b. The organic layer of VI' b was transferred to a three-necked flask, cooled to 0-10℃and then added with tetramethylpiperidine nitroxide (TEMPO, 0.5% eq), followed by dropwise addition of 10% sodium hypochlorite solution, and the mixture was warmed to room temperature for reaction. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified to give 16g of an off-white solid V' b.

EXAMPLE 4 Synthesis of Compound IV' b

16g of the compound V' b obtained in the embodiment 3 is dissolved in 200 ml of 2-methyltetrahydrofuran, cooled to-40 to-78 ℃, dropwise added with a methyl magnesium chloride Grignard reagent, reacted for 2-6 hours at a temperature until the reaction is completed, and quenched by adding a saturated ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with methyl tert-butyl ether. The organic phases were combined and concentrated to give compound IV' b, which was used directly in the next reaction without isolation.

EXAMPLE 5 Synthesis of Compound III' b

The compound IVb', diphenyl carbonate (1.5 eq), sodium hydrogencarbonate (1.0 eq) and phosphoric triamide obtained in example 4 were added to a three-necked flask. Heating to 150deg.C, performing HPLC control to complete reaction, cooling to room temperature, adding water, extracting with chloroform, mixing the extracts, drying with anhydrous sodium sulfate, and filtering. Concentrating, adding n-hexane for crystallization, and obtaining an off-white solid. And (3) recrystallizing to obtain a sample with the purity higher than 99.5%, and sending the sample for nuclear magnetic analysis, wherein the analysis result is consistent with the structure. IHNMR (d 6-DMSO,400 Hz): delta 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).

EXAMPLE 6 Synthesis of Compound II' b

Example 6.1 2g of compound III' b,10mL of DMF (dimethylformamide), 2g of potassium fluoride were added to the flask, heated to 120℃and reacted for 2-4 h, cooled to room temperature, and water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate and separated by column chromatography to give 0.7g of a white solid.

Example 6.2 2.1g of compound III' b,10mL of methylene chloride, 4mL of hydrogen fluoride/pyridine solution were added to the flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The aqueous phase was extracted with dichloromethane and separated by column chromatography to give 1.1g of a white solid.

Example 6.3 1.8g of compound III' b,10mL of chloroform, 4mL of hydrogen fluoride/triethylamine solution were added to the flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The aqueous phase was extracted with chloroform and separated by column chromatography to give 1.2g of a white solid.

Example 6.4 2g of compound III' b,10mL of tetrahydrofuran, 3g of TBAF (tetrabutylammonium fluoride) were added to the flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, concentrated and separated by column chromatography to give 1.0g of a white solid.

Example 6.5 2.2g of compound III' b,10mL of chlorobenzene, 3g of TBAF were added to the flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, concentrated and separated by column chromatography to give 1.3g of a white solid.

EXAMPLE 7 Synthesis of Compound I

6.8g of compound II' b was added to the flask, and 20mL of methanolic amine solution was added and reacted at 25-30℃for 24 hours. 0.7g of activated carbon is added for decolorization, filtration and concentration are carried out to obtain an off-white solid, 20mL of ethyl acetate is added for slurry washing, filtration and drying are carried out to obtain 3.0g of off-white solid.

EXAMPLE 8 Synthesis of Compound VII

EXAMPLE 8.1 Synthesis of Compound VIIa

Compound VIII was synthesized from glucose as a starting material, see document Tetrahedron Letters; vol.48; nb.4; (2007); p.517-520. Compound VIII, triethylamine (5 eq), DMAP (dimethylaminopyridine, 0.1 eq) and acetone were added to the flask and acetic anhydride (5 eq) was added dropwise and reacted at room temperature for 24h. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid.

EXAMPLE 8.2 Synthesis of Compound VIIb

Compound VIII (prepared according to document Tetrahedron Letters; vol.48; nb.4; 2007; p.517-520), pyridine (5V) was added to a flask, benzoyl chloride (5 eq) was added dropwise, and the mixture was reacted at room temperature for 24 hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid.

EXAMPLE 9 preparation of Compound VI

EXAMPLE 9.1 preparation of Compound VIa

Lithium aluminum tri-tert-butoxide (1.2 eq) THF was added to a three-necked flask and cooled to-20 to-40 ℃. And dropwise adding the tetrahydrofuran solution of VIIa, and after the dropwise adding is finished, preserving heat and reacting for 4-6 hours at the temperature of minus 20 to minus 40 ℃. After the reaction was completed, ethyl acetate was added, and then a saturated ammonium chloride solution was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to give an ethyl ester solution of VIa, which was used directly in the next reaction.

EXAMPLE 9.2 preparation of Compound VIb

Lithium aluminum tri-tert-butoxide (1.2 eq) THF was added to a three-necked flask and cooled to-20 to-40 ℃. And dropwise adding the tetrahydrofuran solution of VIIb, and after the dropwise adding is finished, preserving heat and reacting for 4-6 hours at the temperature of minus 20 to minus 40 ℃. After the reaction was completed, ethyl acetate was added, and then a saturated ammonium chloride solution was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered to give an ethyl acetate solution of VIb, which was used directly in the next reaction.

EXAMPLE 9.3 preparation of Compound VIb

Adding 68% of red aluminum toluene solution (1.5 eq) into a flask, adding toluene, stirring, cooling to-20 to-10 ℃, dropwise adding trifluoroethanol (1.5 eq) into the red aluminum toluene solution, and reacting after dropwise adding, returning to 20-25 ℃ to obtain the modified red aluminum solution. VIIb (1 eq) was added to another flask, dissolved in methylene chloride, cooled to-30-10℃and then modified red aluminium solution was added dropwise thereto. After the dripping is finished, the reaction is carried out for 4 to 6 hours under the heat preservation. The reaction mixture was quenched with 37% concentrated hydrochloric acid, and the organic layer was separated, washed with water and then with 8% sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered to give a VIb solution. The solution was used directly in the next reaction without isolation.

EXAMPLE 10 Synthesis of Compound V

EXAMPLE 10.1 Synthesis of Compound Vg

The VIb ethyl acetate solution was added to a three-necked flask, triethylamine (1.5 eq) was further added thereto, the temperature of the mild solution was lowered to 0 to 5℃and acetyl chloride (1.3 eq) was added dropwise. After the dripping is finished, the temperature is returned to the room temperature for reaction for 8 to 12 hours. The reaction was quenched by addition of 2N hydrochloric acid, the organic layer was separated, washed sequentially with 8% sodium bicarbonate, water, the organic phase was separated, concentrated, the residual ethyl acetate was taken away with chlorobenzene, chlorobenzene was added to dissolve the residue to give a solution of Vg in chlorobenzene, which was used directly in the next reaction.

EXAMPLE 10.2 Synthesis of Compound Vh

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The VIb ethyl acetate solution was added to a three-necked flask, triethylamine (1.5 eq) was further added thereto, the temperature of the gentle solution was lowered to 0 to 5℃and benzoyl chloride (1.2 eq) was added dropwise. After the dripping is finished, the temperature is returned to the room temperature for reaction for 8 to 12 hours. The reaction was quenched by addition of 2N hydrochloric acid, the organic layer was separated, washed sequentially with 8% sodium bicarbonate, water, the organic phase was separated, concentrated, the residual ethyl acetate was taken away with chlorobenzene, chlorobenzene was added to dissolve the residue to give a solution of Vh in chlorobenzene, which was used directly in the next reaction.

EXAMPLE 10.3 Synthesis of Compound Vi

The ethyl acetate solution of VIb was concentrated under reduced pressure, the residue was dissolved in dichloromethane, triphenylphosphine (2 eq) was added thereto and cooled to 0-5 ℃, and N-chlorosuccinimide (3 eq) was added in portions. After the addition, the reaction is carried out for 1 to 2 hours after the temperature is returned to the room temperature. The reaction was quenched by addition of 8% sodium bicarbonate, the organic layer was separated, concentrated to dryness, cyclohexane was added to the residue, washed with water, filtered, the filtrate was concentrated, then chlorobenzene was added for distillation, chlorobenzene was added to dissolve the residue to give a chlorobenzene solution of Vi, which was used directly in the next reaction.

EXAMPLE 10.4 Synthesis of Compound Vi

DMF (1.08 eq) is added into a flask, cooled to 0-5 ℃, oxalyl chloride (1.1 eq) is added dropwise, and after the dripping is finished, the temperature is raised to 20-25 ℃ for reaction for 2h, and a Vilsmeier reagent is obtained. The ethyl acetate solution of VIb was concentrated under reduced pressure and the residue was dissolved in dichloromethane and then added to the Vilsmeier reagent prepared in advance. After the addition, the temperature is raised to 35-40 ℃ for reaction for 1-2 hours. The reaction was quenched by addition of 8% sodium bicarbonate, the organic layer was separated, concentrated, distilled with chlorobenzene, and the residue was dissolved with chlorobenzene to give a solution of Vi in chlorobenzene, which was used directly in the next reaction.

EXAMPLE 10.5 Synthesis of Compound Vk

The VIb ethyl acetate solution was added to a three-necked flask, triethylamine (1.5 eq) was further added thereto, the temperature of the mild solution was lowered to 0 to 5℃and methanesulfonyl chloride (1.3 eq) was added dropwise. After the dripping is finished, the temperature is returned to the room temperature for reaction for 8 to 12 hours. The reaction was quenched by addition of 2N hydrochloric acid, the organic layer was separated, washed sequentially with 8% sodium bicarbonate, water, the organic phase was separated, concentrated, the residual ethyl acetate was taken away with chlorobenzene, chlorobenzene was added to dissolve the residue to give a chlorobenzene solution of Vk, which was used directly in the next reaction.

EXAMPLE 10.6 Synthesis of Compound Vl

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The VIb ethyl acetate solution was added to a three-necked flask, triethylamine (1.5 eq) was further added thereto, the temperature of the mild solution was lowered to 0 to 5℃and p-toluenesulfonyl chloride (1.3 eq) was added dropwise. After the dripping is finished, the temperature is returned to the room temperature for reaction for 8 to 12 hours. The reaction was quenched by addition of 2N hydrochloric acid, the organic layer was separated, washed sequentially with 8% sodium bicarbonate, water, the organic phase was separated, concentrated, the residual ethyl acetate was taken away with chlorobenzene, chlorobenzene was added to dissolve the residue to give a chlorobenzene solution of Vl, which was used directly in the next reaction.

EXAMPLE 10.7 Synthesis of Compound Vj

The ethyl acetate solution of VIb was concentrated under reduced pressure, the residue was dissolved in dichloromethane, triphenylphosphine (2 eq) was added thereto and cooled to 0-5 ℃, and N-bromosuccinimide (3 eq) was added in portions. After the addition, the reaction is carried out for 1 to 2 hours after the temperature is returned to the room temperature. The reaction was quenched by addition of 8% sodium bicarbonate, the organic layer was separated, concentrated to dryness, cyclohexane was added to the residue, washed with water, filtered, the filtrate concentrated, then distilled with chlorobenzene, and the residue was dissolved with chlorobenzene to give a solution of Vj in chlorobenzene, which was used directly in the next reaction.

EXAMPLE 11 Synthesis of Compound IV

EXAMPLE 11.1 Synthesis of Compound IVa

Uracil (1.2 eq) and catalytic amount of ammonium sulfate (0.5%w/w) are added, hexamethyldisilazane (1.38 eq) is added, chlorobenzene is added, the temperature is raised to 125-130 ℃ for reaction, after complete dissolution, the temperature is controlled to be 125-130 ℃ for reaction for 2 hours, the temperature is reduced to 40-70 ℃ under the protection of nitrogen, reduced pressure distillation is carried out, chlorobenzene is added for dissolution, and silicon-based activated uracil is obtained. Adding Va chlorobenzene solution (1 eq), adding anhydrous tin tetrachloride (2.5 eq), heating to 60-70 ℃ for reaction, cooling to room temperature after the reaction is completed, adding sodium bicarbonate (6 eq), dichloromethane and water quenching for reaction, filtering with diatomite, concentrating filtrate at 40 ℃ and-0.08 MPa, cooling to-10-0 ℃ for crystallization, filtering and drying to obtain off-white solid IVa, wherein the yield is 65%.

EXAMPLE 11.2 Synthesis of Compound IVb

Uracil (1.2 eq) and catalytic amount of ammonium sulfate (0.5%w/w) are added, hexamethyldisilazane (1.38 eq) is added, chlorobenzene is added, the temperature is raised to 125-130 ℃ for reaction, after complete dissolution, the temperature is controlled to be 125-130 ℃ for reaction for 2 hours, the temperature is reduced to 40-70 ℃ under the protection of nitrogen, reduced pressure distillation is carried out, chlorobenzene is added for dissolution, and silicon-based activated uracil is obtained. Adding a chlorobenzene solution (1 eq) of Vl, adding anhydrous tin tetrachloride (2.5 eq), heating to 60-70 ℃ for reaction, cooling to room temperature after the reaction is completed, adding sodium bicarbonate (6 eq), dichloromethane and water for quenching reaction, filtering with diatomite, concentrating filtrate at 40 ℃, -0.08MPa, cooling to-10-0 ℃ for crystallization, filtering and drying to obtain an off-white solid IVb, wherein the yield is 58%.

EXAMPLE 11.3 Synthesis of Compound IVb

Uracil (1.2 eq) and catalytic amount of ammonium sulfate (0.5%w/w) are added, hexamethyldisilazane (1.38 eq) is added, chlorobenzene is added, the temperature is raised to 125-130 ℃ for reaction, after complete dissolution, the temperature is controlled to be 125-130 ℃ for reaction for 2 hours, the temperature is reduced to 40-70 ℃ under the protection of nitrogen, reduced pressure distillation is carried out, chlorobenzene is added for dissolution, and silicon-based activated uracil is obtained. Adding the chlorobenzene solution (1 eq) of Vi obtained in the last step, adding anhydrous tin tetrachloride (2.5 eq), heating to 60-70 ℃ for reaction, cooling to room temperature after the reaction is completed, adding sodium bicarbonate (6 eq), dichloromethane and water for quenching reaction, filtering with diatomite, concentrating filtrate at 40 ℃, -0.08MPa, cooling to-10-0 ℃ for crystallization, filtering and drying to obtain white-like solid IVb, wherein the total yield of three steps is 62%.

EXAMPLE 12 Synthesis of Compound III

6.8g of Compound IVb was added to the flask, and 20mL of methanolic ammonia solution was added thereto for reaction at 25-30℃for 24 hours. 0.7g of activated carbon is added for decolorization, filtration and concentration are carried out to obtain an off-white solid, 20mL of ethyl acetate is added for slurry washing, filtration and drying are carried out to obtain the compound III, and the off-white solid has the weight of 3.0g.

EXAMPLE 13 Synthesis of Compound II

2g of Compound III, diphenyl carbonate (1.5 eq), 0.8g of sodium bicarbonate and 20mL of phosphoric triamide are heated to 150 ℃ for reaction, cooled to room temperature after the reaction is completed in HPLC, water is added, extraction is performed with chloroform, and the extracts are combined, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled to give compound II as an off-white solid weighing 1.5g.

EXAMPLE 14 Synthesis of Compound III' b

5g of Compound IVb was added to the flask, 20mL of phosphoric acid triamide, 2g of anhydrous potassium carbonate was added, and the mixture was heated to 150℃to react. After the reaction was completed, cooled to room temperature, water was added, extraction was performed with chloroform, and the extracts were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled to give compound III' b as an off-white solid weighing 3.6g.

EXAMPLE 15 Synthesis of Compound II

EXAMPLE 15.1 Synthesis of Compound II' b

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2.0g of compound III' b,10mL of DMF and 2g of potassium fluoride are added into a flask, the mixture is heated to 120 ℃ for reaction for 2 to 4 hours, cooled to room temperature, and water is added for quenching reaction. The aqueous phase was extracted with ethyl acetate and separated by column chromatography to give 0.6g of a white solid.

EXAMPLE 15.2 Synthesis of Compound II' a

3.0g of Compound III' a,10mL of chloroform, 4mL of hydrogen fluoride/triethylamine solution were added to the flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The aqueous phase was extracted with chloroform and separated by column chromatography to give 1.7g of a white solid.

EXAMPLE 16 Synthesis of Compound I

Example 16.1 2g of Compound II,10mL of DMF,2g of potassium fluoride were added to a flask, heated to 120℃and reacted for 2-4 h, cooled to room temperature and quenched with water. The aqueous phase was extracted with ethyl acetate and separated by column chromatography to give 0.7g of a white solid.

Example 16.2 2.1g of compound II,10mL of dichloromethane, 4mL of hydrogen fluoride/pyridine solution were added to the flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The aqueous phase was extracted with dichloromethane and separated by column chromatography to give 1.1g of a white solid.

Example 16.3 1.8g of compound II,10mL of chloroform, 4mL of hydrogen fluoride/triethylamine solution were added to a flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The aqueous phase was extracted with chloroform and separated by column chromatography to give 1.2g of a white solid.

Example 16.4 2g of Compound II,10mL of tetrahydrofuran, 3g of TBAF were added to a flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, concentrated and separated by column chromatography to give 1.0g of a white solid.

Example 16.5 2.2g of compound II,10mL of chlorobenzene, 3g of TBAF were added to the flask, heated to reflux, the reaction was controlled by HPLC, cooled to room temperature after the reaction was completed, and water was added to quench the reaction. The organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, concentrated and separated by column chromatography to give 1.3g of a white solid.

Example 16.6 4.0g of Compound II' b was added to the flask, 20mL of methanolic ammonia solution was added and reacted at 25-30℃for 24h. 0.4g of activated carbon is added for decolorization, filtration and concentration are carried out to obtain an off-white solid, 20mL of ethyl acetate is added for slurry washing, filtration and drying are carried out to obtain the compound I, and the off-white solid has the weight of 1.9g.

Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present application and not for limiting the same, and although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present application, which is intended to be covered by the scope of the claims of the present application.

Claims (7)

1. A method for preparing a compound of formula I,

the method comprises reacting a compound of formula III' with a fluorinating agent,

wherein R is Ac or Bz,

preparing a compound II';

deprotection of a compound of formula II' in the presence of methanolic amine to give a compound of formula I;

the compound of formula III' is prepared as follows:

wherein R is Ac or Bz;

compound V 'is reacted with methyl magnesium chloride Grignard reagent to prepare compound IV'.

2. The process according to claim 1, wherein the fluorinating agent is selected from potassium fluoride, hydrogen fluoride/TEA, hydrogen fluoride/pyridine, tetrabutylammonium fluoride.

3. The process according to claim 1, wherein the step of preparing the compound of formula II 'by the compound of formula III' comprises reacting a solvent selected from DMF, dichloromethane, chloroform, tetrahydrofuran, chlorobenzene, acetonitrile, DMSO, and 2-methyltetrahydrofuran.

4. The process according to claim 1, wherein IX 'is cyclized in the presence of diphenyl carbonate and phosphoric acid triamide to give compound VIII'.

5. The preparation method of claim 1, wherein the compound VII' is obtained by catalytic ring opening of tetrabutylammonium bromide serving as a phase transfer catalyst in a water/organic two-phase system.

6. The preparation method according to claim 1, wherein the compound VI 'is oxidized under the conditions that TEMPO is used as a catalyst and sodium hypochlorite is used as an oxidant to prepare the compound V'.

7. The process according to claim 1, wherein compound IV 'is cyclized in the presence of diphenyl carbonate and phosphoric triamide to give compound III'.