WO2013067669A1

WO2013067669A1 - Method for preparing zidovudine and intermediate thereof

Info

Publication number: WO2013067669A1
Application number: PCT/CN2011/081866
Authority: WO
Inventors: 李金亮; 赵楠; 刘澍; 程风华; 熊玉友; 周春峰
Original assignee: 上海迪赛诺药业有限公司; 上海迪赛诺化学制药有限公司; 江苏普信药物发展有限公司
Priority date: 2011-11-07
Filing date: 2011-11-07
Publication date: 2013-05-16
Also published as: CN103201278A; CN103201278B

Abstract

Provided is a method for preparing zidovudine (C). The method comprises the following steps: 1) 2'-halothymidine (B) is used as the raw material to obtain a compound of formula (I) by protecting the hydroxyl group thereof in the 5'-position; 2) the compound of formula (I) is subjected to the acylation of the hydroxyl group in the 3'-position to obtain a compound of formula (VI); 3) the compound of formula (VI) is subjected to an elimination reaction to obtain a compound of formula (VII); 4) the compound of formula (VII) is dehalogenated to obtain a compound of formula (IV); 5) the compound of formula (IV) is subjected to an azidation reaction to obtain a compound of formula (V); and 6) the compound of formula (V) is deprotected to obtain zidovudine (C); the specific reaction formula is shown in formula (A), wherein: X is a halogen, P₁ is a protecting group for hydroxyl; and P₂ is C₁-C₄ alkylsulfonyl, fluoro-C₁-C₄ alkylsulfonyl, arylsulfonyl or -CS-R, wherein R is C₁-C₄ alkyl.

Description

Method for preparing zidovudine and its intermediates

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for preparing zidovudine and an intermediate for preparing zidovudine. Background technique

Zidovudine is the world's first anti-AIDS drug approved by the US FDA. Because of its exact efficacy, it is the most basic combination of "cocktail" therapy. To date, zidovudine remains one of the first choices for the treatment of AIDS in many developing countries. Its structural formula is as follows:

The current method for producing zidovudine is mainly the route disclosed by US Pat. No. 5,214,442:

Scheme 1 The raw material β_thymidine used is currently produced by chemical synthesis, and the most commonly used chemical synthesis method is 5-methyluridine as a raw material route (see Pharmaceutical Progress, 2005).

Scheme 2 In the experiment, the inventors found that 10%-15% of 3',5'-dihydroxyl retention when selectively protecting the 5'-position hydroxyl group by β-thymidine

This by-product makes the purification of zidovudine products difficult and the total yield is difficult to improve.

Therefore, there is a need in the art for a more efficient, higher yield method of synthesizing zidovudine. Summary of the invention

It is an object of the present invention to provide a novel synthesis method of zidovudine to The percentage of the low 3',5'-dihydroxy protecting agent increases the yield.

Another object of the invention is to provide an intermediate for the preparation of zidovudine. In a first aspect of the invention, a novel method of preparing zidovudine is provided, the method comprising the steps of:

1) 2'-halothymidine is used as a raw material to protect its 5'-hydroxyl group to obtain formula (I)

2) The compound of formula (I) is acylated with a 3'-position hydroxy group to give a compound of formula (VI);

3) a compound of formula (VI) is eliminated to give a compound of formula (VII);

4) Compounds of formula (VII) are dehalogenated to give compounds of formula (IV)

5) a compound of formula (IV) is subjected to azidation to give a compound of formula (V);

6) Deprotection of the compound of formula (V) gives zidovudine;

With :

Scheme 3 where X is a halogen, preferably chlorine or bromine; Is a hydroxy protecting group, preferably a fluorenyl group or a C ₃ _-6 fluorenylcarbonyl group, more preferably a trityl group, a pivaloyl group or a trimethylpropionyl group;

P ₂ is a decylsulfonyl group, a fluorinated d ₄ fluorenylsulfonyl group, an arylsulfonyl group or a -CS-R, wherein R is a d ₄ fluorenyl group; preferably a methylsulfonyl group, a trifluoromethanesulfonyl group, a p-toluene group Sulfonyl or -CS-R, wherein R is methyl. In a preferred embodiment, the compound of the formula (VI) can be directly subjected to the next reaction without separation to achieve a two-pot one-pot frying process.

In a preferred embodiment, the compound of the formula (I) and the compound of the formula (VI) can be directly subjected to the next reaction without isolation, thereby realizing a three-and-one-pot frying process.

In a preferred embodiment, the specific steps can be described as follows:

1) using 2'-halothymidine as a raw material, and reacting with tritylchloromethane to obtain 5'-trityl _ ₂ '-halothymidine;

2) 5'-trityl- 2'-haloththymidine is methanesulfonylated at the 3'-position to give 5'-trityl-3'-methanesulfonyl-2'-halothymidine;

3) 5'-trityl-3'-methanesulfonyl-2'-halothymidine is eliminated under basic conditions to give 5,-trityl-2,3,-anhydro-2,-halo- Thymidine

4) 5'-trityl- 2,3'-anhydro-2'-halo-thymidine is hydrodehalogenated to obtain 5'-trityl- 2,3'-anhydrothymidine;

5) 5'-trityl- 2,3'-anhydrothymidine is subjected to azide reaction to obtain 5'-trityl-3'-azidothymidine;

6) 5'-Trityl-3'-azidothymidine is deprotected under acidic conditions to give zidovudine. The starting material 2'-halothymidine can be prepared by referring to the method reported in U.S. Patent 4,914,233. In a preferred embodiment ( l ):

Preferably, the reaction temperature of the step 1) is 20-80 ° C, preferably 40-70 ° C; and the reaction solvent is a basic organic solvent, preferably pyridine.

Preferably, the reaction reagent of the step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ° C, and the reaction solvent is a halogenated hydrocarbon solvent, preferably dichloromethane.

Preferably, the alkaline condition described in the step 3) is selected from the group consisting of an alkali metal/DMSO, an alcohol solution of sodium alkoxide or potassium alkoxide, an alcohol solution of sodium hydroxide or potassium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate. Aqueous solution, aqueous sodium methanesulfonate, aqueous sodium p-toluenesulfonate, three Ethylamine or DBU, preferably an aqueous solution of sodium carbonate, potassium carbonate or lithium carbonate; the reaction solvent is an alcohol solvent, preferably methanol or ethanol; the reaction temperature is 20-80 ° C, preferably 50-70

°C.

Preferably, the hydrogenation dehydrogenation reagent of the step 4) is Raney nickel/triethylamine and hydrogen, and the reaction temperature is 20-60 ° C, preferably 30-50 ° C; the reaction solvent is an alcohol solvent, preferably methanol. .

Preferably, the reaction reagent of the step 5) is an azide, preferably lithium azide, or sodium azide, or sodium azide/anhydrous lithium chloride/ammonium chloride, and the reaction solvent is DMF; The temperature is 60-120 ° C, preferably 80-110 ° C.

Preferably, the acidic condition described in the step 6) is selected from the group consisting of aqueous hydrochloric acid, aqueous sulfuric acid or acetic acid, p-toluenesulfonic acid, preferably aqueous hydrochloric acid or p-toluenesulfonic acid; the reaction solvent is an alcohol solvent, preferably methanol; It is 10-50 ° C, preferably 25-40 ° C. In a preferred embodiment (1), preferably, the reaction temperature of the step 1) is 20-80 ° C; the reaction solvent is a basic organic solvent; the reaction reagent of the step 2) is methanesulfonyl chloride; 0-5 ° C, the reaction solvent is a halogenated hydrocarbon solvent; the basic conditions described in step 3) are selected from the group consisting of alkali metal / DMSO, sodium alcohol or potassium alcohol solution, sodium hydroxide or potassium hydroxide alcohol solution , aqueous solution of sodium carbonate, potassium carbonate or lithium carbonate, aqueous sodium methanesulfonate solution, aqueous sodium p-toluenesulfonate solution, triethylamine or DBU; reaction solvent is an alcohol solvent; reaction temperature is 20-80 ° C; The hydrogenation dehydrogenation reagent is Raney nickel/triethylamine and hydrogen, the reaction temperature is 20-60 ° C _{; the} reaction solvent is an alcohol solvent; the reaction reagent of the step 5) is an azide, and the reaction solvent is DMF. ; The reaction temperature is 60-120 ° C; and the acidic condition described in the step 6) is selected from the aqueous solution of hydrochloric acid, aqueous sulfuric acid or acetic acid or p-toluenesulfonic acid; the reaction solvent is an alcohol solvent; the reaction temperature is 10-50 ° C .

In a preferred embodiment (1), more preferably, the reaction temperature of the step 1) is 40-70. C; The reaction solvent is pyridine; the reaction reagent of the step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ° C, the reaction solvent is methylene chloride; the basic condition described in the step 3) is selected from the group consisting of sodium carbonate An aqueous solution of potassium carbonate or lithium carbonate; the reaction solvent is methanol or ethanol; the reaction temperature is 50-70 ° C _{; and} the hydrogenation dehydrogenation reagent of step 4) is Raney nickel / triethylamine and hydrogen, The reaction temperature is 30-50 ° C _{; the} reaction solvent is methanol; the reaction reagent of step 5) is lithium azide, or sodium azide / anhydrous lithium chloride / ammonium chloride, and the molar between the three The ratio is 2-3: 0.8-1.2: 1, the reaction solvent is DMF; the reaction temperature is 80-110 ° C; and the acidic condition described in step 6) is aqueous hydrochloric acid or p-toluenesulfonic acid; the reaction solvent is methanol; The reaction temperature is 25-40 °C. In a second aspect of the invention, there is provided an intermediate for the preparation of zidovudine, as shown in the following formula (VI):

Wherein X is a halogen, preferably chlorine or bromine; It is a hydroxy protecting group, preferably a fluorenyl group or a C ₃ _-6 fluorenylcarbonyl group, more preferably a trityl group, a pivaloyl group or a trimethylpropionyl group.

In a preferred embodiment, X is chlorine or bromine; Pi is trityl, pivaloyl or trimethylpropanoyl.

In a more preferred embodiment, X is chlorine or bromine; P1 is trityl or pivaloyl. In a third aspect of the invention, there is provided an intermediate for the preparation of zidovudine, as shown in the following formula (VI):

Wherein X is a halogen, preferably chlorine or bromine; Is a hydroxy protecting group, preferably a fluorenyl group or a C ₃ _-6 fluorenylcarbonyl group, more preferably a trityl group, a pivaloyl group or a trimethylpropionyl group; P ₂ is a fluorenylsulfonyl group, a fluorinated d ₄垸 group Sulfonyl, arylsulfonyl or -CS-R, Wherein R is d ₄ fluorenyl; preferably methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl or -CS-R, wherein R is methyl.

In a preferred embodiment, X is chlorine or bromine; Pi is trityl, pivaloyl or trimethylpropanoyl; and P ₂ is methylsulfonyl or p-toluenesulfonyl.

In a more preferred embodiment, X is chlorine or bromine; P1 is trityl; P ₂ is methylsulfonyl or p-toluenesulfonyl. In a fourth aspect of the invention, there is provided an intermediate for the preparation of zidovudine, as shown in the following formula (I):

Wherein X is halogen, preferably chlorine or bromine; It is a hydroxy protecting group, preferably a fluorenyl group or a C ₃ _-6 fluorenylcarbonyl group, more preferably a trityl group, a pivaloyl group or a trimethylpropionyl group.

In a preferred embodiment, X is chlorine or bromine; is trityl, pivaloyl or trimethylpropanoyl.

In a more preferred embodiment, X is chlorine or bromine; P1 is trityl or pivaloyl. The method of the invention can avoid the production of the 3',5'-dihydroxy protecting agent, thereby greatly improving the total yield of zidovudine, and at the same time, the refining process of the product is simplified due to the large reduction of impurities. It is easier to increase the purity. In the present specification, the technical features of each of the preferred technical solutions and the more preferred technical solutions may be combined with each other to form a new technical solution unless otherwise stated. For the sake of brevity, the applicant has omitted a detailed description of these combinations in the specification, however, all technical solutions combined with these technical features should be considered in a clear manner. The surface is described in this specification. "A/B" as used in the specification and claims means that both A and B are present. For example, "palladium carbon/sodium acetate" means the simultaneous presence of palladium carbon and sodium acetate, and "alkali metal/DMSO" means simultaneous use of alkali metal and DMSO. "Lithium azide, or sodium azide/anhydrous lithium chloride/ammonium chloride" means lithium azide, or both sodium azide, anhydrous lithium chloride and ammonium chloride. "Ranikon/triethylamine" means the simultaneous use of Raney nickel and triethylamine. The invention will now be further described in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Example 1

Preparation of 5,-trityl- 2,-chlorothymidine

150 ml of pyridine, 2'-chlorothymidine (28.0 g, 0.1 mol), triphenylchloroformamidine (35.0 g, 0.13 mol) was added to the reaction flask at room temperature. The temperature was raised to 60 ° C and the reaction was followed by TLC until the starting material was completely reacted. The reaction was terminated by the addition of water. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in 300 ml of methylene chloride and washed twice with water and dried over anhydrous magnesium sulfate. Filtration and concentration to dryness under reduced vacuo afforded &lt ^-NMR: δ 1.39(s, 3H), 3.00(d, IH), 3.41(d, IH), 3.52(d, IH), 4.20(s, IH), 4.48(d, IH), 4.56(t , IH), 6.23(d, IH), 7.23(m, 3H), 7.29(m, 6H), 7.38(m, 6H), 7.51(s, IH), 9.22(s, IH).

Preparation of 5'-trityl-3'-methanesulfonyl-2'-chlorothymidine

40 ml of dichloromethane, 5'-trityl-2'-chlorothymidine (10.0 g, 0.019 mol) was added at room temperature and cooled to 0 °C in an ice bath. At the same time, methanesulfonyl chloride (2.6 ml, 0.026 mol) and 7 ml of triethylamine were separately added to control the reaction temperature below 5 °C. After the TLC traces the completion of the reaction, the insoluble material is filtered off. The filtrate was concentrated to dryness under reduced pressure and the residue was taken directly to the mixture. The product can be obtained by column chromatography (ethyl acetate: hexane = 1 : 2 ) to obtain white H-NMR- δ 1.41 (s, 3H), 3.15 (s, 3H), 3.50 (d, IH), 3.63 (d, IH) 4.53 (d, IH), 4.68 (t, IH), 5.54 ( m, IH), 6.25(d, IH), 7.35-7.45(m, 15H) 7.51(s, IH), 9.06(s, IH).

Preparation of 5'-trityl- 2,3,-anhydro- 2'-chlorothymidine

50 ml of methanol and 20 ml of a saturated aqueous solution of sodium carbonate were added to the residue and the mixture was evaporated to reflux. After the TLC was traced to the reaction of the starting material, the mixture was cooled to 40 ° C, and concentrated under reduced pressure to be viscous. The residue was added to 20 ml of water, extracted with 3 ml of dichloromethane, and the organic phase was combined. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give 10 g of crude material, which was directly applied to the mixture. The product was chromatographed (ethyl acetate: hexanes = 1:1) to give a white solid. iH-NMR: δ 1.41(s, 3H), 3.43(d, IH), 3.63(d, IH), 4.23(s, IH), 4.53(d, IH), 4.64(t, IH), 5.19(d , IH), 6.62(d, IH), 7.28-7.38(m, 15H).

Preparation of 5'-trityl- 2,3,-anhydrothymidine

50 ml of methanol, 15 g of Raney nickel, 5.0 ml of triethylamine were added to the above 10 g of the slurry at room temperature, and hydrogen gas was introduced under normal pressure. The temperature was raised to 40 ° C with stirring, and the hydrogen evolution was stopped after the TLC traced the reaction of the starting material. It was suction filtered, concentrated under reduced pressure to give a residue. 20 ml of methyl tert-butyl ether was added to the residue, which was heated to reflux and beat for 1 hour. After cooling to room temperature, filtration, a small amount of methyl tert-butyl ether was rinsed and dried in vacuo to give 8.2 g of white solid. ^-NMR: δ 1.90 (s, 3H), 2.35 (m, IH), 2.64 (m, IH), 3.38 (m, 2H), 4.28 (m, IH), 5.13 (m, IH), 5.45 (d) , IH), 6.81(m, IH), 7.30-7.48(m, 15H).

Preparation of 5,-trityl-3,-azidothymidine

Under stirring, 250 ml of DMF, lithium azide (19.0 g, 0.39 mol), 5,-trityl-2,3,-anhydrothymidine (60.0 g, 0.13 mol) were added, and the temperature was slowly raised to 100 ° C. . After the TLC traces the reaction of the starting material completely, it is cooled to room temperature, and the insoluble matter is filtered off. 500 ml of water was slowly added dropwise to the filtrate with stirring, and the beating was continued for 2 hours after the completion of the dropwise addition. Filtration and blast drying gave 62.9 g of an off white solid with a yield of 96%. Ifi-NMR: δ 1.55(s, 3H), 2.48(m, IH), 2.66(m, IH), 4.18(m, IH), 4.31(m, IH), 4.58(m, 2H), 6.20(m, IH), 7.15(s, IH), 7.25-7.36(m, 15H), 8.83(s, IH). Preparation of zidovudine

250 ml of methanol, 5,-trityl-3,-azidothymidine (50.0 g, 0.098 mol) and 2 ml of concentrated hydrochloric acid were added under stirring, and the mixture was reacted at room temperature for 3 hours. After the TLC traced the starting material reaction, the reaction was terminated by adding 0.8 g of sodium hydroxide. It was concentrated to a viscous pressure under reduced pressure, and water (250 ml) was added to the residue, and the mixture was heated to 75 ° C and stirred for 1 hour. The insoluble matter was removed by hot filtration. The filtrate was concentrated to dryness under reduced pressure. EtOAc was evaporated, evaporated, evaporated. The crude product was recrystallized from isopropanol to give 24.8 g of zidovudine with a purity of 99.8%, yield 95%. MS: m/z 267 (M+). Example 2

Preparation of 5'-trityl-3'-methanesulfonyl-2'-chlorothymidine

200 ml of pyridine, 2'-chlorothymidine (50.0 g, 0.18 mol) and triphenylchloroformamidine (60.0 g, 0.21 mol) were added to the reaction flask at room temperature. The temperature was raised to 60 ° C and the reaction was followed by TLC until the starting material was completely reacted. The oil bath was removed, cooled to o °c with an ice bath, and methanesulfonyl chloride (16.5 ml, 0.22 mol) was added dropwise to control the reaction temperature below 5 °C. After TLC followed the completion of the reaction of the starting material, water was added to terminate the reaction. The mixture was concentrated to a viscous residue. The residue was dissolved in 1000 ml of dichloromethane, and washed twice with brine. Filtration and concentration to dryness under reduced pressure afforded <1> ¹ H-NMR: δ 1.41 (s, 3H), 3.15 (s, 3H), 3.50 (d, IH), 3.63 (d, IH), 4.53 (d, IH), 4.68 (t, IH), 5.54 ( m, IH), 6.25(d, IH), 7.35-7.45(m, 15H), 7.51(s, IH), 9.06(s, IH). Example 3

Preparation of 5'-pivaloyl-2'-chlorothymidine

100 ml of pyridine, 2,-chlorothymidine (14.0 g, 0.052 mol) and pivaloyl chloride (8.0 ml, 0.065 mol) were added to the reaction flask at room temperature. The temperature was raised to 40 ° C and the reaction was followed by TLC until the starting material was completely reacted. The reaction was terminated by the addition of water. Concentrate under reduced pressure until thick The residue was dissolved in 200 ml of dichloromethane, washed twice with water and dried over anhydrous magnesium sulfate. Filtration and concentration to dryness under reduced pressure afforded 18 g of white powder. ^-NMR: δ 1.20(s, 9H), 1.45(s, 3H), 3.41(d, IH), 3.62(t, IH), 4.14(s, IH), 4.36(d, IH), 4.53(t , IH), 5.02(m, IH), 6.19(d, IH), 7.56(s, IH), 9.47(s, IH).

Preparation of 5'-pivaloyl-3'-methanesulfonyl-2'-chlorothymidine

50 ml of dichloromethane was added to the reaction flask, and the above 18 g of a white foamy solid was stirred and dissolved, and cooled to 0 ° C in an ice bath. At the same time, methanesulfonyl chloride (4.8 ml, 0.062 mol) and 10 ml of pyridine were separately added to control the reaction temperature below 5 °C. After TLC followed the completion of the reaction of the starting material, the reaction was terminated by slowly dropping 30 ml of a saturated aqueous solution of sodium carbonate. The organic layer was concentrated under reduced pressure to recover dichloromethane, and the residue was directly poured into a sputum reaction.

Preparation of 5'-pivaloyl-2,3'-anhydro-2'-chlorothymidine

To the above residue was added 100 ml of ethanol, 20 ml of a saturated aqueous solution of sodium carbonate, and then evaporated to reflux. After the TLC was traced to the reaction of the starting material, the mixture was cooled to 40 ° C, and concentrated under reduced pressure to be viscous. The residue was added to 50 ml of water, extracted with 3 ml of dichloromethane, and the organic phase was combined. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to give 19 g of crude material, which was directly applied to the mixture. The product was obtained by column chromatography (ethyl acetate: hexanes = 1:1) to give a white solid. 1H-NMR: δ 1.18 (s, 9H), 2.35 (s, 3H), 3.45 (m, IH), 4.10-4.35 (m, 2H), 4.15 (m, IH), 4.58 (m, IH), 5.08 (m, IH), 6.52(s, IH).

Preparation of 5'-pivaloyl-2,3'-anhydrothymidine

100 ml of methanol, 2.0 _{g of} 5% palladium on carbon, sodium acetate (5.8 g, 0.070 mol) were added to the above slurry at room temperature, stirred, and hydrogen gas was introduced under normal pressure. The TLC traces the completion of the reaction of the starting material and stops the hydrogen flow. It was suction filtered, concentrated under reduced pressure and dried in vacuo. Ifi-NMR: δ 1.18(s, 9H), 2.05-2.20(d, 2H), 2.35(s, 3H), 3.45(m, IH), 4.05-4.25(m, 2H), 4.48(m, IH) , 4.55(m, 1H) _; 6.48(s, IH). Preparation of 5'-pivaloyl-3'-azidothymidine

Under stirring, 30 ml of DMF, sodium azide (4.5 g, 0.069 mol), 1.5 g of anhydrous lithium chloride (1.5 g, 0.035 mol), ammonium chloride (1.5 g, 0.028 mol), 5,-pentane were added. Acyl-3,2-dihydrothymidine (5.0 g, 0.016 mol) was slowly warmed to 110 ° C to react. After the TLC traces the reaction of the starting material completely, it is cooled to room temperature, and the insoluble matter is filtered off. Slowly drip 50 ml of water into the filtrate with stirring, and continue to beat for 30 minutes after the completion of the dropping. Filtration and blast drying gave 5.1 g of a pale yellow solid with a yield of 91%. Ifi-NMR: δ 1.20(s, 9H), 1.68(s, 3H), 2.10-2.30(m, 2H), 4.15(m, IH), 4.28(m, IH), 4.47(m, IH) 4.54( m, IH), 6.18(t, IH), 7.19(s, IH), 8.39(s, IH). Preparation of zidovudine

65 ml of methanol, 5,-pivaloyl-3,-azidothymidine (5.0 g, 0.014 mol), was added with stirring.

A solution of 6.5 ml of 25% sodium methoxide in methanol was stirred at room temperature for 1 hour. After the TLC traces the raw material reaction completely, it is neutralized with a strong acid resin (Dowex 50-200*8), adjusted to a pH of about 6, and the resin is recovered by filtration and washed with methanol. The filtrate was combined, decolorized with activated carbon, and concentrated to dryness under reduced pressure. The obtained white solid was then recrystallized from isopropyl alcohol. The purity of 99.5% of zidovudine was 3.2 g, yield 86%. MS: m/z 267 (M+). Example 4

Preparation of 5,-trimethylpropanoyl-3,-ethanesulfonyl-2,-bromothymidine

100 ml of dichloromethane, 2,-bromothymidine (16.1 g, 0.050 mol), trimethylpropionyl chloride (8.0 ml, 0.065 mol), and 10 ml of pyridine were added to the reaction flask at room temperature. The temperature was raised to 40 ° C and the reaction was followed by TLC until the starting material was completely reacted. After cooling to 10 ° C, ethionyl chloride (3.0 ml, 0.042 mol) was added dropwise to control the reaction temperature below 15 °C. TLC tracking After the reaction of the starting material was completed, the reaction was terminated by slowly dropping 30 ml of a saturated aqueous solution of sodium carbonate. The chloroform is recovered by concentration under reduced pressure, and the residue is directly introduced into the sputum reaction.

Preparation of 5,-trimethylpropionyl-2,3,-dehydro-2,-bromothymidine 100 ml of acetonitrile, potassium carbonate (8.6 g, 0.062 mol), was added to the upper residue. Heat to reflux. After TLC followed the completion of the reaction of the starting material, the mixture was cooled to 40 ° C, and concentrated under reduced pressure to a viscous. The residue was added to 100 ml of water, extracted with 3 ml portions of dichloromethane, and the organic phases were combined. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure to dryness afforded 8.2 g. The product was obtained by column chromatography (ethyl acetate: hexanes: 1:1) to afford white solid. 1H-NMR: δ 1.01 (m, 9H), 1.95 (m, 2H), 2.31 (s, 3H), 3.88 (m, IH), 4.03-4.16 (m, 2H), 4.25 (m, IH) 4.55 ( m, IH), 5.26(m, IH), 6.55(s, IH).

Preparation of 5,-trimethylpropanoyl-2,3,-anhydrothymidine

75 ml of methanol, 1.5 _{g of} 5% palladium on carbon, sodium acetate (5.0 g, 0.061 mol) were added to the above slurry at room temperature, stirred, and hydrogen gas was introduced under normal pressure. The TLC traces the completion of the reaction of the starting material and stops the hydrogen flow. It was suction filtered, and concentrated under reduced pressure to give 11.5 g. 1H-NMR: δ 1.01 (m, 9H), 1.95 (m, 2H), 2.01-2.15 (d, 2H), 2.31 (s, 3H), 3.43 (m, IH), 4.01-4.15 (m, 2H) , 4.45(m, IH), 4.53(m, IH), 6.50(s IH).

Preparation of 5,-trimethylpropionyl-3,-azidothymidine

Under stirring, 30 ml of DMF, sodium azide (6.5 g, 0.1 mol), DMF 10 ml of the hydrazine product was added, and the temperature was slowly raised to 110 ° C to react. After the TLC traces the raw material reaction completely, it is cooled to room temperature, and the insoluble matter is filtered off. Slowly drip 80 ml of water into the filtrate with stirring, and continue to beat for 1 hour after the completion of the dropping. Filtration and blast drying gave 5.6 g of a yellow solid. 1H-NMR: δ 1.05 (m, 9H), 1.58 (m, 2H), 1.62 (s, 3H), 1.75 (m, IH), 1.88 (m, IH), 2.12 (m, IH), 4.05-4.15 (d, 2H), 4.17(m, IH), 5.35(m, IH), 7.53(s, IH), 9.67(s, IH). Preparation of zidovudine

65 ml of methanol, 5,-trimethylpropanoyl-3,-azidothymidine (5.0 g, 0.014 mol), 6.5 ml of a 25% sodium methoxide in methanol were added under stirring, and the mixture was stirred at room temperature for 1 hour. After the TLC traces the reaction of the starting material, it is neutralized with a strong acid resin (Dowex 50-200*8), adjusted to a pH of about 6, and the resin is recovered by filtration and washed with methanol. Combine the filtrate, decolorize the activated carbon, The organic solid obtained was concentrated to dryness under reduced pressure. MS: m/z 267 (M+). All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it is to be understood that various modifications and changes may be made to the present invention, and the equivalents of the scope of the invention.

Claims

Claim

A new method for preparing zidovudine, the method comprising the steps of:

1) 2'-halothymidine is used as a raw material to protect its 5'-hydroxyl group to obtain the formula (I)

6) Deprotection of the compound of formula (V) gives zidovudine;

With :

Scheme 3

Where: X is halogen; Is a hydroxy protecting group; P ₂ is a fluorenylsulfonyl group, a fluorinated fluorenylsulfonyl group, an arylsulfonyl group or -CS-R, wherein R is a d- ₄ fluorenyl group.

2. The method of claim 1 wherein X is chlorine or bromine; ₁ is trityl, pivaloyl or trimethylpropanoyl; P ₂ is methylsulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl or -CS-R, wherein R is methyl.

3. The method according to claim 1, wherein the compound of the formula (VI) can be directly subjected to the next hydrazine reaction without separation to realize a two-pot simmering process.

4. The method of claim 1 wherein: the compound of formula (I) The compound of the formula (VI) can be directly subjected to the next reaction without isolation, thereby realizing a three-powder one-pot frying process.

5. The method of claim 1 wherein the method is specifically described as comprising the following steps:

6) 5'-Trityl-3'-azidothymidine is deprotected under acidic conditions to give zidovudine.

6. The method of claim 5, wherein

The reaction temperature of the step 1) is 20-80 ° C _{; the} reaction solvent is a basic organic solvent; the reaction reagent of the step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ° C, and the reaction solvent is a halogenated hydrocarbon solvent. ;

The alkaline condition is selected from the group consisting of an alkali metal/DMSO, an alcohol solution of sodium alkoxide or potassium alkoxide, an alcohol solution of sodium hydroxide or potassium hydroxide, an aqueous solution of sodium carbonate, potassium carbonate or lithium carbonate, methanesulfonate. An aqueous sodium solution, an aqueous solution of sodium p-toluenesulfonate, triethylamine or DBU; the reaction solvent is an alcohol solvent; the reaction temperature is 20-80 ° C;

The hydrogenation dehydrogenation reagent of the step 4) is Raney nickel/triethylamine and hydrogen, the reaction temperature is 20-60 ° C _{; the} reaction solvent is an alcohol solvent;

The reaction reagent of the step 5) is an azide, the reaction solvent is DMF; the reaction temperature is 60-120 ° C;

The acidic condition described in step 6) is selected from the group consisting of hydrochloric acid, aqueous sulfuric acid or acetic acid or para Benzenesulfonic acid; the reaction solvent is an alcohol solvent; the reaction temperature is 10-50 ° C.

7. The method of claim 5, wherein

The reaction temperature of the step 1) is 40-70 ° C; the reaction solvent is pyridine;

The reaction reagent of the step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ° C, and the reaction solvent is dichloromethane;

The alkaline condition is selected from the group consisting of sodium carbonate, potassium carbonate or lithium carbonate; the reaction solvent is methanol or ethanol; and the reaction temperature is 50-70 ° C _;

The hydrogenation dehydrogenation reagent of the step 4) is Raney nickel/triethylamine and hydrogen, the reaction temperature is 30-50 ° C _{; the} reaction solvent is methanol;

The reaction reagent of the step 5) is lithium azide, or sodium azide/anhydrous lithium chloride/ammonium chloride, and the molar ratio between the three is 2-3: 0.8-1.2: 1, the reaction solvent Is DMF; reaction temperature is 80-110 ° C _;

The acidic condition described in the step 6) is aqueous hydrochloric acid or p-toluenesulfonic acid; the reaction solvent is methanol; and the reaction temperature is 25-40 °C.

8. Preparation of zidovudine (VI):

Where X is halogen; It is a hydroxy protecting group.

The intermediate according to claim 8, wherein X is chlorine or bromine; and Pi is trityl, pivaloyl or trimethylpropionyl.

The intermediate according to claim 8, wherein X is chlorine or bromine; and P1 is trityl or pivaloyl.