CN103201278A

CN103201278A - Method for preparing zidovudine and intermediate thereof

Info

Publication number: CN103201278A
Application number: CN2011800025164A
Authority: CN
Inventors: 李金亮; 赵楠; 刘澍; 程风华; 熊玉友; 周春峰
Original assignee: Jiangsu Puxin Pharmaceuticals Dev Co ltd; Shanghai Desano Pharmaceutical Investment Co ltd; Shanghai Desano Chemical Pharmaceutical Co Ltd
Current assignee: Jiangsu Puxin Pharmaceuticals Dev Co ltd; Shanghai Desano Pharmaceutical Investment Co ltd; Shanghai Desano Chemical Pharmaceutical Co Ltd
Priority date: 2011-11-07
Filing date: 2011-11-07
Publication date: 2013-07-10
Anticipated expiration: 2031-11-07
Also published as: WO2013067669A1; 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

Process for preparing zidovudine and intermediates thereof

Method for preparing zidovudine and intermediate thereof

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

Zidovudine is the first anti-AIDS drug approved by FDA in the United states in the world and becomes the most basic composition component of the cocktail therapy due to the definite curative effect. Until now, zidovudine is one of the first choice drugs for AIDS treatment in many developing countries, and its structural formula is as follows:the current method of producing zidovudine is mainly the route disclosed in US 5124442:

the β thymidine used as the raw material of Scheme 1 is mostly prepared by chemical synthesis method at present, and the most commonly used chemical synthesis method is a process route using 5-methyluridine as the raw material (see pharmaceutical development, 2005)

Scheme 2 found that when the hydroxyl at the 5' -position is selectively protected by β -thymidine, the inventor has 10% -15% 3',5' -dihydroxyl

The by-product makes the purification of the zidovudine product difficult, and the total yield is difficult to be improved.

Therefore, there is a need in the art for a more efficient and productive method for synthesizing zidovudine. Disclosure of Invention

It is an object of the present invention to provide a novel method of synthesizing zidovudine to reduce the percentage of 3',5' -dihydroxy protecting species and improve yield.

It is another object of the present invention to provide an intermediate for the preparation of zidovudine. In a first aspect of the present invention there is provided a novel process for the preparation of zidovudine, the process comprising the steps of:

1) Taking 2' -halogenated thymidine as a raw material, and protecting 5' -hydroxyl of the 2' -halogenated thymidine to obtain a compound shown in a formula (I)

2) Acylating the compound of the formula (I) by 3' -hydroxyl to obtain a compound of a formula (VI);

3) The compound of the formula (VI) is eliminated to obtain a compound of a formula (VII);

4) dehalogenating the compound of formula (VII) to obtain the compound of formula (IV)

5) Carrying out an azide reaction on the compound of the formula (IV) to obtain a compound of a formula (V);

6) deprotection of the compound of formula (V) to give zidovudine;

the device comprises:

scheme 3 formula (iv): x is halogen, preferably chlorine or bromine; is there a Is a hydroxyl protecting group, preferably alkanyl or C₃_₆Alkanyl carbonyl, more preferably trityl, pivaloyl orTrimethylpropionyl;

P₂d (u) being alkyl sulfonyl, fluoro₄Alkyl sulfonyl, aryl sulfonyl or-CS-R, wherein R is d \ u₄A alkyl group; preferably a methanesulfonyl group, trifluoromethanesulfonyl group, p-toluenesulfonyl group or-CS-R, wherein R is methyl. In a preferred embodiment, the compound of formula (VI) may be subjected to the next reaction without separation, resulting in a two-step one-pot frying process.

In a preferred embodiment, the compound of formula (I) and the compound of formula (VI) may be directly subjected to the next step without separation, thereby realizing a process of frying in one pot.

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

1) 2 '-halogenated thymidine is used as a raw material to react with trityl chloride alkyl to obtain 5' -trityl methyl₂' _ halothymidine;

2) 3 '-mesylation of 5' -trityl-2 '-halothymidine to obtain 5' -trityl-3 '-mesyl-2' -halothymidine;

3) Elimination of 5' -trityl-3 ' -methanesulfonyl-2 ' -halothymidine under basic conditions to give 5, -trityl-2, 3, -anhydro-2, -halo-thymidine;

4) hydrogenating and dehalogenating 5' -trityl-2, 3' -anhydro-2 ' -halo-thymidine to obtain 5' -trityl-2, 3' -anhydrothymidine;

5) Carrying out an azidation reaction on the 5 '-trityl-2, 3' -anhydrothymidine to obtain 5 '-trityl-3' -azidothymidine;

6) 5 '-trityl-3' -azidothymidine is deprotected under acidic condition to obtain zidovudine. The starting 2' -halogenated thymidine may be prepared by reference to the method reported in US 4914233. In a preferred embodiment (l):

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

Preferably, the reaction reagent of step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ℃, the reaction solvent is a halogenated hydrocarbon solvent, and preferably the dichloromethyl alkyl is used.

Preferably, the alkaline conditions in step 3) are selected from alkali metal/DMSO, alcoholic solutions of sodium or potassium alkoxides, alcoholic solutions of sodium or potassium hydroxide, aqueous solutions of sodium, potassium or lithium carbonate, aqueous solutions of sodium methanesulfonate, aqueous solutions of sodium p-toluenesulfonate, triethylamine or DBU, preferably aqueous solutions 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 ℃, preferably 50-70 DEG C

°C。

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

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

Preferably, the acidic conditions in step 6) are selected from aqueous hydrochloric acid solution, aqueous sulfuric acid solution or acetic acid, p-toluenesulfonic acid, preferably aqueous hydrochloric acid solution or p-toluenesulfonic acid; the reaction solvent is an alcohol solvent, preferably methanol; the reaction temperature is from 10 to 50 ℃ and preferably from 25 to 40 ℃. In a preferred embodiment (l), the reaction temperature in step 1) is preferably 20 to 80 ℃; the reaction reagent of the step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ℃, and the reaction solvent is halogenated hydrocarbon solvent; the alkaline condition in the step 3) is selected from alkali metal/DMSO, alcoholic solution of sodium alkoxide or potassium alkoxide, alcoholic solution of sodium hydroxide or potassium hydroxide, aqueous solution of sodium carbonate, potassium carbonate or lithium carbonate, aqueous solution of sodium methanesulfonate, aqueous solution of sodium p-toluenesulfonate, triethylamine or DBU; the reaction temperature is 20-80 ℃, the hydrogenation and dehydrogenation reagent of step 4) is Raney nickel/triethylammonium and hydrogen, and the reaction temperature is 20-60 DEG C_;The reaction solvent is an alcohol solvent; the reaction reagent of the step 5) is azide, the reaction solvent is DMF, the reaction temperature is 60-120 ℃, and the step 6) isThe acidic condition of (A) is selected from aqueous hydrochloric acid solution, aqueous sulfuric acid solution or acetic acid or p-toluenesulfonic acid; the reaction solvent is an alcohol solvent; the reaction temperature is 10-50 ℃.

In a preferred embodiment (l), more preferably, the reaction temperature of step 1) is 40-70. C, pyridine is used as a reaction solvent; the reaction reagent of the step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ℃, and the reaction solvent is the dichloro-methyl; the alkaline condition in step 3) is selected from an aqueous solution of sodium carbonate, potassium carbonate or lithium carbonate; the reaction solvent is methanol or ethanol; the reaction temperature is 50-70 DEG C_;The reagents for hydrogenation and dehydrogenation in the step 4) are Raney nickel/triethylamine and hydrogen, and the reaction temperature is 30-50 DEG C_;The reaction solvent is methanol; the reaction reagent in the step 5) is lithium azide or sodium azide/anhydrous lithium chloride/ammonium chloride, and the molar ratio of the lithium azide to the anhydrous lithium chloride to the ammonium chloride is 2-3: 0.8-1.2: 1, DMF is used as a reaction solvent, the reaction temperature is 80-110 ℃, and the acidic condition in the step 6) is hydrochloric acid aqueous solution or p-toluenesulfonic acid; the reaction solvent is methanol; the reaction temperature is 25-40 ℃. In a second aspect of the present invention, there is provided an intermediate for the preparation of zidovudine, as represented by the following formula (VI):

wherein X is halogen, preferably chlorine or bromine; is there a Is a hydroxyl protecting group, preferably alkanyl or C₃_₆An alkanylcarbonyl group, more preferably a trityl, pivaloyl or trimethylpropionyl group.

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

In a more preferred embodiment, X is chlorine or bromine; p1 is trityl or pivaloyl. In a third aspect of the present invention, there is provided an intermediate for the preparation of zidovudine, as shown in the following formula (VI):

wherein X isHalogen, preferably chlorine or bromine; is there a Is a hydroxyl protecting group, preferably alkanyl or C₃_₆An alkanyl carbonyl group, more preferably a trityl, pivaloyl or trimethylpropionyl group; p₂D (u) being alkyl sulfonyl, fluoro₄Alkyl sulfonyl, aryl sulfonyl or-CS-R, wherein R is d \ u₄A alkyl group; preferably a methanesulfonyl group, trifluoromethanesulfonyl group, p-toluenesulfonyl group or-CS-R, wherein R is methyl.

In a preferred embodiment, X is chlorine or bromine; pi is trityl, pivaloyl or trimethylpropionyl; p₂Is methylsulfonyl or p-toluenesulfonyl.

In a more preferred embodiment, X is chlorine or bromine; p1 is trityl; p₂Is methylsulfonyl or p-toluenesulfonyl. In a fourth aspect of the present invention, there is provided an intermediate for the preparation of zidovudine, as shown in the following formula (I):

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

In a more preferred embodiment, X is chlorine or bromine; p1 is trityl or pivaloyl. The method can avoid generating the 3',5' -dihydroxy protection substance, thereby greatly improving the total yield of the zidovudine, and simultaneously, because the impurities are greatly reduced, the refining process of the product becomes simple, and the purity of the product is easier to improve. In the present specification, the technical features of the respective preferred technical aspects and the more preferred technical aspects may be combined with each other to form a new technical aspect, unless otherwise specified. For the sake of brevity, the applicant omits specific descriptions of these combinations in the specification, however, all technical solutions in which these technical features are combined should be considered to be written in the present specification in an explicit manner. As used in the specification and claims, "A/B" means that both A and B are present, for example "palladium on carbon/sodium acetate" means that both palladium on carbon and sodium acetate are present, "alkali metal/DMSO" means that both alkali metal and DMSO are present, "lithium azide, or sodium azide/anhydrous lithium chloride/ammonium chloride" means lithium azide, or that both sodium azide, anhydrous lithium chloride and ammonium chloride are present. "Raney nickel/triethylamine" means that both Raney nickel and triethylamine are used. The present invention will be further described with reference to the following embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures in the following examples, where specific conditions are not noted, are generally in accordance with conventional conditions, or with conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight. Example 1

Preparation of 5-trityl-2-chlorothymidine

150ml pyridine, 2' -chlorothymidine (28.0 g, O.lOmol), and triphenylchloromethane (35.0 g, 0.13mol) were added to the reaction flask at room temperature. The temperature is raised to 60 ℃, and the TLC tracks the reaction until the raw materials are completely reacted. Water was added to terminate the reaction. The mixture was concentrated under reduced pressure to a viscous state, and the residue was dissolved in 300ml of a methylene chloride, washed with water 2 times, and dried with anhydrous magnesium sulfate. Filtering, concentrating under reduced pressure to dryness to obtain 56g of white foam solid. Delta 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 ' -methylsulfonyl-2 ' -chlorothymidine

40ml of dichloroalkylt, 5 '-trityl-2' -chlorothymidine (10.0 g, 0.019 mol) was added at room temperature and cooled to 0 ℃ in an ice bath. At the same time, methanesulfonyl chloride (2.6 ml, 0.026mol) and 7ml triethylamine were added dropwise, respectively, and the reaction temperature was controlled to be lower than 5 ℃. TLC was used to follow the completion of the reaction of the starting material, and insoluble material was filtered off. Concentrating the filtrate under reduced pressure to dryness, and directly putting the residue into the next step for reaction. The product can be purified by column chromatography (ethyl acetate: n-hexyl alkyl = 1: 2) to give white solid 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

To the residue were added 50ml of methanol and 20ml of a saturated aqueous sodium carbonate solution, and the mixture was heated to reflux. After TLC tracking raw material reaction is completed, cooling to 40 ℃, and concentrating under reduced pressure to be viscous. The residue was extracted 3 times with 20ml of water and 100ml of a methylene chloride and the organic phases were combined. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain 10g of crude slurry, and directly putting into the next step for reaction. The product can be purified by column chromatography (ethyl acetate: n-hexyl = 1: 3) to give a white solid. iH-NMR,. delta.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

To the above 10g of slurry, 50ml of methanol, 15g of Raney nickel and 5.0ml of triethylamine were added at room temperature, and hydrogen gas was introduced under normal pressure. Heating to 40 ℃ under stirring, tracking by TLC that the raw materials are completely reacted, and stopping introducing hydrogen. Filtering, concentrating under reduced pressure, and drying to obtain slurry residue. To the residue was added 20ml of methyl t-butyl ether, heated to reflux and slurried for 1 hour. Cooled to room temperature, filtered, rinsed with a small amount of methyl tert-butyl ether and dried in vacuo to give 8.2g of an off-white solid in 92% yield. Delta 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

250ml of DMF, lithium azide (19.0 g, 0.39mol), 5-trityl-2, 3-anhydrothymidine (60.0 g, 0.13mol) were added successively with stirring, and the temperature was gradually raised to 100 ℃ for reaction. TLC tracks the completion of the reaction of the starting materials, then cool to room temperature and filter the insoluble material. And slowly dripping 500ml of water into the filtrate under stirring, and continuing pulping for 2 hours after dripping. Suction filtration and forced air drying gave 62.9g of an off-white solid with a yield of 96%. Preparation of ifi-NMR,. delta.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). Zidovudine

250ml of methanol, 5-trityl-3-azidothymidine (50.0 g, 0.098mol) and 2ml of concentrated hydrochloric acid were added under stirring, and the mixture was reacted at room temperature for 3 hours. After TLC tracking of the completion of the reaction of the starting materials, 0.8g of sodium hydroxide was added to terminate the reaction. Concentrated under reduced pressure to a viscous state, 250ml of water was added to the residue, heated to 75 ℃ and stirred for 1 hour. The insoluble matter was removed by filtration while hot. The filtrate was concentrated to dryness under reduced pressure, dissolved in 300ml of ethyl acetate, heated to 60 ℃, decolorized with activated carbon, filtered while hot, and the filtrate was concentrated to dryness under reduced pressure to give 26.5g of an off-white solid. The crude product was recrystallized from isopropanol to give 24.8g of zidovudine with a purity of 99.8% in 95% yield. MS: M/z 267 (M +). Example 2

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

200ml of pyridine, 2' -chlorothymidine (50.0 g, 0.18mol) and triphenylchloromethane (60.0 g, 0.21mol) were added to the reaction flask at room temperature. The temperature is raised to 60 ℃, and the TLC tracks the reaction until the raw materials are completely reacted. The oil bath was removed, cooled to o ℃ with an ice bath and methanesulfonyl chloride (16.5 ml, 0.22mol) was added dropwise, controlling the reaction temperature below 5 ℃. After TLC tracking the reaction of the starting materials was complete, water was added to stop the reaction. The mixture was concentrated to a viscous state under reduced pressure, and the residue was dissolved in 1000ml of a methylene chloride solution, washed 2 times with a saline solution, and dried over anhydrous magnesium sulfate. Filtering, concentrating under reduced pressure to dryness to obtain l og white foam solid.¹H-NMR (. delta.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

100ml of pyridine, 2-chlorothymidine (14.0 g, 0.052 mol) and pivaloyl chloride (8.0 ml, 0.065 mol) were added to a reaction flask at room temperature. The temperature was raised to 40 ℃ and the reaction was followed by TLC until the starting material reaction was complete. Water was added to terminate the reaction. The mixture was concentrated to a viscous state under reduced pressure, and the residue was dissolved in 200ml of a methylene chloride solution, washed with water 2 times, and dried with anhydrous magnesium sulfate. Filtering, concentrating under reduced pressure to dry to obtain 18g of class white foam. Delta 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 ' -methylsulfonyl-2 ' -chlorothymidine

50ml of methylene chloride and 18g of the white foamy solid are added into a reaction bottle, stirred and dissolved, and cooled to 0 ℃ in an ice bath. While dropwise adding methanesulfonyl chloride (4.8 ml, 0.062mol) and 10ml of pyridine, respectively, the reaction temperature was controlled to be lower than 5 ℃. After TLC tracking the reaction of the raw materials, 30ml of saturated aqueous sodium carbonate solution was slowly added dropwise to terminate the reaction. The organic layer is decompressed, concentrated and recycled to the dichloro-methyl alka, and the residue is directly put into the next step for reaction.

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

To the residue were added 100ml of ethanol and 20ml of a saturated aqueous sodium carbonate solution, and the mixture was heated to reflux. After TLC tracking raw material reaction is completed, cooling to 40 ℃, and concentrating under reduced pressure to be viscous. The residue was extracted 3 times with 50ml of water and 100ml of a methylene chloride and the organic phases were combined. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain 19g of crude slurry, and directly putting into the next step for reaction. The product can be purified by column chromatography (ethyl acetate: n-hexyl = 1: 3) to give a white solid. 1H-NMR,. delta.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

To the above slurry was added 100ml of methanol, 2.0 at room temperature_g5% palladium carbon, sodium acetate (5.8 g, 0.070mol), stirring, and introducing hydrogen under normal pressure. After TLC tracking the raw material reaction is completed, stopping introducing hydrogen. Filtering, concentrating under reduced pressure, drying,drying in vacuo afforded 9.7g of a pale yellow solid in 61% yield. ifi-NMR,. delta.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)_;Preparation of 6.48(s, IH), 5 '-pivaloyl-3' -azidothymidine

30ml of DMF, sodium azide (4.5 g, 0.069 mol), anhydrous lithium chloride (1.5 g, 0.035mol), ammonium chloride (1.5 g, 0.028mol) and 5-pivaloyl-3, 2-anhydrothymidine (5.0 g, 0.016mol) were added successively with stirring, and the mixture was slowly heated to 110 ℃ for reaction. TLC tracks the completion of the reaction of the starting materials, then cool to room temperature and filter the insoluble material. 50ml of water is slowly dropped into the filtrate while stirring, and the pulping is continued for 30 minutes after the dropping is finished. Suction filtration and forced air drying gave 5.1g of a pale yellow solid in 91% yield. Preparation of ifi-NMR, delta 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), zidovudine

To this was added, while stirring, 65ml of methanol, 5-pivaloyl-3-azidothymidine (5.0 g, 0.014mol),

6.5ml of a 25% sodium methoxide solution in methanol were stirred at room temperature for 1 hour. After TLC tracing of the reaction completion of the starting material, the reaction mixture was neutralized with a strongly acidic resin (Dowex 50-200X 8), the pH was adjusted to about 6, and the resin was recovered by filtration and washed with methanol. Filtrate is combined, decolored by active carbon and concentrated under reduced pressure until the filtrate is dried, and the obtained white-like solid is recrystallized by isopropanol, the purity of the zidovudine is 3.2g, and the yield is 86%. MS: M/z 267 (M +). Example 4

Preparation of 5-trimethylpropionyl-3-ethanethiol-2-bromothymidine

100ml of dichloroalkylt, 2-bromothymidine (16.1 g, 0.050 mol), trimethylpropionyl chloride (8.0 ml, 0.065 mol), 10ml of pyridine were added to the reaction flask at room temperature. The temperature was raised to 40 ℃ and the reaction was followed by TLC until the starting material was reacted completely. Cooled to 10 ℃, and then dropwise added with ethionyl chloride (3.0 ml, 0.042 mol), and the reaction temperature is controlled to be lower than 15 ℃. After TLC tracking the reaction of the raw materials, 30ml of saturated aqueous sodium carbonate solution was slowly added dropwise to terminate the reaction. The pressure is reduced, the dichloromethyl is concentrated and recovered, and residues are directly put into a downward-walking reaction.

Preparation of 5, -trimethylpropionyl-2, 3, -anhydro-2, -bromothymidine to the supernatant 100ml acetonitrile, potassium carbonate (8.6 g, 0.062mol) were added and heated to reflux. And (3) after TLC tracking of the complete reaction of the raw materials, cooling to 40 ℃, and concentrating under reduced pressure to be viscous. The residue was extracted 3 times with 100ml water and 100ml methylene chloride, and the organic phases were combined. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate to dryness under reduced pressure gave 8.2g of yellow syrup. The product can be purified by column chromatography (ethyl acetate: n-hexyl = 1: 3) to give a white solid. 1H-NMR,. delta.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-trimethylpropionyl-2, 3-anhydrothymidine

To the above slurry was added 75ml of methanol, 1.5 at room temperature_g5% palladium carbon, sodium acetate (5.0 g, 0.061mol), stirring, and introducing hydrogen gas under normal pressure. After TLC tracking the raw material reaction is completed, stopping introducing hydrogen. Filtering, concentrating under reduced pressure to dry to obtain 11.5g of yellow foam. 1H-NMR,. delta.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, 30ml of DMF, sodium azide (6.5 g, O.lOmol) and 10ml of DMF solution of the walking product are added in turn, and the temperature is slowly raised to 110 ℃ for reaction. TLC tracks the reaction of the raw materials, then the mixture is cooled to room temperature, and insoluble substances are filtered out. And slowly dripping 80ml of water into the filtrate under stirring, and continuing pulping for 1 hour after dripping. Suction filtration and forced air drying gave 5.6g of a yellow solid. 1H-NMR preparation of. delta.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). Zidovudine

To the mixture were added, while stirring, 65ml of methanol, 5-trimethylpropionyl-3-azidothymidine (5.0 g, 0.014mol) and 6.5ml of a 25% sodium methoxide solution in methanol, and the mixture was stirred at room temperature for 1 hour. TLC was performed to track the completion of the reaction of the starting materials, followed by neutralization with a strongly acidic resin (Dowex 50-200X 8), pH adjustment to about 6, resin recovery by filtration, and washing with methanol. Filtrate is combined, decolored by active carbon and concentrated under reduced pressure until the filtrate is dried, and the obtained white-like solid is recrystallized by isopropanol to obtain 2.2g of zidovudine with the purity of 99 percent. MS: M/z 267 (M +). All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the above disclosure, and equivalents also fall within the scope of the invention as defined by the appended claims.

Claims

Claims

1. A novel method of preparing zidovudine, the method comprising the steps of:

1) 2' -halogenated thymidine is taken as a raw material, and 5' -hydroxyl of the 2' -halogenated thymidine is protected to obtain a compound shown as a formula (I)

2) Acylating the compound of the formula (I) by 3' -hydroxyl to obtain a compound of a formula (VI);

3) The compound of the formula (VI) is eliminated to obtain a compound of a formula (VII);

4) dehalogenating the compound of formula (VII) to obtain the compound of formula (IV)

5) Carrying out an azide reaction on the compound of the formula (IV) to obtain a compound of a formula (V);

6) deprotection of the compound of formula (V) to give zidovudine;

the device comprises:

Scheme 3

in the formula: x is halogen; is there a Is a hydroxy protecting group; p₂Is alkanyl sulfonyl, fluoro-alkanyl sulfonyl, arylsulfonyl or-CS-R, wherein R is d \u₄And (5) priming.
2. The method of claim 1, wherein X is chlorine or bromine; is there a₁Is trityl, pivaloyl or trimethylpropionyl; p₂Is methylsulfonyl, trifluoromethylsulfonyl, p-toluenesulfonyl or-CS-R, wherein R is methyl.
3. The method of claim 1, wherein the compound of formula (VI) can be directly subjected to the next step without separation, thereby realizing a two-step one-pot frying process.
4. The method of claim 1, wherein the compound of formula (I) and the compound of formula (VI) can be directly subjected to the next step without separation, thereby achieving a process of triple-step frying.
5. The method as recited in claim 1, wherein said method may be specifically described as including the steps of:

1) 2 '-halogenated thymidine is used as a raw material to react with trityl chloride alkyl to obtain 5' -trityl methyl₂' _ halothymidine;

2) 3 '-mesylation of 5' -trityl-2 '-halothymidine to obtain 5' -trityl-3 '-mesyl-2' -halothymidine;

3) Elimination of 5' -trityl-3 ' -methanesulfonyl-2 ' -halothymidine under basic conditions to give 5, -trityl-2, 3, -anhydro-2, -halo-thymidine;

4) hydrogenating and dehalogenating 5' -trityl-2, 3' -anhydro-2 ' -halo-thymidine to obtain 5' -trityl-2, 3' -anhydrothymidine;

5) Carrying out an azidation reaction on the 5 '-trityl-2, 3' -anhydrothymidine to obtain 5 '-trityl-3' -azidothymidine;

6) 5 '-trityl-3' -azidothymidine is deprotected under acidic condition to obtain zidovudine.
6. The method of claim 5,

the reaction temperature of the step 1) is 20-80 DEG C_;The reaction solvent is an alkaline organic solvent; the reaction reagent of the step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ℃, and the reaction solvent is halogenated hydrocarbon solvent;

the alkaline condition is selected from alkali metal/DMSO, alcohol solution of sodium alkoxide or potassium alkoxide, alcohol solution of sodium hydroxide or potassium hydroxide, aqueous solution of sodium carbonate, potassium carbonate or lithium carbonate, sodium methanesulfonate aqueous solution, sodium p-toluenesulfonate aqueous solution, triethylamine or DBU, wherein the reaction solvent is alcohol solvent; the reaction temperature is 20-80 ℃;

the reagents for hydrogenation and dehydrogenation in the step 4) are Raney nickel/triethylamine and hydrogen, and the reaction temperature is 20-60 DEG C_;The reaction solvent is an alcohol solvent;

the reaction reagent of the step 5) is azide, the reaction solvent is DMF, the reaction temperature is 60-120 ℃, and

the acidic condition in step 6) is selected from hydrochloric acid, aqueous solution of sulfuric acid or acetic acid or p-toluenesulfonic acid; the reaction solvent is an alcohol solvent; the reaction temperature is 10-50 ℃.
7. The method of claim 5,

the reaction temperature of the step 1) is 40-70 ℃, and the reaction solvent is pyridine;

the reaction reagent of the step 2) is methanesulfonyl chloride; the reaction temperature is 0-5 ℃, and the reaction solvent is the dichloro-methyl;

the alkaline condition in step 3) is selected from an aqueous solution of sodium carbonate, potassium carbonate or lithium carbonate; the reaction solvent is methanol or ethanol; the reaction temperature is 50-70 DEG C_;

The reagents for hydrogenation and dehydrogenation in the step 4) are Raney nickel/triethylamine and hydrogen, and the reaction temperature is 30-50 DEG C_;The reaction solvent is methanol;

the reaction reagent in the step 5) is lithium azide or sodium azide/anhydrous lithium chloride/ammonium chloride, and the molar ratio of the lithium azide to the anhydrous lithium chloride to the ammonium chloride is 2-3: 0.8-1.2: 1, DMF as reaction solvent, at 80-110 deg.C_;And

the acidic condition in the step 6) is hydrochloric acid aqueous solution or p-toluenesulfonic acid; the reaction solvent is methanol; the reaction temperature is 25-40 ℃.
8. Preparation of zidovudine of formula (VI):wherein X is halogen; is there a Is a hydroxyl protecting group.
9. The intermediate of claim 8, wherein X is chloro or bromo; pi is trityl, pivaloyl or trimethylpropionyl.
10. The intermediate of claim 8, wherein X is chloro or bromo; p1 is trityl or pivaloyl.