CN101302239B - Synthetic method of telbivudine and intermediate thereof - Google Patents

Abstract

其中，R为苄基、苯环上有取代的苄基或酰基；R’为CH₃。本发明的方法操作简单，不需要柱层析和特殊设备，所得产品收率较高，纯度高，适合应用于工业化生产。The invention discloses a preparation method of tibivudine and its intermediates, comprising the following steps: in an organic solvent, using Lewis acid as a catalyst, adding trialkyl silicon halides, compounds shown in formula I and formula II, Carry out the reaction to obtain the compound shown in formula I and thymine shown in formula II, carry out the reaction to prepare the mixture of the compound shown in formula III of α and β two isomers, and then separate and extract the β isomer isomer; the β isomer is reacted with a hydrogen donor in an organic solvent in the presence of an organic base to obtain the following

Wherein, R is benzyl, benzyl or acyl substituted on the benzene ring; R' is CH ₃ . The method of the invention is simple to operate, does not need column chromatography and special equipment, and the obtained product has high yield and high purity, and is suitable for industrial production.

Description

Synthetic method of tibivudine and its intermediate

technical field

The invention relates to a synthetic method of a compound and an intermediate thereof, in particular to a synthetic method of tibivudine and an intermediate thereof.

Background technique

Tabivudine is a new nucleoside anti-HBV compound, which has completed phase III clinical trials and is in the pre-registration stage. Its chemical name is: 2'-deoxy-β-L-thymidine. Tibivudine has the pharmacological activity of general nucleoside anti-HBV drugs.

At present, the preparation of tibivudine adopts the method disclosed in the patent document WO2005003374, and the steps are as follows:

(1) Use acetic acid as a solvent, feed HCl gas or drop into saturated HCl acetic acid solution and acetyl chloride to chlorinate the compound (Formula I), and collect the chlorinated product (Formula V) as a white solid by filtration;

(2) reacting thymine (formula II) with a trialkyl silicon halide to obtain a compound (formula VI);

(3) subjecting the product obtained in the above two steps to a condensation reaction to obtain a mixture of compounds (formula III) of α and β two isomers;

(4) Alcohol recrystallization is used to separate α and β two isomers; the β isomer is reacted with a hydrogen donor in an organic solvent in the presence of an organic base to obtain Tabivudine (formula IV ).

In this method, the chlorinated compound is extremely unstable, easily decomposes and turns black during the filtration process, and must be condensed with thymine immediately, the operation is cumbersome, and it is not easy to scale up production.

Contents of the invention

The purpose of the present invention is in order to overcome the defective in the above-mentioned prior art, and provide a kind of simple to operate, the synthetic method of the tibivudine intermediate that gained product yield and purity are higher.

The method of the present invention comprises the following steps: in an organic solvent, using a Lewis acid as a catalyst, adding a trialkyl silicon halide, a compound represented by formula I and thymine represented by formula II, and reacting to obtain both α and β A mixture of the compound shown in formula III of one isomer, and then separate and extract the β isomer.

Wherein, R is benzyl, benzyl or acyl substituted on the benzene ring, preferably PhCH ₂ , 4-CH ₃ OPhCH ₂ , 4-CH ₃ PhCO, Ac or PhCO; R' is CH ₃ . In the present invention, Ph is the abbreviation of phenyl, and Ac is the abbreviation of acetyl.

Wherein, described Lewis acid can be selected common Lewis acid, is preferably aluminum trichloride, tin tetrachloride or titanium tetrachloride; The consumption of Lewis acid is preferably 0.8% of the compound quality as shown in formula I ~1.5 times; the organic solvent is preferably selected from one or more inert solvents, preferably nitriles, halogenated hydrocarbons, esters or ethers; the trialkyl silicon halide is more Preferable is trimethylchlorosilane and/or hexamethyldisilazane, the amount of which can be used conventionally in this field, see patent document WO2005003374; the reaction time is preferably 12 to 24 hours; more preferably 18-23 hours; the best is 20-22 hours; the reaction temperature is preferably 30-80°C; more preferably 38-60°C, the best is 43-55°C; separation and extraction of β isomer It is preferable to use alcohol recrystallization to separate the α and β isomers. For the operating conditions of alcohol recrystallization, please refer to the patent document WO2005003374.

In the present invention, the compound represented by formula I can be prepared by the method disclosed in patent document WO2005003374. For the specific material selection and dosage of the compound represented by formula I, and the dosage of thymine represented by formula II, please refer to the patent document WO2005003374.

The further object of the present invention is to disclose a kind of synthetic method of simple operation, higher yield and purity tabivudine, which comprises the following steps: in an organic solvent, in the presence of an organic base, the prepared by the above method The β-isomer compound Tavivudine intermediate shown in formula III can be reacted with a hydrogen donor to prepare Tabivudine shown in formula IV.

Wherein, the conditions for the reaction between the tabivudine intermediate and the hydrogen donor and the dosage of the reactants can be found in the patent document WO2005003374.

The reagents and raw materials used in the present invention are commercially available unless otherwise specified.

The positive and progressive effects of the present invention are: the method of the present invention is simple to operate, and the intermediate of tibivudine can be prepared by one-step reaction without column chromatography and special equipment, and the yield of the obtained product is high, the purity is high, and the general yield It can reach more than 55%, and the purity can reach more than 95%. It is suitable for industrial production.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples.

Example 1

With 20g (81mmol) of 3,4-di-O-acetyl-β-methyl-2-deoxy-L-nucleoside furanoside (compound of formula I, R is Ac), add 11g (86mmol) thymine, add 19ml (91mmol) of hexamethyldisilazane (HMDS) in 600ml of dichloromethane, 13ml (30g, 101mmol) of trimethylchlorosilane, 10ml (84mmol) of tin tetrachloride (21.8g). React at 30°C for 24 hours, remove the solvent by rotary evaporation, add 1200ml ethyl acetate and 900ml saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with ethyl acetate 1200ml×2, combine the organic phases, and use 1200ml saturated chlorinated Washed with sodium solution, dried, filtered, and rotary evaporated to obtain 22 g of crude product. Add 200ml×2 n-hexane to the solid, stir for 2h, and obtain 20g of compound 2. Recrystallization from methanol gave 16 g of β isomer (yield: 58%, purity: 96.0%).

Example 2

20g (53mmol) of 3,4-di-O-p-methylbenzoyl-α,β-methyl-2-deoxy-L-nucleoside furanoside (compound of formula I, R is 4-CH ₃ PhCO) , add 7g (55mmol) thymine, add 400ml of ethyl acetate containing 12ml (58mmol) hexamethyldisilazane (HMDS), dichloromethane 100ml, 8ml (62mmol) trimethylchlorosilane, 9.5ml (80mmol ) tin tetrachloride (21g). React at 40°C for 20 hours, add 500ml of ethyl acetate and 600ml of saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with 900ml of ethyl acetate x 2, combine the organic phases, wash with 900ml of saturated sodium chloride solution, and dry , filtered, and rotary evaporated to obtain 24 g of crude product. Add 200ml×2 n-hexane to the solid and stir for 2h to obtain 22g of compound 4. Recrystallized with ethanol to obtain β-isomer 19g (yield: 69%, purity: 97.5%, m.p227-229°C (document: 225-227°C))

Example 3

With 20g (56mmol) of 3,4-di-O-benzoyl-β-methyl-2-deoxy-L-nucleoside furanoside (compound of formula I, R is PhCO), add 8g (63mmol) pyrimidine, add Contain 25ml (125mmol) of hexamethyldisilazane (HMDS) in 450ml of ether, 16ml (84mmol) of titanium tetrachloride (16g). React at 50°C for 15 hours, remove the solvent by rotary evaporation, add 900ml ethyl acetate and 600ml saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with ethyl acetate 900ml×2, combine the organic phases, and use 900ml saturated chlorinated Washed with sodium solution, dried, filtered, and rotary evaporated to obtain 20 g of crude product. Add 200ml×2 n-hexane to the solid and stir for 2h to obtain 16g of compound 6. Recrystallized with methanol to obtain β-isomer 15g (yield: 60%, purity: 97.0%, m.p223-225°C (document: 224-225°C))

Example 4

With 20g (60mmol) of 3,4-di-O-benzyl-α,β-methyl-2-deoxy-L-nucleoside furanoside (compound of formula I, R is benzyl), add 9g (72mmol) of thymus For pyrimidine, add 400 ml of ethyl acetate containing 15 ml (120 mmol) of trimethylchlorosilane, and 13.5 ml (115.2 mmol) of tin tetrachloride (30 g). React at 80°C for 12 hours, add 500ml ethyl acetate and 600ml saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with ethyl acetate 900ml×2, combine the organic phases, wash with 900ml saturated sodium chloride solution, and dry , filtered, and rotary evaporated to obtain 24 g of crude product. Add 200ml×2 n-hexane to the solid and stir for 2h to obtain 22g of compound 8. Recrystallized with ethanol to obtain β-isomer 17.5g (yield: 69%, purity: 97%, m.p224-225°C (document: 225-227°C))

Example 5

20g (55mmol) of 3,4-di-O-p-methoxybenzyl-β-methyl-2-deoxy-L-nucleoside (compound of formula I, R is 4-CH ₃ OPhCH ₂ ), Add 8 g (63 mmol) of pyrimidine, 450 ml of diethyl ether containing 25 ml (125 mmol) of hexamethyldisilazane (HMDS), and 25 ml (132.4 mmol) of titanium tetrachloride (25 g). React at 50°C for 18 hours, remove the solvent by rotary evaporation, add 900ml ethyl acetate and 600ml saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with ethyl acetate 900ml×2, combine the organic phases, and use 900ml saturated chlorinated Washed with sodium solution, dried, filtered, and rotary evaporated to obtain 20 g of crude product. Add 200ml×2 n-hexane to the solid and stir for 2h to obtain 16g of compound 10. Recrystallized with methanol to obtain β-isomer 15g (yield: 61%, purity: 97.0%, m.p225-228°C (document: 224-229°C))

Example 6

With 20g (81mmol) of 3,4-di-O-acetyl-α-methyl-2-deoxy-L-nucleoside furanoside (compound of formula I, R is Ac), add 11g (86mmol) thymine, add 660 ml of acetonitrile containing 19 ml (91 mmol) of hexamethyldisilazane (HMDS), 13 ml (101 mmol) of trimethylchlorosilane, and 20 g (150 mmol) of aluminum trichloride. React at 44°C for 22 hours, remove the solvent by rotary evaporation, add 1200ml ethyl acetate and 900ml saturated sodium bicarbonate solution, filter, separate layers, wash the aqueous phase with ethyl acetate 1200ml×2, combine the organic phases, and use 1200ml saturated chlorinated Washed with sodium solution, dried, filtered, and rotary evaporated to obtain 23 g of crude product. Add 200ml×2 n-hexane to the solid and stir for 2h to obtain 22g of compound 12. Recrystallization from ethanol gave 18 g of the β-isomer (yield: 65%, purity: 97.0%, m.p 211°C (document: 212°C)).

Example 7

Sodium metal 1.5g (66mmol) was dissolved in 600ml of methanol, and after 0.5h of reaction, 10g (22mmol) of compound 13 was dissolved in the above solution, stirred at room temperature for 2h, and the reaction was stopped. Add dilute sulfuric acid to neutralize, filter, concentrate the filtrate, grind with 40ml of n-hexane, pour off the supernatant, and recrystallize the residue with ethanol to obtain 3.7g of white solid tibivudine (yield: 69.5%, purity: 98.0%, m.p186-187°C (Document: 185-188°C))

Claims (6)

1. one kind suc as formula the compound telbivudine intermediates preparation shown in the V, it is characterized in that comprising the steps: in the organic solvent, with the Lewis acid is catalyzer, add trialkyl silicon halide, compound shown by formula I and suc as formula the thymus pyrimidine shown in the II, react the mixture of the compound shown in formula III that makes α and two kinds of isomer of β, the separation and Extraction beta isomer gets final product afterwards;

Wherein, R is benzyl, 4-CH ₃OPhCH ₂, 4-CH ₃PhCO, Ac or PhCO; R ' is CH ₃Described Lewis acid is aluminum chloride, tin tetrachloride or titanium tetrachloride; Described organic solvent is one or more in the inert solvent; Described inert solvent is nitrile, halohydrocarbon, ester class or ethers.

2. the method for claim 1, it is characterized in that: described lewis acidic consumption is 0.8～1.5 times of compound shown by formula I quality.

3. the method for claim 1, it is characterized in that: described trialkyl silicon halide is trimethylchlorosilane and/or hexamethyldisilazane.

4. the method for claim 1, it is characterized in that: the time of described reaction is 12～24 hours.

5. the method for claim 1, it is characterized in that: the temperature of described reaction is 30～80 ℃.

6. preparation method suc as formula the telbivudine shown in the IV, it is characterized in that: make suc as formula the compound telbivudine intermediate shown in the V by the method for claim 1, then in organic solvent, under the existence of organic bases, itself and hydrogen donor reacted get final product.