WO2009082846A1

WO2009082846A1 - A capecitabine hydroxyl-derivative, its preparation processes and uses for preparing capecitabine

Info

Publication number: WO2009082846A1
Application number: PCT/CN2007/003873
Authority: WO
Inventors: Jingshan Shen; Xiangrui Jiang; Weiming Chen; Xiujun He; Yang Ou
Original assignee: Topharman Shanghai Co., Ltd.
Priority date: 2007-12-28
Filing date: 2007-12-28
Publication date: 2009-07-09

Abstract

A capecitabine hydroxyl-derivative as the following structure, its preparation processes and intermediates in the processes, and the use of hydrolyzing the said capecitabine hydroxyl-derivative to get capecitabine. The capecitabine hydroxyl-derivative provides the proper protecting group that can be removed by hydrolysis to get capecitabine under a weaker acidic or basic condition. The process of the reaction step is well controlled, the purity of the raw product is high and the resulting capecitabine meets the standard of US pharmacopoeia without complicated purification.

Description

Capecitabine hydroxyl derivative, preparation method thereof and preparation thereof for capecitabine

The present invention relates to the field of medicinal chemistry, and more particularly to a capecitabine hydroxy derivative, a process for its preparation and an intermediate in the preparation process, and to a capecitabine hydroxy derivative for the preparation of capecita The use of the coast. Background technique

Capecitabine is a prodrug of 5-fluorouracil that has a selective effect on tumor cells and can be used as an oral cytotoxic agent.

Capecitabine itself is not cytotoxic, but can be converted to cytotoxic 5-fluorouracil in three steps by the action of enzymes in the body. The enzyme associated with capecitabine is higher in tumor tissues than in normal tissues, giving it selective cytotoxicity against tumor cells. Its structural formula is as follows:

The currently reported synthesis methods of capecitabine mainly include the following:

1. Using racemic triacetoxyribofuranose to interface with 5-fluorocytosine, then reacting with an acid chloride to give an acylated product, followed by hydrolysis to give capecitabine (Bioorganic & Medicinal Chemistry, 2000, 8, 1697-1706) )

2. Using 5'-deoxy-5-fluoro-cytidine as a starting material through two acylation steps, followed by hydrolysis to yield (Drug of the Future, 1996, 21, 358-360).

Using pentyloxycarbonyl chloride as the acylating reagent, the hydroxy group and the amino group are acylated, followed by selective hydrolysis to give the final product (US 5,476,932).

. I have already started using 5-fluoro-cytosine acylated ^p given as a starting material, the reaction with 5-deoxy-1,2,3-triacetyl -D- ribofuranose docking, then dried ammonia - methanol to give a final Hydrolysis Product (CN1660819A) _o

Capecitabine

i. Using ribose as a raw material, after seven steps of reaction, the final product is obtained (Chinese Journal of Medicinal Chemistry, 2005, 15, 173).

Capecitabine

6. Using 5'-deoxy-5-fluoro-cytidine as the starting material, passing through the intermediate of the cyclic carbonate, then reacting with n-amyl chloroantimonate, and finally passing through water to obtain the product (CN1896089A).

In the above methods 1, 2, 3, 4 and 6, the last step uses a method of deprotecting the hydroxyl group under strong basic conditions, and this strong alkaline condition causes the occurrence of side reactions, thereby causing Poor controllability of the process, low purity of the crude product and not easy to purify. Summary of the invention

The present inventors focused on the synthesis of capecitabine, and designed and synthesized a capecitabine hydroxy derivative represented by Formula III during the research process, which provides a suitable protecting group and can be weaker. It is removed by hydrolysis under acidic or basic conditions to obtain capecitabine. The process of this step is highly controllable, the purity of the crude product is high, and no cumbersome purification treatment is required, and the obtained capecitabine can reach the standards of the United States Pharmacopoeia.

Accordingly, it is an object of the present invention to provide a capecitabine hydroxyl derivative of the formula III; Another object of the present invention is to provide a process for preparing a capecitabine hydroxyl derivative; a further object of the present invention is to provide a use of a capecitabine hydroxyl derivative for the preparation of capecitabine;

Still another object of the present invention is to provide two intermediates for preparing a capecitabine hydroxyl derivative, and a process for preparing the intermediate.

According to the present invention, the present invention provides a capecitabine hydroxy derivative represented by the following formula III:

Among them, a hydrocarbon group having 1 to 4 carbon atoms is selected.

In a preferred embodiment of the invention, Ri is an alkyl group having 1 to 4 carbon atoms, and the alkyl group may be a linear or branched alkyl group, for example, a decyl group, an ethyl group, a propyl group or a butyl group. Base.

The capecitabine hydroxyl derivative of the formula III of the present invention can be produced as follows: Method 1:

Starting from 5'-deoxy-5-fluoro-uridine, the steps are as follows:

I II III

In the presence of an acidic catalyst, 5'-deoxy-5-fluoro-uridine is condensed with ortho phthalate HC (OR0 ₃ to give a 5'-deoxy-5-fluoro-uridine derivative of formula I, Wherein the definition is the same as defined in the above compound of formula III; Then, in an aprotic solvent, the 5'-deoxy-5-fluoro-uridine derivative of the formula I is subjected to two substitution reactions with phosphorus oxychloride, an organic base and aqueous ammonia to obtain 5'- of the general formula II. Deoxy-5-fluoro-cytidine derivative;

Then, in the aprotic solvent, the 5'-deoxy-5-fluoro-cytidine derivative of the formula

The acylation reagent of IV R^^o"^^^^ is subjected to an acylation reaction to obtain a capecitabine hydroxy derivative of the formula III, wherein R is a leaving group, which is a halogen, a nitrophenoxy group or a butyl group. Diimideoxy.

Or,

Method Two:

Starting with 5'-deoxy-5-fluoro-cytidine, the steps are as follows: '

II III

5'-deoxy-5-fluoro-cytidine is reacted with orthoformate HC (OR0 ₃ in the presence of an acidic catalyst to give a 5'-deoxy-5-fluoro-cytidine derivative of the general formula II, Wherein the definition is the same as defined in the above compound of formula III;

Then, in the aprotic solvent, the 5'-deoxy-5-fluoro-cytidine derivative of the general formula II and the formula

IV

A pecitabine hydroxy derivative of the formula III is obtained wherein R is a leaving group and is a halogen, nitrophenoxy or succinimideoxy group.

In the above method one:

The condensation reaction of 5'-deoxy-5-fluoro-uridine with orthoformate HC OR^ can be carried out in an aprotic solvent such as toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane. It is also possible to carry out the above two or more mixed solvents; the acidic catalyst, for example For example, p-benzoic acid, zinc chloride, tin chloride or boron trifluoride; the reaction temperature can be varied within a wide range, generally -20. C~120. C, preferably -20. C ~ 80. The molar ratio of C; 5'-deoxy-5-fluoro-uridine to orthoformate ΗΟ) ₃ is from 1:1 to 1:10, and preferably from 1:1 to 1:3.

The two-substitution reaction of the 5'-deoxy-5-fluoro-uridine derivative of the formula I with phosphorus oxychloride, an organic base and aqueous ammonia can be carried out in one or more aprotic solvents, A non-substance such as acetonitrile, tetrahydrofuran, acetone, hydrazine, hydrazine-dihydrazinamide or a mixture thereof; the reaction temperature is -10. C~30 °C, preferably -5.020. C. 5'-deoxy-5-fluoro-cytidine derivative of formula II and formula IV

The acylation reaction of the acylating reagent, wherein the acylating reagent of the formula IV is preferably the following three:

0

>~.

. Factory, C ₅ H"- _n ^ο , ^C5H "- ⁿ

The acylation reaction can be carried out in one or more aprotic solvents such as dichlorosilane, acetonitrile, tetrahydrofuran, acetone, hydrazine, hydrazine-dimethyl hydrazide or mixtures thereof; The reaction is usually carried out in the presence of a basic catalyst such as an inorganic base such as potassium carbonate, triethylamine or pyridine or a compound; the reaction temperature is -10. C~50 °C, preferably at 0. C to 20 ° C; the molar ratio of the 5'-deoxy-5-fluoro-cytidine derivative of the general formula II to the acylating reagent of the formula IV is 1:1 to 1:3, preferably 1: U~1 :2.

In the second method above:

5'-deoxy-5-fluoro-cytidine and orthoformate HC (OR0 ₃ condensation reaction can be carried out in aprotic solvents such as toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane In the above, it may be carried out in the above two or more kinds of mixed solvents; the acidic catalyst, for example, p-toluenesulfonic acid, zinc chloride, tin chloride or boron trifluoride; the reaction temperature may be Change in a larger range, generally -20 ° C ~ 120 ° C, preferably -20 ° C ~ 80 ° C; 5 '-deoxy-5-fluoro-cytidine and orthophthalate HC OR ^ molar ratio 1:1~1:10, excellent 1:1~1:3. After the 5'-deoxy-5-fluoro-cytidine derivative of the general formula II is prepared, the same acylation step in the first method is followed. , the capecitabine hydroxy steroid of the general formula III is obtained. The capecitabine hydroxy derivative of the formula III provided by the present invention can be used for the preparation of capecitabine, that is, the capecitabine hydroxy steroid of the formula III is deprotected by a hydrolysis reaction to obtain capecitabine. The hydrolysis reaction can be carried out in a protic solvent (for example: methanol, ethanol, propanol), an aprotic solvent (for example: tetrahydrofuran, acetonitrile, dimethyl sulfoxide, hydrazine, hydrazine-dimethylformamide, acetone) or water. It is also possible to carry out in the above two or more mixed solvents. The reaction is usually carried out in the presence of an acidic catalyst (for example, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, etc.) (control pH value is 1 to 6), and then an alkaline reagent (for example, sodium hydrogencarbonate, sodium carbonate, carbonic acid) is used. Potassium, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.) adjust the pH value to 7 to 11 to promote the reaction to completion.

The method for synthesizing the capecitabine hydroxyl derivative of the general formula III of the present invention and the method for preparing the capecitabine by hydrolysis thereof have been proved by experiments, the reaction condition is mild, the operation is easy, the yield is high, the quality of the obtained crude product is stable, and the purity is obtained. high. In particular, the reaction conditions required for the preparation of capecitabine in the compound III deprotection group are mild, and the controllability of the reaction process is high, and the obtained crude product purity meets the requirements of the United States Pharmacopoeia, and can be industrially scaled up.

detailed description

Example 1

La

1.0 g (5.8 mmol) of p-benzoic acid was dissolved in a mixture of 20 ml of triethyl orthoformate and 30 ml of acetonitrile, and 1.0.0 g (40.7 mmol) of 5'-deoxy-5-fluoro-uridine was added. Stir at room temperature for 24 hours, dilute with 100 ml of dichloromethane, wash twice with water (30 ml), EtOAc (3 mL). The yield was 97%. The resulting compound is a mixture of a pair of isomers. La: ^ NMR (300 MHz, OMSO-d ₆ ): 811.93 (s, 1H), 11.91 (s, 1H), 8.14 (d, 1H, J = 6.9 Hz), 8.07(d, IH, J 6.9 Hz), 6.12(s, IH), 6.08(s, IH), 5.87(d, IH, J=3.3 Hz), 5.69(d, 1H, J=3.0 Hz), 4.97 (m, 2H), 4.53~4.67(m, 2H), 3.99~4.19(m, 2H), 3.48~3.59(m, 4H), 1.30~1.33(m, 6H), 1.08~1.30(m, 6H) ; ESI-MS m/z (M+23) 325.

Example 2:

0.57 g (4.0 mmol) of boron trifluoride diethyl ether solution was dissolved in a mixture of 20 ml of triethyl orthosilicate and 30 ml of acetonitrile, and 10.0 g (40.7 mmol) of 5'-deoxy-5-fluoro-uridine was added. Stir at room temperature for 24 hours, add 100 liters of dichloromethane, dilute with water, wash twice with water (30 ml), wash with saturated brine 30 liters, dry with anhydrous sodium sulphate, filter, and remove the solvent under reduced pressure to give a colorless oil. Gram, yield 97%.

Example 3:

Lb

0.2 g (1 mmol) of p-toluenesulfonic acid was dissolved in a mixture of 2.12 g (20 mmol) of tridecyl orthophthalate and 20 ml of tetrahydrofuran, and 2.46 g (10 mmol) of 5'-deoxy-5-fluoro- The uridine was heated to reflux for 5 hours, diluted with 100 ml of dichloromethane, washed twice with 30 ml of water, washed with 30 ml of brine, dried over anhydrous sodium sulfate, filtered and evaporated. Lb 2.80 g, yield 99%. Lb: 3⁄4 NMR (300 MHz, DMSO- ₆ ): 811.94 (s, IH), 11.93 (s, IH), 8.13 (d, IH, J = 6.9 Hz), 8.08 (d, 1H, J = 6.9 Hz) , 6.09(s ₅ IH), 6.01(s, IH), 5.84(d, IH, J=3.3 Hz), 5.70(d, 1H, J=3.0 Hz), 4.97(m, 2H), 4.53~4.69( m, 2H), 3.99~4.19 (m, 2H), 3.28 (s, 3H), 3.19 (s, 3H), 1.32 (m, 6H); ESI-MS m/z (M+23) 311.

Example 4:

La Ila

8 g (26.5 mmol) of la was dissolved in 40 ml of anhydrous acetonitrile, and 4 ml (53.0 mmol) of pyridine and 6.46 g (40.0 mmol) of -diaminopyridinium>3⁄4 were added and cooled to 0. C, 6.14 g (40.0 mmol) of phosphorus oxychloride was added dropwise, stirred for 6 hours, and the reaction solution was poured into 0. In a concentrated aqueous ammonia solution, the mixture was stirred for 0.5 hr, and the aqueous layer was washed with methylene chloride. The organic phase was combined and dried over anhydrous sodium sulfate. The resulting compound is a mixture of a pair of isomers. Ila: 3⁄4 NMR (300 MHz, DMSO- ₆ ): δ 7.98 (d, 1 Η, J = 7.2 Hz), 7.94 (d, 1H, J = 7.2 Hz), 6.10 (s, 1H), 6.05 (s, 1H) ), 5.84(d, 1H, J=2.1 Hz), 5.66(d, 1H, J=2.1 Hz), 4.93(m, 2H), 4.53~4.68(m, 2H), 3.97~4.20(m, 2H) , 3.47~3.60(m, 4H), 1.30~1.32(m, 6H), 1.08~1.17(m, 6H); ESI-MS m/z (M+23) 324.

Example 5

Using lb as a starting material, Compound IIb was obtained in the same manner as in Example 4.

Lib

Lib: Ή NMR (300 MHz, DMSO- ₆ ): δ 7.99 (d, 1H, J-7.2 Hz), 7,95 (d, 1H, J = 7.2 Hz), 6.06(s, 1H), 5.98(s , 1H), 5.81(d, 1H, J=2.1 Hz), 5.66(d, 1H, J=2.1 Hz), 4.97(m, 2H), 4.54~4.70(m, 2H), 3.97~4.17(m, 2H), 3.28(s, 3H), 3.18(s, 3H), 1.30~1.32 (m, 6H); ESI-MS m/z (Ml)' 287.

Example 6

Ila

6.4 g (37 mmol) of p-toluenesulfonic acid was dissolved in a mixture of 109 ml (652 mmol) of triethyl orthosilicate and 300 liters of tetrahydrofuran, and 80 g (326 mmol) of 5'-deoxy-5-fluoro- Cytosine was heated to reflux for 5 hours, and after the disappearance of the starting material, it was cooled to room temperature. The reaction mixture was diluted with methylene chloride (500 ml), washed twice with water (200 ml), washed with EtOAc EtOAc EtOAc. Gram, yield 97%.

Example 7

Lib

0.4 g (2.2 mmol) of p-toluenesulfonic acid was dissolved in 4.8 ml (40 mmol) of the original mixture of tris Yue Yue ester and 25 ml of tetrahydrofuran was added 4.9 g (20 mmol) ⁵ '- deoxy - fluoro - Cellular The glycoside was heated to reflux for 5 hours, and after the disappearance of the starting material, it was cooled to room temperature. The reaction mixture was diluted with 50 ml of methylene chloride, washed twice with water (20 mL), EtOAc (EtOAc) Gram, yield 90%.

Example 8

Ila Ilia

86 g (286 mmol) of Ila was dissolved in 400 ml of dichloromethane and 70 ml of pyridine, and 50 ml (345 mmol) of n-pentyl chloroantimonate was added to maintain the reaction temperature of 0. C. After stirring for 3 hours, the reaction mixture was washed once with 100 ml of water, and washed with 100 ml of brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The oil obtained is a mixture of a pair of isomers. Ilia: ^! H NMR (300 MHz, DMSO- ): 511.70 (brs, 1H), 10.57 (brs, IH), 8.27 (brs, 2H), 6.12 (s, IH), 6.07 (s, IH), 5.85 ( d, IH, J=3.3 Hz), 5.69(d, 1H, J=1.8 Hz), 4.98~5.03(m, 2H), 4.58-4.69 (m, 2H), 4.02-4.24 (m, 6H), 3.48 -3.63 (m, 4H), 1.56 (m, 4H), 1.23-1.37 (m, 4H), 1.08~1.18 (m, 14H), 0.83~0.91 (m, 6H); ESI-MS m/z (M +Na ⁺ ) 438.

Example 9

8.1 g (26.8 mmol) of Ila was dissolved in 40 ml of dichloromethane and 7 ml of pyridine, and 7.6 g (26.8 mmol) of N-pentoxy-neoxy succinimide was added to maintain the reaction temperature of 30. After stirring for 3 hours, the reaction mixture was washed with water (20 ml), brine (1 ml), and dried over anhydrous sodium sulfate.

Example 10

8.1 g (26.8 mmol) of Ila was dissolved in 40 ml of dichloromethane and 7 ml of pyridine, and 6.78 g (26.8 mmol) of nitrophenyl n-pentyl carbonate was added to maintain the reaction temperature of 30. After stirring for 3 hours, the reaction mixture was washed once with 20 ml of water, and then washed with 10 ml of saturated salt ice, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give an oil, Ilia, 8.5 g, yield 76 %.

Example 11

Lib Illb

2.83 g (10 mmol) of lib was dissolved in 30 liters of dichloromethane and 2.4 ml of pyridine, and 1.74 ml (12 mmol) of n-pentyl chloroantimonate was added to maintain the reaction temperature -10. After stirring for 3 hours, the reaction mixture was washed twice with 10 ml of water and dried over anhydrous sodium sulfate. The oil obtained is a mixture of a pair of isomers. Illb: 1H NMR (300 MHz, DMSO-): 510.57 (brs, 2H), 8.28 (brs, 2H), 6.08 (s, IH), 6.00 (s, IH), 5.82 (d, 1H, J = 3.3 Hz ), 5.70(d, IH, J=1.8 Hz), 4.01~5.06(m, 2H), 4.69 (dd, IH, J=6.3, 4.8 Hz), 4.59 (dd, IH, J=7.2, 4.2 Hz) , 4.23 (m, IH), 4.02-4.10 (m, 5H), 3.29 (s, 3H), 3.10 (s, 3H), 1.60 (m, 4H), 1.29-1.34 (m, 14H), 0.84~0.90 (m, 6H); ESI- MS m/z (M+Na ⁺ ) 424.

Example 12:

121 g of the crude Ilia oil prepared in Example 8 was dissolved in 500 ml of methanol and 160 ml of water, and 2N diluted hydrochloric acid was added to adjust the pH to 2 to 3. After the reaction of the starting material was completed, the temperature was lowered to 0. C, stirring, adding saturated sodium bicarbonate solution to adjust the pH to 7 ~ 9, 5 hours, add 400 ml of water, the reaction mixture is washed twice with 100 ml of isopropyl ether, water phase with 200 ml two The methyl chloride was extracted three times, and the organic phase was combined, washed with brine (100 ml), dried over anhydrous sodium sulfate, dried, filtered, and evaporated. The step yield was 72%. MR (300 MHz, DMSO- ₆ ): δ 8.03 (brs, IH), 5.67 (d, IH, J-4.8 Hz), 4.08 (m, 3H), 3.90 (m, IH), 3.68 (q, 1H, 1 = 6.0 Hz), 1.60 (m, 2H), 1.22-1.3 l (m, 7H), 0.88 (t, 3H, J = 6.4 Hz); ESI-MS m/z (M ⁺ ) 358.

Example 13:

Using illb as a raw material, in the same manner as in Example 12, capecitabine was obtained in a two-step yield of 69%.

Claims

Rights request

1. A pecitabine hydroxy derivative represented by the following formula III:

III

Among them, a hydrocarbon group having 1 to 4 carbon atoms is selected.

The capecitabine hydroxy derivative according to claim 1, wherein the Ri is an alkyl group having 1 to 4 carbon atoms.

The octopabine hydroxy derivative according to claim 2, which is a thiol group, an ethyl group, a propyl group or a butyl group.

4. A method for preparing a capecitabine hydroxy derivative according to any one of claims 1 to 3, wherein the preparation method is based on 5'-deoxy-5-fluoro-uridine Starting the raw materials, the steps are as follows:

I II III

In the presence of an acidic catalyst, 5'-deoxy-5-fluoro-uridine is condensed with ortho phthalate HC (OR ₃ to give a 5'-deoxy-5-fluoro-uridine derivative of formula I, Wherein the definition is as set forth in any one of claims 1-3; Then, in an aprotic solvent, the 5'-deoxy-5-fluoro-uridine derivative of the formula I is subjected to two substitution reactions with phosphorus oxychloride, an organic base and aqueous ammonia to obtain 5'- of the general formula II. Deoxy-5-fluoro-cytidine glycoside;

IV

The acylating reagent is subjected to an ugly reaction to obtain a capecitabine hydroxy derivative represented by the formula: wherein R is a leaving group and is a halogen, a nitrophenoxy group or a succinimide.

5, according to claim 4, wherein the method for preparing capecitabine, gemcitabine hydroxy derivative, characterized in that said 5'-deoxy-5-fluoro - uridine original Yue ester ΗΟ) used in the condensation reaction ₃ The solvent is toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, dichloroethane or a mixture thereof; the acidic catalyst is p-toluenesulfonic acid, zinc chloride, tin chloride or boron trifluoride; The temperature is -20. C~120. C; 5'-deoxy-5-fluoro-uridine and ortho phthalate HC (OR 3 molar ratio of 1: 1:1: 10;

In the two-substitution reaction of the 5'-deoxy-5-fluoro-uridine derivative of the formula I with a ruthenium oxide, an organic base and an aqueous ammonia, the aprotic solvent is acetonitrile, tetrahydrofuran, acetone. , hydrazine, hydrazine-dimethylformamide or a mixture thereof; the reaction temperature is -10. 030. (The 5'-deoxy-5-fluoro-cytidine derivative of the general formula II and the general formula IV

The acylation reaction of the acylating reagent, wherein the acylating reagent of the formula IV is selected from the following three types:

o. ο 0 ₂₂ ΝN ς,

.

CI \ CsH-ii-n

The aprotic solvent is dichlorodecane, acetonitrile, tetrahydrofuran, acetone, hydrazine, hydrazine-dimethylformamide or a mixture thereof; the reaction temperature is -10. C~50. C; The molar ratio of the 5'-deoxy-5-fluoro-cytidine derivative of the general formula II to the acylating reagent of the formula IV is 1:1 to 1:3.

6. A method for preparing a capecitabine hydroxy derivative according to any one of claims 1 to 3, wherein the preparation method is based on 5'-deoxy-5-fluoro-cytidine Starting the raw materials, the steps are as follows:

II III

In the presence of an acidic catalyst, 5'-deoxy-5-fluoro-cytidine is condensed with ortho phthalate HC (OR0 ₃ to give a 5'-deoxy-5-fluoro-cytidine derivative of the general formula II, Wherein the definition is as set forth in any one of claims 1-3;

IV

A pecitabine hydroxy derivative of the formula III is obtained wherein R is a leaving group and is a steroid, nitrophenoxy or succinimideoxy group.

7. A process for the preparation of a capecitabine hydroxy derivative according to claim 6, characterized in that the condensation reaction of the 5'-deoxy-5-fluoro-cytidine with the orthoformate HCOR The solvent used is toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichlorodecane, dichloroethane or a mixture thereof; the acidic catalyst is p-toluenesulfonic acid, zinc chloride, tin chloride or boron trifluoride; The reaction temperature is -20. 0120 °C; 5'-deoxy-5-fluoro-cytidine and orthophthalate HC OR^ molar ratio of 1 : 1 -1 : 10;

0

An acylation reaction of the 5'-deoxy-5-fluoro-cytidine derivative of the general formula II with an acylating reagent of the formula IV R-^^^^^^, wherein the acylating reagent of the formula IV is selected From the following three:

The aprotic solvent is dichlorodecane, acetonitrile, tetrahydrofuran, acetone, hydrazine, hydrazine-dimethyl phthalamide or a mixture thereof; the base used in the acylation reaction is carbonic acid 4, triethylamine or pyridin ¹ Pyridine; reaction temperature is -10. C~50. C; The molar ratio of the 5'-deoxy-5-fluoro-cytidine derivative of the general formula II to the acylating reagent of the formula IV is 1:1 to 1:3.

8. A 5'-deoxy-5-fluoro-uridine derivative represented by the following formula I,

I

Among them, a hydrocarbon group having 1 to 4 carbon atoms is selected.

The 5'-deoxy-5-fluoro-uridine derivative according to claim 8, wherein the ground is an alkyl group having 1 to 4 carbon atoms.

The 5'-deoxy-5-fluoro-uridine derivative according to claim 9, wherein the thiol group, ethyl group, propyl group or butyl group is used.

11. A 5'-deoxy-5-fluoro-cytidine derivative of the formula II:

II

It is selected from a hydrocarbon group having 1 to 4 carbon atoms.

The 5'-deoxy-5-fluoro-cytidine derivative according to claim 11, characterized in that it is an alkyl group having 1 to 4 carbon atoms.

The 5'-deoxy-5-fluoro-cytidine derivative according to claim 12, wherein the ^ is a mercapto group, an ethyl group, a propyl group or a butyl group.

The use of the capecitabine hydroxy derivative according to any one of claims 1 to 3, wherein the capecitabine hydroxy derivative is hydrolyzed to obtain capecitabine.

The use according to claim 14, wherein the solvent used in the hydrolysis reaction is decyl alcohol, ethanol, propanol, tetrahydrofuran, acetonitrile, disulfoxide, hydrazine, hydrazine-dimethyl phthalamide, acetone. , water or a mixture thereof; the hydrolysis reaction is carried out in the presence of hydrochloric acid, sulfuric acid, phosphoric acid or p-toluenesulfonic acid to control the pH of 1 to 6 to hydrolyze the capecitabine hydroxyl derivative, and then use sodium hydrogencarbonate, sodium carbonate The alkaline reagent of potassium carbonate, potassium hydrogencarbonate, sodium hydroxide or potassium hydroxide is adjusted to a pH of 7 to 11 to promote the reaction to completion.