WO2008144980A1

WO2008144980A1 - The preparation method and intermediates of capecitabine

Info

Publication number: WO2008144980A1
Application number: PCT/CN2007/070051
Authority: WO
Inventors: Xiangrui Jiang; Yang Ou; Jingshan Shen
Original assignee: Topharman Shanghai Co., Ltd.; Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority date: 2007-05-25
Filing date: 2007-05-25
Publication date: 2008-12-04
Also published as: CN101657462A; CN101657462B

Abstract

The present invention relates to the preparation method and intermediates of capecitabine. The present invention provides a new synthesis route for capecitabine, in which doxifluridine is used as the starting material and capecitabine is obtained through three steps of reaction. The present invention also provides the intermediates in the said synthesis route. The synthesis has short route, which can avoid producing stereoisomers. The method has a high yield, the technical process is easy to control and the quality of the products is stable.

Description

Preparation method of capecitabine and its intermediates

The invention relates to a process for preparing capecitabine and an intermediate thereof. Background technique

Capec i tabine 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. Enzymes associated with the metabolism of capecitabine are higher in tumor tissues than in normal tissues, giving them selective cytotoxicity against tumor cells. Its

The structure is as follows:

.

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

1. Docking with trifluoroacetofuranose and 5-fluorocytosine, then reacting with an acid chloride to give an acylated product, followed by hydrolysis to give capecitabine (Bioorganic & Medic ina Chemis s try 8, 2000, 1697-1706 )

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

3. Using pentyloxycarbonyl chloride as the acylating reagent, the hydroxy group and the amino group are subjected to acylation - followed by selective hydrolysis to give the final product (US005476932).

4. Using the already acylated 5-fluorocytosine as a raw material, the docking reaction and then

Final product (CN166089).

Capecitabine

5. Using ribose as a raw material, the final product is obtained by transformation (China; Wood 4^ Gentleman, · 15 , 2005 , 173 ).

Capecitabine Summary of the invention

The present invention provides a novel capecitabine synthesis route for preparing capecitabine from deoxy fluorouridine.

The technical solution of the present invention is as follows:

The present invention provides a compound, a deoxyfluorouridine derivative, as shown in formula (I):

(I) wherein ^ is selected from a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a benzene ring or a substituted benzene ring; and R ₂ may be selected from a hydrogen atom and containing 1 to 8 a linear or branched alkyl group of a carbon atom, a benzene ring or a substituted benzene ring.

The present invention also provides a process for preparing a deoxyfluorouridine derivative of the formula (I), which comprises a condensation reaction of deoxyfluorouridine with an aldehyde or a ketone in the presence of an acidic catalyst to obtain a formula (I). Oxyfluorouridine derivatives.

The present invention provides a compound, a deoxyfluorocytidine derivative, as shown in formula (II):

(Π), wherein ^ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring; and R ₂ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring.

The present invention also provides a method for preparing a deoxyfluorocytidine derivative represented by the formula (II), which is obtained by reacting a deoxyfluorouridine derivative represented by the formula (I) with phosphorus oxychloride, an organic alkali or ammonia water. (II) Deoxyfluorocytidine derivative shown. The present invention provides a deoxyfluorocytidine derivative, as shown by the formula (in):

(III) wherein, ^ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring; and R ₂ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring.

The present invention also provides a process for preparing a deoxyfluorocytidine derivative represented by the formula (in), which comprises reacting a deoxyfluorocytidine derivative represented by the formula (II) with a compound represented by the formula (IV) to obtain a formula ( III) Deoxyfluorocytidine derivative as shown.

(IV), R is a leaving group. Formula (IV)

The next three:

The present invention also provides a process for the preparation of capecitabine which is obtained by deamination of a hydroxy protecting group under acidic conditions with a deoxyfluorocytidine derivative of the formula (in) to give capecitabine.

The deoxyfluorocytidine derivative represented by the formula (III) is reacted with a compound represented by the formula (IV) by a deoxyfluorocytidine derivative represented by the formula (II) to obtain a deoxyfluoride cell represented by the formula (III). Glycoside derivatives.

The deoxyfluorocytidine derivative represented by the formula (II) is reacted with a phosphorus fluorouridine derivative represented by the formula (I), phosphorus oxychloride, an organic alkali or ammonia water to obtain a deoxyfluoride represented by the formula (II). Cytidine derivatives.

The deoxyfluorouridine derivative of the formula (I) is subjected to a condensation reaction of deoxy fluorouridine with an aldehyde or a ketone in the presence of an acidic catalyst to obtain a deoxyfluorouridine derivative of the formula (I). The specific steps of the above method are as follows:

III

The condensation reaction of deoxy fluorouridine with different aldehydes or ketones gives the deoxyfluorouridine derivative of formula (I), and then reacts with phosphorus oxychloride, organic alkali, and ammonia to obtain formula (II). The deoxyfluorocytidine derivative is acylated with an acylating reagent of the formula (IV) to obtain a deoxyfluorocytidine derivative of the formula (III), and finally the hydroxy protecting group is removed under acidic conditions. Capecitabine.

In the above reaction, the condensation reaction of deoxy fluorouridine with an aldehyde or a ketone may be carried out in a mixed solvent of toluene, benzene, acetone, tetrahydrofuran, dichloromethane or dichloroethane of an acidic catalyst or any ratio thereof. get on. The acidic catalyst may be selected from the group consisting of p-toluenesulfonic acid, zinc chloride, and tin chloride. The reaction temperature can be varied within a wide range, generally -2{rC - 120 ° C, preferably 80 ° C - 120 ° C, and the molar ratio of deoxy fluorouridine to aldehyde or ketone is 1: 1-1: 2.

The reaction of the deoxyfluorouridine derivative of the formula (I) with phosphorus oxychloride, an organic base, and aqueous ammonia can be carried out in a mixed solvent of acetonitrile or another water-miscible aprotic solvent. The reaction temperature is -io°c -

It is carried out at 30 ° C, preferably at -5 ° C to 20 ° C.

The deoxyfluorocytidine derivative represented by the formula (II) and the acylating reagent represented by the formula (IV) can be carried out in an acetonitrile or other aprotic solvent to which a basic catalyst is added. The basic catalyst can be The inorganic base or organic base may be specifically selected from the group consisting of potassium carbonate, triethylamine, and pyridine. The reaction temperature is -io°c-

50 ° C, preferably at 0 ° C -20 ° C. The molar ratio of the deoxyfluorocytidine derivative represented by the formula (II) to the acylating reagent represented by the formula (IV) is 1:1.1-1:3, preferably 1:1.1-1:2.

The deprotected group of the deoxyfluorocytidine derivative represented by the formula (III) is obtained by reacting capecitabine, and can be carried out in an aqueous solution of a protic acid, or in an alcohol solution of a protic acid or an ether solution. It can also be carried out in a solution of an aprotic acid. It is preferably carried out in an alcohol solution of a protic acid.

The technical effects achieved by the present invention are as follows:

The method uses the deoxy fluorouridine determined by the configuration as a raw material, and after three steps of reaction, capecitabine is obtained, and the synthetic route is short, and the formation of stereoisomers is avoided. It has been proved by experiments that the yield of the method is high, the process is easy to control, and the product quality is stable. Specific implementation method:

The invention is further illustrated by the following examples, which are merely used to illustrate the preferred embodiments of the invention, and are not intended to limit the invention. The technical solutions of the present invention described above are all technical solutions for achieving the object of the present invention. That is, the temperatures and reagents used in the following examples can be replaced with the corresponding temperatures and reagents described above to achieve the objects of the present invention.

0.26 g (1.5 mmol) of p-toluenesulfonic acid was dissolved in 20 ml of acetone, 3.69 g (15 匪ol) of deoxyfluorouridine was added, and the mixture was stirred at room temperature for 24 hours, and solid potassium carbonate was added to the reaction system to adjust the pH to 7. Filtration, the filtrate was concentrated to give a white solid, which was evaporated, evaporated, mjjjjjjjjjjjjjjjjj 89.2%. La: NMR (300 MHz, CDC1 ₃ ): δ 7.36 (d, 1H, J = 7.6 Hz), 5.67 (s, 1H), 4.67 (dd, 1H, J=8.0, 3.2 Hz), 4.50 (dd, 1H) , J=4.5, 3.6 Hz), 4.24 (m, 1H), 1.56 (s, 3H), 1.40 (d, 3H, J=6.3 Hz), 1.34 (s, 3H); ESI— MS m/z (Μ +Γ) 287.

0.2 g (1.511111101) of zinc chloride was dissolved in 201111 acetone, 3.69 g (15 mmol) of deoxyfluorouridine was added, and stirred at -20 ° C for 24 hours. Potassium carbonate was added to the reaction system to adjust the pH to 7, and filtered. The filtrate was concentrated to give a white solid. EtOAc was evaporated.

0.35 g (2 mmol) of p-toluenesulfonic acid was dissolved in 100 ml of toluene, 4.92 g (20 匪ol) of deoxyfluorouronium and 6.87 g (65.0 匪ol) of benzaldehyde were added and refluxed, stirred for 4 hours, cooled, filtered. The residue was 2.48 g of the material, the filtrate was concentrated, and the residue was crystallised from ethyl acetate and n-hexane to give solid ( lb) 2.80 g. Lb: NMR (300 MHz, CDC1 ₃ ): δ 9.17 (s, 1H), 7.32-7.50 (m, 6H), 6.09 (s, 1H), 5.74 (d, 1H, J=2.7 Hz), 4.96 (dd , 1H, J=3.0, 3.9 Hz), 4.69 (m, 1H), 4.30 (m, 1H), 1.47 (d, 3H, J=6.3 Hz); EI -MS m/z (Μ+Γ) 334.

0.2 g (1.2 mmol) of p-toluenesulfonic acid was dissolved in 40 ml of toluene, 3.0 g (12.2 匪ol) of deoxyfluorouronium and 2.01 g (14.3 匪ol) of m-chlorobenzaldehyde were added, refluxed, stirred for 4 hours, and cooled. The mixture was filtered, and the residue was crystallized from ethyl acetate (yield: EtOAc, EtOAc) Ic: 'HNMR (300 MHz, CDC1 ₃ ): δ 9.17 (s, 1H), 7.32-7.50 (m, 6H), 6.09 (s, 1H), 5.74 (d, 1H, J=2.7 Hz), 4.96 ( Dd, 1H, J=3.0, 3.9 Hz), 4.69 (m, 1H), 4.30 (m, 1H), 1.47 (d, 3H, J=6.3 Hz); EI -MS m/z (Μ+Γ) 368 .

0.2 g (1.2 mmol) of p-toluenesulfonic acid was dissolved in 40 acetonitrile, and 3.0 g (12.2 匪ol) of deoxyfluorouronium and 3.26 g (14.3 匪ol) of dimethoxydiphenylmethane were added, refluxed, and stirred. After 4 hours, it was cooled, filtered, and evaporated. Id: ^NMR (300 MHz, CDC1 ₃ ): δ 9.22 (brs, 1H), 7.31-7.52 (m, 6H), 5.82 (d, 1H, J = 2.1 Hz), 4.88 (dd, 1H, J=6.9 , 2.4 Hz), 4.55 (dd, 1H, J=6.6, 4.2 Hz), 4.42 (dd, 1H, J=6.6, 4.5 Hz), 1.42 (d, 3H, J=6.6 Hz); EI -MS m/ z (M+) 410. Example 6

Ma

3.83 g (13.4 mmol) of la was dissolved in 35 ml of anhydrous acetonitrile, 3.17 g (40.0 mmol) of pyridine and 4.88 g (40.0 mmol) of N,N-dimethylaminopyridine were added, and the mixture was cooled to 0 ° C and added dropwise to 6.14. Gram (40.0 匪ol) phosphorus oxychloride, stirred for 6 hours, the reaction solution was poured into 0 ° C ammonia water, stirred for 0.5 hours, liquid separation, the organic phase was washed with dichloromethane, the organic phase was combined, dried over anhydrous sodium sulfate The solvent was removed under reduced pressure to give crude (IIa), EtOAc. Ila: ^: H NMR (300 MHz, CDC1 ₃ ): δ 7.42 (d, 1H, J = 5.7 Hz), 5.57 (d, 1H, J=l.2 Hz), 4.93 (dd, 1H, J=6.6, 1.8 Hz), 4.49 (dd, 1H, J=6.6, 1.5 Hz), 4.27 (dd, 1H, J=6.3, 4.2 Hz), 1.55 (s, 3H), 1.38 (d, 1H, J=6.6 Hz) , 1.32 (s, 3H); EI-MS m/z (M ⁺ ) 285.

Example 7

3.83 g (13.4 mmol) la was dissolved in 35 ml of anhydrous acetonitrile, and 3.17 g (40.0 mmol) of pyridine and 4.88 g (40.0 mmol) of hydrazine, hydrazine-dimethylaminopyridine were added at 30 ° C, and 6.14 g was added dropwise. 40.0匪ol) Phosphorus oxychloride, stirred for 6 hours, the reaction solution was poured into 0 ° C ammonia water, stirred for 0.5 hours, liquid separation, the organic phase was washed with dichloromethane, the organic phase was combined, dried over anhydrous sodium sulfate, reduced The solvent was removed by pressure to give a crude (Ila).

Example 8-10:

Compounds IIb, lie and IId were obtained in the same manner as in Example 7 using Ib, Ic or Id as starting materials, respectively.

Lib: NMR (300 MHz, CDC1 ₃ ): δ 8.00 (d, 1H, J=8.6 Hz), 7.40-7.54 (m, 5H), 6.11 (s, 1H), 5.88 (d, 1H, J=4.4 Hz ), 4.94 (dd, 1H, J=8.8, 4.0 Hz), 4.69 (m, 1H), 4.20 (m, 1H), 1.36 (d, 3H, J=7.6 Hz); EI -MS m/z (M+ ) 333.

Lie: EI -MS m/z (M+) 367.

Lid: NMR (300 MHz, CDC1 ₃ ): δ 8.00 (d, 1H, J=8.6 Hz), 7.26-7.52 (m, 10H), 6.11 (s, 1H), 5.73 (d, 1H, J=2.4 Hz ), 4.96 (dd, 1H, J=6.8, 2.4 Hz), 4.59 (dd, 1H, J=6.6, 4.2 Hz), 4.46 (m, 1H), 1.42 (d, 3H, J=6.6 Hz). ESI - MS m/z (M+Na ⁺ ) 432.

Example 11

6.0 g of Ila was dissolved in 40 ml of acetonitrile, and 7.6 g (26.8 mmol) of N-pentyloxycarbonyloxysuccinimide and 3.7 g (26.8 匪ol) of potassium carbonate were added, stirred at room temperature for 24 hours, filtered, and decompressed. The solvent was removed, the residue was dissolved in methylene chloride, washed twice with EtOAc EtOAc EtOAc EtOAc EtOAc Gram, the yield in two steps is 64%. Ilia: NMR (300 MHz, CDC1 ₃ ): δ 12.05 (brs, 1H), 7.41 (d, 1H, J=4.8 Hz), 5.65 (s, 1H), 4.87 (d, 1H, J=5.4 Hz), 4.49 (dd, 1H, J=4.2, 6.3 Hz), 4.14-4.28 (m, 1H), 1.70 (m, 2H), 1.56 (s, 3H), 1.28— 1.42 (m, 11H, J=6.3 Hz) , 0.89 (t, 3H, J = 7.2 Hz); ESI- MS m/z (M+Na ⁺ ) 422.

Example 12 6.0 g of Ila was dissolved in 40 ml of acetonitrile, 6.78 g (26.8 mmol) of nitrophenyl n-pentyl carbonate and 3.7 g (26.8 ol) of potassium carbonate were added, and the mixture was stirred at room temperature for 24 hours, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed twice with 1N EtOAc EtOAc (EtOAc)EtOAc. The step yield was 62%.

Example 13

6.0 g of Ila was dissolved in 40 ml of acetonitrile, 4.02 g (26.8 mmol) of n-amyl chloroformate and 2.1 g (26.8 ol) of potassium carbonate were added, and the mixture was stirred at 0 ° C for 2 hours, the solvent was removed under reduced pressure, and the residue was dissolved. Dichloromethane, washed twice with 1 N hydrochloric acid, washed with brine and dried over anhydrous sodium sulfate. %.

Ila Ilia

Examples 14~16:

Compounds IIIb, IIIc and IIId were obtained in the same manner as in Example 11 using lib and lie as raw materials, respectively.

Illb: NMR (300 MHz, CDC1 ₃ ): δ 12.09 (brs, 1H), 7.42-7.58 (m, 6H), 6.13(s, 1H), 5.75 (d, 1H, J=2.7 Hz), 5.03 (m , 1H), 4.74 (m, 1H), 4.19-4.40 (m, 3H), 1.74 (m, 2H), 1.48 (d, 3H, J=8.4 Hz), 1.29— 1.43 (m, 5H, J=6.3 Hz), 0.90 (t, 3H, J = 7.2 Hz); ESI- MS m/z (M+Na ⁺ ) 470.

IIIc: NMR (300 MHz, CDC1 ₃ ): δ 12.05 (brs, 1H), 7.30-7.50 (m, 5H), 6.07 (s, 1H), 5.68 (m, 1H), 4.97—5.11 (m, 1H) , 4.66 (m, 1H), 4.17-4.44 (m, 3H) , 1.70 (m, 2H) , 1.48 (d, 3H, J=8.4 Hz), 1.20— 1.37 (m, 5H), 0.85 (t, 3H, J=7.2 Hz); ESI - MS m/z (M+Na ⁺ ) 504.

Hid: NMR (300 MHz, CDC1 ₃ ): δ 12.03 (brs, 1H), 7.31-7.51 (m, 11H), 5.80 (d, 1H, J = 2.1 Hz), 4.90 (m, 1H), 4.55 (dd , 1H, J=6.9, 4.2 Hz), 4.45 (dd, 1H, J=5.4, 4.8 Hz), 4.01-4.18 (m, 2H) , 1.72 (m, 2H) , 1.40 (d, 3H, J=8.4 Hz) , 1.25-1.37 (m, 5H, J = 6.3 Hz), 0.90 (t, 3H, J = 7.2 Hz).

1Mb lllc Mid

Example π:

Dissolve 1.3 g of Ilia in 10 ml of ethanol, cool to 0 °C, stir, slowly add 10 ml of HCl/ethanol solution, keep the reaction temperature at 0 °C, remove the solvent under reduced pressure after 4 hours, dissolve the residue. dichloromethane, washed with saturated aqueous NaHC0 _3, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 1.0 g product (capecitabine). NMR (300 MHz, d-DMSO): δ 8.03 (brs, 1H), 5.67 (d, 1H, J = 4.8 Hz), 4.08 (m, 3H), 3.90 (m, 1H), 3.68 (q, 1H, J = 6.0 Hz), 1.60 (m, 2H), 1.22-1.31 (m, 7H), 0.88 (t, 3H, J = 6.4 Hz); ESI-MS m/z (M+) 358.

Ilia Capicetabine

Example 18~20:

The capecitabine was obtained in the same manner as in Example 17 using IIIb, IIIc or Illd as the starting materials, respectively.

Claims

Rights request

A compound, a deoxyfluorouridine derivative, as shown in formula (I):

2. A process for the preparation of a deoxyfluorouridine derivative of the formula (I) according to claim 1, which comprises a condensation reaction of deoxyfluorouridine with an aldehyde or a ketone in the presence of an acidic catalyst to obtain a formula (I) Deoxyfluorouridine derivatives are shown.

3. A compound, deoxyfluorocytidine derivative, as shown in formula (II):

A process for producing a deoxyfluorocytidine derivative of the formula (II) according to claim 3, which comprises a deoxyfluorouridine derivative of the formula (I), phosphorus oxychloride, an organic base and an aqueous ammonia. The action gives a deoxyfluorocytidine derivative of the formula (II).

5. A compound, a deoxyfluorocytidine derivative, as shown in formula (III):

(III), wherein ^ may be selected from a hydrogen atom, an alkane: a ring or a substituted benzene ring; and R ₂ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring.

A process for producing a deoxyfluorocytidine derivative of the formula (III) according to claim 5, which comprises reacting a deoxyfluorocytidine derivative represented by the formula (II) with a compound represented by the formula (IV) Obtaining a deoxyfluorocytidine derivative represented by the formula (in);

(IV),

R is a leaving group.

The method according to claim 6, wherein the compound represented by the formula (IV) is preferably the following three types:

A method for producing capecitabine, which comprises deprotecting a deoxyfluorocytidine derivative represented by formula (III) under acidic conditions to obtain capecitabine.

The preparation method according to claim 8, wherein the deoxyfluorocytidine derivative represented by the formula (III) is a deoxyfluorocytidine derivative represented by the formula (II) and the formula (IV) The compound shown is obtained by reaction.

The preparation method according to claim 9, wherein the deoxyfluorocytidine derivative represented by the formula (II) is a deoxyfluorouridine derivative and a phosphorus oxychloride represented by the formula (I). Organic base

The preparation method according to claim 10, wherein the deoxyfluorouridine derivative represented by the formula (I) is subjected to condensation reaction of deoxy fluorouridine with an aldehyde or a ketone in the presence of an acidic catalyst. get.

The preparation method according to claim 11, wherein the condensation reaction of deoxy fluorouridine with an aldehyde or a ketone can be carried out by adding an acid catalyst of toluene, benzene, acetone, tetrahydrofuran, dichloromethane or dichloride. One of ethane or any ratio of it is carried out in a mixed solvent.

The method according to claim 2 or 12, wherein the acidic catalyst is selected from the group consisting of p-toluenesulfonic acid, zinc chloride, and tin chloride.

The preparation method according to claim 12, wherein the reaction temperature of the reaction is -20 ° C - 120 ° C:.

The preparation method according to claim 14, wherein the reaction has a reaction temperature of 80 ° C to 120 ° C.

The method according to claim 12, wherein the molar ratio of deoxy fluorouridine to aldehyde or ketone is 1:1-1:2.

The preparation method according to claim 10, wherein the reaction of the deoxyfluorouridine derivative represented by the formula (I) with phosphorus oxychloride, an organic alkali or ammonia water is miscible with acetonitrile or other water-soluble ones. The aprotic solvent is mixed in a solvent.

The preparation method according to claim 17, wherein the reaction temperature is from -10 ° C to 30 ° C.

The process according to claim 18, wherein the reaction temperature is from -5 ° C to 20 ° C.

The method according to claim 9, wherein the deoxyfluorocytidine derivative represented by the formula (II) and the acylating reagent represented by the formula (IV) are added to a basic catalyst of acetonitrile or the like. Performed in an aprotic solvent.

The production method according to claim 20, wherein the basic catalyst may be an inorganic base or an organic base.

The method according to claim 21, wherein the basic catalyst is selected from the group consisting of potassium carbonate, triethylamine, and pyridine.

The preparation method according to claim 22, wherein the reaction temperature of the reaction is _10 ° C _ 50 ° C.

The preparation method according to claim 23, wherein the reaction temperature of the reaction is 0 ° C -20 ° C:.

The preparation method according to claim 24, wherein the molar ratio of the deoxyfluorocytidine derivative represented by the formula (II) to the acylating reagent represented by the formula (IV) is 1:1.1-1:3. .

The method according to claim 25, wherein the molar ratio of the deoxyfluorocytidine derivative represented by the formula (II) to the acylating reagent represented by the formula (IV) is 1:1.1-1:2. .

The preparation method according to claim 8, wherein the deoxyfluorocytidine derivative represented by the formula (III) is deprotected to obtain a reaction of capecitabine, which can be in an aqueous solution of protonic acid. The progress may be carried out in an alcohol solution of a protic acid or in an ether solution, or in a solution of an aprotic acid.

The preparation method according to claim 27, wherein the deoxyfluorocytidine derivative represented by the formula (III) is deprotected to obtain a reaction of capecitabine in an alcohol solution of a protonic acid. get on.