Preparation method of capecitabine and intermediate thereof

Abstract

The invention relates to a preparation method of capecitabine and an intermediate thereof, in particular to a preparation method of a structure as shown in a formula IV and a method for further preparing capecitabine. 5-deoxy-D-ribose is taken as an initial raw material, and is sequentially subjected to six steps of reactions of 1-site hydroxymethylation, 2, 3-site hydroxyl THP protection, 1-site acetylation, glycosylation, N4-site acylation and deprotection to obtain capecitabine. The preparation method provided by the invention is a brand new technical route and is not reported in any literature and patent. According to the method, the yield of the product can be greatly improved, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis of drugs, in particular to a preparation method of capecitabine and intermediates thereof. BACKGROUND

[0002] Capecitabine is an oral chemotherapy drug developed by Roche, which is widely used in clinical practice. The trade name is Xeloda, which is a "prodrug" that is converted into 5-fluorouracil in the body and takes effect. It was first approved in the United States in 1998 for the treatment of breast cancer, and then the indications have been expanding. The structural formula of capecitabine is as follows:

[0003] There are many literatures and patents about the synthesis of capecitabine, mainly including the following several synthetic routes: Route one: (US20100130734A1)

[0004] This route uses 5-deoxy-D-ribose as the starting material, protects the 2,3-position hydroxyl group with acetonide, then protects the 1-position hydroxyl group with acetyl group, then reacts with N,O-di(trimethylsilyl) protected 5-fluorocytosine under the catalysis of tin tetrachloride, then reacts with n-pentyl chloroformate, and finally removes the protection to obtain capecitabine.

[0005] Route two: (Bioorganic & Medicinal Chemistry 8(2000):1697~1706)

[0006] This route uses triacetyl-5-deoxyribose to react with activated 5-fluorocytosine under the catalysis of tin tetrachloride, then reacts with n-pentyl chloroformate under the basic conditions provided by pyridine, and finally removes the protection group under basic conditions to obtain the target product capecitabine.

[0007] The above two routes have the following problems: (1) 5-fluorocytosine mother nucleus N-isomerization impurities are generated; (2) the proportion of C-1 position α isomer on the sugar ring is high. Therefore, it is urgent to find a new route which can reduce the generation of N-isomerization impurities and reduce the proportion of C-1 position α isomer on the sugar ring. SUMMARY

[0008] In order to solve the problems that the preparation method of capecitabine in the prior art generally generates α isomer and N-isomerization impurities, the purpose of the present application is to provide a method for effectively preparing high-purity capecitabine with high yield.

[0009] The first aspect of the present application provides a method for preparing a compound shown in formula IV, comprising the following steps: , Step (2): reacting the compound shown in formula II with 3,4-dihydro-2H-pyran in the presence of a catalyst Cu(NO3)2, acetic acid and an organic solvent to generate a compound shown in formula III; Step (3): reacting the compound shown in formula III with acetic anhydride in the presence of a catalyst to generate a compound shown in formula IV.

[0010] In some embodiments of the present application, the organic solvent in step (2) is selected from any one or a combination of tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methyl pyrrolidone.

[0011] In some embodiments of the present application, the catalyst in step (3) is selected from one of concentrated sulfuric acid, p-toluenesulfonic acid or acetic acid; the molar ratio of the compound shown in formula III to the catalyst is 1:0.2-1:0.4; the catalyst is added dropwise and the reaction temperature is maintained at -30°C-10°C.

[0012] In some embodiments of the present application, the compound shown in formula II is prepared by the following method: , Step (1): reacting the compound shown in formula I with a strong acid methanol solution in anhydrous methanol solution to generate a compound shown in formula II.

[0013] In some embodiments of the present application, the strong acid in step (1) is one of hydrochloric acid or sulfuric acid.

[0014] The second aspect of the present application provides a method for preparing capecitabine, comprising the following steps: , Step (2): reacting the compound shown in formula II with 3,4-dihydro-2H-pyran in the presence of a catalyst Cu(NO3)2, acetic acid and an organic solvent to generate a compound shown in formula III; Step (3): reacting the compound shown in formula III with acetic anhydride in the presence of a catalyst to generate a compound shown in formula IV; Step (4): reacting the compound shown in formula IV with a compound shown in formula VI in the presence of an organic solvent and TMSOTf under nitrogen protection to generate a compound shown in formula VII; Step (5): reacting the compound shown in formula VII with n-pentyl chloroformate in the presence of a base and dichloromethane to generate a compound shown in formula VIII; Step (6): the compound of formula VIII is subjected to hydrolysis reaction under the action of Lewis acid to generate capecitabine.

[0015] In some embodiments of the present application, the organic solvent in step (2) is selected from any one or a combination of tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methyl pyrrolidone; the catalyst in step (3) is selected from one of concentrated sulfuric acid, p-toluenesulfonic acid or acetic acid; the feeding molar ratio of the compound of formula III to the catalyst is 1:0.2-1:0.4; the catalyst is added dropwise and the reaction temperature is maintained at -30-10°C.

[0016] In some embodiments of the present application, the organic solvent in step (4) is selected from any one or a combination of dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, 1,2-dichloroethane or N-methyl pyrrolidone.

[0017] In some embodiments of the present application, the base in step (5) is selected from any one or a combination of triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine.

[0018] In some embodiments of the present application, the Lewis acid in step (6) is selected from any one or a combination of AlCl3, FeCl3, BF3or ZnCl2.

[0019] The beneficial technical effects of the present application are as follows: (1) The route of the present application is completely new and has not been reported in any literature / patent. The reaction has few impurities, high yield, and the intermediates and products are easy to purify. No column chromatography is needed, and only simple recrystallization operation is needed to obtain products with high purity. The capecitabine prepared meets the pharmacopoeia standard.

[0020] (2) The 2,3 positions of ribose are protected by THP groups, which effectively avoids the generation of α isomer and N-isomer during the synthesis of intermediate VII. DETAILED DESCRIPTION EMBODIMENT

[0021] Synthesis of compound II

[0022] Into a reaction flask, compound I (26.8 g, 200 mmol) and 268 mL of anhydrous methanol were added successively, and stirred at room temperature until the solid was completely dissolved, and the system was a yellowish transparent solution. 90 mL of 1% HC1-methanol solution was added dropwise through a constant pressure funnel, and after the addition was completed, it was stirred for 1 hour. After TLC detection, the reaction was completed, 10 mL of pyridine was added, and stirring was continued for 30 minutes. Filtration, the filtrate was evaporated to dryness under reduced pressure, and an oily compound II (29.6 g, 199.6 mmol) was obtained, with a yield of 99%.

[0023] Synthesis of compound III

[0024] Into a reaction flask, compound II (29.6 g, 199.6 mmol), 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and 300 mL of acetonitrile were weighed, and Cu(NO3)2 (1.50 g, 8 mmol) and acetic acid (9.6 g, 160 mmol) were added successively, and reacted at room temperature for 1 h, and 100 mL of saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the solvent was removed under reduced pressure, and extracted with 100 mL*3 of ethyl acetate, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, and then slurried with methanol to obtain compound III (60.0 g, 190 mmol) with a yield of 95%.

[0025] Synthesis of compound IV

[0026] Compound III (60.0 g, 190 mmol) was dissolved in 600 mL of chloroform, and acetic anhydride (14.8 g, 247 mmol) was added, and the system was cooled to -20°C, and then concentrated sulfuric acid (5.6 g, 57 mmol) was added dropwise. After the addition was completed, the system was maintained at -20°C for reaction, and TLC was used for monitoring. After the reaction was completed, it was quickly stirred and poured into 300 mL of ice water, and extracted with chloroform, and then separated by standing, and the organic phase was neutralized to neutral with saturated aqueous NaHCO3, and then washed with saturated brine, and the organic phase was dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure, and the residue was cooled to 0-5°C, and then 600 mL of purified water was added dropwise under rapid stirring, and stirred for 3 hours for crystallization, and then filtered, washed with ether, and dried under reduced pressure to obtain compound IV (62.8 g, 182 mmol) with a yield of 96%.

[0027] Synthesis of compound VI

[0028] Into a reaction flask, add 5-fluorocytosine (27.5 g, 213 mmol), 120 mL of toluene, HMDS (69.0 g, 426 mmol), trimethylchlorosilane (2.3 g, 21.3 mmol), stir and warm to 100 °C, react for 3-4 hours, after the reaction is completed, remove the solvent under reduced pressure to dryness, to obtain compound VI (58.5 g, 213 mmol), with a yield of 100%.

[0029] Synthesis of compound VII

[0030] Into a reaction flask, add compound VI (58.5 g, 213 mmol) and compound IV (62.8 g, 182 mmol), then add 200 mL of acetonitrile, while stirring, maintain the reaction system at 0-10 °C, drop a solution of TMSOTf (36.4 g, 164 mmol) and 50 mL of acetonitrile, monitor the reaction progress by TLC; after the reaction is completed, add 200 mL of dichloromethane to the reaction solution, wash with 300 mL of water for 2 times; adjust the pH to 7.5 with a saturated sodium bicarbonate solution, stand and separate; wash the organic phase with 300 mL of saturated brine; dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, recrystallize with ethyl acetate-n-hexane to obtain compound VII (72.2 g, 174 mmol), with a yield of 96%, a purity of 99.8% detected by HPLC, no α configuration detected, and no N-isomer detected.

[0031] Synthesis of compound VIII

[0032] Into a reaction flask, add compound VII (72.2 g, 174 mmol), 250 mL of dichloromethane, pyridine (24.7 g, 313 mmol), stir and cool to -15-0 °C, drop a mixture of n-pentyl chloroformate (31.5 g, 209 mmol) and 50 mL of dichloromethane, after the drop is completed, maintain the reaction, until the reaction is completed as monitored by TLC, add 200 mL of water, stir for 20 min, then stand and separate; separate the organic phase, wash with water (200 mL*2), back extract the aqueous phase with dichloromethane (200 mL*2), combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, to obtain compound VIII (91.7 g, 174 mmol), with a yield of 100%.

[0033] Synthesis of capecitabine

[0034] To a reaction flask was added compound VIII (91.7 g, 174 mmol), AICI3(0.23 g, 1.74 mmol) and 200 mL of acetonitrile, methanol (18.0 g, 562 mmol) was added slowly drop wise at room temperature, the reaction was stirred for 2 h, the solvent was removed under reduced pressure, 200 mL of water and 200 mL of dichloromethane was added and extracted, the organic layer was collected and the solvent was removed under reduced pressure, the resulting solid was slurried with diethyl ether to get capecitabine (59.3 g, 165 mmol) with 95% yield, HPLC purity: 99.96%.

[0035] Comparative example 1 (repeat of patent US20100130734A1) Preparation of 5'-deoxy-2',3'-0-isopropylidene-5-fluorocytidine To a reaction flask was added 5-fluorocytosine (2.00 g), hexamethyldisilazane (2.85 ml), trimethylchlorosilane (0.35 ml) and toluene (20 ml) under nitrogen atmosphere, the reaction mixture was heated to 110-120 °C and then stirred for 30 min. The toluene was removed under reduced pressure. Cooled to 25-30 °C, dichloromethane (35 mL) was added. Cooled to 0-5 °C, a solution of 2,3-0-isopropylidene-3-0-acetyl-5-deoxy-D-ribose (3.4 g) in dichloromethane (7 mL) was added slowly drop wise. Tin chloride (2.1 ml) was added to the above reaction suspension at 0-5 °C. Warmed to 25-30 °C, stirred for 2 h. TLC monitored the completion of the reaction. Sodium bicarbonate (5.5 g) and water (2.1 ml) was added to the above reaction solution. Stirred for 2 h at 25-30 °C, the suspension was filtered through a bed of celite, the filtrate was washed with 5% aqueous sodium bicarbonate (35 ml). Dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, purified by column chromatography to get 1.4 g of the title compound. Yield 32%, HPLC purity 95.1%, alpha isomer 0.13%, N-isomerized impurity 4%.

[0036] It is apparent that the above examples are merely illustrative in nature and are not intended to limit the embodiments in any way. Upon the basis of the foregoing disclosure those skilled in the art will be readily able to devise variations and modifications without departing from the scope of the present disclosure. All of the embodiments are intended to be within the scope of the present disclosure. Accordingly, the disclosure is not to be restricted except in the spirit of the claims which follow.

Claims

1. A process for the preparation of a compound of formula IV ###0001### IV characterized in that, Comprising the following steps: ， Step (2): the compound of formula II reacts with 3,4-dihydro-2H-pyran in the presence of a catalyst Cu(NO3)2, acetic acid and an organic solvent to form a compound of formula III; Step (3): the compound of formula III reacts with acetic anhydride in the presence of a catalyst to form a compound of formula IV.

2. The method of claim 1, wherein the compound of formula IV is prepared by the method comprising: ###0002### IV The organic solvent in step (2) is selected from any one or a combination of tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methyl pyrrolidone.

3. The method of claim 1, wherein the compound of Formula IV is prepared by the method comprising: ###0002### Formula IV The catalyst in step (3) is selected from one of concentrated sulfuric acid, p-toluenesulfonic acid, acetic acid; the molar ratio of the compound of formula III to the catalyst is 1:0.2-1:0.4; the catalyst is added dropwise and the reaction temperature is maintained at -30°C to 10°C.

4. The method of claim 1, wherein the compound of Formula IV is prepared by the method comprising: ###0002### Formula IV The compound of formula II is prepared by the following method: ， Step (1): the compound of formula I reacts with a strong acid methanol solution in anhydrous methanol solution to form a compound of formula II.

5. The method of claim 4, wherein the compound of formula IV is prepared by the process comprising: ###00006### IV The strong acid in step (1) is one of hydrochloric acid or sulfuric acid.

6. A process for the preparation of capecitabine, characterized in that, Comprising the following steps: ， Step (2): the compound of formula II reacts with 3,4-dihydro-2H-pyran in the presence of a catalyst Cu(NO3)2, acetic acid and an organic solvent to form a compound of formula III; Step (3): the compound of formula III reacts with acetic anhydride in the presence of a catalyst to form a compound of formula IV; Step (4): the compound of formula IV reacts with the compound of formula VI in the presence of an organic solvent and TMSOTf under nitrogen protection to form a compound of formula VII; Step (5): the compound of formula VII reacts with n-pentyl chloroformate in the presence of a base and dichloromethane to form a compound of formula VIII; Step (6): the compound of formula VIII undergoes hydrolysis in the presence of a Lewis acid to form capecitabine.

7. The method for preparing capecitabine according to claim 6, characterized in that: The organic solvent in step (2) is selected from any one or a combination of tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or N-methyl pyrrolidone; The catalyst in step (3) is selected from one of concentrated sulfuric acid, p-toluenesulfonic acid, acetic acid; the molar ratio of the compound of formula III to the catalyst is 1:0.2-1:0.4; the catalyst is added dropwise and the reaction temperature is maintained at -30°C to 10°C.

8. The process for the preparation of capecitabine according to claim 6, characterized in that, The organic solvent in step (4) is selected from any one or a combination of dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, toluene, 1,2-dichloroethane, N-methyl pyrrolidone.

9. The process for the preparation of capecitabine according to claim 6, characterized in that, The base in step (5) is selected from any one or a combination of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine.

10. The process for the preparation of capecitabine according to claim 6, characterized in that, The Lewis acid in step (6) is selected from any one or a combination of AlCl3, FeCl3, BF3, ZnCl2.

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