Method for synthesizing capecitabine intermediate

Abstract

The invention discloses a method for synthesizing a capecitabine intermediate, which is characterized in that the capecitabine intermediate is synthesized from 5-flucytosine. According to the method, trifluoromethanesulfonic acid or a mixed catalytic system containing trifluoromethanesulfonic acid is adopted as a key glycosylation reaction catalyst, a target product is obtained with high yield and high purity, use of a strong equivalent Lewis acid reagent in a traditional synthesis route is avoided, heavy metal residues are avoided, post-treatment steps are simplified, and the method is suitable for industrial production. The method meets the requirements of green chemical development and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for synthesizing a capecitabine intermediate. Background Art

[0002] Capecitabine (Compound A), chemically known as 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, is a novel 5-fluorouracil prodrug developed by Hoffmann-LaRoche in Switzerland and first marketed in Switzerland in 1998. It was approved for marketing in my country in October 2000 under the trade name Xeloda. It is an antimetabolite fluoropyrimidine deoxynucleoside carbamate drug that is converted into 5-fluorouracil (5-FU) in vivo, inhibiting cell division and interfering with RNA and protein synthesis. It is indicated for the further treatment of advanced primary or metastatic breast cancer that has failed paclitaxel and chemotherapy regimens including anthracyclines. It is primarily used for the treatment of advanced primary or metastatic breast cancer, rectal cancer, colon cancer, and gastric cancer. It is widely used clinically.

[0003]

[0004] Given capecitabine's wide range of anticancer applications and its promising therapeutic effects, the development of novel synthetic methods for capecitabine has been a research hotspot in recent years. The synthesis of its key intermediate, 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-D-cytidine (Compound B), is a key research focus. Currently, the main reported synthetic method for this key intermediate involves starting with 5-fluorocytosine (Compound 1) and 1,2,3-triacetoxy-5-deoxy-D-ribose (Compound 4). Compound 1 is first protected with trimethylsilyl chloride (TMSCl) or hexamethyldisilazane (HMDS). The resulting intermediate is then glycosylated with Compound 4 in the presence of a Lewis acid.

[0005]

[0006] For example, patent No. CN 102212095 B, CN 101845070 B, CN 102977170 B, CN 103570781 B respectively report the conversion achieved using tin tetrachloride. Shanghai Collinsburg Pharmaceutical Technology Co., Ltd. reports the conversion achieved using zinc chloride as a catalyst. Patent document CN 103288905 A reports the reaction achieved using trimethylsilyl trifluoromethanesulfonic acid (TMSOTf) as an equivalent reagent. In addition, there are also reports using other types of Lewis acids such as BF3-E2O, TiCl4, AlCl3 etc. to achieve the reaction. In the current production process of capecitabine bulk drug, the reaction mainly uses equivalent tin tetrachloride. The reagent is highly toxic, easily causes heavy metal pollution and residue, and does not meet green chemistry and environmental protection requirements. In addition, amphoteric oxides are inevitably generated in the post-processing process, resulting in the extraction process accompanied by more serious emulsification, cumbersome operation, time-consuming, and causing the yield of product to be low. When zinc chloride or aluminum chloride is used as a condensing agent, zinc hydroxide or aluminum hydroxide colloids are also produced, which is not conducive to post-processing. Patent document CN 103288905 A uses trimethylsilyltrifluoromethanesulfonic acid (TMSOTf) as a condensing agent, but it is expensive and needs to be used in equivalent amounts, which is not conducive to industrial production. Therefore, finding a green and environmentally friendly catalyst that can reduce the amount of condensing agent used and simplify the post-processing process to meet the needs of industrial production is of great significance for the synthesis of this intermediate. Summary of the Invention

[0007] In order to overcome the shortcomings of the prior art, including the high toxicity of tin tetrachloride, the large amount of use, the complicated post-processing, the high cost, and the heavy metal pollution, the present invention develops a new method for synthesizing a capecitabine intermediate that is more environmentally friendly and has a cost advantage. Starting from 5-fluorocytosine, trifluoromethanesulfonic acid or a mixed catalytic system containing trifluoromethanesulfonic acid is used as a catalyst for the key glycosidation reaction, and the target product is obtained with high yield and high purity. The use of an equivalent strong Lewis acid reagent in the traditional process synthesis route is avoided, heavy metal residues are avoided, and the post-processing steps are greatly simplified. The method meets the requirements of green chemistry development and is suitable for industrial production.

[0008] The present invention proposes a new method for synthesizing capecitabine intermediates. Compared with existing reported methods (such as patent CN103570781B), all use 5-fluorocytosine as a raw material and first perform a silicon-protected treatment on 5-fluorocytosine. The new strategy of the present invention is to use trifluoromethanesulfonic acid or trifluoromethanesulfonic anhydride, which is cheaper and more readily available, as a catalyst to achieve an efficient glycosylation reaction of silicon-protected 5-fluorocytosine with 1,2,3-tri-O-substituted-5-deoxy-β-D-ribofuranose. This new strategy abandons the use of reagents such as trimethylsilyltrifluoromethanesulfonic acid or strong Lewis acids such as tin tetrachloride and zinc dichloride. There are no reports of using such catalysts for this glycosylation reaction in relevant literature and patent documents.

[0009] The present invention provides a method for synthesizing a capecitabine intermediate. 5-Fluorocytosine is used as a raw material, which, after undergoing silicon-protection, undergoes a glycosylation reaction with 1,2,3-tri-O-substituted-5-deoxy-β-D-ribofuranose using trifluoromethanesulfonic acid or a mixed system containing trifluoromethanesulfonic acid as a catalyst to obtain the target product.

[0010] In the present invention, the reaction scheme is as follows:

[0011]

[0012] Wherein, the R substituent in the 1,2,3-tri-O-substituted-5-deoxy-β-D-ribofuranose is one or more of acetyl (Ac), benzoyl (Bz), benzyl (Bn), etc., or the O substituent at position 1 is any one of the above three, and the substituents at positions 2 and 3 are ketal;

[0013] Preferably, the 1,2,3-tri-O-substituted-5-deoxy-β-D-ribofuranose is 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose.

[0014] The catalyst used in the glycosidation reaction is an equivalent or catalytic amount of trifluoromethanesulfonic acid or a mixed system containing trifluoromethanesulfonic acid, including: trifluoromethanesulfonic acid (TfOH), trifluoromethanesulfonic anhydride (Tf2O), trimethylsilyl trifluoromethanesulfonate / trifluoromethanesulfonic acid (TMSOTf / TfOH), trimethylchlorosilane / trifluoromethanesulfonic acid (TMSCl / TfOH), trimethylsilyl trifluoromethanesulfonate / trifluoromethanesulfonic anhydride (TMSOTf / Tf2O), trimethylchlorosilane / trifluoromethanesulfonic anhydride (TMSCl / Tf2O), etc. in any proportion; preferably, it is trifluoromethanesulfonic acid.

[0015] The molar ratio of the 1,2,3-tri-O-substituted-5-deoxy-β-D-ribofuranose, the intermediate 2, and the catalyst is (0.9-1.2): (1.0-1.3): (0.05-1).

[0016] The solvent used in the glycosidation reaction is one or more of chloroform, acetonitrile, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, etc.; preferably, acetonitrile.

[0017] The temperature used for the glycosidation reaction is 20°C to 120°C; preferably, 60°C.

[0018] The glycosidation reaction time is 10 hours to 24 hours; preferably, 16 hours.

[0019] The base used for adjusting the pH in the post-glycosidation reaction treatment is one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, etc., preferably a mixed base of sodium carbonate and sodium bicarbonate in a ratio of 1:1.

[0020] The solvent used for crystallization in the post-glycosidation treatment is one or more of ethyl acetate, petroleum ether, methyl tert-butyl ether, isopropyl ether, isopropyl alcohol, etc., preferably petroleum ether and ethyl acetate.

[0021] The yield of the reaction is 90% to 95%.

[0022] The present invention has the beneficial effect of using a catalytic amount of trifluoromethanesulfonic acid as a catalyst for the glycosidation reaction to efficiently synthesize a capecitabine intermediate. This overcomes the shortcomings of tin tetrachloride, such as high toxicity, large usage amounts, complex post-processing, high costs, and heavy metal pollution, and meets the requirements of green chemistry development. DETAILED DESCRIPTION

[0023] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is further described in detail below in conjunction with preferred embodiments. It should be noted that the embodiments described are only some embodiments of the present invention, not all embodiments, and the preferred embodiments described below should not be regarded as limiting the present invention. The scope of protection of the present invention should be based on the scope defined by the claims. For those skilled in the art, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as within the scope of protection of the present invention.

[0024] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention, its application, or use. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0025] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not limiting. Therefore, other examples of the exemplary embodiments may have different values.

[0026] The present invention provides a novel method for synthesizing a capecitabine intermediate starting from 5-fluorocytosine. By utilizing trifluoromethanesulfonic acid or a mixed catalytic system containing trifluoromethanesulfonic acid as a catalyst for the key glycosidation reaction, the method provides the target product in high yield and purity, avoiding the use of equivalent strong Lewis acid reagents used in traditional synthetic routes, preventing heavy metal residues, and simplifying post-processing steps. This method meets the requirements of green chemistry development and is suitable for industrial production.

[0027] Embodiment one:

[0028] The material 15-fluorocytosine (15 g, 0.1163 mol) and HMDS (hexamethyldisilazane) (20.7 g, 0.1279 mol) were dissolved in toluene (130 g), and then methanesulfonic acid (559 mg, 5.815 mmol) was added. Under nitrogen protection, the mixture was heated to reflux at 115 ° C for 3 h; the toluene was then dried to obtain a white intermediate 2. Under nitrogen protection, the intermediate 2 was dissolved in ACN (acetonitrile) (120 g), the temperature was lowered by 5 ° C, and compound 4 (1,2,3-triacetoxy-5-( ... -deoxy-β-D-ribofuranose) (28.3 g, 0.1047 mol), then TfOH (trifluoromethanesulfonic acid) was added dropwise, the temperature was raised to 80°C, stirred for 12 h, and then TLC (thin layer chromatography) was monitored. There was no raw material 4, and the acetonitrile was then spin-dried, the pH was adjusted to about 8 with NaHCO3 (aq.), and then extracted with DCM (dichloromethane) (300 mLx3). The organic phases were combined, washed with saturated brine, dried, and spin-dried; then slurried with methyl tert-butyl ether to obtain 31.5 g of a white solid with a yield of 91.5%.

[0029] 1 H NMR (400MHz, CDCl3) δ7.39 (d, J = 5.9Hz, 1H), 6.02 (s, 1H), 5.52 (br, 1H), 5.30 ( s,1H),4.98(s,1H),4.24(s,1H),2.09(d,J=4.8Hz,6H),1.45(d,J=6.3Hz,3H).

[0030] Embodiment 2:

[0031] The material 15-fluorocytosine (15 g, 0.1163 mol) and HMDS (20.7 g, 0.1279 mol) were dissolved in toluene (130 g), and then methanesulfonic acid (559 mg, 5.815 mmol) was added. Under nitrogen protection, the mixture was heated to reflux at 115 ° C for 3 h; the toluene was then dried to obtain a white intermediate 2. Under nitrogen protection, the intermediate 2 was dissolved in ACN (120 g), the temperature was lowered by 5 ° C, and compound 41,2,3-triacetoxy-5-deoxy-β-D-furanose (28.3 g, 0.1047 mol) was added. Then TfOH / TMSCl was added dropwise, the temperature was raised to 70 ° C, stirred for 24 h, and then TLC was monitored to show that there was no raw material 4. The acetonitrile was then dried and the pH was adjusted to about 8 with NaHCO3 (aq.), and then washed with DCM (300 mL x 40). 3) The organic phases were combined, washed with saturated brine, dried, and spin-dried; the mixture was then slurried with methyl tert-butyl ether to obtain 31.03 g of a white solid with a yield of 90.2%.

[0032] Example 3:

[0033] The material 15-fluorocytosine (15 g, 0.1163 mol) and HMDS (20.7 g, 0.1279 mol) were dissolved in toluene (130 g), and then methanesulfonic acid (559 mg, 5.815 mmol) was added. Under nitrogen protection, the mixture was heated to reflux at 115 ° C for 3 h; the toluene was then dried to obtain a white intermediate 2. Under nitrogen protection, the intermediate 2 was dissolved in ACN (120 g), the temperature was lowered by 5 ° C, and compound 41,2,3-triacetoxy-5-deoxy-β-D-furanose (28.3 g, 0.1047 mol) was added. Then TfOH / TMSOTf was added dropwise, the temperature was raised to 90 ° C, stirred for 16 h, and then TLC was monitored to show that there was no raw material 4. The acetonitrile was then dried and the pH was adjusted to about 8 with NaHCO3 (aq.), and then washed with DCM (300 mL x 4). 3) The organic phases were combined, washed with saturated brine, dried, and spin-dried; the mixture was then slurried with methyl tert-butyl ether to obtain 31.38 g of a white solid with a yield of 91.2%.

[0034] Example 4:

[0035] The material 15-fluorocytosine (15 g, 0.1163 mol) and HMDS (20.7 g, 0.1279 mol) were dissolved in toluene (130 g), and then methanesulfonic acid (559 mg, 5.815 mmol) was added. Under nitrogen protection, the mixture was heated to reflux at 115 ° C for 3 h; the toluene was then dried to obtain a white intermediate 2. Under nitrogen protection, the intermediate 2 was dissolved in ACN (120 g), the temperature was lowered by 5 ° C, and compound 41,2,3-triacetoxy-5-deoxy-β-D-furanose (28.3 g, 0.1047 mol) was added. Then TMSOTf / Tf2O was added dropwise, the temperature was raised to 50 ° C, and stirred for 10 h. After TLC monitoring, there was no raw material 4. The acetonitrile was then dried and the pH was adjusted to about 8 with NaHCO3 (aq.), and then washed with DCM (300 mL x 4). 3) The organic phases were combined, washed with saturated brine, dried, and spin-dried; the mixture was then slurried with methyl tert-butyl ether to obtain 31.23 g of a white solid with a yield of 90.8%.

[0036] Embodiment 5:

[0037] The material 15-fluorocytosine (15 g, 0.1163 mol) and HMDS (20.7 g, 0.1279 mol) were dissolved in toluene (130 g), and then methanesulfonic acid (559 mg, 5.815 mmol) was added. Under nitrogen protection, the mixture was heated to reflux at 115 ° C for 3 h; the toluene was then dried to obtain a white intermediate 2. Under nitrogen protection, the intermediate 2 was dissolved in ACN (120 g), the temperature was lowered by 5 ° C, and compound 41,2,3-triacetoxy-5-deoxy-β-D-furanose (28.3 g, 0.1047 mol) was added. Then Tf2O was added dropwise, the temperature was raised to 100 ° C, and stirred for 14 h. After TLC monitoring, there was no raw material 4. The acetonitrile was then dried and the pH was adjusted to about 8 with NaHCO3 (aq.), and then DCM (300 mL x 4) was used. 3) The organic phases were combined, washed with saturated brine, dried, and spin-dried; the mixture was then slurried with methyl tert-butyl ether to obtain 31.43 g of a white solid with a yield of 91.4%.

[0038] Example 6:

[0039] The material 15-fluorocytosine (15 g, 0.1163 mol) and HMDS (20.7 g, 0.1279 mol) were dissolved in toluene (130 g), and then methanesulfonic acid (559 mg, 5.815 mmol) was added. Under nitrogen protection, the mixture was heated to reflux at 115 ° C for 3 h; the toluene was then dried to obtain a white intermediate 2. Under nitrogen protection, the intermediate 2 was dissolved in ACN (120 g), the temperature was lowered by 5 ° C, and compound 41, 2,3-tri-O-substituted-5-deoxy-β-D-furanose (28.3 g, 0.1047 mol) was added. Then TMSCl / Tf2O was added dropwise, the temperature was raised to 100 ° C, stirred for 14 h, and then TLC was monitored. There was no raw material 4. The acetonitrile was then dried and the pH was adjusted to about 8 with NaHCO3 (aq.), and then DCM (300 mL x 400 mL) was used. 3) The organic phases were combined, washed with saturated brine, dried, and spin-dried; the mixture was then slurried with methyl tert-butyl ether to obtain 30.96 g of a white solid with a yield of 90.0%.

[0040] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0041] As used in the present invention, the term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other aspects.

[0042] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art, simple technical modifications or equivalent substitutions of the present invention by those skilled in the art are all included in the present invention and are protected by the appended claims.

Claims

1. A method for synthesizing a capecitabine intermediate, characterized in that: 5-Fluorocytosine is used as the raw material. After silicon-protection, trifluoromethanesulfonic acid or a mixed system containing trifluoromethanesulfonic acid is used as a catalyst to undergo glycosylation reaction with 1,2,3-tri-O-substituted-5-deoxy-β-D-ribofuranose to obtain the target product. The reaction scheme is as follows:

2. The method according to claim 1, characterized in that The catalyst includes a combination of trifluoromethanesulfonic acid TfOH, trifluoromethanesulfonic anhydride Tf2O, trimethylsilyl trifluoromethanesulfonic acid / trifluoromethanesulfonic acid TMSOTf / TfOH, trimethylchlorosilane / trifluoromethanesulfonic acid TMSCl / TfOH, trimethylsilyl trifluoromethanesulfonic acid / trifluoromethanesulfonic anhydride TMSOTf / Tf2O, and trimethylchlorosilane / trifluoromethanesulfonic anhydride TMSCl / Tf2O in any proportion.

3. The method according to claim 1, characterized in that The R substituent in the 1,2,3-tri-O-substituted-5-deoxy-β-D-ribofuranose is acetyl, benzoyl, or benzyl, or the O substituent at position 1 is any one of the above three, and the substituents at positions 2 and 3 are ketal.

4. The method according to claim 1, wherein The solvent used in the glycosidation reaction is one or more of chloroform, acetonitrile, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, tetrahydrofuran, and 1,4-dioxane.

5. The method according to claim 1, wherein The temperature of the glycosidation reaction is 20°C to 120°C.

6. The method according to claim 1, characterized in that The glycosidation reaction time is 10 hours to 24 hours.

7. The method according to claim 1, characterized in that The molar ratio of the 1,2,3-tri-O-substituted-5-deoxy-β-D-ribofuranose, the intermediate 2, and the catalyst is (0.9-1.2): (1.0-1.3): (0.05-1).

8. The method according to claim 1, characterized in that The method further includes a post-treatment step after the glycosidation reaction, wherein the inorganic base used for adjusting the pH in the post-treatment step is one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, and sodium hydroxide.

9. The method according to claim 8, characterized in that The solvent used for crystallization in the post-treatment step is one or more of ethyl acetate, petroleum ether, methyl tert-butyl ether, isopropyl ether, and isopropyl alcohol.

10. Use of the method according to any one of claims 1 to 9 in drug synthesis, green chemistry, industrial production, pesticide synthesis, and material synthesis.

Images