A preparation method of trifluridine intermediate

Abstract

The present application relates to a method for preparing a trifluridine intermediate, specifically disclosing a method for preparing a compound of formula I. The method can prepare a compound of formula I with high yield and high purity, and can control the content of dimer impurities at a very low level.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a trifluridine intermediate. Background Art

[0002] TAS-102 is a novel oral nucleoside anti-tumor combination drug developed by Taiho Pharmaceutical Co., Ltd. in Japan for the treatment of advanced metastatic colorectal cancer. TAS-102 contains trifluridine (FTD) and tipiracil hydrochloride (TPI) in a molar ratio of 1.0:0.5. The structural formula is as follows:

[0003]

[0004] Trifluridine, whose chemical name is 2'-deoxy-5-(trifluoromethyl)uridine, is a thymidylate synthase (TS) inhibitor that is incorporated into DNA in the form of triphosphate, thereby destroying DNA to achieve anti-tumor effects.

[0005] The key intermediate involved in the preparation process of trifluridine is 1-chloro-2-deoxy-3,5-di-O-p-chlorobenzoyl-D-ribose (Formula I), the structure of which is shown below.

[0006]

[0007] Studies have found that during the preparation and storage process of the compound of Formula I, a dimer impurity (Formula II) is easily generated. This impurity remains in the key intermediate (Formula I) and will further affect the quality of the trifluridine API product. Therefore, during the preparation process of the compound of Formula I, the content of the dimer impurity (Formula II) needs to be strictly controlled to effectively prevent the generation of the dimer impurity.

[0008] At present, the preparation method of the compound of formula I disclosed in the prior art mainly adopts the following synthetic route:

[0009]

[0010] For example, the method described in Chinese Patent No. 03116591.5 is as follows: 20 to 24 parts by weight of acetic acid are added to the reaction mixture of Formula III, 12 parts by weight of dry hydrogen chloride are introduced, the mixture is stirred at 30° C. for 2 to 4 hours, the mixture is cooled to 0 to 5° C., filtered, and the filter cake is vacuum dried at 40 to 55° C. to obtain the compound of Formula I.

[0011] This method uses 20 to 24 weight percent acetic acid and 12 weight percent hydrogen chloride, producing a large amount of waste acid. Furthermore, studies have found that the intermediate compound of formula I prepared using this method contains an impurity content of formula II exceeding 1.5%, which affects the quality of the subsequent final product.

[0012] To address the above issues, it is necessary to explore a new method for preparing the compound of formula I, which can effectively reduce the production of the dimer impurity shown in formula II while ensuring high yield, thereby ensuring product quality. Summary of the Invention

[0013] In view of this, the main object of the present invention is to provide a method for preparing a trifluridine intermediate compound of formula I. By designing and optimizing the synthesis conditions, especially by studying the reaction solvent, a high-yield and high-purity compound of formula I is prepared, and the content of the dimer impurity represented by formula II is controlled at a very low level, which is beneficial to the preparation and quality control of subsequent products.

[0014] The object of the present invention is to provide a method for preparing a compound of formula I, comprising the following steps:

[0015]

[0016] in:

[0017] The aprotic solvent is controlled at a certain temperature, and the compound of formula IV is added, and then a mixed solution of acetyl chloride / hydrogen chloride / acetic acid is added. The reaction is stirred under controlled temperature, filtered, and the filter cake is vacuum dried to obtain the compound of formula I.

[0018] In some embodiments, in the method for preparing the compound of formula I provided by the present invention, the aprotic solvent is selected from n-heptane, cyclohexane, acetone, ethyl acetate, n-hexane, methyl tert-butyl ether and methyl ethyl ketone; preferably, the aprotic solvent is selected from n-heptane, cyclohexane, acetone and ethyl acetate; more preferably, n-heptane and cyclohexane.

[0019] In some embodiments, in the method for preparing the compound of formula I provided by the present invention, the amount of the aprotic solvent added is 1 to 4 times the mass of the compound of formula IV.

[0020] In some embodiments, in the preparation method of the compound of formula I provided by the present invention, in the acetyl chloride / hydrogen chloride / acetic acid mixed solution, the amount of acetyl chloride used is 0.1-0.3 parts, the amount of hydrogen chloride used is 0.2-0.5 parts, and the amount of acetic acid used is 1-2 parts, based on the mass of the compound of formula IV.

[0021] In some embodiments, in the preparation method of the compound of formula I provided by the present invention, in the acetyl chloride / hydrogen chloride / acetic acid mixed solution, based on the mass of the compound of formula IV, the amount of acetyl chloride used is 0.2 parts, the amount of hydrogen chloride used is 0.30-0.39 parts, and the amount of acetic acid used is 1.68 parts.

[0022] In some embodiments, in the method for preparing the compound of formula I provided by the present invention, the temperature of the aprotic solvent is controlled at 10-20°C.

[0023] In some embodiments, in the method for preparing the compound of formula I provided by the present invention, the stirring reaction temperature is controlled at 0-30°C; preferably controlled at 10-20°C.

[0024] In some embodiments, in the method for preparing the compound of formula I provided by the present invention, the vacuum drying temperature is 10-35°C.

[0025] The technical solution provided by the present invention has the following beneficial effects:

[0026] (1) By optimizing the synthesis conditions, especially the research on reaction solvents, the use of alkyd acid and hydrogen chloride was greatly reduced, and the amount of waste acid generated was significantly reduced, which is beneficial to reducing costs and environmental pollution;

[0027] (2) The preparation method provided in this application has a high yield and high purity of the product, and in particular, it can control the dimer impurity content to a low level, thereby ensuring product quality;

[0028] (3) The reaction steps are simple and the conditions are mild, which is very suitable for large-scale industrial production. DETAILED DESCRIPTION

[0029] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0030] instrument

[0031] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H. 13 C NMR) or mass spectrometry (MS).

[0032] 1 H. 13 C NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (instrument model: BRUKER AVANCE III HD-400 NMR instrument); the solvent was CDCl3-d, and the temperature was 294.8 K.

[0033] LC-MS detection was performed using an Agilent 6120B Ms liquid chromatography-single quadrupole magnetic mass spectrometer, with ionization modes: positive ion mode, negative ion mode, ESI ionization source, and a scan range of 50 m / z to 2000 m / z.

[0034] The purity of the compound prepared in each example was determined by high performance liquid chromatography (HPLC-UV), the detector was an ultraviolet (UV) detector, and the chromatographic column was a C18 reverse phase column (4.6*250 mm, 3.5 μm).

[0035] Example 1: Preparation of compound of formula I

[0036]

[0037] To a 50L reactor, add 8.6kg of n-heptane and control the internal temperature at 10-20°C. Add 2.8kg of the compound of Formula IV to the reactor. After addition, control the internal temperature at 10-20°C and stir for 5-10 minutes. Add a mixed solution of 0.56kg of acetyl chloride / 0.90kg of hydrogen chloride / 4.70kg of acetic acid. After addition, control the internal temperature at 10-20°C and stir for 2-2.5 hours. Centrifuge the reaction solution to remove the solvent and rinse with 1.4kg of n-heptane. Dry the resulting solid in a vacuum drying oven (10-35°C) to obtain 2.7kg of the compound of Formula I, with a yield of 98.5%. HPLC analysis of the resulting sample revealed a purity of 99.1%, including 0.14% of the compound of Formula II.

[0038] 1 H-NMR(400MHz, CDCl3)δ:8.02-7.96(m,2H),7.96-7.93(m,2H),7.46-7.41(m,4H),6.48( d,1H,J=4.9Hz), 5.54(dd,1H), 4.86-4.85(m,1H), 4.70-4.58(m,2H), 2.89-2.73(m,2H).

[0039] Example 2: Preparation of compound of formula I

[0040] To a reaction flask, add 430 g of cyclohexane, control the internal temperature at 10-20°C, add 140 g of the compound of Formula IV, and stir for 5-10 minutes. Then, add a mixed solution of 28 g of acetyl chloride, 45 g of hydrogen chloride, and 235 g of acetic acid. After the addition, control the internal temperature of the reaction solution at 10-20°C and stir for 2-2.5 hours. The reaction solution is filtered and rinsed with 70.0 g of cyclohexane. The resulting solid is dried in a vacuum drying oven (10-35°C) to obtain 131.2 g of the compound of Formula I, with a yield of 95.8%. HPLC analysis shows a purity of 99.2% and a content of the compound of Formula II of 0.10%.

[0041] Example 3: Preparation of compound of formula I

[0042] Add 30g of acetone to the reaction flask, control the internal temperature at 10-20°C, add 10g of the compound of Formula IV, and stir for 5-10 minutes. Then add a mixed solution of 2g of acetyl chloride / 3.2g of hydrogen chloride / 16.8g of acetic acid. After the addition is complete, control the internal temperature of the reaction solution at 20°C and stir for 5 hours. The reaction solution is filtered and rinsed with 5.0g of acetone. The resulting solid is dried in a vacuum drying oven (10-35°C) to obtain 7.09g of the compound of Formula I, with a yield of 72.5%. HPLC analysis shows the sample purity is 97.0%, and the content of the compound of Formula II is 1.18%.

[0043] Example 4: Preparation of compound of formula I

[0044] To the reaction flask, add 30g of ethyl acetate, control the internal temperature at 10-20°C, add 10g of the compound of Formula IV, and stir for 5-10 minutes. Then, add a mixed solution of 2g of acetyl chloride / 3.2g of hydrogen chloride / 16.8g of acetic acid. After the addition, control the internal temperature of the reaction solution at 20°C and stir for 5 hours. The reaction solution is filtered and rinsed with 5.0g of ethyl acetate. The resulting solid is dried in a vacuum drying oven (10-35°C) to obtain 6.72g of the compound of Formula I, with a yield of 68.7%. HPLC analysis shows that the sample is 96.1% pure, and the content of the compound of Formula II is 1.02%.

[0045] Comparative Example 1: Preparation of Compound of Formula I

[0046] To the reaction flask, 10 g of the compound of formula IV and 240 g of acetic acid were added, 120 g of dry hydrogen chloride was introduced, and the mixture was stirred at 30 ° C for 2 to 4 h. The temperature was lowered to 0 to 5 ° C, filtered, and the filter cake was dried under vacuum at 40 to 55 ° C to obtain the compound of formula I with a yield of 86.2%. The sample purity was 96.3% after high performance liquid chromatography, and the content of the compound of formula II was 2.1%.

[0047] Comparative Example 2: Preparation of Compound of Formula I

[0048] To the reaction flask, 10 g of the compound of formula IV, 56 mL of toluene, and 5 ml of acetyl chloride were added, cooled to 5 ° C, 50.0 g of hydrogen chloride was added, and the temperature was maintained below 15 ° C. After the addition, the mixture was stirred at 5 ° C until the reaction was complete, filtered, washed with 10 ml of toluene and 5 ml of n-hexane, and the filter cake was dried under vacuum at 35-40 ° C to obtain the compound of formula I with a yield of 88.5%. The sample purity was 97.2% and the content of the compound of formula II was 1.2% as determined by high performance liquid chromatography.

[0049] The above description is only a preferred embodiment of the present invention and does not limit the patent scope of the present invention. All equivalent structural transformations made by using the present invention specification under the inventive concept of the present invention, or direct / indirect application in other related technical fields are included in the patent protection scope of the present invention.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: ， in: The aprotic solvent is controlled at a certain temperature, and the compound of formula IV is added, and then a mixed solution of acetyl chloride, hydrogen chloride and acetic acid is added. The temperature is controlled and stirred to react, and the filter cake is vacuum dried to obtain the compound of formula I; the aprotic solvent is selected from n-heptane and cyclohexane.

2. The preparation method according to claim 1, wherein the amount of the aprotic solvent added is 1 to 4 times the mass of the compound of formula IV.

3. The preparation method according to any one of claims 1 or 2, wherein In the mixed solution of acetyl chloride, hydrogen chloride and acetic acid, based on the mass of the compound of formula IV, the amount of acetyl chloride is 0.1 to 0.3 parts, the amount of hydrogen chloride is 0.2 to 0.5 parts, and the amount of acetic acid is 1 to 2 parts.

4. The preparation method according to any one of claims 1 or 2, wherein In the mixed solution of acetyl chloride, hydrogen chloride and acetic acid, based on the mass of the compound of formula IV, the amount of acetyl chloride used is 0.2 parts, the amount of hydrogen chloride used is 0.30 to 0.39 parts, and the amount of acetic acid used is 1.68 parts.

5. The preparation method according to any one of claims 1 or 2, wherein The temperature of the aprotic solvent is controlled at 10 to 20°C.

6. The preparation method according to claim 3, wherein The temperature of the aprotic solvent is controlled at 10 to 20°C.

7. The preparation method according to claim 4, wherein The temperature of the aprotic solvent is controlled at 10 to 20°C.

8. The preparation method according to any one of claims 1 or 2, wherein The stirring reaction temperature is controlled at 0 to 30°C.

9. The preparation method according to claim 3, wherein The stirring reaction temperature is controlled at 0 to 30°C.

10. The preparation method according to claim 4, wherein The stirring reaction temperature is controlled at 0 to 30°C.

11. The preparation method according to claim 5, wherein The stirring reaction temperature is controlled at 0 to 30°C.

12. The preparation method according to any one of claims 6 or 7, wherein The stirring reaction temperature is controlled at 0 to 30°C.

13. The preparation method according to claim 8, wherein The stirring reaction temperature is controlled at 10 to 20°C.

14. The preparation method according to any one of claims 9, 10 or 11, wherein The stirring reaction temperature is controlled at 10 to 20°C.

15. The preparation method according to claim 12, wherein The stirring reaction temperature is controlled at 10 to 20°C.

16. The preparation method according to any one of claims 1 or 2, wherein The vacuum drying temperature is 10 to 35°C.

17. The preparation method according to claim 3, wherein The vacuum drying temperature is 10 to 35°C.

18. The preparation method according to claim 4, wherein The vacuum drying temperature is 10 to 35°C.

19. The preparation method according to claim 5, wherein The vacuum drying temperature is 10 to 35°C.

20. The preparation method according to any one of claims 6 or 7, wherein The vacuum drying temperature is 10 to 35°C.

21. The preparation method according to claim 8, wherein The vacuum drying temperature is 10 to 35°C.

22. The preparation method according to any one of claims 9, 10, 11, 13 or 15, wherein The vacuum drying temperature is 10 to 35°C.

23. The preparation method according to claim 12, wherein The vacuum drying temperature is 10 to 35°C.

24. The preparation method according to claim 14, wherein The vacuum drying temperature is 10 to 35°C.

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