A novel gemcitabine intermediate compound

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a new intermediate compound of gemcitabine. The new intermediate compound of gemcitabine is obtained by reacting alpha-cyanoacetamide, triethyl orthoacetate and N,N-dimethylformamide dimethyl acetal as starting materials, and the new intermediate is cyclized to obtain the key intermediate compound 3-cyano-4-methoxy-2(1H)-pyridinone of gemcitabine. In the application, alpha-cyanoacetamide is used as the starting material instead of the toxic malononitrile, so that the operation is safer, the production cost is reduced, the 3-cyano-4-methoxy-2(1H)-pyridinone obtained by the technology has high purity and yield, and is suitable for industrial amplification production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a novel intermediate compound of gimidazine. Background Technology

[0002] Gimeracil (CDHP), chemical name: 5-chloro-4-hydroxy-2(1H)-pyridone, CAS: 103766-25-2, is a component of tegafur, an oral antitumor drug marketed by Taiho Pharmaceutical Co., Ltd. in Japan in March 1999. As an antitumor potentiator in tegafur combination therapy, gimeracil inhibits the catabolism of 5-fluorouracil released from tegafur under the action of dihydropyrimidine dehydrogenase, helping to maintain effective concentrations of 5-fluorouracil in the blood and tumor tissue for extended periods, thus achieving efficacy similar to continuous intravenous infusion of 5-fluorouracil. It is also known as gemeracil or gimeracil. The chemical structural formula of gimeracil is:

[0003]

[0004] Numerous reports have been published regarding the synthesis of gimidazine. Most of these processes involve first synthesizing the key intermediate 3-cyano-4-methoxy-2(1H)-pyridone, followed by chlorination and hydrolysis to obtain gimidazine. For example, in Archiv. der. Pharmazie, 1985, 31:481-486, the starting materials are malononitrile, trimethyl orthoacetate, and N,N-dimethylformamide dimethyl acetal (DMF-DMA). First, 1,1-dicyano-2-methoxy-4-(N,N-dimethylamino)-1,3-butadiene is prepared via condensation. Then, 3-cyano-4-methoxy-2(1H)-pyridone is cyclized with 80% glacial acetic acid (by volume or mass fraction). Chlorination then forms 5-chloro-3-cyano-4-methoxy-2(1H)-pyridone, which is finally hydrolyzed to obtain gimidazine. The relevant reaction route is as follows:

[0005]

[0006] Therefore, the preparation of 3-cyano-4-methoxy-2(1H)-pyridone, a key intermediate, directly affects the production, market supply, and quality of this drug. In the aforementioned literature, the preparation methods for 3-cyano-4-methoxy-2(1H)-pyridone, except for the literature on the synthesis of the dihydropyrimidine dehydrogenase inhibitor gemerexilate (West China Pharmaceutical Journal, 2008, 23(3), 252-254), which separately isolates 2-(1-methoxyethylidene)malonitrile, all other literature uses malononitrile as the starting material in a one-pot process to obtain 1,1-dicyano-2-methoxy-4-(N,N-dimethylamino)-1,3-butadiene, followed by cyclization. However, the starting material malononitrile has high toxicity and low operational safety; furthermore, malononitrile is expensive, resulting in high production costs.

[0007] Given the aforementioned problems in the current preparation of 3-cyano-4-methoxy-2(1H)-pyridone, finding a method suitable for the industrial production of the key intermediate 3-cyano-4-methoxy-2(1H)-pyridone of gimidazine, which has mild reaction conditions, simple operation, high product yield and purity, and low production cost, remains a problem that needs to be solved. Summary of the Invention

[0008] To overcome the shortcomings of existing technologies and find a better method for preparing the key intermediate 3-cyano-4-methoxy-2(1H)-pyridone of gimidazine, the present invention aims to provide a new method for preparing 3-cyano-4-methoxy-2(1H)-pyridone. The target product obtained by this method has high purity and yield, and the reaction conditions are mild, the operation process is simple, and the production cost is lower.

[0009] The specific technical content of this invention is as follows:

[0010] The first aspect of this invention provides a novel intermediate compound of gimidazine, the structure of which is shown in Formula I-1:

[0011]

[0012] A second aspect of this invention provides a method for preparing a novel intermediate compound I-1 of gimbalimide:

[0013] At room temperature, compounds SM-1 and SM-2 were added to the reaction apparatus. The temperature was controlled at T1 until the reaction was complete. The reaction solution was then concentrated to dryness under reduced pressure. Compound SM-3 was then added, and the temperature was controlled at T2 until the reaction was complete. The reaction solution was then concentrated to dryness under reduced pressure to obtain I-1. The synthetic route is as follows:

[0014]

[0015] Preferably, the molar ratio of compounds SM-1, SM-2, and SM-3 is 1:1.0 to 1.8: 1.0 to 1.5, and more preferably 1:1.3:1.25.

[0016] Preferably, the reaction temperature T1 is 50-105℃, more preferably 65-70℃; T2 is 40-110℃, more preferably 50-55℃.

[0017] A third aspect of this invention provides a method for preparing the key intermediate 3-cyano-4-methoxy-2(1H)-pyridone from a novel intermediate compound I-1:

[0018] Compound I-1 was added to an organic solvent, and the reaction was carried out at temperature T3 until the reaction was complete. The reaction solution was then cooled to room temperature to allow crystals to precipitate. The resulting light yellow needle-like crystals were washed with water and dried to obtain the target product I. The synthetic route is as follows:

[0019]

[0020] Preferably, the organic solvent is one or a combination of 80% acetic acid solution and 80% formic acid solution, with 80% acetic acid solution being the most preferred.

[0021] Preferably, the reaction temperature T3 is 80–115°C.

[0022] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0023] 1. This invention provides a novel intermediate compound of gimidazine and a simple and efficient method for preparing the key intermediate of gimidazine, 3-cyano-4-methoxy-2(1H)-pyridone, using this novel intermediate. The entire synthetic route is short, the operation steps are simple, and the reaction yield is high.

[0024] 2. Using α-cyanoacetamide instead of malononitrile, which is more toxic, as the starting material makes the operation safer and reduces production costs.

[0025] 3. The 3-cyano-4-methoxy-2(1H)-pyridone obtained by this technology has high purity and yield, and is suitable for industrial-scale production. Detailed Implementation

[0026] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0027] The structural confirmation data of compound I-1 obtained in this invention are as follows:

[0028]

[0029] ESI-HRMS (m / z): 196.1053 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ: 8.28 (d, J = 12.2 Hz, 1H), 7.40 (s, 2H), 5.24 (d, J = 12.2 Hz, 1H), 3.81 (s, 3H), 2.84 (s, 3H); 13 C NMR (151MHz, CDCl3) δ174.86,168.35,160.37,115.89,89.68,85.46,59.73,40.52.

[0030] The structural confirmation data for compound I obtained in this invention are as follows:

[0031]

[0032] ESI-HRMS (m / z): 191.1508 [M+H] + 301.0934[2M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 12.13 (s, 1H), 7.79 (d, J = 7.8Hz, 1H), 6.35 (d, J = 7.8Hz, 1H), 3.98 (s, 3H); 13 C NMR (151MHz, DMSO-d6) δ: 173.50, 161.48, 142.13, 114.50, 93.70, 86.24, 57.55.

[0033] Synthesis of intermediate I-1

[0034] Example 1

[0035] At room temperature, α-cyanoacetamide (SM-1, 8.41 g, 0.10 mol) and triethyl orthoacetate (SM-2, 15.62 g, 0.13 mol) were added to the reaction apparatus. The temperature was controlled at 65–70 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure. N,N-dimethylformamide dimethyl acetal (SM-3, DMF-DMA, 14.90 g, 0.125 mol) was added, and the reaction was carried out at 50–55 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure to obtain compound I-1, with a yield of 98.6% and an HPLC purity of 99.87%.

[0036] Example 2

[0037] At room temperature, α-cyanoacetamide (SM-1, 8.41 g, 0.10 mol) and triethyl orthoacetate (SM-2, 14.82 g, 0.10 mol) were added to the reaction apparatus. The temperature was controlled at 50–55 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure. N,N-dimethylformamide dimethyl acetal (SM-3, DMF-DMA, 11.92 g, 0.10 mol) was added, and the reaction was carried out at 40–45 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure to obtain compound I-1, with a yield of 94.1% and an HPLC purity of 99.62%.

[0038] Example 3

[0039] At room temperature, α-cyanoacetamide (SM-1, 8.41 g, 0.10 mol) and triethyl orthoacetate (SM-2, 26.68 g, 0.18 mol) were added to the reaction apparatus. The temperature was controlled at 100–105 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure. N,N-dimethylformamide dimethyl acetal (SM-3, DMF-DMA, 17.87 g, 0.15 mol) was added, and the reaction was carried out at 105–110 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure to obtain compound I-1, with a yield of 93.6% and an HPLC purity of 99.55%.

[0040] Example 4

[0041] At room temperature, α-cyanoacetamide (SM-1, 8.41 g, 0.10 mol) and triethyl orthoacetate (SM-2, 29.64 g, 0.20 mol) were added to the reaction apparatus. The temperature was controlled at 105–110 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure. N,N-dimethylformamide dimethyl acetal (SM-3, DMF-DMA, 20.26 g, 0.17 mol) was added, and the reaction was carried out at 110–115 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure to obtain compound I-1, with a yield of 89.5% and an HPLC purity of 98.95%.

[0042] Synthesis of Compound I

[0043] Example 5

[0044] Compound I-1 (9.76 g, 0.05 mol) was added to 60 mL of 80% acetic acid solution at room temperature. The reaction was carried out at 110–115 °C. After the reaction was completed, the reaction solution was cooled to room temperature to crystallize, and light yellow needle-like crystals precipitated out. The crystals were filtered, and the resulting filter cake was washed with water and dried to obtain the target product compound I, with a yield of 98.3% and an HPLC purity of 99.92%.

[0045] Example 6

[0046] Compound I-1 (9.76 g, 0.05 mol) was added to 60 mL of 80% formic acid solution at room temperature. The reaction was carried out at 80–85 °C. After the reaction was completed, the reaction solution was cooled to room temperature to crystallize, and light yellow needle-like crystals precipitated out. The crystals were filtered, and the resulting filter cake was washed with water and dried to obtain the target product compound I, with a yield of 94.2% and an HPLC purity of 99.62%.

[0047] Example 7

[0048] Compound I-1 (9.76 g, 0.05 mol) was added to 60 mL of 80% acetic acid solution at room temperature. The reaction was carried out at 115–118 °C. After the reaction was completed, the reaction solution was cooled to room temperature to crystallize, and a light yellow needle-like crystalline solid precipitated out. The solid was filtered, and the resulting filter cake was washed with water and dried to obtain the target product compound I, with a yield of 89.6% and an HPLC purity of 98.92%.

Claims

1. A method for preparing a novel intermediate compound of gimidazine, characterized in that, The preparation method includes the following steps: At room temperature, 8.41 g of α-cyanoacetamide and 15.62 g of triethyl orthoacetate were added to the reaction apparatus. The temperature was controlled at 65-70°C. After the reaction was detected to be complete, the reaction solution was concentrated to dryness under reduced pressure. Then, 14.90 g of N,N-dimethylformamide dimethyl acetal was added, and the reaction was carried out at 50-55°C. After the reaction was detected to be complete, the reaction solution was concentrated to dryness under reduced pressure to obtain compound I-1. At room temperature, 9.76 g of compound I-1 was added to 60 mL of 80% acetic acid solution, and the reaction was carried out at 110~115℃. After the reaction was detected to be complete, the reaction solution was cooled to room temperature and crystallized, with light yellow needle-shaped crystals precipitating out. The solid was filtered, the filter cake was washed with water, and dried to obtain the target product compound I. The synthesis route is as follows: ； 。

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