A gemcitabine intermediate compound and a preparation method thereof

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a gemigim intermediate compound and a preparation method thereof. The gemigim new intermediate compound is obtained by reacting alpha-cyanoacetamide, triethyl orthoacetate and triethyl orthoformate as starting materials. The new intermediate is cyclized to obtain a gemigim key intermediate compound 3-cyano-4-methoxy-2(1H)-pyridinone. The new intermediate synthesis method provided by the application is simple, triethyl orthoformate is used as a 'one-carbon unit' donor, the reagent only produces ethanol in the cyclization process, the use of DMF-DMA can be effectively avoided, and then the generation of dimethylamine gas or its acetate salt is avoided, so that the reaction operation is safer and more environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a gimbalimide intermediate compound and its preparation method. Background Technology

[0002] Gimeracil (CDHP), chemical name: 5-chloro-4-hydroxy-2(1H)-pyridone, is a component of tegafur, an oral antitumor drug launched by Taiho Pharmaceutical Co., Ltd. in Japan in March 1999. Gimeracil is a reversible competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), which can effectively inhibit DPD in tumor tissue, thereby slowing down the degradation rate of 5-fluorouracil, the active metabolite of tegafur, another component of tegafur. This maintains the concentration of 5-fluorouracil in plasma and tumor tissue for a longer period, prolonging the duration of action of 5-fluorouracil and thus enhancing its antitumor activity. Therefore, the combined use of 5-chloro-2,4-dihydroxypyridine and tegafur can significantly improve the efficacy of the drug. The chemical structural formula of gimeracil is as follows:

[0003]

[0004] The most widely studied synthesis of gimidazine in China is based on the literature Archiv. der. Pharmazie, 1985, 31:481-486. It uses malononitrile, trimethyl orthoacetate, and N,N-dimethylformamide dimethyl acetal (DMF-DMA) as starting materials. First, 1,1-dicyano-2-methoxy-4-(N,N-dimethylamino)-1,3-butadiene is prepared via condensation reaction. Then, 3-cyano-4-methoxy-2(1H)-pyridone is cyclized with 80% glacial acetic acid (volume fraction or mass fraction) to obtain 3-cyano-4-methoxy-2(1H)-pyridone. This is then chlorinated to form 5-chloro-3-cyano-4-methoxy-2(1H)-pyridone, and finally hydrolyzed to obtain gimidazine. In addition, Japanese Patent Application Publication No. 5-78324, CN106316934A, CN112110854A and literature Heterocycles. 1993, 36(1) 145-148, Synthesis of Gimoster. Journal of Shenyang Pharmaceutical University, 2005, 22(6), 420-422, Synthesis of 5-chloro-2,4-dihydroxypyridine. China Medical Guide, 2007, 4(20), 14-15, Dihydropyrimidine Synthesis of the dehydrogenase inhibitor Gemeracil. *West China Journal of Pharmaceutical Sciences*, 2008, 23(3), 252-254; Synthesis of 5-chloro-4-hydroxy-2-(1H)pyridone. *Chemical Reagents*, 2008, 30(12), 939-940; Preparation of Gemeracil and its key intermediates. *Qilu Pharmaceutical Affairs*, 2012, 31(3), 132-133. All of these preparations use the starting materials or key intermediates of this route. The relevant reaction routes are as follows:

[0005]

[0006] As shown above, 3-cyano-4-methoxy-2(1H)-pyridone can be used as a key intermediate in the preparation of gimidazine; therefore, 3-cyano-4-methoxy-2(1H)-pyridone directly affects the production, market supply, and quality of this drug. The structural formulas of the relevant compounds are as follows:

[0007]

[0008] In the aforementioned literature, the preparation methods for 3-cyano-4-methoxy-2(1H)-pyridinone, except for the literature "Synthesis of the dihydropyrimidine dehydrogenase inhibitor Gemeracil" (West China Journal of Pharmaceutical Sciences, 2008, 23(3), 252-254), which separately prepared 2-(1-methoxyethylidene)malonitrile, all other literature used malononitrile as the starting material to prepare 1,1-dicyano-2-methoxy-4-(N,N-dimethylamino)-1,3-butadiene in a "one-pot method" and then cyclized it. However, the cyclization process generates dimethylamine gas with an amine odor and a boiling point of only 9°C, which is toxic and poses a significant environmental hazard. Furthermore, the dimethylamine gas will further react with the solvent acetic acid to form salts and precipitate, resulting in low purity of the product. Further washing, pulping, desalting, and purification are required, making the operation cumbersome. In addition, the starting material malononitrile is highly toxic, resulting in low operational safety. Moreover, malononitrile is expensive, leading to high production costs.

[0009] 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

[0010] 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, this invention provides a new gimidazine intermediate compound and a method for preparing 3-cyano-4-methoxy-2(1H)-pyridone using this new intermediate. 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.

[0011] The specific technical content of this invention is as follows:

[0012] The first aspect of this invention provides a novel intermediate compound of gimidazine, the structure of which is shown in Formula I-1:

[0013]

[0014] A second aspect of this invention provides a method for preparing compound I-1:

[0015] 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:

[0016]

[0017] 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 1:1.3:1.2.

[0018] Preferably, the reaction temperature T1 is 50–100°C, more preferably 65–70°C.

[0019] Preferably, the reaction temperature T2 is 70–100°C, more preferably 80–85°C.

[0020] The present invention provides a method for preparing the key intermediate 3-cyano-4-methoxy-2(1H)-pyridone from compound I-1:

[0021] At room temperature, compound I-1 was added to an organic solvent. After the material was stirred evenly, alkali was added to a certain pH range. The temperature was controlled at T3 until the reaction was completed. The reaction solution was then cooled, and the pH was adjusted to a certain range with acid. A light yellow needle-like crystalline solid precipitated out. After stirring and crystallization, the solid was filtered, the filter cake was washed with water, and dried to obtain the target product I. The synthetic route is as follows:

[0022]

[0023] Preferably, the organic solvent is selected from one or a combination of methanol, ethanol, isopropanol, and tert-butanol, with ethanol being particularly preferred.

[0024] Preferably, the mass-to-volume ratio of compound I-1 to the reaction solvent is 1:5 to 10, with mass expressed in g and volume expressed in mL.

[0025] Preferably, the alkali includes an inorganic alkali or an organic alkali, wherein the inorganic alkali includes, but is not limited to, one or a combination of sodium hydroxide, potassium hydroxide, and barium hydroxide, and the inorganic alkali can be an alkali or an aqueous solution thereof; the organic alkali includes, but is not limited to, one or a combination of sodium methoxide, sodium ethoxide, sodium isopropoxide, and sodium tert-butoxide, wherein sodium hydroxide is particularly preferred.

[0026] Preferably, the pH value obtained after adding alkali is adjusted to 12-14.

[0027] Preferably, the reaction temperature T3 is 60–85°C.

[0028] Preferably, the acid used to adjust the pH is selected from one or a combination of formic acid, acetic acid, hydrochloric acid, and hydrobromic acid, with hydrochloric acid being particularly preferred.

[0029] Preferably, the pH value is adjusted to 6-7 after adding acid.

[0030] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0031] 1. A novel gimidazine intermediate compound is provided, along with a simple and efficient method for preparing the key gimidazine intermediate 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.

[0032] 2. Using α-cyanoacetamide instead of malononitrile, which is more toxic, as the starting material makes the operation safer and reduces production costs.

[0033] 3. Triethyl orthoformate is used as a "one-carbon unit" donor. This reagent only produces ethanol during the cyclization process, which can effectively avoid the use of DMF-DMA, and thus avoid the generation of dimethylamine gas or its acetate, making the reaction operation safer and more environmentally friendly.

[0034] 4. 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

[0035] 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.

[0036] The structure of compound I-1 obtained in this invention has been confirmed:

[0037]

[0038] ESI-HRMS (m / z): 197.0846 [M+H] + ; 1H NMR (600MHz, CDCl3) δ: 7.40 (s, 2H), 6.93 (d, J = 11.6Hz, 1H), 5.63 (d, J = 11.6Hz, 1H), 4.44 (q, J = 7.3Hz, 2H), 3.78 (s, 3H), 1.47 (t, J = 7.3Hz, 3H); 13 C NMR (125MHz, CDCl3) δ174.28, 168.24, 160.65, 112.69, 98.76, 72.78, 65.48, 56.28, 13.68.

[0039] The structural confirmation data for compound I obtained in this invention are as follows:

[0040]

[0041] ESI-HRMS (m / z): 191.1510 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 12.10 (s, 1H), 7.80 (d, J = 7.8Hz, 1H), 6.33 (d, J = 7.8Hz, 1H), 3.95 (s, 3H); 13 C NMR (151MHz, DMSO-d6) δ: 173.48, 162.10, 141.08, 112.78, 92.68, 83.20, 56.49.

[0042] Synthesis of intermediate I-1

[0043] Example 1

[0044] At room temperature, α-cyanoacetamide (SM-1, 8.41 g, 0.10 mol) and trimethyl 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. Triethyl orthoformate (SM-3, 17.78 g, 0.12 mol) was then added, and the reaction was carried out at 80–85 °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 94.6% and an HPLC purity of 99.85%.

[0045] Example 2

[0046] At room temperature, α-cyanoacetamide (SM-1, 8.41 g, 0.10 mol) and trimethyl orthoacetate (SM-2, 12.02 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. Triethyl orthoformate (SM-3, 14.82 g, 0.10 mol) was added, and the reaction was carried out at 70–75 °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 90.2% and an HPLC purity of 99.65%.

[0047] Example 3

[0048] At room temperature, α-cyanoacetamide (SM-1, 8.41 g, 0.10 mol) and trimethyl orthoacetate (SM-2, 21.63 g, 0.18 mol) were added to the reaction apparatus. The temperature was controlled at 95–100 °C. After the reaction was confirmed to be complete, the reaction solution was concentrated to dryness under reduced pressure. Triethyl orthoformate (SM-3, 22.23 g, 0.15 mol) was then added, and the reaction was carried out at 95–100 °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 91.5% and an HPLC purity of 99.46%.

[0049] Example 4

[0050] At room temperature, α-cyanoacetamide (SM-1, 8.41 g, 0.10 mol) and trimethyl orthoacetate (SM-2, 24.03 g, 0.20 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. Triethyl orthoformate (SM-3, 25.19 g, 0.17 mol) was then added, and the reaction was carried out at 100–105 °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 85.6% and an HPLC purity of 98.86%.

[0051] Synthesis of Compound I

[0052] Example 5

[0053] At room temperature, compound I-1 (9.81 g, 0.05 mol) was added to ethanol (60 mL). After the material was stirred evenly, sodium hydroxide aqueous solution (7.0 mol / L) was added to adjust the pH to about 14. The reaction was carried out at 75-80℃. After the reaction was detected to be complete, the reaction solution was cooled to room temperature and the pH was adjusted to about 6 with hydrochloric acid. A light yellow needle-like crystal solid precipitated out. After stirring and crystallization, the solid was filtered, the filter cake was washed with water and dried to obtain the target product compound I, with a yield of 96.7% and a purity of 99.92%.

[0054] Example 6

[0055] At room temperature, compound I-1 (9.81 g, 0.05 mol) was added to methanol (50 mL). After the material was stirred evenly, potassium hydroxide aqueous solution (7.0 mol / L) was added to adjust the pH to about 12. The reaction was carried out at 60-65℃. After the reaction was detected to be complete, the reaction solution was cooled to room temperature and the pH was adjusted to about 6 with acetic acid. A light yellow needle-like crystal solid precipitated out. After stirring and crystallization, the solid was filtered, the filter cake was washed with water and dried to obtain the target product compound I, with a yield of 91.2% and a purity of 99.61%.

[0056] Example 7

[0057] At room temperature, compound I-1 (9.81 g, 0.05 mol) was added to isopropanol (100 mL). After the material was stirred evenly, barium hydroxide aqueous solution (7.0 mol / L) was added to adjust the pH to about 10. The reaction was carried out at 80-85℃. After the reaction was detected to be complete, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with formic acid. A light yellow needle-like crystalline solid precipitated out. After stirring and crystallization, the solid was filtered, the filter cake was washed with water, and dried to obtain the target product compound I, with a yield of 90.8% and a purity of 99.56%.

[0058] Example 8

[0059] At room temperature, compound I-1 (9.81 g, 0.05 mol) was added to tert-butanol (90 mL). After the material was stirred evenly, sodium ethoxide was added to adjust the pH to about 10. The reaction was carried out at 55-60℃. After the reaction was detected to be complete, the reaction solution was cooled to room temperature and the pH was adjusted to about 6 with hydrobromic acid. A light yellow needle-like crystalline solid precipitated out. After stirring and crystallization, the solid was filtered, the filter cake was washed with water, and dried to obtain the target product compound I, with a yield of 88.9% and a purity of 99.42%.

Claims

1. A method for preparing a gimidazine intermediate compound, characterized in that, The synthesis includes the following steps: At room temperature, compounds SM-1 and SM-2 are added to the reaction apparatus. The temperature is controlled at T1 until the reaction is complete. The reaction solution is then concentrated to dryness under reduced pressure. Compound SM-3 is added, and the temperature is controlled at T2 until the reaction is complete. The reaction solution is then concentrated to dryness under reduced pressure to obtain I-1. The synthetic route is as follows: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of compounds SM-1, SM-2, and SM-3 is 1:1.0~1.8:1.0~1.

5.

3. The preparation method according to claim 1, characterized in that, The reaction temperature T1 is 50~100℃.

4. The preparation method according to claim 1, characterized in that, The reaction temperature T2 is 70~100℃.

Images