A kind of preparation method of temozolomide

Abstract

The invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for preparing temozolomide. The method for preparing temozolomide of the invention uses compound II and methylaminocarbonyl chloride as raw materials, the raw materials are cheap and easily available, the whole synthesis step is simple to operate, the reaction conditions are mild, the use of highly toxic reagent methyl isocyanate is avoided, the safety in the production process is relatively improved, the production process is economical and environmentally friendly, the product yield and purity are high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to a method for preparing temozolomide. Background Art

[0002] Temozolomide, chemical name is 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazine-4(3H)-one, molecular formula: C6H6N6O2; molecular weight: 194.15; CAS registration number: 85622-93-1, structural formula is as follows:

[0003]

[0004] Temozolomide was first developed by Aston University in the UK, and then the German Schering-Plough Pharmaceuticals obtained the development rights and was launched in the United States in 1999. Pharmacological studies have shown that temozolomide is a new drug with good efficacy against brain gliomas; it has high bioavailability, can be taken orally, is easy to pass through the blood-brain barrier, has no superimposed toxicity compared with other drugs, and has a wider anti-tumor spectrum. At present, temozolomide is a good anticancer drug for the treatment of brain gliomas and malignant melanomas, and temozolomide capsules have been approved in Europe and the United States for the treatment of malignant gliomas.

[0005] The conventional synthesis method of temozolomide is to react 5-amino-1H-imidazole-4-carboxamide or its hydrochloride as raw material with sodium nitrite, and then react with methyl isocyanate to obtain temozolomide after diazotization (Journal of the Chemical Society, Perkin Transactions 1, 1998, 10: 1669-1775). The synthesis route is as follows. This method has a high atomic utilization rate, so a high-purity and high-yield product temozolomide is obtained, but the toxic methyl isocyanate is used in the synthesis process, which has a high operating risk and is not easy to produce and synthesize.

[0006]

[0007] The second method is the methyl isocyanate substitution method: one is to synthesize temozolomide by deprotonation of 3-carboxyl temozolomide, with a yield of 26% (Journal of the Chemical Society, Chemistry Commum, 19914, 14: 1687-1688); the other is to react 3-trimethylsilylmethyl imidazole tetrazine with tetrabutylamine fluoride in an acetonitrile-acetic acid mixed solvent to obtain temozolomide, with a yield of 78% (Biochemistry, 1994, 33 (31): 9045-9051). Although these two methods avoid the direct use of methyl isocyanate, the yields are not high because the substitutes are not very stable.

[0008]

[0009] The third method is the synthesis method of methylaminoformyl chloride (Journal of the Organic Chemistry, 1997, 62: 7288-7294). Starting from 5-aminoimidazole-4-carboxamide, 5-amino-1-(N-methylaminoformyl)imidazole-4-carboxamide is synthesized, and then temozolomide is obtained through diazotization reaction. This method uses moderately toxic methylaminoformyl chloride to replace highly toxic methyl isocyanate, and 5-amino-1-(N-methylaminoformyl)imidazole-4-carboxamide has multiple diazotization reaction sites. This step will produce isomeric by-products, and the reaction yield needs to be improved.

[0010]

[0011] The fourth method is a new method that does not use 5-diazoimidazole-4-carboxamide and methyl isocyanate (Journal of the Chemical Society, Perkin Transactions 1, 2002, 16: 1877-1880), 5-nitroimidazole reacts with potassium cyanate in the presence of nitric acid to generate 5-nitroimidazole-4-acetonitrile, and then undergoes multiple steps to generate temozolomide. This method has a high yield, but the synthetic route is long and too complicated to be suitable for industrial production.

[0012]

[0013] The fifth method is a new method involving carbonyl diimidazole in the reaction (WO2018 / 112589): starting from carbonyl diimidazole, it undergoes two imidazole ring exchanges and then diazotizes the ring to obtain temozolomide. The reagents in this method have low toxicity and are easy to operate, but the intermediate N-methyl-1-H-imidazolecarboxamide must be purified by silica gel column, which is complicated to operate. At the same time, the intermediate compound to be diazotized has a double reaction site, and the ring is closed to obtain two products, which reduces the yield of this step.

[0014]

[0015] In summary, the existing temozolomide preparation method has the problems of long synthesis route, low yield, low purity, high technical requirements, serious environmental pollution, unstable intermediates and high production cost. Therefore, exploring a process route for temozolomide that is simple to operate, has a higher yield and is more suitable for industrial production is still a problem that needs to be solved at present. Summary of the invention

[0016] In order to solve the problems of long synthesis route, complicated operation, low yield and low purity of temozolomide in the prior art, the present invention provides a novel method for preparing temozolomide. The method has short reaction route, simple operation, milder reaction, high product purity and yield, and is suitable for industrial production.

[0017] The present invention is specifically implemented through the following technical solutions:

[0018] A method for preparing temozolomide, the synthetic route of which is as follows:

[0019]

[0020] A method for preparing temozolomide specifically comprises the following steps:

[0021] 1) Add compound II to organic solvent A, stir to dissolve, add base and compound III under temperature control, continue to react under temperature control, and complete the reaction to obtain intermediate compound IV;

[0022] 2) adding the intermediate compound IV, cuprous salt and trimethylsilyl cyanide to the organic solvent B in sequence, controlling the temperature and stirring to react, and completing the reaction to obtain the intermediate compound V;

[0023] 3) Add the intermediate compound V to the acid solution, control the temperature for hydrolysis, and complete the reaction to obtain compound I.

[0024] Preferably, the base in step 1) is selected from one or a combination of diethylisopropylamine, pyridine and triethylamine, among which diethylisopropylamine is particularly preferred.

[0025] Preferably, the organic solvent A in step 1) is selected from toluene, DMF, DMSO or a combination thereof.

[0026] Preferably, the molar ratio of compound II, base and compound III in step 1) is 1:1.0-4.0:1.0-2.2, with 1:3.0:2.0 being particularly preferred.

[0027] Preferably, the addition of base, compound III and reaction temperature in step 1) are all -5°C to 5°C, with 0°C being particularly preferred.

[0028] Preferably, the compound III in step 1) is added by dissolving the compound III in an organic solvent A and then dripping it into the reaction system.

[0029] In a preferred embodiment, after the reaction of step 1) is completed, a post-treatment operation is required, specifically: after the reaction is completed, the organic phase is concentrated to remove, ice water is added, ice bath is cooled, stirring is performed, and vacuum filtration is performed. The filter cake is washed with ice water and acetone in turn, and dried to obtain the intermediate compound IV.

[0030] Preferably, the cuprous salt in step 2) is selected from cuprous iodide, cuprous chloride, cuprous bromide or a combination thereof, wherein cuprous chloride is particularly preferred.

[0031] Preferably, in step 2), the molar ratio of the intermediate compound IV, the inorganic cuprous salt and trimethylsilyl cyanide is 1:0.05-0.1:1.0-2.0, with 1:0.5:1.2 being particularly preferred.

[0032] Preferably, the organic solvent B in step 2) is selected from one or a combination of DMSO, N,N-dimethylformamide, N-methylpyrrolidone, among which DMSO is particularly preferred.

[0033] Preferably, the reaction temperature in step 2) is 80°C to 90°C.

[0034] In a preferred embodiment, after the reaction of step 2) is completed, a post-treatment operation is required, specifically: after the reaction is completed, a saturated sodium thiosulfate solution is added to quench, filtered, water is added, and then ethyl acetate is added to extract, dried over anhydrous magnesium sulfate, and rotary evaporated to obtain the intermediate compound V.

[0035] Preferably, in step 3), the mass volume ratio of the intermediate compound V to the acid solution is 1:20-50, g / mL.

[0036] Preferably, the acid solution in step 3) is selected from concentrated hydrochloric acid or a mixed acid solution of concentrated hydrochloric acid and glacial acetic acid, wherein a mixed acid solution of concentrated hydrochloric acid and glacial acetic acid is particularly preferred.

[0037] Further preferably, the volume ratio of concentrated hydrochloric acid to glacial acetic acid is 1:0.2-1.0, with 1:0.5 being particularly preferred.

[0038] Preferably, the hydrolysis temperature in step 3) is 70°C to 75°C.

[0039] In a preferred embodiment, after the reaction in step 3) is completed, a post-treatment operation is required, specifically: cooling and stirring after the reaction is completed, filtering with suction, adding the filter cake to DMSO for slurrying, filtering with suction, washing the filter cake with ice ethanol, and drying to obtain compound I.

[0040] Compared with the prior art, the present invention provides a novel method for preparing temozolomide, which uses compound II and methylaminoformyl chloride as raw materials, is cheap and readily available, and the entire synthesis step is simple to operate, the reaction conditions are mild, and the use of the highly toxic reagent methyl isocyanate is avoided, thereby relatively improving the safety of the production process, being economical and environmentally friendly, and having high product yield and purity, and being suitable for industrial production. DETAILED DESCRIPTION

[0041] The present invention is further described below by way of examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, so simple improvements to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0042] The structure of the compound obtained by the present invention is confirmed:

[0043] Structural characterization of compound IV:

[0044]

[0045] High resolution mass spectrum of compound IV: ESI-HRMS: m / z=152.0496[M+H] + ; 1 H-NMR (400MHz, CDCl3): δ8.15(s,1H),7.03(s,2H),2.75(s,3H); 13 C-NMR (400MHz, CDCl3) δ145.8,139.6,136.7,125.9,37.7.

[0046] Structural characterization of compound V:

[0047]

[0048] High resolution mass spectrum of compound V: ESI-HRMS: m / z = 199.0453 [M + Na] + ; 1 H-NMR (400MHz, CDCl3): δ8.14(s,1H),2.74(s,3H); 13 C-NMR (400MHz, CDCl3): δ145.7,139.7,115.6,136.7,71.4,37.8.

[0049] Preparation of intermediate compound IV

[0050] Example 1

[0051] Compound II (14.11 g, 0.15 mol) was added to 270 mL of toluene, stirred to dissolve, and cooled to 0°C. Diisopropylethylamine (58.16 g, 0.45 mol) was slowly added dropwise to the reaction system. After 15 min, compound III (28.05 g, 0.30 mol) was dissolved in 50 mL of toluene and slowly added dropwise to the above reaction system. The temperature was continued to react. After monitoring the completion of the reaction, the toluene was removed by concentration, 250 mL of ice water was added, stirred, and filtered under reduced pressure. The filter cake was washed with ice water and acetone in sequence and dried to obtain 21.42 g of intermediate compound IV with a yield of 94.5% and a HPLC purity of 99.93%.

[0052] Example 2

[0053] Compound II (14.11 g, 0.15 mol) was added to 270 mL of DMF, stirred to dissolve, cooled to 5°C, triethylamine (15.18 g, 0.15 mol) was slowly added dropwise to the reaction system, and after 15 min, compound III (30.86 g, 0.33 mol) was dissolved in 50 mL of DMF and slowly added dropwise to the above reaction system, and the temperature was continued to control the reaction. After monitoring the completion of the reaction, DMF was concentrated to remove, 250 mL of ice water was added, stirred, and filtered under reduced pressure. The filter cake was washed with ice water and acetone in sequence, and dried to obtain 20.67 g of intermediate compound IV with a yield of 91.2% and a HPLC purity of 99.87%.

[0054] Example 3

[0055] Compound II (14.11 g, 0.15 mol) was added to 270 mL of toluene, stirred to dissolve, and cooled to -5°C. Pyridine (47.46 g, 0.60 mol) was slowly added dropwise to the reaction system. After 15 min, compound III (14.03 g, 0.15 mol) was dissolved in 50 mL of toluene and slowly added dropwise to the above reaction system. The temperature was continued to react. After monitoring the completion of the reaction, the toluene was removed by concentration, 250 mL of ice water was added, stirred, and filtered under reduced pressure. The filter cake was washed with ice water and acetone in sequence and dried to obtain 20.56 g of intermediate compound IV with a yield of 90.7% and a HPLC purity of 99.76%.

[0056] Example 4

[0057] Compound II (14.11 g, 0.15 mol) was added to 270 mL of toluene, stirred to dissolve, cooled to 0°C, triethylamine (30.36 g, 0.30 mol) was slowly added dropwise to the reaction system, 15 min later, compound III (21.51 g, 0.23 mol) was dissolved in 50 mL of toluene and slowly added dropwise to the above reaction system, the temperature was continued to control the reaction, and after monitoring the completion of the reaction, toluene was removed by concentration, 250 mL of ice water was added, stirred, and filtered under reduced pressure. The filter cake was washed with ice water and acetone in sequence, and dried to obtain 20.86 g of intermediate compound IV with a yield of 92.0% and a HPLC purity of 99.90%.

[0058] Example 5

[0059] Compound II (14.11 g, 0.15 mol) was added to 270 mL of toluene, stirred to dissolve, cooled to 10°C, diisopropylethylamine (58.16 g, 0.45 mol) was slowly added dropwise to the reaction system, 15 min later, compound III (28.05 g, 0.30 mol) was dissolved in 50 mL of toluene and slowly added dropwise to the above reaction system, the temperature was continued to control the reaction, and after monitoring the completion of the reaction, toluene was removed by concentration, 250 mL of ice water was added, stirred, and filtered under reduced pressure. The filter cake was washed with ice water and acetone in sequence, and dried to obtain 19.84 g of intermediate compound IV with a yield of 87.5% and a HPLC purity of 95.69%.

[0060] Example 6

[0061] Compound II (14.11 g, 0.15 mol) was added to 270 mL of DMF, stirred to dissolve, cooled to 0°C, diisopropylethylamine (96.94 g, 0.75 mol) was slowly added dropwise to the reaction system, and after 15 min, compound III (42.08 g, 0.45 mol) was dissolved in 50 mL of DMF and slowly added dropwise to the above reaction system, and the temperature was continued to react. After monitoring the completion of the reaction, DMF was concentrated to remove, 250 mL of ice water was added, stirred, and filtered under reduced pressure. The filter cake was washed with ice water and acetone in sequence, and dried to obtain 20.24 g of intermediate compound IV with a yield of 89.3% and a HPLC purity of 93.74%.

[0062] Example 7

[0063] Compound II (14.11 g, 0.15 mol) was added to 270 mL of toluene, stirred to dissolve, cooled to 0°C, diisopropylethylamine (38.78 g, 0.30 mol) was slowly added dropwise to the reaction system, 15 min later, compound III (28.05 g, 0.30 mol) was dissolved in 50 mL of toluene and slowly added dropwise to the above reaction system, the temperature was continued to control the reaction, and after monitoring the completion of the reaction, toluene was removed by concentration, 250 mL of ice water was added, stirred, and filtered under reduced pressure. The filter cake was washed with ice water and acetone in sequence, and dried to obtain 21.10 g of intermediate compound IV with a yield of 93.1% and a HPLC purity of 99.91%.

[0064] Preparation of intermediate compound V

[0065] Example 8

[0066] The intermediate compound IV (15.11 g, 0.10 mol), cuprous chloride (0.99 g, 0.01 mol) and trimethylsilyl cyanide (11.90 g, 0.12 mol) were added to 200 mL DMSO in sequence, and the reaction was stirred at 85°C. After the reaction was monitored to be complete, a saturated sodium thiosulfate solution was added to quench the reaction, and the mixture was filtered. 50 mL of water was added, and then ethyl acetate (100 mL×3) was added to extract the mixture. The mixture was dried over anhydrous magnesium sulfate and rotary evaporated to obtain 15.91 g of the intermediate compound V with a yield of 90.3% and a HPLC purity of 99.92%.

[0067] Example 9

[0068] The intermediate compound IV (15.11 g, 0.10 mol), cuprous iodide (0.95 g, 0.005 mol) and trimethylsilyl cyanide (19.84 g, 0.20 mol) were added to 200 mL of N,N-dimethylformamide in sequence, and the reaction was stirred at 80°C. After the reaction was completed, a saturated sodium thiosulfate solution was added to quench the reaction, and the reaction was filtered. 50 mL of water was added, and then ethyl acetate (100 mL×3) was added to extract the reaction. The reaction was dried over anhydrous magnesium sulfate and rotary evaporated to obtain 15.15 g of the intermediate compound V with a yield of 86.0% and a HPLC purity of 99.74%.

[0069] Example 10

[0070] The intermediate compound IV (15.11 g, 0.10 mol), cuprous bromide (2.87 g, 0.02 mol) and trimethylsilyl cyanide (9.92 g, 0.10 mol) were added to 200 mL of N-methylpyrrolidone in sequence, and the reaction was stirred at 90°C. After monitoring the completion of the reaction, a saturated sodium thiosulfate solution was added to quench the reaction, and the reaction was filtered. 50 mL of water was added, and then ethyl acetate (100 mL×3) was added to extract. The reaction was dried over anhydrous magnesium sulfate and rotary evaporated to obtain 15.34 g of the intermediate compound V. The yield was 87.1% and the HPLC purity was 99.80%.

[0071] Embodiment 11

[0072] The intermediate compound IV (15.11 g, 0.10 mol), cuprous iodide (1.90 g, 0.01 mol) and trimethylsilyl cyanide (11.90 g, 0.12 mol) were added to 200 mL of DMSO in sequence, and the reaction was stirred at 90° C. After monitoring the completion of the reaction, a saturated sodium thiosulfate solution was added to quench the reaction, and the mixture was filtered. 50 mL of water was added, and then ethyl acetate (100 mL×3) was added to extract the mixture. The mixture was dried over anhydrous magnesium sulfate and rotary evaporated to obtain 15.61 g of the intermediate compound V with a yield of 88.6% and a HPLC purity of 99.85%.

[0073] Example 12

[0074] The intermediate compound IV (15.11 g, 0.10 mol), cuprous chloride (0.40 g, 0.004 mol) and trimethylsilyl cyanide (14.88 g, 0.15 mol) were added to 200 mL DMSO in sequence, and the reaction was stirred at 85° C. After monitoring the completion of the reaction, a saturated sodium thiosulfate solution was added to quench the reaction, and the reaction was filtered. 50 mL of water was added, and then ethyl acetate (100 mL×3) was added to extract. The reaction was dried over anhydrous magnesium sulfate and rotary evaporated to obtain 14.67 g of the intermediate compound V. The yield was 83.3% and the HPLC purity was 99.67%.

[0075] Example 13

[0076] The intermediate compound IV (15.11 g, 0.10 mol), cuprous chloride (0.99 g, 0.01 mol) and trimethylsilyl cyanide (11.90 g, 0.12 mol) were added to 200 mL of THF in sequence, and the reaction was stirred at 65° C. After monitoring the completion of the reaction, a saturated sodium thiosulfate solution was added to quench the reaction, and the reaction was filtered. 50 mL of water was added, and then ethyl acetate (100 mL×3) was added to extract the reaction. The reaction was dried over anhydrous magnesium sulfate and rotary evaporated to obtain 14.18 g of the intermediate compound V with a yield of 80.5% and a HPLC purity of 99.42%.

[0077] Preparation of Temozolomide

[0078] Embodiment 14

[0079] The intermediate compound V (17.61 g, 0.10 mol) was added to a mixed solution of concentrated hydrochloric acid (400 mL) and glacial acetic acid (200 mL), and the reaction was carried out at 70° C. to 75° C. After the reaction was completed, the reaction solution was cooled to -5° C. and filtered. The filter cake was added to DMSO (100 mL) for slurry and filtered. The filter cake was washed with glacial ethanol (25 mL×2) and dried to obtain 19.08 g of white light powder solid temozolomide with a yield of 98.3% and a purity of 99.95%.

[0080] Embodiment 15

[0081] The intermediate compound V (17.61 g, 0.10 mol) was added to concentrated hydrochloric acid (400 mL), and the reaction was controlled at 70°C to 75°C. After monitoring the completion of the reaction, the reaction solution was cooled to -5°C and filtered. The filter cake was added to DMSO (100 mL) for slurry and filtered. The filter cake was washed with ice ethanol (25 mL×2) and dried to obtain 18.37 g of white light powder solid temozolomide with a yield of 94.6% and a purity of 99.91%.

[0082] Example 16

[0083] The intermediate compound V (17.61 g, 0.10 mol) was added to a mixed solution of concentrated hydrochloric acid (400 mL) and glacial acetic acid (80 mL), and the reaction was carried out at 70° C. to 75° C. After the reaction was completed, the reaction solution was cooled to -5° C. and filtered. The filter cake was added to DMSO (100 mL) for slurry and filtered. The filter cake was washed with glacial ethanol (25 mL×2) and dried to obtain 18.66 g of white light powder solid temozolomide with a yield of 96.1% and a purity of 99.89%.

[0084] Embodiment 17

[0085] The intermediate compound V (17.61 g, 0.10 mol) was added to a mixed solution of concentrated hydrochloric acid (400 mL) and glacial acetic acid (400 mL), and the reaction was carried out at 70° C. to 75° C. After the reaction was completed, the reaction solution was cooled to -5° C. and filtered. The filter cake was added to DMSO (100 mL) for slurry and filtered. The filter cake was washed with glacial ethanol (25 mL×2) and dried to obtain 18.83 g of white light powder solid temozolomide with a yield of 97.0% and a purity of 99.54%.

Claims

1. A method for preparing temozolomide, characterized in that: The method comprises the following steps: , the specific preparation steps are: 1) Add compound II to organic solvent A, stir and dissolve, add base and compound III under temperature control, continue to react under temperature control, and the reaction is completed to obtain intermediate compound IV; 2) Add the intermediate compound IV, cuprous salt and trimethylsilyl cyanide to the organic solvent B in sequence, control the temperature and stir to react, and when the reaction is completed, obtain the intermediate compound V; 3) Adding the intermediate compound V to the acid solution, controlling the temperature for hydrolysis, and completing the reaction to obtain compound I; The base in step 1) is selected from one of diethylisopropylamine, pyridine, triethylamine or a combination thereof; the cuprous salt in step 2) is selected from one of cuprous iodide, cuprous chloride, cuprous bromide or a combination thereof.

2. The preparation method according to claim 1, characterized in that In step 1), the base, compound III and reaction temperature are all -5°C to 5°C.

3. The preparation method according to claim 1, characterized in that: In step 1), the molar ratio of compound II, base and compound III is 1:1.0-4.0:1.0-2.

2.

4. The preparation method according to claim 1, characterized in that: In step 1), the organic solvent A is selected from toluene, DMF, DMSO or a combination thereof.

5. The preparation method according to claim 1, characterized in that: The reaction temperature in step 2) is 80°C to 90°C.

6. The preparation method according to claim 1, characterized in that: In step 2), the organic solvent B is selected from DMSO, N,N-dimethylformamide, N-methylpyrrolidone or a combination thereof.

7. The preparation method according to claim 1, characterized in that: The hydrolysis temperature in step 3) is 70°C to 75°C.

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