Synthetic method of gemcitabine
By using technical means such as nitrogen protection and condensation reaction in gemcitabine synthesis, the problems of low product yield and purity in the prior art have been solved, and efficient and low-cost gemcitabine production has been achieved.
Patent Information
- Application Number
- CN202510203632.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-24
- Publication Date
- 2025-05-13
AI Technical Summary
The existing gemcitabine synthesis methods have low product yield and purity, complex process and high cost.
Under nitrogen protection, cytosine was condensed with 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate, and after salt and decolorization treatment, high-purity gemcitabine was obtained by alkali washing.
The high yield and high purity of gemcitabine are achieved, the process steps are simplified, the cost is reduced, and the use and residue of organic solvents are reduced.
Abstract
Description
Technical Field
[0001] The invention relates to the field of organic synthesis chemical industry, and in particular to a method for synthesizing gemcitabine. Background Art
[0002] Gemcitabine is a new synthetic cytosine nucleoside derivative, with the chemical name 2'-deoxy-2',2'-difluorocytosine (2',2'-difluoro 2'-deoxycytidine, dFdC). It mainly acts on the pre-DNA synthesis phase (G1 phase) and DNA synthesis phase (S phase) of tumor cells, and can prevent cells from entering the S phase from the G1 phase. It is a cell cycle-specific antimetabolite drug with a broad spectrum of anti-tumor activity. Gemcitabine has been approved by the European Medicines Agency and the U.S. Food and Drug Administration for the treatment of non-small cell lung cancer, and was later approved for marketing in China by my country's State Food and Drug Administration in 1999. In recent years, with the continuous expansion of gemcitabine in the field of anti-tumor research, it has been widely used alone or in combination with other drugs to treat various types of malignant tumors such as pancreatic cancer, breast cancer, bladder cancer, cervical cancer, head and neck tumors, and soft tissue sarcomas.
[0003] The earliest synthesis method of gemcitabine is to use R-glyceraldehyde acetonide as the starting material, first react with ethyl difluorobromoacetate to obtain R-type 2,2-difluoro-3-hydroxy-3-(2,2-dimethyloxy-4-)propionate, hydrolyze to obtain 2-deoxy-2,2-difluoro-1-O-ribose, then protect the hydroxyl group and carbonyl group, and then condense with cytosine and deprotect under acidic conditions to obtain gemcitabine. The following method is an improvement based on this method, such as using 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-one-3,5-dibenzoate as raw material, reducing with lithium aluminum tetrahydride and mesylation to obtain 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoate-1-methanesulfonate, condensing with cytosine, deprotecting in methanol containing ammonia, and crystallizing and separating gemcitabine hydrochloride in aqueous acetone after salt formation, with a total yield of 14%. The process route used in the literature has a low total yield and low purity. Summary of the invention
[0004] The technical problem to be solved by the present invention is to provide a method for synthesizing gemcitabine with simple operation, low cost, high product yield and purity.
[0005] To solve the above problems, a method for synthesizing gemcitabine according to the present invention comprises the following steps: ⑴ Under nitrogen protection, add cytosine and acetic anhydride to acetic acid, add potassium iodide and stir evenly, heat and reflux until the liquid is clear, and keep warm for 0.5~2h; after the reaction, reduce pressure and concentrate to recover acetic acid, add toluene to the concentrated liquid, stir and heat to dissolve; after dissolving, add 2-deoxy-2,2-difluoro-D-furanosyl-3,5-dibenzoyl-1-methanesulfonate, and keep the reaction temperature at 105~ 120°C, the reaction is terminated when TLC detects that the raw material is completely converted; the obtained reaction solution A is cooled to room temperature and then slowly added to dilute hydrochloric acid with a volume of 0.28 to 1.10 times its volume, and then heated to 60 to 90°C and stirred for a while, and then filtered while hot to obtain filter cake A; the filter cake A is added to concentrated hydrochloric acid with a volume of 0.91 to 3.61 times its mass, heated to 70 to 85°C and slurried, filtered, rinsed with hot water, and the obtained solid is added to a dilute sodium bicarbonate aqueous solution with a volume of 4.28 to 17.14 times its mass, stirred for 25 to 60 minutes, and then filtered to obtain filter cake B, and the filter cake B is washed with water and dried to constant weight to obtain the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine; (2) The intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is dissolved in methanol, diethylamine is added, and the temperature is slowly raised to 55-70°C. The reaction is terminated after the intermediate is completely converted by TLC detection; the obtained reaction solution B is cooled to room temperature, decolorized, and filtered to obtain a filtrate; concentrated hydrochloric acid is added dropwise to the filtrate, the cooling liquid is closed by dropwise cooling, and a filter cake C is obtained by stirring, crystallizing, and filtering. After the filter cake C is washed with acetone, gemcitabine hydrochloride with a purity greater than 99% is obtained; water is added to the gemcitabine hydrochloride, triethylamine is added dropwise at -5-5°C until the system is weakly alkaline, stirred for 0.5-2h, filtered, and the obtained filter cake D is continuously slurried with 1-10 times its mass of water, and then filtered, washed with acetone, and dried to constant weight to obtain a product gemcitabine with a purity ≥99.9%.
[0006] In the step (1), the mass ratio of cytosine to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0.24-2.43:1; the mass ratio of acetic anhydride to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0.45-0.90:1; the mass ratio of acetic acid to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0. The mass ratio of 5-dibenzoyl-1-methanesulfonate is 2.30~6.91:1; the mass ratio of potassium iodide to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0.007~0.036:1; the mass ratio of toluene to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 1.91~5.70:1.
[0007] The heating reflux temperature in the step (1) is 150-180°C.
[0008] The conditions for reduced pressure concentration in step (1) are a temperature of 95 to 120° C. and a pressure of -0.6 to 0.9 MPa.
[0009] In the step (2), the mass ratio of methanol to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 2.52-5.05:1; the mass ratio of diethylamine to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 0.15-0.47:1; the mass ratio of concentrated hydrochloric acid to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 0.21-0.86:1.
[0010] Decolorization in the step (2) refers to the use of activated carbon.
[0011] Compared with the prior art, the present invention has the following advantages: 1. The present invention uses 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate as a starting material, and obtains gemcitabine hydrochloride through two-step reactions of condensation and salt formation, and then obtains gemcitabine after alkaline washing. Compared with other synthetic routes, this process route has the advantages of less toxic materials, lower cost, simplified synthetic steps, and simple operation.
[0012] 2. In the condensation reaction of the present invention, the equivalent ratio of cytosine to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is about 5, which can highly selectively carry out the glycosylation reaction, improve the stereoselectivity, and make the final product achieve the purpose of high purity.
[0013] 3. After the salt-forming reaction in the present invention is completed, activated carbon decolorization can be directly performed, concentrated hydrochloric acid is added dropwise, gemcitabine hydrochloride is precipitated at low temperature, and then the base is adjusted and slurried in water to obtain high-purity gemcitabine, which can effectively reduce the usage and residue of organic solvents.
[0014] 4. The purity of the product obtained by the method of the present invention is ≥99.9%, the overall indicators meet the requirements, and the product specifications reach the high standards for commercial use. DETAILED DESCRIPTION
[0015] A method for synthesizing gemcitabine comprises the following steps: ⑴ Under nitrogen protection, add cytosine and acetic anhydride to acetic acid, add potassium iodide and stir evenly, heat and reflux at 150~180℃ until the feed liquid is clear, and keep the temperature for reaction for 0.5~2h; after the reaction is completed, reduce pressure and concentrate to recover acetic acid. The conditions for reduced pressure and concentration refer to temperature of 95~120℃ and pressure of -0.6~0.9MPa. Add toluene to the concentrated feed liquid, stir and heat to dissolve; after dissolving, add 2-deoxy-2,2-difluoro-D-furanosyl-3,5-dibenzoyl-1-methanesulfonate, maintain the reaction temperature at 105~120℃, and terminate the reaction when TLC detects that the raw material is completely converted; after the reaction liquid A is cooled to room temperature, slowly add it to 0.28~1.10 times its volume of dilute hydrochloric acid, then heat it to 60~90℃, stir it for a while, and filter it while hot to obtain filter cake A. Filter cake A is added to concentrated hydrochloric acid with a mass of 0.91 to 3.61 times its mass, heated to 70 to 85°C and slurried. The solid obtained after filtration and hot water rinsing is added to a dilute sodium bicarbonate aqueous solution with a mass of 4.28 to 17.14 times its mass, stirred for 25 to 60 minutes and filtered to obtain filter cake B. The filter cake B is washed with water and dried to constant weight to obtain the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine.
[0016] Among them: the mass ratio of cytosine to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate (g / g) is 0.24~2.43:1; the mass ratio of acetic anhydride to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate (g / g) is 0.45~0.90:1; the mass ratio of acetic acid to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate (g / g) is 0. The mass ratio (g / g) of formyl-1-methanesulfonate is 2.30~6.91:1; the mass ratio (g / g) of potassium iodide to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0.007~0.036:1; the mass ratio (g / g) of toluene to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 1.91~5.70:1.
[0017] (2) The intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is dissolved in methanol, diethylamine is added, and the temperature is slowly raised to 55~70°C. The reaction is terminated after TLC detection of the complete conversion of the intermediate; the obtained reaction solution B is cooled to room temperature, decolorized with activated carbon, and filtered to obtain a filtrate; concentrated hydrochloric acid is added dropwise to the filtrate, and the cooling liquid is closed by dropwise cooling, and a filter cake C is obtained by stirring, crystallizing, and filtering. After the filter cake C is washed with acetone, gemcitabine hydrochloride with a purity greater than 99% is obtained; water is added to gemcitabine hydrochloride, and triethylamine is added dropwise at -5~5°C until the system is weakly alkaline, stirred for 0.5~2h, filtered, and the obtained filter cake D is continuously slurried with 1~10 times its mass of water, and then filtered, washed with acetone, and dried to constant weight to obtain a product gemcitabine with a purity ≥99.9%.
[0018] Among them: the mass ratio (g / g) of methanol to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 2.52~5.05:1; the mass ratio (g / g) of diethylamine to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 0.15~0.47:1; the mass ratio (g / g) of concentrated hydrochloric acid to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 0.21~0.86:1.
[0019] Example 1 A method for synthesizing gemcitabine comprises the following steps: ⑴ Under nitrogen protection, add 11.11g cytosine and 20.42g acetic anhydride to 105g acetic acid, add 0.33g potassium iodide and stir evenly, heat and reflux at 150~180℃ until the liquid is clear, and keep the reaction for 0.5h; after the reaction, reduce the pressure and concentrate to recover the acetic acid, add 87g toluene to the concentrated liquid, stir and heat to dissolve; after the solution is clear, add 45.61g 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate, the reaction temperature is maintained at 105°C, and the reaction is terminated when the raw material is completely converted by TLC detection; after the reaction solution A is cooled to room temperature, it is slowly added to 36 mL of dilute hydrochloric acid, and then heated to 60-90°C and stirred for a while, and then filtered while hot to obtain filter cake A; filter cake A is added to 43 mL of concentrated hydrochloric acid, heated to 70°C and slurried, and the solid obtained after filtration and hot water rinsing is added to 202 mL of dilute sodium bicarbonate aqueous solution, stirred for 25 minutes, and then filtered to obtain filter cake B, and the filter cake B is washed with water and dried to constant weight to obtain the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine, with a yield of 75%.
[0020] (2) Dissolve 47.14 g of the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine in 119 g of methanol, add 7.3 g of diethylamine, slowly raise the temperature to 55 ° C, and terminate the reaction after TLC detection of the complete conversion of the intermediate; the resulting reaction solution B is cooled to room temperature, decolorized with activated carbon, and filtered to obtain a filtrate; add 10.13 g of concentrated hydrochloric acid to the filtrate, and close the cooling liquid by dripping , after stirring, crystallizing and filtering, filter cake C was obtained. After washing filter cake C with acetone, gemcitabine hydrochloride with a purity of 99.15% was obtained. Water was added to gemcitabine hydrochloride, triethylamine was added dropwise at -5°C until the system was weakly alkaline, stirred for 0.5h, filtered, and the obtained filter cake D was slurried with 26g of water, filtered, washed with acetone, and dried to constant weight to obtain 18.42g of product gemcitabine with a purity of 99.96%, with a yield of 70%.
[0021] Example 2 A method for synthesizing gemcitabine comprises the following steps: ⑴ Under nitrogen protection, add 44.44g cytosine and 30.63g acetic anhydride to 158g acetic acid, add 0.66g potassium iodide and stir evenly, heat and reflux at 150-180℃ until the liquid is clear, and keep the reaction for 1h; after the reaction, reduce pressure and concentrate to recover acetic acid, add 173g toluene to the concentrated liquid, stir and heat to dissolve; after dissolving, add 45.61g 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate, the reaction temperature was maintained at 110°C, and the reaction was terminated when the raw material was completely converted by TLC detection; after the reaction solution A was cooled to room temperature, it was slowly added to 72 mL of dilute hydrochloric acid, and then heated to 70°C and stirred for a while, and then filtered while hot to obtain filter cake A; filter cake A was added to 85 mL of concentrated hydrochloric acid, heated to 75°C and slurried, and the solid obtained after filtration and hot water rinsing was added to 404 mL of dilute sodium bicarbonate aqueous solution, stirred for 30 minutes, and then filtered to obtain filter cake B, and the filter cake B was washed with water and dried to constant weight to obtain the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine, with a yield of 78%.
[0022] (2) Dissolve 47.14 g of the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine in 158 g of methanol, add 14.63 g of diethylamine, slowly raise the temperature to 60 ° C, and terminate the reaction after TLC detection of the complete conversion of the intermediate; cool the resulting reaction solution B to room temperature, decolorize it with activated carbon, and filter it to obtain a filtrate; add 20.26 g of concentrated hydrochloric acid dropwise to the filtrate, and cool it down to room temperature. The feed liquid was cooled, stirred, crystallized and filtered to obtain filter cake C. After the filter cake C was washed with acetone, gemcitabine hydrochloride with a purity of 99.19% was obtained. Water was added to gemcitabine hydrochloride, and triethylamine was added dropwise at 0°C until the system was weakly alkaline. The mixture was stirred for 1 hour and filtered. The obtained filter cake D was slurried with 53g of water, filtered, washed with acetone and dried to constant weight to obtain 19.48g of product gemcitabine with a purity of 99.95%, with a yield of 74%.
[0023] Example 3 A method for synthesizing gemcitabine comprises the following steps: ⑴ Under nitrogen protection, add 66.66g cytosine and 40.84g acetic anhydride to 210g acetic acid, add 1.00g potassium iodide and stir evenly, heat and reflux at 150~180℃ until the liquid is clear, and keep the reaction for 1.5h; after the reaction, reduce the pressure and concentrate to recover acetic acid, add 260g toluene to the concentrated liquid, stir and heat to dissolve; after dissolving, add 45.61g 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate, the reaction temperature was maintained at 115°C, and the reaction was terminated when the raw material conversion was complete as detected by TLC; after the reaction solution A was cooled to room temperature, it was slowly added to 108 mL of dilute hydrochloric acid, then heated to 80°C and stirred for a while, and then filtered while hot to obtain filter cake A; filter cake A was added to 129 mL of concentrated hydrochloric acid, heated to 80°C and slurried, and the solid obtained after filtration and hot water rinsing was added to 606 mL of dilute sodium bicarbonate aqueous solution, stirred for 40 minutes, and then filtered to obtain filter cake B, and the filter cake B was washed with water and dried to constant weight to obtain the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine, with a yield of 81%.
[0024] (2) Dissolve 47.14 g of the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine in 198 g of methanol, add 18.29 g of diethylamine, slowly raise the temperature to 65 ° C, and terminate the reaction after TLC detection of the complete conversion of the intermediate; cool the resulting reaction solution B to room temperature, decolorize it with activated carbon, and filter it to obtain a filtrate; add 30.38 g of concentrated hydrochloric acid to the filtrate, and add the cooling material to close the cooling material. The solution was stirred for crystallization and filtered to obtain filter cake C. After washing the filter cake C with acetone, gemcitabine hydrochloride with a purity of 99.23% was obtained. Water was added to gemcitabine hydrochloride, and triethylamine was added dropwise at 5°C until the system was weakly alkaline. The mixture was stirred for 1.5 hours and filtered. The obtained filter cake D was slurried with 132g of water, filtered, washed with acetone, and dried to constant weight to obtain 20.27g of gemcitabine with a purity of 99.97%, with a yield of 77%.
[0025] Example 4 A method for synthesizing gemcitabine comprises the following steps: ⑴ Under nitrogen protection, add 88.88g cytosine and 30.63g acetic anhydride to 263g acetic acid, add 1.33g potassium iodide and stir evenly, heat and reflux at 150~180℃ until the liquid is clear, and keep the reaction for 2h; after the reaction, reduce the pressure and concentrate to recover the acetic acid, add 173g toluene to the concentrated liquid, stir and heat to dissolve; after the solution is clear, add 45.61g 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate, the reaction temperature was maintained at 120°C, and the reaction was terminated when the raw material conversion was complete as detected by TLC; the reaction solution A was cooled to room temperature and slowly added to 143 mL of dilute hydrochloric acid, then heated to 90°C and stirred for a while, and then filtered while hot to obtain filter cake A; the filter cake A was added to 170 mL of concentrated hydrochloric acid, heated to 80°C and slurried, filtered, rinsed with hot water, and the obtained solid was added to 808 mL of dilute sodium bicarbonate aqueous solution, stirred for 50 minutes, and then filtered to obtain filter cake B, which was washed with water and dried to constant weight to obtain the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine, with a yield of 82%.
[0026] (2) Dissolve 47.14 g of the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine in 238 g of methanol, add 21.94 g of diethylamine, slowly raise the temperature to 70°C, and terminate the reaction after TLC detection of complete conversion of the intermediate; cool the resulting reaction solution B to room temperature, decolorize it with activated carbon, and filter it to obtain a filtrate; add 40.51 g of concentrated hydrochloric acid dropwise to the filtrate, and cool it dropwise. The feed liquid was stirred for crystallization and filtered to obtain filter cake C. After the filter cake C was washed with acetone, gemcitabine hydrochloride with a purity of 99.41% was obtained. Water was added to gemcitabine hydrochloride, and triethylamine was added dropwise at 0°C until the system was weakly alkaline. The mixture was stirred for 2 hours and filtered. The obtained filter cake D was slurried with 211 g of water, filtered, washed with acetone, and dried to constant weight to obtain 20.00 g of product gemcitabine with a purity of 99.96%, with a yield of 76%.
[0027] Example 5 A method for synthesizing gemcitabine comprises the following steps: ⑴ Under nitrogen protection, add 111.12g cytosine and 30.63g acetic anhydride to 315g acetic acid, add 1.66g potassium iodide and stir evenly, heat and reflux at 150~180℃ until the liquid is clear, and keep warm for 1h; after the reaction, concentrate under reduced pressure and recover acetic acid, add 173g toluene to the concentrated liquid, stir and heat to dissolve; after dissolving, add 45.61g 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate, the reaction temperature was maintained at 110°C, and the reaction was terminated when the raw material was completely converted by TLC detection; after the reaction solution A was cooled to room temperature, it was slowly added to 108 mL of dilute hydrochloric acid, and then heated to 90°C and stirred for a while, and then filtered while hot to obtain filter cake A; filter cake A was added to 129 mL of concentrated hydrochloric acid, heated to 80°C and slurried, and the solid obtained after filtration and hot water rinsing was added to 630 mL of dilute sodium bicarbonate aqueous solution, stirred for 60 minutes, and then filtered to obtain filter cake B, and the filter cake B was washed with water and dried to constant weight to obtain the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine, with a yield of 85%.
[0028] (2) Dissolve 47.14 g of the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine in 198 g of methanol, add 18.29 g of diethylamine, slowly raise the temperature to 60°C, and terminate the reaction after TLC detection of complete conversion of the intermediate; cool the resulting reaction solution B to room temperature, decolorize it with activated carbon, and filter it to obtain a filtrate; add 40.51 g of concentrated hydrochloric acid dropwise to the filtrate, and cool it dropwise. The feed liquid was stirred for crystallization and filtered to obtain filter cake C. After the filter cake C was washed with acetone, gemcitabine hydrochloride with a purity of 99.37% was obtained. Water was added to gemcitabine hydrochloride, and triethylamine was added dropwise at 0°C until the system was weakly alkaline. The mixture was stirred for 1 hour and filtered. The obtained filter cake D was slurried with 263g of water, filtered, washed with acetone, and dried to constant weight to obtain 21.32g of product gemcitabine with a purity of 99.97%, with a yield of 81%.
Claims
1. A method for synthesizing gemcitabine, comprising the following steps: ⑴ Under nitrogen protection, add cytosine and acetic anhydride to acetic acid, add potassium iodide and stir evenly, heat and reflux until the liquid is clear, and keep warm for 0.5~2h; after the reaction, reduce pressure and concentrate to recover acetic acid, add toluene to the concentrated liquid, stir and heat to dissolve; after dissolving, add 2-deoxy-2,2-difluoro-D-furanosyl-3,5-dibenzoyl-1-methanesulfonate, and keep the reaction temperature at 105~ 120°C, the reaction is terminated when TLC detects that the raw material is completely converted; the obtained reaction solution A is cooled to room temperature and then slowly added to dilute hydrochloric acid with a volume of 0.28 to 1.10 times its volume, and then heated to 60 to 90°C and stirred for a while, and then filtered while hot to obtain filter cake A; the filter cake A is added to concentrated hydrochloric acid with a volume of 0.91 to 3.61 times its mass, heated to 70 to 85°C and slurried, filtered, rinsed with hot water, and the obtained solid is added to a dilute sodium bicarbonate aqueous solution with a volume of 4.28 to 17.14 times its mass, stirred for 25 to 60 minutes, and then filtered to obtain filter cake B, and the filter cake B is washed with water and dried to constant weight to obtain the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine; (2) The intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is dissolved in methanol, diethylamine is added, and the temperature is slowly raised to 55-70°C. The reaction is terminated after the intermediate is completely converted by TLC detection; the obtained reaction solution B is cooled to room temperature, decolorized, and filtered to obtain a filtrate; concentrated hydrochloric acid is added dropwise to the filtrate, the cooling liquid is closed by dropwise cooling, and a filter cake C is obtained by stirring, crystallizing, and filtering. After the filter cake C is washed with acetone, gemcitabine hydrochloride with a purity greater than 99% is obtained; water is added to the gemcitabine hydrochloride, triethylamine is added dropwise at -5-5°C until the system is weakly alkaline, stirred for 0.5-2h, filtered, and the obtained filter cake D is continuously slurried with 1-10 times its mass of water, and then filtered, washed with acetone, and dried to constant weight to obtain a product gemcitabine with a purity ≥99.9%.
2. A method for synthesizing gemcitabine as claimed in claim 1, characterized in that: In the step (1), the mass ratio of cytosine to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0.24-2.43:1; the mass ratio of acetic anhydride to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0.45-0.90:1; the mass ratio of acetic acid to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0. The mass ratio of 5-dibenzoyl-1-methanesulfonate is 2.30~6.91:1; the mass ratio of potassium iodide to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 0.007~0.036:1; the mass ratio of toluene to 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-methanesulfonate is 1.91~5.70:
1.
3. A method for synthesizing gemcitabine as claimed in claim 1, characterized in that: The heating reflux temperature in the step (1) is 150-180°C.
4. A method for synthesizing gemcitabine as claimed in claim 1, characterized in that: The conditions for reduced pressure concentration in step (1) are a temperature of 95 to 120° C. and a pressure of -0.6 to 0.9 MPa.
5. A method for synthesizing gemcitabine as claimed in claim 1, characterized in that: In the step (2), the mass ratio of methanol to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 2.52-5.05:1; the mass ratio of diethylamine to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 0.15-0.47:1; the mass ratio of concentrated hydrochloric acid to the intermediate 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-cytosine is 0.21-0.86:
1.
6. A method for synthesizing gemcitabine as claimed in claim 1, characterized in that: Decolorization in the step (2) refers to the use of activated carbon.