CN110655506A - Preparation method of tegafur - Google Patents
Preparation method of tegafur Download PDFInfo
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- CN110655506A CN110655506A CN201810700352.6A CN201810700352A CN110655506A CN 110655506 A CN110655506 A CN 110655506A CN 201810700352 A CN201810700352 A CN 201810700352A CN 110655506 A CN110655506 A CN 110655506A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a preparation method of tegafur. The method mainly comprises the steps of reacting 5-fluorouracil with tetrahydrofuran under the action of a catalyst, and then extracting and recrystallizing to obtain a high-purity tegafur product. Compared with the prior art, the preparation method provided by the invention is simple to operate, mild in reaction conditions, high in product yield, high in purity, less in pollution and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of tegafur.
Background
The compound related to the invention is Tegafur (also known as Tegafur, Ftorafur, FT207), and the chemical name is: 1- (tetrahydro-2-furyl) -5-fluoro-2, 4(1H,3H) -pyrimidinedione, which is one of pyrimidine anticancer drugs, is a prodrug of 5-fluorouracil, has an inhibitory effect on most solid tumors, and has the following structural formula:
tegafur is a derivative of 5-fluorouracil, which is first synthesized in 1967 by Hiller (Hiller) of the former Soviet Union, and is marketed in Japan in 1974, and is successfully developed by Shandong Jinnan pharmaceutical factories in 1979 in China. The anticancer spectrum and the curative effect of the tegafur are similar to those of 5-fluorouracil, and when the tegafur enters the body by oral administration, the tegafur firstly enters the liver P450The activated enzyme is converted into 5-fluorouracil under the catalysis of the activating enzyme, then about 10 percent of the activated enzyme enters the intestinal tract and is phosphorylated under the catalysis of Orotate Ribosyltransferase (ORTC), and about 90 percent of the activated enzyme is converted into two active products of floxuridine triphosphate (FUTP) and deoxyfloxuridine monophosphate (FdUMP) under the catalysis of liver dihydropyrimidine dehydrogenase (DPD), and the biosynthesis of DNA, RNA and protein can be interfered and blocked in vivo, so that the anticancer effect is generatedThe chemotherapy index of the traditional Chinese medicine is 2 times of that of 5-fluorouracil, and the toxicity of the traditional Chinese medicine is only 1/4-1/7 of that of 5-fluorouracil. Unlike 5-fluorouracil, tegafur is fat-soluble, is well absorbed by oral administration, can maintain a high concentration in blood for a long time, and easily passes through the blood brain barrier, so tegafur is widely applied to chemotherapy of cancer patients. The preparation is mainly used for treating digestive tract tumors such as gastric cancer, rectal cancer, pancreatic cancer and liver cancer in clinic, and can also be used for treating breast cancer, and preparations on the market at home mainly comprise injection and oral preparations.
One strategy for synthesizing tegafur is to subject the two starting materials to a pre-derivatization treatment. The methods known so far use mercury or silver salts of 5-fluorouracil (BP1168391), 2, 4-bis (alkylsilyl) -5-fluorouracil (JP-53-135989, US4024143A, CN201610801535, etc.), 2, 4-bis (trialkyltin) -5-fluorouracil (DE2648239, JP-53-137973) as reactants for providing the 5-fluorouracil moiety. The preparation processes have technical difficulties or technical defects of complex operation, harsh conditions and the like of group protection reaction to a certain extent. As the reactant for providing the tetrahydrofuran moiety, methods using 2-chlorotetrahydrofuran (JP-49-10510, JP-51-8282, JP-53-12518, etc.), 2-alkoxytetrahydrofuran (JP-49-127981, JP-52-118479, etc.), 2-acyloxytetrahydrofuran (JP-50-50383, JP-53-7688, chem.Pharm.Bull.,31 (11)) and the like have been reported, but these compounds are low in chemical stability, and in particular, 2-chlorotetrahydrofuran is a particularly unstable compound, and the reaction needs to be carried out at a low temperature of-60 to 10 ℃ so that the operation of the reaction is also extremely inconvenient. Furthermore, JP-53-119881 reports that tetrahydrofuran is used as a reactant for providing a tetrahydrofuranyl moiety under the action of thiophosgene, but since the conversion of tegafur under such conditions is low, thiophosgene having strong toxicity needs to be used, and hydrogen chloride gas having corrosiveness can be generated in the reaction, making it difficult to adapt the method to industrial production.
The other synthesis strategy is carried out under the condition of adding an additive (or a catalyst), and CN103159746A and US4174446 disclose a method for industrially producing tegafur by reacting 5-fluorouracil and 2, 3-dihydrofuran under the condition of adding additives (such as Lewis acid, organic protonic acid, amine salt and the like) at high temperature of 150-180 ℃ and high pressure, but the method has longer reaction time, needs heating and pressurizing, has higher requirements on equipment and lower yield; in CN102285972A, the reaction process is accelerated by microwaves under the catalysis of copper chloride, and although small-scale research has made a certain progress, the method has higher requirements on equipment for scale-up production and limits the industrialization process; CN104513230A describes a method for using hydroxyapatite to support magnesium chloride or magnesium trifluoromethanesulfonate catalyst, but the reaction still needs to be carried out for 12 hours at high temperature under the condition of inert gas pressurization protection, and compared with the traditional Lewis catalyst, the method is not greatly improved or promoted; CN107235967A provides a method for obtaining 1, 3-disubstituted tegafur after reacting for 8 hours at 50-100 ℃ under the action of alkali and an oxidant, and then obtaining tegafur after heating treatment of an alcohol-water mixed solution, but carbon tetrabromide, carbon tetrachloride, bromotrichloromethane, perfluorohaloalkane or dichloroethane and other substances with high toxicity need to be applied in the reaction, and the reaction temperature and the production period are not effectively improved; the reaction conditions are severe, so that the reaction selectivity in the technical method is poor, a large amount of 1, 3-di (furan-2-yl) -5-fluorouracil and 3- (furan-2-yl) -5-fluoro-uracil impurities introduced by participation of 3-site groups in the reaction are generated, and the post-treatment is more complicated.
In view of the above, the reported technical process for preparing tegafur mainly has the following problems:
(1) the method for carrying out pre-derivatization treatment on the starting material leads the reaction operation to be more complicated, and part of pre-derivatization reagents have lower chemical stability, the reaction needs to be carried out at lower temperature, and the requirement on reaction equipment is higher.
(2) The thiophosgene with strong toxicity is needed to be used in partial reaction, and hydrogen chloride gas with strong corrosivity can be generated in the reaction, so that the requirements on reaction equipment are high, and certain pressure is caused on environmental protection.
(3) The reaction needs to be carried out under the conditions of high temperature and high pressure, so that the reaction time is long, and the reaction selectivity in the technical method is poor due to the severe reaction conditions, so that a large amount of 1, 3-di (furan-2-yl) -5-fluorouracil and 3- (furan-2-yl) -5-fluoro-uracil impurities introduced by the participation of 3-site groups in the reaction are generated, and the post-treatment is more complicated.
Therefore, the research and search for a process which is suitable for industrial production of tegafur and has mild reaction conditions, simple and convenient operation process, high product yield and high purity is still a problem to be solved at present.
Disclosure of Invention
Aiming at the problems of harsh reaction conditions, complex operation and more generated impurities in the existing preparation process, the invention provides a method suitable for industrial production of tegafur, and the method has the characteristics of simple and convenient operation, mild reaction conditions, high reaction process efficiency, high reaction selectivity, high yield and the like.
The specific technical content of the invention is as follows:
a preparation method of tegafur shown as a formula (I) comprises the following steps:
adding 5-fluorouracil, tetrahydrofuran, a catalyst and peroxide into a certain solvent at room temperature, heating a reaction system until the reaction is finished, filtering, pouring filtrate into extract liquor for extraction and separation, washing an organic phase with purified water and saturated saline solution in turn, drying with anhydrous sodium sulfate, concentrating the filtered filtrate under reduced pressure to be dry to obtain a tegafur crude product, and recrystallizing to obtain a tegafur refined product.
The preferable scheme is that the reaction solvent is N, N-dimethylformamide or dimethyl sulfoxide.
In a preferable scheme, the preparation method of the tegafur shown in the formula (I) is characterized in that the catalyst is copper acetate, nickel acetate or palladium acetate, wherein the copper acetate is particularly preferable.
In a preferred embodiment, the preparation method of the tegafur shown in the formula (I) is that the peroxide is hydrogen peroxide or tert-butyl peroxide, wherein hydrogen peroxide is particularly preferred.
The preferable scheme is that the preparation method of tegafur shown as the formula (I) is characterized in that the mass volume ratio of the 5-fluorouracil to the reaction solvent is 1: 8-15 g/mL.
The preferable scheme is that the preparation method of tegafur shown as the formula (I) is characterized in that the feeding molar ratio of 5-fluorouracil to tetrahydrofuran is 1: 1 to 2, particularly preferably 1: 1.6.
the preferable scheme is that the preparation method of tegafur shown as the formula (I) is characterized in that the feeding molar ratio of 5-fluorouracil to the catalyst is 1: 0.01 to 0.04, and particularly preferably 1: 0.02.
the preferable scheme is that the preparation method of tegafur shown in formula (I) is characterized in that the feeding molar ratio of 5-fluorouracil to peroxide is as follows: 1: 1.2 to 4, wherein 1: 2.5.
the preferable scheme is that the reaction temperature is 35-50 ℃ in the preparation method of the tegafur shown in the formula (I).
In a preferable scheme, the reaction time is 3.0-8.0 h.
Preferably, the preparation method of the tegafur shown in the formula (I) comprises the step of preparing an extract liquid by using an ice water/ethyl acetate mixed liquid, an ice water/dichloromethane mixed liquid, an ice water/chloroform mixed liquid or an ice water/methyl tert-butyl ether mixed liquid.
The preferable scheme is that the solvent used in the recrystallization process is absolute methanol or absolute ethanol.
Compared with the prior art, the invention has the following technical effects:
1. by means of cross dehydrogenation coupling reaction, the activation energy of the reaction can be obviously reduced and the reaction temperature can be reduced under the condition of the existence of a catalyst and an oxidant, so that the reaction condition is simplified and the reaction time is greatly shortened.
2. The reduction of the activation energy and the reaction temperature in the reaction system increases the selectivity of the reaction, so that the yield and the purity of the final product are obviously improved; the product yield reaches more than 88 percent, the purity is more than 99.8, and the maximum single impurity is less than 0.1 percent.
3. In the invention, the two starting materials do not need pre-derivatization treatment, the production operation steps are simplified, and the high selectivity of the reaction system reduces the generation of byproducts, thereby simplifying the refining process and reducing the production cost and energy consumption.
In a word, the invention records a preparation method of tegafur, and the whole process has the advantages of simple and easily-obtained raw materials, high reaction efficiency, high reaction selectivity, mild reaction conditions, simple and convenient operation steps, high product yield, no pollution to the environment and suitability for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The invention adopts HPLC to measure the purity of tegafur, and the chromatographic conditions are as follows: [ column for chromatography: agilent 20RBAX SB-Aq (4.6 mm. times.250 mm,5.0 μm); mobile phase A: methanol-acetonitrile-water (5: 5: 90); mobile phase B: methanol-acetonitrile (50: 50), gradient elution (0 → 25 min: A100%; 25 → 40 min: A100% → 40; 40 → 60 min: A40 → 100%); column temperature: 25 ℃; detection wavelength: 271 nm; flow rate: 1.0 mL/min-1(ii) a Sample introduction amount: 20 μ L]。
Example 1
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (11.54g, 0.16mol), copper acetate (399.30mg, 2.0mmol), hydrogen peroxide solution (28.33g, 0.25mol, 30%), N, N-dimethylformamide (150mL) into a flask, starting stirring, heating to 40 ℃, reacting for 5h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and ethyl acetate (300mL), stirring for 15min, separating, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, and filteringConcentrating the filtered filtrate under reduced pressure to dry to obtain crude tegafur product, recrystallizing with anhydrous methanol to obtain refined tegafur product with yield of 92.35%, and detecting by HPLC, wherein t isRThe product obtained in 13.926min is tegafur, the purity is 99.952%, and the maximum single impurity is 0.016%.
Example 2
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (7.21g, 0.10mol), copper acetate (399.30mg, 2.0mmol), hydrogen peroxide solution (28.33g, 0.25mol, 30%), N, N-dimethylformamide (150mL) into a flask, starting stirring, heating to 40 ℃, reacting for 5h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and dichloromethane (300mL), stirring for 15min, separating, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous methanol to obtain a refined product of tegafur, wherein the yield is 90.16%, and detecting by HPLC, wherein t is tRThe obtained product is tegafur at 13.875min, the purity is 99.894%, and the maximum single impurity is 0.019%.
Example 3
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (14.42g, 0.20mol), copper acetate (399.30mg, 2.0mmol), hydrogen peroxide solution (28.33g, 0.25mol, 30%), N, N-dimethylformamide (150mL) into a flask, starting stirring, heating to 40 ℃, reacting for 5h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and ethyl acetate (300mL), stirring for 15min, separating, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous methanol to obtain a refined product of tegafur, wherein t is detected by HPLC, and the yield is 91.38%, wherein t is tRThe product obtained in 13.863min is tegafur, the purity is 99.927%, and the maximum single impurity is 0.016%.
Example 4
5-Fluorouracil (13.00g, 0.10mol), tetrahydrofuran (18.03g, 0.25mol), copper acetate (399.30mg, 2.0mmol), hydrogen peroxide solution (28.33g, 0.25mol, 30%), N, N-dimethylformamide (150mL) were added to the flask, stirred, heated to 40 deg.C, reacted for 5h, and then filteredFiltering, pouring the filtrate into a mixed solution of ice water (500mL) and ethyl acetate (300mL), stirring for 15min, separating liquid, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, concentrating the filtered filtrate under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous methanol to obtain a refined product of tegafur with a yield of 90.56%, and detecting by HPLC (high performance liquid chromatography), wherein t isRTegafur 13.903min, 99.882% purity, max mono-hetero 0.025%.
Example 5
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (11.54g, 0.16mol), copper acetate (199.65mg, 1.0mmol), tert-butyl peroxide (22.53g, 0.25mol) and N, N-dimethylformamide (100mL) into a flask, stirring, heating to 40 ℃, reacting for 6h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and trichloromethane (300mL), stirring for 15min, separating liquid, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous methanol to obtain a refined product of tegafur, wherein t is detected by HPLC (detection), wherein t is tR13.850min is tegafur, purity 99.916%, maximum single hetero 0.021%.
Example 6
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (11.54g, 0.16mol), copper acetate (179.69mg, 0.9mmol), hydrogen peroxide solution (28.33g, 0.25mol, 30%), N, N-dimethylformamide (100mL) into a flask, starting stirring, heating to 40 ℃, reacting for 8h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and trichloromethane (300mL), stirring for 15min, separating, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous methanol to obtain a refined product of tegafur, wherein t is detected by HPLC (88.37 percent), and detecting the content of tR13.886min is tegafur, purity 99.815%, maximum single hetero 0.031%.
Example 7
Mixing 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (11.5)4g, 0.16mol), copper acetate (798.60mg, 4.0mmol), hydrogen peroxide solution (28.33g, 0.25mol, 30%), N, N-dimethylformamide (200mL) are added into a flask, stirring is started, heating is carried out to 40 ℃, reaction is carried out for 3h, filtration is carried out, filtrate is poured into mixed solution of ice water (500mL) and ethyl acetate (300mL), liquid separation is carried out after stirring for 15min, an organic phase is washed by purified water (100mL multiplied by 3) and saturated saline solution (100mL) in sequence, anhydrous sodium sulfate is dried, filtrate is reduced pressure and concentrated to dryness after filtration to obtain crude tegafur product, refined tegafur product is obtained after recrystallization of anhydrous methanol, yield is 91.69%, detection is carried out by HPLC, wherein t is tRThe obtained product is tegafur with the purity of 99.934% and the maximum single impurity content of 0.023% in 13.859 min.
Example 8
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (11.54g, 0.16mol), copper acetate (898.43mg, 4.5mmol), tert-butyl peroxide (22.53g, 0.25mol) and N, N-dimethylformamide (150mL) into a flask, stirring, heating to 40 ℃, reacting for 3h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and ethyl acetate (300mL), stirring for 15min, separating liquid, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous methanol to obtain a refined product of tegafur with yield of 89.69%, detecting by HPLC, wherein t is tR13.929min is tegafur, purity 99.937%, maximum single hetero 0.031%.
Example 9
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (11.54g, 0.16mol), palladium acetate (448.98mg, 2.0mmol), hydrogen peroxide solution (13.60g, 0.12mol, 30%) and dimethyl sulfoxide (150mL) into a flask, stirring, heating to 50 ℃, reacting for 6h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and ethyl acetate (300mL), stirring for 15min for liquid separation, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, concentrating the filtered filtrate under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous methanol to obtain a refined product of tegafur with yield of 90.12%, and detecting by HPLC, wherein t is tR13.874min is tegafur, pureThe degree was 99.936%, the maximum single impurity was 0.022%.
Example 10
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (11.54g, 0.16mol), nickel acetate (353.60mg, 2.0mmol), hydrogen peroxide solution (45.33g, 0.40mol, 30%) and dimethyl sulfoxide (150mL) into a flask, stirring, heating to 40 ℃, reacting for 5h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and methyl tert-butyl ether (300mL), stirring for 15min, separating liquid, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, concentrating the filtered liquid under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous methanol to obtain a refined product of tegafur, wherein the yield is 91.83%, and detecting by HPLC, wherein t is tRThe 13.913min is tegafur, the purity is 99.914%, and the maximum single impurity is 0.035%.
Example 11
Adding 5-fluorouracil (13.00g, 0.10mol), tetrahydrofuran (11.54g, 0.16mol), copper acetate (363.3mg, 2.0mmol), hydrogen peroxide solution (51.00g, 0.45mol, 30%), N, N-dimethylformamide (150mL) into a flask, starting stirring, heating to 35 ℃, reacting for 5h, filtering, pouring the filtrate into a mixed solution of ice water (500mL) and ethyl acetate (300mL), stirring for 15min for liquid separation, washing an organic phase with purified water (100mL multiplied by 3) and saturated saline (100mL) in sequence, drying with anhydrous sodium sulfate, concentrating the filtered filtrate under reduced pressure to dryness to obtain a crude product of tegafur, recrystallizing with anhydrous ethanol to obtain a refined product of tegafur, wherein the yield is 89.52%, and detecting by HPLC, wherein t is tRThe product obtained at 13.846min is tegafur, the purity is 99.879%, and the maximum single impurity is 0.038%.
Claims (10)
1. A preparation method of tegafur is characterized by comprising the following steps:
adding 5-fluorouracil, tetrahydrofuran, a catalyst and peroxide into a certain solvent at room temperature, heating a reaction system until the reaction is finished, filtering, pouring filtrate into extract liquor for extraction and separation, washing an organic phase with purified water and saturated saline solution in turn, drying with anhydrous sodium sulfate, concentrating the filtered filtrate under reduced pressure to dryness to obtain a tegafur crude product, and recrystallizing to obtain a tegafur refined product.
2. The process according to claim 1, wherein the reaction solvent is N, N-dimethylformamide or dimethylsulfoxide.
3. The method for preparing tegafur according to claim 1, wherein the catalyst is copper acetate, nickel acetate or palladium acetate.
4. A process for preparing tegafur according to claim 1, wherein said peroxide is hydrogen peroxide or t-butyl peroxide.
5. A preparation method of tegafur according to claim 1, characterized in that the mass volume ratio of 5-fluorouracil to the reaction solvent is 1: 8-15 g/mL.
6. A preparation method of tegafur according to claim 1, characterized in that the feeding mole ratio of 5-fluorouracil to tetrahydrofuran, catalyst and peroxide is 1: 1-2: 0.01-0.04: 1.2 to 4.
7. The method for preparing tegafur according to claim 1, wherein the reaction temperature is 35 to 50 ℃.
8. The preparation method of tegafur according to claim 1, wherein the reaction time is 3.0 to 8.0 hours.
9. The method of claim 1, wherein the extract is ice water/ethyl acetate mixture, ice water/dichloromethane mixture, ice water/chloroform mixture, or ice water/methyl tert-butyl ether mixture.
10. The method for preparing tegafur according to claim 1, wherein the solvent used in the recrystallization is absolute methanol or absolute ethanol.
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| CN111925361A (en) * | 2020-08-18 | 2020-11-13 | 江苏集萃分子工程研究院有限公司 | Preparation method of antineoplastic drug tegafur |
| CN112679479A (en) * | 2019-10-18 | 2021-04-20 | 鲁南制药集团股份有限公司 | Tegafur crystal form |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107235967A (en) * | 2017-07-27 | 2017-10-10 | 福州大学 | The synthesis technique of antineoplastic Tegafur |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107235967A (en) * | 2017-07-27 | 2017-10-10 | 福州大学 | The synthesis technique of antineoplastic Tegafur |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679479A (en) * | 2019-10-18 | 2021-04-20 | 鲁南制药集团股份有限公司 | Tegafur crystal form |
| CN112679479B (en) * | 2019-10-18 | 2023-06-27 | 鲁南制药集团股份有限公司 | Tegafur crystal form |
| CN111925361A (en) * | 2020-08-18 | 2020-11-13 | 江苏集萃分子工程研究院有限公司 | Preparation method of antineoplastic drug tegafur |
| CN111925361B (en) * | 2020-08-18 | 2021-07-16 | 江苏集萃分子工程研究院有限公司 | Preparation method of antineoplastic drug tegafur |
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