CN112110854A - Preparation method of gimeracil intermediate - Google Patents
Preparation method of gimeracil intermediate Download PDFInfo
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- CN112110854A CN112110854A CN201910544170.9A CN201910544170A CN112110854A CN 112110854 A CN112110854 A CN 112110854A CN 201910544170 A CN201910544170 A CN 201910544170A CN 112110854 A CN112110854 A CN 112110854A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to the technical field of chemical synthesis, and provides a method for preparing a gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone, which takes 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene as a starting material, and performs reflux cyclization in an acetic acid aqueous solution with the mass fraction of 80%, the temperature of a reaction solution is reduced, acetic anhydride is added, the temperature is raised to a required temperature, and sulfonyl chloride is added dropwise to perform chlorination reaction to obtain a product; the method has the advantages of good yield, high purity, easy operation, production cost saving and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a gimeracil intermediate.
Background
Gemfibrozil (I), chemical name: 5-chloro-4-hydroxy-2- (lH) -pyridone, CAS number 103766-25-2, having the following structural formula:
gimeracil is one of the components of a new medicine tegafur for treating gastric cancer, can inhibit the catabolism of 5-fluorouracil released from tegafur under the action of dihydropyrimidine dehydrogenase, and is beneficial to keeping the effective concentration of 5-fluorouracil in blood and tumor tissues for a long time, thereby achieving the curative effect similar to the continuous intravenous infusion of 5-fluorouracil.
Tegafur is a fluorouracil derivative oral anticancer agent, which comprises tegafur and the following two types of regulators: gimeracil and oteracil. The effects of the three components are as follows: tegafur is a prodrug of 5-Fu, has excellent oral bioavailability, and can be converted into 5-Fu in vivo. Gimeracil inhibits the catabolism of 5-Fu released from FT by dihydropyrimidine dehydrogenase, and helps to maintain an effective concentration of 5-Fu in blood and tumor tissue for a prolonged period of time, thereby achieving a therapeutic effect similar to that achieved by continuous intravenous infusion of 5-Fu.
The oxiracetam can block the phosphorylation of 5-Fu, and after oral administration, the oxiracetam has high distribution concentration in gastrointestinal tissues, thereby influencing the distribution of 5-Fu in the gastrointestinal tract and further reducing the toxic effect of 5-Fu. Tegafur has the following advantages compared with 5-Fu: firstly, can maintain higher blood concentration and improve anticancer activity; ② the toxicity of the medicine is obviously reduced; and thirdly, the medicine is convenient to administer.
In japan, tegafur was approved for the treatment of advanced gastric cancer in 1999, for the treatment of head and neck cancer in 2001, for the treatment of colorectal cancer in 2003, and for the treatment of non-small cell lung cancer in 2004. Years of clinical application prove that tegafur is a safe and effective anti-cancer drug. According to statistics, the tegafur is used in more than 80% of cases in the chemotherapy of the advanced gastric cancer in Japan, and the treatment effective rate can reach 44.6%.
At present, the synthesis methods of gimeracil are researched more at home and abroad, wherein the most researched method is to prepare 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene by taking malononitrile, trimethyl orthoacetate and 1, 1-dimethoxytrimethylamine as starting materials, cyclize the raw materials by glacial acetic acid with volume fraction (or mass fraction) of 80% to obtain 3-cyano-4-methoxy-2 (1H) -pyridone, form 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone by chlorination, and obtain the gimeracil by hydrolysis, and the reaction route is as follows:
the above route is disclosed in the literature (Shin-go Yano, equivalent. HETEROCYCLES, 1993, Vol.36.NO.1, 145-148.). Wherein in the disclosure of this document the yield of intermediate IV described in the above scheme is 95%; the yield of the intermediate V is 91 percent, but the purity of the intermediate V is not high, and the impurities are excessive even if the intermediate V is refined by methanol and isopropyl ether, so that the quality of the finished product of the gimeracil is influenced.
Helichrysum et al disclose a method for synthesizing gimeracil (Shenyang pharmaceutical university, 11.2005, vol. 22, 6 th, 420-; and the chlorinating reagent for reacting the intermediate V is changed into N-chlorosuccinimide (NCS), and the yield of the intermediate V is 92.3 percent. Finally, the gimeracil product is refined by ethanol, and the total yield is 65.6%.
The literature (Shamei et al, 5-chloro-2, 4-dihydroxypyridine synthesis [ J ]. Chinese pharmaceutical guidance, vol.4, 20, 2007, 14-15.) discloses the situation of the above route, wherein the yield of intermediate IV described in the above route is 92.2%, and the yield of intermediate V is 77.4%. Heating and refluxing the intermediate V by 47% HBr for 24h, finally obtaining crude guaiamidine by an alkali dissolution and acid precipitation method with the yield of 91.4%, and refining the crude guaiamidine by adopting 90% ethanol with the yield of 90%.
The document (Liuyu, et al, Synthesis [ J ] of dihydropyrimidine dehydrogenase inhibitor gimeracil, 2008, 3 rd stage, 252. 254.), also discloses the situation of the above route, wherein the yield of the intermediate IV described in the above route is 86.1%, when the intermediate IV is subjected to chlorination synthesis of the intermediate V, the reaction solution is decompressed and concentrated to 1/5 volume, 400ml of ice water is added, the yield of crystallization is 84.4%, and finally, hydrolysis is carried out by 48% HBr, and alkali dissolution and acidification are carried out to refine to obtain the gimeracil content which is not less than 99%.
The above-mentioned route was further studied in the literature (synthesis of 5-chloro-4-hydroxy-2- (1H) pyridone [ J ]. Chemicals, vol.30, 12, 2008, 939-940.) where the yield of intermediate V described in the above-mentioned route was 96% after the intermediate IV was synthesized by evaporating the solvent and freezing it in a refrigerator, and the yield of intermediate V described in the above-mentioned route was 87.9% after the intermediate IV was chlorinated and evaporated under reduced pressure and treated with methanol and isopropyl ether (1: 1).
The reaction conditions of the above-mentioned routes are also improved in the literature (ligustrum martiani et al, gemfibrozil and key intermediate preparation [ J ]. zilu drug 2012, 31 vol.3 phase 132-133.), and first, the research on the previously disclosed routes has found that the final product is purified by recrystallization, the yield is low, the effect is poor, and it is difficult to control the single impurity content of gemfibrozil to be less than 0.1%. Through improvement, the yield of the intermediate IV described in the above route is 91%, the yield of the crude intermediate V is 84.8%, the crude intermediate is dissolved by 10% sodium hydroxide, the pH value is adjusted to 9.3, the filtrate is filtered, the pH value is adjusted to 5 by acetic acid, a large amount of white solid is separated out, the refining yield is 90%, HPLC related substances are more than 99.8%, and single impurities are less than 0.1%. Finally, the yield of gimeracil was 90% and the HPLC related substance was 99.9%. The purity of the key intermediate 5-chloro-3-cyano-4-methoxy-2 (H) -pyridone (i.e., intermediate V in the above route) affects the purity of the final product, which needs to be purified to achieve, but the overall intermediate and product yields are affected.
A study of the route disclosed in the literature (Shin-go Yano, equivalent. HETEROCYCLES, 1993, vol.36.NO.1,145-148.) in the CN200610086191.3 patent revealed that chlorination with sulfuryl chloride produced the intermediate 5-chloro-3-cyano-4-methoxy-2 (H) -pyridone (i.e., intermediate V of the above route) with very poor purity. Further research shows that the new intermediate is obtained in the chlorination process, and the intermediate is used for preparing gemfibrozil with the content of 99 percent and related substances of less than 0.5 percent. Also, the yield is low and the purity is poor.
The CN201310371750.5 patent discloses a preparation scheme of intermediate 5-chloro-3-cyano-4-methoxy-2 (H) -pyridone (i.e. intermediate V of the above route) with yield 80-85% and HPLC > 99.0%.
The CN201310620434.7 patent discloses a preparation scheme of using thionyl chloride to replace sulfuryl chloride, and using 3-cyano-4-methoxy-2 (1H) -pyridone as raw material to chlorinate to obtain intermediate 5-chloro-3-cyano-4-methoxy-2 (H) -pyridone (i.e. intermediate V in the above route). The yield of the intermediate 5-chloro-3-cyano-4-methoxy-2 (H) -pyridone was 92.7%, and the purity effect was not observed.
The CN201610674757.8 patent discloses a preparation scheme of chlorination of 3-cyano-4-methoxy-2 (1H) -pyridone as a raw material to obtain an intermediate 5-chloro-3-cyano-4-methoxy-2 (H) -pyridone (i.e., the intermediate V in the above route). The yield of intermediate 5-chloro-3-cyano-4-methoxy-2 (H) -pyridone was 95.0%. The purity of the finished product of the gimeracil is more than 99.5 percent, and the single impurity is less than 0.1 percent.
Patent CN201110364653.4 discloses a preparation method of high-purity gimeracil, which adopts 2-hydroxy-4-methoxy-3-cyanopyridine as a starting material to prepare a gimeracil crude product through chlorination addition and hydrolysis reaction, and adopts a column chromatography method to refine the gimeracil to obtain the high-purity gimeracil. The 2-hydroxy-4-methoxy-3-cyanopyridine is used as a starting material to prepare the crude gimeracil product, which contains more impurities, and can be refined for multiple times to reach more than 99 percent, and the single impurity exceeds 0.1 percent and is difficult to remove.
5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone, is a key intermediate for preparing gimeracil. The inventor verifies the existing synthesis scheme and finds that the yield and the purity are poor, and the requirement of industrial production cannot be met. Most of the prior art disclosed in the prior art are obtained by cyclization and chlorination of the compound III in the above route, and the yield and purity of the compound III seriously affect the quality of the gimeracil, but most of the prior art solves the problem by purifying 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone or purifying the final product gimeracil. It can be seen that the improvement of the yield and purity of 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone is a problem to be solved urgently.
Disclosure of Invention
Aiming at the problems in the existing gemfibrozil preparation technology, the invention provides a preparation method of an important midbody 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone of gemfibrozil. The intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone prepared by the method has the advantages of good yield, high purity and easiness in operation, and is suitable for industrial production.
The invention is realized by the following technical scheme:
a preparation method of a gimeracil intermediate takes 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene, namely a compound III, as a starting material, and performs reflux cyclization in an acetic acid aqueous solution with the mass fraction of 80%, the reaction liquid is cooled, acetic anhydride is added, the temperature is raised to a required temperature, sulfonyl chloride is added dropwise to perform chlorination, and the gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone, namely a compound V, is obtained through treatment, and the reaction formula is as follows:
preferably, the mass ratio of the 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene to the 80% acetic acid aqueous solution is 1: 3-5, preferably 1: 4.
Preferably, the mass ratio of the 80% acetic acid aqueous solution to the acetic anhydride feeding material is 1: 1.15-1.3, preferably 1: 1.2.
Preferably, the molar ratio of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene to sulfonyl chloride is 1: 1.2 to 1.4, preferably 1: 1.3.
In the preferable scheme, the temperature of the reaction liquid is reduced to 20-25 ℃.
In a preferred scheme, the temperature rise temperature is 50-55 ℃.
In the scheme of the invention, after the chlorination reaction is finished, the scheme of post-treatment can use the treatment mode disclosed by the prior art;
in a preferable scheme, after the chlorination reaction is finished, decompressing and concentrating the reaction liquid until no liquid flows out, adding ice water, controlling the temperature to be 0-5 ℃, stirring and crystallizing, performing suction filtration, washing a filter cake by the ice water until the washing liquid is neutral, and drying a product, namely the intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone formula V. Wherein the mass-volume ratio of the 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene to the ice water is 1: 3-5 g/ml.
The technical advantages of the invention are as follows:
1. provides a method for directly synthesizing an important intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) of gimeracil by using 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene as a starting material and adopting one-step reaction.
2. The invention does not process the intermediate IV, 80 percent of acetic acid is utilized in the next step, and the post-processing step of synthesizing the intermediate V is used for distilling off the acetic acid under reduced pressure, so the acetic acid can be recycled, and the reaction step and the cost are saved.
3. The yield of the intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) is improved, particularly, in the chlorination process, the purity of the chlorinated product intermediate (V) is greatly improved to 99.9% due to the existence of acetic anhydride, and the problem that the quality of a gimeracil product is influenced due to a large amount of impurities in the actual production is solved.
Drawings
FIG. 1 is an HPLC chromatogram of the intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) obtained in example 1.
Detailed Description
The benefits of the present invention will now be further illustrated by the following examples, which are intended for the purpose of illustration only and should not be construed as limiting the invention, and all such obvious modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention.
The structure of the intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) is confirmed by the following data:1H-NMR(400MHz，DMSO-d6):11.37(s,1H)，8.09(s,1H)，4.03(s,3H)。
IR(KBr)cm-1:3191.82，3063.15，2225.53，1670.10，1606.33。
in addition, due to the reasons of detecting instruments, operating and the like, data can have errors, and the structure of the data is not influenced; melting points are also subject to error due to devitrification conditions. The following examples are illustrative of the conditions in the protocol.
Example 1
Adding 177.2g (1mol) of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene (III) and 708.8g of acetic acid aqueous solution with the mass fraction of 80% into a three-neck flask under stirring, adding a reflux device, heating for reflux reaction, detecting by TLC, cooling to 20-25 ℃ after the reaction is finished, adding 850.5g of acetic anhydride, and continuously stirring for 1-1.5 hours; heating to 50-55 ℃, then dropwise adding 175.5g (1.3mol) of sulfonyl chloride, and after dropwise adding is finished, keeping the temperature and continuing to react; TLC detection, after the reaction is finished, evaporating the solvent under reduced pressure, adding 886ml of ice water into the residue, stirring at 0-5 ℃ for crystallization for 2-3 hours, filtering, washing a filter cake with the ice water until the filtrate is neutral, and drying; the off-white gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) is obtained, and the yield is 96.5%; HPLC purity 99.928%, maximum single impurity less than 0.1%; m.p.208-210 ℃.
Example 2
Adding 177.2g (1mol) of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene (III) and 531.6g of acetic acid aqueous solution with the mass fraction of 80% into a three-neck flask under stirring, adding a reflux device, heating for reflux reaction, detecting by TLC, cooling to 20-25 ℃ after the reaction is finished, adding 611.4g of acetic anhydride, and continuously stirring for 1-1.5 hours; heating to 50-55 ℃, then dropwise adding 162g (1.2mol) of sulfonyl chloride, and after dropwise adding is completed, keeping the temperature and continuing to react; TLC detection, after the reaction is finished, evaporating the solvent under reduced pressure, adding 708ml of ice water into the residue, stirring at 0-5 ℃ for crystallization for 2-3 hours, filtering, washing the filtrate with ice water to be neutral, and drying; obtain the white gemfibrozil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) with the yield of 94.38%; HPLC purity 99.920% with maximum single impurity less than 0.1%.
Example 3
Adding 177.2g (1mol) of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene (III) and 886.0g of acetic acid aqueous solution with the mass fraction of 80% into a three-neck flask under stirring, adding a reflux device, heating for reflux reaction, detecting by TLC, cooling to 20-25 ℃ after the reaction is finished, adding 1151.8g of acetic anhydride, and continuing stirring for 1-1.5 hours; heating to 50-55 ℃, then dropwise adding 189.0g (1.4mol) of sulfonyl chloride, and after dropwise adding is finished, keeping the temperature and continuing to react; TLC detection, after the reaction is finished, evaporating the solvent under reduced pressure, adding 532ml of ice water into the residue, stirring at 0-5 ℃ for crystallization for 2-3 hours, filtering, washing the filtrate with the ice water to be neutral, and drying; the off-white gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) is obtained with the yield of 95.6 percent; HPLC purity 99.917% with maximum single impurity less than 0.1%.
Example 4
Adding 177.2g (1mol) of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene (III) and 708.8g of acetic acid aqueous solution with the mass fraction of 80% into a three-neck flask under stirring, adding a reflux device, heating for reflux reaction, detecting by TLC, cooling to 20-25 ℃ after the reaction is finished, adding 992.3g of acetic anhydride, and continuing stirring for 1-1.5 hours; heating to 50-55 ℃, then dropwise adding 175.5g (1.3mol) of sulfonyl chloride, and after dropwise adding is finished, keeping the temperature and continuing to react; TLC detection, after the reaction is finished, evaporating the solvent under reduced pressure, adding 886ml of ice water into the residue, stirring at 0-5 ℃ for crystallization for 2-3 hours, filtering, washing a filter cake with the ice water until the filtrate is neutral, and drying; the off-white gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) is obtained with a yield of 95.2%; HPLC purity 99.911% with maximum single impurity less than 0.1%.
Example 5
Adding 177.2g (1mol) of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene (III) and 708.8g of acetic acid aqueous solution with the mass fraction of 80% into a three-neck flask under stirring, adding a reflux device, heating for reflux reaction, detecting by TLC, cooling to 20-25 ℃ after the reaction is finished, adding 850.5g of acetic anhydride, and continuously stirring for 1-1.5 hours; heating to 50-55 ℃, then dropwise adding 175.5g (1.3mol) of sulfonyl chloride, and after dropwise adding is finished, keeping the temperature and continuing to react; TLC detection, after the reaction is finished, concentrating under reduced pressure to 1/5 volume, adding 886ml of ice water into the residue, stirring at 0-5 ℃ for crystallization for 2-3 hours, filtering, washing the filter cake with the ice water, washing the filtrate to be neutral, and drying; the off-white gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) is obtained with the yield of 92.4 percent; HPLC purity 99.918% with maximum single impurity less than 0.1%.
Example 6
Adding 177.2g (1mol) of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene (III) and 708.8g of acetic acid aqueous solution with the mass fraction of 80% into a three-neck flask under stirring, adding a reflux device, heating for reflux reaction, detecting by TLC, cooling to 20-25 ℃ after the reaction is finished, adding 850.5g of acetic anhydride, and continuously stirring for 1-1.5 hours; heating to 50-55 ℃, then dropwise adding 175.5g (1.3mol) of sulfonyl chloride, and after dropwise adding is finished, keeping the temperature and continuing to react; TLC detection, adding 1700ml of ice water after the reaction is finished, stirring at 0-5 ℃ for crystallization for 2-3 hours, filtering and drying; the off-white gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) is obtained with a yield of 87.6%; HPLC purity 99.925%, maximum single impurity less than 0.1%; m.p.207-210 ℃.
Example 7
Adding 177.2g (1mol) of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene (III) and 708.8g of acetic acid aqueous solution with the mass fraction of 80% into a three-neck flask under stirring, adding a reflux device, heating for reflux reaction, detecting by TLC, cooling to 20-25 ℃ after the reaction is finished, adding 850.5g of acetic anhydride, and continuously stirring for 1-1.5 hours; heating to 50-55 ℃, then dropwise adding 175.5g (1.3mol) of sulfonyl chloride, and after dropwise adding is finished, keeping the temperature and continuing to react; TLC detection, after the reaction is finished, concentrating under reduced pressure to be dry, adding 400ml of methanol and 400ml of isopropyl ether into the residue, stirring at 0-5 ℃ for crystallization for 2-3 hours, filtering, washing a filter cake with methanol, and drying; to obtain the white gemfibrozil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) with the yield of 88.2 percent; HPLC purity 99.928%, maximum single impurity less than 0.1%; m.p.209-211 ℃.
Example 8
Adding 177.2g (1mol) of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene (III) and 708.8g of acetic acid aqueous solution with the mass fraction of 80% into a three-neck flask under stirring, adding a reflux device, heating for reflux reaction, detecting by TLC, cooling to 20-25 ℃ after the reaction is finished, adding 803.3g of acetic anhydride, and continuing stirring for 1-1.5 hours; heating to 50-55 ℃, then dropwise adding 189.0g (1.4mol) of sulfonyl chloride, and after dropwise adding is finished, keeping the temperature and continuing to react; TLC detection, after the reaction is finished, evaporating the solvent under reduced pressure, adding 532ml of ice water into the residue, stirring at 0-5 ℃ for crystallization for 2-3 hours, filtering, washing the filtrate with the ice water to be neutral, and drying; the off-white gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone (V) is obtained with the yield of 83.2 percent; HPLC purity 99.576%, max monohetero 0.17%.
Claims (6)
1. A preparation method of a gimeracil intermediate is characterized in that 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene, namely a compound III, is used as a starting material, reflux cyclization is carried out in an acetic acid aqueous solution with the mass fraction of 80%, the temperature of a reaction liquid is reduced, acetic anhydride is added, the temperature is raised to a required temperature, sulfonyl chloride is added dropwise for chlorination, and the gimeracil intermediate 5-chloro-3-cyano-4-methoxy-2 (1H) -pyridone, namely a compound V, is obtained through treatment, and the reaction formula is as follows:
2. the method of claim 1, wherein the mass ratio of 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene to 80% aqueous acetic acid is 1: 3 to 5; preferably 1: 4.
3. The method for preparing gemfibrozil intermediate according to claim 1, wherein the mass ratio of the 80% aqueous acetic acid solution to the acetic anhydride fed is 1: 1.15-1.3; preferably 1: 1.2.
4. The process for preparing gemfibrozil intermediates according to claim 1, wherein 1, 1-dicyano-2-methoxy-4- (N, N-dimethylamino) -1, 3-butadiene and sulfonyl chloride are fed in a molar ratio of 1: 1.2 to 1.4; preferably 1: 1.3.
5. The method for preparing gemfibrozil intermediate as claimed in claim 1, wherein the temperature of the reaction solution is reduced to 20-25 ℃.
6. The method for preparing gemfibrozil intermediate according to claim 1, wherein the temperature rise is 50-55 ℃.
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| CN113861106A (en) * | 2021-10-26 | 2021-12-31 | 山东安舜制药有限公司 | Production process of high-purity medicinal gimeracil |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113861106A (en) * | 2021-10-26 | 2021-12-31 | 山东安舜制药有限公司 | Production process of high-purity medicinal gimeracil |
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