CN112028838B - Preparation method of 2-ethoxy-5-fluorouracil impurity - Google Patents
Preparation method of 2-ethoxy-5-fluorouracil impurity Download PDFInfo
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Abstract
The utility model discloses a preparation method of 2-ethoxy-5-fluorouracil impurities. The preparation method of the 2-ethoxy-5-fluorouracil impurity comprises the following steps: (1) methyl methoxyacetate or ethyl ethoxyacetate is taken as a raw material, sodium methoxide is taken as alkali to extract hydrogen, and toluene is taken as a solvent, and the raw material and ethyl formate are respectively dripped into a uniform mixing system and react to form a 2-ethoxy-5-fluorouracil impurity intermediate; (2) dripping ethoxy isourea into the 2-ethoxy-5-fluorouracil impurity intermediate, adjusting the pH to 9-10, and then sequentially heating, distilling under reduced pressure, dissolving in water, and purifying to obtain a crude product of the 2-ethoxy-5-fluorouracil impurity; (3) adding water into the crude product of the 2-ethoxy-5-fluorouracil impurity for dissolving, then cooling and crystallizing by ice water, filtering, washing by water, and drying to obtain the 2-ethoxy-5-fluorouracil impurity. The preparation method has the advantages of short route and simple post-treatment, and the prepared 2-ethoxy-5-fluorouracil has high impurity purity and can be applied to the research of reference substances.
Description
Technical Field
The utility model belongs to the field of drug synthesis, relates to preparation of drug impurities, and particularly relates to a preparation method of 2-ethoxy-5-fluorouracil impurities.
Background
2-ethoxy-5-fluorouracil (CAS number: 56177-80-1) is an odorless white crystalline powder of formula C6H7FN2O2158.13 molecular weight, water insolubility, density 1.36g/cm3Melting point 180-. 2-ethoxy-5-fluorouracil is an important pharmaceutical intermediate.
The medicine impurities are closely related to the quality and safety of the medicine. The research on 2-ethoxy-5-fluorouracil impurities in Chinese pharmacopoeia is less, and no published data reports an efficient synthesis method of 1 (2-ethoxy-5-methoxy-4- (3H) -uracil) impurity and 2(2, 5-diethoxy-4- (3H) -uracil impurity so far.
Disclosure of Invention
The utility model mainly aims to provide a preparation method of 2-ethoxy-5-fluorouracil impurities, and provides a qualified reference substance for quality control of 2-ethoxy-5-fluorouracil.
In order to achieve the purpose, the technical scheme adopted by the utility model comprises the following steps:
the embodiment of the utility model provides a preparation method of 2-ethoxy-5-fluorouracil impurities, which comprises the following steps:
(1) respectively dripping the raw material and ethyl formate into a uniform mixed system which takes methyl methoxyacetate as a raw material, sodium methoxide as alkali and toluene as a solvent, and reacting to form a 2-ethoxy-5-fluorouracil impurity intermediate;
(2) dripping ethoxy isourea into the 2-ethoxy-5-fluorouracil impurity intermediate, adjusting the pH to 9-10, and then sequentially heating, distilling under reduced pressure, dissolving in water, and purifying to obtain a crude product of the 2-ethoxy-5-fluorouracil impurity;
(3) and adding water into the crude product of the 2-ethoxy-5-fluorouracil impurity to dissolve, and then sequentially cooling and crystallizing with ice water, filtering, washing with water and drying to obtain the 2-ethoxy-5-fluorouracil impurity.
Further, in the step (1), the organic solvent includes toluene.
Further, the purification treatment in the step (2) specifically comprises: adding a small amount of saturated saline solution for demulsification, extracting with dichloromethane, collecting organic phase, and concentrating.
Correspondingly, the preparation synthetic route is as follows:
the embodiment of the utility model also provides a preparation method of the 2-ethoxy-5-fluorouracil impurity, which comprises the following steps:
(1) respectively dripping the raw material and ethyl formate in a uniform mixed system which takes ethoxy ethyl acetate as a raw material, sodium methoxide as alkali to extract hydrogen and toluene as a solvent, and reacting to form a 2-ethoxy-5-fluorouracil impurity intermediate;
(2) dripping ethoxy isourea into the 2-ethoxy-5-fluorouracil impurity intermediate, adjusting the pH to 9-10, and then sequentially heating, distilling under reduced pressure, dissolving in water, and purifying to obtain a crude product of the 2-ethoxy-5-fluorouracil impurity;
(3) adding water into the crude product of the 2-ethoxy-5-fluorouracil impurity for dissolving, then cooling and crystallizing by ice water, filtering, washing by water, and drying to obtain the 2-ethoxy-5-fluorouracil impurity.
Further, in the step (1), the organic solvent includes toluene.
Further, the purification treatment in the step (2) specifically comprises: acidifying with refined hydrochloric acid to pH 3-4, cooling for crystallization, suction filtering and washing filter cake with small amount of water.
Correspondingly, the preparation synthetic route is as follows:
compared with the prior art, the utility model has the following beneficial effects:
the utility model provides a method for preparing 2-ethoxy-5-fluorouracil impurity 1 and impurity 2, which is simple to operate, provides a qualified reference substance for quality control of 2-ethoxy-5-fluorouracil, has short route and simple post-treatment, and the prepared 2-ethoxy-5-fluorouracil impurity 1 and impurity 2 have high purity (HPLC purity is more than 98 percent), and can be applied to reference substance research.
Detailed Description
Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the utility model, which can be embodied in various forms. Therefore, specific functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed embodiment.
In view of the defects of the prior art, the inventor of the present invention provides the technical scheme of the present invention through long-term research and a great deal of practice, and the prepared 2-ethoxy-5-fluorouracil impurity 1 and impurity 2 have high purity (HPLC purity is up to more than 98%), and can be applied to reference substance research; the technical solution, its implementation and principles will be further explained as follows.
One aspect of the embodiments of the present invention provides a method for preparing 2-ethoxy-5-fluorouracil impurities, which comprises the following steps:
(1) methyl methoxyacetate or ethyl ethoxyacetate is taken as a raw material, sodium methoxide is taken as alkali to extract hydrogen, and toluene is taken as a solvent, and the raw material and ethyl formate are respectively dripped into a uniform mixing system and react to form a 2-ethoxy-5-fluorouracil hybrid intermediate;
(2) dripping ethoxy isourea into the 2-ethoxy-5-fluorouracil impurity intermediate, adjusting the pH to 9-10, and then sequentially heating, distilling under reduced pressure, dissolving in water, and purifying to obtain a crude product of the 2-ethoxy-5-fluorouracil impurity;
(3) and adding water into the crude product of the 2-ethoxy-5-fluorouracil impurity to dissolve, and then sequentially cooling and crystallizing with ice water, filtering, washing with water and drying to obtain the 2-ethoxy-5-fluorouracil impurity.
In some preferred embodiments, in step (1), the organic solvent may include, but is not limited to, toluene.
In some preferred embodiments, in step (1), the temperature of the uniform mixed system with sodium methoxide as base and toluene as solvent is controlled to be 10-15 ℃.
In some preferred embodiments, in step (1), the dropping temperature of the raw material and the ethyl formate is 10 to 15 ℃ and the dropping time is 30 to 50 min.
In some preferred embodiments, methyl methoxyacetate is used as a raw material, and the purification treatment in the step (2) specifically comprises: adding a small amount of saturated saline solution for demulsification, extracting with dichloromethane, collecting organic phase, and concentrating.
In some preferred embodiments, the ethoxy ethyl acetate is used as a raw material, and the purification treatment in the step (2) specifically comprises: acidifying with refined hydrochloric acid to pH 3-4, cooling, crystallizing, suction filtering and washing filter cake with small amount of water.
In some preferred embodiments, in the step (3), the heating temperature for dissolving by adding water is 85-90 ℃.
In some typical examples, starting from methyl methoxyacetate, the 2-ethoxy-5-fluorouracil impurity 1: the synthetic route of the 2-ethoxy-5-methoxy-4- (3H) -uracil is as follows:
the synthetic route of the impurity 1 is as follows:
the method comprises the following steps:
(1) distilling a methanol solution of sodium methoxide to be fine powder under reduced pressure, adding a solvent of toluene while stirring, controlling the temperature to be 10-15 ℃, respectively dropwise adding ethyl formate and methyl methoxyacetate at the dropwise adding temperature of 10-15 ℃ for 30-50min, naturally raising the temperature to room temperature after the dropwise adding is finished, heating to 40 ℃, preserving the temperature for reacting for 4-5h, and standing overnight.
(2) Controlling the temperature of a reaction system to be 10-15 ℃, dropwise adding the ethoxy isourea, adjusting the pH value to be 9-10, heating to 40 ℃, preserving the heat, and reacting for 4-5 hours, wherein the reaction system is dark yellow and turbid; and (3) distilling under reduced pressure to remove the solvent, adding water into the system to stir and dissolve the system to obtain a dark yellow viscous syrup, adding a small amount of saturated saline solution to perform demulsification, extracting by using dichloromethane, collecting an organic phase, and concentrating to obtain a crude product (2-ethoxy-5-methoxy-4- (3H) -uracil) of the target product 2-ethoxy-5-fluorouracil impurity 1.
(3) Washing with water to refine crude product of impurity 1, adding 6-8ml of water, heating to dissolve completely, heating to 85-90 ℃, cooling with ice water for crystallization, performing suction filtration, washing filter cake with a small amount of water, and drying to obtain refined product of impurity 1.
Impurity 1 was characterized as follows:1H NMR(400MHz,DMSO-d6):δ12.40(s,1H),7.31(s, 1H),4.27(q,J＝7.1Hz,2H),3.67(s,3H),1.28(t,J＝7.1Hz,3H).13C NMR (101MHz,DMSO-d6):δ158.70,151.68,142.57,131.17,63.55,56.82,14.59. HRMS(ESI):m/z calcd for C7H10N2O3170.07; 171.10, the structure is correct.
In some typical examples, ethyl ethoxyacetate was used as the starting material, 2-ethoxy-5-fluorouracil impurity 2: the synthetic route of 2, 5-diethoxy-4- (3H) -uracil is as follows:
the synthetic route of the impurity 2 is as follows:
the method comprises the following steps:
(1) distilling a methanol solution of sodium methoxide to be fine powder under reduced pressure, adding a solvent of toluene while stirring, controlling the temperature to be 10-15 ℃, respectively dropwise adding ethyl formate and ethyl ethoxyacetate at the dropwise adding temperature of 10-15 ℃ for 30-50min, naturally raising the temperature to room temperature after the dropwise adding is finished, heating to 40 ℃, preserving the temperature for reacting for 4-5h, and standing overnight.
(2) Controlling the temperature of a reaction system to be 10-15 ℃, dropwise adding ethoxy isourea, adjusting the pH to be 9-10, heating to 40 ℃, and keeping the temperature to react for 4-5 h; distilling under reduced pressure to remove the solvent, adding water, stirring for dissolving, acidifying with refined hydrochloric acid to pH 3-4, cooling, crystallizing, filtering, and washing the filter cake with a small amount of water to obtain the crude product of the target product 2-ethoxy-5-fluorouracil impurity 2(2, 5-diethoxy-4- (3H) -uracil).
(3) Washing with water to refine crude product of impurity 2, adding water, heating to dissolve completely at 85-90 deg.C, cooling with ice water for crystallization, vacuum filtering, washing filter cake with small amount of water, and drying to obtain refined product of impurity 2.
Impurity 2 was characterized as follows:1H NMR(400MHz,DMSO-d6):δ7.29(s,1H),4.26(q, J＝7.1Hz,2H),3.88(q,J＝7.0Hz,2H),1.26(td,J＝7.0,4.2Hz,6H).13C NMR (101MHz,DMSO-d6):δ158.95,152.80,141.48,132.90,65.05,63.56,15.08, 14.61.HRMS(ESI):m/z calcd for C8H12N2O3184.08; 185.00 of found, and the structure is correct.
The technical solution of the present invention is further explained by the following embodiments. It will be readily understood by those skilled in the art that the examples are only for the purpose of facilitating understanding of the present invention and should not be construed as specifically limiting the present invention.
Example 1
Synthesis of impurity 1:
adding 157g of methanol solution of sodium methoxide into a dry and clean 500mL three-necked bottle, stirring, distilling under reduced pressure to form fine powder, adding 67g of solvent toluene, stirring while adding, controlling the temperature to be 10-15 ℃, respectively dropwise adding 56g of ethyl formate and 35g of methyl methoxyacetate, naturally raising the temperature to room temperature after dropwise adding, heating to 40 ℃, preserving heat for reaction for 4-5h, recovering to the room temperature, and standing overnight.
Controlling the temperature of the reaction system to be 10-15 ℃, dropwise adding 95g of ethoxy isourea, adjusting the pH to be 9-10, heating to 40 ℃, and carrying out heat preservation reaction for 4-5 h. Distilling under reduced pressure to remove solvent, adding 100g of water into dark yellow viscous syrup, stirring and dissolving, adding 30ml of saturated saline solution for demulsification, extracting with dichloromethane, collecting organic phase, concentrating to obtain 8.1g of crude product, adding 6-8ml of water into the crude product, heating to completely dissolve the crude product to about 90 ℃, cooling and crystallizing, filtering, and washing a filter cake with a small amount of water to obtain a white solid, namely a refined product of 2-ethoxy-5-fluorouracil impurity 1. Drying at 85 ℃ to obtain 1 mass of impurities of 3.1g, the total yield of 0.06 percent and the purity of 99.0 percent.
Synthesis of impurity 2:
adding 180g of methanol solution of sodium methoxide into a dry and clean 500mL three-necked bottle, distilling under reduced pressure to be fine powder, adding 70g of solvent toluene, stirring while adding, controlling the temperature to be 10-15 ℃, respectively dropwise adding 60g of ethyl formate and 41g of ethyl ethoxyacetate, naturally raising the temperature to room temperature after dropwise adding, heating to 40 ℃, preserving the temperature for reaction for 4-5h, and standing overnight after returning to the room temperature.
Controlling the temperature of the reaction system to be 10-15 ℃, dropwise adding 112g of ethoxy isourea, adjusting the pH to be 9-10, heating to 40 ℃, and carrying out heat preservation reaction for 4-5 h. Distilling under reduced pressure to remove the solvent, adding water, stirring for dissolving, acidifying with refined hydrochloric acid until the pH value is 3-4, cooling for crystallization, performing suction filtration, and washing a filter cake with a small amount of water to obtain 59g of impurity 2 crude product. Adding 100g of water into the crude product, heating until the crude product is completely dissolved to about 90 ℃, cooling and crystallizing, filtering, and washing a filter cake with a small amount of water to obtain a white solid, namely a refined 2-ethoxy-5-fluorouracil impurity. Drying at 85 ℃ to obtain 34.8g of impurity 2, the total yield is 61%, and the purity is 99.2%.
Example 2
Synthesis of impurity 1:
adding 157g of methanol solution of sodium methoxide into a dry and clean 500mL three-necked bottle, stirring, distilling under reduced pressure to form fine powder, adding 67g of solvent toluene, stirring while adding, controlling the temperature to be 10-15 ℃, respectively dropwise adding 56.2g of ethyl formate and 35.4g of methyl methoxyacetate, naturally raising the temperature to room temperature after dropwise adding, heating to 40 ℃, preserving the temperature for reacting for 4-5h, recovering to the room temperature, and standing overnight.
Controlling the temperature of the reaction system to be 10-15 ℃, dropwise adding 99g of ethoxy isourea, adjusting the pH to be 9-10, heating to 40 ℃, and carrying out heat preservation reaction for 4-5 h. Distilling under reduced pressure to remove solvent, adding 100g of water into dark yellow viscous syrup, stirring and dissolving, adding 30ml of saturated saline solution for demulsification, extracting with dichloromethane, collecting organic phase, concentrating to obtain 8.7g of crude product, adding 6-8ml of water into the crude product, heating to completely dissolve the crude product to about 90 ℃, cooling and crystallizing, filtering, and washing a filter cake with a small amount of water to obtain a white solid, namely a refined product of 2-ethoxy-5-fluorouracil impurity 1. Drying at 85 ℃ to obtain 1 mass of the impurity of 3.5g, the total yield of 0.07 percent and the purity of 98.3 percent.
Synthesis of impurity 2:
adding 180g of methanol solution of sodium methoxide into a dry and clean 500mL three-necked bottle, distilling under reduced pressure to be fine powder, adding 70g of solvent toluene, stirring while adding, controlling the temperature to be 10-15 ℃, respectively dropwise adding 60g of ethyl formate and 41g of ethyl ethoxyacetate, naturally raising the temperature to room temperature after dropwise adding, heating to 40 ℃, preserving the temperature for reaction for 4-5h, and standing overnight after returning to the room temperature.
Controlling the temperature of the reaction system to be 10-15 ℃, dropwise adding 120g of ethoxy isourea, adjusting the pH to be 9-10, heating to 40 ℃, and carrying out heat preservation reaction for 4-5 h. Distilling under reduced pressure to remove the solvent, adding water, stirring for dissolving, acidifying with refined hydrochloric acid until the pH value is 3-4, cooling for crystallization, performing suction filtration, and washing a filter cake with a small amount of water to obtain 61g of impurity 2 crude product. Adding 100g of water into the crude product, heating until the crude product is completely dissolved to about 90 ℃, cooling and crystallizing, filtering, and washing a filter cake with a small amount of water to obtain a white solid, namely a refined 2-ethoxy-5-fluorouracil impurity. Drying at 85 ℃ to obtain the impurity 2 with the mass of 36.0g, the total yield of 63 percent and the purity of 99.2 percent.
Example 3
Synthesis of impurity 1:
adding 157g of 29.8% sodium methoxide methanol solution into a dry and clean 500mL three-necked bottle, stirring, distilling under reduced pressure to be fine powder, adding 67g of solvent toluene, stirring while adding, controlling the temperature to be 10-15 ℃, respectively dropwise adding 56.2g of ethyl formate and 35.4g of methoxy methyl acetate, naturally raising the temperature to room temperature after dropwise adding, heating to 40 ℃, keeping the temperature for reaction for 4-5h, and standing overnight after recovering to the room temperature.
And controlling the temperature of the reaction system to be 10-15 ℃, dropwise adding 93g of ethoxy isourea, adjusting the pH to be 9-10, heating to 40 ℃, and carrying out heat preservation reaction for 4-5 h. Distilling under reduced pressure to remove solvent, adding 100g of water into dark yellow viscous syrup, stirring and dissolving, adding 30ml of saturated saline solution for demulsification, extracting with dichloromethane, collecting organic phase, concentrating to obtain 8.5g of crude product, adding 6-8ml of water into the crude product, heating to completely dissolve the crude product to about 90 ℃, cooling and crystallizing, filtering, and washing a filter cake with a small amount of water to obtain a white solid, namely a refined product of 2-ethoxy-5-fluorouracil impurity 1. Drying at 85 ℃ to obtain 1 mass of impurities of 3.3g, the total yield of 0.06 percent and the purity of 98.9 percent.
Synthesis of impurity 2:
adding 180g of methanol solution of sodium methoxide into a dry and clean 500mL three-necked bottle, distilling under reduced pressure to be fine powder, adding 70g of solvent toluene, stirring while adding, controlling the temperature to be 10-15 ℃, respectively dropwise adding 60g of ethyl formate and 41g of ethyl ethoxyacetate, naturally raising the temperature to room temperature after dropwise adding, heating to 40 ℃, preserving the temperature for reaction for 4-5h, and standing overnight after returning to the room temperature.
And controlling the temperature of the reaction system to be 10-15 ℃, dropwise adding 116g of ethoxy isourea, adjusting the pH to be 9-10, heating to 40 ℃, and carrying out heat preservation reaction for 4-5 h. Distilling under reduced pressure to remove the solvent, adding water, stirring for dissolving, acidifying with refined hydrochloric acid to pH 3-4, cooling for crystallization, filtering, and washing the filter cake with a small amount of water to obtain crude product 59g of impurity 2. And adding 100g of water into the crude product, heating until the crude product is completely dissolved at about 90 ℃, cooling and crystallizing, filtering, and washing a filter cake by using a small amount of water to obtain a white solid, namely a refined 2-ethoxy-5-fluorouracil impurity. Drying at 85 ℃ to obtain 34.8g of impurity 2 with the total yield of 61% and the purity of 98.9%.
Example 4
Synthesis of impurity 1:
adding 157g of 29.8% sodium methoxide methanol solution into a dry and clean 500mL three-necked bottle, stirring, distilling under reduced pressure to be fine powder, adding 67g of solvent toluene, stirring while adding, controlling the temperature to be 10-15 ℃, respectively dropwise adding 56.2g of ethyl formate and 35.4g of methoxy methyl acetate, naturally raising the temperature to room temperature after dropwise adding, heating to 40 ℃, keeping the temperature for reaction for 4-5h, and standing overnight after recovering to the room temperature.
Controlling the temperature of the reaction system to be 10-15 ℃, dropwise adding 95g of ethoxy isourea, adjusting the pH value to be 9-10, heating to 40 ℃, and carrying out heat preservation reaction for 4-5 h. Distilling under reduced pressure to remove solvent, adding 100g of water into dark yellow viscous syrup, stirring and dissolving, adding 30ml of saturated saline solution for demulsification, extracting with dichloromethane, collecting organic phase, concentrating to obtain 8.9g of crude product, adding 6-8ml of water into the crude product, heating to completely dissolve the crude product to about 90 ℃, cooling and crystallizing, filtering, and washing a filter cake with a small amount of water to obtain a white solid, namely a refined product of 2-ethoxy-5-fluorouracil impurity 1. Drying at 85 ℃ to obtain 1 mass of the impurity of 3.6g, wherein the total yield is 0.07 percent and the purity is 98.3 percent.
Synthesis of impurity 2:
adding 180g of methanol solution of sodium methoxide into a dry and clean 500mL three-necked bottle, distilling under reduced pressure to be fine powder, adding 70g of solvent toluene, stirring while adding, controlling the temperature to be 10-15 ℃, respectively dropwise adding 60g of ethyl formate and 41g of ethyl ethoxyacetate, naturally raising the temperature to room temperature after dropwise adding, heating to 40 ℃, preserving the temperature for reaction for 4-5h, and standing overnight after returning to the room temperature.
Controlling the temperature of the reaction system to be 10-15 ℃, dropwise adding 118g of ethoxy isourea, adjusting the pH value to be 9-10, heating to 40 ℃, and carrying out heat preservation reaction for 4-5 h. Distilling under reduced pressure to remove the solvent, adding water, stirring for dissolving, acidifying with refined hydrochloric acid to pH 3-4, cooling for crystallization, filtering, and washing the filter cake with a small amount of water to obtain 62g of impurity 2 crude product. Adding 100g of water into the crude product, heating until the crude product is completely dissolved to about 90 ℃, cooling and crystallizing, filtering, and washing a filter cake with a small amount of water to obtain a white solid, namely a refined 2-ethoxy-5-fluorouracil impurity. Drying at 85 ℃ to obtain 37.1g of impurity 2 with the total yield of 65 percent and the purity of 99.2 percent.
The aspects, embodiments, features and examples of the present invention should be considered as illustrative in all respects and not intended to be limiting of the utility model, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.
The use of headings and sections in this patent (this invention) is not meant to limit the utility model; each section may apply to any aspect, embodiment, or feature of the utility model.
Throughout this specification, where a composition is described as having, containing or comprising specific components or where a process is described as having, containing or comprising specific process steps, it is contemplated that the compositions taught by the present invention also consist essentially of or consist of the recited components and that the processes taught by the present invention also consist essentially of or consist of the recited process steps.
Unless specifically stated otherwise, use of the terms "comprising", "including", "having" or "having" is generally to be understood as open-ended and not limiting.
It should be understood that the order of steps or the order in which particular actions are performed is not critical, as long as the teachings of the utility model remain operable. Further, two or more steps or actions may be performed simultaneously.
In addition, the inventors of the present invention have also conducted experiments with reference to the above examples using other materials, process operations, and process conditions described in the present specification, and have obtained preferable results.
While the utility model has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the utility model. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the utility model without departing from its scope. Therefore, it is intended that the utility model not be limited to the particular embodiment disclosed for carrying out this invention, but that the utility model will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated any use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.
Claims (6)
1. A preparation method of 2-ethoxy-5-fluorouracil impurities is characterized by comprising the following steps:
(1) methyl methoxyacetate or ethyl ethoxyacetate is taken as a raw material, the raw material and ethyl formate are respectively dripped into a uniform mixing system taking sodium methoxide as alkali to extract hydrogen and toluene as a solvent, and a reaction is carried out to form a 2-ethoxy-5-fluorouracil impurity intermediate;
(2) dripping ethoxy isourea into the 2-ethoxy-5-fluorouracil impurity intermediate, adjusting the pH to 9-10, and then sequentially heating, distilling under reduced pressure, dissolving in water, and purifying to obtain a crude product of the 2-ethoxy-5-fluorouracil impurity;
(3) adding water into the crude product of the 2-ethoxy-5-fluorouracil impurity for dissolving, and then sequentially cooling and crystallizing by ice water, filtering, washing and drying to obtain the 2-ethoxy-5-fluorouracil impurity;
the 2-ethoxy-5-fluorouracil impurity is
Or
。
2. The process for the preparation of 2-ethoxy-5-fluorouracil impurity as claimed in claim 1, characterized in that: in the step (1), the temperature of a uniform mixed system with sodium methoxide as alkali to extract hydrogen and toluene as solvent is controlled to be 10-15 ℃.
3. The process for the preparation of 2-ethoxy-5-fluorouracil impurity as claimed in claim 1, characterized in that: in the step (1), the dropping temperature of the raw materials and the ethyl formate is 10-15 ℃, and the dropping time is 30-50 min.
4. The method for preparing 2-ethoxy-5-fluorouracil impurities according to claim 1, wherein methyl methoxyacetate is used as a raw material, and the purification treatment in step (2) specifically comprises: adding a small amount of saturated saline solution for demulsification, extracting with dichloromethane, collecting organic phase, and concentrating.
5. The method for preparing 2-ethoxy-5-fluorouracil impurities according to claim 1, wherein ethoxyethyl acetate is used as a raw material, and the purification treatment in step (2) specifically comprises: acidifying with refined hydrochloric acid to pH 3-4, cooling, crystallizing, suction filtering and washing filter cake with small amount of water.
6. A process for the preparation of 2-ethoxy-5-fluorouracil impurities according to claim 1, 4 or 5, characterized in that: in the step (3), the heating temperature for dissolving by adding water is 85-90 ℃.
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|---|---|---|---|---|
| CN101486684A (en) * | 2009-02-20 | 2009-07-22 | 常熟华益化工有限公司 | Preparation of 2,4-dichloro-5-methoxy pyrimidine |
| CN102482232A (en) * | 2009-09-02 | 2012-05-30 | 维福（国际）股份公司 | Novel pyrimidine and triazine hepcidine antagonists |
| CN106928152A (en) * | 2017-03-03 | 2017-07-07 | 符爱清 | A kind of preparation method of uracil |
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2020
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101486684A (en) * | 2009-02-20 | 2009-07-22 | 常熟华益化工有限公司 | Preparation of 2,4-dichloro-5-methoxy pyrimidine |
| CN102482232A (en) * | 2009-09-02 | 2012-05-30 | 维福（国际）股份公司 | Novel pyrimidine and triazine hepcidine antagonists |
| CN106928152A (en) * | 2017-03-03 | 2017-07-07 | 符爱清 | A kind of preparation method of uracil |
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