CN111362875A - Industrial production method of 4-amino-5-imidazole formamide - Google Patents
Industrial production method of 4-amino-5-imidazole formamide Download PDFInfo
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Abstract
The invention discloses an industrial production method of 4-amino-5-imidazole formamide, belonging to the technical field of organic synthesis and comprising the following steps: s1: reacting diaminomaleonitrile with formamide under the action of phosphorus oxychloride to generate an intermediate 1; s2: the intermediate 1 is subjected to ring closure reaction under alkaline condition to generate 4-amino-5-imidazole formamide; the method has the advantages of simple raw materials, low price, short reaction steps, short production period, simple operation, easy realization of industrial production, avoidance of generation of cyano-containing wastewater, nitrogen-containing wastewater and the like in the traditional synthetic method, low environmental protection pressure and capability of obtaining the high-quality 4-amino-5-imidazole formamide only by two-step reaction.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an industrial production method of 4-amino-5-imidazole formamide.
Background
As is known, Temozolomide (TMZ) is a drug for treating brain glioma, and has many unique advantages over other types of antitumor drugs: for example, the compound has a wider anti-tumor spectrum, can be orally taken, has a good absorption effect, is easy to permeate through a brain blood barrier, has good tolerance and small bone marrow suppression effect, does not produce superimposed toxicity when being taken together with other medicines, and has good safety. Magical to be more wonderful is that temozolomide has good curative effect on brain glioma, and also has good curative effect on lymphoma, solid tumor, leukemia and melanoma { oral antitumor new drug temozolomide [ J ]. medicine oncology: foreign brochure, 1999,26(1): 292-. Temozolomide drug was first developed by Schering-plough company in the united kingdom and marketed in europe in 1997 { synthesis of antitumor drug temozolomide [ J ]. fine chemical intermediate, 2004,34(5):27-28 }, after european marketing, approval by FDA in the united states at 8/11 of 1999, and the company has filed a marketing application for the drug to 16 countries including canada, australia, new zealand [ synthesis of temozolomide [ J ]. eastern pharmaceutical industry, 2003,22(4):1 ]. The new antineoplastic agent temozolomide is on the market, which brings good news to a plurality of brain tumor patients, relieves the pain of the brain tumor patients, prolongs the service life of the brain tumor patients and improves the life quality of the brain tumor patients.
4-amino-5-imidazole formamide is an important intermediate for the synthesis of temozolomide medicaments, and the synthesis and industrialization of the intermediate are concerned by extensive researchers. Currently, there are two major synthetic routes for the synthesis of 4-amino-5-imidazolecarboxamide: synthetic route 1 is a synthesis using cyanide as a raw material [ synthetic route 1, WO 2014013151; WO2004035529] has great limitation on industrial production because all the methods use highly toxic cyanides (sodium cyanide, hydrocyanic acid and cyanopropanol), because only enterprises with cyanide use qualification can use the method for industrial production, and most common chemical production enterprises cannot use the synthesis method for industrial production because the enterprises do not have cyanide use qualification; on the other hand, even in chemical industry enterprises qualified for cyanide use, since cyanide is a highly toxic substance, personnel management in the production process and wastewater treatment in the production process need to be strictly controlled, and incorrect or non-strict control measures can bring fatal influences to personnel or environment.
In addition to the two major synthetic methods reported in the literature, there are some other synthetic methods reported { Tetrahedron Letters,25(49) }, 5701-5704, 1984; canadian Journal of Chemistry,59(9),1347-1356, 1981; agricultural and Biological Chemistry,41(12),2331-2334, 1977; journal of the American Chemical Society,82, 3144-; journal of organic Chemistry,24, 256-one 257, 1959; journal of Biological Chemistry,181,89-93,1949}, but these methods all require starting from very complex intermediate raw materials, most of which are not available on a large scale, and the price of these complex intermediate raw materials is generally high, resulting in synthesis of 4-amino-5-imidazole carboxamide, which is not economically efficient.
In conclusion, the existing synthesis methods of 4-amino-5-imidazole formamide can not meet the requirements of industrial production.
Disclosure of Invention
In order to solve the problems, the invention discloses an industrial production method of 4-amino-5-imidazole formamide.
An industrial production method of 4-amino-5-imidazole formamide comprises the following steps:
s1: reacting diaminomaleonitrile with formamide under the action of phosphorus oxychloride to generate an intermediate 1;
s2: the intermediate 1 is subjected to ring closure reaction under alkaline condition to generate 4-amino-5-imidazole formamide;
the synthetic route is as follows:
preferably, the S1 specifically includes the following steps:
under the protection of inert gas, dissolving diaminomaleonitrile and formamide in THF, adding phosphorus oxychloride at 0-5 ℃, then controlling the temperature to 5-35 ℃ for reaction to prepare a reaction solution, and carrying out aftertreatment on the reaction solution to prepare an intermediate 1.
Preferably, the diaminomaleonitrile: formamide mole ratio of 1: 1.2-1.5, diamino maleonitrile: the molar ratio of phosphorus oxychloride is 1: 1.2 to 1.5; diamino maleonitrile: the mass ratio of tetrahydrofuran is 1: 4.4-8.
Preferably, the temperature-controlled reaction time of S1 is 3 h.
Preferably, the reaction liquid post-treatment comprises the steps of: adding methanol into the reaction solution, stirring, then quenching with water, adjusting the pH value to 8-8.5, extracting with ethyl acetate, drying an organic phase with anhydrous magnesium sulfate, filtering, concentrating the filtrate, adding petroleum ether into the concentrate, pulping, filtering, and drying a filter cake.
Preferably, the S2 specifically includes the following steps:
under the protection of inert gas, mixing the intermediate 1 of S1 with water and alkali, controlling the temperature to be 95-100 ℃ for reaction to prepare a mixed solution, and carrying out aftertreatment on the mixed solution to prepare the 4-amino-5-imidazole formamide.
Preferably, the intermediate 1: the molar ratio of the alkali is 1: 3.3-3.4, wherein the mass ratio of the intermediate 1 to water is 1: 5.
preferably, the base is sodium hydroxide.
Preferably, the temperature-controlled reaction time of S2 is 3 h.
Preferably, the mixed liquor post-treatment comprises the following steps: and (3) regulating the pH value of the mixed solution to 6.5-7 by using hydrochloric acid at 0-5 ℃, filtering, washing and drying a filter cake, recrystallizing by using water, washing by using absolute ethyl alcohol, and drying.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention takes diaminomaleonitrile as raw material to synthesize 4-amino-5-imidazole formamide through two-step reaction, which is a brand new synthesis method, and is not reported in domestic and foreign documents, and as for the green and environment-friendly synthesis route, compared with the virulent cyanide method (sodium cyanide, hydrocyanic acid, cyanopropanol) or the ammonia methanol synthesis method in the background technology, the raw material used in the invention is simple and low-toxic, and can not generate cyanide-containing (virulent) or nitrogen-containing wastewater, and only can generate a small amount of phosphorus-containing wastewater, and the synthesis technology of the invention is relatively environment-friendly;
(2) compared with the virulent cyanide method (sodium cyanide, hydrocyanic acid and cyanopropanol) or the synthetic method of the ammonia methanol in the background technology, the conventional reaction equipment can meet the requirements of industrial production, and the special qualification of the factory is not needed;
(3) in terms of the quality of the final product, compared with a virulent cyanide method (sodium cyanide, hydrocyanic acid and cyanopropanol) or an ammonia methanol synthesis method in the background art, the method can obtain a target product with the purity of more than 99.8 percent, and has stable quality and good repeatability;
(4) compared with the highly toxic cyanide method (sodium cyanide, hydrocyanic acid and cyanopropanol) or the synthetic method of the ammonia methanol in the background art, the method has the advantages that the raw materials used in the synthetic route are simple and low in price, and the total synthetic yield can reach 58.81%, so that the raw material cost of unit product is low; the synthesis route is only two-step reaction, the reaction time and post-treatment time of each step of reaction are short, and the post-treatment is simple, so the manufacturing cost of unit products is low; because the materials used in the synthetic route are relatively environment-friendly and do not generate a large amount of waste water, waste solids and waste gas, the environment-friendly cost of the unit product is low, and the unit raw material cost, the unit manufacturing cost and the unit environment-friendly cost of the product are comprehensively considered, so that the comprehensive cost of the product has very obvious advantages compared with the virulent cyanide method (sodium cyanide, hydrocyanic acid and cyanopropanol) or the synthetic method of the ammonia methanol in the background art.
Drawings
FIG. 1 is an LC spectrum of 4-amino-5-imidazolecarboxamide obtained in example 1;
FIG. 2 is a nuclear magnetic hydrogen spectrum of 4-amino-5-imidazolecarboxamide obtained in example 1.
Detailed Description
In order to make the technical solutions of the present invention better understood and implemented by those skilled in the art, the present invention is further described below with reference to the following specific embodiments and the accompanying drawings, but the embodiments are not meant to limit the present invention.
The experimental methods and the detection methods described in the following examples are all conventional methods unless otherwise specified; the starting materials and reagents are commercially available unless otherwise specified.
An industrial production method of 4-amino-5-imidazole formamide comprises the following steps:
s1: reacting diaminomaleonitrile with formamide under the action of phosphorus oxychloride to generate an intermediate 1;
s2: the S1 intermediate 1 is subjected to ring closure reaction under alkaline condition to generate 4-amino-5-imidazole formamide;
the synthetic route is as follows:
example 1
An industrial production method of 4-amino-5-imidazole formamide specifically comprises the following steps:
under the protection of argon, THF 1620mL, diaminomaleonitrile 324g and formamide 162g (1.2eq.) are sequentially added into a 5L three-neck flask with a thermometer, a dropping funnel and mechanical stirring, a low-temperature bath is cooled to 5 ℃, phosphorus oxychloride 550.8g (1.2eq.) is added, the temperature is kept at 5 ℃ after dropping, the reaction is carried out for 2 hours, sampling is carried out every 1 hour, and the reaction is stopped when the diaminomaleonitrile LC is less than 0.3%.
And (3) post-treatment: controlling the temperature to be 20 ℃, dropwise adding 345.6g of methanol into the reaction liquid, controlling the temperature to be 20 ℃ after dropwise adding, reacting for 2h, slowly pouring the system into 4.2L of water for quenching, keeping the temperature for 20 ℃ after quenching and stirring for 20min, adding 795g of sodium carbonate powder in batches until the pH value of the system is 8, keeping the temperature for 20 ℃ after adding, stirring for 30min, adding 4800mL of ethyl acetate for 1 extraction, continuously extracting water phase with ethyl acetate for 1620mL for 2 times, combining organic phases, washing with water for 3240mL for 2 times, separating, stirring and drying the organic phases with 162g of anhydrous magnesium sulfate for 2h, filtering, rinsing filter cakes with ethyl acetate for 162mL for 3 times, combining filtrates, concentrating under negative pressure (35 ℃ and-0.09 MPa and 4h) to about 900g of the residual paste, adding petroleum ether 1620mL, pulping at 20 ℃ for 2h, filtering, rinsing the filter cakes with 162mL of petroleum ether for 2 times, collecting, vacuum drying (25 ℃ and-0.09 MPa, about 4h) to a volatiles < 2% to give 307g of a grey solid powder with a purity of 97.8885% and a yield of 75.80% (based on diaminomaleonitrile);
under the protection of argon, 1450mL of water, 290g of sodium hydroxide and 290g of intermediate 1 are added into a 3L three-mouth bottle provided with a thermometer, a reflux condenser tube and a tail gas absorber, after the temperature is raised to 95 ℃ and the reaction is kept for 2 hours, sampling analysis is started every 1 hour, the reaction is completed in about 3 hours, the reaction is stopped, and the temperature is naturally reduced to 20 ℃.
And (3) post-treatment: and (3) further cooling the system to 0 ℃, controlling the temperature to be 0 ℃, dropwise adding hydrochloric acid (the concentration is 35%), adjusting the system until the pH value is 6.5, stirring for 1h after dropwise adding, filtering, leaching a filter cake with 100mL of water for 2 times, drying the filter cake after pumping, and drying the filter cake (50 ℃, normal pressure, 8h) until the water content is less than 15% to obtain 265g of a gray-green solid crude product.
And (3) recrystallization: under the protection of argon, 1060mL of water and 265g of crude product are added into a 2L three-necked bottle, the mixture is heated to 60 ℃ for dissolution, the mixture is kept warm (60 ℃) and stirred for 30min, the mixture passes through a sand core funnel, filter cakes are rinsed with 50mL of hot water at 60 ℃ for 2 times, the filter liquors are combined and added into the 2L three-necked bottle, the mixture is stirred and cooled to 3 ℃ for crystallization for 1h, the filter cake is filtered, the wet weight of the filter cake is about 360g after being dried, 400mL of absolute ethyl alcohol is added, the mixture is pulped for 2h at-10 ℃ to-15 ℃, the filter cake is filtered, the filter cake is dried, and the mixture is dried in vacuum (50 ℃ and-0.09 MPa) until the water content is less than 12.5%, so that 210g of gray green solid powder is obtained, the purity LC (99.8596% of 4-amino-5-imidazole formamide and the yield is 77.59% (based on an intermediate 1), namely.
Example 2
An industrial production method of 4-amino-5-imidazole formamide comprises the following steps:
under the protection of argon, sequentially adding 1458mL of THF, 162g of diaminomaleonitrile and 101.3g (1.5eq.) of formamide into a 5L three-necked bottle provided with a thermometer, a dropping funnel and a mechanical stirrer, cooling the bath to 0 ℃, beginning to drop 344.7g (1.5eq.) of phosphorus oxychloride, preserving the temperature at 35 ℃ after dropping, reacting for 2 hours, beginning to sample every 1 hour, and stopping the reaction when the LC of the diaminomaleonitrile is less than 0.3%.
And (3) post-treatment: controlling the temperature to be 30 ℃, dropwise adding 216g of methanol into the reaction liquid, controlling the temperature to be 30 ℃ after dropwise adding, reacting for 2h, slowly pouring the system into 2.6L of water, quenching, keeping the temperature for 30 ℃ after quenching, stirring for 20min, adding 487g of sodium carbonate powder in batches until the pH value of the system is 8.5, keeping the temperature for 30min after adding, stirring for 30min, adding 2400mL of ethyl acetate, extracting for 1 time, continuously extracting for 810mL for 2 times by using ethyl acetate for the aqueous phase, combining the organic phases, washing for 1620mL for 2 times by using water, separating, stirring and drying for 2h by using 80g of anhydrous magnesium sulfate for the organic phases, filtering, leaching for 80mL for 3 times by using ethyl acetate for the filter cake, combining the filtrates, concentrating under negative pressure (40 ℃, minus 0.08MPa, 4h) to about 450g of the residual paste, adding 810mL of petroleum ether, pulping for 2h at 30 ℃, filtering, leaching the filter cake by using 80mL of petroleum ether for 2 times, collecting, vacuum drying (30 ℃ and minus 0.08MPa, 4h) to a volatiles < 2% 148g of a grey solid powder was obtained with a purity of 97.8133% and a yield of 73.08% (based on diaminomaleonitrile);
Example 1 is similar to example 2, and only the characterization results of example 1 are taken as examplesIn this connection, FIG. 1 is an LC spectrum of 4-amino-5-imidazolecarboxamide obtained in example 1, from which FIG. 1 can be derived: the purity of the obtained target product LC is 99.8596%, and the LC content of the product is high. FIG. 2 is a nuclear magnetic hydrogen spectrum of 4-amino-5-imidazolecarboxamide obtained in example 1, from which FIG. 2 it can be derived: delta 11.1-11.8 ppm (d,1H, NH), 7.0-7.5 ppm (d,1H, CH), 6.5-6.9 ppm (m,2H, CONH)2),5.2ppm～5.8ppm(m,2H,C-NH2) And the nuclear magnetic hydrogen spectrum of the target product is met.
Therefore, the 4-amino-5-imidazole formamide is successfully synthesized by two-step reaction by taking the diaminomaleonitrile as a raw material, the used raw material is simple and low in toxicity, cyanide-containing (virulent) or nitrogen-containing wastewater is not generated, only a small amount of phosphorus-containing wastewater is generated, and the synthesis technology is relatively environment-friendly; the conventional reaction equipment can meet the requirements of industrial production, and a factory does not need special qualification; the purity of the obtained product is as high as more than 99.8%, and the product has stable quality and good repeatability; the raw materials used in the synthetic route are simple and low in price, and the total synthetic yield can reach 58.81% (while the yield in the background technology is 32% at most), so that the raw material cost of a unit product is low; the synthesis route is only two-step reaction, the reaction time and post-treatment time of each step of reaction are short, and the post-treatment is simple, so the manufacturing cost of unit products is low; the materials used in the synthetic route are relatively environment-friendly, and a large amount of wastewater, waste solids and waste gas can not be generated, so that the environment-friendly cost of a unit product is low, and the unit raw material cost, the unit manufacturing cost and the unit environment-friendly cost of the product are comprehensively considered, so that the comprehensive cost of the product has very obvious advantages compared with the highly toxic cyanide method (sodium cyanide, hydrocyanic acid and cyanopropanol) or the synthetic method of the ammonia methanol in the background art, and the method is suitable for industrial production.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, it is intended that such changes and modifications be included within the scope of the appended claims and their equivalents.
Claims (10)
1. An industrial production method of 4-amino-5-imidazole formamide is characterized by comprising the following steps:
s1: reacting diaminomaleonitrile with formamide under the action of phosphorus oxychloride to generate an intermediate 1;
s2: the intermediate 1 is subjected to ring closure reaction under alkaline condition to generate 4-amino-5-imidazole formamide;
the synthetic route is as follows:
2. the industrial production method of 4-amino-5-imidazolecarboxamide according to claim 1, characterized in that said S1 comprises in particular the following steps:
under the protection of inert gas, dissolving diaminomaleonitrile and formamide in tetrahydrofuran, adding phosphorus oxychloride at 0-5 ℃, then controlling the temperature to 5-35 ℃ for reaction to prepare a reaction solution, and carrying out aftertreatment on the reaction solution to prepare an intermediate 1.
3. The industrial production method of 4-amino-5-imidazolecarboxamide according to claim 2, characterized in that the diaminomaleonitrile: formamide mole ratio of 1: 1.2-1.5, diamino maleonitrile: the molar ratio of phosphorus oxychloride is 1: 1.2 to 1.5; diamino maleonitrile: the mass ratio of tetrahydrofuran is 1: 4.4-8.
4. The industrial production method of 4-amino-5-imidazole carboxamide according to claim 2, characterized in that S1 temperature-controlled reaction time is 3 h.
5. The method for industrially producing 4-amino-5-imidazolecarboxamide according to claim 2, characterized in that the reaction liquid post-treatment comprises the steps of: adding methanol into the reaction solution, stirring, then quenching with water, adjusting the pH value to 8-8.5, extracting with ethyl acetate, drying an organic phase with anhydrous magnesium sulfate, filtering, concentrating the filtrate, adding petroleum ether into the concentrate, pulping, filtering, and drying a filter cake.
6. The industrial production method of 4-amino-5-imidazolecarboxamide according to claim 1, characterized in that said S2 comprises in particular the following steps:
under the protection of inert gas, mixing the intermediate 1 of S1 with water and alkali, controlling the temperature to be 95-100 ℃ for reaction to prepare a mixed solution, and carrying out aftertreatment on the mixed solution to prepare the 4-amino-5-imidazole formamide.
7. The method for industrially producing 4-amino-5-imidazolecarboxamide according to claim 6, wherein the intermediate 1: the molar ratio of the alkali is 1: 3.3-3.4, wherein the mass ratio of the intermediate 1 to water is 1: 5.
8. the method for industrially producing 4-amino-5-imidazolecarboxamide according to claim 6, characterized in that the base is sodium hydroxide.
9. The industrial production method of 4-amino-5-imidazole carboxamide according to claim 6, characterized in that the temperature-controlled reaction time of S2 is 3 h.
10. The method for industrially producing 4-amino-5-imidazolecarboxamide according to claim 6, characterized in that the mixed liquor post-treatment comprises the steps of: and (3) regulating the pH value of the mixed solution to 6.5-7 by using hydrochloric acid at 0-5 ℃, filtering, washing and drying a filter cake, recrystallizing by using water, washing by using absolute ethyl alcohol, and drying.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002155059A (en) * | 2000-11-17 | 2002-05-28 | Nippon Soda Co Ltd | Method for producing 4-amino-5-cyanoimidazole derivative and intermediate thereof |
| CN1374951A (en) * | 1999-09-20 | 2002-10-16 | 日本曹达株式会社 | Process for the preparation of 4(5)-amino-5(4) carboxamidoimidazoles and intermediates thereof |
| WO2004035529A1 (en) * | 2002-10-16 | 2004-04-29 | Nippon Soda Co.,Ltd. | Process for producing n-(2-amino-1,2-dicyanovinyl)formamidine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1374951A (en) * | 1999-09-20 | 2002-10-16 | 日本曹达株式会社 | Process for the preparation of 4(5)-amino-5(4) carboxamidoimidazoles and intermediates thereof |
| JP2002155059A (en) * | 2000-11-17 | 2002-05-28 | Nippon Soda Co Ltd | Method for producing 4-amino-5-cyanoimidazole derivative and intermediate thereof |
| WO2004035529A1 (en) * | 2002-10-16 | 2004-04-29 | Nippon Soda Co.,Ltd. | Process for producing n-(2-amino-1,2-dicyanovinyl)formamidine |
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