CN101219997B - Synthesis of 2-chlorine-5- amido pyrimidine - Google Patents
Synthesis of 2-chlorine-5- amido pyrimidine Download PDFInfo
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- CN101219997B CN101219997B CN2008100194459A CN200810019445A CN101219997B CN 101219997 B CN101219997 B CN 101219997B CN 2008100194459 A CN2008100194459 A CN 2008100194459A CN 200810019445 A CN200810019445 A CN 200810019445A CN 101219997 B CN101219997 B CN 101219997B
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- aminopyrimidine
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Abstract
The invention discloses a synthetic method for 2-chlor-5-aminopyrimidine, which comprises the following steps: 1) mixing 5-nitrourea pyrimidine, phosphorus oxychloride and an organic base with a weight ratio of 1:5 to 10: 3 to 7 and implementing a chlorination reaction for 2 to 6 hours under a temperature of 30 to 105 DEG C, being extracted by an organic solvent to acquire 2, 4- dichloro-5-nitropyrimidine; 2) mixing the product with zinc dust with a weight ratio of 1: 0.5 to 3, heating and refluxing for 7-15 hours in weak acidic aqueous liquor in a temperature between 30-100 DEG C, merging an aqueous layer after filtering and washing the product, being extracted by the organic solvent, recrystallizing after being dried and condensed, and acquiring the 2-chlor-5-aminopyrimidine. The synthetic method for 2-chlor-5-aminopyrimidine only needs 2 steps to acquire a target object and has the advantages of high gross production rate, short time and simple operation; meanwhile, 5-nitropyrimidine is adopted as a starting material, which has a large amount of commercial supply and has the advantages of low cost and ready availability; in addition, the cost is obviously reduced, thereby having a favorable industrialized application prospect.
Description
Technical field
The present invention relates to a kind of synthetic method of pyrimidine derivatives, be specifically related to a kind of synthetic method of 2-chloro-5-aminopyrimidine.
Background technology
2-chloro-5-aminopyrimidine is a very useful pyrimidine derivatives, also is a very important midbody compound.About the report of the synthetic method of 2-chloro-5-aminopyrimidine seldom, known method is to be starting raw material with the 2-furancarboxylic acid, comprises following 6 steps: 1. 2-furancarboxylic acid and liquid bromine reaction obtain dibromo-succinic acid; 2. dibromo-succinic acid and Sodium Nitrite reaction obtains the nitro mda; 3. nitro mda and Guanidinium carbonate reaction is a catalyzer with the piperidines, obtains 2-amino-5-nitro-pyrimidine; 4. hydrolysis reaction takes place in 2-amino-5-nitro-pyrimidine in the ethanolic soln of the sodium hydroxide that contains 0.5mol/L, obtains 2-hydroxyl-5-nitro-pyrimidine; 5. 2-hydroxyl-5-nitro-pyrimidine and phosphorus oxychloride generation chlorination obtain 2-chloro-5-nitro-pyrimidine; 6. 2-chloro-5-nitro-pyrimidine nitro in the presence of reduced iron powder is reduced, and obtains 2-chloro-5-aminopyrimidine.Main synthetic route is as follows:
Yet in the said synthesis route, have following several shortcoming: 1) need just can obtain target compound through the reaction of 6 steps, step is long, and total recovery is low, is not suitable for suitability for industrialized production; 2) need in the reaction process to use the bigger raw materials of toxicity such as liquid bromine, Sodium Nitrite, not only toxic to workman's health, and also can pollute environment, do not meet the theme of the Green Chemistry of advocating now.
Summary of the invention
The object of the invention provides a kind of synthetic method of 2-chloro-5-aminopyrimidine, and synthetic route is long in the prior art, yield is low, material toxicity is big, the shortcoming of environmental pollution to solve.
For achieving the above object, the technical solution used in the present invention is: a kind of synthetic method of 2-chloro-5-aminopyrimidine comprises the steps:
1) 5-nitrourea pyrimidine, phosphorus oxychloride and organic bases are mixed by the proportioning of mass ratio 1: 5～10: 3～7 and carry out chlorination reaction, reacted 2～6 hours down at 30～105 ℃, mixture cooling back concentrating under reduced pressure is removed unnecessary phosphorus oxychloride, use organic solvent extraction again after adding water, obtain intermediate product 2,4-two chloro-5-nitro-pyrimidines after dry, concentrated; Wherein, described organic bases is selected from triethylamine, diisopropyl ethyl amine, triisopropylamine, N, accelerine, N, N-lutidine base amine, pyridine, 1,8-diaza-dicyclo (5,4,0) undecylene-7 (DBU), two ring [4.3.0]-1,5-phenodiazine-5-hendecene (DBN) or their mixture;
2) with above-mentioned intermediate product 2,4-two chloro-5-nitro-pyrimidines and zinc powder are pressed mass ratio, and 1: 0.5～3 proportioning is mixed, reflux is 7～15 hours in weakly acidic water solution, temperature of reaction is 30～100 ℃, behind the reaction product filtration washing, combining water layer is used organic solvent extraction, the dry back recrystallization that concentrates promptly obtains required 2-chloro-5-aminopyrimidine; Described weakly acidic water solution is selected from the aqueous solution of formic acid, acetate, ammonia chloride, primary ammonium phosphate or SODIUM PHOSPHATE, MONOBASIC, and mass concentration is 3～20%.
The reaction formula of technique scheme can be expressed as:
Principle of the present invention is as follows: the first step is a starting raw material with 5-nitrourea pyrimidine, adopts chloro method commonly used to replace 2 hydroxyls with phosphorus oxychloride, obtains 2,4-two chloro-5-nitro-pyrimidines; Second step, creatively will be described 2, the nitroreduction of 4-two chloro-5-nitro-pyrimidines and select the dechlorination two-step reaction to unite two into one obtains target compound, and has obtained good yield by the optimization processing condition.
Wherein, the concentration of chloro-product in weakly acidic water solution that obtains of step 1) is advisable 5～20%.
In the technique scheme, the organic solvent of described extraction usefulness is selected from methylene dichloride, trichloromethane, tetracol phenixin, ethyl acetate, isopropyl acetate, butylacetate, benzene, toluene, ether, isopropyl ether or methyl tertiary butyl ether; The solvent of described recrystallization is selected from sherwood oil, normal hexane, normal heptane, ethyl acetate, isopropyl acetate, butylacetate, isopropyl ether, methyl tertiary butyl ether or their mixture.
The step of described chlorination reaction is, 5-nitrourea pyrimidine is distributed in the phosphorus oxychloride, is cooled to-5～10 ℃, drips organic bases, adds the post-heating reaction.
For obtaining better reaction effect, described reacting by heating is a heating reflux reaction.
In the technique scheme, described raw material 5-nitrourea pyrimidine is existing commercialization product supplied, it also can prepare by the following method: with nitrosonitric acid and Glacial acetic acid mixing and cooling, add uracil, stirring at normal temperature 3 hours, the mol ratio of described nitrosonitric acid, Glacial acetic acid and uracil are 2～4: 1～2: 1 in batches, cooling mixture and pouring in the frozen water then, stir, filter, successively with cold water, ethanol, ether washing for several times, be drying to obtain 5-nitrourea pyrimidine.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1. the inventive method only needed for 2 steps can obtain target compound, the overall yield height, and the time is short, and is simple to operate; Simultaneously, adopting 5-nitrourea pyrimidine is starting raw material, cheap and easy to get because this raw material has a large amount of commercial offers, can be significantly reduced to this, has the favorable industrial application prospect.
2. the recyclable utilizations of auxiliary material such as used raw material of the present invention and solvent greatly reduce production cost, are fit to industrial applications.
3. because the present invention has selected proper raw material and auxiliary material for use, avoided that toxic substance has also improved the security of operating process to the pollution of environment in the production process.
Embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment one
The first step is with 400mlPOCl
3Join in the 5-nitrourea pyrimidine of 913g, be cooled to about 0 ℃, slowly drip 1000ml triethylamine (produce many white cigarettes, it is violent to heat up).After treating that triethylamine adds, reflux 2-5 hour.Be chilled to room temperature, concentrating under reduced pressure removes unnecessary POCl
3, resistates slowly is poured in the 8-10Kg trash ice, stir after 30-60 minute, use the 5000ml ether extraction, ether is washed 1 time with frozen water, uses saturated NaHCO again
3Wash 2 times, wash 1 time anhydrous Na with saturated NaCl
2SO
4Dry 5-7 hour, concentrated dry diethyl ether got intermediate product 2,4-two chloro-5-nitro-pyrimidine 987g, and purity is greater than 98.2%, yield 88%.
In second step, with 2,4-two chloro-5-nitro-pyrimidine 520g are added in the 6000ml water, add 1500g zinc powder and 600g ammonium chloride, heating reflux reaction 8-10 hour.After question response finishes, filtered while hot, filter cake washs with hot water 100ml.Combining water layer extracts with methylene dichloride 2500ml, saturated NaCl washing, and filtering and concentrating gets target compound 234g with sherwood oil and re-crystallizing in ethyl acetate, and purity is greater than 98.3%, yield 67.7%.
The nuclear magnetic data of product is:
1HNMR (CDCl
3) δ 8.14 (s, 2H, 4H, 6H), 3.78 (s, 2H, 2-NH
2) ppm
MS(ESI)m/e：129(M+H)
+。
Embodiment two
The first step adds 4500mlPOCl with 5-nitrourea pyrimidine 913g
3In, be cooled to about 0-5 ℃, slowly drip 1200ml triethylamine (produce many white cigarettes, it is violent to heat up).After treating that triethylamine adds, be heated to 90 ℃ of reactions 4-6 hour.Be chilled to room temperature, concentrating under reduced pressure removes unnecessary POCl
3, resistates slowly is poured in the 9-10Kg trash ice, stir after 30-60 minute, use the 5000ml ether extraction, ether is washed 1 time with frozen water, uses saturated NaHCO again
3Wash 2 times, wash 1 time anhydrous Na with saturated NaCl
2SO
4Dry 5-8 hour, concentrated dry diethyl ether got intermediate product 2,4-two chloro-5-nitro-pyrimidine 1036g, and purity is greater than 98.3%, yield 92.4%.
In second step, with 2,4-two chloro-5-nitro-pyrimidine 520g are added in the 5000ml water, add 160g zinc powder and 300ml acetic acid, heating reflux reaction 8 hours.After question response finishes, filtered while hot, filter cake washs with hot water 1000ml.Combining water layer extracts with methylene dichloride 2500ml, saturated NaCl washing, and filtering and concentrating gets target compound 245.7g with sherwood oil and re-crystallizing in ethyl acetate, and purity is greater than 98.1%, yield 71.1%.
The nuclear magnetic data of product is:
1HNMR (CDCl
3) δ 8.15 (s, 2H, 4H, 6H), 3.77 (s, 2H, 2-NH
2) ppm
MS(ESI)m/e：129(M+H)
+。
Embodiment three
The first step, 913g is scattered in 3500mlPOCl with 5-nitrourea pyrimidine
3In the adding, be cooled to slowly drip the 1000ml diisopropyl ethyl amine about-5～10 ℃.After treating that diisopropyl ethyl amine adds, reflux 2～6 hours.Be chilled to 20～30 ℃, concentrating under reduced pressure removes unnecessary POCl
3, resistates slowly is poured in 6～10Kg trash ice, stirred 1～2 hour, extract with isopropyl acetate 2000ml, frozen water is washed 1 time, saturated NaHCO
3Wash 2 times, saturated NaCl washes 1 time, anhydrous Na
2SO
4Dry 4～8 hours, concentrate dried organic solvent and get intermediate product 2,4-two chloro-5-nitro-pyrimidine 1068g, purity is greater than 98.3%, yield 95.2%.
In second step, with 2,4-two chloro-5-nitro-pyrimidine 520g are added in the 5000ml water, add 1200g zinc powder and 500ml acetic acid, are heated to 90 ℃ of reactions 10～15 hours.After question response finishes, filtered while hot, filter cake washs with hot water 2000～3000ml.Combining water layer extracts with isopropyl acetate 5000ml, saturated NaCl1000ml washing, and filtering and concentrating gets target compound 252.7g with sherwood oil and isopropyl acetate (3: 1) recrystallization, and purity is greater than 98%, yield 73.1%.
The nuclear magnetic data of product is:
1HNMR (CDCl
3) δ 8.14 (s, 2H, 4H, 6H), 3.77 (s, 2H, 2-NH
2) ppm
MS(ESI)m/e：129(M+H)
+。
Embodiment four
The first step, 913g is scattered in 3500mlPOCl with 5-nitrourea pyrimidine
3In the adding, be cooled to slowly drip 1200mlN, accelerine about-5～10 ℃.Treat N, after accelerine adds, reflux 3～6 hours.Be chilled to 20～30 ℃, concentrating under reduced pressure removes unnecessary POCl
3, resistates slowly is poured in 6～12Kg trash ice, stirred 1～2 hour, extract with isopropyl acetate 2000ml, frozen water is washed 1 time, saturated NaHCO
3Wash 2 times, saturated NaCl washes 1 time, anhydrous Na
2SO
4Dry 4～8 hours, concentrate dried organic solvent and get intermediate product 2,4-two chloro-5-nitro-pyrimidine 968g, purity is greater than 97.8%, yield 86.3%.
In second step, with 2,4-two chloro-5-nitro-pyrimidine 520g are added in the 5000ml water, add 1200g zinc powder and 500g ammonium chloride, heating reflux reaction 8～15 hours.After question response finishes, filtered while hot, filter cake washs with hot water 500～1000ml.Combining water layer extracts with isopropyl acetate 2000ml, saturated NaCl1000ml washing, and filtering and concentrating gets target compound 214g with sherwood oil and isopropyl acetate (3: 1) recrystallization, and purity is greater than 98%, yield 61.9%.
The nuclear magnetic data of product is:
1HNMR (CDCl
3) δ 8.16 (s, 2H, 4H, 6H), 3.79 (s, 2H, 2-NH
2) ppm
MS(ESI)m/e：129(M+H)
+。
Embodiment five
The first step, 913g is scattered in 4000mlPOCl with 5-nitrourea pyrimidine
3In the adding, be cooled to slowly drip the 1500ml pyridine about 0～10 ℃.After treating that pyridine adds, be heated to 90 ℃ of reactions 5～6 hours.Be chilled to 20～30 ℃, concentrating under reduced pressure removes unnecessary POCl
3, resistates slowly is poured in 6～12Kg trash ice, stirred 1～2 hour, extract with isopropyl acetate 2000ml, frozen water is washed 1 time, saturated NaHCO
3Wash 2 times, saturated NaCl washes 1 time, anhydrous Na
2SO
4Dry 4～8 hours, concentrate dried organic solvent and get intermediate product 2,4-two chloro-5-nitro-pyrimidine 871.2g, purity is greater than 97.5%, yield 77.7%.
In second step, with 2,4-two chloro-5-nitro-pyrimidine 520g are added in the 5000ml water, add 1200g zinc powder and 600g ammonium chloride, are heated to 90 ℃ of reactions 12～15 hours.After question response finishes, filtered while hot, filter cake washs with hot water 500～1000ml.Combining water layer extracts with isopropyl acetate 2000ml, saturated NaCl1000ml washing, and filtering and concentrating gets target compound 235.4g with sherwood oil and isopropyl acetate (3: 1) recrystallization, and purity is greater than 98.2%, yield 68.1%.
The nuclear magnetic data of product is:
1HNMR (CDCl
3) δ 8.16 (s, 2H, 4H, 6H), 3.79 (s, 2H, 2-NH
2) ppm
MS(ESI)m/e：129(M+H)
+。
Claims (4)
1. the synthetic method of a 2-chloro-5-aminopyrimidine is characterized in that, comprises the steps:
1) 5-nitrourea pyrimidine, phosphorus oxychloride and organic bases are mixed by the proportioning of mass ratio 1: 5～10: 3～7 and carry out chlorination reaction, reacted 2～6 hours down at 30～105 ℃, mixture cooling back concentrating under reduced pressure is removed unnecessary phosphorus oxychloride, use organic solvent extraction again after adding water, obtain intermediate product 2,4-two chloro-5-nitro-pyrimidines after dry, concentrated; Wherein, described organic bases is selected from triethylamine, diisopropyl ethyl amine, triisopropylamine, N, accelerine, N, N-lutidine base amine, pyridine, 1,8-diaza-dicyclo (5,4,0) undecylene-7, two ring [4.3.0]-1,5-phenodiazine-5-hendecene or their mixture;
2) with above-mentioned intermediate product 2,4-two chloro-5-nitro-pyrimidines and zinc powder are pressed mass ratio, and 1: 0.5～3 proportioning is mixed, reflux is 7～15 hours in weakly acidic water solution, temperature of reaction is 30～100 ℃, behind the reaction product filtration washing, combining water layer is used organic solvent extraction, the dry back recrystallization that concentrates promptly obtains required 2-chloro-5-aminopyrimidine; Described weakly acidic water solution is selected from the aqueous solution of formic acid, acetate, ammonia chloride, primary ammonium phosphate or SODIUM PHOSPHATE, MONOBASIC, and mass concentration is 3～20%.
2. the synthetic method of 2-chloro-5-aminopyrimidine according to claim 1, it is characterized in that: the organic solvent of described extraction usefulness is selected from methylene dichloride, trichloromethane, tetracol phenixin, ethyl acetate, isopropyl acetate, butylacetate, benzene, toluene, ether, isopropyl ether or methyl tertiary butyl ether; The solvent of described recrystallization is selected from sherwood oil, normal hexane, normal heptane, ethyl acetate, isopropyl acetate, butylacetate, isopropyl ether, methyl tertiary butyl ether or their mixture.
3. the synthetic method of 2-chloro-5-aminopyrimidine according to claim 1 is characterized in that: the step of described chlorination reaction is, 5-nitrourea pyrimidine is distributed in the phosphorus oxychloride, is cooled to-5～10 ℃, drips organic bases, adds the post-heating reaction.
4. the synthetic method of 2-chloro-5-aminopyrimidine according to claim 3 is characterized in that: described reacting by heating is a heating reflux reaction.
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102276537B (en) * | 2011-06-22 | 2013-01-23 | 山西大学 | Preparation method of 2-cyan-5-amiopyrimidine |
| CN108904503B (en) * | 2018-07-02 | 2021-09-28 | 陕西科技大学 | Application of 6-chloro-5-nitro-2, 4-diaminopyrimidine in medicine for treating chronic granulocytic leukemia |
| CN109293578A (en) * | 2018-10-29 | 2019-02-01 | 淮安万邦香料工业有限公司 | A kind of preparation method of the chloro- 5- nitro-pyrimidine of 2,4- bis- |
| CN110372602A (en) * | 2019-06-24 | 2019-10-25 | 南京普锐达医药科技有限公司 | A kind of synthetic method of 4- chloro-2-methyl pyrimidine |
| CN110372605B (en) * | 2019-06-24 | 2022-05-13 | 南京普锐达医药科技有限公司 | Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine |
| CN110294715B (en) * | 2019-06-24 | 2022-05-13 | 南京普锐达医药科技有限公司 | Synthesis method of 2,4, 6-trichloro-5-methoxypyrimidine |
| CN110372603A (en) * | 2019-06-24 | 2019-10-25 | 南京普锐达医药科技有限公司 | A kind of synthetic method of the fluoro- 6- ethyl-pyrimidine of the chloro- 5- of 2- |
| CN110452180A (en) * | 2019-06-25 | 2019-11-15 | 南京普锐达医药科技有限公司 | A method of the synthesis chloro- 5- amino -6- pyrimidinecarboxylic acid ethyl ester of 2- |
| CN110372584A (en) * | 2019-06-25 | 2019-10-25 | 南京普锐达医药科技有限公司 | A kind of synthetic method of the chloro- 6- cyanopyrimidine of 2,4- bis- |
| CN110343074B (en) * | 2019-06-25 | 2022-05-13 | 南京普锐达医药科技有限公司 | Synthesis method of 2-amino-4-chloro-5-fluoropyrimidine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6380206B1 (en) * | 1998-11-23 | 2002-04-30 | Cell Pathways, Inc. | Method of inhibiting neoplastic cells with 4,5-diaminopyrimidine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6380206B1 (en) * | 1998-11-23 | 2002-04-30 | Cell Pathways, Inc. | Method of inhibiting neoplastic cells with 4,5-diaminopyrimidine derivatives |
Non-Patent Citations (2)
| Title |
|---|
| CA147:365312.2006, * |
| WO 2005000246 A,全文. |
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