CN102702115A - Synthetic method of 4-chloro-7-fluoro-6-nitro quinazoline - Google Patents
Synthetic method of 4-chloro-7-fluoro-6-nitro quinazoline Download PDFInfo
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- CN102702115A CN102702115A CN2012101627069A CN201210162706A CN102702115A CN 102702115 A CN102702115 A CN 102702115A CN 2012101627069 A CN2012101627069 A CN 2012101627069A CN 201210162706 A CN201210162706 A CN 201210162706A CN 102702115 A CN102702115 A CN 102702115A
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Abstract
The invention discloses a synthetic method of 4-chloro-7-fluoro-6-nitro quinazoline, aiming at the obvious shortages of low yield, complex production process and low product purify in the prior art. In the method, 2-amino-4-fluorobenzoic acid and formamidine acetate are used as raw materials and subjected to synthesis in ethylene glycol monomethylether under certain conditions, so as to obtain 7-fluoro-4-hydroxy quinazoline; the obtained 7-fluoro-4-hydroxy quinazoline is subjected to nitration, so as to obtain 7-fluoro-6-nitro-4-hydroxy quinazoline, because the obtained 7-fluoro-6-nitro-4-hydroxy quinazoline contains an amount of isomers, the 7-fluoro-6-nitro-4-hydroxy quinazoline are subjected to special treatments to remove the isomers, so as to obtain pure 7-fluoro-6-nitro-4-hydroxy quinazoline; and the obtained pure 7-fluoro-6-nitro-4-hydroxy quinazoline is subjected to treatment by sulfoxide chloride, so as to obtain the 4-chloro-7-fluoro-6-nitro quinazoline. With the adoption of the method, the production yield is greatly enhanced, the production process is simplified, and the production efficiency is improved.
Description
Technical field
The present invention relates to a kind of compound method of 4-chloro-7-fluoro-6-nitro-quinazoline, belong to medicine, chemical technology field.
Background technology
4-chloro-7-fluoro-6-nitro-quinazoline is a kind of yellow solid, is a kind of important medicinal intermediates.
Summary of the invention
4-chloro-7-fluoro-6-nitro-quinazoline is a kind of important medicinal intermediates, and traditional synthesis process exists productive rate low, and production sequence is complicated, and the not high obvious deficiency of product purity is necessary existing technology is optimized.Major advantage of the present invention is to have improved the production productive rate greatly, has simplified production sequence, and has improved the production productive rate.
The compound method of 4-chloro-7-fluoro-6-nitro-quinazoline according to the invention; Be that to narrow with 2-amino-4-fluorobenzoic acid and acetic acid first be raw material; The synthetic under certain condition 7-fluoro-4-hydroxyl quinazoline that obtains in EGME; The nitrated 7-fluoro-6-nitro-4-hydroxyl quinazoline that obtains of resultant 7-fluoro-4-hydroxyl quinazoline; Owing to contain a certain amount of isomers in resulting 7-fluoro-6-nitro-4-hydroxyl quinazoline; Remove the isomers that is contained in 7-fluoro-6-nitro-4-hydroxyl quinazoline through special processing, obtain purified 7-fluoro-6-nitro-4-hydroxyl quinazoline, resultant purified 7-fluoro-6-nitro-4-hydroxyl quinazoline just can obtain 4-chloro-7-fluoro-6-nitro-quinazoline through the processing of sulfur oxychloride.
The compound method of above-mentioned 4-chloro-7-fluoro-6-nitro-quinazoline is characterized in that: described raw material is that 2-amino-4-fluorobenzoic acid and acetic acid first are narrowed.
The compound method of above-mentioned 4-chloro-7-fluoro-6-nitro-quinazoline is characterized in that: remove isomers special processing in 7-fluoro-6-nitro-4-hydroxyl quinazoline and refer to and use the methyl alcohol repetitive scrubbing.
Above-mentioned 7-fluoro-6-nitro-4-hydroxyl quinazoline compound method is characterized in that: the compound method of said 7-fluoro-6-nitro-4-hydroxyl quinazoline makes: the 2-amino-4-fluorobenzoic acid and the 402 gram acetic acid first that in the there-necked flask of 3L, drop into 200 grams are narrowed, and add the 1.2L EGME again; The mechanical stirring reflux; Stop heating when reacting completely, cool to room temperature is poured reaction solution in 2 premium on currency that stirring into; Filter, 60 degree oven dry obtain the gray 7-fluoro-4-hydroxyl quinazoline of 183 grams.183 gram 7-fluoro-4-hydroxyl quinazolines of gained are joined in 3 liters of there-necked flasks that contain 800 milliliters of vitriol oils, and ice-water bath cools to 10 degree, drips the mixing acid of 160 milliliters of nitrosonitric acids and 40 milliliters of vitriol oils; After reacting completely, reaction solution is slowly poured in the trash ice, and stirred; Add a large amount of water dilutions, have yellow solid to separate out, filter; Solid is washed (about mechanical stirring 2 hours, can wash isomers off) with 2 liters of methyl alcohol and is filtered, and gets yellow solid; Aforesaid operations is 4 times repeatedly, dry 168 gram yellow solid 7-fluoro-6-nitro-4-hydroxyl quinazolines.In the there-necked flask of 3L, add 168 gram 7-fluoro-6-nitro-4-hydroxyl quinazolines, 1500 milliliters of sulfur oxychlorides, mechanical stirring, 0 milliliter of DMF of Dropwise 5, after dripping, reflux, solid dissolves gradually in the reaction solution, reacts completely.Spin off sulfur oxychloride, obtain yellow solid, solid is used sherwood oil: the solvent of ETHYLE ACETATE=10:1 is washed for 1000 milliliters, and mechanical stirring was filtered in 10 minutes, and oil pump draws dried, and getting 133 gram yellow crystals is exactly purified 4-chloro-7-fluoro-6-nitro-quinazoline.
Above-mentioned narrowing etc. with 2-amino-4-fluorobenzoic acid and acetic acid first is that the chemical reaction and the reaction formula of the synthetic 4-chloro-7-fluoro-6-nitro-quinazoline of raw material is following:
The reaction equation that (1) 2-amino-4-fluorobenzoic acid and acetic acid first are narrowed is:
(2) reaction is accomplished, and nitrated reaction equation is after the filtering drying:
(3) reaction is accomplished, and the reaction equation with sulfur oxychloride behind the purifying is:
(4) react completely after, revolve dried sulfur oxychloride, wash with the mixing solutions of sherwood oil and ETHYLE ACETATE and just can obtain purified 4-chloro-7-fluoro-6-nitro-quinazoline.
Embodiment
Embodiment:
The compound method of said 7-fluoro-6-nitro-4-hydroxyl quinazoline makes: the 2-amino-4-fluorobenzoic acid and the 402 gram acetic acid first that in the there-necked flask of 3L, drop into 200 grams are narrowed; Add the 1.2L EGME again, the mechanical stirring reflux stops heating when reacting completely; Cool to room temperature; Reaction solution is poured in 2 premium on currency that stirring, filtered, 60 degree oven dry obtain the gray 7-fluoro-4-hydroxyl quinazoline of 183 grams.183 gram 7-fluoro-4-hydroxyl quinazolines of gained are joined in 3 liters of there-necked flasks that contain 800 milliliters of vitriol oils, and ice-water bath cools to 10 degree, drips the mixing acid of 160 milliliters of nitrosonitric acids and 40 milliliters of vitriol oils; After reacting completely, reaction solution is slowly poured in the trash ice, and stirred; Add a large amount of water dilutions, have yellow solid to separate out, filter; Solid is washed (about mechanical stirring 2 hours, can wash isomers off) with 2 liters of methyl alcohol and is filtered, and gets yellow solid; Aforesaid operations is 4 times repeatedly, dry 168 gram yellow solid 7-fluoro-6-nitro-4-hydroxyl quinazolines.In the there-necked flask of 3L, add 168 gram 7-fluoro-6-nitro-4-hydroxyl quinazolines, 1500 milliliters of sulfur oxychlorides, mechanical stirring, 0 milliliter of DMF of Dropwise 5, after dripping, reflux, solid dissolves gradually in the reaction solution, reacts completely.Spin off sulfur oxychloride, obtain yellow solid, solid is used sherwood oil: the solvent of ETHYLE ACETATE=10:1 is washed for 1000 milliliters, and mechanical stirring was filtered in 10 minutes, and oil pump draws dried, and getting 133 gram yellow crystals is exactly purified 4-chloro-7-fluoro-6-nitro-quinazoline.
Claims (4)
1.4-the compound method of chloro-7-fluoro-6-nitro-quinazoline; Be that to narrow with 2-amino-4-fluorobenzoic acid and acetic acid first be raw material; The synthetic under certain condition 7-fluoro-4-hydroxyl quinazoline that obtains in EGME; The nitrated 7-fluoro-6-nitro-4-hydroxyl quinazoline that obtains of resultant 7-fluoro-4-hydroxyl quinazoline; Owing to contain a certain amount of isomers in resulting 7-fluoro-6-nitro-4-hydroxyl quinazoline; Remove the isomers that is contained in 7-fluoro-6-nitro-4-hydroxyl quinazoline through special processing, obtain purified 7-fluoro-6-nitro-4-hydroxyl quinazoline, resultant purified 7-fluoro-6-nitro-4-hydroxyl quinazoline just can obtain 4-chloro-7-fluoro-6-nitro-quinazoline through the processing of sulfur oxychloride.
2. the compound method of 4-chloro-7-fluoro-6-nitro-quinazoline as claimed in claim, it is characterized in that: said new initial feed is meant that narrowing with 2-amino-4-fluorobenzoic acid and acetic acid first is raw material.
3. the compound method of 4-chloro-7-fluoro-6-nitro-quinazoline as claimed in claim, it is characterized in that: 2-amino-4-fluorobenzoic acid and acetic acid first are narrowed the certain condition that synthetic 7-fluoro-4-hydroxyl quinazoline is in EGME and are referred to stirring and refluxing.
4. 4-chloro-7-fluoro-6-nitro-quinazoline compound method as claimed in claim is characterized in that: remove in 7-fluoro-6-nitro-4-hydroxyl quinazoline the special processing of isomers and refer to and use the methyl alcohol repetitive scrubbing.
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| CN2012101627069A CN102702115A (en) | 2012-05-24 | 2012-05-24 | Synthetic method of 4-chloro-7-fluoro-6-nitro quinazoline |
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| CN2012101627069A CN102702115A (en) | 2012-05-24 | 2012-05-24 | Synthetic method of 4-chloro-7-fluoro-6-nitro quinazoline |
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Citations (7)
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| US20030100573A1 (en) * | 2001-06-21 | 2003-05-29 | Yihan Wang | Novel quinazolines and uses thereof |
| CN1948314A (en) * | 2006-10-17 | 2007-04-18 | 浙江理工大学 | 8-arylamine-3H-imidazole [4,5-g] quinazoline derivatives and its solid phase synthesis method |
| US20080056990A1 (en) * | 2005-09-06 | 2008-03-06 | T.K. Signal Ltd. | Polyalkylene glycol derivatives of inhibitors of epidermal growth factor receptor tyrosine kinase |
| CN101619043A (en) * | 2008-06-30 | 2010-01-06 | 和记黄埔医药（上海）有限公司 | Quinazoline derivant and medical application thereof |
| US20100009958A1 (en) * | 2008-06-30 | 2010-01-14 | Hutchison Medipharma Enterprises Limited | Quinazoline derivatives |
| CN101926802A (en) * | 2009-06-18 | 2010-12-29 | 湘北威尔曼制药有限公司 | Application of quinazoline compounds |
| WO2012030160A2 (en) * | 2010-08-31 | 2012-03-08 | Hanmi Holdings Co., Ltd. | Quinoline or quinazoline derivatives with apoptosis inducing activity on cells |
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- 2012-05-24 CN CN2012101627069A patent/CN102702115A/en active Pending
Patent Citations (7)
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| US20030100573A1 (en) * | 2001-06-21 | 2003-05-29 | Yihan Wang | Novel quinazolines and uses thereof |
| US20080056990A1 (en) * | 2005-09-06 | 2008-03-06 | T.K. Signal Ltd. | Polyalkylene glycol derivatives of inhibitors of epidermal growth factor receptor tyrosine kinase |
| CN1948314A (en) * | 2006-10-17 | 2007-04-18 | 浙江理工大学 | 8-arylamine-3H-imidazole [4,5-g] quinazoline derivatives and its solid phase synthesis method |
| CN101619043A (en) * | 2008-06-30 | 2010-01-06 | 和记黄埔医药（上海）有限公司 | Quinazoline derivant and medical application thereof |
| US20100009958A1 (en) * | 2008-06-30 | 2010-01-14 | Hutchison Medipharma Enterprises Limited | Quinazoline derivatives |
| CN101926802A (en) * | 2009-06-18 | 2010-12-29 | 湘北威尔曼制药有限公司 | Application of quinazoline compounds |
| WO2012030160A2 (en) * | 2010-08-31 | 2012-03-08 | Hanmi Holdings Co., Ltd. | Quinoline or quinazoline derivatives with apoptosis inducing activity on cells |
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| D.KOBUS,等: "A fully automated two-step synthesis of an 18F-labelled tyrosine kinase inhibitor for EGFR kinase activity imaging in tumors", 《APPLIED RADIATION AND ISOTOPES》 * |
| KYUNGIK LEE, 等: "Structure-based virtual screening of Src kinase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| YANDONG ZHANG, 等: "Scaffold Approach for Solid-Phase Synthesis of 2,3-Disubstituted 8-Arylamino-3H-imidazo[4,5-g]quinazolines", 《J. COMB. CHEM.》 * |
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Application publication date: 20121003 |