（一）技术领域(1) Technical field
本发明涉及一种6-氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮(简称氟喹酮)的制备方法，特别涉及一种以靛红酸酐为起始原料制备氟喹酮的方法。The present invention relates to a preparation method of 6-amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-phthalazinone (fluoroquinone for short), In particular, it relates to a method for preparing fluoroquinone by using isatoic anhydride as a starting material.
（二）背景技术(2) Background technology
氟喹酮1983年在日本首次上市，由日本田边株式会社开发，经过二十多年的临床应用，证明是一个对面、颈部肌肉痉挛有良好疗效的松弛剂。作为肌肉松弛药，氟喹酮主要作用于脊上位中枢较广泛的部位而使肌肉紧张性亢进状态缓解。它的中枢肌肉松弛活性大约是甲苯丙醇的22-29倍，是氯美扎酮的8-10倍。与已知的肌松药相比，氟喹酮的副作用和毒性都较小，具有很好的安全性。Fluoroquinone was first listed in Japan in 1983 and was developed by Japan Tanabe Co., Ltd. After more than 20 years of clinical application, it has been proved to be a relaxant with good curative effect on facial and neck muscle spasm. As a muscle relaxant, fluoroquinone mainly acts on a wider area of the supraspinal center to relieve the hypertonic state of the muscles. Its central muscle relaxation activity is about 22-29 times that of toluene propanol and 8-10 times that of clomezaldone. Compared with known muscle relaxants, fluoroquinone has less side effects and toxicity, and has good safety.
在本发明给出之前，氟喹酮的主要合成方法：Before the present invention provides, the main synthetic method of fluoroquinone:
1）US3966731报道了以N-（2-氨基-5-硝基苯甲酰基）邻甲苯胺为原料，先与氟代乙酰氯缩合后再在醋酸酐作用下环合生成6-硝基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮，最后在Pd-C催化作用下氢化还原得到氟喹酮。反应工艺路线如图1。1) US3966731 reported that N-(2-amino-5-nitrobenzoyl) o-toluidine was used as raw material, first condensed with fluoroacetyl chloride and then cyclized under the action of acetic anhydride to generate 6-nitro-2 -Fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-phthalazinone, and finally hydrogenated and reduced under the catalysis of Pd-C to obtain fluoroquinone. The reaction process route is shown in Figure 1.
该工艺总收率达66.6%，但是该工艺使用了氟代乙酰氯，该化合物沸点低，毒性大、腐蚀性大且价格昂贵，目前尚未产业化。The total yield of this process reaches 66.6%, but this process uses fluoroacetyl chloride, which has a low boiling point, high toxicity, high corrosion and high price, and has not yet been industrialized.
2）JP51105083报道了以N-（2-氨基-5-硝基苯甲酰基）邻甲苯胺为原料，首先与氯乙酰氯直接环合生成2-氯甲基-3-（2-甲基苯基）-6-硝基-4(3H)-喹唑啉酮，接着进行氟交换和还原反应生成最终产品氟喹酮。反应工艺路线如图2。2) JP51105083 reported that N-(2-amino-5-nitrobenzoyl) o-toluidine was used as a raw material, firstly cyclized directly with chloroacetyl chloride to generate 2-chloromethyl-3-(2-methylbenzene base)-6-nitro-4(3H)-quinazolinone, followed by fluorine exchange and reduction reaction to generate the final product fluoroquinone. The reaction process route is shown in Figure 2.
该工艺总收率41.1%，该法用氯乙酰氯替代氟代乙酰氯，操作更安全，但是在对该工艺进行验证过程中发现关键的氟交换步骤硝基同时也能被氟取代，导致该步反应收率非常低，生产成本居高不下。The total yield of this process is 41.1%. This method replaces fluoroacetyl chloride with chloroacetyl chloride, and the operation is safer. However, during the process of verifying the process, it was found that the nitro group in the key fluorine exchange step can also be replaced by fluorine, resulting in this The first-step reaction yield is very low, and the production cost remains high.
3）JP51105082报道了以N-(2-氨基-5-硝基苯甲酰基)邻甲苯胺为原料，先与氯乙酰氯环合，再进行硝基还原后上保护，接着进行氟交换和水解脱保护得到最终产品氟喹酮。反应工艺路线如图3。3) JP51105082 reported that N-(2-amino-5-nitrobenzoyl) o-toluidine was used as a raw material, firstly cyclized with chloroacetyl chloride, then carried out nitro reduction and up protection, followed by fluorine exchange and water The deprotection obtains the final product fluoroquinone. The reaction process route is shown in Figure 3.
该工艺总收率28%，该法同样用氯乙酰氯替代氟乙酰氯，但不仅增加了氟交换反应还增加了上保护和脱保护反应，反应步骤多，总收率较低，成本高。对该工艺进行验证过程中发现在Pd-C通氢还原过程中发现脱氯现象，导致该步反应的收率非常低。如图4所示。The total yield of this process is 28%. This method also uses chloroacetyl chloride instead of fluoroacetyl chloride, but not only increases the fluorine exchange reaction but also increases the protection and deprotection reactions. The reaction steps are many, the total yield is low, and the cost is high. During the process of verifying the process, it was found that the dechlorination phenomenon was found in the process of hydrogen reduction of Pd-C, resulting in a very low yield of this step reaction. As shown in Figure 4.
（三）发明内容(3) Contents of the invention
本发明的目的在于提供一种反应条件温和、操作简便、产品收率高、生产成本低、绿色安全的氟喹酮的制备方法。The object of the present invention is to provide a kind of preparation method of fluoroquinone with mild reaction conditions, simple and convenient operation, high product yield, low production cost, green and safe.
为实现上述目的，本发明采用的技术方案为：To achieve the above object, the technical solution adopted in the present invention is:
一种氟喹酮的制备方法，包括如下步骤：A preparation method for fluoroquinone, comprising the steps of:
（1）、将靛红酸酐1溶于质量浓度为95%-98%的浓硫酸中，于0-10℃内缓慢滴加硝化试剂，滴完后保温反应0.5-2h，反应液缓慢倾倒入冰水混合物中，析出黄色固体，抽滤、水洗、真空干燥得5-硝基靛红酸酐2；所述靛红酸酐1与硝化试剂的投料物质的量比为1:1.1-1.3；(1) Dissolve isatoic anhydride 1 in concentrated sulfuric acid with a mass concentration of 95%-98%, slowly add nitration reagent dropwise at 0-10°C, keep warm for 0.5-2h after dropping, and slowly pour the reaction solution into In the ice-water mixture, a yellow solid was precipitated, which was filtered by suction, washed with water, and dried in vacuum to obtain 5-nitroisatoic anhydride 2; the ratio of the isatoic anhydride 1 to the feeding material of the nitrating reagent was 1:1.1-1.3;
（2）、将5-硝基靛红酸酐2、有机溶剂A及雷尼镍加入高压釜中，通氢气维持釜内压力为0.5-2.0MPa，搅拌并升温至30-80℃反应0.5-4h，过滤回收雷尼镍，滤液中直接加入乙酸酐，室温下继续搅拌反应0.5-2h，减压浓缩回收溶剂，残留物经真空干燥得5-乙酰氨基靛红酸酐3；所述5-硝基靛红酸酐2与雷尼镍的投料质量比为1:0.03-0.08；5-硝基靛红酸酐2与乙酸酐的投料物质的量比为1:1.0-1.2；(2) Add 5-nitroisatoic anhydride 2, organic solvent A and Raney nickel into the autoclave, pass hydrogen to maintain the pressure in the autoclave at 0.5-2.0MPa, stir and heat up to 30-80°C for 0.5-4h , recover Raney nickel by filtration, directly add acetic anhydride to the filtrate, continue to stir the reaction at room temperature for 0.5-2h, concentrate and recover the solvent under reduced pressure, and dry the residue to obtain 5-acetylaminoisatoic anhydride 3; the 5-nitro The mass ratio of isatoic anhydride 2 to Raney nickel is 1:0.03-0.08; the mass ratio of 5-nitroisatoic anhydride 2 to acetic anhydride is 1:1.0-1.2;
（3）、将5-乙酰氨基靛红酸酐3溶于有机溶剂B中，加入邻甲苯胺，50-110℃内反应3-5h，减压浓缩回收溶剂和过量的邻甲苯胺，残留物经真空干燥得N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4；所述5-乙酰氨基靛红酸酐3与邻甲苯胺的投料物质的量比为1:1.0-1.5；(3) Dissolve 5-acetylaminoisatoic anhydride 3 in organic solvent B, add o-toluidine, react at 50-110°C for 3-5h, concentrate under reduced pressure to recover the solvent and excess o-toluidine, and pass through Vacuum drying to obtain N-(2-amino-5-acetamidobenzoyl)-o-toluidine 4; the amount ratio of the 5-acetamidoisatoic anhydride 3 to o-toluidine is 1:1.0-1.5;
（4）、将N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4溶于冰醋酸中，室温搅拌下缓慢滴加氯乙酰氯，滴加完毕后，搅拌并升温回流反应1-5h，减压浓缩至干，残留物经真空干燥得6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5；所述N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4与氯乙酰氯的投料物质的量比为1:0.9-1.1；(4) Dissolve N-(2-amino-5-acetylaminobenzoyl) o-toluidine 4 in glacial acetic acid, slowly add chloroacetyl chloride dropwise under stirring at room temperature, after the dropwise addition, stir and heat up to reflux reaction 1-5h, concentrated to dryness under reduced pressure, and the residue was vacuum-dried to obtain 6-acetylamino-2-chloromethyl-3-(2-methylphenyl)-4(3H)-1,3-diazepine Naphthalene 5; the amount ratio of the N-(2-amino-5-acetylaminobenzoyl)-o-toluidine 4 and chloroacetyl chloride is 1:0.9-1.1;
（5）、将6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5溶于有机溶剂C中，再加入现烘活化过的氟化钾，在季铵盐相转移催化剂的作用下搅拌回流反应1-5h，反应结束后经分离纯化得到6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6；所述6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5与氟化钾、季铵盐相转移催化剂的投料物质的量比为1:3.0-5.0:0.1-0.2；(5) Dissolve 6-acetylamino-2-chloromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 5 in organic solvent C, and then Add freshly activated potassium fluoride, stir and reflux for 1-5h under the action of a quaternary ammonium salt phase transfer catalyst, and obtain 6-acetylamino-2-fluoromethyl-3-(2- methylphenyl)-4(3H)-1,3-naphthyridine 6; the 6-acetamido-2-chloromethyl-3-(2-methylphenyl)-4(3H) -1,3-Naphthyridine 5 and potassium fluoride, quaternary ammonium salt phase-transfer catalyst feed material ratio is 1:3.0-5.0:0.1-0.2;
（6）、将6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6投入到NaOH的乙醇-水混合溶液中，升温至40-80℃搅拌反应1-3h，反应结束后先减压回收乙醇，水层再用二氯甲烷萃取，有机层减压浓缩至干，所得残留物经异丙醇重结晶，真空干燥后得到6-氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮7，即氟喹酮。(6) Put 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 6 into NaOH ethanol-water mixture In the solution, heat up to 40-80°C and stir for 1-3 hours. After the reaction, first recover the ethanol under reduced pressure, then extract the water layer with dichloromethane, concentrate the organic layer to dryness under reduced pressure, and recrystallize the obtained residue through isopropanol , after vacuum drying, 6-amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 7, namely fluoroquinone, was obtained.
本发明所述氟喹酮的制备方法步骤（1）中，所述浓硫酸的用量以靛红酸酐1的质量计为3-6mL/g；所述硝化试剂选自浓硝酸或发烟硝酸；优选所述硝化试剂为65wt%-68wt%的浓硝酸。In step (1) of the preparation method of fluoroquinone according to the present invention, the amount of the concentrated sulfuric acid is 3-6mL/g based on the mass of isatoic anhydride 1; the nitrating reagent is selected from concentrated nitric acid or fuming nitric acid; Preferably, the nitrating reagent is 65wt%-68wt% concentrated nitric acid.
本发明步骤（2）中，所述有机溶剂A选自乙腈、四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或它们任意比例的混合溶剂；优选所述有机溶剂A为四氢呋喃；所述有机溶剂A的加入量以5-硝基靛红酸酐2的质量计为10-15mL/g；优选所述5-硝基靛红酸酐2与雷尼镍的投料质量比为1:0.03-0.05；优选5-硝基靛红酸酐2与乙酸酐的投料物质的量比为1:1.0-1.1。In the step (2) of the present invention, the organic solvent A is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or their mixed solvents in any proportion; preferably the organic The solvent A is tetrahydrofuran; the addition amount of the organic solvent A is 10-15mL/g based on the quality of the 5-nitroisatoic anhydride 2; preferably the feeding quality of the 5-nitroisatoic anhydride 2 and Raney nickel The ratio is 1:0.03-0.05; preferably the amount ratio of the feed material of 5-nitroisatoic anhydride 2 to acetic anhydride is 1:1.0-1.1.
本发明步骤（3）中，所述有机溶剂B选自乙腈、四氢呋喃、C1-C4的醇或它们任意比例的混合溶剂；优选所述有机溶剂B为乙醇；所述的机溶剂B的加入量以5-乙酰氨基靛红酸酐3的质量计为4-6mL/g；优选所述5-乙酰氨基靛红酸酐3与邻甲苯胺的投料物质的量比为1:1.1-1.3。In the step (3) of the present invention, the organic solvent B is selected from acetonitrile, tetrahydrofuran, C1-C4 alcohol or their mixed solvents in any proportion; preferably the organic solvent B is ethanol; the amount of the organic solvent B added The mass of 5-acetylaminoisatoic anhydride 3 is 4-6mL/g; preferably, the ratio of 5-acetylaminoisatoic anhydride 3 to o-toluidine is 1:1.1-1.3.
本发明步骤（4）中，所述冰醋酸的加入量以N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺计4的质量计为4-6mL/g；优选所述N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4与氯乙酰氯的投料物质的量比为1:0.95-1.05。In the step (4) of the present invention, the addition of the glacial acetic acid is 4-6mL/g based on the mass of N-(2-amino-5-acetylaminobenzoyl) o-toluidine; preferably the N -(2-Amino-5-acetylaminobenzoyl)-o-toluidine 4 and chloroacetyl chloride are fed at a ratio of 1:0.95-1.05.
本发明步骤（5）中，所述有机溶剂C选自N,N-二甲基甲酰胺、硝基苯、环丁砜、乙腈、苯甲腈或它们任意比例的混合溶剂；优选所述有机溶剂C为乙腈；所述有机溶剂C的加入量以6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5的质量计为4-6mL/g；所述季铵盐相转移催化剂选自苯基三甲基溴化铵、苯基三甲基氯化铵、苄基三乙基溴化铵、十六烷基三甲基溴化铵、四丁基溴化铵或四丁基氯化铵；优选所述季铵盐相转移催化剂为四丁基溴化铵；优选所述6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5与氟化钾、季铵盐相转移催化剂的投料物质的量比为1:3.0-3.5:0.1-0.15。In step (5) of the present invention, the organic solvent C is selected from N,N-dimethylformamide, nitrobenzene, sulfolane, acetonitrile, benzonitrile or their mixed solvents in any proportion; preferably the organic solvent C It is acetonitrile; the addition amount of the organic solvent C is 5 The mass is 4-6mL/g; the quaternary ammonium salt phase transfer catalyst is selected from phenyltrimethylammonium bromide, phenyltrimethylammonium chloride, benzyltriethylammonium bromide, cetyl Trimethylammonium bromide, tetrabutylammonium bromide or tetrabutylammonium chloride; Preferably the quaternary ammonium salt phase transfer catalyst is tetrabutylammonium bromide; Preferably the 6-acetamido-2-chloroform The molar ratio of base-3-(2-methylphenyl)-4(3H)-1,3-phthalazinone 5 to potassium fluoride and quaternary ammonium salt phase transfer catalyst is 1:3.0- 3.5:0.1-0.15.
本发明步骤（5）中，所述分离纯化的方法为：反应结束后反应液减压浓缩至干，加入二氯甲烷，过滤回收过量的氟化钾，滤液浓缩所得粗品用乙醇重结晶，真空干燥得6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6。In the step (5) of the present invention, the separation and purification method is as follows: after the reaction, the reaction solution is concentrated to dryness under reduced pressure, dichloromethane is added, excess potassium fluoride is recovered by filtration, the crude product obtained by concentrating the filtrate is recrystallized with ethanol, vacuum Drying gave 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 6.
本发明步骤（6）中，所述NaOH的乙醇-水混合溶液的溶剂是乙醇、水体积比配比1:0.4-0.6的混合溶液；所述NaOH的乙醇-水混合溶液中NaOH的质量浓度为4%-8%；所述6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6与NaOH的投料物质的量比为1:1.5-2.0。In step (6) of the present invention, the solvent of the ethanol-water mixed solution of NaOH is a mixed solution with a volume ratio of ethanol and water of 1:0.4-0.6; the mass concentration of NaOH in the ethanol-water mixed solution of NaOH is 4%-8%; the feeding of the 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 6 and NaOH The amount ratio of substances is 1:1.5-2.0.
与现有技术相比，本发明的积极效果在于以价廉易得的靛红酸酐为起始原料合成关键中间体N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺，大大降低了生产成本。革除了现有文献方法中高毒高害试剂氟代乙酰氯的使用，具有安全、环保的优点。在氟交换反应中使用四丁基溴化铵作为反应的相转移催化剂，大大提高了该步反应的转化率。由起始原料靛红酸酐制备目标产物氟喹酮的总收率可达60.0%以上。Compared with the prior art, the positive effect of the present invention is that the key intermediate N-(2-amino-5-acetamidobenzoyl) o-toluidine is synthesized as a starting material with cheap and easy-to-get isatoic anhydride, greatly Reduced production costs. The use of highly toxic and highly harmful reagent fluoroacetyl chloride in the existing literature methods is eliminated, and the method has the advantages of safety and environmental protection. Using tetrabutylammonium bromide as a phase transfer catalyst in the fluorine exchange reaction greatly improves the conversion rate of this step. The total yield of the target product fluoroquinone from the starting material isatoic anhydride can reach more than 60.0%.
（四）附图说明(4) Description of drawings
图1是US3966731报道的合成氟喹酮的反应工艺路线；Fig. 1 is the reaction process scheme of the synthetic fluoroquinone of US3966731 report;
图2是JP51105083报道的合成氟喹酮的反应工艺路线；Fig. 2 is the reaction process route of the synthetic fluoroquinone reported by JP51105083;
图3是JP51105082报道的合成氟喹酮的反应工艺路线；Fig. 3 is the reaction process route of the synthetic fluoroquinone reported by JP51105082;
图4是JP51105082报道的合成氟喹酮的反应工艺路线中，Pd-C通氢还原反应过程。Fig. 4 is the reaction process of Pd-C hydrogen reduction reaction in the reaction process route for the synthesis of fluoroquinone reported by JP51105082.
（五）具体实施方式：(5) Specific implementation methods:
以下以具体实施例用来进一步说明本发明的技术方案，但本发明的保护范围不限于此：The following are used to further illustrate the technical scheme of the present invention with specific examples, but the protection scope of the present invention is not limited thereto:
实施例1Example 1
5-硝基靛红酸酐2的合成Synthesis of 5-Nitroisatoic Anhydride 2
在250mL三口烧瓶中加入浓硫酸（100mL），机械搅拌下在0-10℃时缓慢加入靛红酸酐1(30.0g,0.18mol)，搅拌溶解后滴加65%的浓硝酸(21.4g,0.22mol)，维持温度0-10℃，1h滴加完毕，并保温继续反应1h，停止搅拌，将反应液缓慢倒入300mL冰水混合物中，搅拌20min，固体充分析出，过滤，水洗，干燥后得5-硝基靛红酸酐2(37.5g,收率：97.9%)。m.p.264.8-265.5℃；HPLC测量纯度为98.4%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=30:70，V/V）。Add concentrated sulfuric acid (100mL) into a 250mL three-necked flask, add isatoic anhydride 1 (30.0g, 0.18mol) slowly at 0-10°C under mechanical stirring, and add 65% concentrated nitric acid (21.4g, 0.22 mol), maintain the temperature at 0-10°C, dropwise addition is completed for 1 hour, keep warm and continue to react for 1 hour, stop stirring, slowly pour the reaction solution into 300mL ice-water mixture, stir for 20 minutes, the solid is fully separated out, filtered, washed with water, and dried to obtain 5-nitroisatoic anhydride 2 (37.5 g, yield: 97.9%). mp264.8-265.5°C; the purity measured by HPLC is 98.4% (the mobile phase is acetonitrile:20mmol/LKH2 PO4 aqueous solution (pH3.25)=30:70, V/V).
实施例2Example 2
5-硝基靛红酸酐2的合成Synthesis of 5-Nitroisatoic Anhydride 2
在250mL三口烧瓶中加入浓硫酸（100mL），机械搅拌下在0-10℃时缓慢加入靛红酸酐1(30.0g,0.18mol)，搅拌溶解后滴加98%的发烟硝酸(14.2g,0.22mol)，维持温度0-5℃，1h滴加完毕，并保温继续反应1h，停止搅拌，将反应液缓慢倒入300mL冰水混合物中，搅拌20min，固体充分析出，过滤，水洗，干燥后得5-硝基靛红酸酐2(37.0g,收率：96.6%)。m.p.263.8-265.3℃；HPLC测量纯度为97.2%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=30:70，V/V）。Add concentrated sulfuric acid (100mL) into a 250mL three-necked flask, slowly add isatoic anhydride 1 (30.0g, 0.18mol) at 0-10°C under mechanical stirring, stir and dissolve, then add dropwise 98% fuming nitric acid (14.2g, 0.22mol), maintain the temperature at 0-5°C, add dropwise for 1h, keep warm and continue to react for 1h, stop stirring, slowly pour the reaction solution into 300mL ice-water mixture, stir for 20min, the solid is fully separated out, filtered, washed with water, and dried 5-nitroisatoic anhydride 2 (37.0 g, yield: 96.6%) was obtained. mp263.8-265.3°C; the purity measured by HPLC is 97.2% (the mobile phase is acetonitrile: 20mmol/LKH2 PO4 aqueous solution (pH3.25)=30:70, V/V).
实施例3Example 3
5-乙酰氨基靛红酸酐3的合成Synthesis of 5-Acetamidoisatoic Anhydride 3
在500mL高压釜内依次加入5-硝基靛红酸酐2(20.0g,96.0mmol)，四氢呋喃(200mL)，雷尼镍(1.00g，购买自阿拉丁试剂(上海)有限公司，货号为R111435，规格为500g，20-40目，本说明书其他实施例所用的雷尼镍与此相同），先用氮气置换空气三次，检查气密性后再用氢气置换氮气三次，通氢气维持压力为2.0Mpa，在60℃下反应2h，停止反应，滤除雷尼镍，在室温条件下，向滤液中加入醋酐(9.79g,96.0mmol)，搅拌反应1h后减压浓缩，干燥得到5-乙酰氨基靛红酸酐3(20.1g,收率：95.0%)。m.p.215.1-216.0℃；HPLC测量纯度为98.0%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=50:50，V/V）。In a 500mL autoclave, add 5-nitroisatoic anhydride 2 (20.0g, 96.0mmol), tetrahydrofuran (200mL), Raney nickel (1.00g, purchased from Aladdin Reagents (Shanghai) Co., Ltd., product number R111435, The specification is 500g, 20-40 mesh, and the Raney nickel used in other examples of this specification is the same), first replace the air with nitrogen three times, check the air tightness, then replace the nitrogen with hydrogen three times, and maintain the pressure at 2.0Mpa with hydrogen , react at 60°C for 2h, stop the reaction, filter out Raney nickel, add acetic anhydride (9.79g, 96.0mmol) to the filtrate at room temperature, stir and react for 1h, then concentrate under reduced pressure and dry to obtain 5-acetamido Isatoic anhydride 3 (20.1 g, yield: 95.0%). mp215.1-216.0°C; the purity measured by HPLC is 98.0% (the mobile phase is acetonitrile:20mmol/LKH2 PO4 aqueous solution (pH3.25)=50:50, V/V).
实施例4Example 4
5-乙酰氨基靛红酸酐3的合成Synthesis of 5-Acetamidoisatoic Anhydride 3
在500mL高压釜内依次加入5-硝基靛红酸酐2(20.0g,96.0mmol)，乙腈(200mL)，雷尼镍(0.80g)，先用氮气置换空气三次，检查气密性后再用氢气置换氮气三次，通氢气维持压力为1.0Mpa，在50℃下反应4h，停止反应，滤除雷尼镍，在室温条件下，向滤液中加入醋酐(9.79g,96.0mmol)，搅拌反应1h后减压浓缩，干燥得到5-乙酰氨基靛红酸酐3(19.9g,收率：94.0%)。m.p.214.5-215.9℃；HPLC测量纯度为97.0%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=50:50，V/V）。Add 5-nitroisatoic anhydride 2 (20.0g, 96.0mmol), acetonitrile (200mL), and Raney nickel (0.80g) successively in a 500mL autoclave, first replace the air with nitrogen three times, check the air tightness before using Replace the nitrogen with hydrogen for three times, maintain the pressure at 1.0Mpa with hydrogen, react at 50°C for 4h, stop the reaction, filter out Raney nickel, add acetic anhydride (9.79g, 96.0mmol) to the filtrate at room temperature, and stir the reaction After 1 h, it was concentrated under reduced pressure and dried to obtain 5-acetylaminoisatoic anhydride 3 (19.9 g, yield: 94.0%). mp214.5-215.9°C; the purity measured by HPLC is 97.0% (the mobile phase is acetonitrile:20mmol/LKH2 PO4 aqueous solution (pH3.25)=50:50, V/V).
实施例5Example 5
N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4的合成Synthesis of N-(2-amino-5-acetylaminobenzoyl)o-toluidine 4
在100mL三口烧瓶中依次加入5-乙酰氨基靛红酸酐3(8.00g,36.3mmol)，邻甲苯胺(4.27g,39.9mmol)，乙醇(40mL)，升温回流反应4h，反应完毕，冷却至室温，减压浓缩回收乙醇得N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4(9.79g,收率：95.0%)。m.p.209.6-210.9℃；HPLC测量纯度为98.8%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=25:75，V/V）。Add 5-acetylaminoisatoic anhydride 3 (8.00g, 36.3mmol), o-toluidine (4.27g, 39.9mmol), and ethanol (40mL) successively into a 100mL three-neck flask, heat up and reflux for 4h, after the reaction is complete, cool to room temperature , concentrated under reduced pressure to recover ethanol to give N-(2-amino-5-acetylaminobenzoyl) o-toluidine 4 (9.79g, yield: 95.0%). mp209.6-210.9°C; the purity measured by HPLC is 98.8% (the mobile phase is acetonitrile: 20mmol/LKH2 PO4 aqueous solution (pH3.25)=25:75, V/V).
实施例6Example 6
N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4的合成Synthesis of N-(2-amino-5-acetylaminobenzoyl)o-toluidine 4
在100mL三口烧瓶中依次加入5-乙酰氨基靛红酸酐3(8.00g,36.3mmol)，邻甲苯胺(5.05g,47.2mmol)，四氢呋喃(40mL)，升温回流反应4h，反应完毕，冷却至室温，减压浓缩回收四氢呋喃得N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4(9.70g,收率：94.2%)。m.p.208.9-210.9℃；HPLC测量纯度为97.8%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=25:75，V/V）。Add 5-acetylaminoisatoic anhydride 3 (8.00g, 36.3mmol), o-toluidine (5.05g, 47.2mmol), tetrahydrofuran (40mL) in sequence in a 100mL three-necked flask, heat up and reflux for 4h, after the reaction is complete, cool to room temperature , and concentrated under reduced pressure to recover THF to obtain N-(2-amino-5-acetylaminobenzoyl)o-toluidine 4 (9.70 g, yield: 94.2%). mp208.9-210.9°C; the purity measured by HPLC is 97.8% (the mobile phase is acetonitrile: 20mmol/LKH2 PO4 aqueous solution (pH3.25)=25:75, V/V).
实施例7Example 7
6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5的合成Synthesis of 6-acetylamino-2-chloromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 5
在100mL三口烧瓶中，依次加入冰醋酸（40mL）、N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4(8.00g,28.3mmol)，室温搅拌下缓缓滴加氯乙酰氯(3.20g,28.3mmol)，20min滴加完毕，搅拌并升温回流4h后，冷却至室温，减压浓缩回收冰醋酸得灰白色固体，干燥得到6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5(8.88g,收率：92.0%)。m.p.208.9-210.0℃；HPLC测量纯度为97.5%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=35:65，V/V）。In a 100mL three-necked flask, add glacial acetic acid (40mL) and N-(2-amino-5-acetylaminobenzoyl) o-toluidine 4 (8.00g, 28.3mmol) in sequence, slowly add ethyl chloride dropwise under stirring at room temperature Acyl chloride (3.20g, 28.3mmol), after 20min dropwise addition, stirred and heated to reflux for 4h, cooled to room temperature, concentrated under reduced pressure and recovered glacial acetic acid to obtain off-white solid, dried to obtain 6-acetylamino-2-chloromethyl-3- (2-Methylphenyl)-4(3H)-1,3-naphthyridine 5 (8.88 g, yield: 92.0%). mp208.9-210.0°C; the purity measured by HPLC is 97.5% (mobile phase is acetonitrile:20mmol/LKH2 PO4 aqueous solution (pH3.25)=35:65, V/V).
实施例8Example 8
6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5的合成Synthesis of 6-acetylamino-2-chloromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 5
在100mL三口烧瓶中,依次加入冰醋酸（40mL）、N-（2-氨基-5-乙酰氨基苯甲酰基）邻甲苯胺4(8.00g,28.3mmol)，室温搅拌下缓缓滴加氯乙酰氯(3.50g,31.1mmol)，20min滴加完毕，搅拌并升温回流4h后，冷却至室温，减压浓缩回收冰醋酸得灰白色固体，干燥得到6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5(8.69g,收率：90.1%)。m.p.208.5-210.0℃；HPLC测量纯度为96.5%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=35:65，V/V）。In a 100mL three-neck flask, add glacial acetic acid (40mL), N-(2-amino-5-acetylaminobenzoyl) o-toluidine 4 (8.00g, 28.3mmol) in sequence, slowly add ethyl chloride dropwise under stirring at room temperature Acyl chloride (3.50g, 31.1mmol), after 20 minutes of dropwise addition, stirred and refluxed for 4 hours, cooled to room temperature, concentrated under reduced pressure and recovered glacial acetic acid to obtain off-white solid, dried to obtain 6-acetylamino-2-chloromethyl-3- (2-Methylphenyl)-4(3H)-1,3-naphthyridine 5 (8.69 g, yield: 90.1%). mp208.5-210.0°C; the purity measured by HPLC is 96.5% (the mobile phase is acetonitrile: 20mmol/LKH2 PO4 aqueous solution (pH3.25)=35:65, V/V).
实施例9Example 9
6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6的合成Synthesis of 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 6
在100mL二口圆底烧瓶中，依次加入6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5(7.50g,22mmol)，无水乙腈(40mL)、现烘活化过的氟化钾(3.83g,66mmol)和催化剂四丁基溴化铵(0.71g,2.2mmol)，搅拌回流4h后，反应毕减压浓缩回收乙腈至干，残余物加入30mL二氯甲烷，过滤回收过量的KF。滤液二氯甲烷层减压浓缩得粗品。加入20mL乙醇重结晶得6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6(6.45g,收率：90.2%)。m.p.249.3-250.3℃；HPLC测量纯度为97.6%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=35:65，V/V）。In a 100mL two-necked round bottom flask, add 6-acetamido-2-chloromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 5(7.50 g, 22mmol), anhydrous acetonitrile (40mL), now activated potassium fluoride (3.83g, 66mmol) and catalyst tetrabutylammonium bromide (0.71g, 2.2mmol), after stirring and refluxing for 4h, the reaction decreased Concentrate under reduced pressure to recover acetonitrile to dryness, add 30 mL of dichloromethane to the residue, and recover excess KF by filtration. The dichloromethane layer of the filtrate was concentrated under reduced pressure to obtain a crude product. Add 20 mL of ethanol for recrystallization to obtain 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 6 (6.45 g, yield: 90.2%). mp249.3-250.3°C; the purity measured by HPLC is 97.6% (the mobile phase is acetonitrile: 20mmol/LKH2 PO4 aqueous solution (pH3.25)=35:65, V/V).
实施例10Example 10
6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6的合成Synthesis of 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 6
在100mL二口圆底烧瓶中，依次加入6-乙酰氨基-2-氯甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮5(7.50g,22mmol)，无水环丁砜(40mL)、现烘活化过的氟化钾(3.83g,66mmol)和催化剂四丁基溴化铵(0.71g,2.2mmol)，回流搅拌4h，反应毕减压浓缩回收环丁砜至干，残余物加入30mL二氯甲烷，过滤回收过量的KF。滤液二氯甲烷层减压浓缩得粗品。加入20mL乙醇重结晶得6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6(6.30g,收率：88.2%)。m.p.249.3-250.3℃；HPLC测量纯度为97.1%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=35:65，V/V）。In a 100mL two-necked round bottom flask, add 6-acetamido-2-chloromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 5(7.50 g, 22mmol), anhydrous sulfolane (40mL), now activated potassium fluoride (3.83g, 66mmol) and catalyst tetrabutylammonium bromide (0.71g, 2.2mmol), stirred at reflux for 4h, and decompressed after the reaction Concentrate and recover sulfolane to dryness, add 30 mL of dichloromethane to the residue, and recover excess KF by filtration. The dichloromethane layer of the filtrate was concentrated under reduced pressure to obtain a crude product. Add 20 mL of ethanol for recrystallization to obtain 6-acetylamino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 6 (6.30 g, yield: 88.2%). mp249.3-250.3°C; the purity measured by HPLC is 97.1% (the mobile phase is acetonitrile: 20mmol/LKH2 PO4 aqueous solution (pH3.25)=35:65, V/V).
实施例11Example 11
6-氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮7的合成Synthesis of 6-amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 7
在100mL二口烧瓶中，加入氢氧化钠（0.92g，23.0mmol），再加入7.50mL水和15.0mL乙醇使之溶解，最后加入6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6(5.00g,15.4mmol)。70℃下搅拌2h后，先减压浓缩回收乙醇，水层再用二氯甲烷萃取(20mL×2)。合并有机层，减压浓缩至干得棕色黏稠油状物，加入25mL异丙醇重结晶得6-氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮7(3.86g,收率：88.5%)。m.p.194.5-195.5℃；HPLC测量纯度为99.3%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=35:65，V/V）；1HNMR(400MHz,DMSO-d6):δ=2.01(s,3H),4.81-5.02(m,2H),5.85(s,2H),7.15(dd,J1=2.8Hz,J2=8.8Hz,1H),7.23(d,J=2.8Hz,1H),7.35-7.44(m,4H),7.51(d,J=8.8Hz,1H)；MS(ESI):m/z(%)=284[M+H]+。In a 100mL two-necked flask, add sodium hydroxide (0.92g, 23.0mmol), then add 7.50mL water and 15.0mL ethanol to dissolve it, and finally add 6-acetylamino-2-fluoromethyl-3-(2- Methylphenyl)-4(3H)-1,3-phthalazinone 6 (5.00 g, 15.4 mmol). After stirring at 70°C for 2 h, the mixture was concentrated under reduced pressure to recover ethanol, and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layers were combined, concentrated under reduced pressure to dryness to obtain a brown viscous oil, which was recrystallized by adding 25 mL of isopropanol to obtain 6-amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1 , 3-Naphthyridine 7 (3.86g, yield: 88.5%). mp194.5-195.5°C; the purity measured by HPLC is 99.3% (the mobile phase is acetonitrile: 20mmol/LKH2 PO4 aqueous solution (pH3.25)=35:65, V/V);1 HNMR (400MHz, DMSO-d6 ):δ=2.01(s,3H),4.81-5.02(m,2H),5.85(s,2H),7.15(dd,J1 =2.8Hz,J2 =8.8Hz,1H),7.23(d, J=2.8Hz, 1H), 7.35-7.44(m, 4H), 7.51(d, J=8.8Hz, 1H); MS(ESI): m/z(%)=284[M+H]+ .
实施例12Example 12
6-氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮7的合成Synthesis of 6-amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1,3-naphthyridine 7
在100mL二口烧瓶中，加入氢氧化钠（1.23g，30.8mol），再加入7.50mL水和15.0mL乙醇使之溶解，最后加入6-乙酰氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮6(5.00g,15.4mmol)。70℃下搅拌2h后，先减压浓缩回收乙醇，水层再用二氯甲烷萃取（20mL×2)。合并有机层，减压浓缩至干得棕色黏稠油状物，加入25mL异丙醇重结晶得6-氨基-2-氟甲基-3-（2-甲基苯基）-4（3H）-1,3-二氮杂萘酮7(3.71g,收率：85.0%)。m.p.194.2-195.7℃；HPLC测量纯度为99.0%（流动相为乙腈:20mmol/LKH2PO4水溶液(pH3.25)=35:65，V/V）。In a 100mL two-necked flask, add sodium hydroxide (1.23g, 30.8mol), then add 7.50mL water and 15.0mL ethanol to dissolve it, and finally add 6-acetylamino-2-fluoromethyl-3-(2- Methylphenyl)-4(3H)-1,3-phthalazinone 6 (5.00 g, 15.4 mmol). After stirring at 70°C for 2 h, the ethanol was recovered by concentration under reduced pressure, and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layers were combined, concentrated under reduced pressure to dryness to obtain a brown viscous oil, which was recrystallized by adding 25 mL of isopropanol to obtain 6-amino-2-fluoromethyl-3-(2-methylphenyl)-4(3H)-1 , 3-naphthyridine 7 (3.71 g, yield: 85.0%). mp194.2-195.7°C; the purity measured by HPLC is 99.0% (the mobile phase is acetonitrile: 20mmol/LKH2 PO4 aqueous solution (pH3.25)=35:65, V/V).
| Application Number | Priority Date | Filing Date | Title |
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| CN201310473405.2ACN103613549B (en) | 2013-10-11 | 2013-10-11 | A kind of preparation method of afloqualone |
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| CN201310473405.2ACN103613549B (en) | 2013-10-11 | 2013-10-11 | A kind of preparation method of afloqualone |
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| CN103613549A CN103613549A (en) | 2014-03-05 |
| CN103613549Btrue CN103613549B (en) | 2016-04-20 |
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| CN201310473405.2AActiveCN103613549B (en) | 2013-10-11 | 2013-10-11 | A kind of preparation method of afloqualone |
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| CN (1) | CN103613549B (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106397338A (en)* | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High yield preparation method of afloqualone |
| CN106496145A (en)* | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of preparation method of afloqualone |
| CN106496144A (en)* | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of synthesis technique of afloqualone |
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| CN1665804A (en)* | 2002-04-25 | 2005-09-07 | 帝人株式会社 | 4,4-disubstituted piperidine derivatives with CCR3 antagonistic effect |
| US20070032525A1 (en)* | 2002-04-16 | 2007-02-08 | Yoshiyuki Matsumoto | Piperidine derivatives having ccr3 antagonism |
| US20130253179A1 (en)* | 2010-12-06 | 2013-09-26 | Arnaud Burr | Functionalization Processes and Reactants Used in Such Processes Using an Isatoic Anhydride or a Derivative Thereof, Biological Molecules Thus Treated and Kits |
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| JPS51105082A (en)* | 1975-03-07 | 1976-09-17 | Tanabe Seiyaku Co | KINAZORINON JUDOTAINO SEIHO |
| JPS51105083A (en)* | 1975-03-13 | 1976-09-17 | Tanabe Seiyaku Co | KINAZORINON JUDOTAINOSEIHO |
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| JPS5920668B2 (en)* | 1975-10-03 | 1984-05-15 | 田辺製薬株式会社 | Process for producing quinazoline derivatives |
| JPS5920670B2 (en)* | 1976-04-10 | 1984-05-15 | 田辺製薬株式会社 | Production method of quinazolinone derivatives |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966731A (en)* | 1973-10-15 | 1976-06-29 | Tanabe Seiyaku Co., Ltd. | 2-Fluoromethyl-3-o-tolyl-6-amino-4(3H)-quinazolinone |
| US6274383B1 (en)* | 1997-12-15 | 2001-08-14 | Sepracor Inc. | Methods for synthesizing libraries of dihydro-quinazolinones |
| US20070032525A1 (en)* | 2002-04-16 | 2007-02-08 | Yoshiyuki Matsumoto | Piperidine derivatives having ccr3 antagonism |
| CN1665804A (en)* | 2002-04-25 | 2005-09-07 | 帝人株式会社 | 4,4-disubstituted piperidine derivatives with CCR3 antagonistic effect |
| US20130253179A1 (en)* | 2010-12-06 | 2013-09-26 | Arnaud Burr | Functionalization Processes and Reactants Used in Such Processes Using an Isatoic Anhydride or a Derivative Thereof, Biological Molecules Thus Treated and Kits |
| Title |
|---|
| Studies on Biologically Active Halogenated Compounds. 1.Synthesis and Central Nervous System Depressant Activity of 2-(Fluoromethyl)-3-aryl-4(3H)-quinazolinone Derivatives;Junichi Tani,等;《Journal of Medicinal Chemistry》;19790101;第22卷(第1期);第95-99页* |
| 氟喹酮的合成;肖瑞琪,等;《华西药学杂志》;20060430;第21卷(第02期);第160-162页* |
| Publication number | Publication date |
|---|---|
| CN103613549A (en) | 2014-03-05 |
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