CN103508965B - Synthetic method for dibenzepin derivative - Google Patents

Synthetic method for dibenzepin derivative Download PDF

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CN103508965B
CN103508965B CN201310455049.1A CN201310455049A CN103508965B CN 103508965 B CN103508965 B CN 103508965B CN 201310455049 A CN201310455049 A CN 201310455049A CN 103508965 B CN103508965 B CN 103508965B
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杜云飞
李旭明
张翔
赵康
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Tianjin University
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Abstract

本发明公开了一种二苯西平类衍生物的合成方法，步骤为：取代邻溴苯甲酸、氧化亚铜、氮甲基吗啉与取代苯胺反应，生成2-（N-取代苯基）氨基苯甲酸衍生物（IV）；化合物（IV）与氢化钠和碘甲烷反应生成2-（N-甲基-N-取代苯基）氨基苯甲酸甲酯衍生物（V）；化合物（V）碱性水解得到2-（N-甲基-N-取代苯基）氨基苯甲酸衍生物（VI）；化合物（VI）在羰基二咪唑作用下与甲氧胺盐酸盐缩合生成2-（N-甲基-N-取代苯基）氨基-N’-甲氧基苯甲酰胺衍生物（VII）；化合物（VII）与二乙酰氧基碘苯在乙腈中室温下反应得到二苯西平类衍生物（I）；本发明具有操作简单，反应原料以及反应试剂易得，收率较高等优点。The invention discloses a synthesis method of diphenazepine derivatives. The steps are: react substituted o-bromobenzoic acid, cuprous oxide, nitrogen methylmorpholine and substituted aniline to generate 2-(N-substituted phenyl)amino Benzoic acid derivative (IV); compound (IV) reacts with sodium hydride and methyl iodide to generate 2-(N-methyl-N-substituted phenyl)aminobenzoic acid methyl ester derivative (V); compound (V) base 2-(N-methyl-N-substituted phenyl)aminobenzoic acid derivatives (VI) were obtained by sexual hydrolysis; compound (VI) was condensed with methoxyamine hydrochloride under the action of carbonyldiimidazole to generate 2-(N- Methyl-N-substituted phenyl) amino-N'-methoxybenzamide derivatives (VII); Compound (VII) reacts with diacetoxyiodobenzene in acetonitrile at room temperature to obtain diphenazepine derivatives (I); The present invention has the advantages of simple operation, easy access to reaction raw materials and reaction reagents, and higher yield.

Description

一种二苯西平类衍生物的合成方法A kind of synthetic method of diphenazepine derivatives

技术领域 technical field

本发明涉及一种二苯西平类衍生物的合成方法。 The invention relates to a method for synthesizing diphenazepine derivatives.

背景技术 Background technique

二苯西平结构存在于多种药用分子或合成某些天然产物的重要中间体中，如抗抑郁药物Dibenzepin[1]（A）、组蛋白去乙酰化酶抑制剂[2]（B）、抗炎药[3]（C）、精神分裂症药物氯氮平[4]（D）、第一代M1选择型毒蕈碱的受体拮抗剂Gastrozepin[5]（E）、对1型免疫缺陷病毒有生理活性的药物Dibenzoxazepinone[6]（F）等。故对于含有这类结构的药用分子或天然产物，可以通过从这类二苯西平化合物制备得到。 The dibenzepine structure exists in a variety of pharmaceutical molecules or important intermediates in the synthesis of some natural products, such as antidepressant Dibenzepin [1] (A), histone deacetylase inhibitors [2] (B), Anti-inflammatory drugs [3] (C), schizophrenia drug clozapine [4] (D), first-generation M1-selective muscarinic receptor antagonist Gastrozepin [5] (E), immune to type 1 Deficient virus has a physiologically active drug Dibenzoxazepinone [6] (F) et al. Therefore, the pharmaceutical molecule or natural product containing this type of structure can be prepared from this type of dibenzazepine compound.

相关文献如下： The relevant literature is as follows:

Attwood,D.;Gibson,J.J.Pharm.Pharmac.1978,30,176-180. Attwood, D.; Gibson, J. J. Pharm. Pharmac. 1978, 30, 176-180.

Binaschi,M.;Boldetti,A.;Gianni,M.;Maggi,C.A.;Gensini,M.;Bigioni,M.;Parlani,M.;Giolitti,A.;Fratelli,M.;Valli,C.;Terao,M.;Garattini,E.ACSMed.Chem.Lett.2010,1,411-415.  Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C.A.; Gensini, M.; Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli, M.; Valli, C.; Terao ,M.;Garattini,E.ACSMed.Chem.Lett.2010,1,411-415. 

Coyne,W.E.;Cusic,J.W.J.Med.Chem.1967,10,541-546. Coyne, W. E.; Cusic, J. W. J. Med. Chem. 1967, 10, 541-546.

(a)Liegeois,J.F.;Rogister,F.A.;Bruhwyler,J.;Damas,J.;Nguyen,T.P.;Inarejos,M.O.;Chleide,E.M.G.;Mercier,M.G.A.;Delarge,J.E.J.Med.Chem.1994,37,519-525.(b)Liegeois,J.F.;Bruhwyler,J.;Damas,J.;Nguyen,T.P.;Chleide,E.;Mercier,M.;Rogister,F.;Delarge,J.J.Med.Chem.1993,36,2107-2114.(c)Chakrabarti,J.K.;Hotten,T.M.;Pullar,I.A.;Steggles,D.J.J.Med.Chem.1989,32,2375-2381.  (a) Liegeois, J.F.; Rogister, F.A.; Bruhwyler, J.; Damas, J.; Nguyen, T.P.; Inarejos, M.O.; (b) Liegeois, J.F.; Bruhwyler, J.; Damas, J.; Nguyen, T.P.; Chleide, E.; Mercier, M.; .(c)Chakrabarti, J.K.;Hotten,T.M.;Pullar,I.A.;Steggles,D.J.J.Med.Chem.1989,32,2375-2381. 

Eberlein,G.W.;Trummlitz,G.;Engel,W.W.;Schmidt,G.;Pelzer,H.;Mayer,N.J.Med.Chem.1987,30,1378-1382.  Eberlein, G.W.;Trummlitz,G.;Engel,W.W.;Schmidt,G.;Pelzer,H.;Mayer,N.J.Med.Chem.1987,30,1378-1382. 

KlunderJ.M.;Hargrave,K.D.;West,M.;Cullen,E.;Pal,K.;Behnke,M.L.;Kapadia,S.R.;Mcneil,D.W.;Wu,J.C.;Chow,G.C.;Adams,J.J.Med.Chem.1992,35,1887-1897.  Klunder, J.M.; Hargrave, K.D.; West, M.; Cullen, E.; Pal, K.; Behnke, M.L.; Kapadia, S.R.; Mcneil, D.W.; Wu, J.C.; .1992,35,1887-1897.

目前文献报道的二苯西平化合物的合成方法有六种，如下所示： There are six synthetic methods of the diphenazepine compound reported in the literature at present, as follows:

Giani等使用铜粉催化偶联碳氮键同时酰胺化[7]一锅法构建二苯西平母核，该方法是使用取代邻氯苯甲酸和取代邻苯二胺以铜粉作催化剂，在氯苯中加热回流的条件下，反应生成二苯西平母核，如下式所示： Giani et al. used copper powder to catalyze coupling of carbon-nitrogen bond and simultaneous amidation [7] to construct diphenazepine core in one pot. This method uses substituted o-chlorobenzoic acid and substituted o-phenylenediamine with copper powder as catalyst, Under the condition of heating and refluxing in benzene, the reaction generates the diphenazepine mother nucleus, as shown in the following formula:

此方法的缺点是金属催化剂造成一定污染，不易处理，且产率较低。 The disadvantage of this method is that the metal catalyst causes some pollution, is not easy to handle, and the yield is low.

Lu等利用硅胶负载钯化合物催化偶联反应[8]构建二苯西平骨架，其方法是使用硅胶负载的钯化合物为催化剂，在用甲苯为溶剂，二异丙基乙基胺作碱，高压一氧化碳的环境下使原料生成二苯西平母核，如下式所示： Lu et al. used silica-supported palladium compounds to catalyze the coupling reaction [8] to construct diphenylzepine skeletons. The method is to use silica-supported palladium compounds as catalysts, use toluene as solvent, diisopropylethylamine as base, and high-pressure carbon monoxide Under the environment that makes raw material generate diphenazepine mother nucleus, as shown in the following formula:

此方法缺点是其原料非常见易得，催化剂为贵金属价格昂贵，反应条件需要高压加热，不利于操作。 The disadvantage of this method is that its raw materials are very common and easy to obtain, the catalyst is expensive, and the reaction conditions require high-pressure heating, which is not conducive to operation.

Bunce使用2-氟硝基苯与邻碘苯甲酸甲酯为起始原料，最后通过高温下铁粉还原-缩合得到二苯西平母核结构[9]，其缺点是底物中取代硝基苯类化合物闪点较低，反应温度较高，应用安全性较低。 Bunce uses 2-fluoronitrobenzene and methyl o-iodobenzoate as starting materials, and finally obtains the diphenazepine core structure through reduction-condensation of iron powder at high temperature [9] . The disadvantage is that nitrobenzene is substituted in the substrate The flash point of similar compounds is low, the reaction temperature is high, and the application safety is low.

Al-Tel使用三氯氧磷作催化剂，通过芳香亲电取代反应环合得二苯西平母核结构[10]，其缺点是反应温度较高，时间较长，收率不高。 Al-Tel uses phosphorus oxychloride as a catalyst to obtain the diphenazepine core structure through aromatic electrophilic substitution reaction [10] . The disadvantage is that the reaction temperature is high, the time is long, and the yield is not high.

Tsvelikhovsky使用邻氨基苯甲酸乙酯与邻氯溴苯为原料，三（二亚苄基丙酮）二钯与配体作催化剂，在溶剂叔丁醇中先催化偶联得二苯胺类底物，再用二氧六环为溶剂，配体钯催化底物与氨反应得到二苯西平母核结构[11]，其缺点是反应温度较高，时间较长，贵金属催化剂价格昂贵。 Tsvelikhovsky used ethyl anthranilate and o-chlorobromobenzene as raw materials, tris(dibenzylideneacetone) dipalladium and ligand as catalysts, and first catalyzed coupling in solvent tert-butanol to obtain diphenylamine substrates, and then Using dioxane as a solvent, the ligand palladium catalyzes the reaction of the substrate and ammonia to obtain the dibenzepine core structure [11] . The disadvantage is that the reaction temperature is high, the time is long, and the noble metal catalyst is expensive.

Diao使用氯化亚铜作催化剂，筛选邻二氮杂菲为碱，完成了一步双氨基化构建二苯西平母核结构[12]。 Diao used cuprous chloride as a catalyst, screened o-phenanthrene as a base, and completed a one-step double amination to construct the core structure of diphenazepine [12] .

其缺点是金属催化剂后处理不方便，对环境有一定污染性。 The disadvantage is that the post-processing of the metal catalyst is inconvenient and pollutes the environment.

具体参见以下文献： See the following documents for details:

Giani,R.P.;Borsa,M.;Parini,E.;Tonton,G.C.Synthesis.1985,1,550.  Giani, R.P.; Borsa, M.; Parini, E.; Tonton, G.C.Synthesis.1985,1,550. 

Lu,S.;Alper,H.J.Am.Chem.Soc.2005,127,14776-14784. Lu, S.; Alper, H. J. Am. Chem. Soc. 2005, 127, 14776-14784.

Bunce,R.A.,Schammerhorn,J.E.J.HeterocyclicChem.2006,43,1031. Bunce, R.A., Schammerhorn, J.E.J. Heterocyclic Chem. 2006, 43, 1031.

Al-Tel,T.H.;Al-Qawasmeh,R.A.;Schmidt,M.F.;Al-Aboudi,A.;Rao,S.N.;Sabri,S.S.;Voelter,W.J.Med.Chem.2009,52,6484-6488.  Al-Tel, T.H.; Al-Qawasmeh, R.A.; Schmidt, M.F.; Al-Aboudi, A.; Rao, S.N.;

TsvelikhovskyD.;Buchwald,S.L.J.Am.Chem.Soc.2011,133,14228-14231.  TsvelikhovskyD.;Buchwald,S.L.J.Am.Chem.Soc.2011,133,14228-14231. 

Diao,X.;Xu,L.;Zhu,W.;Jiang,Y.;Wang,H.;Guo,Y.;Ma,D.Org.Lett.2011,13,6422-6425.  Diao,X.;Xu,L.;Zhu,W.;Jiang,Y.;Wang,H.;Guo,Y.;Ma,D.Org.Lett.2011,13,6422-6425. 

发明内容 Contents of the invention

本发明的目的在于提供一种二苯西平类衍生物（I）的合成方法。 The object of the present invention is to provide a method for synthesizing diphenazepine derivatives (I).

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）以取代邻溴苯甲酸（II）为原料，以氧化亚铜为氧化剂，以氮甲基吗啉为碱，在溶剂二氧六环中与取代苯胺（III）反应，生成2-（N-取代苯基）氨基苯甲酸衍生物（IV）； (1) Using substituted o-bromobenzoic acid (II) as raw material, cuprous oxide as oxidant, and nitrogen methylmorpholine as base, react with substituted aniline (III) in dioxane solvent to generate 2-( N-substituted phenyl) aminobenzoic acid derivatives (IV);

（2）所述2-（N-取代苯基）氨基苯甲酸衍生物（IV）与氢化钠和碘甲烷在氮、氮-二甲基甲酰胺中发生甲基化反应生成2-（N-甲基-N-取代苯基）氨基苯甲酸甲酯衍生物（V）； (2) The 2-(N-substituted phenyl) aminobenzoic acid derivative (IV) undergoes methylation reaction with sodium hydride and methyl iodide in nitrogen, nitrogen-dimethylformamide to generate 2-(N- Methyl-N-substituted phenyl) aminobenzoic acid methyl ester derivative (V);

（3）所述2-（N-甲基-N-取代苯基）氨基苯甲酸甲酯衍生物（V）在甲醇与水的混合溶剂中经氢氧化钾碱性水解得到2-（N-甲基-N-取代苯基）氨基苯甲酸衍生物（VI）； (3) The methyl 2-(N-methyl-N-substituted phenyl)aminobenzoate derivative (V) is alkaline hydrolyzed by potassium hydroxide in a mixed solvent of methanol and water to obtain 2-(N- Methyl-N-substituted phenyl) aminobenzoic acid derivatives (VI);

（4）所述2-（N-甲基-N-取代苯基）氨基苯甲酸衍生物（VI）在羰基二咪唑作用下，于四氢呋喃中与甲氧胺盐酸盐在室温下缩合生成2-（N-甲基-N-取代苯基）氨基-N’-甲氧基苯甲酰胺衍生物（VII）； (4) The 2-(N-methyl-N-substituted phenyl)aminobenzoic acid derivative (VI) is condensed with methoxyamine hydrochloride in tetrahydrofuran under the action of carbonyldiimidazole at room temperature to form 2 - (N-methyl-N-substituted phenyl)amino-N'-methoxybenzamide derivatives (VII);

（5）所述2-（N-甲基-N-取代苯基）氨基-N’-甲氧基苯甲酰胺衍生物（VII）与二乙酰氧基碘苯在乙腈中室温下反应得到二苯西平类衍生物（I）；反应式为： (5) The 2-(N-methyl-N-substituted phenyl)amino-N'-methoxybenzamide derivative (VII) reacts with diacetoxyiodobenzene in acetonitrile at room temperature to obtain di Benzepine derivatives (I); the reaction formula is:

本发明具有操作简单，反应原料以及反应试剂易得，收率较高等优点。 The invention has the advantages of simple operation, easy availability of reaction raw materials and reagents, high yield and the like.

具体实施方式 Detailed ways

下述各实施例中所用的反应原料取代邻溴苯甲酸（II）、取代苯胺（III）、甲氧胺盐酸盐等均可以方便买到。 The reaction raw materials used in the following examples are substituted o-bromobenzoic acid (II), substituted aniline (III), methoxyamine hydrochloride, etc., which can be purchased conveniently.

下面结合具体实施例对本发明作进一步的说明。 The present invention will be further described below in conjunction with specific examples.

下面各实施例是为了使本领域的技术人员能够更好地理解本发明，但本发明的内容并不限于所举实施例。 The following embodiments are intended to enable those skilled in the art to better understand the present invention, but the content of the present invention is not limited to the examples given.

实施例1 Example 1

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）2-（N-甲基-N-苯基）氨基-N’-甲氧基苯甲酰胺（VII-a）的制备 (1) Preparation of 2-(N-methyl-N-phenyl)amino-N’-methoxybenzamide (VII-a)

将邻溴苯甲酸（II-a）（4.00g），苯胺（III-a）（2.79g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为2-（N-苯基）氨基苯甲酸（IV-a）。 Add o-bromobenzoic acid (II-a) (4.00 g), aniline (III-a) (2.79 g), nitrogenmethylmorpholine (3.3 mL), cuprous oxide (1.43 g) to dioxane ( 50 mL), heated to reflux for 4 hours under nitrogen protection. After the reaction was completed, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate with 1M aqueous hydrochloric acid to pH=5, and obtain a white solid as 2-(N-phenyl)aminobenzoic acid (IV-a) by suction filtration.

将化合物（IV-a）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品2-（N-甲基-N-苯基）氨基苯甲酸甲酯（V-a）。 Compound (IV-a) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction is over, slowly add water in an ice bath to quench excess sodium hydride, extract with ethyl acetate, dry the organic phase and remove the solvent under reduced pressure to obtain a yellow oily crude product 2-(N-methyl-N-phenyl) Methyl aminobenzoate (V-a).

化合物（V-a）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体2-（N-甲基-N-苯基）氨基苯甲酸（VI-a）。 Compound (V-a) was dissolved in methanol: water (v/v) = 5:1 mixed solvent (40 mL), potassium hydroxide (3.36 g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were precipitated, and then recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 2-(N-methyl-N-benzene base) aminobenzoic acid (VI-a).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到淡黄色固体2-（N-甲基-N-苯基）氨基-N’-甲氧基苯甲酰胺（VII-a）3.3g，四步总收率64%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain 3.3 g of 2-(N-methyl-N-phenyl)amino-N'-methoxybenzamide (VII-a) as a light yellow solid, with a total yield of 64% in four steps.

1H NMR(600MHz,CDCl3):δ3.19(s,3H),3.67(s,3H),6.77～6.78(d,J=7.2Hz,2H),6.89～6.91(t,J=7.2Hz,1H),7.10～7.11(d,1H),7.22～7.25(t,J=7.2Hz,2H),7.33～7.36(t,J=7.2Hz,1H),7.45～7.48(t,J=7.2Hz,1H),10.64(s,1H).13CNMR(151MHz,CDCl3):δ164.53,148.98,148.03,133.22,131.35,129.67,129.30,127.72,126.84,120.47,116.30,64.10,40.95.  1 H NMR (600MHz, CDCl 3 ): δ3.19(s,3H),3.67(s,3H),6.77～6.78(d,J=7.2Hz,2H),6.89～6.91(t,J=7.2Hz ,1H),7.10～7.11(d,1H),7.22～7.25(t,J=7.2Hz,2H),7.33～7.36(t,J=7.2Hz,1H),7.45～7.48(t,J=7.2 Hz,1H),10.64(s,1H) .13 CNMR(151MHz,CDCl 3 ):δ164.53,148.98,148.03,133.22,131.35,129.67,129.30,127.72,126.84,120.47,116.30,64.10,40.95

（2）5-甲基-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-a）的制备 (2) Preparation of 5-methyl-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-a)

将2-（N-甲基-N-苯基）氨基-N’-甲氧基苯甲酰胺（VII-a）(0.51g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到白色固体5-甲基-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-a）0.4g，产率：82%。 Dissolve 2-(N-methyl-N-phenyl)amino-N'-methoxybenzamide (VII-a) (0.51g) in acetonitrile (40mL), and add two Acetoxyiodobenzene solid (0.97g), stirred at room temperature for 30min to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain 0.4 g of white solid 5-methyl-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-a), yield: 82%.

1H NMR(600MHz,CDCl3):δ3.36(s,3H),3.87(s,3H),7.06～7.08(t,J=7.2Hz,2H),7.12～7.19(m,3H),7.39～7.42(t,J=7.2Hz,1H),7.49～7.50(m,1H),7.89～7.90(d,J=7.2Hz,1H).13C NMR(151MHz,CDCl3):δ165.03,152.98,145.81,133.84,132.76,132.05,126.45,125.58,124.35,123.05,121.04,118.46,116.67,62.31,37.66.  1 H NMR (600MHz, CDCl 3 ): δ3.36(s,3H),3.87(s,3H),7.06～7.08(t,J=7.2Hz,2H),7.12～7.19(m,3H),7.39 ～7.42(t, J=7.2Hz, 1H), 7.49～7.50(m, 1H), 7.89～7.90(d, J=7.2Hz, 1H). 13 C NMR(151MHz, CDCl 3 ): δ165.03, 152.98, 145.81, 133.84, 132.76, 132.05, 126.45, 125.58, 124.35, 123.05, 121.04, 118.46, 116.67, 62.31, 37.66.

实施例2 Example 2

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）2-[N-甲基-N-（4-甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-b）的制备 (1) Preparation of 2-[N-methyl-N-(4-methoxy)phenyl]amino-N’-methoxybenzamide (VII-b)

将邻溴苯甲酸（II-a）（4.00g），4-甲氧基苯胺（III-b）（3.69g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为2-[N-（4-甲氧基）苯基]氨基苯甲酸（IV-b）。 Add o-bromobenzoic acid (II-a) (4.00g), 4-methoxyaniline (III-b) (3.69g), nitrogenmethylmorpholine (3.3mL), cuprous oxide (1.43g) to Dioxane (50 mL) was heated to reflux for 4 hours under the protection of nitrogen. After the reaction was completed, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate to pH=5 with 1M aqueous hydrochloric acid solution, and obtain a white solid of 2-[N-(4-methoxy)phenyl]aminobenzene by suction filtration Formic acid (IV-b).

将化合物（IV-b）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品2-[N-甲基N-（4-甲氧基）苯基]氨基苯甲酸甲酯（V-b）。 Compound (IV-b) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction was completed, water was slowly added in an ice bath to quench excess sodium hydride, extracted with ethyl acetate, the organic phase was dried and the solvent was removed under reduced pressure to obtain a yellow oily crude product 2-[N-methyl N-(4-methyl oxy)phenyl]aminobenzoic acid methyl ester (V-b).

化合物（V-b）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体2-[N-甲基-N-（4-甲氧基）苯基]氨基苯甲酸（VI-b）。 Compound (V-b) was dissolved in methanol:water (v/v)=5:1 mixed solvent (40 mL), potassium hydroxide (3.36 g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were precipitated, and recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 2-[N-methyl-N-( 4-methoxy)phenyl]aminobenzoic acid (VI-b).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到淡黄色固体2-[N-甲基-N-（4-甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-b）2.8g，四步总收率49%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain 2.8 g of light yellow solid 2-[N-methyl-N-(4-methoxy)phenyl]amino-N'-methoxybenzamide (VII-b), four steps The total yield is 49%.

1H NMR(600MHz,CDCl3):δ3.15(s,3H),3.75(s,3H),6.76～6.78(d,J=9.0Hz,2H),6.81～6.83(d,J=9.0Hz,2H),7.05～7.07(d,J=7.8Hz,1H),7.30～7.33(t,J=7.2Hz,2H),7.43～7.45(t,J=7.2Hz,1H),11.06(s,1H).13C NMR(151MHz,CDCl3):δ164.65,154.46,149.12,142.98,133.08,131.35,128.81,126.71,126.34,118.65,114.66,64.15,55.59,55.57,41.71.  1 H NMR (600MHz, CDCl 3 ): δ3.15(s,3H),3.75(s,3H),6.76～6.78(d,J=9.0Hz,2H),6.81～6.83(d,J=9.0Hz ,2H),7.05～7.07(d,J=7.8Hz,1H),7.30～7.33(t,J=7.2Hz,2H),7.43～7.45(t,J=7.2Hz,1H),11.06(s, 1H). 13 C NMR (151MHz, CDCl 3 ): δ164.65, 154.46, 149.12, 142.98, 133.08, 131.35, 128.81, 126.71, 126.34, 118.65, 114.66, 64.15, 55.59, 55.57, 41.71.

（2）5-甲基-8，10-二甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-b）的制备 (2) Preparation of 5-methyl-8,10-dimethoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-b)

将2-[N-甲基-N-（4-甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-b）(0.57g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到浅黄色固体5-甲基-8，10-二甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-b）0.51g，产率：90%。 2-[N-Methyl-N-(4-methoxy)phenyl]amino-N'-methoxybenzamide (VII-b) (0.57g) was dissolved in acetonitrile (40mL), ice Diacetoxyiodobenzene solid (0.97 g) was added to the bath several times, and stirred at room temperature for 30 minutes to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain 0.51 g of light yellow solid 5-methyl-8,10-dimethoxy-11H-dibenzo[b,e][1,4]diazepin-11one (I-b), yield: 90%.

1H NMR(600MHz,CDCl3):δ3.31(s,3H),3.77(s,3H),3.89(s,3H),6.72～6.73(d,J=9.0Hz,1H),7.03(s,1H),7.03～7.06(m,3H),7.38～7.41(t,J=7.2Hz,1H),7.89～7.90(d,J=7.2Hz,1H).13C NMR(151MHz,CDCl3):δ165.23,156.59,153.37,138.78,134.90,132.79,132.17,125.40,122.77,119.16,116.31,112.24,105.86,99.99,62.43,55.71,37.71.  1 H NMR (600MHz, CDCl3): δ3.31(s,3H),3.77(s,3H),3.89(s,3H),6.72～6.73(d,J=9.0Hz,1H),7.03(s, 1H),7.03～7.06(m,3H),7.38～7.41(t,J=7.2Hz,1H),7.89～7.90(d,J=7.2Hz,1H). 13 C NMR(151MHz,CDCl 3 ): δ165.23, 156.59, 153.37, 138.78, 134.90, 132.79, 132.17, 125.40, 122.77, 119.16, 116.31, 112.24, 105.86, 99.99, 62.43, 55.71, 37.71.

实施例3 Example 3

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）2-[N-甲基-N-（3-甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-c）的制备 (1) Preparation of 2-[N-methyl-N-(3-methoxy)phenyl]amino-N’-methoxybenzamide (VII-c)

将邻溴苯甲酸（II-a）（4.00g），3-甲氧基苯胺（III-c）（3.69g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液化至pH=5，抽滤得白色固体为2-[N-（3-甲氧基）苯基]氨基苯甲酸（IV-c）。 Add o-bromobenzoic acid (II-a) (4.00 g), 3-methoxyaniline (III-c) (3.69 g), nitrogen methylmorpholine (3.3 mL), cuprous oxide (1.43 g) to Dioxane (50 mL) was heated to reflux for 4 hours under the protection of nitrogen. After the reaction, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, the filtrate is adjusted to pH=5 with 1M hydrochloric acid aqueous solution, and the white solid is 2-[N-(3-methoxy)phenyl]aminobenzene by suction filtration Formic acid (IV-c).

将化合物（IV-c）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品2-[N-甲基-N-（3-甲氧基）苯基]氨基苯甲酸甲酯（V-c）。 Compound (IV-c) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction was completed, water was slowly added in an ice bath to quench excess sodium hydride, extracted with ethyl acetate, the organic phase was dried and the solvent was removed under reduced pressure to obtain a yellow oily crude product 2-[N-methyl-N-(3- Methoxy)phenyl]aminobenzoic acid methyl ester (V-c).

化合物（V-c）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体2-[N-甲基-N-（3-甲氧基）苯基]氨基苯甲酸（VI-c）。 Compound (V-c) was dissolved in methanol:water (v/v)=5:1 mixed solvent (40mL), potassium hydroxide (3.36g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were precipitated, and recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 2-[N-methyl-N-( 3-methoxy)phenyl]aminobenzoic acid (VI-c).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到浅黄色固体2-[N-甲基-N-（3-甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-c）2.8g，四步总收率49%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain 2.8 g of light yellow solid 2-[N-methyl-N-(3-methoxy)phenyl]amino-N'-methoxybenzamide (VII-c), four steps The total yield is 49%.

1H NMR(600MHz,CDCl3):δ3.18(s,3H),3.72(s,3H),3.74(s,3H),6.32(s,1H),6.34～6.35(d,J=8.4Hz,1H),6.46～6.48(d,J=7.8Hz,1H),7.71～7.72(d,J=7.8Hz,1H),7.13～7.16(t,J=7.8Hz,1H),7.36～7.38(t,J=7.8Hz,1H),7.46～7.49(t,J=7.8Hz,1H),8.15～8.16(d,J=6.0Hz,1H),10.46(s,1H).13C NMR(151MHz,CDCl3):δ164.46,160.65,150.30,147.66,133.21,131.45,130.11,127.90,127.11,127.06,109.04,105.08,102.83,64.18,55.24,40.94.  1 H NMR (600MHz, CDCl 3 ): δ3.18(s,3H),3.72(s,3H),3.74(s,3H),6.32(s,1H),6.34～6.35(d,J=8.4Hz ,1H),6.46～6.48(d,J=7.8Hz,1H),7.71～7.72(d,J=7.8Hz,1H),7.13～7.16(t,J=7.8Hz,1H),7.36～7.38( t,J=7.8Hz,1H),7.46～7.49(t,J=7.8Hz,1H),8.15～8.16(d,J=6.0Hz,1H),10.46(s,1H). 13 C NMR(151MHz , CDCl 3 ): δ164.46, 160.65, 150.30, 147.66, 133.21, 131.45, 130.11, 127.90, 127.11, 127.06, 109.04, 105.08, 102.83, 64.18, 55.24, 40.94.

（2）5-甲基-7，10-二甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-c）的制备 (2) Preparation of 5-methyl-7,10-dimethoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-c)

将2-[N-甲基-N-（3-甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-c）(0.57g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到浅黄色固体5-甲基-7，10-二甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-c）0.43g，产率：76%。 2-[N-Methyl-N-(3-methoxy)phenyl]amino-N'-methoxybenzamide (VII-c) (0.57g) was dissolved in acetonitrile (40mL), ice Diacetoxyiodobenzene solid (0.97 g) was added to the bath several times, and stirred at room temperature for 30 minutes to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain 0.43 g of light yellow solid 5-methyl-7,10-dimethoxy-11H-dibenzo[b,e][1,4]diazepin-11one (I-c), yield: 76%.

1H NMR(600MHz,CDCl3):δ3.32(s,3H),3.79(s,3H),3.83(s,3H),6.66～6.69(m,2H),7.04～7.05(d,J=8.4Hz,1H),7.06～7.08(t,J=7.8Hz,1H),7.37～7.40(m,2H),7.86～7.87(d,J=7.8Hz,1H).13C NMR(151MHz,CDCl3):δ164.64,158.36,152.75,147.66,132.52,131.87,126.64,126.04,123.24,122.32,116.75,109.01,104.69,61.95,55.60,37.48.  1 H NMR (600MHz, CDCl 3 ): δ3.32(s,3H),3.79(s,3H),3.83(s,3H),6.66～6.69(m,2H),7.04～7.05(d,J= 8.4Hz, 1H), 7.06～7.08(t, J=7.8Hz, 1H), 7.37～7.40(m, 2H), 7.86～7.87(d, J=7.8Hz, 1H). 13 C NMR (151MHz, CDCl 3 ).

实施例4 Example 4

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）2-[N-甲基-N-（3，4-二甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-d）的制备 (1) Preparation of 2-[N-methyl-N-(3,4-dimethoxy)phenyl]amino-N’-methoxybenzamide (VII-d)

将邻溴苯甲酸（II-a）（4.00g），3，4-二甲氧基苯胺（III-d）（4.59g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为2-[N-（3，4-二甲氧基）苯基]氨基苯甲酸（IV-d）。 O-bromobenzoic acid (II-a) (4.00g), 3,4-dimethoxyaniline (III-d) (4.59g), nitrogen methylmorpholine (3.3mL), cuprous oxide (1.43g ) was added into dioxane (50 mL), and heated to reflux under nitrogen protection for 4 hours. After the reaction, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate to pH=5 with 1M aqueous hydrochloric acid solution, and obtain a white solid of 2-[N-(3,4-dimethoxy)phenyl by suction filtration ] Aminobenzoic acid (IV-d).

将化合物（IV-d）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品2-[N-甲基-N-（3，4-二甲氧基）苯基]氨基苯甲酸甲酯（V-d）。 Compound (IV-d) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction was completed, water was slowly added in an ice bath to quench excess sodium hydride, extracted with ethyl acetate, the organic phase was dried and the solvent was removed under reduced pressure to obtain a yellow oily crude product 2-[N-methyl-N-(3, 4-Dimethoxy)phenyl]aminobenzoic acid methyl ester (V-d).

化合物（V-d）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体2-[N-甲基-N-（3，4-二甲氧基）苯基]氨基苯甲酸（VI-d）。 Compound (V-d) was dissolved in methanol:water (v/v)=5:1 mixed solvent (40mL), potassium hydroxide (3.36g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were precipitated, and recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 2-[N-methyl-N-( 3,4-Dimethoxy)phenyl]aminobenzoic acid (VI-d).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离 纯化，得到浅黄色固体2-[N-甲基-N-（3，4-二甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-d）3.6g，四步总收率57%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain 3.6g of light yellow solid 2-[N-methyl-N-(3,4-dimethoxy)phenyl]amino-N'-methoxybenzamide (VII-d) , the total yield of four steps is 57%.

1H NMR(600MHz,CDCl3):δ3.16(s,3H),3.74(s,3H),3.76(s,3H),3.85(s,3H),6.33(s,1H),6.39～6.41(d,J=9.0Hz,1H),6.79～6.80(d,J=8.4Hz,1H),7.08～7.09(d,J=8.4Hz,1H),7.33～7.35(t,J=7.8Hz,1H),7.44～7.47(t,J=7.8Hz,1H),8.18～8.19(d,J=7.2Hz,1H),10.99(s,1H).13C NMR(151MHz,CDCl3):δ164.61,149.72,148.84,144.15,143.42,133.11,131.42,128.85,126.88,126.54,112.18,108.53,102.85,64.21,56.34,55.95,41.68.  1 H NMR (600MHz, CDCl 3 ): δ3.16(s,3H),3.74(s,3H),3.76(s,3H),3.85(s,3H),6.33(s,1H),6.39～6.41 (d, J=9.0Hz, 1H), 6.79～6.80(d, J=8.4Hz, 1H), 7.08～7.09(d, J=8.4Hz, 1H), 7.33～7.35(t, J=7.8Hz, 1H), 7.44～7.47(t, J=7.8Hz, 1H), 8.18～8.19(d, J=7.2Hz, 1H), 10.99(s, 1H). 13 C NMR(151MHz, CDCl 3 ): δ164. 61,149.72,148.84,144.15,143.42,133.11,131.42,128.85,126.88,126.54,112.18,108.53,102.85,64.21,56.34,55.95,41.68.

（2）5-甲基-7，8，10-三甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-d）的制备 (2) Preparation of 5-methyl-7,8,10-trimethoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-d)

将2-[N-甲基-N-（3，4-二甲氧基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-d）(0.63g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到浅黄色固体5-甲基-7，8，10-三甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-d）0.38g，产率：60%。 2-[N-Methyl-N-(3,4-dimethoxy)phenyl]amino-N'-methoxybenzamide (VII-d) (0.63g) was dissolved in acetonitrile (40mL) In the ice bath, diacetoxy iodobenzene solid (0.97 g) was added several times in an ice bath, and stirred at room temperature for 30 minutes to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain Light yellow solid 5-methyl-7,8,10-trimethoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-d) 0.38g, yield: 60% .

1H NMR(600MHz,CDCl3):δ3.33(s,3H),3.85(s,3H),3.87(s,3H),3.88(s,3H),6.65(s,1H),7.02(s,1H),7.04～7.08(q,J=7.8Hz,2H),7.38～7.41(t,J=7.8Hz,1H),7.87～7.89(d,J=7.8Hz,1H).13C NMR(151MHz,CDCl3):δ165.00,153.65,147.59,146.16,139.05,132.54,132.07,126.24,125.91,122.99,116.37,104.79,102.22,62.12,56.32,56.27,37.46.  1 H NMR (600MHz, CDCl 3 ): δ3.33(s,3H),3.85(s,3H),3.87(s,3H),3.88(s,3H),6.65(s,1H),7.02(s ,1H),7.04～7.08(q,J=7.8Hz,2H),7.38～7.41(t,J=7.8Hz,1H),7.87～7.89(d,J=7.8Hz,1H). 13 C NMR( 151MHz, CDCl 3 ):δ165.00,153.65,147.59,146.16,139.05,132.54,132.07,126.24,125.91,122.99,116.37,104.79,102.22,62.12,56.32,56.267.37.

实施例5 Example 5

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）4-氯-2-[N-甲基-N-（4-甲基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-e）的制备 (1) Preparation of 4-chloro-2-[N-methyl-N-(4-methyl)phenyl]amino-N’-methoxybenzamide (VII-e)

将2-溴-4-氯苯甲酸（II-e）（4.70g），对甲基苯胺（III-e）（3.21g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为4-氯-2-[N-（4-甲基）苯基]氨基苯甲酸（IV-e）。 2-Bromo-4-chlorobenzoic acid (II-e) (4.70g), p-methylaniline (III-e) (3.21g), nitrogen methylmorpholine (3.3mL), cuprous oxide (1.43g ) was added into dioxane (50 mL), and heated to reflux under nitrogen protection for 4 hours. After the reaction was completed, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate to pH=5 with 1M aqueous hydrochloric acid solution, and obtain a white solid of 4-chloro-2-[N-(4-methyl)phenyl by suction filtration. ] Aminobenzoic acid (IV-e).

将化合物（IV-e）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品4-氯-2-[N-甲基-N-（4-甲基）苯基]氨基苯甲酸甲酯（V-e）。 Compound (IV-e) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction was completed, water was slowly added in an ice bath to quench excess sodium hydride, extracted with ethyl acetate, the organic phase was dried and the solvent was removed under reduced pressure to obtain a yellow oily crude product 4-chloro-2-[N-methyl-N -Methyl(4-methyl)phenyl]aminobenzoate (V-e).

化合物（V-e）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体4-氯-2-[N-甲基-N-（4-甲基）苯基]氨基苯甲酸（VI-e）。 Compound (V-e) was dissolved in methanol:water (v/v)=5:1 mixed solvent (40mL), potassium hydroxide (3.36g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were separated out, then recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 4-chloro-2-[N-methyl -N-(4-Methyl)phenyl]aminobenzoic acid (VI-e).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到浅黄色固体4-氯-2-[N-甲基-N-（4-甲基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-e）3.5g，四步总收率58%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain 3.5 g of light yellow solid 4-chloro-2-[N-methyl-N-(4-methyl)phenyl]amino-N'-methoxybenzamide (VII-e) , the total yield of four steps is 58%.

1H NMR(600MHz,CDCl3):δ2.30(s,3H),3.16(s,3H),3.73(s,3H),6.72～6.73(d,J=8.4Hz,2H),7.06(s,1H),7.08～7.10(d,J=8.4Hz,2H),7.31～7.32(d,J=9.0Hz,1H),8.13～8.14(d,J=8.4Hz,1H),10.70(s,1H).13C NMR(151MHz,CDCl3):δ163.64,149.73,146.16,138.69,132.79,131.16,130.02,127.54,127.19,126.88,117.35,64.24,41.37,20.48.  1 H NMR (600MHz, CDCl 3 ): δ2.30(s,3H),3.16(s,3H),3.73(s,3H),6.72～6.73(d,J=8.4Hz,2H),7.06(s ,1H),7.08～7.10(d,J=8.4Hz,2H),7.31～7.32(d,J=9.0Hz,1H),8.13～8.14(d,J=8.4Hz,1H),10.70(s, 1H). 13 C NMR (151MHz, CDCl 3 ): δ163.64, 149.73, 146.16, 138.69, 132.79, 131.16, 130.02, 127.54, 127.19, 126.88, 117.35, 64.24, 41.37, 20.48.

（2）3-氯-5，8二-甲基-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-e）的制备 (2) Preparation of 3-chloro-5,8-di-methyl-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-e)

将4-氯-2-[N-甲基-N-（4-甲基）苯基]氨基-N’-甲氧基苯甲酰胺（VII-e）(0.61g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到浅黄色固体3-氯-5，8-二甲基-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-e）0.48g，产率：81%。 4-Chloro-2-[N-methyl-N-(4-methyl)phenyl]amino-N'-methoxybenzamide (VII-e) (0.61 g) was dissolved in acetonitrile (40 mL) In the ice bath, diacetoxy iodobenzene solid (0.97 g) was added several times in an ice bath, and stirred at room temperature for 30 minutes to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain Pale yellow solid 3-chloro-5,8-dimethyl-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-e) 0.48g, yield : 81%.

1H NMR(600MHz,CDCl3):δ2.32(s,3H),3.31(s,3H),3.86(s,3H),6.99～7.03(m,4H),7.30(s,1H),7.82～7.84(d,J=9.0Hz,1H).13C NMR(151MHz,CDCl3):δ164.34,153.96,142.42,138.91,134.75,133.50,133.36,127.26,123.89,123.06,121.28,118.44,116.97,62.39,37.75,20.82.  1 H NMR (600MHz, CDCl 3 ): δ2.32(s,3H),3.31(s,3H),3.86(s,3H),6.99～7.03(m,4H),7.30(s,1H),7.82 ～7.84(d,J=9.0Hz,1H). 13 C NMR(151MHz,CDCl 3 ):δ164.34,153.96,142.42,138.91,134.75,133.50,133.36,127.26,123.89,123.06,121.28,118.394,116 ,37.75,20.82.

实施例6 Example 6

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）2-[N-甲基-N-（4-甲基）苯基]氨基-5-甲基-N’-甲氧基苯甲酰胺（VII-f）的制备 (1) Preparation of 2-[N-methyl-N-(4-methyl)phenyl]amino-5-methyl-N’-methoxybenzamide (VII-f)

将2-溴-5-甲基苯甲酸（II-f）（4.30g），对甲基苯胺（III-f）（3.21g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液 用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为2-[N-（4-甲基）苯基]氨基-5-甲基苯甲酸（IV-f）。 2-Bromo-5-methylbenzoic acid (II-f) (4.30g), p-methylaniline (III-f) (3.21g), nitrogen methylmorpholine (3.3mL), cuprous oxide (1.43 g) Add it into dioxane (50 mL), and heat to reflux for 4 hours under the protection of nitrogen. After the reaction was completed, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate to pH=5 with 1M aqueous hydrochloric acid solution, and obtain a white solid as 2-[N-(4-methyl)phenyl]amino-5 - methylbenzoic acid (IV-f).

将化合物（IV-f）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品2-[N-甲基-N-（4-甲基）苯基]氨基-5-甲基苯甲酸甲酯（V-f）。 Compound (IV-f) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction was completed, water was slowly added in an ice bath to quench excess sodium hydride, extracted with ethyl acetate, the organic phase was dried and the solvent was removed under reduced pressure to obtain a yellow oily crude product 2-[N-methyl-N-(4- Methyl)phenyl]amino-5-methylbenzoate (V-f).

化合物（V-f）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体2-[N-甲基-N-（4-甲基）苯基]氨基-5-甲基苯甲酸（VI-f）。 Compound (V-f) was dissolved in methanol:water (v/v)=5:1 mixed solvent (40mL), potassium hydroxide (3.36g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were precipitated, and recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 2-[N-methyl-N-( 4-Methyl)phenyl]amino-5-methylbenzoic acid (VI-f).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到浅黄色固体2-[N-甲基-N-（4-甲基）苯基]氨基-5-甲基-N’-甲氧基苯甲酰胺（VII–f）3.5g，四步总收率58%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain light yellow solid 2-[N-methyl-N-(4-methyl)phenyl]amino-5-methyl-N'-methoxybenzamide (VII–f) 3.5 g, the total yield of four steps is 58%.

1H NMR(600MHz,CDCl3):δ2.27(s,3H),2.39(s,3H),3.13(s,3H),3.73(s,3H),6.68～6.70(d,J=8.4Hz,2H),6.95～6.96(d,J=7.8Hz,1H),7.04～7.06(d,J=8.4Hz,2H),7.25～7.26(d,J=8.4Hz,1H),8.02(s,1H),10.96(s,1H).13C NMR(151MHz,CDCl3):δ164.64,146.92,146.04,136.82,133.96,131.66,130.02,129.79,128.83,127.30,116.56,64.14,41.12,20.87,20.41.  1 H NMR (600MHz, CDCl 3 ): δ2.27(s,3H),2.39(s,3H),3.13(s,3H),3.73(s,3H),6.68～6.70(d,J=8.4Hz ,2H),6.95～6.96(d,J=7.8Hz,1H),7.04～7.06(d,J=8.4Hz,2H),7.25～7.26(d,J=8.4Hz,1H),8.02(s, 1H), 10.96(s, 1H). 13 C NMR (151MHz, CDCl 3 ): δ164.64, 146.92, 146.04, 136.82, 133.96, 131.66, 130.02, 129.79, 128.83, 127.30, 116.56, 64.14, 40.812, 2

（2）2，5，8-三甲基-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-f）的制备 (2) Preparation of 2,5,8-trimethyl-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-f)

将2-[N-甲基-N-（4-甲基）苯基]氨基-5-甲基-N’-甲氧基苯甲酰胺（VII-f）(0.57g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到浅黄色固体2，5，8-三甲基-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-f）0.47g，产率：84%。 Dissolve 2-[N-methyl-N-(4-methyl)phenyl]amino-5-methyl-N'-methoxybenzamide (VII-f) (0.57g) in acetonitrile (40mL ), added diacetoxy iodobenzene solid (0.97 g) in several batches in an ice bath, and stirred at room temperature for 30 minutes to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain Light yellow solid 2,5,8-trimethyl-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11one (I-f) 0.47g, yield: 84 %.

1H NMR(600MHz,CDCl3):δ2.27(s,3H),2.31(s,3H),3.29(s,3H),3.86(s,3H),6.92～6.94(d,J=8.4Hz,1H),6.96～7.00(m,2H),7.18～7.19(d,J=8.4Hz,1H),7.29(s,1H),7.67(s,1H).13C NMR(151MHz,CDCl3):δ165.18,150.95,143.81,133.99,133.37,132.48,132.03,127.07,125.36,121.38,117.90,116.31,62.27,37.50,20.78,20.35.  1 H NMR (600MHz, CDCl 3 ): δ2.27(s,3H),2.31(s,3H),3.29(s,3H),3.86(s,3H),6.92～6.94(d,J=8.4Hz ,1H),6.96～7.00(m,2H),7.18～7.19(d,J=8.4Hz,1H),7.29(s,1H),7.67(s,1H). 13 C NMR(151MHz,CDCl 3 ) : δ165.18, 150.95, 143.81, 133.99, 133.37, 132.48, 132.03, 127.07, 125.36, 121.38, 117.90, 116.31, 62.27, 37.50, 20.78, 20.35.

实施例7 Example 7

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）5-氟-2-[N-甲基-N-（4-氯）苯基]氨基-N’-甲氧基苯甲酰胺（VII-g）的制备 (1) Preparation of 5-fluoro-2-[N-methyl-N-(4-chloro)phenyl]amino-N’-methoxybenzamide (VII-g)

将5-氟-2-溴苯甲酸（II-g）（4.38g），对氯苯胺（III-g）（3.81g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为5-氟-2-[N-（4-氯）苯基]氨基苯甲酸（IV-g）。 5-fluoro-2-bromobenzoic acid (II-g) (4.38g), p-chloroaniline (III-g) (3.81g), nitrogen methylmorpholine (3.3mL), cuprous oxide (1.43g) Add it into dioxane (50 mL), and heat to reflux for 4 hours under the protection of nitrogen. Cool to room temperature after the reaction, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate to pH=5 with 1M aqueous hydrochloric acid solution, and obtain a white solid of 5-fluoro-2-[N-(4-chloro)phenyl] by suction filtration Aminobenzoic acid (IV-g).

将化合物（IV-g）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品5-氟-2-[N-甲基-N-（4-氯）苯基]氨基苯甲酸甲酯（V-g）。 Compound (IV-g) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction was completed, water was slowly added in an ice bath to quench excess sodium hydride, extracted with ethyl acetate, the organic phase was dried and the solvent was removed under reduced pressure to obtain a yellow oily crude product 5-fluoro-2-[N-methyl-N -(4-Chloro)phenyl]aminobenzoic acid methyl ester (V-g).

化合物（V-g）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体5-氟-2-[N-甲基-N-（4-氯苯基）]氨基苯甲酸（VI-g）。 Compound (V-g) was dissolved in methanol:water (v/v)=5:1 mixed solvent (40mL), potassium hydroxide (3.36g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were precipitated, then recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 5-fluoro-2-[N-methyl -N-(4-Chlorophenyl)]aminobenzoic acid (VI-g).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到浅黄色固体5-氟-2-[N-甲基-N-（4-氯）苯基]氨基-N’-甲氧基苯甲酰胺（VII–g）3.43g，四步总收率56%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain 3.43 g of 5-fluoro-2-[N-methyl-N-(4-chloro)phenyl]amino-N'-methoxybenzamide (VII–g) as a light yellow solid, The total yield of four steps is 56%.

1H NMR(600MHz,CDCl3):δ2.27(s,3H),2.39(s,3H),3.13(s,3H),3.73(s,3H),6.68～6.70(d,J=8.4Hz,2H),6.95～6.96(d,J=7.8Hz,1H),7.04～7.06(d,J=8.4Hz,2H),7.25～7.26(d,J=8.4Hz,1H),8.02(s,1H),10.96(s,1H).13C NMR(151MHz,CDCl3):δ164.64,146.92,146.04,136.82,133.96,131.66,130.02,129.79,128.83,127.30,116.56,64.14,41.12,20.87,20.41.  1 H NMR (600MHz, CDCl 3 ): δ2.27(s,3H),2.39(s,3H),3.13(s,3H),3.73(s,3H),6.68～6.70(d,J=8.4Hz ,2H),6.95～6.96(d,J=7.8Hz,1H),7.04～7.06(d,J=8.4Hz,2H),7.25～7.26(d,J=8.4Hz,1H),8.02(s, 1H), 10.96(s, 1H). 13 C NMR (151MHz, CDCl 3 ): δ164.64, 146.92, 146.04, 136.82, 133.96, 131.66, 130.02, 129.79, 128.83, 127.30, 116.56, 64.14, 40.812, 2

（2）2-氟-8-氯-5-甲基-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-g）的制备 (2) Preparation of 2-fluoro-8-chloro-5-methyl-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11one (I-g)

将5-氟-2-[N-甲基-N-（4-氯）苯基]氨基-N’-甲氧基苯甲酰胺（VII-g）(0.62g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产 物，粗品经柱色谱分离纯化，得到浅黄色固体2-氟-8-氯-5-甲基-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-g）0.51g，产率：83%。 5-Fluoro-2-[N-methyl-N-(4-chloro)phenyl]amino-N'-methoxybenzamide (VII-g) (0.62 g) was dissolved in acetonitrile (40 mL) , Add diacetoxy iodobenzene solid (0.97g) in several times in an ice bath, and stir at room temperature for 30min to complete the reaction. Add saturated aqueous sodium bicarbonate (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography, 0.51 g of light yellow solid 2-fluoro-8-chloro-5-methyl-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-g) was obtained, Yield: 83%.

1H NMR(600MHz,CDCl3):δ3.31(s,3H),3.88(s,3H),7.00～7.03(q,J=4.2Hz,1H),7.04～7.06(d,J=8.4Hz,1H),7.10～7.16(m,2H),7.47～7.49(m,1H),7.56～7.59(m,1H).13C NMR(151MHz,CDCl3):δ182.55,163.67,159.33,157.72,148.62,144.05,134.82,129.87,126.48,120.88,119.90,119.75,119.50,118.28,118.23,118.18,118.12,62.69,37.98.  1 H NMR (600MHz, CDCl 3 ): δ3.31(s, 3H), 3.88(s, 3H), 7.00～7.03(q, J=4.2Hz, 1H), 7.04～7.06(d, J=8.4Hz ,1H),7.10～7.16(m,2H),7.47～7.49(m,1H),7.56～7.59(m,1H). 13 C NMR(151MHz,CDCl 3 ):δ182.55,163.67,159.33,157.72,148.62 ,144.05,134.82,129.87,126.48,120.88,119.90,119.75,119.50,118.28,118.23,118.18,118.12,62.69,37.98.

实施例8 Example 8

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）5-甲氧基-2-[N-甲基-N-（4-氯）苯基]氨基-N’-甲氧基苯甲酰胺（VII-h）的制备 (1) Preparation of 5-methoxy-2-[N-methyl-N-(4-chloro)phenyl]amino-N’-methoxybenzamide (VII-h)

将5-甲氧基-2-溴苯甲酸（II-h）（4.62g），对氯苯胺（III-h）（3.81g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为5-甲氧基-2-[N-（4-氯）苯基]氨基苯甲酸（IV-h）。 5-methoxy-2-bromobenzoic acid (II-h) (4.62g), p-chloroaniline (III-h) (3.81g), nitrogen methylmorpholine (3.3mL), cuprous oxide (1.43 g) Add it into dioxane (50 mL), and heat to reflux for 4 hours under the protection of nitrogen. After the reaction, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate to pH=5 with 1M aqueous hydrochloric acid solution, and obtain a white solid of 5-methoxy-2-[N-(4-chloro)benzene by suction filtration. Base] aminobenzoic acid (IV-h).

将化合物（IV-h）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品5-甲氧基-2-[N-甲基-N-（4-氯）苯基]氨基苯甲酸甲酯（V-h）。 Compound (IV-h) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction, add water slowly in an ice bath to quench excess sodium hydride, extract with ethyl acetate, dry the organic phase and remove the solvent under reduced pressure to obtain the yellow oily crude product 5-methoxy-2-[N-methyl -Methyl N-(4-chloro)phenyl]aminobenzoate (V-h).

化合物（V-h）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体5-甲氧基-2-[N-甲基-N-（4-氯）苯基]氨基苯甲酸（VI-h）。 Compound (V-h) was dissolved in methanol:water (v/v)=5:1 mixed solvent (40mL), potassium hydroxide (3.36g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were precipitated, and recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 5-methoxy-2-[N- Methyl-N-(4-chloro)phenyl]aminobenzoic acid (VI-h).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到浅黄色固体5-甲氧基-2-[N-甲基-N-（4-氯）苯基]氨基-N’-甲氧基苯甲酰胺（VII–h）2.58g，四步总收率37%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain light yellow solid 5-methoxy-2-[N-methyl-N-(4-chloro)phenyl]amino-N'-methoxybenzamide (VII–h) 2.58 g, the total yield of four steps is 37%.

1H NMR(600MHz,CDCl3):δ.3.15(s,3H),3.74(s,3H),3.88(s,3H),6.65～6.67(dd,Jaa=12.0Hz,Jab=3.0Hz,2H),6.97～6.98(d,J=9.0Hz,1H),7.02～7.03(dd,Jaa=9.0Hz,Jab=3.0Hz,1H),7.18～7.20(dd,Jaa=12.0Hz,Jab=3.0Hz,2H),7.71(s,1H),10.56(s,1H).13C NMR(151MHz,CDCl3):δ164.03,158.42, 147.87,140.12,130.63,129.16,129.07,125.32,120.39,116.94,114.55,64.25,55.76,41.05.  1 H NMR (600MHz, CDCl 3 ): δ.3.15(s,3H),3.74(s,3H),3.88(s,3H),6.65～6.67(dd,J aa =12.0Hz,J ab =3.0Hz ,2H),6.97～6.98(d,J=9.0Hz,1H),7.02～7.03(dd,J aa =9.0Hz,J ab =3.0Hz,1H),7.18～7.20(dd,J aa =12.0Hz ,J ab =3.0Hz,2H),7.71(s,1H),10.56(s,1H). 13 C NMR(151MHz,CDCl 3 ):δ164.03,158.42,147.87,140.12,130.63,129.16,129.07,125.32, 120.39, 116.94, 114.55, 64.25, 55.76, 41.05.

（2）2，10-二甲氧基-8-氯-5-甲基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-h）的制备 (2) Preparation of 2,10-dimethoxy-8-chloro-5-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one (I-h)

将5-甲氧基-2-[N-甲基-N-（4-氯）苯基]氨基-N’-甲氧基苯甲酰胺（VII-h）(0.64g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到浅黄色固体2，10-二甲氧基-8-氯-5-甲基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-h）0.50g，产率：78%。 Dissolve 5-methoxy-2-[N-methyl-N-(4-chloro)phenyl]amino-N'-methoxybenzamide (VII-h) (0.64g) in acetonitrile (40mL ), added diacetoxy iodobenzene solid (0.97 g) in several batches in an ice bath, and stirred at room temperature for 30 min to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain Pale yellow solid 2,10-dimethoxy-8-chloro-5-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one (I-h) 0.50g, yield : 78%.

1H NMR(600MHz,CDCl3):δ3.29(s,3H),3.79(s,3H),3.88(s,3H),6.99(s,2H),7.02～7.04(d,J=9.0Hz,1H),7.13～7.14(d,J=9.0Hz,1H),7.39(s,1H),7.47(s,1H).13C NMR(151MHz,CDCl3):δ164.61,155.56,146.03,144.79,134.90,129.38,126.27,126.07,120.87,120.05,119.08,117.95,115.03,62.62,55.72,37.76.  1 H NMR (600MHz, CDCl 3 ): δ3.29(s,3H),3.79(s,3H),3.88(s,3H),6.99(s,2H),7.02～7.04(d,J=9.0Hz ,1H),7.13～7.14(d,J=9.0Hz,1H),7.39(s,1H),7.47(s,1H). 13 C NMR(151MHz,CDCl 3 ):δ164.61,155.56,146.03,144.79, 134.90, 129.38, 126.27, 126.07, 120.87, 120.05, 119.08, 117.95, 115.03, 62.62, 55.72, 37.76.

实施例9 Example 9

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）5-甲基-2-[N-甲基-N-（4-溴）苯基]氨基-N’-甲氧基苯甲酰胺（VII-i）的制备 (1) Preparation of 5-methyl-2-[N-methyl-N-(4-bromo)phenyl]amino-N’-methoxybenzamide (VII-i)

将2-溴-5-甲基苯甲酸（II-i）（4.30g），对溴苯胺（III-i）（5.16g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为5-甲基-2-[N-（4-溴）苯基]氨基苯甲酸（IV-i）。 2-Bromo-5-methylbenzoic acid (II-i) (4.30g), p-bromoaniline (III-i) (5.16g), nitrogen methylmorpholine (3.3mL), cuprous oxide (1.43g ) was added into dioxane (50 mL), and heated to reflux under nitrogen protection for 4 hours. After the reaction, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate to pH=5 with 1M aqueous hydrochloric acid solution, and obtain a white solid of 5-methyl-2-[N-(4-bromo)phenyl by suction filtration ] aminobenzoic acid (IV-i).

将化合物（IV-i）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品5-甲基-2-[N-甲基-N-（4-溴）苯基]氨基苯甲酸甲酯（V-i）。 Compound (IV-i) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction, add water slowly in an ice bath to quench excess sodium hydride, extract with ethyl acetate, dry the organic phase and remove the solvent under reduced pressure to obtain the crude product 5-methyl-2-[N-methyl- Methyl N-(4-bromo)phenyl]aminobenzoate (V-i).

化合物（V-i）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体5-甲基-2-[N-甲基-N-（4-溴）苯基]氨基苯甲酸（VI-i）。 Compound (V-i) was dissolved in methanol: water (v/v) = 5:1 mixed solvent (40 mL), potassium hydroxide (3.36 g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were separated out, and then recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 5-methyl-2-[N-methyl Base-N-(4-bromo)phenyl]aminobenzoic acid (VI-i).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并 减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到浅黄色固体5-甲基-2-[N-甲基-N-（4-溴）苯基]氨基-N’-甲氧基苯甲酰胺（VII-i）2.37g，四步总收率37%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain 2.37g of light yellow solid 5-methyl-2-[N-methyl-N-(4-bromo)phenyl]amino-N'-methoxybenzamide (VII-i) , The total yield of four steps is 37%.

1H NMR(600MHz,CDCl3):δ.2.40(s,3H),3.15(s,3H),3.72(s,3H),6.61～6.63(m,2H),6.96～6.97(d,J=8.4Hz,1H),7.28～7.30(dd,J=7.8Hz,1H),7.31～7.33(m,2H),7.97(s,1H),10.33(s,1H).13C NMR(151MHz,CDCl3):δ164.57,148.20,144.67,137.41,134.11,132.04,131.75,129.28,127.61,117.44,112.54,64.23,40.94,20.92.  1 H NMR (600MHz, CDCl 3 ): δ.2.40(s,3H),3.15(s,3H),3.72(s,3H),6.61～6.63(m,2H),6.96～6.97(d,J= 8.4Hz, 1H), 7.28～7.30(dd, J=7.8Hz, 1H), 7.31～7.33(m, 2H), 7.97(s, 1H), 10.33(s, 1H). 13 C NMR (151MHz, CDCl 3 ).

（2）2，5-二甲基-8-溴-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-i）的制备 (2) Preparation of 2,5-dimethyl-8-bromo-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11-one (I-i)

将5-甲基-2-[N-甲基-N-（4-溴）苯基]氨基-N’-甲氧基苯甲酰胺（VII-i）(0.70g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到浅黄色固体2，5-二甲基-8-溴-10-甲氧基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-i）0.49g，产率：71%。 Dissolve 5-methyl-2-[N-methyl-N-(4-bromo)phenyl]amino-N'-methoxybenzamide (VII-i) (0.70 g) in acetonitrile (40 mL) In the ice bath, diacetoxy iodobenzene solid (0.97 g) was added several times in an ice bath, and stirred at room temperature for 30 minutes to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain Pale yellow solid 2,5-dimethyl-8-bromo-10-methoxy-11H-dibenzo[b,e][1,4]diazepin-11one (I-i) 0.49g, yield : 71%.

1H NMR(600MHz,CDCl3):δ2.29(s,3H),3.30(s,3H),3.88(s,3H),6.94～6.95(d,J=7.8Hz,1H),6.97～6.98(d,J=7.8Hz,1H),7.21～7.23(d,J=8.4Hz,1H),7.26～7.28(d,J=8.4Hz,1H),7.61(s,1H),7.68(s,1H).13C NMR(151MHz,CDCl3):δ164.95,150.17,144.96,135.23,133.74,133.04,132.19,129.12,124.86,123.70,119.64,116.78,116.58,62.63,37.68,20.37.  1 H NMR (600MHz, CDCl 3 ): δ2.29(s,3H),3.30(s,3H),3.88(s,3H),6.94～6.95(d,J=7.8Hz,1H),6.97～6.98 (d,J=7.8Hz,1H),7.21～7.23(d,J=8.4Hz,1H),7.26～7.28(d,J=8.4Hz,1H),7.61(s,1H),7.68(s, 1H). 13 C NMR (151MHz, CDCl 3 ): δ164.95,150.17,144.96,135.23,133.74,133.04,132.19,129.12,124.86,123.70,119.64,116.78,116.58,62.63,20.38.

实施例10 Example 10

一种二苯西平类衍生物（I）的合成方法，包括如下步骤： A method for synthesizing diphenazepine derivatives (I), comprising the steps of:

（1）5-甲氧基-2-[N-甲基-N-（3-溴）苯基]氨基-N’-甲氧基苯甲酰胺（VII-j）的制备 (1) Preparation of 5-methoxy-2-[N-methyl-N-(3-bromo)phenyl]amino-N’-methoxybenzamide (VII-j)

将2-溴-5-甲氧基苯甲酸（II-j）（4.62g），间溴苯胺（III-j）（5.16g），氮甲基吗啉（3.3mL），氧化亚铜（1.43g）加入到二氧六环（50mL）中，氮气保护下加热回流4小时。反应结束后冷却至室温，减压抽滤除去固体残渣，滤液用1M的盐酸水溶液酸化至pH=5，抽滤得白色固体为5-甲氧基-2-[N-（3-溴）苯基]氨基苯甲酸（IV-j）。 2-Bromo-5-methoxybenzoic acid (II-j) (4.62g), m-bromoaniline (III-j) (5.16g), nitrogen methylmorpholine (3.3mL), cuprous oxide (1.43 g) Add it into dioxane (50 mL), and heat to reflux for 4 hours under the protection of nitrogen. After the reaction was completed, cool to room temperature, remove the solid residue by suction filtration under reduced pressure, acidify the filtrate to pH=5 with 1M aqueous hydrochloric acid solution, and obtain a white solid of 5-methoxy-2-[N-(3-bromo)benzene by suction filtration. Base] aminobenzoic acid (IV-j).

将化合物（IV-j）溶于N，N-二甲基甲酰胺（40mL）中，冰浴下加入氢化钠（0.96g），室温搅拌半小时。转至冰浴，滴加碘甲烷（3.7mL），0℃搅拌一小时。反应结束后，冰浴中缓慢加入水将过量氢化钠淬灭，用乙酸乙酯萃取，有机相干燥后减压除去溶剂，得黄色油状粗产品5-甲氧基-2-[N-甲基-N-（3-溴）苯基]氨基苯甲酸甲酯（V-j）。 Compound (IV-j) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (0.96 g) was added under ice cooling, and stirred at room temperature for half an hour. Transfer to an ice bath, add iodomethane (3.7 mL) dropwise, and stir at 0°C for one hour. After the reaction, add water slowly in an ice bath to quench excess sodium hydride, extract with ethyl acetate, dry the organic phase and remove the solvent under reduced pressure to obtain the yellow oily crude product 5-methoxy-2-[N-methyl -Methyl N-(3-bromo)phenyl]aminobenzoate (V-j).

化合物（V-j）溶于甲醇：水(v/v)=5:1的混合溶剂（40mL）中，加入氢氧化钾（3.36g）后加热至70℃。反应结束后用1M的盐酸酸化至沉淀全部析出，抽滤后重结晶（乙酸乙酯：石油醚(v/v)=1:20），得白色固体5-甲氧基-2-[N-甲基-N-（3-溴）苯基]氨基苯甲酸（VI-j）。 Compound (V-j) was dissolved in methanol:water (v/v)=5:1 mixed solvent (40mL), potassium hydroxide (3.36g) was added and heated to 70°C. After the reaction was completed, it was acidified with 1M hydrochloric acid until all the precipitates were precipitated, and recrystallized after suction filtration (ethyl acetate:petroleum ether (v/v)=1:20) to obtain a white solid 5-methoxy-2-[N- Methyl-N-(3-bromo)phenyl]aminobenzoic acid (VI-j).

将上步所得白色固体溶于四氢呋喃（40mL）中，加入羰基二咪唑（3.89g），室温搅拌半小时后加入甲氧胺盐酸盐（5.01g），室温搅拌，反应结束后加入2mol/L碳酸钠水溶液（30mL），用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱（乙酸乙酯：石油醚(v/v)=1:10）分离纯化，得到浅黄色固体5-甲氧基-2-[N-甲基-N-（3-溴）苯基]氨基-N’-甲氧基苯甲酰胺（VII-j）3.94g，四步总收率54%。 Dissolve the white solid obtained in the previous step in tetrahydrofuran (40mL), add carbonyldiimidazole (3.89g), stir at room temperature for half an hour, add methoxyamine hydrochloride (5.01g), stir at room temperature, and add 2mol/L Sodium carbonate aqueous solution (30mL), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (ethyl acetate:petroleum ether (v/v)=1: 10) Separation and purification to obtain light yellow solid 5-methoxy-2-[N-methyl-N-(3-bromo)phenyl]amino-N'-methoxybenzamide (VII-j) 3.94 g, the total yield of four steps is 54%.

1H NMR(600MHz,CDCl3):δ.3.16(s,3H),3.72(s,3H),3.88(s,3H),6.60～6.61(d,J=8.4Hz,2H),6.88(s,1H),6.99～7.00(d,J=9.0Hz,2H),7.03～7.05(dd,Jaa=9.0Hz,Jab=3.0Hz,1H),7.06～7.09(t,J=8.4Hz,1H),7.67(s,1H),10.33(s,1H).13C NMR(151MHz,CDCl3):δ163.98,158.50,150.53,139.47,130.84,130.53,129.36,123.39,122.79,120.29,118.12,114.67,114.24,64.24,55.76,40.88.  1 H NMR (600MHz, CDCl 3 ): δ.3.16(s,3H),3.72(s,3H),3.88(s,3H),6.60～6.61(d,J=8.4Hz,2H),6.88(s ,1H),6.99～7.00(d,J=9.0Hz,2H),7.03～7.05(dd,J aa =9.0Hz,J ab =3.0Hz,1H),7.06～7.09(t,J=8.4Hz, 1H), 7.67(s, 1H), 10.33(s, 1H). 13 C NMR (151MHz, CDCl 3 ): δ163.98, 158.50, 150.53, 139.47, 130.84, 130.53, 129.36, 123.39, 122.79, 120.29, 114.167, 1 ,114.24,64.24,55.76,40.88.

（2）7（9）-溴-2，10-二甲氧基-5-甲基-11H-二苯并[b,e][1,4]二氮杂-11酮（I-j）的制备 (2) Preparation of 7(9)-bromo-2,10-dimethoxy-5-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one (I-j)

将5-甲氧基-2-[N-甲基-N-（3-溴）苯基]氨基-N’-甲氧基苯甲酰胺（VII-j）(0.70g)溶于乙腈（40mL）中，冰浴中分多次加入二乙酰氧基碘苯固体（0.97g），室温搅拌30min反应完全。加入饱和碳酸氢钠水溶液（10mL）后搅拌5min，在分液漏斗中用乙酸乙酯萃取，有机相经无水硫酸钠干燥并减压浓缩后，得粗品产物，粗品经柱色谱分离纯化，得到淡黄色固体7-溴-2，10-二甲氧基-5-甲基-11H-二苯并[b,e][1,4]二氮杂-11酮0.49g，产率：28%；得到淡黄色固体9-溴-2，10-二甲氧基-5-甲基-11H-二苯并[b,e][1,4]二氮杂-11酮，产率：51%。 Dissolve 5-methoxy-2-[N-methyl-N-(3-bromo)phenyl]amino-N'-methoxybenzamide (VII-j) (0.70g) in acetonitrile (40mL ), added diacetoxy iodobenzene solid (0.97 g) in several batches in an ice bath, and stirred at room temperature for 30 minutes to complete the reaction. Add saturated aqueous sodium bicarbonate solution (10 mL) and stir for 5 min, extract with ethyl acetate in a separatory funnel, dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography to obtain Pale yellow solid 7-bromo-2,10-dimethoxy-5-methyl-11H-dibenzo[b,e][1,4]diazepin-11one 0.49g, yield: 28% ; Obtained 9-bromo-2,10-dimethoxy-5-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one as light yellow solid, yield: 51% .

7-溴-2，10-二甲氧基-5-甲基-11H-二苯并[b,e][1,4]二氮杂-11酮：1H NMR(600MHz,CDCl3):δ3.32(s,3H),3.73(s,3H),3.79(s,3H),6.92～6.94(dd,Jaa=9.0Hz,Jab=3.0Hz,1H),6.98～7.00(d,J=9.0Hz,1H),7.09～7.15(m,2H),7.31(s,1H),7.37～7.38(d,J=7.2Hz,1H).13C NMR(151MHz,CDCl3):δ164.65,156.02,153.02,146.71,130.89,129.38,128.64,127.32,119.99,119.49,118.22,116.41,114.25,61.83,55.74,37.31.  7-Bromo-2,10-dimethoxy-5-methyl-11H-dibenzo[b,e][1,4]diazepin-11one: 1 H NMR (600MHz, CDCl 3 ): δ3.32(s,3H),3.73(s,3H),3.79(s,3H),6.92～6.94(dd,J aa =9.0Hz,J ab =3.0Hz,1H),6.98～7.00(d, J=9.0Hz,1H),7.09～7.15(m,2H),7.31(s,1H),7.37～7.38(d,J=7.2Hz,1H). 13 C NMR(151MHz,CDCl3):δ164.65,156.02 ,153.02,146.71,130.89,129.38,128.64,127.32,119.99,119.49,118.22,116.41,114.25,61.83,55.74,37.31.

9-溴-2，10-二甲氧基-5-甲基-11H-二苯并[b,e][1,4]二氮杂-11酮：1H NMR(600MHz,CDCl3):δ3.29(s,3H),3.78(s,3H),3.85(s,3H),6.97～7.00(m,2H),7.22～7.28(m,2H),7.33～7.34(t,J=4.8Hz,1H),7.38(s,1H).13C NMR(151MHz,CDCl3):δ164.41,155.68,147.54,145.73,132.93,127.13,126.29,122.33,121.44,119.88,119.58,118.14,115.03,62.40,55.70,37.72.  9-Bromo-2,10-dimethoxy-5-methyl-11H-dibenzo[b,e][1,4]diazepin-11one: 1 H NMR (600MHz, CDCl 3 ): δ3.29(s,3H),3.78(s,3H),3.85(s,3H),6.97～7.00(m,2H),7.22～7.28(m,2H),7.33～7.34(t,J=4.8 Hz, 1H), 7.38(s, 1H). 13 C NMR (151MHz, CDCl 3 ): δ164.41, 155.68, 147.54, 145.73, 132.93, 127.13, 126.29, 122.33, 121.44, 119.88, 119.58, 118.13, 1625.0. 55.70,37.72.

以上仅是本发明的部分实施例而已，并非对本发明做任何形式上的限制，凡是依据本发明的技术实质对上述实施例作的任何简单的修改，等同变化与修饰，均属于本发明技术方案范围内。 The above are only some embodiments of the present invention, and do not limit the present invention in any form. Any simple modifications made to the above-mentioned embodiments according to the technical essence of the present invention, equivalent changes and modifications, all belong to the technical solution of the present invention within range.

Claims (1)

1. a synthetic method for dibenzepin derivative (I), is characterized in that comprising the steps:
(1) to replace o-bromobenzoic acid (II) for raw material, take Red copper oxide as oxygenant, with nitrogen methylmorpholine for alkali, in solvent dioxane, under reflux conditions react with substituted aniline (III), generate 2-(N-substituted-phenyl) aminobenzoic acid derivative (IV);
(2) there is methylation reaction and generate 2-(N-methyl-N-substituted-phenyl) Methyl anthranilate derivative (V) in described 2-(N-substituted-phenyl) aminobenzoic acid derivative (IV) and sodium hydride and methyl iodide in nitrogen, nitrogen-dimethyl formamide;
(3) described 2-(N-methyl-N-substituted-phenyl) Methyl anthranilate derivative (V) is hydrolyzed through potassium hydroxide basic and obtains 2-(N-methyl-N-substituted-phenyl) aminobenzoic acid derivative (VI) in the mixed solvent of methyl alcohol and water;
(4) described 2-(N-methyl-N-substituted-phenyl) aminobenzoic acid derivative (VI) is under carbonyl dimidazoles effect, generates 2-(N-methyl-N-substituted-phenyl) amino-N '-methoxy benzamide derivative (VII) in tetrahydrofuran (THF) with methoxamine hydrochloride at room temperature condensation;
(5) described 2-(N-methyl-N-substituted-phenyl) amino-N '-methoxy benzamide derivative (VII) and iodobenzene diacetate are obtained by reacting dibenzepin derivative (I) in acetonitrile under room temperature; Reaction formula is:
R 1=H, Me, MeO, Cl, or F
R 2=H, Me, MeO, Cl, or Br.
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