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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methyl
phenyl
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room temperature
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杜云飞
李旭明
张翔
赵康
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Tianjin University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses a synthetic method for a dibenzepin derivative. The method comprises the steps that substituted bromobenzoic acid, cuprous oxide and N-methylmorpholine are reacted with substituted aniline, so that 2-(N-substituted phenyl) aminobenzoic acid derivative (IV) is produced; the compound (IV) is reacted with sodium hydride and methyl iodide, so that 2-(N-methyl-N-substituted phenyl) aminobenzoic acid methyl ester derivative (V) is produced; the compound (V) is subjected to basic hydrolysis, so that 2-(N-methyl-N-substituted phenyl) aminobenzoic acid derivative (VI) is obtained; the compound (VI) is condensed with methoxy lamine hydrochloride under the effect of carbonyldiimidazole, so that 2-(N-methyl-N-substituted phenyl) amino-N'-methoxybenzamide derivative (VII) is produced; the compound (VII) is reacted with iodobenzene diacetate in acetonitrile at room temperature, so that the dibenzepin derivative (I) is obtained. The method has the advantages that the operation is simple, the reaction raw materials and reaction reagents are easy to obtain, the yield is higher and the like.

Description

A kind of synthetic method of dibenzepin derivative
Technical field
The present invention relates to a kind of synthetic method of dibenzepin derivative.
Background technology
Dibenzepin structure is present in multiple molecule of pharmaceutical or synthesizes in the important intermediate of some natural product, as antidepressant drug Dibenzepin [1](A), NSC 630176 [2](B), antiphlogiston [3](C), schizophrenia drug leoponex [4](D), the muscarinic receptor antagonist Gastrozepin of first-generation M1 selection type [5](E), 1 type immunodeficiency virus is had to the medicine Dibenzoxazepinone of physiologically active [6](F) etc.Therefore for the molecule of pharmaceutical containing this class formation or natural product, can by preparing from this kind of dibenzepin compound.
Pertinent literature is as follows:
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.
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.
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.
The synthetic method of the dibenzepin compound of current bibliographical information has six kinds, as follows:
Giani etc. use the amidation simultaneously of copper powder catalytic coupling carbonnitrogen bond [7]one kettle way builds dibenzepin parent nucleus, and the method uses to replace 0-chloro-benzoic acid and substituted o-phenylenediamine makes catalyzer with copper powder, in chlorobenzene reflux condition under, reaction generates dibenzepin parent nucleus, is shown below:
The shortcoming of this method is that metal catalyst causes certain pollution, not easily process, and productive rate is lower.
Lu etc. utilize silica gel load palladium compound catalyzed coupling reaction [8]build dibenzepin skeleton, its method is the palladium compound of use silica gel load is catalyzer, and be solvent with toluene, diisopropyl ethyl amine makes alkali, makes raw material generate dibenzepin parent nucleus, be shown below under the environment of high pressure carbon monoxide:
To be that its raw material is non-be commonly easy to get this method shortcoming, and catalyzer is that precious metal is expensive, and reaction conditions needs hyperbaric heating, is unfavorable for operation.
Bunce uses 2-fluoronitrobenzene and o-iodobenzoic acid methyl esters to be starting raw material, obtains dibenzepin mother nucleus structure finally by iron powder reducing-condensation under high temperature [9], its shortcoming is that in substrate, substituted mirbane oil compound flash-point is lower, and temperature of reaction is higher, and application security is lower.
Al-Tel uses phosphorus oxychloride to make catalyzer, obtains dibenzepin mother nucleus structure by fragrant electrophilic substitution reaction cyclization [10], its shortcoming is that temperature of reaction is higher, and the time is longer, and yield is not high.
Tsvelikhovsky uses ethyl o-aminobenzoate and adjacent chloro-bromobenzene to be raw material, three (dibenzalacetone) two palladium and part make catalyzer, in solvent tertiary butanol, first catalytic coupling obtains diphenylamine substrate, be solvent with dioxane again, part palladium chtalyst substrate and ammonia react obtain dibenzepin mother nucleus structure [11], its shortcoming is that temperature of reaction is higher, and the time is longer, and noble metal catalyst is expensive.
Diao uses cuprous chloride to make catalyzer, and screening phenanthrolene is alkali, completes a step bisamination and builds dibenzepin mother nucleus structure [12].
Its shortcoming is that metal catalyst aftertreatment is inconvenient, has certain contaminative to environment.
Specifically see with Publication about Document:
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.
Bunce,R.A.,Schammerhorn,J.E.J.HeterocyclicChem.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.
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.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of dibenzepin derivative (I).
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) to replace o-bromobenzoic acid (II) for raw material, take Red copper oxide as oxygenant, with nitrogen methylmorpholine for alkali, react with substituted aniline (III) in solvent dioxane, generate 2-(N-substituted-phenyl) aminobenzoic acid derivative (IV);
(2) described 2-(N-substituted-phenyl) in nitrogen, nitrogen-dimethyl formamide, there is methylation reaction generate 2-(N-methyl-N-substituted-phenyl in aminobenzoic acid derivative (IV) and sodium hydride and methyl iodide) Methyl anthranilate derivative (V);
(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 in the mixed solvent of methyl alcohol and water) aminobenzoic acid derivative (VI);
(4) described 2-(N-methyl-N-substituted-phenyl) aminobenzoic acid derivative (VI) under carbonyl dimidazoles effect, in tetrahydrofuran (THF), generate 2-(N-methyl-N-substituted-phenyl with methoxamine hydrochloride at room temperature condensation) amino-N '-methoxy benzamide derivative (VII);
(5) described 2-(N-methyl-N-substituted-phenyl) amino-N '-methoxy benzamide derivative (VII) and iodobenzene diacetate be obtained by reacting dibenzepin derivative (I) in acetonitrile under room temperature; Reaction formula is:
The present invention has simple to operate, and reaction raw materials and reaction reagent are easy to get, and yield is advantages of higher comparatively.
Embodiment
Reaction raw materials used in following each embodiment replaces o-bromobenzoic acid (II), substituted aniline (III), methoxamine hydrochloride etc. and all can conveniently buy.
Below in conjunction with specific embodiment, the present invention is further illustrated.
Each embodiment understands the present invention better to enable those skilled in the art to below, but content of the present invention is not limited to illustrated embodiment.
Embodiment 1
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) 2-(N-Methyl-N-phenyl) preparation of amino-N '-methoxy benzamide (VII-a)
By o-bromobenzoic acid (II-a) (4.00g), aniline (III-a) (2.79g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is 2-(N-phenyl that suction filtration obtains white solid) benzaminic acid (IV-a).
Compound (IV-a) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, slowly add water in ice bath by excessive sodium hydride cancellation, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain yellow oily thick product 2-(N-Methyl-N-phenyl) Methyl anthranilate (V-a).
Compound (V-a) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is all separated out to precipitation, and after suction filtration, recrystallization (ethyl acetate: sherwood oil (v/v)=1:20), obtains white solid 2-(N-Methyl-N-phenyl) benzaminic acid (VI-a).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain faint yellow solid 2-(N-Methyl-N-phenyl) amino-N '-methoxy benzamide (VII-a) 3.3g, four step total recoverys 64%.
1H 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=7.2Hz,1H),10.64(s,1H). 13CNMR(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) preparation of 5-methyl isophthalic acid 0-methoxyl group-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-a)
By 2-(N-Methyl-N-phenyl) amino-N '-methoxy benzamide (VII-a) (0.51g) be dissolved in acetonitrile (40mL), and add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product, through column chromatography separating purification, obtains white solid 5-methyl isophthalic acid 0-methoxyl group-11H-dibenzo [b, e] [1,4] diaza-11 ketone (I-a) 0.4g, productive rate: 82%.
1H 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). 13C 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.
Embodiment 2
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of 2-[N-methyl-N-(4-methoxyl group) phenyl] amino-N '-methoxy benzamide (VII-b)
By o-bromobenzoic acid (II-a) (4.00g), 4-anisidine (III-b) (3.69g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is 2-[N-(4-methoxyl group) phenyl] benzaminic acid (IV-b) that suction filtration obtains white solid.
Compound (IV-b) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, slowly add water in ice bath by excessive sodium hydride cancellation, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain the thick product 2-of yellow oily [N-methyl N-(4-methoxyl group) phenyl] Methyl anthranilate (V-b).
Compound (V-b) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains white solid 2-[N-methyl-N-(4-methoxyl group) phenyl] benzaminic acid (VI-b).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain faint yellow solid 2-[N-methyl-N-(4-methoxyl group) phenyl] amino-N '-methoxy benzamide (VII-b) 2.8g, four step total recoverys 49%.
1H 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). 13C 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) preparation of 5-methyl-8,10-dimethoxy-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-b)
2-[N-methyl-N-(4-methoxyl group) phenyl] amino-N '-methoxy benzamide (VII-b) (0.57g) is dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product, through column chromatography separating purification, obtains light yellow solid 5-methyl-8,10-dimethoxy-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-b) 0.51g, productive rate: 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,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.
Embodiment 3
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of 2-[N-methyl-N-(3-methoxyl group) phenyl] amino-N '-methoxy benzamide (VII-c)
By o-bromobenzoic acid (II-a) (4.00g), 3-anisidine (III-c) (3.69g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is to pH=5, and it is 2-[N-(3-methoxyl group) phenyl] benzaminic acid (IV-c) that suction filtration obtains white solid.
Compound (IV-c) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, slowly add water in ice bath by excessive sodium hydride cancellation, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain the thick product 2-of yellow oily [N-methyl-N-(3-methoxyl group) phenyl] Methyl anthranilate (V-c).
Compound (V-c) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains white solid 2-[N-methyl-N-(3-methoxyl group) phenyl] benzaminic acid (VI-c).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain light yellow solid 2-[N-methyl-N-(3-methoxyl group) phenyl] amino-N '-methoxy benzamide (VII-c) 2.8g, four step total recoverys 49%.
1H 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). 13C 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) preparation of 5-methyl-7,10-dimethoxy-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-c)
2-[N-methyl-N-(3-methoxyl group) phenyl] amino-N '-methoxy benzamide (VII-c) (0.57g) is dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product, through column chromatography separating purification, obtains light yellow solid 5-methyl-7,10-dimethoxy-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-c) 0.43g, productive rate: 76%.
1H 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). 13C NMR(151MHz,CDCl 3):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.
Embodiment 4
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of 2-[N-methyl-N-(3,4-dimethoxy) phenyl] amino-N '-methoxy benzamide (VII-d)
By o-bromobenzoic acid (II-a) (4.00g), 3,4-dimethoxyaniline (III-d) (4.59g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is 2-[N-(3,4-dimethoxy) phenyl] benzaminic acid (IV-d) that suction filtration obtains white solid.
Compound (IV-d) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, slowly add water in ice bath by excessive sodium hydride cancellation, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, the thick product 2-of yellow oily [N-methyl-N-(3,4-dimethoxy) phenyl] Methyl anthranilate (V-d).
Compound (V-d) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains white solid 2-[N-methyl-N-(3,4-dimethoxy) phenyl] benzaminic acid (VI-d).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain light yellow solid 2-[N-methyl-N-(3, 4-dimethoxy) phenyl] amino-N '-methoxy benzamide (VII-d) 3.6g, four step total recoverys 57%.
1H 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). 13C 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) preparation of 5-methyl-7,8,10-trimethoxy-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-d)
By 2-[N-methyl-N-(3,4-dimethoxy) phenyl] amino-N '-methoxy benzamide (VII-d) (0.63g) be dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, and crude product is through column chromatography separating purification, obtain light yellow solid 5-methyl-7,8,10-trimethoxy-11H-dibenzo [b, e] [1,4] diaza-11 ketone (I-d) 0.38g, productive rate: 60%.
1H 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). 13C NMR(151MHz,CDCl 3):δ165.00,153.65,147.59,146.16,139.05,132.54,132.07,126.24,125.91,122.99,116.37,104.79,102.22,62.12,56.32,56.27,37.46.
Embodiment 5
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of the chloro-2-of 4-[N-methyl-N-(4-methyl) phenyl] amino-N '-methoxy benzamide (VII-e)
By bromo-for 2-4-chloro-benzoic acid (II-e) (4.70g), open-chain crown ether (III-e) (3.21g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is the chloro-2-of 4-[N-(4-methyl) phenyl] benzaminic acid (IV-e) that suction filtration obtains white solid.
Compound (IV-e) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, slowly add water in ice bath by excessive sodium hydride cancellation, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain the chloro-2-of yellow oily thick product 4-[N-methyl-N-(4-methyl) phenyl] Methyl anthranilate (V-e).
Compound (V-e) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains the chloro-2-of white solid 4-[N-methyl-N-(4-methyl) phenyl] benzaminic acid (VI-e).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain the chloro-2-of light yellow solid 4-[N-methyl-N-(4-methyl) phenyl] amino-N '-methoxy benzamide (VII-e) 3.5g, four step total recoverys 58%.
1H 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). 13C 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) preparation of 3-chloro-5,8 two-methyl isophthalic acid 0-methoxyl group-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-e)
Chloro-for 4-2-[N-methyl-N-(4-methyl) phenyl] amino-N '-methoxy benzamide (VII-e) (0.61g) is dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product, through column chromatography separating purification, obtains light yellow solid 3-chloro-5,8-dimethyl-10-methoxyl group-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-e) 0.48g, productive rate: 81%.
1H 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). 13C NMR(151MHz,CDCl 3):δ164.34,153.96,142.42,138.91,134.75,133.50,133.36,127.26,123.89,123.06,121.28,118.44,116.97,62.39,37.75,20.82.
Embodiment 6
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of 2-[N-methyl-N-(4-methyl) phenyl] amino-5-methyl-N '-methoxy benzamide (VII-f)
By bromo-for 2-5-tolyl acid (II-f) (4.30g), open-chain crown ether (III-f) (3.21g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is 2-[N-(4-methyl) phenyl] amino-5-tolyl acid (IV-f) that suction filtration obtains white solid.
Compound (IV-f) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, water is slowly added by excessive sodium hydride cancellation in ice bath, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain the thick product 2-of yellow oily [N-methyl-N-(4-methyl) phenyl] amino-5-methyl-toluate (V-f).
Compound (V-f) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains white solid 2-[N-methyl-N-(4-methyl) phenyl] amino-5-tolyl acid (VI-f).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain light yellow solid 2-[N-methyl-N-(4-methyl) phenyl] amino-5-methyl-N '-methoxy benzamide (VII – f) 3.5g, four step total recoverys 58%.
1H 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). 13C NMR(151MHz,CDCl 3):δ164.64,146.92,146.04,136.82,133.96,131.66,130.02,129.79,128.83,127.30,116.56,64.14,41.12,20.87,20.41.
The preparation of (2) 2,5,8-trimethylammonium-10-methoxyl group-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-f)
2-[N-methyl-N-(4-methyl) phenyl] amino-5-methyl-N '-methoxy benzamide (VII-f) (0.57g) is dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, and crude product is through column chromatography separating purification, obtain light yellow solid 2,5,8-trimethylammonium-10-methoxyl group-11H-dibenzo [b, e] [1,4] diaza-11 ketone (I-f) 0.47g, productive rate: 84%.
1H 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). 13C 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.
Embodiment 7
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of the fluoro-2-of 5-[N-methyl-N-(4-chlorine) phenyl] amino-N '-methoxy benzamide (VII-g)
By fluoro-for 5-2-bromo-benzoic acid (II-g) (4.38g), p-Chlorobenzoic acid amide (III-g) (3.81g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is the fluoro-2-of 5-[N-(4-chlorine) phenyl] benzaminic acid (IV-g) that suction filtration obtains white solid.
Compound (IV-g) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, slowly add water in ice bath by excessive sodium hydride cancellation, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain the fluoro-2-of yellow oily thick product 5-[N-methyl-N-(4-chlorine) phenyl] Methyl anthranilate (V-g).
Compound (V-g) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains the fluoro-2-of white solid 5-[N-methyl-N-(4-chloro-phenyl-)] benzaminic acid (VI-g).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain the fluoro-2-of light yellow solid 5-[N-methyl-N-(4-chlorine) phenyl] amino-N '-methoxy benzamide (VII – g) 3.43g, four step total recoverys 56%.
1H 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). 13C NMR(151MHz,CDCl 3):δ164.64,146.92,146.04,136.82,133.96,131.66,130.02,129.79,128.83,127.30,116.56,64.14,41.12,20.87,20.41.
(2) preparation of the fluoro-8-of 2-chloro-5-methyl isophthalic acid 0-methoxyl group-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-g)
Fluoro-for 5-2-[N-methyl-N-(4-chlorine) phenyl] amino-N '-methoxy benzamide (VII-g) (0.62g) is dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product, through column chromatography separating purification, obtains the fluoro-8-of light yellow solid 2-chloro-5-methyl isophthalic acid 0-methoxyl group-11H-dibenzo [b, e] [1,4] diaza-11 ketone (I-g) 0.51g, productive rate: 83%.
1H 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). 13C 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.
Embodiment 8
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of 5-methoxyl group-2-[N-methyl-N-(4-chlorine) phenyl] amino-N '-methoxy benzamide (VII-h)
By 5-methoxyl group-2-bromo-benzoic acid (II-h) (4.62g), p-Chlorobenzoic acid amide (III-h) (3.81g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is 5-methoxyl group-2-[N-(4-chlorine) phenyl] benzaminic acid (IV-h) that suction filtration obtains white solid.
Compound (IV-h) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, water is slowly added by excessive sodium hydride cancellation in ice bath, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain yellow oily thick product 5-methoxyl group-2-[N-methyl-N-(4-chlorine) phenyl] Methyl anthranilate (V-h).
Compound (V-h) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains white solid 5-methoxyl group-2-[N-methyl-N-(4-chlorine) phenyl] benzaminic acid (VI-h).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain light yellow solid 5-methoxyl group-2-[N-methyl-N-(4-chlorine) phenyl] amino-N '-methoxy benzamide (VII – h) 2.58g, four step total recoverys 37%.
1H 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). 13C 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.
The preparation of (2) 2,10-dimethoxy-8-chloro-5-methyl isophthalic acid 1H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-h)
5-methoxyl group-2-[N-methyl-N-(4-chlorine) phenyl] amino-N '-methoxy benzamide (VII-h) (0.64g) is dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product, through column chromatography separating purification, obtains light yellow solid 2,10-dimethoxy-8-chloro-5-methyl isophthalic acid 1H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-h) 0.50g, productive rate: 78%.
1H 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). 13C 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.
Embodiment 9
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of 5-methyl-2-[N-methyl-N-(4-bromine) phenyl] amino-N '-methoxy benzamide (VII-i)
By bromo-for 2-5-tolyl acid (II-i) (4.30g), para-bromoaniline (III-i) (5.16g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is 5-methyl-2-[N-(4-bromine) phenyl] benzaminic acid (IV-i) that suction filtration obtains white solid.
Compound (IV-i) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, slowly add water in ice bath by excessive sodium hydride cancellation, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain yellow oily thick product 5-methyl-2-[N-methyl-N-(4-bromine) phenyl] Methyl anthranilate (V-i).
Compound (V-i) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains white solid 5-methyl-2-[N-methyl-N-(4-bromine) phenyl] benzaminic acid (VI-i).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain light yellow solid 5-methyl-2-[N-methyl-N-(4-bromine) phenyl] amino-N '-methoxy benzamide (VII-i) 2.37g, four step total recoverys 37%.
1H 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). 13C NMR(151MHz,CDCl 3):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.
The preparation of (2) 2,5-dimethyl-8-bromo-10-methoxyl group-11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-i)
5-methyl-2-[N-methyl-N-(4-bromine) phenyl] amino-N '-methoxy benzamide (VII-i) (0.70g) is dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product, through column chromatography separating purification, obtains light yellow solid 2, the bromo-10-methoxyl group of 5-dimethyl-8--11H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-i) 0.49g, productive rate: 71%.
1H 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). 13C NMR(151MHz,CDCl 3):δ164.95,150.17,144.96,135.23,133.74,133.04,132.19,129.12,124.86,123.70,119.64,116.78,116.58,62.63,37.68,20.37.
Embodiment 10
A kind of synthetic method of dibenzepin derivative (I), comprises the steps:
(1) preparation of 5-methoxyl group-2-[N-methyl-N-(3-bromine) phenyl] amino-N '-methoxy benzamide (VII-j)
By bromo-for 2-5-methoxybenzoic acid (II-j) (4.62g), m-bromoaniline (III-j) (5.16g), nitrogen methylmorpholine (3.3mL), Red copper oxide (1.43g) joins in dioxane (50mL), reflux 4 hours under nitrogen protection.Be cooled to room temperature after reaction terminates, decompress filter removing solid residue, the aqueous hydrochloric acid of filtrate 1M is acidified to pH=5, and it is 5-methoxyl group-2-[N-(3-bromine) phenyl] benzaminic acid (IV-j) that suction filtration obtains white solid.
Compound (IV-j) is dissolved in DMF (40mL), under ice bath, adds sodium hydride (0.96g), stirring at room temperature half an hour.Go to ice bath, drip methyl iodide (3.7mL), 0 DEG C is stirred one hour.After reaction terminates, water is slowly added by excessive sodium hydride cancellation in ice bath, be extracted with ethyl acetate, removal of solvent under reduced pressure after organic phase drying, obtain yellow oily thick product 5-methoxyl group-2-[N-methyl-N-(3-bromine) phenyl] Methyl anthranilate (V-j).
Compound (V-j) is dissolved in methyl alcohol: in the mixed solvent (40mL) of water (v/v)=5:1, add potassium hydroxide (3.36g) post-heating to 70 DEG C.The hcl acidifying that reaction terminates rear 1M is to precipitation all precipitations, and recrystallization (ethyl acetate: sherwood oil (v/v)=1:20) after suction filtration, obtains white solid 5-methoxyl group-2-[N-methyl-N-(3-bromine) phenyl] benzaminic acid (VI-j).
Upper step gained white solid is dissolved in tetrahydrofuran (THF) (40mL), add carbonyl dimidazoles (3.89g), stirring at room temperature adds methoxamine hydrochloride (5.01g) after half an hour, stirring at room temperature, 2mol/L aqueous sodium carbonate (30mL) is added after reaction terminates, be extracted with ethyl acetate, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product is through column chromatography (ethyl acetate: sherwood oil (v/v)=1:10) separation and purification, obtain light yellow solid 5-methoxyl group-2-[N-methyl-N-(3-bromine) phenyl] amino-N '-methoxy benzamide (VII-j) 3.94g, four step total recoverys 54%.
1H 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). 13C NMR(151MHz,CDCl 3):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.
(2) 7(9) preparation of-bromo-2,10-dimethoxy-5-methyl isophthalic acid 1H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone (I-j)
5-methoxyl group-2-[N-methyl-N-(3-bromine) phenyl] amino-N '-methoxy benzamide (VII-j) (0.70g) is dissolved in acetonitrile (40mL), add iodobenzene diacetate solid (0.97g) in ice bath several times, stirring at room temperature 30min reacts completely.Add saturated sodium bicarbonate aqueous solution (10mL) and stir 5min afterwards, be extracted with ethyl acetate in separating funnel, organic phase is through anhydrous sodium sulfate drying and after concentrating under reduced pressure, obtain crude material, crude product, through column chromatography separating purification, obtains faint yellow solid 7-bromo-2,10-dimethoxy-5-methyl isophthalic acid 1H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone 0.49g, productive rate: 28%; Obtain bromo-2,10-dimethoxy-5-methyl isophthalic acid 1H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone of faint yellow solid 9-, productive rate: 51%.
Bromo-2,10-dimethoxy-5-methyl isophthalic acid 1H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone of 7-: 1h NMR (600MHz, CDCl 3): δ 3.32 (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). 13c NMR (151MHz, CDCl3): δ 164.65,156.02,153.02,146.71,130.89,129.38,128.64,127.32,119.99,119.49,118.22,116.41,114.25,61.83,55.74,37.31.
Bromo-2,10-dimethoxy-5-methyl isophthalic acid 1H-dibenzo [b, e] [Isosorbide-5-Nitrae] diaza-11 ketone of 9-: 1h NMR (600MHz, CDCl 3): δ 3.29 (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, CDCl 3): δ 164.41,155.68,147.54,145.73,132.93,127.13,126.29,122.33,121.44,119.88,119.58,118.14,115.03,62.40,55.70,37.72.
Below be only section Example of the present invention, not any pro forma restriction is done to the present invention, every any simple amendment done above-described embodiment according to technical spirit of the present invention, equivalent variations and modification, all belong within the scope of technical solution of the present invention.

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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