CN108997250A - The method of multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [1,4] oxygen azatropylidene - Google Patents

Abstract

The invention discloses a kind of methods of multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, belong to technical field of organic synthesis.1- nitro -2- (propinyl oxygroup methyl)-benzene is obtained at ether using o-nitro benzyl alcohol and propargyl bromide or propilolic alcohol, then it restores to obtain 2- (propinyl oxygroup methyl)-aniline using iron powder/acetic acid or NiCl2 (dppp)/two boron of tetrahydroxy/organic base, Sonogashira then occurs with iodobenzene to be coupled to obtain 2- [(3- phenyl -2- alkynyloxy group) methyl]-aniline, then after carrying out p-toluenesulfonyl protection to amino, by cuprous bromide/cesium carbonate cyclization, deprotection obtains 2- benzyl -1 under the conditions of subsequent metallic sodium/naphthalene, 5- dihydrobenzo [e] [1, 4] oxygen azatropylidene.

Description

The method of multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [1,4] oxygen azatropylidene

Technical field

The invention belongs to technical field of medicine synthesis, and in particular to a kind of multistep synthesis (E) -2- benzal -1,2,3,5- The method of tetrahydro benzo [e] [1,4] oxygen azatropylidene and 2- benzyl -1,5- dihydrobenzo [e] [1,4] oxygen azatropylidene.

Background technique

The organic compound of the benzoxazine derivative containing 1,4- causes in chemistry and medical research extensive in recent years Concern, this may be the diversity due to its pharmacological action, especially heterocyclic compound containing N/O, and its some derivatives Show extensive bioactivity such as anticancer, treating tuberculosis, anti-hypertension, antirheumatic, serotonin -3 (5-HT3) receptor antagonist Agent, neuroprotective antioxidant etc..

Therefore, Isosorbide-5-Nitrae-benzoxazine is a kind of skeleton of high special efficacy in drug discovery process, potential anti-for developing Tubercular drugs.In view of its medical value, in the past few decades it has been reported that 3,4- dihydros-Isosorbide-5-Nitrae-benzo oxygen azatropylidene Several synthetic strategies and method.However, these methods have certain limitation to molecular diversity.There are many although Report is about 2H-1, the synthesis of 4- benzo oxygen azatropylidene, but few stereoselective syntheses (E) -2- benzal -1,2, and 3,5- The method of tetrahydro benzo [e] [1,4] oxygen azatropylidene and 2- benzyl -1,5- dihydrobenzo [e] [1,4] oxygen azatropylidene.

Summary of the invention

The present invention provides a kind of stabilization easy to operate, synthesis (E) -2- that yield is higher, environmental-friendly, route is relatively reasonable Benzal -1,2,3,5- tetrahydro benzo [e] [1,4] oxygen azatropylidene and 2- benzyl -1,5- dihydrobenzo [e] [1,4] oxygen azatropylidene Method.

Preparation method provided by the invention is completed from o-nitro benzyl alcohol by five steps or six steps.

Route one, the reaction of five steps, reaction equation are as follows:

The realization of technical solution of the present invention, which is characterized in that comprise the following steps that

Step 1: the synthesis of 2- (propinyl oxygroup methyl) nitrobenzene (4)

Method one reacts o-nitro benzyl alcohol 3, propargyl bromide to obtain 2- (propinyl oxygroup methyl) nitrobenzene at ether.Its Middle agents useful for same is sodium hydride or methyl Grignard, and the solvent of selection is tetrahydrofuran, and wherein reaction temperature is selected from -20 DEG C extremely 25℃。

Sodium hydride method is used in this method, and 1-2 equivalent is added, in common reactant solvent THF, DMSO, DMF, reaction Yield 20-30%.It when using methyl Grignard, is reacted at -20 DEG C to 0 DEG C, yield is improved to 65-70%.

However, being flowed back in acetone instead using o-nitro benzyl alcohol 3,1-1.2 equivalent potassium carbonate and 1-1.2 equivalent propargyl bromide At once, no product generates.

Method two, by under the conditions of o-nitro benzyl alcohol 3, propilolic alcohol, triphenyl phosphorus and azodiformate anhydrous and oxygen-free at ether Obtain 2- (propinyl oxygroup methyl) nitrobenzene.The solvent of selection is methylene chloride or toluene, and wherein reaction temperature is selected from 20 DEG C To 25 DEG C.This method reaction condition is milder, and separation yield is 90% or more.

Further, in the above-mentioned technical solutions, in first step reaction, nitro alcohol 3 and propargyl bromide molar ratio Example is 1:1.5-1.6；The nitro alcohol 3 is 1:1.2-1.3 with propargyl alcohol molar ratio.

Further, in the above-mentioned technical solutions, in first step reaction, nitro alcohol 3 and propargyl bromide are used at ether To 1-2 equivalent methyl Grignard Reagent.It is preferred that equivalent is that 1.2-1.5 times of 3 equivalent of raw material is added.

Further, in the above-mentioned technical solutions, in first step reaction, nitro alcohol, triphenyl phosphorus and azo two Formic acid esters molar ratio is selected from 1:1-2:1-2.Both triphenyl phosphorus and azodiformate are equimolar ratio simultaneously.

Further, in the above-mentioned technical solutions, in first step reaction, azodiformate is selected from azo-dicarboxylate (vehicle economy AD) or azoformic acid isopropyl ester (abbreviation DIAD).

Step 2: the synthesis of 2- (propinyl oxygroup methyl)-aniline (5)

Method one, raw material 4 back flow reaction in iron powder/acetic acid/ethanol system obtain 2- (propinyl oxygroup methyl)-aniline 5。

Wherein, iron powder uses after overactivation, and additional amount is the 2-5 equivalent of raw material 4, and preferably equivalent is 4-4.5 equivalent.

Method two, raw material 4 back flow reaction in NiCl2 (dppp)/two boron of tetrahydroxy/organic base/ethanol system obtain 2- (propinyl oxygroup methyl)-aniline 5.

Wherein, wherein organic base is selected from triethylamine or diisopropyl ethyl amine；It is NiCl2 (dppp), two boron of tetrahydroxy, organic Alkali equivalent ratio is 0.01-0.03:2-3:2.5-4.

Two methods of this step raw material can convert completely, and separation yield can be examined when 85% or more, TLC detects reaction process Measure the intermediate product by partial reduction.In two schemes, from useless solid process angle, preferred method two.

Step 3: the synthesis of 2- [(3- phenyl -2- alkynyloxy group) methyl]-aniline (6)

2- (propinyl oxygroup methyl)-aniline 5 and iodobenzene, under palladium catalyst and cuprous iodide catalysis, triethylamine condition It is lower to be coupled to obtain 2- [(3- phenyl -2- alkynyloxy group) methyl]-aniline 6 by Sonogashira.Wherein solvent is triethylamine, palladium Catalyst is selected from Pd (PPh3) 2Cl2, respectively corresponds the 1.5-2.5% and 3-5% for raw material equivalent, and the two with CuI additional amount Holding ratio is 1:2.

Further, in the above-mentioned technical solutions, in third step reaction, 2- (propinyl oxygroup methyl)-aniline 5 and Pd (PPh3) 2Cl2, iodobenzene, triethylamine, iodate Asia ketone molar ratio be 1:0.025-0.03:1.05-1.2:1.5-1.7: 0.05-0.08。

Step 4: the synthesis of 2- [(3- phenyl -2- alkynyloxy group) methyl]-PG aniline (7)

It includes: Ac (acetyl group), Bz (benzoyl), Ts (p-toluenesulfonyl) that PG (protecting group) is introduced on amido.

In the presence of an organic base, 2- [(3- phenyl -2- alkynyloxy group) methyl]-aniline 6 and amido protecting agent, after reaction To corresponding protection product 2- [(3- phenyl -2- alkynyloxy group) methyl]-PG aniline 7.Wherein reaction temperature is selected from -10 DEG C to 25 DEG C, The solvent of selection is tetrahydrofuran, methylene chloride.

Amido protecting agent is selected from: chloroacetic chloride, acetic anhydride, chlorobenzoyl chloride or paratoluensulfonyl chloride.Organic base is selected from three second Amine or pyridine, preferably triethylamine.

Further, in the above-mentioned technical solutions, in four-step reaction, 2- [(3- phenyl -2- alkynyloxy group) methyl]-aniline 6, amido protecting agent and organic alkali equivalent ratio are 1:1-1.5:1.1-1.6.

This step Reaction Separation yield is usually between 83-95%.

Step 5: (E) -2- benzal -1,2,3,5- tetrahydro benzo [e] [1,4] oxygen azatropylidene (1) and 2- benzyl -1,5- The synthesis of dihydrobenzo [e] [1,4] oxygen azatropylidene (2)

2- [(3- phenyl -2- alkynyloxy group) methyl]-PG aniline 7 and tetrabutylammonium iodide or tetrabutylammonium bromide, protobromide Copper or cuprous bromide-dimethyl sulphide, the cyclization of cesium carbonate elder generation generate benzal -1,2,3 corresponding intermediate product N-PG- (E) -2-, 5- tetrahydro benzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 8 and N-PG-2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 9 are then logical It crosses deprotection and obtains (E) -2- benzal -1,2,3,5- tetrahydro benzo [e] [1,4] oxygen azatropylidene 1 and 2- benzyl -1,5- dihydrobenzene And [e] [1,4] oxygen azatropylidene 2.Wherein reaction temperature is selected from 80 DEG C to 110 DEG C, and the solvent of selection is glycol dimethyl ether, second Nitrile, 1,4- dioxane.

Further, in the above-mentioned technical solutions, in the reaction of the 5th step, two kinds of reaction conditions are in alkaline condition Under, and tetrabutylammonium iodide or tetrabutylammonium bromide, cuprous bromide or cuprous bromide-dimethyl sulphide, the cyclization of cesium carbonate elder generation, then Acetyl group (Ac) or benzoyl (Bz) protection are by sodium hydroxide or potassium hydroxide/methanol aqueous systems deprotection, to toluene sulphur Acyl group (Ts) is deprotected to obtain target product by sodium/naphthalene.

Further, in the above-mentioned technical solutions, in the 5th step, 2- [(3- phenyl -2- alkynyloxy group) methyl]-PG aniline 7 Molar ratio with n-Bu4NI, cuprous bromide, cesium carbonate is 1:1.1-1.3:0.35-0.4:1.1-1.5.When ring closure reaction, adopt It is nearly no detectable product when with the organic bases such as inorganic base K2CO3, Na2CO3, Li2CO3 and DBU, DBN, after being refluxed overnight, TLC The new point estimation of observation is no more than 5%.

Further, in the above-mentioned technical solutions, the product that the 5th step obtains can be distinguished obviously on TLC, be passed through After column chromatography, (E) -2- benzal -1,2,3,5- tetrahydro benzos [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 1 and 2- benzyl can be easily separated Base -1,5- dihydrobenzo [e] [1,4] oxygen azatropylidene 2.Final product, after differently protection group reaction, both 1 and 2 ratios The two is in 1-3:1.

Further, in the above-mentioned technical solutions, when the 5th step product column chromatographs, eluent petroleum ether and acetic acid second used The eluting solvent volume ratio of ester mixed system is gradually increased to 3:1 from 15:1.

For successive reaction separation yield usually between 55-73%, ring closure reaction supposition is in alkaline condition twice in this step Under first pass through connection alkene process, then carry out cyclization again.Optimize by different alkali, in common alkaline reagent (inorganic base K2CO3,KHCO3,Na2CO3,NaHCO3,Li2CO3,Cs2CO3；Organic base DBU, DBN, TMG), additive (such as KI, n- Bu4NI, n-Bu4NBr) and after copper salt catalyst (CuBr, CuI, CuCl, CuBr-Me2S) optimizes screening, find optimal Group is combined into CuBr or CuBr-Me2S, n-Bu4NI or n-Bu4NBr and Cs2CO3 system.

Route two, four-step reaction, reaction equation are as follows:

In the reaction route, o-nitro benzyl alcohol 3 or adjacent nitro benzyl bromine 10 first react to obtain 12 with phenyl alkynol 11, then pass through It crosses iron powder/acetic acid or NiCl2 (dppp)/two boron of tetrahydroxy/organic base restores to obtain 6.Other reaction steps are identical as route one.

Step 1: the synthesis of 2- (phenylpropyl alcohol ynyloxymethyl) nitrobenzene (12)

Method one, by o-nitro benzyl alcohol 3, phenyl propyne alcohol 10, triphenyl phosphorus and azoformic acid diester, (Mitsunbo is anti- Answer) 2- (phenylpropyl alcohol ynyloxymethyl) nitrobenzene 12 is obtained at ether under the conditions of anhydrous and oxygen-free.The solvent of selection is methylene chloride, first Benzene or tetrahydrofuran, wherein reaction temperature is selected from 20 DEG C to 25 DEG C.This method Reaction Separation yield is 86% or more.

Method two obtains 12 after nucleophilic displacement of fluorine occurs using adjacent nitro bromobenzyl 10 and phenyl propyne alcohol 11.When operation, four In hydrogen THF solvent, after phenyl propyne alcohol 11 and 1-1.1 equivalent butyl lithium or sodium hydride deprotonation, then in 40-60 DEG C of item Under part, adjacent nitro bromobenzyl 10 is added dropwise and enters system reaction, separation yield is in 75-80%.

Step 2: the synthesis of 2- (phenylpropyl alcohol ynyloxymethyl)-aniline (6)

The back flow reaction in iron powder/acetic acid/ethanol system of raw material 12 obtains 2- (phenylpropyl alcohol ynyloxymethyl)-aniline 6.

Wherein, iron powder uses after overactivation, and additional amount is the 2-5 equivalent of raw material 11, and preferably equivalent is 3.5-4 equivalent.

Method two, raw material 12 back flow reaction in NiCl2 (dppp)/two boron of tetrahydroxy/organic base/ethanol system obtain 2- (propinyl oxygroup methyl)-aniline 6.

Wherein, wherein organic base is selected from triethylamine or diisopropyl ethyl amine；It is NiCl2 (dppp), two boron of tetrahydroxy, organic Alkali equivalent ratio is 0.01-0.03:2-3:2.5-4.

Third step to step 5:

Subsequent step and operating condition are the same as route one.

Invention the utility model has the advantages that

Synthetic route advantages of simple of the present invention, raw material are easy to get, and reaction condition is mild, and especially the first step is reacted at ether, lead to It crosses using methyl Grignard or Mitsunobu into ether, solves the problems, such as that routine operation yield is low, final step uses protobromide Ketone ring closure reaction can generate cyclization product in the outer cyclization of ring and ring simultaneously, and there are significantly different with hexa-atomic cyclics for this.

Specific embodiment

Below by specific example, invention is further explained.

These embodiments are interpreted as being merely to illustrate the present invention rather than limit the scope of the invention.It is reading After the content of the invention recorded, those skilled in the art can make various modifications or changes to the present invention, these equivalent changes Change and modification equally falls into the scope of the claims in the present invention.

Test method without specific conditions in following embodiment of the present invention carries out usually according to normal condition, and It is carried out under nitrogen protection.

Raw material used in following embodiment of the present invention or reagent are commercially available in addition to special instruction.

20-25 DEG C of room temperature mean value described in following embodiment of the present invention.Unless otherwise indicated, the reagent is not special Explanation is to be used without further purification.All solvents are purchased from commercialization supplier, and just can be used without processing.Reaction Process is mainly detected by TLC, and HNMR identifies structure, and the termination of reaction is judged by the consumption of starting material.

Embodiment 1

Step 1: the synthesis of 1- nitro -2- (propinyl oxygroup methyl)-benzene 4.

O-nitro benzyl alcohol 3 (15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) are added to by method one After the anhydrous THF of 110mL, after mixing evenly, system temperature is down to 0 DEG C, and 60%NaH (4.8g, 0.12mol) is added portionwise and keeps Temperature is finished at -20 DEG C to -10 DEG C, is slowly increased to be stirred at room temperature and be reacted 4-5 hours, after TLC detects raw material disappearance, pours into In 200g water, MTBE100mL is extracted three times, merges organic phase, and saturated sodium bicarbonate water is washed, saturated common salt washing, and organic phase is dense Contracting carries out column chromatography for separation using normal heptane/ethyl acetate 10:1 to 6:1, obtains 6.3g pale yellowish oil liquid 4, yield 33%.1H NMR(400MHz,CDCl3):7.78(dd,1H),7.54-7.58(m,2H),7.50(d,1H),7.06-7.09(m, 1H),4.86(s,2H),4.79(d,2H),2.58(t,1H)；M/z=192.11 (M+H).

Method two mixes o-nitro benzyl alcohol 3 (15.3g, 0.1mol) and the anhydrous THF of 85mL, and subsequent system temperature is down to 0 DEG C, 60%NaH (4.8g, 0.12mol) is added portionwise, finishes insulated and stirred 30 minutes, start be added dropwise propargyl bromide (14.3g, 0.12mol) keeps temperature to be no more than 0 DEG C with the anhydrous THF mixed solution of 30mL, dropwise addition in the process, be then slowly increased to room temperature and stir Reaction 3-5 hours is mixed to pour into 200g water after TLC detects raw material disappearance, 100mLMTBE is extracted three times, merge organic phase, Saturated sodium bicarbonate water is washed, saturated common salt washing, and organic phase concentration carries out column layer using normal heptane/ethyl acetate 10:1 to 6:1 Analysis separation, obtains 4.8g yellow oily liquid 4, yield 25%.

O-nitro benzyl alcohol 3 (15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) are added to by method three After the anhydrous THF of 110mL, after mixing evenly, system temperature is down to -10 DEG C, and 3M methyl-magnesium-chloride tetrahydrofuran solution is added dropwise (0.12mol) is no more than 0 DEG C, insulation reaction 1 hour, is then slowly increased to that reaction 4-5 hours is stirred at room temperature during being added dropwise, It after TLC detects raw material disappearance, pours into 200g water, MTBE100mL is extracted three times, merges organic phase, saturated sodium bicarbonate water It washes, saturated common salt washing, organic phase concentration carries out column chromatography for separation using normal heptane/ethyl acetate 10:1 to 6:1, obtains 13.0g yellow oily liquid 4, yield 68%.

Using 1M methyl-magnesium-bromide tetrahydrofuran solution, similarly operated according to method three, separation yield 70%.

Method four, by o-nitro benzyl alcohol (15.3g, 0.1mol), propargyl alcohol (6.1g, 0.11mol) and triphenyl phosphorus After (31.4g, 0.12mol) is added to 180mL methylene chloride, after stirring complete dissolved clarification, starts to be added dropwise at room temperature and contain azo two Formic acid diethylester (20.9g, 1.2eq) and 50mL methylene chloride mixed solution, drop Bi Jixu are stirred overnight at room temperature, and TLC detection is former Material disappears, and system is cooled to -40 DEG C of standings, filters out complex solid by-product, filtrate concentration, and column chromatographic elution is obtained 17.6g yellow oily liquid 4, yield 92%.

Embodiment 2

Step 2: the synthesis of 2- (propinyl oxygroup methyl)-aniline 5

Under method one, mechanical stirring, by 1- nitro -2- (propinyl oxygroup methyl)-benzene 4 (19.1g, 0.1mol) and reduction After iron powder (4.5eq) is added to 220mL ethyl alcohol, 55-65 DEG C of dropwise addition acetum (2.5eq) of temperature is controlled, heating is added dropwise To back flow reaction 3 hours, TLC detection raw material disappeared substantially, was cooled to 50 DEG C, and diatomite filtering, filter cake is eluted with ethyl alcohol, Filtrate decompression is concentrated to dryness, and methylene chloride 120mL is added, and water layer adjusts pH=9-10 with saturated aqueous sodium carbonate, is saturated chlorine Change sodium to wash, anhydrous sodium sulfate dries, filters reduced pressure, carries out column chromatography point using normal heptane/ethyl acetate 10:1 to 6:1 From obtaining yellow oily liquid 16.9g, yield 88%.1H NMR(400MHz,CDCl3):7.44(s,2H),7.10-7.13 (m,1H),6.91-6.93(m,1H),6.77-6.79(m,1H),6.69-6.71(m,1H),5.06(s,2H),4.53(d,2H), 2.52(t,1H)；M/z=162.20 (M+H).

Under method two, mechanical stirring, by 1- nitro -2- (propinyl oxygroup methyl)-benzene 4 (19.1g, 0.1mol), three second After amine (3eq) and NiCl2 (dppp) (0.02eq) are added to 220mL ethyl alcohol, 40-45 DEG C of temperature is controlled, divides 5-8 batches four hydroxyls are added Two boron solid (2.5eq) of base after every batch of is added, stirs 20 minutes, followed by being added lower batch, is added dropwise and is warming up to reflux instead It answers 3 hours, TLC detects raw material point and disappears, and is down to room temperature, diatomite filtering, and filter cake is eluted with ethyl alcohol, filtrate decompression concentration To dry, addition methylene chloride 120mL, water layer 5% sodium bicarbonate aqueous solution adjusting pH=9-10, saturated sodium-chloride is washed, anhydrous Sodium sulphate dries, filters reduced pressure, carries out column chromatography for separation using normal heptane/ethyl acetate 10:1 to 6:1, obtains yellow oil Shape liquid 14.6g, yield 91%.1H NMR(400MHz,CDCl3):7.44(s,2H),7.10-7.13(m,1H),6.91- 6.93(m,1H),6.77-6.79(m,1H),6.69-6.71(m,1H),5.06(s,2H),4.53(d,2H),2.52(t,1H)； M/z=162.20 (M+H).

Embodiment 3

Step 3: the synthesis of 2- [(3- phenyl -2- alkynyloxy group) methyl]-aniline 6

By iodobenzene (10.7g, 1.05eq), cuprous iodide (0.5g, 5mol%) and bis- (triphenyl) palladium chlorides (0.86g, 2.5mol%) be added to 100mL triethylamine, room temperature be added dropwise containing 2- (propinyl oxygroup methyl)-aniline 5 (8g, 0.05mol) and 18mL triethylamine mixed solution, during dropwise addition, solution gradually becomes clarification, and then overnight, system salts out for room temperature reaction, by Fade to aaerosol solution.HPLC detects product and material rate is greater than 80:1, is concentrated under reduced pressure and removes triethylamine, and 80mL dichloro is added Methane extraction is saturated ammonia scrubbing, saturated common salt washing, after anhydrous magnesium sulfate dries, filters revolving, using normal heptane/acetic acid Ethyl ester 15:1 to 6:1 carries out column chromatography for separation, obtains yellow oily liquid 11.7g, yield 98%.1H NMR(400MHz, CDCl3):7.42(s,2H),7.38-7.42(m,4H),7.22-7.25(m,2H),7.05-7.08(m,3H),5.05(s,2H), 4.94(s,2H)；M/z=238.16 (M+H).

By o-nitro benzyl alcohol 3 (15.3g, 0.1mol), benzyne propyl alcohol 11 (13.5g, 0.102mol) and triphenyl phosphorus After (31.4g, 0.12mol) is added to 200mL methylene chloride, after stirring complete dissolved clarification, starts to be added dropwise at room temperature and contain azo two Formic acid diethylester (20.9g, 1.2eq) and 50mL methylene chloride mixed solution, drop Bi Jixu are stirred overnight at room temperature, and TLC detection is former Material disappears, and system is cooled to -40 DEG C of standings, filters out complex solid by-product and is directly added into and is added to after filtrate concentration After 250mL ethyl alcohol and 3.5eq reduced iron powder, 55-65 DEG C of dropwise addition acetum (2.5eq) of temperature is controlled, is added dropwise and is warming up to Back flow reaction 3 hours, TLC detection raw material disappeared substantially, was cooled to 50 DEG C, and diatomite filtering, filter cake is eluted with ethyl alcohol, is filtered Liquid is concentrated to dryness, and methylene chloride 150mL is added, and water layer adjusts pH=9-10 with saturated aqueous sodium carbonate, is saturated chlorination Sodium is washed, and anhydrous sodium sulfate dries, filters reduced pressure, carries out column chromatography for separation using normal heptane/ethyl acetate 10:1 to 6:1, Obtain yellow oily liquid 19.2g, two step yields 81%.1H NMR(400MHz,CDCl3):7.42(s,2H),7.38-7.42 (m,4H),7.22-7.25(m,2H),7.05-7.08(m,3H),5.05(s,2H),4.94(s,2H)；M/z=238.16 (M+ H)。

Using 1.0 equivalent sodium hydrides or 1.0 equivalent butyl lithiums first with phenylpropyl alcohol alkynol in -10 DEG C to 0 DEG C deprotonations, then again It reacts at room temperature, then 3.5eq iron powder/2.5eq acetic acid/ethyl alcohol again, is restored under counterflow condition, two with 0.95 equivalent adjacent nitro bromobenzyl Walking separation yield is respectively 63% and 67%.

Embodiment 4

Step 4: the synthesis of 2- [(3- phenyl -2- alkynyloxy group) methyl]-PG aniline 7

7a:PG=Ac:2- [(3- phenyl -2- alkynyloxy group) methyl]-aniline 6 (8.8g, 37mmol), 13mL pyridine, 0.3g After the mixing of DMAP and 65mL methylene chloride, it is completely dissolved under stirring.Temperature is reduced to 0 DEG C, control temperature is added dropwise at 0-5 DEG C Acetic anhydride (4.2g, 1.1eq) and 20mL methylene chloride mixed solution, are added dropwise rear insulated and stirred 1h.Room is then risen to naturally Temperature reaction 4 hours, TLC detection reaction terminate.Successively use 5% salt acid elution, saturated sodium bicarbonate solution washing, saturated common salt Washing after anhydrous sodium sulfate dries, filters revolving, using normal heptane/ethyl acetate 10:1 to 5:1 column chromatography for separation, obtains shallow Yellow solid 9.8g, yield 96%.1H NMR(400MHz,CDCl3):8.38(d,1H),7.82(s,1H),7.40-7.44(m, 3H),7.30-7.35(m,2H),7.06-7.08(m,3H),5.08(s,2H),4.97(s,2H),2.19(s,3H)；M/z= 280.11(M+H)。

7b:PG=Bz: using above-mentioned same method, and chlorobenzoyl chloride substitution acetic anhydride is reacted, pale yellow after processing Color solid, yield 91%.1H NMR(400MHz,CDCl3):8.53-8.66(m,2H),7.88-7.90(m,3H),7.33- 7.52(m,7H),7.06-7.12(m,3H),5.04(s,2H),4.98(s,2H)；M/z=342.16 (M+H).

7c:PG=Ts:2- [(3- phenyl -2- alkynyloxy group) methyl]-aniline 6 (8.8g, 37mmol), triethylamine (2eq), After the mixing of 0.3g DMAP and 65mL methylene chloride, it is completely dissolved under stirring.Temperature is reduced to 0 DEG C, controls temperature at 0-5 DEG C Lower dropwise addition TsCl (7.8g, 1.1eq) and 20mL methylene chloride mixed solution, are added dropwise rear insulated and stirred 1h.Then rise naturally To room temperature reaction 4 hours, TLC detection reaction terminated.Successively use 5% salt acid elution, saturated sodium bicarbonate solution washing, saturation Salt washing after anhydrous sodium sulfate dries, filters revolving, is recrystallized using ethyl alcohol and heptane, obtains light yellow solid 13.5g, Yield 93%.1H NMR(400MHz,CDCl3):8.43-8.55(m,2H),7.78-7.88(m,3H),7.21-7.46(m, 6H),7.01-7.06(m,3H),5.03(s,2H),4.92(s,2H),2.43(s,3H)；M/z=392.20 (M+H).

Embodiment 5

Step 5: (E) -2- benzal -1,2,3,5- tetrahydro benzo [e] [1,4] oxygen azatropylidene 1 and 2- benzyl -1,5- two The synthesis of hydrogen benzo [e] [1,4] oxygen azatropylidene 2

By 7a (9.8g, 35mmol), CuBr-Me2S (0.3eq), tetrabutylammonium bromide (1eq), cesium carbonate (11.4g, 1eq) it is uniformly mixed with 1,4- dioxane 250mL.It is then to slowly warm up to back flow reaction again to stay overnight, TLC shows that raw material is basic It disappears, generates two new points, ratio is about 2:1, stops reaction, and after being spin-dried for organic solvent, 150mL bis- is added in diatomite filtering Chloromethanes and moisture liquid, organic phase are successively washed with concentrated ammonia liquor, saturated common salt again, organic solvent are spin-dried for, using normal heptane/acetic acid Ethyl ester 15:1 obtains 5.2g cyclization isomers 8a and 2.1g cyclization isomers 9b to 5:1 column chromatography for separation.Then, by respective product 30% sodium hydroxide 5eq is added and 6 times of volumes methanols are warming up to reflux deprotection reaction 6 hours, TLC detects raw material and disappears, eventually It only reacts, is concentrated under reduced pressure and removes methanol, 5% hydrochloric acid solution is added and adjusts pH=2-3, methylene chloride is extracted twice, and organic layer is again PH=8-9 is adjusted with 5% sodium bicarbonate aqueous solution, saturated common salt washing, anhydrous sodium sulfate is dry, using normal heptane/acetic acid second Ester 10:1 respectively obtains 3.7g light yellow liquid to 3:1 column chromatography for separation, is compound 1,45% He of yield through structure determination 1.6g light yellow solid is compound 2, yield 19% through structure determination.

Using same method, using 7b as raw material, respectively obtaining the separation yield of compound 1 and 2 is 41% and 32%.

(E) -2- benzal -1,2,3,5- tetrahydro benzos [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 1,¹H NMR(400MHz,CDCl3): 8.52(s,1H),7.60(d,2H),7.33-7.39(m,3H),7.02-7.10(m,2H),6.79(m,1H),6.47(d,1H), 6.08(s,1H),4.66(s,2H),4.08(s,2H)；¹³C NMR(100MHz,CDCl3):142.9,141.5,136.8, 135.1,128.6,128.5,126.2,124.3,109.4,104.5,76.2,75.0；M/z=237.11 (M+H).

2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 2,1H NMR (400MHz, CDCl3): 8.48 (s, 1H), 7.37(m,2H),7.22-7.26(m,3H),7.02-7.08(m,2H),6.78(m,1H),6.47(d,1H),5.15(s,1H), 5.22(s,2H),4.23(s,2H)；¹³C NMR(100MHz,CDCl3):141.3,140.6,135.5,129.0,128.6, 128.5,128.4,125.9,125.7,124.4,115.3,110.2,70.6,39.7；M/z=237.11 (M+H).

By 7c (13.5g, 35mmol), CuI (0.3eq), tetrabutylammonium bromide (1eq), cesium carbonate (11.4g, 1eq) and 1, 4- dioxane 250mL is uniformly mixed.It is then to slowly warm up to back flow reaction again to stay overnight, TLC shows that raw material disappears substantially, generates Two new points, ratio is about 1:1, stops reaction, and after being spin-dried for organic solvent, 150mL methylene chloride and water is added in diatomite filtering Liquid separation, organic phase are successively washed with concentrated ammonia liquor, saturated common salt again, are spin-dried for organic solvent, extremely using normal heptane/ethyl acetate 15:1 5:1 column chromatography for separation obtains 5.6g cyclization isomers 8c and 5.1g cyclization isomers 9c.Then, naphthalene solution is added in respective product In, using 4eq metallic sodium deprotection reaction, 50-90 DEG C of reaction temperature is controlled, is reacted 4 hours, TLC detects raw material and disappears, cooling It is slowly added dropwise to 0 DEG C and is quenched into methanol, be concentrated under reduced pressure and remove methanol, 5% hydrochloric acid solution is added and adjusts pH=2-3, methylene chloride It being extracted twice, organic layer uses 5% sodium bicarbonate aqueous solution to adjust pH=8-9 again, and saturated common salt washing, anhydrous sodium sulfate is dry, 3.6g light yellow liquid is respectively obtained using normal heptane/ethyl acetate 10:1 to 3:1 column chromatography for separation, is chemical combination through structure determination Object 1, yield 44% and 3.1g light yellow solid are compound 2, yield 38% through structure determination.

The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto, Anyone skilled in the art within the technical scope of the present disclosure, according to the technique and scheme of the present invention and its Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.

Claims (9)

1. a kind of method of multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, which is characterized in that reaction side Formula are as follows:

Include the following steps: that 1) nitro alcohol 3, propargyl bromide use methyl Grignard exchange reaction to obtain chemical combination at ether Object 2；2) compound 2 restores to obtain compound 5 using iron powder/acetic acid or NiCl2 (dppp)/two boron of tetrahydroxy/organic base；3) change Object 5 is closed to be coupled to obtain compound 6 with iodobenzene under bis- (triphenyl phosphorus) palladium chlorides and cuprous iodide catalysis；4) compound 6 draws Enter p-toluenesulfonyl to protect to obtain compound 7；5) compound 7 is in cuprous salt, tetrabutyl ammonium halide and cesium carbonate condition ShiShimonoseki Ring obtains 9, then is deprotected to obtain 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene 2 using metallic sodium/naphthalene.

2. the method for multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature according to claim 1 Be: in first step reaction, nitro alcohol 3 and propargyl bromide molar ratio are 1:1.5-1.6.

3. the method for multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature according to claim 1 Be: in second step, iron powder uses after overactivation, and additional amount is the 2-5 equivalent of raw material 4；Organic base is selected from triethylamine or two Diisopropylethylamine, NiCl2 (dppp), two boron of tetrahydroxy and organic alkali equivalent ratio are 0.01-0.03:2-3:2.5-4.

4. the method for multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature according to claim 1 It is: in third step reaction, 2- (propinyl oxygroup methyl)-aniline 5 and Pd (PPh3) 2Cl2, iodobenzene, triethylamine, iodate Asia ketone Molar ratio be 1:0.025-0.03:1.05-1.2:1.5-1.7:0.05-0.08.

5. the method for multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature according to claim 1 It is: in four-step reaction, introduces p-toluenesulfonyl and reacted under the conditions of organic base using paratoluensulfonyl chloride；Organic base choosing From pyridine or triethylamine.

6. according to the method for multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene in claim 5, feature Be: in four-step reaction, compound 6, paratoluensulfonyl chloride and organic alkali equivalent ratio are 1:1-1.5:1.1-1.6.

7. the method for multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature according to claim 1 Be: in the reaction of the 5th step, tetrabutyl ammonium halide is selected from tetrabutylammonium iodide or tetrabutylammonium bromide, and cuprous salt is selected from protobromide Copper or cuprous bromide-dimethyl sulphide.

8. the method for multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature according to claim 1 Be: in the reaction of the 5th step, compound 7 and the molar ratio of tetrabutyl ammonium halide, cuprous salt, cesium carbonate are 1:1.1-1.3: 0.35-0.4:1.1-1.5。

9. the method for multistep synthesis 2- benzyl -1,5- dihydrobenzo [e] [Isosorbide-5-Nitrae] oxygen azatropylidene, feature exist according to claim 1 In: where it is as follows that compound 6 replaces synthetic method:

O-nitro benzyl alcohol 3 reacts to obtain compound 12 with phenyl alkynol 11 by Mitsunbo, or with phenyl alkynol 11 in butyl Compound 12 is obtained after lithium or sodium hydride deprotonation with 10 nucleophilic displacement of fluorine of adjacent nitro benzyl bromine, subsequent compound 12 passes through iron powder/second Acid or NiCl2 (dppp)/two boron of tetrahydroxy/organic base restore to obtain compound 6.