CN108774192B - Method for synthesizing (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine - Google Patents
Method for synthesizing (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine Download PDFInfo
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- CN108774192B CN108774192B CN201810655348.2A CN201810655348A CN108774192B CN 108774192 B CN108774192 B CN 108774192B CN 201810655348 A CN201810655348 A CN 201810655348A CN 108774192 B CN108774192 B CN 108774192B
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Abstract
The invention discloses a method for synthesizing (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine in multiple steps, and belongs to the technical field of organic synthesis. The method comprises the steps of forming ether by adopting o-nitrobenzyl alcohol and propargyl bromide or propargyl alcohol to obtain 1-nitro-2- (propynyloxymethyl) -benzene, then reducing by adopting iron powder/acetic acid or NiCl2 (dppp)/tetrahydroxy diboron/organic base to obtain 2- (propynyloxymethyl) -aniline, carrying out Sonogashira coupling with iodobenzene to obtain 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline, carrying out benzoyl protection on amino, carrying out ring closure by cuprous bromide/cesium carbonate, and then carrying out deprotection under alkaline conditions to obtain (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine and 2-benzyl-1, 5-dihydrobenzo [ E ] [1,4] oxazepine in a multi-step manner.
Background
Organic compounds containing 1, 4-benzoxazine derivatives have attracted considerable attention in recent years in chemical and medical research, probably due to the diversity of their pharmacological actions, in particular N/O-containing heterocyclic compounds, and some of their derivatives show a wide range of biological activities such as anticancer, antitubercular, antihypertensive, antirheumatic, 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, neuroprotective antioxidants, etc.
Therefore, 1, 4-benzoxazine is a highly specific skeleton in the drug discovery process and is used for developing potential antitubercular drugs. In view of their pharmaceutical value, several synthetic strategies and methods for 3, 4-dihydro-1, 4-benzoxazepine have been reported over the last several decades. However, these methods have certain limitations in the generation of molecular diversity. Although there are many reports on the synthesis of 2H-1, 4-benzoxazepine, there are few stereoselective methods for the synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine and 2-benzyl-1, 5-dihydrobenzo [ E ] [1,4] oxazepine.
Disclosure of Invention
The invention provides a method for synthesizing (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine and 2-benzyl-1, 5-dihydrobenzo [ E ] [1,4] oxazepine, which has the advantages of simple and stable operation, high yield, environmental friendliness and relatively reasonable route.
The preparation method provided by the invention is completed by five steps or six steps from o-nitrobenzyl alcohol.
The reaction in the first and fifth steps has the following reaction equation:
the technical scheme is realized by the following steps:
the first step is as follows: synthesis of 2- (propynyloxymethyl) nitrobenzene (4)
The first method is to react o-nitrobenzyl alcohol 3 and propargyl bromide in ether to obtain 2- (propynyl oxymethyl) nitrobenzene. Wherein the reagent is sodium hydride or methyl Grignard reagent, the solvent is tetrahydrofuran, and the reaction temperature is selected from-20 ℃ to 25 ℃.
In the method, a sodium hydride method is adopted, 1-2 equivalents are added, and the reaction yield is 20-30% in common reaction solvents of THF, DMSO and DMF. When the methyl Grignard reagent is adopted, the reaction is carried out at the temperature of between 20 ℃ below zero and 0 ℃, and the yield is improved to 65 to 70 percent.
However, when o-nitrobenzyl alcohol 3, 1 to 1.2 equivalents of potassium carbonate and 1 to 1.2 equivalents of propargyl bromide are used in acetone under reflux, no product is formed.
And secondly, forming ether by o-nitrobenzyl alcohol 3, propiolic alcohol, triphenyl phosphorus and azodicarboxylate under anhydrous and anaerobic conditions to obtain the 2- (propinyloxymethyl) nitrobenzene. The solvent is selected from dichloromethane or toluene, wherein the reaction temperature is selected from 20 ℃ to 25 ℃. The method has mild reaction conditions and separation yield of over 90 percent.
Further, in the technical scheme, in the first-step reaction, the molar ratio of the o-nitrobenzyl alcohol 3 to the propargyl bromide is 1: 1.5-1.6; the molar ratio of the o-nitrobenzyl alcohol 3 to the propargyl alcohol is 1: 1.2-1.3.
Further, in the technical scheme, in the first step of reaction, 1-2 equivalents of methyl Grignard reagent is used for forming ether by the o-nitrobenzyl alcohol 3 and the propargyl bromide. Preferably, the equivalent is 1.2 to 1.5 times that of 3 equivalents of the raw materials.
Further, in the technical scheme, in the first step of reaction, the mol ratio of the o-nitrobenzyl alcohol, the triphenyl phosphorus and the azodicarboxylate is selected from 1:1-2: 1-2. Meanwhile, the molar ratio of the triphenyl phosphine to the azodicarbonic acid ester is equal.
Further, in the above technical scheme, in the first step of reaction, the azodicarboxylate is selected from ethyl azodicarboxylate (DEAD) or isopropyl azodicarboxylate (DIAD).
The second step is that: synthesis of 2- (propynyloxymethyl) -aniline (5)
In the first method, the raw material 4 is refluxed in an iron powder/acetic acid/ethanol system to obtain 2- (propynyloxymethyl) -aniline 5.
Wherein, the iron powder is used after being activated, and the adding amount is 2 to 5 equivalents of the raw material 4, and the preferred equivalent is 4 to 4.5 equivalents.
And secondly, carrying out reflux reaction on the raw material 4 in a NiCl2 (dppp)/tetrahydroxy diboron/organic base/ethanol system to obtain the 2- (propynyloxymethyl) -aniline 5.
Wherein the organic base is selected from triethylamine or diisopropylethylamine; NiCl2(dppp), tetrahydroxy diboron and organic base equivalent ratio of 0.01-0.03:2-3: 2.5-4.
In the two methods, the raw materials can be completely converted, the separation yield is over 85 percent, and a partially reduced intermediate product can be detected in the T L C detection reaction process.
The third step: synthesis of 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline (6)
The 2- (propynyloxymethyl) -aniline 5 and iodobenzene are subjected to Sonogashira coupling under the conditions of palladium catalyst, cuprous iodide and triethylamine to obtain 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline 6. Wherein the solvent is triethylamine, the palladium catalyst is selected from Pd (PPh3)2Cl2, the adding amount of the palladium catalyst and the CuI respectively correspond to 1.5-2.5% and 3-5% of the equivalent of the raw materials, and the keeping ratio of the two is 1: 2.
Further, in the above technical scheme, in the third step of the reaction, the molar ratio of 2- (propynyloxymethyl) -aniline 5 to Pd (PPh3)2Cl2, iodobenzene, triethylamine, and iodoidene is 1:0.025-0.03:1.05-1.2:1.5-1.7: 0.05-0.08.
The fourth step: synthesis of 2- [ (3-phenyl-2-alkynyloxy) methyl ] -PG aniline (7)
Introducing PG (protecting group) on an amine group includes: ac (acetyl), Bz (benzoyl), Ts (p-toluenesulfonyl).
In the presence of organic base, 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline 6 reacts with amino protecting reagent to obtain corresponding protected product 2- [ (3-phenyl-2-alkynyloxy) methyl ] -PG aniline 7. Wherein the reaction temperature is selected from-10 ℃ to 25 ℃, and the selected solvent is tetrahydrofuran and dichloromethane.
The amino protecting agent is selected from: acetyl chloride, acetic anhydride, benzoyl chloride or p-toluenesulfonyl chloride. The organic base is selected from triethylamine or pyridine, preferably triethylamine.
Further, in the technical scheme, in the fourth step of reaction, the equivalent ratio of the 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline 6, the amino protecting reagent and the organic base is 1:1-1.5: 1.1-1.6.
The isolated yield of this step is typically between 83-95%.
The fifth step: (E) synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ e ] [1,4] oxazepine (1) and (E) 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine (2)
The 2- [ (3-phenyl-2-alkynyloxy) methyl ] -PG aniline 7, tetrabutylammonium iodide or tetrabutylammonium bromide, cuprous bromide or cuprous bromide-dimethylsulfide and cesium carbonate are subjected to ring closure to generate corresponding intermediate products of N-PG- (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine 8 and N-PG-2-benzyl-1, 5-dihydrobenzo [ E ] [1,4] oxazepine 9, followed by deprotection to give (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine 1 and 2-benzyl-1, 5-dihydrobenzo [ E ] [1,4] oxazepine 2. Wherein the reaction temperature is selected from 80 ℃ to 110 ℃, and the selected solvent is ethylene glycol dimethyl ether, acetonitrile and 1, 4-dioxane.
Further, in the above technical scheme, in the fifth step of the reaction, the two reaction conditions are that under an alkaline condition, the target product is obtained by first ring closure with tetrabutylammonium iodide or tetrabutylammonium bromide, cuprous bromide or cuprous-dimethyl sulfide bromide, and cesium carbonate, subsequent deprotection of acetyl (Ac) or benzoyl (Bz) by a sodium hydroxide or potassium hydroxide/methanol water system, and deprotection of p-toluenesulfonyl (Ts) by sodium/naphthalene.
Furthermore, in the above technical scheme, in the fifth step, the molar ratio of 2- [ (3-phenyl-2-alkynyloxy) methyl ] -PG aniline 7 to n-Bu4NI, cuprous bromide and cesium carbonate is 1:1.1-1.3:0.35-0.4: 1.1-1.5. during the ring closing reaction, almost no product can be detected by using inorganic bases K2CO3, Na2CO3, L i2CO3 and organic bases such as DBU and DBN, and the new point of T L C is estimated not to exceed 5% after refluxing overnight.
Furthermore, in the technical scheme, the products obtained in the fifth step can be obviously distinguished on T L C, and after column chromatography, the (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine 1 and 2-benzyl-1, 5-dihydrobenzo [ E ] [1,4] oxazepine 2 can be easily separated out, and the ratio of 1 to 2 is 1-3:1 after different protecting groups react with the final product.
Further, in the technical scheme, during the column chromatography of the product in the fifth step, the volume ratio of the elution solvent of the mixed system of the petroleum ether and the ethyl acetate used as the eluent is gradually increased from 15:1 to 3:1.
In the step, the separation yield of two continuous reactions is usually between 55 and 73 percent, and the ring closing reaction is supposed to be carried out by an alkene linking process under an alkaline condition and then ring closing, and after different alkali optimization, the optimal combination of CuBr or CuBr-Me2S, n-Bu4NI or n-Bu4NBr and Cs2CO3 systems is found after optimization screening is carried out on common alkaline reagents (inorganic alkali K2CO3, KHCO3, Na2CO3, NaHCO3, L i2CO3, Cs2CO3, organic alkali DBU, DBN and TMG), additives (such as KI, n-Bu4NI and n-Bu4NBr) and copper salt catalysts (CuBr, CuI, CuCl and CuBr-Me 2S).
The reaction equation of the two-step and four-step route is as follows:
in the reaction route, o-nitrobenzyl alcohol 3 or o-nitrobenzyl bromide 10 firstly reacts with phenyl alkynol 11 to obtain 12, and then the reaction product is reduced by iron powder/acetic acid or NiCl2 (dppp)/tetrahydroxy diboron/organic base to obtain 6. The other reaction steps are the same as in route one.
The first step is as follows: synthesis of 2- (phenylpropargyloxymethyl) nitrobenzene (12)
The first method is to prepare 2- (phenylpropargyloxymethyl) nitrobenzene 12 by etherifying o-nitrobenzyl alcohol 3, phenyl propiolic alcohol 10, triphenylphosphine and azodicarbonic diester (Mitsunobo reaction) under anhydrous and anaerobic conditions. The solvent is selected from dichloromethane, toluene or tetrahydrofuran, wherein the reaction temperature is selected from 20 ℃ to 25 ℃. The reaction separation yield of the method is over 86 percent.
And secondly, nucleophilic substitution is carried out on o-nitrobenzyl bromide 10 and phenyl propiolic alcohol 11 to obtain the compound 12. During operation, after deprotonation is carried out on phenyl propiolic alcohol 11 and 1-1.1 equivalent of butyl lithium or sodium hydride in a tetrahydrofuran solvent, o-nitrobenzyl bromide 10 is dropwise added into a system to react at the temperature of 40-60 ℃, and the separation yield is 75-80%.
The second step is that: synthesis of 2- (phenylpropargyloxymethyl) -aniline (6)
The raw material 12 is refluxed in an iron powder/acetic acid/ethanol system to obtain 2- (phenylpropargyloxymethyl) -aniline 6.
Wherein, the iron powder is used after being activated, and the adding amount is 2 to 5 equivalents of the raw material 11, and the preferred equivalent is 3.5 to 4 equivalents.
In the second method, the raw material 12 is refluxed and reacted in a NiCl2 (dppp)/tetrahydroxy diboron/organic base/ethanol system to obtain the 2- (propynyloxymethyl) -aniline 6.
Wherein the organic base is selected from triethylamine or diisopropylethylamine; NiCl2(dppp), tetrahydroxy diboron and organic base equivalent ratio of 0.01-0.03:2-3: 2.5-4.
The third step to the fifth step:
the subsequent steps and operating conditions are in line one.
The invention has the beneficial effects that:
the method has the advantages of simple and reasonable synthetic route, easily obtained raw materials and mild reaction conditions, particularly the first step of ether forming reaction, solves the problem of low yield of conventional operation by adopting methyl Grignard reagent or Mitsunobu ether forming reaction, and can simultaneously generate ring external ring closing products and ring internal ring closing products by adopting the ring closing reaction of the bromoiminoketone in the last step, which is obviously different from the six-membered ring compounds.
Detailed Description
The invention is further illustrated by the following specific examples.
These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
The experimental method of the present invention, in which specific conditions are not specified in the following examples, is generally performed under conventional conditions and under a nitrogen atmosphere.
The starting materials or reagents used in the following examples of the present invention are commercially available unless otherwise specified.
The room temperature averages 20-25 ℃ are described in the following examples of the invention unless otherwise indicated, the reagents are not specifically indicated and are used without purification, all solvents are commercially available and can be used without treatment.
Example 1
The first step is as follows: synthesis of 1-nitro-2- (propynyloxymethyl) -benzene 4.
Method one, adding o-nitrobenzyl alcohol 3(15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) into 110M L anhydrous THF, stirring uniformly, cooling the system to 0 ℃, adding 60% NaH (4.8g,0.12mol) in portions, keeping the temperature at-20 ℃ to-10 ℃, slowly raising the temperature to room temperature, stirring for 4-5 hours, pouring into 200g of water after detecting the disappearance of the raw materials by T L C, extracting MTBE100M L three times, combining organic phases, washing with saturated sodium bicarbonate water, washing with saturated saline water, concentrating the organic phase, and carrying out column chromatography separation by adopting n-heptane/ethyl acetate 10:1 to 6:1 to obtain 6.3g of light yellow oily liquid 4, 33%. 1HNMR (400MHz, CDCl3):7.78(dd,1H),7.54-7.58(M,2H),7.50(d,1H), 7.06%, 1H (M,2H), 2H, 79(M, 2H), 2H, 2H, and m.79).
Method II, mixing o-nitrobenzyl alcohol 3(15.3g, 0.1mol) and 85m L anhydrous THF, then cooling the system to 0 ℃, adding 60% NaH (4.8g,0.12mol) in batches, stirring for 30 minutes under heat preservation after adding, beginning to dropwise add the mixed solution of propargyl bromide (14.3g, 0.12mol) and 30m L anhydrous THF, keeping the temperature not more than 0 ℃ during dropwise adding, then slowly raising to room temperature, stirring and reacting for 3-5 hours, pouring into 200g of water after detecting the disappearance of raw materials by T L C, extracting for three times by 100m L MTBE, combining organic phases, washing with saturated sodium bicarbonate water, washing with saturated saline water, concentrating the organic phase, and separating by adopting n-heptane/ethyl acetate 10: 1-6: 1 to obtain 4.8g yellow oily liquid 4 with the yield of 25%.
Adding o-nitrobenzyl alcohol 3(15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) into 110M L anhydrous THF, uniformly stirring, reducing the system temperature to-10 ℃, dropwise adding 3M methyl magnesium chloride tetrahydrofuran solution (0.12mol), keeping the temperature for reaction for 1 hour when the dropwise adding process is not more than 0 ℃, slowly raising the temperature to room temperature, stirring for reaction for 4-5 hours, pouring into 200g of water after detecting that the raw materials disappear by T L C, extracting MTBE100M L for three times, combining organic phases, washing with saturated sodium bicarbonate water, washing with saturated salt water, concentrating the organic phases, and performing column chromatography separation by adopting n-heptane/ethyl acetate 10: 1-6: 1 to obtain 13.0g of yellow oily liquid 4 with the yield of 68%.
The same operation as in the third method was followed using 1M methylmagnesium bromide in tetrahydrofuran, with an isolated yield of 70%.
Adding 15.3g of o-nitrobenzyl alcohol (0.1 mol), 6.1g of propargyl alcohol (0.11 mol) and 31.4g of triphenylphosphine (31.12 mol) into 180m L dichloromethane, stirring to completely dissolve, dropwise adding a mixed solution containing diethyl azodicarboxylate (20.9g,1.2eq) and 50m L dichloromethane at room temperature, continuously stirring at room temperature overnight after dropwise adding, detecting that the raw material disappears by T L C, cooling the system to-40 ℃, standing, filtering out a complex solid by-product, concentrating the filtrate, and eluting by column chromatography to obtain 17.6g of yellow oily liquid 4 with the yield of 92%.
Example 2
The second step is that: synthesis of 2- (propynyloxymethyl) -aniline 5
The method I comprises the steps of adding 1-nitro-2- (propynyloxymethyl) -benzene 4(19.1g,0.1mol) and reduced iron powder (4.5eq) into 220M L ethanol under mechanical stirring, then dropwise adding an acetic acid solution (2.5eq) at a controlled temperature of 55-65 ℃, heating to reflux reaction for 3 hours after dropwise adding, detecting that raw materials are basically disappeared by T L C, cooling to 50 ℃, filtering by diatomite, leaching a filter cake by ethanol, concentrating a filtrate under reduced pressure to dryness, adding dichloromethane 120M L, adjusting the pH of a water layer to 9-10 by using a saturated sodium carbonate aqueous solution, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and carrying out column chromatography by using n-heptane/ethyl acetate 10: 1-6: 1 to obtain a yellow oily liquid of 16.9g, 88%. 1HNMR (400MHz, CDCl3):7.44(s,2H),7.10-7.13(M,1H),6.91-6.93(M, 6H), 6.6H 6.7.7, 5H + 1, 5H, 5M, 3H, 5M, 5H, 2H, 5H, 2H.
Method II, adding 1-nitro-2- (propynyloxymethyl) -benzene 4(19.1g,0.1mol), triethylamine (3eq) and NiCl2(dppp) (0.02eq) into 220M L ethanol under mechanical stirring, controlling the temperature to 40-45 ℃, adding tetrahydroxy diboron solid (2.5eq) in 5-8 batches, stirring for 20 minutes after each batch is added, then adding the next batch, heating to reflux for 3 hours after the dropwise addition is finished, detecting the material point to disappear by T L C, cooling to room temperature, filtering by diatomite, leaching filter cakes by ethanol, concentrating the filtrate under reduced pressure to be dry, adding dichloromethane 120M L, adjusting the pH of a water layer by 5% sodium bicarbonate aqueous solution to 9-10, washing by saturated sodium chloride, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, performing column chromatography by using n-heptane/ethyl acetate 10: 1-6: 1 to 6:1, obtaining yellow oily liquid 14.6g, yield 91%. 1 MHz (400, Cl 57), 7.7H (7.7), 7.6H 2H (7.7.7.7M, 1H 2H 3-6H (1H), 7H 3H, 3H, 3M, 3H, 7H 3H, 7H 3H, 7H 3H, 7H, 3H.
Example 3
The third step: synthesis of 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline 6
Iodobenzene (10.7g,1.05eq), cuprous iodide (0.5g,5 mol%) and bis (triphenyl) palladium dichloride (0.86g,2.5 mol%) were added to 100M L triethylamine, a mixed solution containing 2- (propynyloxymethyl) -aniline 5(8g,0.05mol) and 18M L triethylamine was added dropwise at room temperature, the solution gradually became clear during the addition, and then reacted overnight at room temperature, and the system was salted out and gradually became a suspension solution, the ratio of the product to the raw materials was determined to be more than 80:1 at HP L C, triethylamine was removed by concentration under reduced pressure, 80M L dichloromethane was added for extraction, saturated ammonia water was washed, saturated brine was washed, anhydrous magnesium sulfate was dried, and after rotary evaporation by filtration, separation was performed using n-heptane/ethyl acetate 15:1 to 6:1 to obtain 11.7g, yield 98%. 1HNMR (400MHz, cl3):7.42 (cds, 2H),7.38 to 7.42(M,4H), column chromatography was performed 7.22.25 to 7.5H 238.16H, 7.5M 2H, M3M 238.16H, M3H 2H 1, M.
Adding o-nitrobenzyl alcohol 3(15.3g, 0.1mol), phenyl propargyl alcohol 11(13.5g, 0.102mol) and triphenyl phosphorus (31.4g,0.12mol) into 200M L dichloromethane, stirring to completely dissolve, then dropwise adding a mixed solution containing diethyl azodicarboxylate (20.9g,1.2eq) and 50M L dichloromethane at room temperature, continuously stirring overnight at room temperature, detecting the disappearance of the raw material by T L C, cooling the system to-40 ℃, standing, filtering out a complex solid by-product, concentrating the filtrate, directly adding into 250M L ethanol and 3.5eq reduced iron powder, dropwise adding an acetic acid solution (2.5eq) at 55-65 ℃, heating to reflux reaction for 3 hours, detecting the disappearance of the raw material by T L C, cooling to 50 ℃, filtering with diatomite, leaching the filter cake with ethanol, concentrating to dryness under reduced pressure, adding dichloromethane 150M 2, adjusting the pH of the water layer to 9-10 MHz with saturated aqueous solution, filtering with saturated sodium chloride, drying with saturated sodium chloride (1.42H, 10H) and separating the filtrate with sodium chloride (1.7H, 2H 42H, 2H 7H 42M < 7H 10, H7H.
Deprotonation is carried out on 1.0 equivalent of sodium hydride or 1.0 equivalent of butyl lithium and phenyl propiolic alcohol at-10 ℃ to 0 ℃, then the deprotonation is carried out on the deprotonated sodium hydride or the butyl lithium and 0.95 equivalent of o-nitrobenzyl bromide at room temperature, then 3.5eq of iron powder/2.5 eq of acetic acid/ethanol are reduced under the reflux condition, and the separation yield of two steps is 63 percent and 67 percent respectively.
Example 4
The fourth step: synthesis of 2- [ (3-phenyl-2-alkynyloxy) methyl ] -PG aniline 7
7a, PG ═ Ac ═ 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline 6(8.8g,37mmol), 13M L pyridine, 0.3g DMAP and 65M L dichloromethane are mixed and then completely dissolved under stirring, the temperature is reduced to 0 ℃, the temperature is controlled to 0 ℃ and a mixed solution of acetic anhydride (4.2g,1.1eq) and 20M L dichloromethane is added dropwise, after the dropwise addition, the mixture is kept at a constant temperature and stirred for 1H, then the mixture is naturally raised to room temperature to react for 4H, T L C detects the end of the reaction, and the mixture is washed by 5% hydrochloric acid, washed by a saturated sodium bicarbonate solution, washed by a saturated common salt solution, dried by anhydrous sodium sulfate, filtered and evaporated, and then separated by n-heptane/ethyl acetate 10:1 to 5:1 column chromatography to obtain a light yellow solid, 9.8.8 g, 96% yield 1HNMR (400MHz, CDCl3):8.38(d,1H),7.82(s,1H), 7.40-7.44.7.7H, 3.3H, 7.3.3.3H + 7.08, 7.2H, 7.3H, 7.06, 7.2M + 7.3H, 7.3H, 3H, 7.2H, 7.06, 7.2H, 7.3.
PG ═ Bz: by adopting the same method, benzoyl chloride replaces acetic anhydride to react, and the obtained product is a light yellow solid after treatment, and the yield is 91%. 1HNMR (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); 342.16(M + H).
7C, mixing PG (Ts) with 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline 6(8.8g,37mmol), triethylamine (2eq), 0.3g of DMAP and 65M L dichloromethane, and then completely dissolving under stirring, reducing the temperature to 0 ℃, controlling the temperature to 0 ℃ and dropwise adding a mixed solution of TsCl (7.8g,1.1eq) and 20M L dichloromethane, after dropwise adding, keeping the temperature and stirring for 1H, then naturally raising the temperature to room temperature for reaction for 4H, detecting the end of the reaction by T L C, washing with 5% hydrochloric acid, washing with a saturated sodium bicarbonate solution, washing with saturated common salt water, drying anhydrous sodium sulfate, filtering and evaporating by rotation, and recrystallizing with ethanol and heptane to obtain 13.5g of a light yellow solid, yield 93%, 1HNMR (400MHz, CDCl3), 8.43-8.55(M,2H),7.78-7.88(M,3H),7.21-7.46(M,6H), 7.01-7.01H, 7.06(M, 2H), 3H + 2s), 3H, 2H, 3.06 (M,3H), 2 z).
Example 5
The fifth step: (E) synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ e ] [1,4] oxazepine 1 and 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine 2
7a (9.8g,35mmol), CuBr-Me2S (0.3eq), tetrabutylammonium bromide (1eq), cesium carbonate (11.4g,1eq) and 1, 4-dioxane 250m L were mixed uniformly, then slowly heated to reflux reaction overnight, T L C showed substantial disappearance of the raw material, two new points were generated, the reaction was stopped, diatomaceous earth was filtered, 150m L m dichloromethane and water were added after the organic solvent was spin-dried, the organic phase was then washed with concentrated ammonia water and saturated common salt in sequence, the organic solvent was spin-dried, column chromatography was performed using n-heptane/ethyl acetate 15:1 to 5:1 to obtain 5.2g of the closed-cyclic isomer 8a and 2.1g of the closed-cyclic isomer 9b, then each product was added with 30% sodium hydroxide 5eq and 6 times volume of methanol to reflux reaction for 6 hours, T L C detected disappearance of the raw material, the reaction was terminated, methanol was concentrated to remove methanol, the pH was adjusted to 5% aqueous solution under reduced pressure, the aqueous solution was added to pH 3-2.1 g, the aqueous solution was then the aqueous solution was extracted to obtain a pale yellow solid, the compound, the pale yellow solid was determined to be a pale yellow compound, the solid was determined to be a pale yellow compound by column chromatography after column chromatography was dried, the yield was determined to be 1.1: 1, the yield was determined to be 7.1, the yield was then washed with sodium carbonate to be10, the yellow solid to be 10.
In the same manner, using 7b as the starting material, the isolation yields of compounds 1 and 2 were 41% and 32%, respectively.
(E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ e ]][1,4]The content of the oxazepine 1 is shown in the specification,1HNMR(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)；13CNMR(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][1,4]Oxazepine 2, 1HNMR (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);13CNMR(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)。
7C (13.5g,35mmol), CuI (0.3eq), tetrabutylammonium bromide (1eq), cesium carbonate (11.4g,1eq) and 1, 4-dioxane 250m L are uniformly mixed, then the mixture is slowly heated to reflux reaction overnight, T L C shows that the raw material basically disappears, two new points are generated, the reaction is stopped, diatomite is filtered, 150m L dichloromethane and water are added for liquid separation after the organic solvent is dried, the organic phase is sequentially washed by concentrated ammonia water and saturated common salt, the organic solvent is dried, sodium water and sodium chloride are adopted for column chromatography separation by n-heptane/ethyl acetate 15:1 to 5:1 to obtain 5.6g of closed-ring isomer 8C and 5.1g of closed-ring isomer 9C, then the respective products are added into a naphthalene solution, 4eq sodium metal is adopted for reaction, the reaction temperature is controlled to be 50-90 ℃, the reaction is carried out for 4 hours, the raw material disappearance is detected by T L C, the sodium water is slowly added with methanol for quenching, the reaction is concentrated under reduced pressure to remove methanol, the pH value is adjusted to be 2%, the pH value is adjusted to be 3, the mixture is added into a yellowish solid, the mixture is separated by sodium bicarbonate solution, the organic phase is determined by column chromatography yield is determined by sodium bicarbonate solution, the sodium bicarbonate solution is determined, the sodium carbonate solution is determined by sodium carbonate solution, the sodium carbonate solution is determined, the yellow solid is determined by sodium carbonate solution, the yellow solid yield is determined.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (7)
1. A method for synthesizing (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine in multiple steps is characterized in that the reaction equation is as follows:
the method comprises the following steps: 1) o-nitrobenzyl alcohol 3, propargyl alcohol, triphenyl phosphorus and azodicarboxylate are etherified under anhydrous and oxygen-free conditions to obtain a compound 4; the solvent is dichloromethane or toluene, wherein the reaction temperature is 20-25 deg.CDEG C; the molar ratio of the o-nitrobenzyl alcohol 3 to the propargyl alcohol is 1: 1.2-1.3; the mol ratio of the o-nitrobenzyl alcohol, the triphenyl phosphine and the azodicarboxylate is selected from 1:1-2: 1-2; meanwhile, the triphenyl phosphine and the azodicarbonic acid ester are in equal molar ratio; the azodicarboxylate is selected from ethyl azodicarboxylate or isopropyl azodicarboxylate; 2) the compound 4 adopts NiCl2(dppp)/tetrahydroxydiboron/organic base reduction to give compound 5; the organic base is selected from triethylamine or diisopropylethylamine and NiCl2(dppp) the equivalent ratio of tetrahydroxydiboron to organic base is 0.01-0.03:2-3: 2.5-4; 3) the compound 5 is coupled with iodobenzene under the catalysis of bis (triphenylphosphine) palladium chloride and cuprous iodide to obtain a compound 6; 4) introducing benzoyl protection into the compound 6 to obtain a compound 7; 5) the compound 7 is subjected to ring closing under the conditions of cuprous salt, tetrabutylammonium halide and cesium carbonate, and deprotection under the alkaline condition to obtain (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E][1,4]Oxazepine 1.
2. The multistep synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] according to claim 1][1,4]A method of oxazepine characterized by: in the third reaction step, compound 5 is reacted with Pd (PPh)3)2Cl2The molar ratio of iodobenzene to iodoidene is 1:0.025-0.03:1.05-1.2: 0.05-0.08.
3. A process for the multistep synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine according to claim 1 characterized in that: in the fourth step of reaction, introducing benzoyl and reacting the benzoyl chloride under the condition of organic alkali; the organic base is selected from pyridine or triethylamine.
4. A process for the multistep synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine according to claim 3 characterized in that: in the fourth step of reaction, the equivalent ratio of the compound 6, the benzoyl chloride and the organic base is 1:1-1.5: 1.1-1.6.
5. A process for the multistep synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine according to claim 1 characterized in that: in the fifth step, the tetrabutylammonium halide is selected from tetrabutylammonium iodide or tetrabutylammonium bromide, and the cuprous salt is selected from cuprous bromide or cuprous bromide-dimethyl sulfide.
6. A process for the multistep synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine according to claim 1 characterized in that: in the fifth step of reaction, the molar ratio of the compound 7 to tetrabutylammonium halide, cuprous salt and cesium carbonate is 1:1.1-1.3:0.35-0.4: 1.1-1.5.
7. A process for the multistep synthesis of (E) -2-benzylidene-1, 2,3, 5-tetrahydrobenzo [ E ] [1,4] oxazepine according to claim 1 characterized in that: in the fifth step, alkaline deprotection is selected from sodium hydroxide or potassium hydroxide methanol water solution.
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| AgNO3 Catalyzed Regio-Selective Synthesis of 3-Alkyl/Aryl-idene 3,4-dihydro-4-tosyl-2H-1,4-Benzoxazine: Novel Anti-Tubercular Scaffolds;Sivanandhan Karunanidhi et al.;《J. Heterocyclic Chem.》;20150828;第53卷;第1611-1616页，SI1-7 * |
| Gold(I)-Catalyzed Rearrangement of Propargyl Benzyl Ethers: A Practical Method for the Generation and in Situ Transformation of Substituted Allenes;Benoit Bolte et al.;《J. AM. CHEM. SOC.》;20100705;第132卷;S1-7 * |
| Synthesis and Cytotoxicity Studies of Novel Triazolo- Benzoxazepine as New Anticancer Agents;Biswadip Banerji et al.;《Chem Biol Drug Des》;20130503;第82卷;第401-409页 * |
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