CN108546253B - Method for multi-step synthesis of 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine - Google Patents
Method for multi-step synthesis of 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 2-benzyl-1, 5-dihydrobenzo [ 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 acetyl protection on amino, carrying out ring closure by cuprous bromide/cesium carbonate, and then carrying out deprotection under an alkaline condition to obtain 2-benzyl-1, 5-dihydrobenzo [ 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 the intermediate product after partial reduction can be detected in the TLC detection reaction process. In both cases, the second method is preferred from the viewpoint of waste solids disposal.
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 technical scheme, in the fifth step, the molar ratio of the 2- [ (3-phenyl-2-alkynyloxy) methyl ] -PG aniline 7 to the n-Bu4NI, the cuprous bromide and the 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 when inorganic bases such as K2CO3, Na2CO3, Li2CO3, DBU, DBN and the like are used, and after refluxing overnight, a new point observed by TLC is estimated to be not more than 5%.
Furthermore, in the technical scheme, the products obtained in the fifth step can be obviously distinguished on TLC, and (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 after column chromatography. The final product, after reaction for different protecting groups, has a ratio of both 1 and 2 of 1-3: 1.
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.
The separation yield of two continuous reactions in the step is usually between 55 and 73 percent, and the ring closing reaction is supposed to be carried out by an allene linking process under alkaline conditions and then ring closing. Through different alkali optimization, after common alkaline reagents (inorganic alkali K2CO3, KHCO3, Na2CO3, NaHCO3, Li2CO3 and Cs2CO 3; organic alkali DBU, DBN and TMG), additives (such as KI, n-Bu4NI and n-Bu4NBr) and copper salt catalysts (CuBr, CuI, CuCl and CuBr-Me2S) are subjected to optimization screening, the optimal combination is found to be CuBr or CuBr-Me2S, n-Bu4NI or n-Bu4NBr and Cs2CO3 systems.
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 average room temperature described in the following examples of the invention is 20-25 ℃. Unless otherwise indicated, the reagents are not specifically indicated and are all used without purification. All solvents were purchased from commercial suppliers and used without treatment. The reaction process was mainly detected by TLC, the structure was identified by HNMR, and the termination of the reaction was judged by the consumption of starting material.
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 110mL of anhydrous THF, stirring uniformly, cooling the system temperature to 0 ℃, adding 60% NaH (4.8g,0.12mol) in batches, keeping the temperature at-20 ℃ to-10 ℃, slowly raising the temperature to room temperature, stirring and reacting for 4-5 hours after adding, pouring into 200g of water after TLC detection of disappearance of raw materials, extracting MTBE100mL 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 to 6:1 to obtain 6.3g of light yellow oily liquid 4 with the yield of 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); 192.11(M + H).
Method II, mixing o-nitrobenzyl alcohol 3(15.3g, 0.1mol) and 85mL of 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 the addition is finished, beginning to dropwise add propargyl bromide (14.3g, 0.12mol) and 30mL of anhydrous THF mixed solution, keeping the temperature not to exceed 0 ℃ during dropwise adding, then slowly raising to room temperature, stirring for reaction for 3-5 hours, pouring into 200g of water after TLC detection raw materials disappear, extracting 100mL of MTBE for three times, combining organic phases, washing with saturated sodium bicarbonate water, washing with saturated saline water, concentrating the organic phase, and performing column chromatography separation by adopting n-heptane/ethyl acetate 10: 1-6: 1 to obtain 4.8g of yellow oily liquid with the yield of 25%.
Adding o-nitrobenzyl alcohol 3(15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) into 110mL of anhydrous THF, uniformly stirring, reducing the system temperature to-10 ℃, dropwise adding a 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 TLC detection of raw materials disappears, extracting MTBE100mL 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 oily yellow 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), propargyl alcohol (6.1g, 0.11mol) and triphenylphosphine (31.4g,0.12mol) into 180mL of dichloromethane, stirring to be completely dissolved, then dropwise adding a mixed solution containing diethyl azodicarboxylate (20.9g,1.2eq) and 50mL of dichloromethane at room temperature, continuing stirring at room temperature overnight after dropwise adding, detecting by TLC that the raw materials disappear, cooling the system to-40 ℃, standing, filtering out a complex solid byproduct, concentrating the filtrate, and carrying out column chromatography elution 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 first method is that 1-nitro-2- (propynyloxymethyl) -benzene 4(19.1g,0.1mol) and reduced iron powder (4.5eq) are added into 220mL ethanol under mechanical stirring, acetic acid solution (2.5eq) is added dropwise at 55-65 ℃, the temperature is controlled to be 55-65 ℃, the temperature is raised to reflux reaction for 3 hours after the dropwise addition is finished, TLC detection is carried out to ensure that raw materials basically disappear, the temperature is reduced to 50 ℃, diatomite is filtered, a filter cake is leached by ethanol, filtrate is concentrated to be dry under reduced pressure, 120mL of dichloromethane is added, a water layer is adjusted to have a pH value of 9-10 by saturated sodium carbonate aqueous solution, saturated sodium chloride is washed, anhydrous sodium sulfate is dried, filtration and concentration under reduced pressure are carried out, column chromatography separation is carried out by adopting n-heptane/ethyl acetate 10: 1-6: 1, and yellow oily liquid is obtained. 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); 162.20(M + H).
Method II, adding 1-nitro-2- (propynyloxymethyl) -benzene 4(19.1g,0.1mol), triethylamine (3eq) and NiCl2(dppp) (0.02eq) into 220mL of ethanol under mechanical stirring, controlling the temperature to 40-45 ℃, adding tetrahydroxy diboron solid (2.5eq) into 5-8 batches, stirring for 20 minutes after each batch is added, then adding the next batch, heating to reflux reaction for 3 hours after the dropwise addition is finished, detecting the disappearance of a raw material point by TLC, cooling to room temperature, filtering by using kieselguhr, leaching a filter cake by using ethanol, concentrating a filtrate under reduced pressure to be dry, adding 120mL of dichloromethane, adjusting the pH of an aqueous layer to 9-10 by using a 5% sodium bicarbonate aqueous solution, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure, performing column chromatography by using n-heptane/ethyl acetate 10: 1-6: 1, 14.6g of a yellow oily liquid was obtained in a yield of 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); 162.20(M + H).
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 100mL of triethylamine, a mixed solution containing 2- (propynyloxymethyl) -aniline 5(8g,0.05mol) and 18mL of triethylamine was added dropwise at room temperature, and during the dropwise addition, the solution gradually became clear, and then reacted overnight at room temperature, and the system was separated with salt and gradually became a suspension solution. HPLC (high performance liquid chromatography) detection shows that the ratio of the product to the raw material is more than 80:1, triethylamine is removed through concentration under reduced pressure, 80mL of dichloromethane is added for extraction, saturated ammonia water is used for washing, saturated salt water is used for washing, anhydrous magnesium sulfate is used for drying, filtration and rotary evaporation are carried out, column chromatography separation is carried out by adopting n-heptane/ethyl acetate 15: 1-6: 1, 11.7g of yellow oily liquid is obtained, and the yield is 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); 238.16(M + H).
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 200mL of dichloromethane, stirring to be completely dissolved, then beginning to dropwise add a mixed solution containing diethyl azodicarboxylate (20.9g,1.2eq) and 50mL of dichloromethane at room temperature, continuing to stir at room temperature overnight after dropwise addition, detecting that the raw material disappears by TLC, cooling the system to-40 ℃, standing, filtering out a complex solid byproduct, concentrating the filtrate, directly adding into 250mL of ethanol and 3.5eq reduced iron powder, controlling the temperature to 55-65 ℃, dropwise adding an acetic acid solution (2.5eq), heating to reflux reaction for 3 hours after dropwise addition, detecting that the raw material basically disappears by TLC, cooling to 50 ℃, filtering by diatomite, leaching the filter cake by ethanol, concentrating the filtrate under reduced pressure to be dry, adding 150mL of dichloromethane, adjusting the pH of the water layer to 9-10 by using a saturated aqueous solution, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography using n-heptane/ethyl acetate 10:1 to 6:1 to give 19.2g of a yellow oily liquid with a yield of 81% in two steps. 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); 238.16(M + H).
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
PG ═ Ac: 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline 6(8.8g,37mmol), 13mL of pyridine, 0.3g of DMAP and 65mL of dichloromethane were mixed and then completely dissolved with stirring. The temperature is reduced to 0 ℃, the mixed solution of acetic anhydride (4.2g,1.1eq) and 20mL of dichloromethane is dripped at the temperature of 0-5 ℃, and after the dripping is finished, the mixture is kept warm and stirred for 1 h. The reaction was then allowed to warm to room temperature for 4 hours and the reaction was complete by TLC. Washing with 5% hydrochloric acid, washing with saturated sodium bicarbonate solution, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, rotary-steaming, and separating by column chromatography with n-heptane/ethyl acetate 10:1 to 5:1 to obtain light yellow solid 9.8g with 96% yield. 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); 280.11(M + H).
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%. 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); 342.16(M + H).
PG ═ Ts: 2- [ (3-phenyl-2-alkynyloxy) methyl ] -aniline 6(8.8g,37mmol), triethylamine (2eq), 0.3g DMAP and 65mL of dichloromethane were mixed and then dissolved completely with stirring. The temperature is reduced to 0 ℃, the mixed solution of TsCl (7.8g,1.1eq) and 20mL of dichloromethane is dripped at the temperature of 0-5 ℃, and the mixture is kept warm and stirred for 1h after the dripping is finished. The reaction was then allowed to warm to room temperature for 4 hours and the reaction was complete by TLC. Washing with 5% hydrochloric acid, washing with a saturated sodium bicarbonate solution, washing with a saturated common salt solution, drying with anhydrous sodium sulfate, filtering, rotary-steaming, and recrystallizing with ethanol and heptane to obtain light yellow solid 13.5g with a yield of 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); 392.20(M + H).
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 250mL of 1, 4-dioxane were mixed well. And then slowly heating to reflux reaction overnight, TLC shows that the raw materials basically disappear to generate two new points with the ratio of 2:1, stopping the reaction, filtering by using kieselguhr, spinning off the organic solvent, adding 150mL of dichloromethane and aqueous solution, washing the organic phase by using concentrated ammonia water and saturated salt in sequence, spinning off the organic solvent, and performing column chromatography separation by using n-heptane/ethyl acetate 15:1 to 5:1 to obtain 5.2g of the closed-loop isomer 8a and 2.1g of the closed-loop isomer 9 b. Subsequently, 5eq of 30% sodium hydroxide and 6 times the volume of methanol were added to each product, and the mixture was heated to reflux deprotection reaction for 6 hours, TLC detected the disappearance of the raw material, the reaction was terminated, methanol was removed by concentration under reduced pressure, 5% hydrochloric acid solution was added to adjust pH 2-3, dichloromethane was extracted twice, the organic layer was adjusted pH 8-9 with 5% sodium bicarbonate aqueous solution, washed with saturated common salt water, dried over anhydrous sodium sulfate, and each was separated by column chromatography using n-heptane/ethyl acetate 10:1 to 3:1 to give 3.7g of pale yellow liquid, which was structurally identified as compound 1, yield 45% and 1.6g of pale yellow solid, which was structurally identified as compound 2, yield 19%.
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,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][1,4]Oxazepine 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)。
7c (13.5g,35mmol), CuI (0.3eq), tetrabutylammonium bromide (1eq), cesium carbonate (11.4g,1eq) and 250mL of 1, 4-dioxane were mixed well. And then slowly heating to reflux reaction overnight, TLC shows that the raw materials basically disappear to generate two new points with the ratio of about 1:1, stopping the reaction, filtering by using kieselguhr, spinning off the organic solvent, adding 150mL of dichloromethane and aqueous solution, washing the organic phase by using concentrated ammonia water and saturated salt in sequence, spinning off the organic solvent, and performing column chromatography by using n-heptane/ethyl acetate 15:1 to 5:1 to obtain 5.6g of the closed-loop isomer 8c and 5.1g of the closed-loop isomer 9 c. Then, adding the respective products into a naphthalene solution, carrying out deprotection reaction by using 4eq of metal sodium, controlling the reaction temperature to be 50-90 ℃, reacting for 4 hours, detecting the disappearance of raw materials by TLC, cooling to 0 ℃, slowly dropwise adding methanol for quenching, carrying out concentration under reduced pressure to remove the methanol, adding a 5% hydrochloric acid solution for adjusting the pH to be 2-3, extracting with dichloromethane twice, adjusting the pH of an organic layer to be 8-9 by using a 5% sodium bicarbonate aqueous solution, washing with saturated salt water, drying by using anhydrous sodium sulfate, carrying out column chromatography separation by using n-heptane/ethyl acetate 10:1 to 3:1 to obtain 3.6g of light yellow liquid respectively, determining the organic layer to be a compound 1 through a structure, obtaining a yield of 44% and 3.1g of light yellow solid through a structure determination of a compound 2, and.
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 (8)
1. A method for synthesizing 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine in multiple steps is characterized in that the reaction equation is as follows:
the method comprises the following steps: 1) carrying out exchange reaction on the o-nitrobenzyl alcohol 3 and the propargyl bromide by adopting a methyl Grignard reagent to obtain an ether so as to obtain a compound 4; 2) the compound 4 adopts iron powder/acetic acid or NiCl2(dppp)/tetrahydroxydiboron/organic base reduction to give compound 5; 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) the compound 6 is protected by introducing acetyl to obtain a compound7; 5) the compound 7 is subjected to ring closure under the conditions of cuprous salt, tetrabutylammonium halide and cesium carbonate to obtain 9, and deprotection under alkaline conditions is carried out to obtain 2-benzyl-1, 5-dihydrobenzo [ e][1,4]Oxazepine 2; wherein, in the step 5), 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; the mol 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.
2. A process for the multistep synthesis of 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine according to claim 1, characterized in that: in the first step of reaction, the molar ratio of the o-nitrobenzyl alcohol 3 to the propargyl bromide is 1: 1.5-1.6.
3. The multistep synthesis of 2-benzyl-1, 5-dihydrobenzo [ e ] according to claim 1][1,4]A method of oxazepine characterized by: in the second step, the iron powder is used after being activated, and the adding amount is 2-5 equivalent of the raw material 4; the organic base is selected from triethylamine or diisopropylethylamine; NiCl2(dppp) and the equivalent ratio of tetrahydroxydiboron to organic base is 0.01-0.03:2-3: 2.5-4.
4. The multistep synthesis of 2-benzyl-1, 5-dihydrobenzo [ e ] according to claim 1][1,4]A method of oxazepine characterized by: in the third step, 2- (propynyloxymethyl) -aniline 5 and Pd (PPh)3)2Cl2The molar ratio of iodobenzene to iodoidene is 1:0.025-0.03:1.05-1.2: 0.05-0.08.
5. A process for the multistep synthesis of 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine according to claim 1, characterized in that: in the fourth step of reaction, acetyl is introduced and reacts with acetyl chloride or acetic anhydride under the condition of organic alkali; the organic base is selected from pyridine or triethylamine.
6. The multistep synthesis of 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine according to claim 5, characterized in that: in the fourth step of reaction, the equivalent ratio of the compound 6, the acetylation reagent and the organic base is 1:1-1.5: 1.1-1.6.
7. A process for the multistep synthesis of 2-benzyl-1, 5-dihydrobenzo [ 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.
8. The process for the multistep synthesis of 2-benzyl-1, 5-dihydrobenzo [ e ] [1,4] oxazepine according to claim 1, characterized in that: wherein, the substitution synthesis method of the compound 6 is as follows:
o-nitrobenzyl alcohol 3 and phenylalkynyl alcohol 11 are reacted by Mitsunobo to obtain a compound 12, or phenylalkynyl alcohol 11 is deprotonated by butyl lithium or sodium hydride and then nucleophilic substituted by o-nitrobenzyl bromide 10 to obtain a compound 12, and then the compound 12 is treated by iron powder/acetic acid or NiCl2(dppp)/tetrahydroxydiboron/organic base reduction to give compound 6.
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