CN104262283A - 1,2-oxa-cyclic compound derivative and preparation method thereof - Google Patents

1,2-oxa-cyclic compound derivative and preparation method thereof Download PDF

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CN104262283A
CN104262283A CN201410409341.4A CN201410409341A CN104262283A CN 104262283 A CN104262283 A CN 104262283A CN 201410409341 A CN201410409341 A CN 201410409341A CN 104262283 A CN104262283 A CN 104262283A
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hydroxyl
oxygen
ethanoyl
derivative
preparation
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CN104262283B (en
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赵劲
段平平
严义勇
兰霞
陈波
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Peking University Shenzhen Graduate School
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/04—Seven-membered rings having the hetero atoms in positions 1 and 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

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Abstract

The invention discloses a 1,2-oxa-cyclic compound derivative and a preparation method thereof. A molecular structural general formula of 1,2-oxa-cyclic compound derivative is (I), wherein in the formula, A is (hetero) aromatic ring or non-aromatic ring; R1 is selected from C1-C4 straight-chain alkyl or alkyl with substituent group side chains and alkoxycarbonyl ; R2 and R3 are selected from C1-C4 straight-chain alkyl or alkyl with substituent group side chains, aryl and hydrogen. The preparation method of the 1,2-oxa-cyclic compound derivative comprises a step of performing reaction in the presence of rhodium catalyst precursors, silver salts and organic solvents under an oxygen-free environment to obtain the 1,2-oxa-cyclic compound derivative shown in the structural general formula (I) in the specification.

Description

1,2-oxygen azepine cyclics derivative and preparation method thereof
Technical field
The invention belongs to organic compound synthesis technical field, relate to a kind of 1,2-oxygen azepine specifically and cyclics derivative and preparation method thereof.
Background technology
1,2-oxaza compound has biological activity widely.Report the synthesis of the compound of following structural formula a in the eighties, author has also carried out the test of medicine and biological chemistry aspect to this structure simultaneously.Result shows, and under high dosage condition, this compounds exhibit goes out slight anxiolytic property.Therefore the activity of this compound is not high, and anxiolytic property effect is undesirable.
Summary of the invention
The object of the invention is to the above-mentioned deficiency overcoming prior art, provide a kind of 1,2-oxygen azepine and cyclics derivative and preparation method thereof.To overcome existing 1,2-oxygen azepine and cyclics derivative is less, synthetic method is less, and the technical problem that existing 1,2-oxaza compound biological activity is not high.
In order to realize foregoing invention object, technical scheme of the present invention is as follows:
A kind of 1,2-oxygen azepine cyclics derivative, its general formula of molecular structure is following (I):
In described (I) formula, A is (mixing) aromatic nucleus or non-aromatic ring; R 1be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, carbalkoxy; R 2, R 3be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, aryl, hydrogen.
And a kind of 1,2-oxygen azepine the preparation method of cyclics derivative, comprise the steps:
Compd A, B that following structural formula represents are provided respectively,
In oxygen-free environment and under rhodium catalyst precursor and silver salt and organic solvent existent condition, described compd A, B are reacted, obtain following general structure for 1,2-oxygen azepine shown in (I) and cyclics derivative,
Wherein, the A in described compd A, B and (I) structural formula is (mixing) aromatic nucleus or non-aromatic ring; R 1be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, carbalkoxy; R 2, R 3be selected from C 1-C 4straight chain or containing the one in the alkyl of substituting group side chain, aryl, hydrogen.
Above-mentioned 1,2-oxygen azepine cyclics derivative has relatively high biological activity, it has stronger restraining effect to myeloma cell line LP-1 cell.Therefore 1,2-oxygen azepine of the present invention cyclics derivative can be used for preparing anticancer medicine.
Above-mentioned 1,2-oxygen azepine cyclics derivative preparation method technique are simple, require low to equipment and reaction conditions.The yield of target product is high, its easy purifying, and therefore, its production cost is low.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the invention will be further described, in accompanying drawing:
2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-phenyl-1, the 2-benzo oxygen azepine that Fig. 1 provides for the employing embodiment of the present invention 10 tests the state graph of basis of microscopic observation cells survival to the Proliferation Ability of myeloma cell line LP-1 cell and cytotoxicity; Wherein, Fig. 1 a is that solvent control group examines under a microscope cells survival state such as schemed, and Fig. 1 b is that the dosing group containing 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen azepine examines under a microscope cells survival state;
2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-phenyl-1, the 2-benzo oxygen azepine that Fig. 2 embodiment of the present invention 10 provides is to the proliferation activity test pattern of LP-1 cell.
Embodiment
In order to make the technical problem to be solved in the present invention, technical scheme and beneficial effect clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
The embodiment of the present invention provides a kind of 1,2-oxygen azepine and cyclics derivative, and its general formula of molecular structure is following (I):
Wherein, the A in this general formula of molecular structure (I) is (mixing) aromatic nucleus or non-aromatic ring; R 1be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, carbalkoxy; R 2, R 3be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, aryl, hydrogen.
In one embodiment, when above-mentioned A is (mixing) aromatic nucleus, (mixing) aromatic group representated by this A is can be at least any one in following group, wherein, and what (mixing) aromatic nucleus represented is aromatic nucleus and containing heteroatomic aromatic nucleus.
In another specific embodiment, when above-mentioned A is non-aromatic ring, the nonaromatic cyclic group representated by this A is can be at least any one in following group:
wherein, n=0,1, X=O, S, N-PG.PG is the abbreviation of protecting group, namely refers to blocking group, and this concrete PG can be ethanoyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl etc.
In another specific embodiment, above-mentioned, R 1be selected from C 1-C 4straight chain or containing the alkyl of substituting group side chain time, it can be methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, any one in the tertiary butyl; R 1when being selected from carbalkoxy, it can be any one in benzyloxy group, tertiary butyl oxygen groups.
R 2, R 3be selected from C 1-C 4when straight chain or the alkyl containing substituting group side chain, R 2, R 3can be methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, any one in the tertiary butyl.
Therefore, 1,2-oxygen azepine shown in above-mentioned general formula of molecular structure (I) cyclics derivative can be at least following compound:
I:(mixes) fragrance also 1,2-oxaza compounds derivative:
I-a:2-N-ethanoyl-3-hydroxyl-4,5-dihydro-1,2 benzo oxygen azepine;
I-b:2-N-carbobenzoxy-(Cbz)-3-hydroxyl-4,5-dihydro-1,2 benzo oxygen azepine;
I-c:2-N-ethanoyl-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, 2 benzo oxygen azepines;
I-d:2-N-ethanoyl-3-hydroxyl-4,5-dihydro-8-fluoro-1,2 benzo oxygen azepine;
I-e:2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-chloro-1,2 benzo oxygen azepine;
I-f:2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-methyl esters-1,2 benzo oxygen azepine;
I-g:2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7,8-dimethyl-1,2 benzo oxygen azepine;
I-h:2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-ethyl-1,2 benzo oxygen azepine;
I-i:2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-propyl group-1,2 benzo oxygen azepine;
I-j:2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen azepine;
I-k:3-hydroxyl-2-phenol oxygen-4,5-dihydro-1H-benzazepine-1-ketone;
I-m:N-(chroman) ethanamide.
II non-aromatic ring is 1,2-oxaza compounds derivative also:
II-a:2-N-ethanoyl-3-hydroxyl-4,5,7,8,9,9a-hexahydrobenzene is [f] [1,2] oxygen azepine also;
II-b: benzyl-2-ethanoyl-3-hydroxyl-2,3,4,5,9,9a-hexahydropyridine base [4,3-f] [1,2] oxygen azepine-8 (7H)-carboxylic acid.
Certainly, above-mentioned (mixing) fragrance and 1,2-oxaza compounds derivative and non-aromatic ring also 1,2-oxaza compounds derivative are not only only above-mentioned several concrete compound, can also be by A, the R in general formula of molecular structure (I) 1, R 2, R 3represented group connects arbitrarily other formed compounds.
Relatively high biological activity in the various embodiments described above, it has stronger restraining effect to myeloma cell line LP-1 cell.
Correspondingly, the embodiment of the present invention additionally provides above-mentioned 1,2-oxygen azepine and a kind of preparation method of cyclics derivative.The method comprises the steps:
S01: compounds X, Y that following structural formula represents are provided respectively,
S02: with under rhodium catalyst precursor and silver salt and organic solvent existent condition in oxygen-free environment, thing X, the Y of chemical combination in step S01 are reacted, obtain following general structure for 1,2-oxygen azepine shown in (I) and cyclics derivative
A in described compounds X, Y and (I) structural formula is (mixing) aromatic nucleus or non-aromatic ring; R 1be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, carbalkoxy; R 2, R 3be selected from C 1-C 4straight chain or containing the one in the alkyl of substituting group side chain, aryl, hydrogen.
Particularly, in above-mentioned steps S01, in compounds X general structure, A is (mixing) aromatic nucleus or non-aromatic ring; R 1be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, carbalkoxy.
Wherein, as described above, in a preferred embodiment, when A is as (mixing) aromatic nucleus, (mixing) aromatic group representated by this A is can be at least any one in following group:
In another specific embodiment, when above-mentioned A is non-aromatic ring, the nonaromatic cyclic group representated by this A is can be at least any one in following group:
wherein, n=0,1, X=O, S, N-PG.
In another specific embodiment, above-mentioned, R 1be selected from C 1-C 4straight chain or containing the alkyl of substituting group side chain time, it can be methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, any one in the tertiary butyl; R 1when being selected from carbalkoxy, it can be any one in benzyloxy group, tertiary butyl oxygen groups.
In this step S01, R in compound Y general structure 2, R 3be selected from C 1-C 4when straight chain or the alkyl containing substituting group side chain, R 2, R 3can be methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, any one in the tertiary butyl.
In addition, the compounds X in this step S01 can be prepared by existing method, and Y can direct commercial acquisition.
In above-mentioned steps S02, carrying out reacting the general structure generated as described above in reaction environment in step S02 of compounds X, Y and system is (I) compound.
When A group in compounds X is (mixing) aromatic nucleus, compounds X, Y can be expressed as follows a at the chemical equation of reaction system:
When in compounds X, A group is non-aromatic ring, compounds X, Y can be expressed as follows b at the chemical equation of reaction system:
In above-mentioned chemical equation a, chemical equation b reaction system, the oxygen-free environment of reaction system can effectively avoid catalyzer as oxidized in rhodium catalyst precursor or and lost efficacy, thus ensure above-mentioned chemical equation a, the reaction of chemical equation b carries out smoothly, and ensures that target product general structure is the yield of (I) compound.
In above-mentioned chemical equation a, chemical equation b reaction system, before rhodium catalyst, cognition and silver salt react and generate real active catalyst, thus impel reactants of X, Y to carry out reaction generation target product.
In one embodiment, in above-mentioned chemical equation a, chemical equation b reaction system, the mol ratio of rhodium catalyst precursor and compounds X is (0.03-0.1): 1.In a particular embodiment, the mol ratio of rhodium catalyst precursor and compounds X can be 0.03:1,0.04:1,0.05:1,0.06:1,0.07:1,0.08:1,0.09:1 or 0.1:1 etc.
In another embodiment, the mol ratio of rhodium catalyst precursor and silver salt is 1:(2-33).In a particular embodiment, the mol ratio of rhodium catalyst precursor and silver salt can be 1:2,1:5,1:8,1:10,1:15,1:20,1:25,1:30 or 1:33 etc.
In a particular embodiment, this rhodium catalyst precursor can select dichloro (pentamethylcyclopentadiene) rhodium (III) dimer; This silver salt can select silver carbonate, Silver monoacetate, silver hexafluoroantimonate, and tetrafluoride boron silver waits at least one in silver salt.Chlorion in the rhodium catalyst precursor of such preferred kind can be seized by with the silver ions in silver salt, generates real active catalyst, thus effectively impels the reaction between reactants of X, Y, improves the yield of atom utilization and product.
By to the control of the consumptions such as rhodium catalyst precursor, silver salt or adjust its ratio or control the kind of rhodium catalyst precursor and silver salt further, the general structure that can improve target product is further the yield of (I) compound, and reduce as far as possible the reactants such as rhodium catalyst precursor, silver salt consumption, thus the general structure improving productive target product is (I) production of chemicals efficiency, reduce production cost.Meanwhile, this preferred rhodium catalyst precursor above-mentioned, silver salt consumption or the control of ratio both adjustment or selecting of both kinds, the reaction conditions requirement between compounds X, Y can also be reduced, can directly at room temperature carry out as made the temperature of the reaction between this compounds X, Y, thus further to the control of reaction conditions, thus reduce production cost further.
In addition, the compounds X in above-mentioned chemical equation a, chemical equation b reaction system, Y mole with can adding according to the reactant molar ratio example in chemical equation a, chemical equation b.In order to impel this reaction to carry out to forward further, improve speed of reaction and efficiency of pcr product.In one embodiment, the mol ratio of compounds X, Y is 1:(1-3).In a particular embodiment, the mol ratio of X and Y can be 1:1,1:2,1:3 etc.In order to improve above-mentioned chemical equation a, the reaction efficiency of chemical equation b reaction system and efficiency of pcr product further, in a preferred embodiment, be also added with sour additive in above-mentioned chemical equation a, chemical equation b reaction system.In further preferred embodiment, the addition of this sour additive and the mol ratio of compounds X are 1:(1-0.5).In a particular embodiment, the addition of sour additive and the mol ratio of compounds X can be 1:0.5,1:0.7,1:0.8,1:0.9,1:1 etc.In a particular embodiment, described in this, sour additive selects at least one in the organic acids such as trimethylacetic acid, acetic acid, trifluoroacetic acid, phenylformic acid.The existence of this sour additive, can change the environment of reaction system, thus realizes the reaction efficiency and the efficiency of pcr product that improve above-mentioned reaction system.
In above-mentioned reaction system, this sour additive can directly and reactants of X, Y and catalyzer, reaction solvent etc. be mixed together and react.In order to play its effect further, in one embodiment, by this sour additive first with described compounds X, rhodium catalyst precursor and silver salt combination treatment after, then in described mixed solution, drip compound Y and organic solvent reacts.
On the basis of the various embodiments described above, the reaction solvent in above-mentioned chemical equation a, chemical equation b reaction system selects organic solvent, and this organic solvent can select at least one in acetonitrile, liquid alcohols.
Therefore, above-mentioned 1,2-oxygen azepine cyclics derivative preparation method only need provide oxygen-free environment, low for equipment requirements, its technique is simple.By to the environment of reaction system and the control of catalyzer, the yield of target product is high, its easy purifying, and therefore, its production cost is low.
1, the 2-oxygen azepine just provided because of above-described embodiment cyclics derivative has above-mentioned advantage, and its preparation method technique is simple, yield is high, and easy purifying, production cost is low.Therefore, it may be used for the preparation of cancer therapy drug.
Now in conjunction with the embodiments, the present invention is further elaborated.
Embodiment 1
2-N-ethanoyl-3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine and preparation method thereof.Shown in the following molecular structural formula I-a of structural formula of 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S11.N-phenol acetamide oxide:
HP (1.0eq) is added, cuprous chloride (1.0eq), activation in round-bottomed flask molecular sieve (250mg/mmol), with phenylo boric acid (2.0eq), then add 1,2-dichloroethane solvent (0.2M). in suspension, add pyridine (1.1eq), mixed system is uncovered, room temperature reaction 24-48 hour.Question response is complete, adds silica gel, revolve desolventizing in flask, crosses post and obtains 2-benzene oxygen isoindolinone-1,3-diketone;
2-benzene oxygen isoindolinone-1,3-diketone (1.0eq) is dissolved in the chloroform (0.1M) containing 10% methyl alcohol.Then single hydrazine hydrate (3.0eq) is added wherein.Mixture stirred overnight at room temperature, then filters, and filtrate concentrates, and crosses post and obtains O-phenylhydroxylamine;
O-phenylhydroxylamine (1.0eq) is dissolved in (0.2M) in ether. slowly add acetic anhydride (2.0eq) under condition of ice bath, then return to room temperature, stir 3 hours.Mixture is concentrated, crosses post and obtain corresponding N-phenol acetamide oxide product.
Chemical equation prepared by N-phenol acetamide oxide is as follows:
S12.2-N-ethanoyl-3-hydroxyl-4; 5-dihydro-1; the preparation of 2-benzo oxygen azepine: add N-phenol acetamide oxide (60.5mg in the tube sealing of 15ml; 0.4mmol); dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg; 0.012mmol); silver carbonate (11.0mg; 0.04mmol) with trimethylacetic acid (81.7mg; 0.8mmol), then operate in glove box, bleed for three times; three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-a through column chromatography purification, yield 93%.N-phenol acetamide oxide and propenal chemical equation as follows:
The product I-a of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CDCl 3) δ 7.15 (dd, J=7.1,5.5Hz, 2H), 7.07 (dt, J=14.0,4.6Hz, 2H), 6.01 (t, J=7.5Hz, 1H), 2.94 – 2.85 (m, 2H), 2.36 (dd, J=7.8,4.3Hz, 2H), 2.24 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 174.98,158.21,131.52,129.82,126.92,124.79,117.92,80.11,30.08,27.78,21.77.IR (cm -1): 3334,2940,2359,1653,1386,760.HRMS (ESI) calculated for C 11h 13nO 3na (+): 230.0793; Found:230.0787. this result further demonstrate that product I-a molecular structure is as above-mentioned molecular structure I-a.
Embodiment 2
2-N-carbobenzoxy-(Cbz)-3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine and preparation method thereof.Shown in the following molecular structural formula I-b of structural formula of 2-N-carbobenzoxy-(Cbz)-3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S21.N-phenol oxygen benzyloxy acid amides: similar with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11, difference is just substrate to be become corresponding phenyl boronic acid derivative.
S22.2-N-carbobenzoxy-(Cbz)-3-hydroxyl-4,5-dihydro-1, the preparation of 2-benzo oxygen azepine: add N-phenol oxygen benzyloxy acid amides (97.3mg in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver carbonate (11.0mg, 0.04mmol) with trimethylacetic acid (81.7mg, 0.8mmol). then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-b through column chromatography purification, yield 40%.N-phenol oxygen benzyloxy acid amides and propenal chemical equation as follows:
The product I-b of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CDCl 3) δ 7.39 – 7.32 (m, 5H), 7.17 – 7.09 (m, 3H), 7.09 – 7.02 (m, 1H), 5.81 (t, J=7.2Hz, 1H), 5.22 (q, J=12.4Hz, 2H), 2.92 (dd, J=9.1,4.0Hz, 2H), 2.41 – 2.29 (m, 2H); 13c NMR (101MHz, CDCl 3) δ 158.95,156.28,135.53,130.86,130.24,128.56,128.29,127.83,126.85,124.77,118.86,82.79,68.15,30.97,27.82.IR (cm -1): 3429,2941,1701,1485,1319,760.HRMS (ESI) calculated for C 17h 17nO 4na (+): 322.1056; Found:322.1047. this result further demonstrate that product I-a molecular structure is as above-mentioned molecular structure I-b.
Embodiment 3
2-N-ethanoyl-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, 2-benzo oxygen azepine and preparation method thereof.2-N-ethanoyl-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, shown in the following molecular structural formula I-c of structural formula of 2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S31.2-methyl-N-phenol acetamide oxide: similar with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11, difference is just substrate to be become corresponding phenyl boronic acid derivative.
S32.2-N-ethanoyl-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, the preparation of 2-benzo oxygen azepine:
2-methyl-N-phenol acetamide oxide (66.1mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), Silver monoacetate (0.04mmol) and trimethylacetic acid (81.7mg, 0.8mmol), then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-c through column chromatography purification, yield 90%.2-methyl-N-phenol acetamide oxide and propenal chemical equation as follows:
The product I-c of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (500MHz, CDCl 3) δ 7.05 – 6.95 (m, 1H), 6.91 (d, J=6.7Hz, 2H), 6.07 (t, 1H), 2.94 – 2.82 (m, 1H), 2.73 (dd, J=16.6,5.8Hz, 1H), 2.39 – 2.30 (m, 4H), 2.24 (dd, J=23.1,12.6Hz, 1H), 2.20 (d, J=10.0Hz, 3H); 13c NMR (126MHz, CDCl 3) δ 174.27,156.56,129.38,129.04,128.97,126.41,123.77,79.98,30.30,28.22,21.89,16.11.HRMS (ESI) calculated for C 12h 15nO 3na (+): 244.0950; Found:244.0944. this result further demonstrate that product I-c molecular structure is as above-mentioned molecular structure I-c.
Embodiment 4
Fluoro-1,2-benzo oxygen azepine of 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-8-and preparation method thereof.Shown in the following molecular structural formula I-d of structural formula of fluoro-1, the 2-benzo oxygen azepine of 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-8-:
Its preparation process is as follows:
The preparation of S41.3-fluoro-N-phenol acetamide oxide: similar with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11, difference is just substrate to be become corresponding phenyl boronic acid derivative.
The preparation of fluoro-1, the 2-benzo oxygen nitrogen of S42.2-N-ethanoyl-3-hydroxyl-4,5-dihydro-8-:
3-fluoro-N-phenol acetamide oxide (67.7mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver hexafluoroantimonate (0.04mmol) and trifluoroacetic acid (0.8mmol). then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-d through column chromatography purification, yield 92%.3-fluoro-N-phenol acetamide oxide and propenal chemical equation as follows:
The product I-d of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CD 2cl 2) δ 7.17 (dd, J=14.6,7.9Hz, 1H), 6.99 – 6.80 (m, 2H), 5.97 (s, 1H), (4.00 d, J=4.2Hz, 1H), 3.11 (dd, J=17.5,6.3Hz, 1H), 2.70 – 2.55 (m, 1H), 2.45 – 2.21 (m, 2H), 2.26 – 2.15 (s, 3H). 13c NMR (101MHz, CD 2cl 2) δ 174.77,161.42 (J=246.2), 159.63 (J=6.1), 127.11 (J=10.4), 118.30 (J=18.9), 113.55,11154 (J=23.4), 80.37,29.32,21.55,19.98 (J=5.7) .IR (cm -1): 3374,2359,1684,1462,1024.HRMS (ESI) calculated for C 11h 12nO 3fNa (+): 248.0699; Found:248.0693. this result further demonstrate that product I-d molecular structure is as above-mentioned molecular structure I-d.
Embodiment 5
Chloro-1,2-benzo oxygen azepine of 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-and preparation method thereof.Shown in the following molecular structural formula I-e of structural formula of chloro-1, the 2-benzo oxygen azepine of 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-:
Its preparation process is as follows:
The preparation of S51.4-chloro-N-phenol acetamide oxide: similar with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11, difference is just substrate to be become corresponding phenyl boronic acid derivative.
The preparation of chloro-1, the 2-benzo oxygen azepine of S52.2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-:
4-chloro-N-phenol acetamide oxide (74.2mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver carbonate (11.0mg, 0.04mmol) and phenylformic acid (0.8mmol). then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-e through column chromatography purification, yield 93%.4-chloro-N-phenol acetamide oxide and propenal chemical equation as follows:
The product I-e of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (500MHz, CDCl 3) δ 7.11 (s, 2H), 6.96 (d, J=8.9Hz, 1H), 5.98 (s, 1H), 2.82 (d, J=7.9Hz, 2H), 2.31 (dd, J=10.0,3.9Hz, 2H), 2.18 (s, 3H); 13c NMR (126MHz, CDCl 3) δ 174.85,156.84,131.77,131.21,129.86,126.81,119.16,80.05,29.90,27.61,21.63.IR (cm -1): 3435,2359,1663,1481,1379,1028,822.HRMS (ESI) calculated for C 11h 12nO 3naCl (+): 264.0404; Found:264.0397. this result further demonstrate that product I-e molecular structure is as above-mentioned molecular structure I-e.
Embodiment 6
2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-methyl esters-1,2-benzo oxygen azepine and preparation method thereof.Shown in the following molecular structural formula I-f of structural formula of 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-methyl esters-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S61.4-methyl esters-N-phenol acetamide oxide: similar with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11, difference is just substrate to be become corresponding phenyl boronic acid derivative.
The preparation of S62.2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-methyl esters-1,2-benzo oxygen azepine:
4-methyl esters-N-phenol acetamide oxide (83.7mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), tetrafluoride boron silver (0.36mmol) and trimethylacetic acid (0.4mmol), then operate in glove box, bleeds for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-f through column chromatography purification, yield 70%.4-methyl esters-N-phenol acetamide oxide and propenal chemical equation as follows:
The product I-f of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CDCl 3) δ=7.81 (dd, J=4.3,2.4,2H), (7.04 d, J=8.9,1H), 6.01 (s, 1H), 4.71 (s, 1H), 3.86 (s, 3H), 2.87 (t, J=5.0,2H), 2.51 – 2.31 (m, 1H), 2.31 – 2.20 (m, 1H), 2.16 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 174.79,166.27,161.62,133.38,129.83,128.75,126.54,117.78,79.85,52.19,29.98,27.82,21.73.IR (cm -1): 3374,2357,1715,1285,1115,1032.HRMS (ESI) calculated for C 13h 15nO 5na (+): 288.0848; Found:288.0840. this result further demonstrate that product I-f molecular structure is as above-mentioned molecular structure I-f.
Embodiment 7
2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7,8-dimethyl-1,2-benzo oxygen azepine and preparation method thereof.Shown in the following molecular structural formula I-g of structural formula of 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7,8-dimethyl-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S71.3,4-dimethyl-N-phenol acetamide oxide: similar with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11, difference is just substrate to be become corresponding phenyl boronic acid derivative.
The preparation of S72.2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7,8-dimethyl-1,2-benzo oxygen azepine:
3 are added in the tube sealing of 15ml, 4-dimethyl-N-phenol acetamide oxide (71.7mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (0.04mmol), silver carbonate (0.08mmol) and trimethylacetic acid (81.7mg, 0.8mmol).Then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (526.7ul, 0.4mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-g through column chromatography purification, yield 83%.3,4-dimethyl-N-phenol acetamide oxide and propenal chemical equation as follows:
The product I-g of preparation is carried out proton nmr spectra ( 1h NMR) to analyze, its result is: 1h NMR (500MHz, CD 2cl 2) δ 6.91 (d, J=5.3Hz, 1H), 6.86 (s, 1H), 5.98 (d, J=6.1Hz, 1H), 2.87 – 2.74 (m, 2H), 2.31 – 2.26 (m, 2H), 2.26 – 2.20 (m, 9H); 13c NMR (126MHz, CDCl 3) δ 174.80,156.21,135.18,132.86,132.35,126.67,118.78,80.12,30.35,27.21,21.66,19.23,18.82.IR (cm -1): 3375,2934,1674,1504,1260,1028,800.HRMS (ESI) calculated for C 13h 17nO 3na (+): 258.1106; Found:258.1100. this result further demonstrate that product I-g molecular structure is as above-mentioned molecular structure I-g.
Embodiment 8
2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-ethyl-1,2-benzo oxygen azepine and preparation method thereof.Shown in the following molecular structural formula I-h of structural formula of 2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-ethyl-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S81.N-phenol acetamide oxide: with reference to the preparation method of N-phenol acetamide oxide in embodiment 1 step S11.
The preparation of S82.2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-ethyl-1,2-benzo oxygen azepine:
N-phenol acetamide oxide (60.5mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver carbonate (11.0mg, 0.04mmol) and trimethylacetic acid (81.7mg, 0.8mmol). then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Add in tube sealing (E)-amyl group-2-olefine aldehydr ((78.3ul, 0.8mmol) and acetonitrile (2.0ml). stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-h through column chromatography purification, yield 96%.N-phenol acetamide oxide is as follows with (E)-amyl group-2-olefine aldehydr chemical equation:
The product I-h of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CDCl 3) δ 7.15 (ddd, J=6.9,5.1,2.4Hz, 2H), (7.08 ddd, J=15.7,10.6,4.5Hz, 2H), 6.08 (dd, J=9.6,5.9Hz, 1H), 4.56 – 4.08 (m, 1H), 2.88 (d, J=7.1Hz, 1H), 2.57 – 2.31 (m, 2H), 2.23 (d, J=2.7Hz, 3H), 1.70 – 1.56 (m, 2H), 1.07 (t, J=7.4Hz, 3H); 13c NMR (101MHz, CDCl 3) δ 174.28,157.86,134.14,132.34,126.81,124.75,118.10,79.94,41.42,31.74,28.23,21.79,12.51.HRMS (ESI) calculated for C 13h 17nO 3na (+): 258.1106; Found:258.1098. this result further demonstrate that product I-h molecular structure is as above-mentioned molecular structure I-h.
Embodiment 9
2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-propyl group-1,2-benzo oxygen azepine and preparation method thereof.Shown in the following molecular structural formula I-i of structural formula of 2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-propyl group-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S91.N-phenol acetamide oxide: with reference to the preparation method of N-phenol acetamide oxide in embodiment 1 step S11.
The preparation of S92.2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-propyl group-1,2-benzo oxygen azepine:
N-phenol acetamide oxide (60.5mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver carbonate (11.0mg, 0.04mmol) and trimethylacetic acid (81.7mg, 0.8mmol). then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.(E)-hexyl-2-olefine aldehydr (92.8ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-i through column chromatography purification, yield 88%.N-phenol acetamide oxide is as follows with (E)-hexyl-2-olefine aldehydr chemical equation:
The product I-i of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (500MHz, CD 2cl 2) δ=7.18 (dd, J=11.3,4.3,2H), 7.11 (ddd, J=16.9,11.0,4.5,2H), 6.08 (dd, J=8.8,6.0,1H), 4.50 (s, 1H), 3.14 – 2.98 (m, 1H), 2.51 – 2.32 (m, 2H), 2.23 (s, 3H), 1.74 – 1.52 (m, 3H), 1.50 – 1.42 (m, 1H), 0.99 (t, J=6.9,3H). 13c NMR (126MHz, CD 2cl 2) δ 173.83,158.04,134.53,132.17,126.65,124.64,118.03,76.72,39.33,37.43,32.45,21.48,20.74,13.77.IR (cm -1): 3381,2955,2357,1645,1485,1379,1192,766.HRMS (ESI) calculated for C 14h 19nO 3na (+): 272.1263; Found:272.1254. this result further demonstrate that product I-i molecular structure is as above-mentioned molecular structure I-i.
Embodiment 10
2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen azepine and preparation method thereof.Shown in the following molecular structural formula I-j of structural formula of 2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S101.4-phenyl-N-phenol acetamide oxide: similar with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11, difference is just substrate to be become corresponding phenyl boronic acid derivative.
The preparation of S102.2-N-ethanoyl-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen azepine:
4-phenyl-N-phenol acetamide oxide (91mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver carbonate (11.0mg, 0.04mmol) and trimethylacetic acid (81.7mg, 0.8mmol). then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product I-j through column chromatography purification, yield 66%.4-phenyl-N-phenol acetamide oxide and propenal chemical equation as follows:
The product I-j of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CDCl 3) δ 7.54 (dd, J=5.2,3.4,2H), 7.44 (dd, J=10.3,4.8,2H), 7.41 – 7.31 (m, 3H), 7.12 (d, J=8.2,1H), 6.06 (d, J=4.2,1H), 4.38 (d, J=4.6,1H), 3.02 – 2.90 (m, 2H), 2.39 (td, J=7.5,3.0,2H), 2.27 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 175.01,157.73,140.15,138.01,130.28,130.12,128.83,127.36,127.00,125.61,118.30,80.13,30.11,27.97,21.81.IR (cm -1): 2922,2359,1337,1109,669.HRMS (ESI) calculated for C 17h 17nO 3na (+): 306.1106; Found:306.1103. this result further demonstrate that product I-j molecular structure is as above-mentioned molecular structure I-j.
Embodiment 11
2-N-ethanoyl-3-hydroxyl-4,5,7,8,9,9a-hexahydrobenzene is [f] [1,2] oxygen azepine and preparation method thereof also.Shown in the following molecular structural formula II-a of structural formula of 2-N-ethanoyl-3-hydroxyl-4,5,7,8,9,9a-hexahydrobenzene also [f] [1,2] oxygen azepine:
Its preparation process is as follows:
The preparation of S111.N-(hexamethylene-2-alkene-1-base oxygen base) ethanamide:
By HP (1.1eq), triphenylphosphine (1.5eq) is dissolved in dry tetrahydrofuran (THF), then adds 2-tetrahydrobenzene-1-alcohol (1eq) wherein.Reaction system is cooled to 0 DEG C, then dropwise adds diethyl azodiformate (1.5eq).Reaction mixture returns to room temperature, after stirred overnight, is concentrated by solution, crosses post and obtains 2-(hexamethylene-2-alkene-1-base oxygen base) isoindolinone-1,3-diketone;
By 2-(hexamethylene-2-alkene-1-base oxygen base) isoindolinone-1,3-diketone (1.0eq) is dissolved in the chloroform (0.1M) containing 10% methyl alcohol, then single hydrazine hydrate (3.0eq) is added wherein, mixture stirred overnight at room temperature, then filter, filtrate concentrates, and crosses post;
The product (1.0eq) crossing post acquisition is dissolved in (0.2M) in ether. slowly add acetic anhydride (2.0eq) under condition of ice bath, then return to room temperature, stir 3 hours.Mixture is concentrated, crosses post and obtain corresponding N-(hexamethylene-2-alkene-1-base oxygen base) acetamide product.
Chemical equation prepared by N-(hexamethylene-2-alkene-1-base oxygen base) ethanamide is as follows:
S112.2-N-ethanoyl-3-hydroxyl-4; 5; 7; 8; 9; the preparation of 9a-hexahydrobenzene also [f] [1,2] oxygen azepine: add N-(hexamethylene-2-alkene-1-base oxygen base) ethanamide (62.1mg, 0.4mmol) in the tube sealing of 15ml; dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg; 0.012mmol), silver carbonate (11.0mg, 0.04mmol) and trimethylacetic acid (81.7mg; 0.8mmol). then operate in glove box; bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product 1-through column chromatography purification, and (3-hydroxyl-4,5,7,8,9,9a-hexahydrobenzene is [f] [1,2] oxygen azepine-2 (3H) ethanoyl II-a also, yield 81%.N-(hexamethylene-2-alkene-1-base oxygen base) ethanamide and propenal chemical equation as follows:
The product II-a of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CDCl 3) δ 5.75 (dd, J=9.5,5.8Hz, 1H), 5.53 (s, 1H), 4.24 – 4.14 (m, 1H), (4.03 s, 1H), 2.27 (dd, J=14.1,7.9Hz, 1H), 2.18 (s, 3H), 2.13 – 1.88 (m, 5H), 1.85 – 1.73 (m, 2H), 1.64 (m, 1H), 1.56 – 1.46 (m, 1H); 13c NMR (101MHz, CDCl 3) δ 174.88,137.48,126.36,85.88,80.54,31.47,30.85,28.07,24.99,21.16,20.79.IR (cm -1): 3445,2930,2359,1639,1393,1076,1024.HRMS (ESI) calculated for C 11h 17nO 3na (+): 234.1106; Found:234.1100. this result further demonstrate that product II-a molecular structure is as above-mentioned molecular structure II-a.
Embodiment 12
Benzyl-2-ethanoyl-3-hydroxyl-2,3,4,5,9,9a-hexahydropyridine base [4,3-f] [1,2] oxygen azepine-8 (7H)-carboxylic acid and preparation method thereof.Shown in the following molecular structural formula II-b of structural formula of benzyl-2-ethanoyl-3-hydroxyl-2,3,4,5,9,9a-hexahydropyridine base [4,3-f] [1,2] oxygen azepine-8 (7H)-carboxylic acid:
Its preparation process is as follows:
S121. the preparation of benzyl-5-(kharophen)-5,6-dihydropyridine-1 (2H)-carboxylic acid:
Butadiene monoxide (1eq) is added, allylamine (2eq) and 0.4mL water in tube sealing.Then be heated to 100 DEG C, after reaction 6h. question response terminates, be directly spin-dried for, obtain crude product 1-(allyl amino) butyl-3-alkene-2-alcohol, be directly used in next step reaction;
Above-mentioned product being dissolved in methylene dichloride, then adding triethylamine (1.2eq), be cooled to 0 DEG C, slowly drip chloroformic acid benzyl ester (1eq). recovery temperature is to room temperature, and mixture at room temperature reacts.Treat that feedstock conversion is complete, in system, add some methyl alcohol, be then spin-dried for, cross post, obtain benzyl allyl (2-hydroxybutyl-3-alkene-1-alkynes) carbamate;
At room temperature above-mentioned product is dissolved in methylene dichloride, then adds Grubbs 1 ' the st catalyzer of catalytic amount, keep reaction system concentration to be 0.01M.React about 10h, obtain product benzyl-5-hydroxyl-5,6-dihydropyridine-1 (2H)-carboxylic acid;
Chemical equation prepared by benzyl-5-hydroxyl-5,6-dihydropyridine-1 (2H)-carboxylic acid is as follows:
By benzyl-5-hydroxyl-5,6-dihydropyridine-1 (2H)-carboxylic acid is to benzyl-5-(kharophen)-5, in the reaction process of 6-dihydropyridine-1 (2H)-carboxylic acid and embodiment 1, S11 is similar, and do not repeat them here, its reactive chemistry formula is as follows:
S122. benzyl-2-ethanoyl-3-hydroxyl-2, 3, 4, 5, 9, 9a-hexahydropyridine base [4, 3-f] [1, 2] preparation of oxygen azepine-8 (7H)-carboxylic acid: add benzyl-5-(kharophen)-5 in the tube sealing of 15ml, 6-dihydropyridine-1 (2H)-carboxylic acid (116.1mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver carbonate (11.0mg, 0.04mmol) with trimethylacetic acid (81.7mg, 0.8mmol). then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product benzyl-2-ethanoyl-3-hydroxyl-2,3,4,5,9,9a-hexahydropyridine base [4,3-f] [1,2] oxygen azepine-8 (7H)-carboxylic acid II-b through column chromatography purification, yield 70%.Benzyl-5-(kharophen)-5,6-dihydropyridine-1 (2H)-carboxylic acid and propenal chemical equation as follows:
The product II-b of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, oxygen azepine-8 (7H)-carboxylic acid II-b, yield 70%. 1h NMR (400MHz, CDCl 3) δ 7.45 – 7.29 (m, 5H), 5.77 (dt, J=14.4,7.1Hz, 1H), 5.58 (dd, J=47.2,29.5Hz, 1H), 5.14 (s, 2H), 4.61 – 3.78 (m, 4H), 3.66 (d, J=18.0Hz, 1H), 3.10 – 2.61 (m, 1H), 2.44 – 2.33 (m, 1H), 2.34 – 2.05 (m, 5H), 1.93 – 1.78 (m, 1H); 13c NMR (101MHz, CDCl 3) δ 175.21,155.23,137.10,136.32,128.56 (2C), 128.23,128.09,128.02,121.73,80.84,80.53,67.50,43.15,30.90,29.93,28.04,21.20.HRMS (ESI) calculated for C 18h 22n 2o 5na (+): 369.1427; Found:369.1420. this result further demonstrate that product II-b molecular structure is as above-mentioned molecular structure II-b.
Embodiment 13
N-(two (3-oxygen amyl group) the phenol oxygen of 2,6-) ethanamide and preparation method thereof.Shown in the following molecular structure formula III of structural formula of N-(two (3-oxygen amyl group) the phenol oxygen of 2,6-) ethanamide:
Its preparation process is as follows:
N-phenol acetamide oxide (60.5mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver carbonate (11.0mg, 0.04mmol) with trimethylacetic acid (81.7mg, 0.8mmol).Then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Penten-3-one (78.3ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product III through column chromatography purification, yield 48%.N-phenol acetamide oxide and penten-3-one chemical equation as follows:
The product III of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, MeOD) δ 7.08 (m, 3H), 2.96 (t, J=7.6,4H), 2.80 (t, J=7.6,4H), 2.47 (q, J=7.3,4H), 1.92 (s, 3H), 1.01 (t, J=7.3,6H). 13c NMR (126MHz, MeOD) δ 212.26,167.64,153.88,134.94,128.20,126.09,42.49,35.18,24.05,17.94,6.64.IR (cm -1): 3215,2359,1709,1454,669.HRMS (ESI) calculated for C 18h 25nO 4na (+): 342.1682; Found:342.1677.
Embodiment 14
3-hydroxyl-2-phenol oxygen-4,5-dihydro-1H-benzazepine-1-ketone.Shown in the following molecular structural formula IV of structural formula of 3-hydroxyl-2-phenol oxygen-2,3,4,5-tetrahydrochysene-1H-benzazepine-1-ketone:
Its preparation process is as follows:
N-phenol oxy benzamide (85.3mg is added in the tube sealing of 15ml, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), silver carbonate (11.0mg, 0.04mmol) with trimethylacetic acid (81.7mg, 0.8mmol).Then operate in glove box, bleed for three times, three inflations, make to keep nitrogen atmosphere in system.Propenal (53.4ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. stirred at ambient temperature about 18 hours again after dripping.After reaction terminates, filter, concentrate and obtain crude product.Crude product is obtained product IV through column chromatography purification, yield 80%.N-phenol oxy benzamide and propenal chemical equation as follows:
The product IV of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CD 2cl 2) δ 8.07 (dd, J=7.7,1.0,1H), 7.57 (td, J=7.5,1.2,1H), 7.42 (dd, J=11.0,4.1,1H), 7.38 (d, J=7.5,1H), 7.32 (dd, J=8.5,7.5,2H), 7.09 (t, J=7.3,1H), 7.01 (d, J=7.9,2H), 5.58 (dd, J=7.5,2.3,1H), 5.43 (s, 1H), 3.38 – 3.16 (m, 1H), 2.97 (dt, J=14.1,4.4,1H), 2.70 (ddt, J=9.6,7.6,4.9,1H), 2.19 (m, 1H). 13c NMR (101MHz, CD 2cl 2) δ 170.75,158.90,141.04,132.61,132.52,130.82,129.55,129.15,126.90,122.90,113.56,86.54,36.96,30.86.IR (cm -1): 3391,2940,2359,1647,1487,1202,752.HRMS (ESI) calculated for C 16h 15nO 3na (+): 292.0950; Found:292.0945.
Embodiment 15
N-(chroman) ethanamide.Shown in the following molecular structural formula V of structural formula of N-(chroman) ethanamide:
Its preparation process is as follows:
Be dissolved in methylene dichloride by the product I-a of gained, then add palladium carbon, insert hydrogen balloon, carry out three ventilations, make system keep nitrogen atmosphere, reaction mixture at room temperature stirs and spends the night.Finally filter, filtrate be spin-dried for and obtain product V, yield 80%, corresponding chemical equation is as follows:
The product V of preparation is carried out proton nmr spectra (H NMR) analysis, its result is: 1h NMR (400MHz, CDCl 3) δ 7.19 – 6.98 (m, 2H), 6.86 (ddd, J=18.1,12.2,4.6Hz, 2H), 6.27 (d, J=8.0Hz, 1H), 5.89 (ddd, J=9.2,8.5,2.7Hz, 1H), 2.96 (ddd, J=15.8,9.5,6.0Hz, 1H), 2.81 (dt, J=16.8,5.6Hz, 1H), 2.15 (dtd, J=14.2,5.8,2.7Hz, 1H), 2.05 (s, 3H), 1.92 (m, 1H). 13c NMR (101MHz, CDCl 3) δ 169.87,153.37,129.22,127.63,120.84,120.70,117.15,75.84,26.97,23.52,23.31.HRMS (ESI) calculated for C 11h 14nO 3(+): 192.0954; Found:192.1000.
Application Example 1
Detection example: compound (I-j) is to the Proliferation Ability of myeloma cell line LP-1 cell and cytotoxicity test
Compound (I-j) uses DMSO to be made into 100mM liquid storage.
Cell suspension (making cell detachment through 0.25% tryptic digestion) 0.5-1.0 × 10 of the LP-1 taken the logarithm vegetative period 4/ hole, be sub-packed in 96 well culture plates, 100 μ L/ holes, cultivate 24 hours, after cell attachment, add medicine or the test solution of the corresponding different concns of 10 μ L respectively, negative control group (physiological saline), solvent control group (add 2%DMSO and make final concentration as 0.5%) and 6 different concns administration groups are set in experiment.Often group establishes 3 parallel holes.Put constant temperature 5%CO 2incubator 37 DEG C cultivates 24,48 and 72 hours respectively.Examine under a microscope cells survival state, can find that cell is effectively suppressed more than 10 μMs of drug levels, its result as shown in Figure 1.Wherein, this solvent control group examines under a microscope cells survival state as shown in Figure 1a, and dosing group examines under a microscope cells survival state as shown in Figure 1 b.
Before experiment terminates, 1 hour every hole adds 10 μ L WST-1 solution, and plate shaker jolts 1 minute rearmounted enzyme connection detector, surveys the OD value in each hole, make Fig. 2 in 450nm wavelength.And ask growth inhibition ratio by following formula, and obtain half-inhibition concentration IC50 by B1iss method: calculation formula: drug on tumor cell inhibitory rate=(1-medication group mean OD value/control group mean OD value) × 100%.
Result shows that compound described in this patent (I-j) has stronger restraining effect to myeloma cell line LP-1 cell.
In addition, adopt embodiment 1-9 and embodiment 11-15 provide 1,2-oxygen azepine cyclics derivative are tested according to the experimental technique of compound (I-j) respectively, show that those compounds have similar biological activity to compound (I-j), all show, to myeloma cell line LP-1 cell, there is stronger restraining effect.Therefore 1,2-oxygen azepine described in the embodiment of the present invention cyclics derivative can be used for preparing anticancer medicine.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.

Claims (10)

1. an oxygen azepine cyclics derivative, its general formula of molecular structure is following (I):
In formula, A is (mixing) aromatic nucleus or non-aromatic ring; R 1be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, carbalkoxy; R 2, R 3be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, aryl, hydrogen.
2. 1,2-oxygen azepine according to claim 1 cyclics derivative, it is characterized in that: described A is (mixing) aromatic nucleus, and described (mixing) aromatic nucleus is any one group following:
3. according to claim 21, 2-oxygen azepine cyclics derivative, it is characterized in that: described 1, 2-oxygen azepine cyclics derivative is 2-N-ethanoyl-3-hydroxyl-4, 5-dihydro-1, 2 benzo oxygen azepines, 2-N-carbobenzoxy-(Cbz)-3-hydroxyl-4, 5-dihydro-1, 2 benzo oxygen azepines, 2-N-ethanoyl-3-hydroxyl-4, 5-dihydro-9-methyl isophthalic acid, 2 benzo oxygen azepines, 2-N-ethanoyl-3-hydroxyl-4, 5-dihydro-8-fluoro-1, 2 benzo oxygen azepines, 2-N-ethanoyl-3-hydroxyl-4, 5-dihydro-7-chloro-1, 2 benzo oxygen azepines, 2-N-ethanoyl-3-hydroxyl-4, 5-dihydro-7-methyl esters-1, 2 benzo oxygen azepines, 2-N-ethanoyl-3-hydroxyl-4, 5-dihydro-7, 8-dimethyl-1, 2 benzo oxygen azepines, 2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-ethyl-1, 2 benzo oxygen azepines, 2-N-ethanoyl-3-hydroxyl-4-hydrogen-5-propyl group-1, 2 benzo oxygen azepines, 2-N-ethanoyl-3-hydroxyl-4, 5-dihydro-7-phenyl-1, 2-benzo oxygen azepine, 3-hydroxyl-2-phenol oxygen-4, 5-dihydro-1H-benzazepine-1-ketone, at least one in N-(chroman) ethanamide.
4. 1,2-oxygen azepine according to claim 1 cyclics derivative, it is characterized in that: described A is non-aromatic ring, and described non-aromatic ring is any one group following:
wherein, n=0,1, X=O, S, N-PG.
5. 1,2-oxygen azepine according to claim 4 cyclics derivative, is characterized in that: described 1; 2-oxygen azepine cyclics derivative is 2-N-ethanoyl-3-hydroxyl-4,5,7; 8,9,9a-hexahydrobenzene is [f] [1 also; 2] oxygen azepine, benzyl-2-ethanoyl-3-hydroxyl-2,3,4; 5,9,9a-hexahydropyridine base [4; 3-f] at least one in [1,2] oxygen azepine-8 (7H)-carboxylic acid.
6. an oxygen azepine the preparation method of cyclics derivative, comprises the steps:
Compounds X, Y that following structural formula represents are provided respectively,
In oxygen-free environment and under rhodium catalyst precursor and silver salt and organic solvent existent condition, described compounds X, Y are reacted, obtain following general structure for 1,2-oxygen azepine shown in (I) and cyclics derivative,
A in described compounds X, Y and (I) structural formula is (mixing) aromatic nucleus or non-aromatic ring; R 1be selected from C 1-C 4straight chain or containing any one in the alkyl of substituting group side chain, carbalkoxy; R 2, R 3be selected from C 1-C 4straight chain or containing the one in the alkyl of substituting group side chain, aryl, hydrogen.
7. according to claim 61,2-oxygen azepine the preparation method of cyclics derivative, it is characterized in that: carry out, in reaction system, being also added with sour additive at described compounds X, Y, the mol ratio of described sour additive and compounds X is 1:(1-0.5); And/or
Described sour additive is at least one in the organic acids such as trimethylacetic acid, acetic acid, trifluoroacetic acid, phenylformic acid.
8. 1,2-oxygen azepine according to claim 7 the preparation method of cyclics derivative, is characterized in that: it is as follows described compounds X, Y to be carried out reactions steps:
In oxygen-free environment, first by described compounds X and rhodium catalyst precursor and silver salt and sour additives mixed process, then in described mixed solution, drip compound Y and organic solvent reacts.
9. according to arbitrary 1, the 2-described oxygen azepine of claim 6-8 and the preparation method of cyclics derivative, it is characterized in that: the mol ratio of described compounds X, Y is 1:(1-3); And/or
The mol ratio of described compounds X and described rhodium catalyst precursor is 1:(0.03-0.1); And/or
The mol ratio of described rhodium catalyst precursor and silver salt is 1:(2-33).
10., according to arbitrary 1, the 2-described oxygen azepine of claim 6-8 and the preparation method of cyclics derivative, it is characterized in that: described rhodium catalyst precursor is dichloro (pentamethylcyclopentadiene) rhodium (III) dimer; And/or
Described silver salt is silver carbonate, Silver monoacetate, silver hexafluoroantimonate, and tetrafluoride boron silver waits at least one in silver salt.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104829550A (en) * 2015-05-04 2015-08-12 四川大学 Method for high-efficiency preparation of an o-hydroxyphenyl heterocyclic derivative through C-H/C-H oxidative coupling reaction based on transition metal catalysis
WO2016149899A1 (en) * 2015-03-23 2016-09-29 北京大学深圳研究生院 Biological orthogonal reagent, activator and precursor, and biological orthogonal reagent kit
CN114989108A (en) * 2022-05-09 2022-09-02 长沙学院 1, 4-oxazepine-2, 5-dione compound and preparation method and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1033130A1 (en) * 1998-07-29 2000-09-06 Taiho Pharmaceutical Company Limited Urokinase production inhibitors, angiogenesis inhibitors and methods of prevention or treatment with both
US20130053365A1 (en) * 2011-08-30 2013-02-28 Biomarin Pharmaceutical, Inc. Dihydropyridophthalazinone inhibitors of poly(adp-ribose)polymerase (parp)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1033130A1 (en) * 1998-07-29 2000-09-06 Taiho Pharmaceutical Company Limited Urokinase production inhibitors, angiogenesis inhibitors and methods of prevention or treatment with both
US20130053365A1 (en) * 2011-08-30 2013-02-28 Biomarin Pharmaceutical, Inc. Dihydropyridophthalazinone inhibitors of poly(adp-ribose)polymerase (parp)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PINGPING DUAN 等: "Rhodium(III)-catalyzed C–H activation/[4+3] annulation of N-phenoxyacetamides and α,β-unsaturated aldehydes: an efficient route to 1,2-oxazepines at room temperature", 《CHEM. COMMUN.》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016149899A1 (en) * 2015-03-23 2016-09-29 北京大学深圳研究生院 Biological orthogonal reagent, activator and precursor, and biological orthogonal reagent kit
CN106170304A (en) * 2015-03-23 2016-11-30 北京大学深圳研究生院 Bio-orthogonal reagent, activator and precursor and bio-orthogonal test kit
CN104829550A (en) * 2015-05-04 2015-08-12 四川大学 Method for high-efficiency preparation of an o-hydroxyphenyl heterocyclic derivative through C-H/C-H oxidative coupling reaction based on transition metal catalysis
CN114989108A (en) * 2022-05-09 2022-09-02 长沙学院 1, 4-oxazepine-2, 5-dione compound and preparation method and use thereof

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