CN104262283B - Application of 1,2-oxa-cyclic compound derivative for preparing myeloma treamtnet medicine - Google Patents

Application of 1,2-oxa-cyclic compound derivative for preparing myeloma treamtnet medicine Download PDF

Info

Publication number
CN104262283B
CN104262283B CN201410409341.4A CN201410409341A CN104262283B CN 104262283 B CN104262283 B CN 104262283B CN 201410409341 A CN201410409341 A CN 201410409341A CN 104262283 B CN104262283 B CN 104262283B
Authority
CN
China
Prior art keywords
hydroxyl
group
oxygen azepine
preparation
dihydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410409341.4A
Other languages
Chinese (zh)
Other versions
CN104262283A (en
Inventor
赵劲
段平平
严义勇
兰霞
陈波
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Peking University Shenzhen Graduate School
Original Assignee
Peking University Shenzhen Graduate School
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peking University Shenzhen Graduate School filed Critical Peking University Shenzhen Graduate School
Priority to CN201410409341.4A priority Critical patent/CN104262283B/en
Publication of CN104262283A publication Critical patent/CN104262283A/en
Application granted granted Critical
Publication of CN104262283B publication Critical patent/CN104262283B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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 derivant are as preparation treatment myeloma medicine Application
Technical field
The invention belongs to organic compound synthesis technical field, particularly relate to a kind of 1,2-oxygen azepine ring class Compound derivant and preparation method thereof.
Background technology
1,2-oxaza compound has biological activity widely.The chemical combination of following structural formula a is reported in the eighties The synthesis of thing, the test in terms of author has also carried out medicine and biochemistry to this structure simultaneously.Result shows, at high dose bar Under part, this compound shows slight anxiolytic property.Therefore the activity of this compound is the highest, and anxiolytic property effect is not Preferable.
Summary of the invention
It is an object of the invention to overcome the above-mentioned deficiency of prior art, it is provided that a kind of 1,2-oxygen azepine cyclics Derivant and preparation method thereof.To overcome existing 1,2-oxygen azepine cyclics derivant are less, and synthetic method is less, with And the technical problem that existing 1,2-oxaza compound biological activity is the highest.
In order to realize foregoing invention purpose, technical scheme is as follows:
A kind of 1,2-oxygen azepine cyclics derivant, its general formula of molecular structure is following (I):
In described (I) formula, A is (miscellaneous) aromatic rings or non-aromatic ring；R1Selected from C1-C4Straight chain or containing substituent group side chain Any one in alkyl, alkoxy carbonyl group；R2、R3Selected from C1-C4Straight chain or containing appointing in the alkyl of substituent group side chain, aryl, hydrogen A kind of.
And, a kind of 1,2-oxygen azepine the preparation method of cyclics derivant, comprise the steps:
Compound A, B that following structural formula represents are provided respectively,
Under conditions of oxygen-free environment exists with silver salt and organic solvent with rhodium catalyst precursor, by described compound A, B react, and obtain following general structure for 1 shown in (I), 2-oxygen azepine cyclics derivant,
Wherein, the A in described compound A, B and (I) structural formula is (miscellaneous) aromatic rings or non-aromatic ring；R1Selected from C1-C4Directly Chain or containing any one in the alkyl of substituent group side chain, alkoxy carbonyl group；R2、R3Selected from C1-C4Straight chain or containing substituent group side chain Alkyl, aryl, one in hydrogen.
Above-mentioned 1,2-oxygen azepine cyclics derivant have of a relatively high biological activity, and it is to myeloma cell It is that LP-1 cell has stronger inhibitory action.1,2-oxygen azepine the most of the present invention cyclics derivant can be used In preparing anticancer medicine.
Above-mentioned 1,2-oxygen azepine cyclics derivative preparation method technique are simple, to equipment and reaction condition requirement Low.The yield of target product is high, and its easy purification, 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-acetyl group-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-the benzene that Fig. 1 provides for using the embodiment of the present invention 10 And oxygen azepine is to the Proliferation Ability of myeloma cell line LP-1 cell and cytotoxicity test basis of microscopic observation cells survival shape State figure；Wherein, Fig. 1 a is that solvent control group examines under a microscope cells survival state such as figure, and Fig. 1 b is containing 2-N-acetyl The dosing group of base-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen azepine examines under a microscope cells survival state；
2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen the nitrogen that Fig. 2 embodiment of the present invention 10 provides The miscellaneous proliferation activity to LP-1 cell tests figure.
Detailed description of the invention
In order to make the technical problem to be solved in the present invention, technical scheme and beneficial effect clearer, below in conjunction with Embodiment, is further elaborated to the present invention.Should be appreciated that specific embodiment described herein is only in order to explain The present invention, is not intended to limit the present invention.
The embodiment of the present invention provides a kind of 1, and 2-oxygen azepine cyclics derivant, its general formula of molecular structure is following (I):
Wherein, the A in this general formula of molecular structure (I) is (miscellaneous) aromatic rings or non-aromatic ring；R1Selected from C1-C4Straight chain or contain Any one in the alkyl of substituted base side chain, alkoxy carbonyl group；R2、R3Selected from C1-C4Straight chain or the alkane containing substituent group side chain Any one in base, aryl, hydrogen.
In one embodiment, when above-mentioned A is (miscellaneous) aromatic rings, (miscellaneous) aromatic group representated by this A be to Can be any one in following group less, wherein, what (miscellaneous) aromatic rings represented is aromatic rings and containing heteroatomic aromatic rings.
In another specific embodiment, when above-mentioned A is non-aromatic ring, the nonaromatic cyclic group representated by this A is at least Can be any one in following group:
Wherein, n=0,1, X=O, S, N-PG. PG is the abbreviation of protecting group, i.e. refers to that blocking group, this concrete PG can be acetyl group, benzyloxycarbonyl group, tertiary fourth Oxygen carbonyl, methoxycarbonyl group, carbethoxyl group etc..
In still another embodiment, above-mentioned, R1Selected from C1-C4When straight chain or the alkyl containing substituent group side chain, it is permissible It is methyl, ethyl, propyl group, butyl, isopropyl, isobutyl group, any one in the tert-butyl group；R1When alkoxy carbonyl group, it is permissible It is any one in benzyloxy group, tert-butyl group oxygen groups.
R2、R3Selected from C1-C4When straight chain or the alkyl containing substituent group side chain, R2、R3Can be methyl, ethyl, propyl group, fourth Base, isopropyl, isobutyl group, any one in the tert-butyl group.
Therefore, 1 shown in above-mentioned general formula of molecular structure (I), 2-oxygen azepine cyclics derivant can be at least Following compound:
I:(is miscellaneous) fragrance also 1,2-oxaza compounds derivant:
I-a:2-N-acetyl group-3-hydroxyl-4,5-dihydro-1,2 benzo oxygen azepine；
I-b:2-N-benzyloxycarbonyl group-3-hydroxyl-4,5-dihydro-1,2 benzo oxygen azepine；
I-c:2-N-acetyl group-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, 2 benzo oxygen azepines；
The I-d:2-N-acetyl group fluoro-1,2 benzo oxygen azepines of-3-hydroxyl-4,5-dihydro-8-；
The I-e:2-N-acetyl group chloro-1,2 benzo oxygen azepines of-3-hydroxyl-4,5-dihydro-7-；
I-f:2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-methyl ester-1,2 benzo oxygen azepine；
I-g:2-N-acetyl group-3-hydroxyl-4,5-dihydro-7,8-dimethyl-1,2 benzo oxygen azepine；
I-h:2-N-acetyl group-3-hydroxyl-4-hydrogen-5-ethyl-1,2 benzo oxygen azepine；
I-i:2-N-acetyl group-3-hydroxyl-4-hydrogen-5-propyl group-1,2 benzo oxygen azepine；
I-j:2-N-acetyl group-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-(chromane) acetamide.
II non-aromatic ring 1,2-oxaza compounds derivant:
II-a:2-N-acetyl group-3-hydroxyl-4,5,7,8,9,9a-hexahydro benzo [f] [1,2] oxygen azepine；
II-b: benzyl-2-acetyl group-3-hydroxyl-2,3,4,5,9,9a-hexahydropyridine base [4,3-f] [1,2] oxygen azepine-8 (7H)-carboxylic acid.
Certainly, above-mentioned (miscellaneous) fragrance 1,2-oxaza compounds derivant and non-aromatic ring 1,2-oxaza Compounds derivant is not just for above-mentioned several concrete compounds, it is also possible to be by A, the R in general formula of molecular structure (I)1、 R2、R3Represented group arbitrarily connects other compounds formed.
Of a relatively high biological activity in the various embodiments described above, myeloma cell line LP-1 cell is had stronger by it Inhibitory action.
Correspondingly, the embodiment of the present invention additionally provides above-mentioned 1, prepared by the one of 2-oxygen azepine cyclics derivant Method.The method comprises the steps:
S01: compounds X, Y that following structural formula represents are provided respectively,
S02: under conditions of existing with silver salt and organic solvent with rhodium catalyst precursor in oxygen-free environment, by step In S01, thing X, Y of chemical combination react, and obtain following general structure for 1 shown in (I), and 2-oxygen azepine cyclics spread out Biology,
A in described compounds X, Y and (I) structural formula is (miscellaneous) aromatic rings or non-aromatic ring；R1Selected from C1-C4Straight chain or Any one in alkyl containing substituent group side chain, alkoxy carbonyl group；R2、R3Selected from C1-C4Straight chain or the alkane containing substituent group side chain One in base, aryl, hydrogen.
Specifically, in above-mentioned steps S01, in compounds X general structure, A is (miscellaneous) aromatic rings or non-aromatic ring；R1Choosing From C1-C4Straight chain or containing any one in the alkyl of substituent group side chain, alkoxy carbonyl group.
Wherein, as described above, in a preferred embodiment (miscellaneous) virtue, when A is as (miscellaneous) aromatic rings, representated by this A Fragrant cyclic group 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 at least Can be any one in following group:
Wherein, n=0,1, X=O, S, N-PG.
In still another embodiment, above-mentioned, R1Selected from C1-C4When straight chain or the alkyl containing substituent group side chain, it is permissible It is methyl, ethyl, propyl group, butyl, isopropyl, isobutyl group, any one in the tert-butyl group；R1When alkoxy carbonyl group, it is permissible It is any one in benzyloxy group, tert-butyl group oxygen groups.
In this step S01, R in compound Y structure formula2、R3Selected from C1-C4Straight chain or the alkyl containing substituent group side chain Time, R2、R3Can be methyl, ethyl, propyl group, butyl, isopropyl, isobutyl group, any one in the tert-butyl group.
It addition, the compounds X in this step S01 can be prepared by existing method, and Y can directly city available from.
In above-mentioned steps S02, reaction environment in step S02 of compounds X, Y and system carry out reaction and generates as above General structure described in literary composition is (I) compound.
When in compounds X, A group is (miscellaneous) aromatic rings, compounds X, Y can represent at the chemical equation of reaction system Following a:
When in compounds X, A group is non-aromatic ring, compounds X, Y can represent such as at the chemical equation of reaction system Lower b:
In above-mentioned chemical equation a, chemical equation b reaction system, the oxygen-free environment of reaction system can be prevented effectively from Catalyst such as rhodium catalyst precursor oxidized or and lost efficacy, thus ensure above-mentioned chemical equation a, the reaction of chemical equation b It is smoothed out, and ensures the yield that target product general structure is (I) compound.
In above-mentioned chemical equation a, chemical equation b reaction system, know from experience before rhodium catalyst and react with silver salt Generate real active catalyst, thus promote reactants of X, Y to carry out reaction and generate target product.
In one embodiment, rhodium catalyst precursor and chemical combination in above-mentioned chemical equation a, chemical equation b reaction system The mol ratio of thing X is (0.03-0.1): 1.In a particular embodiment, rhodium catalyst precursor with the mol ratio of 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, rhodium catalyst precursor is 1:(2-33 with the mol ratio of silver salt).In a particular embodiment, rhodium Catalyst precarsor can be 1:2,1:5,1:8,1:10,1:15,1:20,1:25,1:30 or 1:33 etc. with the mol ratio of silver salt.
In a particular embodiment, this rhodium catalyst precursor can select dichloro (pentamethylcyclopentadiene) rhodium (III) dimerization Body；This silver salt can select Disilver carbonate, silver acetate, silver hexafluoroantimonate, at least one in the silver salt such as tetrafluoride boron is silver-colored.Such is excellent Chloride ion in the rhodium catalyst precursor of seed selection class can be seized with the silver ion in silver salt, generates real active catalyst, Thus effectively promote the reaction between reactants of X, Y, improve atom utilization and the yield of product.
Before to the control of the consumptions such as rhodium catalyst precursor, silver salt or adjusting its ratio or control rhodium catalyst further Body and the kind of silver salt, can improve the yield that general structure is (I) compound of target product further, and reduce rhodium as far as possible The reactant such as catalyst precarsor, silver salt consumption, thus the general structure improving productive target product is (I) production of chemicals Efficiency, reduces production cost.Meanwhile, this preferred rhodium catalyst precursor above-mentioned, silver salt consumption or adjust both ratio Control or the selection of both kinds, moreover it is possible to reduce reaction condition requirement between compounds X, Y, as made this compounds X, Y Between the temperature of reaction can the most at room temperature carry out, thus control to reaction condition further, thus drop further Low production cost.
It addition, compounds X in above-mentioned chemical equation a, chemical equation b reaction system, Y mole with can be according to Reactant molar ratio example in chemical equation a, chemical equation b is added.In order to promote this reaction to forward further Carry out, improve reaction rate and efficiency of pcr product.In one embodiment, compounds X, the mol ratio of Y are 1:(1-3).Concrete real Executing in example, the mol ratio of X Yu Y can be 1:1,1:2,1:3 etc..In order to improve above-mentioned chemical equation a, chemical reaction further The reaction efficiency of formula b reaction system and efficiency of pcr product, in a preferred embodiment, at above-mentioned chemical equation a, chemical equation b Reaction system has been also added with acid additive.In further preferred embodiments, the addition of this acid additive rubs with compounds X That ratio is 1:(1-0.5).In a particular embodiment, the acid addition of 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, this described acid additive selects pivalic acid, acetic acid, trifluoro second At least one in the organic acid such as acid, benzoic acid.The existence of this acid additive, can change the environment of reaction system, thus realize Improve reaction efficiency and the efficiency of pcr product of above-mentioned reaction system.
In above-mentioned reaction system, this acid additive can be directly together with reactants of X, Y and catalyst, reaction dissolvent etc. Mixing is reacted.In order to play its effect further, in one embodiment, by first for this acid additive and described compounds X, rhodium After catalyst precarsor and silver salt mixed processing, then dropping compound Y and organic solvent react in described mixed liquor.
On the basis of the various embodiments described above, the reaction in above-mentioned chemical equation a, chemical equation b reaction system is molten Agent select organic solvent, this organic solvent can select acetonitrile, liquid alcohol apoplexy due to endogenous wind at least one.
Therefore, above-mentioned 1,2-oxygen azepine cyclics derivative preparation method only need to provide oxygen-free environment, to equipment Requiring low, its technique is simple.By to the environment of reaction system and the control of catalyst, the yield of target product is high, and it is the purest Changing, therefore, its production cost is low.
Just because of the 1 of above-described embodiment offer, 2-oxygen azepine cyclics derivant have above-mentioned advantage, and it is prepared Method technique is simple, and yield is high, and easy purification, production cost is low.Therefore, it may be used for the preparation of cancer therapy drug.
In conjunction with embodiment, the present invention is further elaborated.
Embodiment 1
2-N-acetyl group-3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine and preparation method thereof.2-N-acetyl group-3-hydroxyl Shown in the structural formula following molecular structural formula I-a of base-4,5-dihydro-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S11.N-phenol acetamide oxide:
Addition HP (1.0eq) in round-bottomed flask, Cu-lyt. (1.0eq), activationMolecular sieve (250mg/mmol), and phenylboric acid (2.0eq), be subsequently adding 1,2-dichloroethane solvent (0.2M). to suspension Adding pyridine (1.1eq) in liquid, mixed system is uncovered, room temperature reaction 24-48 hour.Question response is complete, adds silicon in flask Glue, rotation is removed solvent, is crossed post and obtain 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% methanol.So After be added thereto to monohydrate hydrazine (3.0eq).Mixture stirred overnight at room temperature, then filters, and filtrate concentrates, and crosses post and obtains O-benzene Base azanol；
O-phenylhydroxylamine (1.0eq) is dissolved in ether (0.2M). it is slowly added to acetic anhydride under condition of ice bath (2.0eq), then recover 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:
The preparation of S12.2-N-acetyl group-3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine: add in the tube sealing of 15ml Enter N-phenol acetamide oxide (60.5mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol), then carry out in glove box Operation, bleeds for three times, three inflations, makes to keep in system nitrogen atmosphere.In tube sealing add acrylic aldehyde (53.5ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.After reaction terminates, filter, be concentrated to give thick Product.Crude product is obtained product I-a, yield 93% through column chromatography purification.N-phenol acetamide oxide is as follows with acrylic aldehyde chemical equation:
The product I-a of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz, CDCl3) 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,CDCl3)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 C11H13NO3Na(+): 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-benzyloxycarbonyl group-3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine and preparation method thereof.2-N-benzyloxycarbonyl group- Shown in the structural formula following molecular structural formula I-b of 3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S21.N-phenol oxygen benzyloxy amide: with the preparation method class of N-phenol acetamide oxide in embodiment 1 step S11 Seemingly, difference is simply to be become by substrate corresponding phenyl boronic acid derivative.
The preparation of S22.2-N-benzyloxycarbonyl group-3-hydroxyl-4,5-dihydro-1,2-benzo oxygen azepine: in the tube sealing of 15ml Addition N-phenol oxygen benzyloxy amide (97.3mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol). then carry out in glove box Operation, bleeds for three times, three inflations, makes to keep in system nitrogen atmosphere.In tube sealing add acrylic aldehyde (53.5ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.After reaction terminates, filter, be concentrated to give thick Product.Crude product is obtained product I-b, yield 40% through column chromatography purification.N-phenol oxygen benzyloxy amide is with acrylic aldehyde chemical equation such as Under:
The product I-b of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz, CDCl3) 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, CDCl3)δ158.95,156.28,135.53,130.86,130.24,128.56,128.29,127.83,126.85,124.77, 118.86,82.79,68.15,30.97,27.82.IR(cm-1):3429,2941,1701,1485,1319,760.HRMS(ESI) calculated for C17H17NO4Na(+):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-acetyl group-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, 2-benzo oxygen azepine and preparation method thereof.2-N-acetyl Base-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, shown in the structural formula following molecular structural formula I-c of 2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S31.2-methyl-N-phenol acetamide oxide: with the preparation side of N-phenol acetamide oxide in embodiment 1 step S11 Method is similar to, and difference is simply to be become by substrate corresponding phenyl boronic acid derivative.
S32.2-N-acetyl group-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, the preparation of 2-benzo oxygen azepine:
2-methyl-N-phenol acetamide oxide (66.1mg, 0.4mmol), dichloro (pentamethyl ring penta is added in the tube sealing of 15ml Diene) rhodium (III) dimer (7.4mg, 0.012mmol), silver acetate (0.04mmol) and pivalic acid (81.7mg, 0.8mmol), Then operate in glove box, bleed for three times, three inflations, make system keeps nitrogen atmosphere.Third is added in tube sealing Olefine aldehydr (53.5ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.After reaction terminates, mistake Filter, is concentrated to give crude product.Crude product is obtained product I-c, yield 90% through column chromatography purification.2-methyl-N-phenol acetamide oxide with Acrylic aldehyde chemical equation is as follows:
The product I-c of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(500MHz, CDCl3) 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,CDCl3)δ174.27,156.56,129.38,129.04,128.97,126.41, 123.77,79.98,30.30,28.22,21.89,16.11.HRMS(ESI)calculated for C12H15NO3Na(+): 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
2-N-acetyl group-3-hydroxyl-4,5-dihydro-8-fluoro-1,2-benzo oxygen azepine and preparation method thereof.2-N-acetyl Shown in the structural formula following molecular structural formula I-d of base-3-hydroxyl-4,5-dihydro-8-fluoro-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S41.3-fluoro-N-phenol acetamide oxide: with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11 Similar, difference is simply to be become by substrate corresponding phenyl boronic acid derivative.
The preparation of S42.2-N-acetyl group-3-hydroxyl-4,5-dihydro-8-fluoro-1,2-benzo oxygen nitrogen:
3-fluoro-N-phenol acetamide oxide (67.7mg, 0.4mmol), dichloro (pentamethyl ring penta 2 is added in the tube sealing of 15ml Alkene) rhodium (III) dimer (7.4mg, 0.012mmol), silver hexafluoroantimonate (0.04mmol) and trifluoroacetic acid (0.8mmol). so After operate in glove box, bleed for three times, three times inflation, make in system keep nitrogen atmosphere.Propylene is added in tube sealing Aldehyde (53.5ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.After reaction terminates, filter, It is concentrated to give crude product.Crude product is obtained product I-d, yield 92% through column chromatography purification.3-fluoro-N-phenol acetamide oxide and acrylic aldehyde Chemical equation is as follows:
The product I-d of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz, CD2Cl2) 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,CD2Cl2) 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 C11H12NO3FNa(+): 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
2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-chloro-1,2-benzo oxygen azepine and preparation method thereof.2-N-acetyl Shown in the structural formula following molecular structural formula I-e of base-3-hydroxyl-4,5-dihydro-7-chloro-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S51.4-chloro-N-phenol acetamide oxide: with the preparation method of N-phenol acetamide oxide in embodiment 1 step S11 Similar, difference is simply to be become by substrate corresponding phenyl boronic acid derivative.
The preparation of S52.2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-chloro-1,2-benzo oxygen azepine:
4-chloro-N-phenol acetamide oxide (74.2mg, 0.4mmol), dichloro (pentamethyl ring penta 2 is added in the tube sealing of 15ml Alkene) rhodium (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and benzoic acid (0.8mmol). so After operate in glove box, bleed for three times, three times inflation, make in system keep nitrogen atmosphere.Propylene is added in tube sealing Aldehyde (53.5ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.After reaction terminates, filter, It is concentrated to give crude product.Crude product is obtained product I-e, yield 93% through column chromatography purification.4-chloro-N-phenol acetamide oxide and acrylic aldehyde Chemical equation is as follows:
The product I-e of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(500MHz, CDCl3) 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,CDCl3)δ174.85,156.84,131.77, 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 C11H12NO3NaCl(+):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-acetyl group-3-hydroxyl-4,5-dihydro-7-methyl ester-1,2-benzo oxygen azepine and preparation method thereof.2-N-acetyl Shown in the structural formula following molecular structural formula I-f of base-3-hydroxyl-4,5-dihydro-7-methyl ester-1,2-benzo oxygen azepine:
Its preparation process is as follows:
The preparation of S61.4-methyl ester-N-phenol acetamide oxide: with the preparation side of N-phenol acetamide oxide in embodiment 1 step S11 Method is similar to, and difference is simply to be become by substrate corresponding phenyl boronic acid derivative.
The preparation of S62.2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-methyl ester-1,2-benzo oxygen azepine:
4-methyl ester-N-phenol acetamide oxide (83.7mg, 0.4mmol), dichloro (pentamethyl ring penta is added in the tube sealing of 15ml Diene) rhodium (III) dimer (7.4mg, 0.012mmol), tetrafluoride boron silver (0.36mmol) and pivalic acid (0.4mmol), so After operate in glove box, bleed for three times, three times inflation, make in system keep nitrogen atmosphere.Propylene is added in tube sealing Aldehyde (53.5ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.After reaction terminates, filter, It is concentrated to give crude product.Crude product is obtained product I-f, yield 70% through column chromatography purification.4-methyl ester-N-phenol acetamide oxide and propylene Aldehyde chemical equation is as follows:
The product I-f of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz, CDCl3) 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,CDCl3)δ174.79,166.27,161.62,133.38,129.83,128.75,126.54,117.78,79.85, 52.19,29.98,27.82,21.73.IR(cm-1):3374,2357,1715,1285,1115,1032.HRMS(ESI) calculated for C13H15NO5Na(+):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-acetyl group-3-hydroxyl-4,5-dihydro-7,8-dimethyl-1,2-benzo oxygen azepine and preparation method thereof.2-N- The structural formula following molecular structural formula I-g institute of acetyl group-3-hydroxyl-4,5-dihydro-7,8-dimethyl-1,2-benzo oxygen azepine Show:
Its preparation process is as follows:
The preparation of S71.3,4-dimethyl-N-phenol acetamide oxide: with the system of N-phenol acetamide oxide in embodiment 1 step S11 Preparation Method is similar to, and difference is simply to be become by substrate corresponding phenyl boronic acid derivative.
The preparation of S72.2-N-acetyl group-3-hydroxyl-4,5-dihydro-7,8-dimethyl-1,2-benzo oxygen azepine:
3,4-dimethyl-N-phenol acetamide oxide (71.7mg, 0.4mmol), dichloro (pentamethyl is added in the tube sealing of 15ml Cyclopentadiene) rhodium (III) dimer (0.04mmol), Disilver carbonate (0.08mmol) and pivalic acid (81.7mg, 0.8mmol).So After operate in glove box, bleed for three times, three times inflation, make in system keep nitrogen atmosphere.Propylene is added in tube sealing Aldehyde (526.7ul, 0.4mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.After reaction terminates, mistake Filter, is concentrated to give crude product.Crude product is obtained product I-g, yield 83% through column chromatography purification.3,4-dimethyl-N-phenol oxygen acetyl Amine is as follows with acrylic aldehyde chemical equation:
The product I-g of preparation is carried out proton nmr spectra (1H NMR) to analyze, its result is:1H NMR(500MHz, CD2Cl2) 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,CDCl3)δ174.80,156.21,135.18, 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 C13H17NO3Na(+):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-acetyl group-3-hydroxyl-4-hydrogen-5-ethyl-1,2-benzo oxygen azepine and preparation method thereof.2-N-acetyl group- Shown in the structural formula following molecular structural formula I-h of 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-acetyl group-3-hydroxyl-4-hydrogen-5-ethyl-1,2-benzo oxygen azepine:
N-phenol acetamide oxide (60.5mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium is added in the tube sealing of 15ml (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol). Then operate in glove box, bleed for three times, three inflations, make system keeps nitrogen atmosphere.Add in tube sealing (E)-amyl group-2-olefine aldehydr ((78.3ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.Instead After should terminating, filter, be concentrated to give crude product.Crude product is obtained product I-h, yield 96% through column chromatography purification.N-phenol oxygen acetyl Amine is as follows with (E)-amyl group-2-olefine aldehydr chemical equation:
The product I-h of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz, CDCl3) 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,CDCl3)δ174.28, 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 C13H17NO3Na(+):258.1106；Found:258.1098. this result enters one Step confirms that product I-h molecular structure is as above-mentioned molecular structure I-h.
Embodiment 9
2-N-acetyl group-3-hydroxyl-4-hydrogen-5-propyl group-1,2-benzo oxygen azepine and preparation method thereof.2-N-acetyl group- Shown in the structural formula following molecular structural formula I-i of 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-acetyl group-3-hydroxyl-4-hydrogen-5-propyl group-1,2-benzo oxygen azepine:
N-phenol acetamide oxide (60.5mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium is added in the tube sealing of 15ml (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol). Then operate in glove box, bleed for three times, three inflations, make system keeps nitrogen atmosphere.Add in tube sealing (E)-hexyl-2-olefine aldehydr (92.8ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.Instead After should terminating, filter, be concentrated to give crude product.Crude product is obtained product I-i, yield 88% through column chromatography purification.N-phenol oxygen acetyl Amine is as follows with (E)-hexyl-2-olefine aldehydr chemical equation:
The product I-i of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(500MHz, CD2Cl2) 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,CD2Cl2)δ173.83,158.04, 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 C14H19NO3Na(+):272.1263；Found:272.1254. this result further demonstrate that product I-i molecular structure is as upper State molecular structure I-i.
Embodiment 10
2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen azepine and preparation method thereof.2-N-acetyl Shown in the structural formula following molecular structural formula I-j of base-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: with the preparation side of N-phenol acetamide oxide in embodiment 1 step S11 Method is similar to, and difference is simply to be become by substrate corresponding phenyl boronic acid derivative.
The preparation of S102.2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzo oxygen azepine:
4-phenyl-N-phenol acetamide oxide (91mg, 0.4mmol), dichloro (pentamethyl ring penta 2 is added in the tube sealing of 15ml Alkene) rhodium (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol). then operate in glove box, bleed for three times, three inflations, make system keeps nitrogen atmosphere.To tube sealing Middle addition acrylic aldehyde (53.5ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.Reaction knot Shu Hou, filters, is concentrated to give crude product.Crude product is obtained product I-j, yield 66% through column chromatography purification.4-phenyl-N-phenol oxygen second Amide is as follows with acrylic aldehyde chemical equation:
The product I-j of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz, CDCl3) 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,CDCl3)δ175.01,157.73,140.15,138.01, 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 C17H17NO3Na(+):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-acetyl group-3-hydroxyl-4,5,7,8,9,9a-hexahydro benzo [f] [1,2] oxygen azepine and preparation method thereof.2- The structural formula following molecular structural formula II-a of N-acetyl group-3-hydroxyl-4,5,7,8,9,9a-hexahydro benzo [f] [1,2] oxygen azepine Shown in:
Its preparation process is as follows:
The preparation of S111.N-(hexamethylene-2-alkene-1-base epoxide) acetamide:
By HP (1.1eq), triphenylphosphine (1.5eq) is dissolved in dry oxolane, so After be added thereto to 2-cyclohexene-1-alcohol (1eq).Reaction system is cooled to 0 DEG C, is then added dropwise over azoformic acid diethyl Ester (1.5eq).Reactant mixture returns to room temperature, after stirred overnight, is concentrated by solution, crosses post and obtains 2-(hexamethylene-2-alkene-1- Base epoxide) isoindolinone-1,3-diketone；
2-(hexamethylene-2-alkene-1-base epoxide) isoindolinone-1,3-diketone (1.0eq) is dissolved in containing 10% methanol Chloroform (0.1M) in, be then added thereto to monohydrate hydrazine (3.0eq), mixture stirred overnight at room temperature, then filter, filtrate Concentrate, cross post；
The product (1.0eq) crossing post acquisition is dissolved in ether (0.2M). it is slowly added to acetic anhydride under condition of ice bath (2.0eq), then recover to room temperature, stir 3 hours.Mixture is concentrated, crosses post and obtain corresponding N-(hexamethylene-2-alkene-1-base Epoxide) acetamide product.
Chemical equation prepared by N-(hexamethylene-2-alkene-1-base epoxide) acetamide is as follows:
The preparation of S112.2-N-acetyl group-3-hydroxyl-4,5,7,8,9,9a-hexahydro benzo [f] [1,2] oxygen azepine: The tube sealing of 15ml adds N-(hexamethylene-2-alkene-1-base epoxide) acetamide (62.1mg, 0.4mmol), dichloro (pentamethyl ring penta Diene) rhodium (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol). then operate in glove box, bleed for three times, three inflations, make system keeps nitrogen atmosphere.To tube sealing Middle addition acrylic aldehyde (53.5ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.Reaction knot Shu Hou, filters, is concentrated to give crude product.Crude product is obtained product 1-(3-hydroxyl-4,5,7,8,9,9a-hexahydro through column chromatography purification Benzo [f] [1,2] oxygen azepine-2 (3H) acetyl group II-a, yield 81%.N-(hexamethylene-2-alkene-1-base epoxide) acetamide and third Olefine aldehydr chemical equation is as follows:
The product II-a of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz, CDCl3) 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,CDCl3)δ174.88,137.48,126.36,85.88,80.54,31.47, 30.85,28.07,24.99,21.16,20.79.IR(cm-1):3445,2930,2359,1639,1393,1076,1024.HRMS (ESI)calculated for C11H17NO3Na(+):234.1106；Found:234.1100. this result further demonstrate that product Thing II-a molecular structure is as above-mentioned molecular structure II-a.
Embodiment 12
Benzyl-2-acetyl group-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.Benzyl-2-acetyl group-3-hydroxyl-2,3,4,5,9,9a-hexahydropyridine base [4,3-f] [1,2] oxygen nitrogen Shown in the structural formula following molecular structural formula II-b of miscellaneous-8 (7H)-carboxylic acids:
Its preparation process is as follows:
S121. the preparation of benzyl-5-(acetylamino)-5,6-dihydropyridine-1 (2H)-carboxylic acid:
Butadiene monoxide (1eq), allylamine (2eq) and 0.4mL water is added in tube sealing.It is then heated to 100 DEG C, reaction After 6h. question response terminates, directly it is spin-dried for, obtains crude product 1-(allyl amino) butyl-3-alkene-2-alcohol, be directly used in next Step reaction；
Above-mentioned product is dissolved in dichloromethane, is subsequently adding triethylamine (1.2eq), is cooled to 0 DEG C, is slowly added dropwise chlorine Benzyl formate (1eq). recovery temperature to room temperature, mixture at room temperature reacts.Treat that raw material converts completely, add in system Enter some methanol, 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 dichloromethane, is subsequently adding Grubbs 1 ' the st catalyst of catalytic amount, Keeping reaction system concentration is 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 to benzyl-5-(acetylamino)-5,6-dihydro pyrrole The course of reaction of pyridine-1 (2H)-carboxylic acid is similar with S11 in embodiment 1, does not repeats them here, and its reactive chemistry formula is as follows:
S122. benzyl-2-acetyl group-3-hydroxyl-2,3,4,5,9,9a-hexahydropyridine base [4,3-f] [1,2] oxygen azepine-8 (7H) preparation of-carboxylic acid: add benzyl-5-(acetylamino)-5,6-dihydropyridine-1 (2H)-carboxylic acid in the tube sealing of 15ml (116.1mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol). then operate in glove box, bleed for three times, three Secondary inflation, makes to keep in system nitrogen atmosphere.Acrylic aldehyde (53.5ul, 0.8mmol) and acetonitrile (2.0ml) is added in tube sealing. Stir about 18 hours under room temperature again after dripping.After reaction terminates, filter, be concentrated to give crude product.By crude product through column chromatography purification Obtain product benzyl-2-acetyl group-3-hydroxyl-2,3,4,5,9,9a-hexahydropyridine base [4,3-f] [1,2] oxygen azepine-8 (7H)- Carboxylic acid II-b, yield 70%.Benzyl-5-(acetylamino)-5,6-dihydropyridine-1 (2H)-carboxylic acid and acrylic aldehyde chemical equation As follows:
The product II-b of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR (400MHz, oxygen Azepine-8 (7H)-carboxylic acid II-b, yield 70%.1H NMR(400MHz,CDCl3) 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,CDCl3)δ175.21,155.23,137.10,136.32,128.56(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 C18H22N2O5Na(+):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-(double (3-oxygen amyl group) the phenol oxygen of 2,6-) acetamide and preparation method thereof.N-(double (3-oxygen amyl group) the phenol oxygen of 2,6-) second Shown in the structural formula following molecular structure formula III of amide:
Its preparation process is as follows:
N-phenol acetamide oxide (60.5mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) rhodium is added in the tube sealing of 15ml (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol). Then operate in glove box, bleed for three times, three inflations, make system keeps nitrogen atmosphere.Penta is added in tube sealing Alkene-3-ketone (78.3ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.After reaction terminates, Filter, be concentrated to give crude product.Crude product is obtained product III, yield 48% through column chromatography purification.N-phenol acetamide oxide and amylene- 3-ketone chemical equation is as follows:
The product III of preparation carrying out proton nmr spectra (H NMR) analyze, 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)δ212.26,167.64,153.88,134.94, 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 C18H25NO4Na(+):342.1682；Found:342.1677.
Embodiment 14
3-hydroxyl-2-phenol oxygen-4,5-dihydro-1H-benzazepine-1-ketone.3-hydroxyl-2-phenol oxygen-2,3,4,5-tetrahydrochysene- Shown in the structural formula following molecular structure formula IV of 1H-benzazepine-1-ketone:
Its preparation process is as follows:
N-phenol oxy benzamide (85.3mg, 0.4mmol), dichloro (pentamethylcyclopentadiene) is added in the tube sealing of 15ml Rhodium (III) dimer (7.4mg, 0.012mmol), Disilver carbonate (11.0mg, 0.04mmol) and pivalic acid (81.7mg, 0.8mmol).Then operate in glove box, bleed for three times, three inflations, make system keeps nitrogen atmosphere.To tube sealing Middle addition acrylic aldehyde (53.4ul, 0.8mmol) and acetonitrile (2.0ml). stir about 18 hours under room temperature again after dripping.Reaction knot Shu Hou, filters, is concentrated to give crude product.Crude product is obtained product IV, yield 80% through column chromatography purification.N-phenol oxy benzamide with Acrylic aldehyde chemical equation is as follows:
The product IV of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz, CD2Cl2) 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,CD2Cl2)δ170.75,158.90, 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 C16H15NO3Na(+):292.0950；Found:292.0945.
Embodiment 15
N-(chromane) acetamide.Shown in the structural formula following molecular structure Formula V of N-(chromane) acetamide:
Its preparation process is as follows:
The product I-a of gained is dissolved in dichloromethane, is subsequently adding palladium carbon, insert hydrogen balloon, carry out three ventilations, Making system keep nitrogen atmosphere, reactant mixture is stirred at room temperature overnight.Finally filter, be spin-dried for filtrate i.e. obtaining product V, yield 80%, corresponding chemical equation is as follows:
The product V of preparation carrying out proton nmr spectra (H NMR) analyze, its result is:1H NMR(400MHz,CDCl3) 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, CDCl3)δ169.87,153.37,129.22,127.63,120.84,120.70,117.15,75.84,26.97,23.52, 23.31.HRMS(ESI)calculated for C11H14NO3(+):192.0954；Found:192.1000.
Application Example 1
Detection example: Proliferation Ability and the cytotoxicity of myeloma cell line LP-1 cell are tested by compound (I-j)
Compound (I-j) uses DMSO to be made into 100mM liquid storage.
Take the logarithm trophophase LP-1 cell suspension (making cell detachment through 0.25% trypsinization) 0.5-1.0 × 104/ hole, is sub-packed in 96 well culture plates, 100 μ L/ holes, cultivates 24 hours, after cell attachment, is separately added into 10 μ L corresponding not With medicine or the test solution of concentration, experiment sets negative control group (normal saline), solvent control group (adds 2%DMSO and makes final concentration It is 0.5%) and 6 variable concentrations administration groups.Often group sets 3 parallel holes.Put constant temperature 5%CO2Incubator 37 DEG C cultivates 24 respectively, 48 and 72 hours.Examine under a microscope cells survival state, it is possible to find cell effectively presses down 10 μMs of drug level are derived above System, its result is as shown in Figure 1.Wherein, this solvent control group examines under a microscope cells survival state as shown in Figure 1a, 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 shakes rearmounted enzyme joint inspection in 1 minute and surveys Instrument, surveys the OD value in each hole, makees Fig. 2 in 450nm wavelength.And seek growth inhibition ratio by following equation, and obtain half by B1iss method Inhibition concentration IC50: computing formula: drug on tumor cell inhibitory rate=(1-medication group mean OD value/matched group mean OD value) × 100%.
Result shows that compound described in this patent (I-j) has stronger suppression and makees myeloma cell line LP-1 cell With.
It addition, use embodiment 1-9 and the 1 of the offer of embodiment 11-15,2-oxygen azepine cyclics derivant are respectively Test according to the experimental technique of compound (I-j), show that those compounds have similar biology and live to compound (I-j) Property, all show and myeloma cell line LP-1 cell is had stronger inhibitory action.Therefore 1 described in the embodiment of the present invention, 2-oxygen azepine cyclics derivant can be used for preparing anticancer medicine.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention Any amendment, equivalent and the improvement etc. made within god and principle, should be included within the scope of the present invention.

Claims (3)

1. one kind 1,2-oxygen azepine cyclics derivant treat the application of myeloma medicine, its molecular structure as preparation Formula is following (I):
In formula, A is aromatic rings or non-aromatic ring；R1For ethyl；R2、R3Any one in hydrogen, ethyl, propyl group；
When described A is aromatic rings, described aromatic rings is any one group following:
When described A is non-aromatic ring, and described non-aromatic ring is any one group following:
Wherein, n=1, X=N-Cbz.
1,2-oxygen azepine the most according to claim 1 cyclics derivant are as preparation treatment myeloma medicine Application, it is characterised in that: described 1,2-oxygen azepine cyclics derivant are 2-N-acetyl group-3-hydroxyl-4,5-dihydro- 1,2 benzo oxygen azepines, 2-N-acetyl group-3-hydroxyl-4,5-dihydro-9-methyl isophthalic acid, 2 benzo oxygen azepines, 2-N-acetyl group-3-hydroxyl The fluoro-1,2 benzo oxygen azepines of base-4,5-dihydro-8-, the 2-N-acetyl group chloro-1,2 benzo oxygen azepines of-3-hydroxyl-4,5-dihydro-7-, 2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-methyl ester-1,2 benzo oxygen azepine, 2-N-acetyl group-3-hydroxyl-4,5-dihydro-7, 8-dimethyl-1,2 benzo oxygen azepine, 2-N-acetyl group-3-hydroxyl-4-hydrogen-5-ethyl-1,2 benzo oxygen azepine, 2-N-acetyl Base-3-hydroxyl-4-hydrogen-5-propyl group-1,2 benzo oxygen azepine, 2-N-acetyl group-3-hydroxyl-4,5-dihydro-7-phenyl-1,2-benzene And at least one in oxygen azepine.
1,2-oxygen azepine the most according to claim 1 cyclics derivant are as preparation treatment myeloma medicine Application, it is characterised in that: described 1,2-oxygen azepine cyclics derivant are 2-N-acetyl group-3-hydroxyl-4,5,7,8, 9,9a-hexahydro benzo [f] [1,2] oxygen azepine, benzyl-2-acetyl group-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.
CN201410409341.4A 2014-08-19 2014-08-19 Application of 1,2-oxa-cyclic compound derivative for preparing myeloma treamtnet medicine Active CN104262283B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410409341.4A CN104262283B (en) 2014-08-19 2014-08-19 Application of 1,2-oxa-cyclic compound derivative for preparing myeloma treamtnet medicine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410409341.4A CN104262283B (en) 2014-08-19 2014-08-19 Application of 1,2-oxa-cyclic compound derivative for preparing myeloma treamtnet medicine

Publications (2)

Publication Number Publication Date
CN104262283A CN104262283A (en) 2015-01-07
CN104262283B true CN104262283B (en) 2017-01-11

Family

ID=52153898

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410409341.4A Active CN104262283B (en) 2014-08-19 2014-08-19 Application of 1,2-oxa-cyclic compound derivative for preparing myeloma treamtnet medicine

Country Status (1)

Country Link
CN (1) CN104262283B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104829550B (en) * 2015-05-04 2016-10-05 四川大学 The method efficiently preparing o-hydroxy-phenyl heterocyclic derivative based on transition metal-catalyzed C-H/C-H oxidative coupling reaction
CN114989108B (en) * 2022-05-09 2024-08-09 长沙学院 1, 4-Oxazapine-2, 5-diketone compound and preparation method and application 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
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;Pingping Duan 等;《Chem. Commun.》;20140818;第50卷(第81期);第12135-12138页 *

Also Published As

Publication number Publication date
CN104262283A (en) 2015-01-07

Similar Documents

Publication Publication Date Title
Cook et al. Terminal ynamides: synthesis, coupling reactions, and additions to common electrophiles
Wang et al. Synthesis of isonitriles from N-substituted formamides using triphenylphosphine and iodine
Fujii et al. Efficient synthesis of 2-oxazolidinones and quinazoline-2, 4 (1H, 3H)-diones from CO2 catalyzed by tetrabutylammonium fluoride
CN104262283B (en) Application of 1,2-oxa-cyclic compound derivative for preparing myeloma treamtnet medicine
CN107660206A (en) For preparing the method and intermediate of { base of 1 (ethylsulfonyl) 3 [base of 4 (base of 7H pyrrolo-es [2,3 d] pyrimidine 4) 1H pyrazoles 1] azetidine 3 } acetonitrile
CN103554122B (en) A kind of containing chromone structure pyrazoles norcantharidin derivative and preparation method thereof and application
CN107056668A (en) Thiocarbamide is He oxazolidine thioketone and its synthetic method and application
CN104447755A (en) Hexahydropyrrole[2,3-b]indole carboxylate compound and synthesis method thereof
CN106946972B (en) A kind of ursolic acid derivative with anti-tumor activity and preparation method thereof
CN105175329A (en) New synthesis route and method of bedaquiline racemate
CN1953963A (en) Process for producing cyclic N-hydroxyimide compound
CN108456227B (en) A kind of chloro- 3- cyclobutenyl phosphonate compound of the fluoro- 3- sulfonyl -2- of 1,1- bis- and its synthetic method and application
CN102633741B (en) Application of thiazole compounds in aspect of killing fresh water algae
CN106188044A (en) A kind of synthetic method of 3 arylthio imidazos [1,5 a] the N heterocyclic compound of catalysis of iodine
CN106977415A (en) One planting sand storehouse must be bent intermediate and preparation method thereof
Zhang et al. Application of asymmetric aminohydroxylation to heteroaromatic acrylates
La et al. Facile synthesis of diphenylmethyl esters from 2-diphenylmethoxypyridine using catalytic boron trifluoride· diethyl etherate
CN102863361A (en) Chiral catalytic synthesis method of thiamphenicol
CN103980282A (en) Method for synthesizing 3-oxo-pyrrol[2,3-b]indole compounds
CN108727399B (en) A kind of benzo dioxane indole derivatives and its preparation method and application
Monbaliu et al. [4+ 2] Cycloaddition of 1-phosphono-1, 3-butadiene with azo-and nitroso-heterodienophiles
CN109666006B (en) Aryl derivative bithiazole compound and preparation method and application thereof
Kore et al. Ionic-tag-assisted synthesis of nucleoside triphosphates
Khan et al. Asymmetric synthesis of α-aminophosphonate esters by the addition of dialkyl phosphites to tert-butanesulfinyl imines
CN104045643B (en) A kind of method that copper catalysis water phase prepares pyrazolo [1,5-c] quinazoline framework compound

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant