CN106928156B - A kind of one step simple and convenient process for preparing of cyclic annular (8-11) compound of interior bisamide - Google Patents

A kind of one step simple and convenient process for preparing of cyclic annular (8-11) compound of interior bisamide Download PDF

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CN106928156B
CN106928156B CN201511027501.XA CN201511027501A CN106928156B CN 106928156 B CN106928156 B CN 106928156B CN 201511027501 A CN201511027501 A CN 201511027501A CN 106928156 B CN106928156 B CN 106928156B
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CN106928156A (en
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王巍
杨剑
李俊
吴丹
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Wuhan University WHU
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract

Containing there are three the interior bisamide cyclic compound of peptide bond, the compound of this kind of cyclization is 8-11 member ring the present invention relates to a kind of, all has the skeleton containing two lactams.The present invention takes multi-component reaction means, select the combination of specific reaction raw materials acid anhydrides, aldehyde, diamines and isonitrile, one pot under conditions of common, a step form four chemical bonds and cyclization, the size of ring can be regulated and controled according to raw material, finally obtain cyclic amide (8-11 member ring) class compound containing multiple side-chain structures, this kind of novel screening study that can be used for new drug containing bisamide cyclic structure compound in 8-11 member.

Description

A kind of one step simple and convenient process for preparing of cyclic annular (8-11) compound of interior bisamide
Technical field
The present invention relates to the preparation methods of a kind of interior bisamide cyclic compound and the compound.One kind is specifically disclosed to contain There is the synthetic method of 8-11 member cyclic lactames framework compound.
Background technique
Cyclic amide is a kind of important drug molecule skeleton, such as 4 member ring beta- beta-lactam antibiotics drugs, such Molecule of the skeleton is widely used in new drug discovery research.Furthermore the drug of another kind of cyclic lactames structure is with cyclic bisamide structure For the molecule of skeleton, there is no the cis- amido bond of the ionizable property of C and N-terminal and height ratio due to cyclic lactames so that it The degradation of enzyme can be resisted in vivo and improves membrane permeability；Cyclic structure largely decreases the flexibility of structure, mentions Its high selectivity and affinity to receptor, such as 6 member ring piperazinediones, 7 member ring Benzodiazepine diketone and 8 member ring phenodiazines virtues Acetyl caproyl structure, 6 member rings and 7 member rings in such bisamide cyclic structure are the primary study object of drug research for a long time, And octatomic ring is more difficult due to synthesizing, the derivative of synthesis is less, studies accordingly less.Furthermore lactam structure in document The method preparation of multistep protection deprotection is usually taken, also forms ring after replacing ester etc. to be replaced frequently with bromine, these sides Method is applied in 7 member rings and the synthesis below of 7 member rings.Above method is primary disadvantage is that raw material needs after protecting or being derivative It can use, and the diversity of product is limited by raw material type is less.Cyclic amides more than 8 member rings is at present then because of system Standby difficulty reason, the type of synthesis is fewer, also more rare to its activity research.
In US5770590 patent, it was recently reported that a kind of 8 member ring diazocine diketone (diazocine-dione) swash in speed Peptide receptor antagonism and its synthetic method.Synthesis uses multistep synthetic intermediate, and last cyclization mode is amide in alkaline item Nucleophilic displacement of fluorine forms 8 member rings to methoxy sulphonyl ester group under part.The synthesis of known diazocine diketone can also take such as double carboxylics The double acyl chlorides and diamine of sour substep activation it is directly cyclic (Chemische Berichte, 1958,91,1775-81；Polish Journal of Chemistry, 1984,58 (7-9), 877-80), dibasic acid esters and diamine condensation (Heterocycles, 1985,23 (6),1425-30；Journal of the American Chemical Society,1988,110(12),3979-82；) logical The reaction of ring expansion is crossed, heptatomic ring oxime obtains octatomic ring (Synthetic by Beckmann rearrangement ring expansion Communications,2002,32(13),1929–1936)。
Multi-component reaction (Multicomponent Reaction, MCR) is placed on multiple substrates in one reactor, Without the separation of intermediate, a step constructs the operating method of product.It synthesizes with various structures rapid, high volume may be implemented The compound of property and complexity simultaneously establishes corresponding compound library, thus the extensive concern by Pharmaceutical Chemist.It is known more Component reaction type has relevant report in the literature (Chem.Rev.2012,112,3083-3135), is mainly used in amide In the synthesis of key and heterocycle, the selection meticulously of reaction type and raw material is closely related.
So far, there are no multi-component reactions for a kind of containing there are three the conjunctions of the interior bisamide cyclic compound of peptide bond At this kind of cyclic compound is 8-11 member ring.
Summary of the invention
The present invention takes multi-component reaction means, selects specific reaction raw materials acid anhydrides, aldehyde, the group of diamines and isonitrile It closes, the synthesis of a few class 8-11 member rings can be completed under conditions of one pot and one-step method, the structure of this kind of cyclic compound all has There are two the skeletons of lactams.
Therefore, the present invention provides a kind of interior bisamide cyclic compound, and the compound of this kind of cyclization is 8-11 member ring, all has There is the cyclic skeleton containing two lactams, and there is structure shown in logical formula (I):
Wherein,
R1-NH2For(n-ethylethylenediamine),(N- methyl 1,3- propane diamine),(N- benzyl ethylenediamine),((S) -2- (aminomethyl) pyrrolidine hydrochloride),(N- methyl-1,2- phenylene diamine hydrochlorate)；
R2- CHO be HCHO (formaldehyde),(propionic aldehyde),(p-chlorobenzaldehyde),(to fluorobenzene first Aldehyde),(p-tolyl aldehyde)；
R3Series acid anhydrides be(phthalic anhydride),(maleic anhydride),(heterocyclic acids Acid anhydride),(1,8- naphthalene dicarboxylic anhydride),(biphenyl acid anhydrides)；
R4- NC is(tert-butyl isonitrile),(adamantane isonitrile),(hexamethylene isonitrile),(benzyl isonitrile),(glycine methyl ester isonitrile)；
The compound of structure shown in logical formula (I) be preferably compound M1, M2, M3, M4, M5, M6, M7, M8, M9, M10, M11、M12、M13、M14、M15、M16、M17、M18、M19、M20、M21、M22、M23、M24、M25、M26、M27、M28、M29、 M30,
A method of prepare above-mentioned containing a kind of interior bisamide cyclic compound, comprising the following steps: with methanol be it is molten Agent after carrying out the aminated compounds containing R1 hybrid reaction 4 hours with the aldehyde compound containing R2, is added the acid anhydrides containing R3 and contains The different nitrile compounds of R4 are stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and then uses silica gel column chromatography for reaction Column is separated to get to the compound for leading to structure shown in formula (I).
Preferably:
The aminated compounds containing R1 is(n-ethylethylenediamine),(N- Methyl 1,3- propane diamine),(N- benzyl ethylenediamine),((S) -2- (ammonia first Base) pyrrolidine hydrochloride),(N- methyl-1,2- phenylene diamine hydrochlorate)；
The aldehyde compound containing R2 be HCHO (formaldehyde),(propionic aldehyde),(p-chlorobenzaldehyde),(4-Fluorobenzaldehyde),(p-tolyl aldehyde)；
The acid anhydrides containing R3 is(phthalic anhydride),(maleic anhydride),It is (miscellaneous Cyclic acid anhydride),(1,8- naphthalene dicarboxylic anhydride),(biphenyl acid anhydrides)；
The different nitrile compounds containing R4 are(tert-butyl isonitrile),(adamantane isonitrile), (hexamethylene isonitrile),(benzyl isonitrile),(glycine methyl ester isonitrile)；
Preferably: the aminated compounds containing R1, the aldehyde compound containing R2, the acid anhydrides containing R3 and the isonitrile class chemical combination containing R4 The molar ratio of object is 1:1:1:1.
The present invention takes multi-component reaction means, by reasonable employment raw material diamine simple and easy to get, acid anhydrides, and aldehyde and different Nitrile, by way for the treatment of different things alike, one step forms four chemical bonds and cyclization under conditions of common, and the size of ring can be according to original Material is regulated and controled, and cyclic amide (8-11 member ring) class compound containing multiple side-chain structures, the conjunction of this kind of simplicity are finally obtained The novel screening study that can be not only used for new drug containing bisamide cyclic structure compound in 8-11 member obtained at method, also can be used The macrocyclic compound prepared by other means is difficult in the reaction preparation of other chemical derivatizations.
Specific embodiment
By following detailed description it will be further appreciated that the features and advantages of the invention.Provided embodiment is only pair The explanation of the method for the present invention, remaining content without limiting the invention in any way announcement.
[embodiment 1]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), cyclohexyl isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 32%.Products therefrom M1 structure is as follows:
M1:N- cyclohexyl -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine two Ketone -2 (H) base) acetamide；Molecular formula: C20H27N3O3
1H NMR(400MHz,CDCl3) δ 7.87 (dd, J=5.4,3.1Hz, 2H), 7.75 (dd, J=5.5,3.0Hz, 2H), 7.01 (d, J=8.0Hz, 1H), 3.78 (t, J=6.0Hz, 2H), 3.70 (m, 1H), 3.10 (s, 2H), 2.78 (t, J= 6.0Hz, 2H), 2.57 (q, J=7.1Hz, 2H), 1.77 (dd, J=12.6,3.6Hz, 2H), 1.60 (m, 3H), 1.31 (d, J= 13.1Hz, 2H), 1.08 (m, 2H), 0.95 (t, J=7.1Hz, 4H).
13C NMR(100MHz,CDCl3)δ170.1(2C),168.3,134.1(2C),131.9(2C),123.3(2C), 59.07(s),53.0,48.8,47.3,36.5,32.8,25.5(2C),24.7(2C),12.1。
[embodiment 2]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), benzyl isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for for reaction, With silica gel post separation, yield 22%.Products therefrom M2 structure is as follows:
M2:N- benzyl -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine diketone -2 (1H)) acetamide；Molecular formula: C21H23N3O3
1H NMR(400MHz,CDCl3) δ 7.76 (dd, J=5.5,3.1Hz, 2H), 7.69 (dd, J=5.4,3.1Hz, 2H), 7.52 (s, 1H), 7.26 (dd, J=16.6,13.4Hz, 5H), 4.38 (d, J=6.0Hz, 2H), 3.75 (t, J= 6.1Hz, 2H), 3.21 (s, 2H), 2.78 (t, J=6.1Hz, 2H), 2.57 (q, J=7.1Hz, 2H), 0.91 (t, J=7.1Hz, 3H)。
13C NMR(100MHz,CDCl3)δ171.1(2C),168.4,138.4(2C),134.1(2C),131.8(2C), 128.5(2C),127.5(2C),127.2,123.3,58.9,52.8,49.1,42.9,36.6,12.0。
[embodiment 3]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 40%.Products therefrom M3 structure is as follows:
M3:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo - 2 (1H) base of [f] [1,4] diazocine diketone) acetamide；Molecular formula: C24H31N3O3
1H NMR(400MHz,CDCl3) δ 7.87 (dd, J=5.4,3.1Hz, 2H), 7.75 (dd, J=5.4,3.0Hz, 2H), 6.78 (s, 1H), 3.78 (t, J=6.1Hz, 2H), 3.00 (s, 2H), 2.78 (t, J=6.1Hz, 2H), 2.57 (q, J= 7.1Hz, 2H), 1.99 (s, 3H), 1.84 (d, J=2.4Hz, 6H), 1.62 (s, 6H), 0.97 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ169.9(2C),168.2,134.0(2C),132.0(2C),123.3(2C), 59.6,52.5,50.9(2C),48.7,41.3(3C),36.3(3C),29.37(3C),12.1。
[embodiment 4]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), tert-butyl base isonitrile (83mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 28%.Products therefrom M4 structure is as follows:
M4:N- (tert-butyl) -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine two Ketone -2 (1H) base) acetamide；Molecular formula: C18H25N3O3
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.4,3.1Hz, 2H), 7.74 (dd, J=5.5,3.1Hz, 2H), 6.90 (s, 1H), 3.77 (t, J=6.2Hz, 2H), 3.02 (s, 2H), 2.77 (t, J=6.2Hz, 2H), 2.55 (q, J= 7.1Hz, 2H), 1.26 (s, 9H), 0.95 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ170.2(2C),168.3(s),134.1(2C),131.9(2C),123.3 (2C),59.6,52.4,50.3,48.9,36.4,28.5(3C),12.2。
[embodiment 5]
It weighs respectively n-ethylethylenediamine (88mg, 1mmol), p-chlorobenzaldehyde (140mg, 1mmol) is in the round bottom of 25mL In flask, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic acid Acid anhydride (148mg, 1mmol), cyclohexyl isonitrile (109mg, 1mmol), is stirred at room temperature, and reaction overnight, after complete reaction, is depressurized It is spin-dried for, with silica gel post separation, yield 15%.Products therefrom M5 structure is as follows:
M5:2- (4- chlorphenyl)-N- cyclohexyl -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1, 4] diazocine diketone -2 (1H) yl acetamide；Molecular formula: C26H30ClN3O3
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.4,3.1Hz, 2H), 7.75 (dd, J=5.4,3.1Hz, 2H), 7.22 (m, 4H), 4.22 (s, 1H), 3.81-3.71 (m, 2H), 3.60 (m, 1H), 2.74 (dd, J=13.6,6.9Hz, 1H), 2.64 (m, 2H), 2.42 (dd, J=13.3,6.8Hz, 1H), 1.80 (m, 2H), 1.62 (m, 3H), 1.40 (m, 3H), 1.20 (m, 2H), 0.94 (t, J=7.0Hz, 3H).
13C NMR(100MHz,CDCl3)δ170.2(2C),168.4,134.2(2C),134.1(2C),133.9(2C), 132.0(2C),131.1(2C),128.4,123.3,70.7,48.1,47.7,37.1,32.8,32.7,25.5(2C),24.8 (2C),12.1。
[embodiment 6]
It weighs respectively n-ethylethylenediamine (88mg, 1mmol), p-chlorobenzaldehyde (140mg, 1mmol) is in the round bottom of 25mL In flask, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic acid Acid anhydride (148mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), is stirred at room temperature, and reaction overnight, after complete reaction, is depressurized It is spin-dried for, with silica gel post separation, yield 12%.Products therefrom M6 structure is as follows:
M6:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (4- chlorphenyl) -2- (dioxo -3,4 5- ethyl -1,6-, - 2 (1H) base of 5,6- tetrahydro benzo [f] [1,4] diazocine diketone) acetamide；Molecular formula: C30H34ClN3O3
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.4,3.0Hz, 2H), 7.75 (dd, J=5.4,3.1Hz, 2H),7.21(m,4H),4.20(s,1H),3.77(m,1H),3.65(m,1H),2.70(m,3H),2.42(m,1H),2.04(d, J=1.8Hz, 3H), 1.95 (d, J=2.3Hz, 6H), 1.66 (s, 6H), 0.96 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ170.1(2C),168.3,134.1(2C),133.7(2C),132.0(2C), 131.1(2C),128.3(2C),123.3(2C),71.0,51.4,48.0,45.9,41.3(3C),36.8,36.3(3C),29.4 (3C),12.3。
[embodiment 7]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add maleic anhydride (100mg, 1mmol), cyclohexyl isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silicon for reaction Rubber column gel column separation, yield 25%.Products therefrom M7 structure is as follows:
M7:(Z)-N- cyclohexyl -2- (4- ethyl -5,8- dioxo 3,4,5,8- tetrahydro -1,4- diazocine diketone -1 (2H) base) acetamide；Molecular formula: C16H25N3O3
1H NMR(400MHz,CDCl3) δ 7.03 (d, J=8.0Hz, 1H), 6.75 (s, 2H), 3.71 (m, 1H), 3.60 (t, J=6.1Hz, 2H), 3.08 (s, 2H), 2.67 (t, J=6.1Hz, 2H), 2.52 (q, J=7.1Hz, 2H), 1.87 (d, J= 15.7Hz, 3H), 1.67 (t, J=25.5Hz, 3H), 1.26 (dd, J=51.4,44.9Hz, 4H), 0.96 (t, J=7.1Hz, 3H)。
13C NMR(100MHz,CDCl3)δ170.7(2C),170.0,134.2(2C),59.0,52.8,49.1,47.5, 36.6,33.0,25.5(2C),24.8(2C),12.2。
[embodiment 8]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add maleic anhydride (100mg, 1mmol), benzyl isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silicagel column for reaction Separation, yield 18%.Products therefrom M8 structure is as follows:
M8:(Z)-N- benzyl -2- (4- ethyl -5,8- dioxo 3,4,5,8- tetrahydro -1,4- diazocine diketone -1 (2H) Base) acetamide；Molecular formula: C17H21N3O3
1H NMR(400MHz,CDCl3) δ 7.44 (s, 1H), 7.30 (dt, J=11.9,5.1Hz, 5H), 6.51 (s, 2H), 4.44 (d, J=6.0Hz, 2H), 3.56 (dd, J=7.4,4.7Hz, 2H), 3.16 (s, 2H), 2.68 (t, J=6.1Hz, 2H), 2.55 (q, J=7.1Hz, 2H), 0.94 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ166.8(2C),166.4,134.1,129.6,124.3(2C),123.4(2C), 123.0,54.5,48.5,44.6,38.7,32.1,7.7。
[embodiment 9]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add maleic anhydride (100mg, 1mmol), tert-butyl isonitrile (83mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silica gel for reaction Post separation, yield 16%.Products therefrom M9 structure is as follows:
M9:(Z)-N- (tert-butyl) -2- (4- ethyl -5,8- dioxo 3,4,5,8- tetrahydro -1,4- diazocine diketone -1 (2H) base) acetamide；Molecular formula: C14H23N3O3
1H NMR(400MHz,CDCl3) δ 6.90 (s, 1H), 6.73 (s, 2H), 3.60 (t, J=6.2Hz, 2H), 2.99 (s, 2H), 2.66 (t, J=6.2Hz, 2H), 2.52 (q, J=7.1Hz, 2H), 1.34 (s, 9H), 0.97 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ166.3(2C),165.9,129.9(2C),55.3,48.0,46.1,44.7, 32.0,24.3(3C),7.9。
[embodiment 10]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add maleic anhydride (100mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silicon for reaction Rubber column gel column separation, yield 10%.Products therefrom M10 structure is as follows:
Tetrahydro -1 M10:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (Z) -4- ethyl -5,8- dioxo 3,4,5,8-, 4- diazocine diketone -1 (2H) base) acetamide；Molecular formula: C20H29N3O3
1H NMR(400MHz,CDCl3) δ 6.79 (s, 1H), 6.74 (s, 2H), 3.60 (t, J=6.3Hz, 2H), 2.98 (s, 2H), 2.66 (t, J=6.3Hz, 2H), 2.53 (q, J=7.1Hz, 2H), 2.07 (s, 3H), 1.98 (d, J=2.8Hz, 6H), 1.68 (s, 6H), 0.97 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ170.6(2C),169.9,134.2(2C),59.6,52.3,51.1,48.9, 41.5(3C),36.3(3C),29.7,29.4(3C),12.3。
[embodiment 11]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), propionic aldehyde (58mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), cyclohexyl isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 18%.Products therefrom M11 structure is as follows:
M11:N- cyclohexyl -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine two Ketone -2 (1H) base) butyramide；Molecular formula: C22H31N3O3
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.4,3.1Hz, 2H), 7.75 (dd, J=5.5,3.0Hz, 2H), 6.93 (d, J=8.3Hz, 1H), 3.80 (dd, J=13.5,6.7Hz, 1H), 3.60 (m, 2H), 3.05 (dd, J=8.3, 4.8Hz, 1H), 2.85 (t, J=6.0Hz, 2H), 2.49 (q, J=7.1Hz, 2H), 1.82 (m, 2H), 1.65 (m, 3H), 1.31 (m, 3H), 1.12 (m, 4H), 1.00 (t, J=7.4Hz, 3H), 0.87 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ172.3(2C),168.6,134.1(2C),131.9(2C),123.2(2C), 67.4,49.1,47.6,45.1,37.6,33.0,32.8,25.6,25.0,24.9,19.7,13.6,12.6。
[embodiment 12]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add heterocycle acid anhydrides (166mg, 1mmol), cyclohexyl isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silicon for reaction Rubber column gel column separation, yield 32%.Products therefrom M12 structure is as follows:
M12:N- cyclohexyl -2- (5- ethyl -1,6- dioxo 3,4,5,6,6a, 7,10,10a octahydro -7,10- epoxy benzene And simultaneously -2 (1H) base of [f] [1,4] diazocine diketone) acetamide；Molecular formula: C20H29N3O4
1H NMR(400MHz,CDCl3) δ 7.11 (d, J=8.5Hz, 1H), 6.54 (s, 2H), 5.28 (s, 2H), 3.85- 3.67 (m, 1H), 3.56 (t, J=6.3Hz, 2H), 3.08 (s, 2H), 2.86 (s, 2H), 2.66 (t, J=6.3Hz, 2H), 2.50 (q, J=7.1Hz, 2H), 1.90 (m, 2H), 1.61 (m, 3H), 1.25 (m, 5H), 0.97 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ176.2(2C),170.1,136.5(2C),80.9(2C),58.9,51.7 (2C),49.4,47.6,47.4,37.6,33.0(2C),25.5,24.9(2C),12.1。
[embodiment 13]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add heterocycle acid anhydrides (166mg, 1mmol), benzyl isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silicagel column for reaction Separation, yield 28%.Products therefrom M13 structure is as follows:
M13:- benzyl -2- (5- ethyl -1,6- dioxo 3,4,5,6,6a, 7,10,10a octahydro 7,10- epoxy benzo [f] [1,4] diazocine diketone -2 (1H) base) acetamide；Molecular formula: C21H25N3O4
1H NMR(400MHz,CDCl3) δ 7.53 (s, 1H), 7.29 (dd, J=19.1,6.8Hz, 5H), 6.43 (s, 2H), 5.00 (s, 2H), 4.43 (d, J=6.1Hz, 2H), 3.55 (t, J=6.0Hz, 2H), 3.15 (s, 2H), 2.71 (t, J= 6.0Hz, 2H), 2.67 (s, 2H), 2.52 (q, J=7.1Hz, 2H), 0.93 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ171.9(2C),166.9,134.4,132.0(2C),124.2(2C),123.4 (2C),122.9(s),76.4(2C),54.4,47.0,44.4(2C),42.9,38.6,32.9,7.3。
[embodiment 14]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add heterocycle acid anhydrides (166mg, 1mmol), tert-butyl isonitrile (83mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silica gel for reaction Post separation, yield 28%.Products therefrom M14 structure is as follows:
M14:N- (tert-butyl) -2- (5- ethyl -1,6- dioxo 3,4,5,6,6a, 7,10,10a octahydro 7,10- epoxy benzene And -2 (1H) base of [f] [1,4] diazocine diketone) acetamide；Molecular formula: C18H27N3O4
1H NMR(400MHz,CDCl3) δ 6.98 (s, 1H), 6.53 (s, 2H), 5.27 (s, 2H), 3.55 (t, J=6.5Hz, 2H), 3.00 (s, 2H), 2.85 (s, 2H), 2.63 (t, J=6.5Hz, 2H), 2.51 (q, J=7.1Hz, 2H), 1.37 (s, 9H), 0.98 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ171.9(2C),166.0,132.3(2C),76.6(2C),55.2,47.2, 46.2,44.9(2C),43.2,33.2,24.4(3C),8.0。
[embodiment 15]
Weigh respectively n-ethylethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add heterocycle acid anhydrides (166mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silicon for reaction Rubber column gel column separation, yield 23%.Products therefrom M15 structure is as follows:
M15:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (5- ethyl -1,6- dioxo 3,4,5,6,6a, 7,10, - 2 (1H) base of 10a- octahydro -7,10- epoxy benzo [f] [1,4] diazocine diketone) acetamide；Molecular formula: C24H33N3O4
1H NMR(400MHz,CDCl3) δ 6.90 (s, 1H), 6.53 (s, 2H), 5.27 (s, 2H), 3.55 (t, J=6.5Hz, 2H), 3.01 (s, 2H), 2.87 (s, 2H), 2.65 (s, 2H), 2.53 (d, J=7.1Hz, 2H), 2.08 (s, 3H), 2.02 (d, J =2.6Hz, 6H), 1.69 (s, 6H), 1.00 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ176.2(3C),136.5(2C),80.8(2C),51.4,51.3,49.3,47.5 (2C),41.5(3C),37.3,36.3(3C),29.4(3C),12.3。
[embodiment 16]
It weighs respectively n-ethylethylenediamine (88mg, 1mmol), 4-Fluorobenzaldehyde (124mg, 1mmol) is in the round bottom of 25mL In flask, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic acid Acid anhydride (148mg, 1mmol), cyclohexyl isonitrile (109mg, 1mmol), is stirred at room temperature, and reaction overnight, after complete reaction, is depressurized It is spin-dried for, with silica gel post separation, yield 35%.Products therefrom M16 structure is as follows:
M16:N- cyclohexyl -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine two Ketone -2 (1H)) -2- (4- fluorophenyl) acetamide；Molecular formula: C26H30FN3O3
1H NMR(400MHz,CDCl3) δ 7.87 (dd, J=5.4,3.0Hz, 2H), 7.76 (dd, J=5.4,3.1Hz, 2H), 7.22 (m, 2H), 7.16 (d, J=8.6Hz, 1H), 6.93 (t, J=8.7Hz, 2H), 4.26 (s, 1H), 3.74 (dd, J= 7.2,5.5Hz,2H),3.64(s,1H),2.69(m,3H),2.48(s,1H),1.75(m,6H),1.37(m,2H),1.15(m, 2H), 0.96 (t, J=7.1Hz, 3H).
13C NMR(101MHz,CDCl3)δ170.5(2C),168.5,134.2(2C),132.1(2C),131.4(d,JC-F =8.1Hz), 131.3 (2C), 123.3 (2C), 115.3 (2C), 115.1,70.8,48.0,47.8,46.3,37.2,32.8, 32.9,29.7,25.6,24.9,12.1。
[embodiment 17]
It weighs respectively n-ethylethylenediamine (88mg, 1mmol), p-tolyl aldehyde (120mg, 1mmol) is in the circle of 25mL In the flask of bottom, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add O-phthalic Acid anhydrides (148mg, 1mmol), cyclohexyl isonitrile (109mg, 1mmol), is stirred at room temperature, and reaction overnight, after complete reaction, subtracts Pressure is spin-dried for, with silica gel post separation, yield 35%.Products therefrom M17 structure is as follows:
M17:N- cyclohexyl -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine two Ketone -2 (1H)) -2- (p-methylphenyl) acetamide；Molecular formula: C27H33N3O3
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.5,3.0Hz, 2H), 7.75 (dd, J=5.4,3.1Hz, 2H), 7.17 (d, J=8.7Hz, 1H), 7.12 (d, J=8.1Hz, 2H), 7.02 (d, J=7.8Hz, 2H), 4.21 (s, 1H), 3.75(m,2H),3.63(s,1H),2.63(m,4H),2.29(s,3H),1.87(m,2H),1.64(m,3H),1.36(m,3H), 1.16 (m, 2H), 0.96 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ170.9(2C),168.5,137.8(2C),134.1(2C),132.7(2C), 132.1(2C),129.6(2C),129.0,123.3,71.6,48.0,47.6,46.5,37.4,33.0,32.9,29.7,25.6, 24.9,21.2,11.9。
[embodiment 18]
It weighs respectively n-ethylethylenediamine (88mg, 1mmol), 4-Fluorobenzaldehyde (124mg, 1mmol) is in the round bottom of 25mL In flask, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic acid Acid anhydride (148mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), is stirred at room temperature, and reaction overnight, after complete reaction, is depressurized It is spin-dried for, with silica gel post separation, yield 26%.Products therefrom M18 structure is as follows:
M18:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine diketone -2 (1H)) -2- (4- fluorophenyl) acetamide；Molecular formula: C30H34FN3O
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.4,3.0Hz, 2H), 7.75 (dd, J=5.5,3.1Hz, 2H), 7.23 (m, 2H), 6.95 (t, J=8.7Hz, 2H), 4.20 (s, 1H), 3.75 (dd, J=7.3,5.8Hz, 1H), 3.64 (dd, J=12.6,7.0Hz, 1H), 2.69 (m, 3H), 2.44 (dq, J=13.8,7.0Hz, 1H), 2.05 (s, 3H), 1.95 (d, J=2.7Hz, 6H), 1.66 (t, J=2.8Hz, 6H), 0.96 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ170.3(2C),168.4,134.13(2C),132.01(2C),131.47(d, JC-F=8.1Hz), 123.3 (2C), 115.2 (3C), 115.0 (2C), 71.0,51.4,47.9,45.9,41.3 (3C), 36.8, 36.3(3C),29.4(3C),12.2。
[embodiment 19]
It weighs respectively n-ethylethylenediamine (88mg, 1mmol), p-tolyl aldehyde (120mg, 1mmol) is in the circle of 25mL In the flask of bottom, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add O-phthalic Acid anhydrides (148mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), is stirred at room temperature, and reaction overnight, after complete reaction, subtracts Pressure is spin-dried for, with silica gel post separation, yield 30%.Products therefrom M19 structure is as follows:
M19:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo - 2 (1H) base of [f] [1,4] diazocine diketone) -2- (p-methylphenyl) acetamide；Molecular formula: C31H37N3O3；
1H NMR(400MHz,CDCl3) δ 7.85 (dd, J=5.5,2.9Hz, 2H), 7.75 (dd, J=5.5,2.9Hz, 2H), 7.23 (m, 1H), 7.13 (d, J=8.0Hz, 2H), 7.04 (d, J=7.9Hz, 1H), 4.13 (s, 1H), 3.82-3.69 (m, 1H), 3.76 (m, 1H), 2.71 (m, 3H), 2.49 (m, 1H), 2.30 (s, 2H), 2.04 (d, J=3.9Hz, 3H), 1.96 (d, J=2.1Hz, 6H), 1.66 (s, 6H), 0.96 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ168.4(3C),134.0(2C),132.1(2C),129.6(2C),128.9 (2C),123.2(2C),115.2,115.0,71.8,51.3,47.9,46.1,41.3(3C),36.4(3C),29.4(3C), 21.1,12.1。
[embodiment 20]
N- methyl 1 is weighed respectively, and 3- propane diamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) is in the round-bottomed flask of 25mL In, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), cyclohexyl isonitrile (161mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 26%.Products therefrom M20 structure is as follows:
M20:N- cyclohexyl -2- (6- methyl-1,7- dioxo 1,3,4,5,6,7- hexahydro -2H- benzo [g] [1,5] phenodiazine Fragrant nonyl diketo) acetamide；Molecular formula: C20H27N3O3
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.5,3.0Hz, 2H), 7.74 (dd, J=5.5,3.0Hz, 2H), 7.25 (s, 1H), 3.76 (t, J=6.9Hz, 3H), 2.96 (s, 2H), 2.45 (t, J=7.0Hz, 2H), 2.24 (s, 3H), 1.89 (m, 4H), 1.72 (m, 2H), 1.60 (m, 1H), 1.36 (dd, J=13.6,11.4Hz, 3H), 1.20 (m, 2H).
13C NMR(100MHz,CDCl3)δ168.4(3C),134.1(2C),131.9(2C),123.3(2C),61.0, 54.6,47.6,42.7,35.6,32.9,26.1(2C),25.5(2C),24.9。
[embodiment 21]
N- methyl 1 is weighed respectively, and 3- propane diamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) is in the round-bottomed flask of 25mL In, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), tert-butyl isonitrile (83mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for for reaction, With silica gel post separation, yield 15%.Products therefrom M21 structure is as follows:
M21:N- (tert-butyl) -2- (6- methyl-1,7- dioxo 1,3,4,5,6,7- hexahydro -2H- benzo [g] [1,5] two Nitrogen virtue nonyl diketo) acetamide；Molecular formula: C18H25N3O3
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.5,3.0Hz, 2H), 7.74 (dd, J=5.4,3.1Hz, 2H), 7.16 (s, 1H), 3.75 (t, J=7.1Hz, 2H), 2.90 (s, 2H), 2.46 (t, J=7.0Hz, 2H), 2.27 (s, 3H), 1.86(m,2H),1.37(s,9H)。
13C NMR(100MHz,CDCl3)δ168.3(3C),134.1(2C),131.9(2C),123.3(2C),61.9, 54.7,50.5,42.6,35.7,28.7(3C),26.3。
[embodiment 22]
N- methyl 1 is weighed respectively, and 3- propane diamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) is in the round-bottomed flask of 25mL In, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), benzyl isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for for reaction, With silica gel post separation, yield 16%.Products therefrom M22 structure is as follows:
M22:N- benzyl -2- (6- methyl-1,7- dioxo 1,3,4,5,6,7- hexahydro -2H- benzo [g] [1,5] phenodiazine virtue Nonyl diketo) acetamide；Molecular formula: C21H23N3O3
1H NMR(400MHz,CDCl3) δ 7.81 (dd, J=5.5,3.0Hz, 2H), 7.71 (dd, J=5.5,3.1Hz, 2H), 7.33 (m, 4H), 7.25 (ddd, J=6.2,4.1,3.3Hz, 1H), 4.50 (d, J=6.2Hz, 2H), 3.69 (t, J= 6.9Hz, 2H), 3.05 (s, 2H), 2.47 (t, J=6.9Hz, 2H), 2.24 (s, 3H), 1.86 (m, 2H).
13C NMR(100MHz,CDCl3)δ170.4(2C),168.4,138.6(2C),134.0(2C),131.9(2C), 128.6(2C),127.6(2C),127.3,123.3,61.2,54.8,42.9(2C),35.6,26.1。
[embodiment 23]
N- methyl 1 is weighed respectively, and 3- propane diamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) is in the round-bottomed flask of 25mL In, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 32%.Products therefrom M23 structure is as follows:
M23:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (6- methyl-1,7- dioxo 1,3,4,5,6,7- hexahydro - 2H- benzo [g] [1,5] phenodiazine virtue nonyl diketo) acetamide；Molecular formula: C24H31N3O3
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.5,3.0Hz, 2H), 7.73 (dd, J=5.5,3.0Hz, 2H), 7.02 (s, 1H), 3.75 (t, J=7.0Hz, 2H), 2.88 (s, 2H), 2.46 (t, J=7.0Hz, 2H), 2.27 (s, 3H), 2.06 (s, 3H), 2.01 (d, J=2.7Hz, 6H), 1.87 (m, 2H), 1.68 (d, J=2.0Hz, 6H).
13C NMR(100MHz,CDCl3)δ168.3(3C),134.0(2C),132.0(2C),123.3(2C),62.1, 54.7,51.2,44.2,42.6(3C),41.5(3C),36.3,29.4(3C),26.4。
[embodiment 24]
Weigh N- benzyl ethylenediamine (150mg, 1mmol) respectively, formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 37%.Products therefrom M24 structure is as follows:
M24:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (5- benzyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine diketone -2- (1H) base) acetamide；Molecular formula: C29H33N3O3
1H NMR(400MHz,CDCl3) δ 7.82 (m, 2H), 7.77 (m, 2H), 7.07 (t, J=6.5Hz, 3H), 6.98 (d, J=7.5Hz, 2H), 6.85 (s, 1H), 3.83 (m, 2H), 3.52 (s, 2H), 3.12 (s, 2H), 2.68 (m, 2H), 2.05 (s, 3H), 1.96 (d, J=2.8Hz, 6H), 1.66 (s, 6H).
13C NMR(100MHz,CDCl3)δ169.6(2C),168.2,133.9(2C),132.1(2C),128.9(2C), 128.3(2C),127.3(2C),123.2(2C),60.1(2C),59.2,51.9,51.2,41.3(3C),36.3(3C),29.7, 29.4(3C)。
[embodiment 25]
Weigh (S) -2- (aminomethyl) pyrrolidine hydrochloride (171mg, 1mmol) respectively, triethylamine (202mg, 1mmol), Formaldehyde (30mg, 1mmol) is added the methanol of 1.5mL, reacts 4h at room temperature in the round-bottomed flask of 25mL, after can be added in addition Several reactants sequentially add phthalic anhydride (148mg, 1mmol), and adamantyl isonitrile (161mg, 1mmol), room temperature is stirred It mixes, overnight, after complete reaction, decompression is spin-dried for, with silica gel post separation, yield 10% for reaction.Products therefrom M25 structure is such as Under:
M25:N- ((3S, 5S, 7S)-adamantane -1- base) -2- ((R) -6,11- dioxo -2,3,3a, 4,6,11 hexahydrobenzenes And [1,2- α] pyrroles [f] [1,4] diazocine diketone -5- (1H) base) acetamide；Molecular formula: C25H31N3O3
1H NMR(400MHz,CDCl3) δ 7.85 (dd, J=5.5,3.0Hz, 2H), 7.74 (dd, J=5.5,3.1Hz, 2H), 6.85 (s, 1H), 3.67 (dd, J=20.1,6.0Hz, 2H), 3.34 (d, J=16.0Hz, 1H), 3.10 (d, J= 5.0Hz, 2H), 2.91 (d, J=16.0Hz, 1H), 2.32 (d, J=9.4Hz, 1H), 2.06 (s, 3H), 1.96 (s, 6H), 1.82 (m,4H),1.68(s,6H)。
13C NMR(100MHz,CDCl3)δ168.6(3C),134.1(2C),131.(2C),123.4(2C),62.8, 60.9,55.1,51.1,44.2,41.4(3C),36.4(3C),29.4(3C),28.9,23.8。
[embodiment 26]
Weigh respectively N- methyl ethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add phthalic anhydride (148mg, 1mmol), glycine isonitrile (99mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for for reaction, With silica gel post separation, yield 15%.Products therefrom M26 structure is as follows:
M26: methyl (2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro benzo [f] [1,4] diazocine diketone -2 (1H)) acetyl group) glycine；Molecular formula: C17H21N3O5
1H NMR(400MHz,CDCl3) δ 7.86 (dd, J=5.5,3.0Hz, 2H), 7.74 (dd, J=5.5,3.0Hz, 2H), 4.00 (d, J=5.8Hz, 2H), 3.82 (t, J=6.1Hz, 2H), 3.69 (s, 3H), 3.21 (s, 2H), 2.83 (t, J= 6.1Hz, 2H), 2.62 (q, J=7.1Hz, 2H), 1.00 (t, J=7.1Hz, 3H).
13C NMR(100MHz,CDCl3)δ171.7(2C),170.1,168.5,134.1(2C),132.0(2C),123.3 (2C),58.6,52.9,52.2,49.3,40.7,36.7,12.1。
[embodiment 27]
Weigh respectively N- methyl ethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add 1,8- naphthalic anhydride (198mg, 1mmol), hexamethylene isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 18%.Products therefrom M27 structure is as follows:
M27:N- cyclohexyl -2- (5- ethyl -1,6- dioxo -3,4,5,6- tetrahydro naphtho- [1,8-fg] [1,4] phenodiazine virtue Nonyl diketone -2 (1H) base) acetamide；Molecular formula: C24H29N3O3
1H NMR(400MHz,CDCl3) δ 8.61 (dd, J=7.3,1.1Hz, 2H), 8.25 (dd, J=8.3,1.0Hz, 2H), 7.78 (dd, J=8.2,7.4Hz, 2H), 7.14 (d, J=8.2Hz, 1H), 4.31 (t, J=6.5Hz, 2H), 3.67 (d, J =8.7Hz, 1H), 3.17 (s, 2H), 2.88 (t, J=6.5Hz, 2H), 2.64 (q, J=7.1Hz, 2H), 1.72 (m, 2H), 1.54 (m, 3H), 1.25 (m, 3H), 0.99 (t, J=7.1Hz, 3H), 0.82 (m, 2H).
13C NMR(100MHz,CDCl3)δ164.2(3C),134.2(2C),131.4(2C),128.2(2C),127.5 (2C),127.0,122.4,58.8,52.7,49.1,47.4,38.4,32.8,25.4(2C),24.7(2C),12.1。
[embodiment 28]
N- methyl 1 is weighed respectively, and 3- propane diamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) is in the round-bottomed flask of 25mL In, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add 1,8- naphthalic anhydride (198mg, 1mmol), hexamethylene isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 28%.Products therefrom M28 structure is as follows:
M28:N- cyclohexyl -2- (6- methyl-1,7- dioxo -4,5,6,7- tetrahydro naphtho- [1,8-gh] [1,5] phenodiazine virtue Last of the ten Heavenly stems diketone -2 (3H) base) acetamide；Molecular formula: C24H29N3O3
1H NMR(400MHz,CDCl3) δ 8.61 (dd, J=7.3,1.1Hz, 2H), 8.24 (dd, J=8.3,1.0Hz, 2H), 7.78 (dd, J=8.2,7.3Hz, 2H), 7.29 (d, J=9.1Hz, 1H), 4.27 (m, 2H), 3.75 (m, 1H), 3.01 (s, 2H), 2.56 (t, J=6.8Hz, 2H), 2.31 (s, 3H), 1.94 (s, 4H), 1.68 (dd, J=10.4,6.6Hz, 2H), 1.22 (d, J=27.7Hz, 6H).
13C NMR(100MHz,CDCl3)δ164.2(3C),134.1(2C),131.6(2C),131.3(2C),128.1 (2C),126.9,122.5,61.5,55.3,47.5,42.7,38.2,33.0,26.1(2C),25.5(2C),24.9。
[embodiment 29]
Weigh respectively N- methyl ethylenediamine (88mg, 1mmol), formaldehyde (30mg, 1mmol) in the round-bottomed flask of 25mL, The methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add biphenyl acid anhydrides (224mg, 1mmol), hexamethylene isonitrile (109mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and uses silica gel for reaction Post separation, yield 35%.Products therefrom M29 structure is as follows:
M29:N- cyclohexyl -2- (10- methyl -5,11- dioxo -5,7,8,9,10,11- hexahydro -6H- biphenyl [g, i] [1,5] phenodiazine virtue hendecane diketone -6- base) acetamide；Molecular formula: C26H31N3O3
1H NMR(400MHz,CDCl3) δ 7.87 (d, J=7.8Hz, 2H), 7.65 (d, J=3.8Hz, 4H), 7.53 (dd, J =7.9,4.2Hz, 2H), 4.16 (t, J=7.1Hz, 2H), 3.86 (m, 1H), 2.98 (s, 2H), 2.47 (t, J=6.9Hz, 2H),2.27(s,3H),1.91(s,3H),1.75(m,3H),1.43(m,6H)。
13C NMR(100MHz,CDCl3)δ171.1(3C),134.9(2C),134.7(2C),132.2(2C),131.0 (2C),128.7(2C),128.3(2C)61.2,55.1,47.6,45.2,42.7,33.0,26.4(2C),25.5(2C),24.9。
[embodiment 30]
N- methyl-1,2- phenylenediamine (195mg, 1mmol) are weighed respectively, and formaldehyde (30mg, 1mmol) is burnt in the round bottom of 25mL In bottle, the methanol of 1.5mL is added, reacts 4h at room temperature, after other several reactants can be added, sequentially add biphenyl acid anhydrides (224mg, 1mmol), adamantane isonitrile (161mg, 1mmol), is stirred at room temperature, and overnight, after complete reaction, decompression is revolved for reaction It is dry, with silica gel post separation, yield 16%.Products therefrom M30 structure is as follows:
M30:N- ((3S, 5S, 7S)-adamantane -1- base) -2- (9- ethyl -5,10- dioxo -7,8,9,10- tetrahydro two - 6 (5H) base of benzo [f, h] [1,4] diazocine diketone) acetamide；Molecular formula: C27H29N3O3
1H NMR(400MHz,CDCl3) δ 7.97 (dd, J=5.5,3.0Hz, 2H), 7.83 (dd, J=5.5,3.1Hz, 2H),7.45(m,1H),7.23(m,3H),6.79(s,1H),3.50(s,2H),2.60(s,3H),1.98(s,3H),1.79(d, J=2.8Hz, 6H), 1.60 (s, 6H).
13C NMR(100MHz,CDCl3)δ168.3(2C),167.4,149.6(2C),134.5(2C),132.0(2C), 130.4(2C),124.9(2C),124.0,120.6,61.0,51.4,42.6,41.0(3C),36.3(3C),29.3(3C)。

Claims (2)

1. a kind of prepare containing there are three the methods of the interior bisamide cyclic compound of peptide bond, which comprises the following steps: Using methanol as solvent, after aminated compounds and aldehyde compound are carried out hybrid reaction 4 hours, acid anhydrides and isonitrile class chemical combination is added Object is stirred at room temperature, and overnight, after complete reaction, decompression is spin-dried for, and is then separated with silica gel column chromatography for reaction；
The aminated compounds is
The aldehyde compound be HCHO,The acid anhydrides isThe different nitrile compounds areThe interior bisamide ring-type chemical combination of peptide bond containing there are three Object be selected from M1, M2, M3, M4, M5, M6, M7, M8, M9, M10, M11, M12, M13, M14, M15, M16, M17, M18, M19, M20, Any one in M21, M22, M23, M24, M25, M26, M27, M28, M29, M30, structural formula is as follows:
2. preparation according to claim 1 is containing there are three the method for the interior bisamide cyclic compound of peptide bond, feature exists In the molar ratio of, the aminated compounds, aldehyde compound, acid anhydrides and different nitrile compounds be 1:1:1:1.
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US5770590A (en) * 1995-03-24 1998-06-23 Takeda Chemical Industries, Ltd. Cyclic compounds, their prudiction and use
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5770590A (en) * 1995-03-24 1998-06-23 Takeda Chemical Industries, Ltd. Cyclic compounds, their prudiction and use
CN102584725A (en) * 2011-01-12 2012-07-18 中国科学院青岛生物能源与过程研究所 Method for preparing dinitrogen heterocyclooctatetraene

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KINETIC STUDY OF THE FORMATION AND RUPTURE OF STABLE TETRAHEDRAL INTERMEDIATES. C-0, C-N and C-S BOND FORMATION;OSWALDO NUNEZ et al;《JOURNAL OF PHYSICAL ORGANIC CHEMISTRY》;19931231;第7卷;80-89

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