CN107522697B - Pyrroles [2,1-a] morphinane alkaloid and its preparation method and application - Google Patents

Pyrroles [2,1-a] morphinane alkaloid and its preparation method and application Download PDF

Info

Publication number
CN107522697B
CN107522697B CN201710883888.1A CN201710883888A CN107522697B CN 107522697 B CN107522697 B CN 107522697B CN 201710883888 A CN201710883888 A CN 201710883888A CN 107522697 B CN107522697 B CN 107522697B
Authority
CN
China
Prior art keywords
pyrroles
phenyl
tetrahydro
dioxo
cdcl
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
CN201710883888.1A
Other languages
Chinese (zh)
Other versions
CN107522697A (en
Inventor
谢智宇
李飞
许志红
段迎超
司路路
蒋莉伟
刘雨晴
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.)
Xuchang University
Original Assignee
Xuchang University
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 Xuchang University filed Critical Xuchang University
Priority to CN201710883888.1A priority Critical patent/CN107522697B/en
Publication of CN107522697A publication Critical patent/CN107522697A/en
Application granted granted Critical
Publication of CN107522697B publication Critical patent/CN107522697B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention discloses a kind of pyrroles [2,1-a] morphinane alkaloid, preparation method and medical applications, belong to field of medicinal chemistry.The general structure of pyrroles [2,1-a] morphinane alkaloid of the present invention such as (1) is shown, R1For C1‑4Alkyl, C1‑4Alkoxy, hydrogen atom, halogen atom；R2For C1‑4Alkyl, C1‑4Alkoxy, hydrogen atom, halogen atom；R3For C1‑4Alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl；R4For hydrogen, C1‑C6Alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl.This patent also discloses the environment-friendly preparation method thereof of pyrroles [2,1-a] morphinane alkaloid and the pharmaceutical composition application in preparation of anti-tumor drugs including them and their salt.

Description

Pyrroles [2,1-a] morphinane alkaloid and its preparation method and application
Technical field
The present invention relates to a kind of pyrroles [2,1-a] morphinane alkaloid and the pharmaceutical composition including their salt, they Green synthesis method and they anti-tumor drug preparation in purposes, belong to field of medicinal chemistry.
Background technique
In recent years, malignant tumour has become the Health Killer for being only second to blood cranial vascular disease, and disease incidence is still continuous Rise.For at present, safe and effective antineoplastic is still the final means for the treatment of of cancer, although facing there are many drug It is successfully used on bed, but still is not able to satisfy the market demand, develop low toxicity, the anti-tumor drug of high selection type, Small side effects is still The emphasis of new drug development.Natural products due to its various structures, type is abundant, pharmacological activity is extensive the features such as, be still that new drug is opened Send out important sources.Azepine ring structure, especially quinoline, isoquinolin, pyrrole structure are present in numerous bioactive natural products, It is structure fragment common in the synthesis of drug design level.Isolated lamellarin (the piece spiral shell element) from marine natural products Alkaloid just contains pyrroles [2,1-a] isoquinoline structure, and piece spiral shell element alkaloid possess antitumor, AntiHIV1 RT activity, it is antimicrobial, The multiple biological activities such as immunological regulation, anti-oxidant.[C.Bailly,et al.WO 2004014917；M.V.R.Reddy,et al.J.Med.Chem.1999,42,1901；C.P.Ridley,et al.Bioorg.Med.Chem.2002,10,3285； A.Hamasaki,et al.J.Am.Chem.Soc.2005,127,10767；S.Manzanaro,et al.J.Nat.Prod.2006,69,1485；T.C.Chou,et al.WO 2006026496；P.Krishnaiah,et al.J.Nat.Prod.2004,67,1168；H.C.Vervoort,et al.J.Org.Chem.1997,62,1486].However piece Spiral shell element alkaloid structure is complicated cause its analog synthesis have certain difficulty, it is similar therefore, it is necessary to develop its structure The simple synthesis of object.It is similar that Wang study group using mantoquita as catalyst, tert-butyl hydroperoxide is that oxidant realizes Work [W.W, et al.Chem.Commun., 2011,47,1036-1038].Rueping research group reports photocatalytic synthesis At the simple and easy method of substance of this kind, however due to light-catalysed weak oxide, the aromatisation of pyrrole ring cannot achieve [M.Rueping,et al.Chem.Commun,2011,47,9615–9617].The Xiao Wenjing study group benefit of Central China Normal University Photoactivation oxidation, and using N- bromo-succinimide as auxiliary oxidizing agent realizes the aromatisation of pyrrole ring and obtains such object Matter [W.J.Xiao, et al.Angew.Chem.Int.Ed.2011,50,7171-7175].
However the reported method for synthesizing this class formation will use peroxide, N- bromo-succinimide, valuable Transition metal or photochemical catalyst cause certain environmental pollution and the wasting of resources.Green non-pollution preparation method is current drug The development trend of synthesis is of great significance to pyrroles [2,1-a] the morphinane alkaloid anti-tumor drug for developing novel.
Summary of the invention
The purpose of the present invention is to provide a kind of new pyrroles [2,1-a] morphinane alkaloids for having medical value.
The purpose of the present invention is to provide a kind of preparations of new pyrroles [2,1-a] morphinane alkaloid for having medical value Method.
Another object of the present invention is to provide a kind of new pyrroles's [2,1-a] morphinane alkaloid for having medical value and Its salt form application in preparation of anti-tumor drugs.
The purpose of the present invention is achieved through the following technical solutions:
New pyrroles's [2,1-a] morphinane alkaloid has the structure as shown in general formula (1):
Wherein, R1For C1-C4Alkyl, C1-C4Alkoxy, hydrogen or halogen；
R2For C1-4Alkyl, C1-4Alkoxy, hydrogen or halogen；
R3For C1-4Alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl；Substituent group be methyl, methoxyl group, fluorine, chlorine, Bromine, nitro or hydroxyl, it is monosubstituted or disubstituted；
R4For hydrogen, C1-6Alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl；Substituent group be methyl, methoxyl group, fluorine, Chlorine, bromine, nitro or hydroxyl, it is monosubstituted or disubstituted；
The C1-C4Alkyl is the alkyl of linear chain or branched chain；
It is preferred that:
R1For hydrogen, straight chained alkyl, the C of 1-4 carbon1-C4Alkoxy；
R2For hydrogen, straight chained alkyl, the C of 1-4 carbon1-C4Alkoxy, chlorine, bromine or fluorine；
R3For phenyl or monosubstituted phenyl, benzyl or monosubstituted benzyl；Substituent group is methyl, methoxyl group, fluorine, chlorine or bromine；
R4For C1-4Alkyl, phenyl or benzyl.
The present invention preferred pyrroles [2,1-a] morphinane alkaloid is following compound:
I1: 9,11- dioxo -10- phenyl -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] is different Quinoline -8- carboxylic acid, ethyl ester；
I2: 10- (2,4- 3,5-dimethylphenyl) -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] Pyrroles [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester；
I3: 9,11- dioxo -10- (2- aminomethyl phenyl) -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester；
I4: 9,11- dioxo -10- (3- aminomethyl phenyl) -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester；
I5: 9,11- dioxo -10- (4- aminomethyl phenyl) -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester；
I6: 10- (4- bromophenyl) -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2, 1-a] isoquinolin -8- carboxylic acid, ethyl ester；
I7: 10- (4- chlorphenyl) -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2, 1-a] isoquinolin -8- carboxylic acid, ethyl ester；
I8: 10- (4- methoxyphenyl) -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrrole Cough up [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester；
I9: 10- benzyl -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] is different Quinoline -8- carboxylic acid, ethyl ester；
I10: 10-4- chlorobenzyl -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1- A] isoquinolin -8- carboxylic acid, ethyl ester；
I11: 10-4- methoxy-benzyl -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester；
II1: 9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] is different Quinoline -8- carboxylate methyl ester；
II2: 9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] is different Quinoline -8- carboxylic acid tert-butyl ester；
II3: 9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] is different Quinoline -8- carboxylate；
II4: 9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] is different Quinoline -8- carboxylic acid isopropyl；
II5: 9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] is different Quinoline -8- carboxylic acid phenyl ester；
II6: 9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3,4] pyrroles [2,1-a] is different Quinoline -8- benzyl carboxylate；
II7: bromo- 9,11- dioxo -10- phenyl -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': the 3,4] pyrroles of 2- [2, 1-a] isoquinolin -8- carboxylic acid, ethyl ester；
II8: 2,3- dimethoxy -9,11- dioxo -10- phenyl -6,9,10,11- tetrahydro -5H- pyrroles [3 ', 4 ': 3, 4] pyrroles [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester.
General formula (1) compound the preparation method is as follows:
Compound II (tetrahydro isoquinoline derivative, 0.4mmol) is placed in the drying round-bottomed flask containing magneton, in succession Be added anhydrous acetonitrile (2ml), cuprous bromide (5.7mg, 0.04mmol), N- hydroxy benzo succimide III (6.5mg, 0.04mmol), N-phenylmaleimide (0.2mmol) replaces the air in reaction flask, and is placed in 60- under Oxygen Condition It in 70 DEG C of oil bath pan, is stirred to react, vacuum distillation removes solvent after reaction, and residue carries out column chromatographic purifying and obtains sterling production Object I.
Illustrate that pyrroles's [2,1-a] morphinane alkaloid has certain inhibiting effect to tumour cell by pharmacological evaluation.
1. experimental method
164 culture medium of RPMI containing 10% fetal calf serum of mass percentage is added in 96 orifice plates, in each hole 4000-5000 gland cell system PC3 cell is added, and cultivates for 24 hours.The test compound of multiple concentration is added and hatches for 24 hours, 5mg/mL MTT solution is added and measures its optical density OD with microplate reader with the lysigenous crystal of DMSO in 37 DEG C of hatching 4h (Optical Density), cell survival rate (Cell viability) are calculated by the following formula to obtain:
Cell viability (%)=100 × (ODsample–ODblank)/(ODcontrol–ODblank)
The compounds of this invention is determined to the inhibitory activity of liver cancer cell lines HepG3 cell simultaneously, and determination of activity is used suitable Platinum is as control.
2. experimental result
One, of table pyrroles 2,1-a of the present invention] morphinane alkaloid Cytostatic to tumor cell effect
Innovative point of the present invention and advantage: preparing object by [3+2] cyclization under metal salt catalyst dioxygen oxidation, Only with purity oxygen oxidant is made, green non-pollution, operation is simple and high income, and total recovery is up to 78% or more, while for the first time Antitumor activity evaluation is carried out to substance of this kind, can be seen by the inhibiting tumour cells Activity evaluation to the above compound Out, majority of compounds has certain antitumous effect, compound I7、I8、I10、II8With apparent inhibitory effect, activity Better than cis-platinum, wherein I10、II8Value with further developmental research is conducive to research and develop novel pyrroles [2,1-a] isoquinolin Alkaloid anti-tumor drug.
Specific embodiment
Embodiment 1
9,11- dioxo -10- phenyl -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] isoquinoline The preparation of quinoline -8- carboxylic acid, ethyl ester:
2- (3,4- dihydro-isoquinoline -2 (1H) base)-ethyl acetate (87.7mg, 0.4mmol) is placed in containing magneton In the dry round-bottomed flask of 10ml, it is sequentially added anhydrous acetonitrile (2ml), cuprous bromide (5.7mg, 0.04mmol), N- hydroxy benzo Succimide III (6.5mg, 0.04mmol), N-phenylmaleimide (34.6mg, 0.2mmol), with high purity oxygen gas Air in the threeway displacement reaction flask of ball, and be placed in 60 DEG C of oil bath pan under Oxygen Condition, it is stirred to react 10h, directly Vacuum distillation removes solvent, and residue directly carries out column chromatographic purifying and obtains solid pure product product I (72.7mg, 0.18mmol, yield 90%).1H NMR(400MHz,CDCl3)δ8.63–8.56(m,1H),7.53–7.46(m,2H),7.45–7.35(m,5H), 7.31 (d, J=6.9Hz, 1H), 4.79 (t, J=6.9Hz, 2H), 4.45 (q, J=7.1Hz, 2H), 3.20 (t, J=6.9Hz, 2H), 1.48 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ163.35,161.85,159.93,133.72, 132.84,132.65,130.57,129.16,128.26,128.24,128.03,127.89,127.40,125.82,125.49, 118.92,116.50,61.88,43.64,28.61,14.42。
Embodiment 2
10- (2,4- 3,5-dimethylphenyl) -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles The preparation of [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester:
Referring to the method for embodiment 1, yield 82%.1H NMR(400MHz,CDCl3) δ 8.55 (d, J=5.6Hz, 1H), 7.48-7.24 (m, 2H), 7.20-6.86 (m, 3H), 4.92-4.60 (m, 2H), 4.39 (d, J=6.3Hz, 2H), 3.17 (s, 2H),2.34(s,3H),2.17(s,3H),1.43(s,3H)；13C NMR(101MHz,CDCl3)δ163.52,162.12, 159.98,139.24,136.69,133.56,132.61,131.89,130.48,129.18,129.08,128.25,127.85, 127.68,125.88,118.78,116.77,61.85,43.61,28.62,21.38,18.15,14.33。
Embodiment 3
9,11- dioxo -10- (2- aminomethyl phenyl) -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2, 1-a] isoquinolin -8- carboxylic acid, ethyl ester preparation:
Referring to the method for embodiment 1, yield 87%.1H NMR(400MHz,CDCl3) δ 8.58 (d, J=6.8Hz, 1H), 7.50-7.28 (m, 6H), 7.22 (d, J=7.3Hz, 1H), 4.91-4.80 (m, 1H), 4.79-4.69 (m, 1H), 4.43 (q, J =7.1Hz, 2H), 3.21 (t, J=6.8Hz, 2H), 2.25 (s, 3H), 1.47 (t, J=7.1Hz, 3H)；13C NMR(101MHz, CDCl3)δ163.39,161.95,159.96,137.13,133.65,132.63,131.88,131.17,130.54,129.38, 129.35,128.26,127.87,126.94,125.86,125.82,118.87,116.72,77.55,77.23,76.91, 61.87,43.64,28.63,18.26,14.36。
Embodiment 4
9,11- dioxo -10- (3- aminomethyl phenyl) -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2, 1-a] isoquinolin -8- carboxylic acid, ethyl ester preparation:
Referring to the method for embodiment 1, yield 87%.1H NMR(400MHz,CDCl3)δ8.69–8.53(m,1H),7.46– 7.35 (m, 3H), 7.30 (d, J=6.8Hz, 1H), 7.20 (d, J=8.0Hz, 3H), 4.79 (t, J=6.9Hz, 2H), 4.44 (q, J=7.1Hz, 2H), 3.20 (t, J=6.8Hz, 2H), 2.41 (s, 3H), 1.48 (t, J=7.1Hz, 3H)；13C NMR (101MHz,CDCl3)δ163.45,161.92,159.95,139.08,133.66,132.71,132.64,130.53, 128.96,128.25,128.07,127.87,125.85,125.57,124.54,118.88,116.57,61.85,43.63, 28.61,21.59,14.42。
Embodiment 5
9,11- dioxo -10- (4- aminomethyl phenyl) -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2, 1-a] isoquinolin -8- carboxylic acid, ethyl ester preparation:
Referring to the method for embodiment 1, yield 86%.1H NMR(400MHz,CDCl3) δ 8.61 (d, J=7.1Hz, 1H), 7.53-7.37 (m, 2H), 7.3-7.29 (m, 5H), 4.80 (t, J=5.9Hz, 2H), 4.45 (q, J=6.7Hz, 2H), 3.21 (t, J=5.7,2H), 2.42 (s, 3H), 1.49 (t, J=6.7Hz, 3H)；13C NMR(101MHz,CDCl3)δ163.29, 161.83,159.76,137.81,133.42,132.42,130.31,129.95,129.63,128.04,127.67,127.05, 125.65,125.38,118.62,116.38,61.66,43.41,28.40,21.23,14.19。
Embodiment 6
10- (4- bromophenyl) -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1- A] isoquinolin -8- carboxylic acid, ethyl ester preparation:
Referring to the method for embodiment 1, yield 85%.1H NMR(400MHz,CDCl3) δ 8.57 (d, J=7.1Hz, 1H), 7.62 (d, J=7.8Hz, 2H), 7.50-7.37 (m, 2H), 7.36-7.28 (m, 3H), 4.79 (t, J=6.5Hz, 2H), 4.45 (q, J=7.0Hz, 2H), 3.20 (t, J=6.4Hz, 2H), 1.48 (t, J=7.0Hz, 3H)；13C NMR(101MHz,CDCl3)δ 162.94,161.45,159.81,133.90,132.67,132.29,131.90,130.69,128.78,128.29,128.19, 127.94,125.70,125.20,121.67,119.10,116.24,61.94,43.67,28.57,14.41。
Embodiment 7
10- (4- chlorphenyl) -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1- A] isoquinolin -8- carboxylic acid, ethyl ester preparation:
Referring to the method for embodiment 1, yield 86%.1H NMR(400MHz,CDCl3) δ 8.57 (d, J=7.0Hz, 1H), 7.50-7.35 (m, 6H), 7.31 (d, J=7.0Hz, 1H), 4.79 (t, J=6.7Hz, 2H), 4.45 (q, J=7.0Hz, 2H), 3.20 (t, J=6.7Hz, 2H), 1.48 (t, J=7.0Hz, 3H)；13C NMR(101MHz,CDCl3)δ163.03,161.53, 159.82,133.89,133.66,132.67,131.38,130.69,129.33,128.50,128.29,128.19,127.94, 125.71,125.22,119.09,116.25,61.94,43.67,28.57,14.42。
Embodiment 8
9,11- dioxo -10- (4- methoxyphenyl) -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles The preparation of [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester:
Referring to the method for embodiment 1, yield 83%.1H NMR(400MHz,CDCl3) δ 8.59 (d, J=7.1Hz, 1H), 7.48-7.35 (m, 2H), 7.31 (d, J=7.1Hz, 3H), 7.01 (d, J=7.7Hz, 2H), 4.79 (t, J=6.6Hz, 2H), 4.44 (q, J=7.0Hz, 2H), 3.85 (s, 3H), 3.20 (t, J=6.6Hz, 2H), 1.48 (t, J=7.0Hz, 3H)；13C NMR (101MHz,CDCl3)δ163.65,162.21,159.96,159.29,133.63,132.63,130.53,128.73, 128.25,128.23,127.88,125.84,125.54,125.29,118.83,116.53,114.55,61.87,55.73, 43.61,28.61,14.40。
Embodiment 9
10- benzyl -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] isoquinoline The preparation of quinoline -8- carboxylic acid, ethyl ester:
Referring to the method for embodiment 1, yield 78%.1H NMR(400MHz,CDCl3) δ 8.53 (d, J=7.1Hz, 1H), 7.50-7.17 (m, 8H), 4.81 (s, 2H), 4.73 (t, J=6.0Hz, 2H), 4.44 (q, J=6.7Hz, 2H), 3.15 (t, J= 5.6Hz, 2H), 1.49 (t, J=6.7Hz, 3H)；13C NMR(101MHz,CDCl3)δ164.08,162.52,159.91, 137.34,133.26,132.56,130.41,128.77,128.67,128.18,128.11,127.83,127.71,125.89, 125.81,118.55,116.74,61.79,43.51,42.06,28.56,14.48。
Embodiment 10
10-4- chlorobenzyl -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] The preparation of isoquinolin -8- carboxylic acid, ethyl ester:
Referring to the method for embodiment 1, yield 73%.1H NMR(400MHz,CDCl3) δ 8.51 (d, J=7.3Hz, 1H), 7.49-7.33 (m, 4H), 7.29 (s, 2H), 4.82-4.65 (m, 4H), 4.44 (q, J=7.1Hz, 2H), 3.15 (t, J= 6.7Hz, 2H), 1.48 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ163.97,162.42,159.83, 135.81,133.62,133.39,132.58,130.50,130.17,128.92,128.20,128.08,127.87,125.75, 125.73,118.67,116.56,61.83,43.53,41.38,28.54,14.47。
Embodiment 11
10-4- methoxy-benzyl -9,11- dioxo -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2, 1-a] isoquinolin -8- carboxylic acid, ethyl ester preparation:
Referring to the method for embodiment 1, yield 72%.1H NMR(400MHz,CDCl3) δ 8.53 (d, J=7.4Hz, 1H), 7.55-7.33 (m, 5H), 6.84 (d, J=8.6Hz, 2H), 4.78-4.67 (m, 4H), 4.44 (q, J=7.1Hz, 2H), 3.78 (s, 3H), 3.15 (t, J=6.8Hz, 2H), 1.49 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ164.13, 162.55,159.93,159.23,133.21,132.56,130.39,130.19,129.69,128.18,128.13,127.83, 125.99,125.86,118.51,116.84,114.13,61.77,55.47,43.51,41.51,28.58,14.49。
Embodiment 12
9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] isoquinoline The preparation of quinoline -8- carboxylate methyl ester:
Referring to the method for embodiment 1, yield 88%.1H NMR(400MHz,CDCl3) δ 8.40 (d, J=7.3Hz, 1H), 7.46 (s, 1H), 7.30-7.19 (m, 3H), 4.57 (t, J=5.4Hz, 2H), 4.29 (q, J=6.7Hz, 2H), 3.83 (s, 3H), 3.00 (d, J=5.3Hz, 2H), 1.35 (t, J=6.7Hz, 3H)；13C NMR(101MHz,CDCl3)δ165.19, 161.18,138.08,134.29,129.14,128.71,127.52,127.35,127.20,121.59,121.42,112.18, 60.57,51.63,42.59,29.71,14.61。
Embodiment 13
9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] isoquinoline The preparation of quinoline -8- carboxylic acid tert-butyl ester:
Referring to the method for embodiment 1, yield 87%.1H NMR(400MHz,CDCl3) δ 8.55 (d, J=7.1Hz, 1H), 7.45 (t, J=7.1Hz, 2H), 7.40-7.30 (m, 4H), 7.26-7.18 (m, 2H), 4.75 (t, J=6.3Hz, 2H), 3.96 (s, 3H), 3.16 (t, J=6.0Hz, 2H)；13C NMR(101MHz,CDCl3)δ163.26,161.91,160.35,134.64, 133.92,132.79,132.65,130.65,129.09,128.29,128.00,127.91,127.28,125.76,125.61, 118.41,116.54,52.56,43.68,28.59。
Embodiment 14
9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] isoquinoline The preparation of quinoline -8- carboxylate:
Referring to the method for embodiment 1, yield 88%.1H NMR(400MHz,CDCl3) δ 8.59 (d, J=7.1Hz, 1H), 7.50 (t, J=7.7Hz, 2H), 7.44-7.32 (m, 5H), 7.30 (d, J=7.0Hz, 1H), 4.77 (t, J=6.8Hz, 2H), 3.18 (t, J=6.8Hz, 2H), 1.67 (s, 9H)；13C NMR(101MHz,CDCl3)δ163.46,161.80,159.24, 133.24,132.94,132.64,130.37,129.16,128.18,128.16,127.98,127.83,127.49,125.95, 124.90,120.45,116.26,83.66,43.53,28.64,28.52。
Embodiment 15
9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] isoquinoline The preparation of quinoline -8- carboxylic acid isopropyl:
Referring to the method for embodiment 1, yield 86%.1H NMR(400MHz,CDCl3) δ 8.57 (d, J=7.0Hz, 1H), 7.49-7.30 (m, 7H), 7.27-7.19 (m, 1H), 4.76 (t, J=6.4Hz, 2H), 4.13 (d, J=6.4Hz, 2H), 3.16 (t, J=6.4Hz, 2H), 2.26-2.06 (m, 1H), 1.03 (d, J=6.5Hz, 6H)；13C NMR(101MHz,CDCl3)δ 163.35,161.62,160.10,133.69,132.85,132.65,130.52,129.13,128.21,127.98,127.85, 127.41,125.80,125.35,118.77,116.57,72.06,43.68,28.60,28.04,19.39。
Embodiment 16
9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] isoquinoline The preparation of quinoline -8- carboxylic acid phenyl ester:
Referring to the method for embodiment 1, yield 83%.1H NMR(400MHz,CDCl3) δ 8.64 (d, J=7.0Hz, 1H), 7.78-7.27 (m, 13H), 4.83 (t, J=6.7Hz, 2H), 3.24 (t, J=6.6Hz, 2H)；13C NMR(101MHz,CDCl3) δ163.23,161.65,158.01,150.61,134.57,132.78,132.71,130.83,129.65,129.14, 128.39,128.34,128.06,127.96,127.33,126.65,126.29,125.66,121.65,117.82,116.94, 43.73,28.55。
Embodiment 17
9,11- dioxo -10- phenyl 6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrroles [2,1-a] isoquinoline The preparation of quinoline -8- benzyl carboxylate:
Referring to the method for embodiment 1, yield 82%.1H NMR(400MHz,CDCl3)δ8.65–8.55(m,1H),7.60 (d, J=7.3Hz, 2H), 7.54-7.47 (m, 2H), 7.46-7.27 (m, 9H), 5.46 (s, 2H), 4.78 (t, J=6.9Hz, 2H), 3.18 (t, J=6.9Hz, 2H)；13C NMR(101MHz,CDCl3)δ163.28,161.66,159.67,135.72, 133.89,132.85,132.65,130.60,129.12,128.79,128.59,128.50,128.24,128.00,127.86, 127.39,125.73,118.46,116.62,67.26,43.70,28.55。
Embodiment 18
Bromo- 9,11- dioxo -10- phenyl -6,9,10,11- tetrahydro -5H- pyrroles [3', the 4':3,4] pyrroles [2,1-a] of 2- Isoquinolin -8- carboxylic acid, ethyl ester:
Referring to the method for embodiment 1, yield 88%.1H NMR(400MHz,CDCl3)δ8.78(s,1H),7.63-7.35 (m, 6H), 7.17 (d, J=8.1Hz, 1H), 4.79 (t, J=6.9Hz, 2H), 4.44 (q, J=7.1Hz, 2H), 3.15 (t, J= 6.8Hz, 2H), 1.48 (t, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ163.21,161.64,159.80, 133.35,132.70,132.01,131.24,130.76,129.47,129.24,128.20,127.57,127.43,125.47, 121.95,119.34,117.13,62.01,43.49,28.18,14.39。
Embodiment 19
2,3- dimethoxy -9,11- dioxo -10- phenyl -6,9,10,11- tetrahydro -5H- pyrroles [3', 4':3,4] pyrrole Cough up [2,1-a] isoquinolin -8- carboxylic acid, ethyl ester:
Referring to the method for embodiment 1, yield 80%.1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.54-7.47 (m, 2H), 7.38 (d, J=6.8Hz, 3H), 6.75 (s, 1H), 4.75 (t, J=7.0Hz, 2H), 4.44 (q, J=7.1Hz, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.15 (t, J=7.0Hz, 2H), 1.48 (t, J=7.1Hz, 3H)；13C NMR (100MHz,CDCl3)δ163.55,161.71,159.67,150.62,148.52,134.08,132.52,129.07, 127.95,127.32,125.57,125.04,118.31,118.10,114.76,110.41,110.18,61.55,56.18, 56.00,43.44,27.88,14.15。

Claims (1)

1. preparing pyrroles [2,1-a] morphinane alkaloid method described in logical formula (I), which is characterized in that set formula compound II In the drying flask containing magneton, it is sequentially added anhydrous acetonitrile, cuprous bromide, compound III, N-phenylmaleimide, The air in reaction flask is replaced, and in the oil bath pan for being placed in 60-70 DEG C under Oxygen Condition, is stirred to react, subtracts after reaction Solvent is distilled off in pressure, and residue carries out column chromatographic purifying and obtains purified product I；
(II) (III) (I)
Wherein, R1For hydrogen, methoxyl group；R2For hydrogen, methoxyl group；R3For phenyl, rubigan, p-methoxyphenyl, p-chlorobenzyl；R4 For ethyl.
CN201710883888.1A 2017-09-26 2017-09-26 Pyrroles [2,1-a] morphinane alkaloid and its preparation method and application Active CN107522697B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710883888.1A CN107522697B (en) 2017-09-26 2017-09-26 Pyrroles [2,1-a] morphinane alkaloid and its preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710883888.1A CN107522697B (en) 2017-09-26 2017-09-26 Pyrroles [2,1-a] morphinane alkaloid and its preparation method and application

Publications (2)

Publication Number Publication Date
CN107522697A CN107522697A (en) 2017-12-29
CN107522697B true CN107522697B (en) 2019-11-12

Family

ID=60737546

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710883888.1A Active CN107522697B (en) 2017-09-26 2017-09-26 Pyrroles [2,1-a] morphinane alkaloid and its preparation method and application

Country Status (1)

Country Link
CN (1) CN107522697B (en)

Also Published As

Publication number Publication date
CN107522697A (en) 2017-12-29

Similar Documents

Publication Publication Date Title
EP2497775A1 (en) Ferrocene-based compounds and their use as ROS regulating prodrugs
Patti et al. Synthesis of 2-ferrocenylquinoline derivatives and evaluation of their antimalarial activity
Takasu et al. Synthesis and evaluation of β-carbolinium cations as new antimalarial agents based on π-delocalized lipophilic cation (DLC) hypothesis
CN103420990B (en) 7-oxygen, sulphur or azepine substituted cumarin and derivative thereof and purposes
CN102731493B (en) Anti-tumor compound containing benzothiazole heterocyclic structure and application thereof
CN107522697B (en) Pyrroles [2,1-a] morphinane alkaloid and its preparation method and application
CN104892485B (en) 2 perfluoroalkyl indole derivativeses and its synthetic method
CN115636809B (en) Synthesis and pharmaceutical application of chalcone derivatives
CN113698385B (en) 2, 2-disubstituted indoline-3-ketone alkaloid, preparation method and application thereof
Al-Trawneh et al. A new efficient route to 7-aryl-6-fluoro-8-nitroquinolones as potent antibacterial agents
CN111303027A (en) Fluroxacin acrylketone derivative and preparation method and application thereof
CN109574967A (en) The method of aphthofurans derivative is synthesized using titanium tetrachloride as dehydrated reagent
CN114437114B (en) Application and preparation of diketopiperazine natural product and derivative and obtained derivative
CN106565657A (en) Hesperetin cinnamate compound with anti-tumor activity and synthetic method thereof
CN107459536A (en) A kind of green synthesis method of 4 ferrocenyl quinoline
CN110143927B (en) Benzimidazole chalcone derivative and preparation method and application thereof
CN107573336A (en) Benzheterocycle carboxamide pyridine ketone derivatives and its production and use
CN110272417B (en) 2-methyl-1, 8-naphthyridine compound and preparation method and application thereof
CN104744421B (en) A kind of derivative of Mansonone F and its preparation method and application
CN102351870B (en) Method for preparing benzacridine derivative and application of benzacridine derivative as anti-cancer medicine
CN101985449B (en) Coumarin derivative, and preparation method and use thereof as anti-cancer medicament
CN109422724B (en) Indole-substituted isoquinoline compound and synthesis method thereof
CN101050179B (en) 2,3,4,5-tetrasubstituted derivatives of benzyl ethylene class, preparation method and application
CN103896958B (en) Oridonin and ent-6,7-open loop dammara ene-type derivative purposes in terms of preparing antituberculotic thereof
CN104761568B (en) One class Fourth Ring Nai Bing oxazole derivatives and preparation method thereof

Legal Events

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