CN110041349A - One kind dihydropyrimidine derivatives containing spiral shell and its preparation method and application - Google Patents
One kind dihydropyrimidine derivatives containing spiral shell and its preparation method and application Download PDFInfo
- Publication number
- CN110041349A CN110041349A CN201910408220.0A CN201910408220A CN110041349A CN 110041349 A CN110041349 A CN 110041349A CN 201910408220 A CN201910408220 A CN 201910408220A CN 110041349 A CN110041349 A CN 110041349A
- Authority
- CN
- China
- Prior art keywords
- reaction
- spiral shell
- pyrimidine
- methyl
- phenyl
- 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.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/20—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides one kind novel 5- aryl -4'- hydroxyl -7- methyl -3- oxo -2'- aryl -3,4' as shown in the formula, and 5,5'- tetrahydro -2'H- spiral shell [thiazole [3,2-a] pyrimidine -2,3'- thiophene] -6- Ethyl formate derivative, in formula (I), substituent R1It is H, F, Cl, Br, C1‑4Alkyl, alkoxy, hydroxyl, itrile group, nitro, carboxyl or/and sulfonic group;R2It is H, F, Cl, Br, C1‑4Alkyl, alkoxy, hydroxyl, itrile group, acetyl group, carboxyl or/and sulfonic group.5- aryl -4'- hydroxyl -7- methyl -3- oxo -2'- aryl -3,4' of the invention, 5,5'- tetrahydro -2'H- spiral shell [thiazole [3,2-a] pyrimidine -2,3'- thiophene] -6- acid ethyl ester derivatives have certain inhibitory activity to tumour cell, and its synthetic method is simple, and material is easy to get.It can be used for making anti-tumor drug.
Description
Technical field
The present invention relates to a kind of oxadiazole derivatives as comt inhibitors, specifically, are related to a kind of 5- aryl -4'- hydroxyl -7- methyl -3-
Oxo -2'- aryl -3,4', 5,5'- tetrahydro -2'H- spiral shell [thiazole [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester is derivative
Object and preparation method thereof and application as anticancer drug.
Background technique
Cancer is to seriously threaten one of the major disease of human life and social development at present, in recent decades, with disease
The transformation and aging of population trend of disease, China's cancer burden increasingly increase, and prevention and control of cancer faces severe situation.Therefore anticancer
The research and development of drug are always the hot spot of chemist and drug scholar concern.Find efficient, highly selective and toxic side effect
Small anticancer drug is one of Main way of drug development research.
Pyrimidine ring is widely present in nature, is the necessary molecular structure unit of life system.The synthesis of pyrimidine derivatives
It has attracted people's attention with conversion, bioactivity and metabolism research.Dihydropyrimidinonesand is a kind of important nitrogen-containing heterocycle chemical combination
Object, mostly have bioactivity, medicine, in terms of have important application.Some 3,4- dihydropyrimidine-2-keto chemical combination
Object (DHPMs) have significant pharmacological activity, be important treatment hypertension, coronary heart disease, cardiovascular and cerebrovascular disease drug, such as may be used
As calcium antagonist (J. Med. Chem., 1995,38,119-129.), depressor (SQ 32,547, SQ 32,926)
(J. Med. Chem., 1991,34,806-811), α1aAntagonist is also used as developing the primer of anticancer drug
(Chem. Biol., 2000,7,275-286) etc., and have in drug fields such as antimicrobial, antiviral, sterilization, anti-inflammatory
Wide application.Thus synthesizing dihydro pyrimidone parent nucleus become in recent years bioactivity organic heterocyclic molecule research hot spot it
One.
Nearly ten years, characteristic and bioactivity of the people to 3,4- dihydropyrimidinone derivative in acology and pharmaceutics
Further research.As a result, it has been found that its derivative S-Monastrol is inhibited to mitosis (Eg5) driving albumen,
This provides a new idea and method for the treatment of tumor disease.But since 3,4- dihydropyrimidinone derivative is active
The deficiencies of low, poor selectivity, therefore, clinical application is considerably restricted.It therefore is first with 3,4- dihydropyrimidinone derivative
Compound is led, structural modification is carried out, novel, safe and efficient anti-tumor drug is found and has become the domestic and international scientist in the field
The important topic studied.
Summary of the invention
The purpose of the present invention is to provide a kind of dihydropyrimidine derivatives containing spiral shell, i.e., a kind of novel 5- aryl -4'- hydroxyls
Base -7- methyl -3- oxo -2'- aryl -3,4', 5,5'- tetrahydro -2'H- spiral shell [thiazole [3,2-a] pyrimidine -2,3'- thiophene] -6-
Acid ethyl ester derivatives.
The purpose of the present invention, which is lain also in, provides a kind of preparation method of dihydropyrimidine derivatives containing spiral shell.
The purpose of the present invention, which is lain also in, provides a kind of application in preparation of anti-tumor drugs of dihydropyrimidine derivatives containing spiral shell.
Above-mentioned purpose of the invention is achieved by following scheme: a kind of dihydropyrimidine derivatives containing spiral shell, special
Sign is that chemical structural formula is shown in formula I:
In formula (I), substituent R1It is H, F, Cl, Br, C1-4Alkyl, alkoxy, hydroxyl, itrile group, nitro, carboxyl or/and sulfonic acid
Base.
In formula (I), substituent R2It is H, F, Cl, Br, C1-4Alkyl, alkoxy, hydroxyl, itrile group, acetyl group, carboxyl or/
And sulfonic group.
A kind of preparation method of the dihydropyrimidine derivatives containing spiral shell, reaction formula are as follows:
Specific step is as follows:
(1) aromatic aldehyde, ethyl acetoacetate, thiocarbamide and catalyst are dissolved in reaction dissolvent, under reflux condition instead
It answers, it is after the reaction was completed, cooling that solid is precipitated, filter to obtain intermediate 2- sulfydryl -4- methyl -6- substituted-phenyl -1,6- dihydro-pyrimidin -
5- carboxylic acid, ethyl ester;
(2) by above-mentioned intermediate 2- sulfydryl -4- methyl -6- substituted-phenyl -1,6- dilzydro-pyrimidine -5- carboxylic acid, ethyl ester, alkali, bromine second
Acetoacetic ester is dissolved in reaction dissolvent, is heated to reflux, after the reaction was completed, cooling intermediate product 7- methyl -3- oxo -5- substituted benzene
Base -3,5- dihydro -2H- thiazole simultaneously [3,2-a] pyrimidine -6- carboxylic acid, ethyl ester, this intermediate is not post-treated to be directly used in next step
Reaction, is added substituted benzaldehyde in former reaction system and piperidines continues back flow reaction, after completion of the reaction, cooling that solid is precipitated,
Column chromatography for separation purifies to obtain intermediate 2- substitution benzylidene -7- methyl -3- oxo -5- substituted-phenyl -2,3- dihydro -5H- thiophene
Azoles simultaneously [3,2-a] pyrimidine -6- carboxylic acid, ethyl ester;
(3) above-mentioned intermediate 2- is replaced into benzylidene -7- methyl -3- oxo -5- substituted-phenyl -2,3- dihydro -5H- thiazole
And [3,2-a] pyrimidine -6- carboxylic acid, ethyl ester, 2,5- dihydroxy-Isosorbide-5-Nitrae-dithiane and alkali soluble are in reaction dissolvent, it is anti-at 25 DEG C
It answers, to which after reaction, column chromatography for separation purifies to obtain product 5- substituted-phenyl -4'- hydroxyl -7- methyl -3- oxo -2'- substitution
Phenyl -3,4', 5,5'- tetrahydro -2'H- spiral shells [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester, i.e. dihydro containing spiral shell
Pyrimidine derivatives.
It is demonstrated experimentally that dihydropyrimidine derivatives containing spiral shell of the invention have good inhibitory activity to tumour cell, can be used for
Preparation inhibits the drug of tumour cell, and synthetic method is simple, and material is easy to get, and provides one kind newly to solve anti-tumor drug
Development approach.
Specific embodiment
In order to better understand the present invention, preparation 5- aryl -4'- hydroxyl -7- methyl -3- oxo -2'- aryl-is now provided
3,4', 5,5'- tetrahydro -2'H- spiral shell [thiazole [3,2-a] pyrimidine -2,3'- thiophene] -6- acid ethyl ester derivatives (i.e. dihydro containing spiral shell
Pyrimidine derivatives) embodiment, the present invention includes but is not limited to this preparation method.
Embodiment 1:5- phenyl -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetrahydro -2'H- spiral shell [thiophene
Azoles simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ia) synthesis.
By benzaldehyde (20 mmol), ethyl acetoacetate (24 mmol), thiocarbamide (30 mmol) and sulfamic acid (16
Mmol 20 ml dehydrated alcohols) are dissolved in, are heated to reflux, TCL tracking reaction process is cooled to room temperature after the reaction was completed, is filtered, water
It washes, dries to obtain intermediate 2- sulfydryl -4- methyl -6- substituted-phenyl -1,6- dihydro-pyrimidin -5- carboxylic acid, ethyl ester 1.
It will be by above-mentioned intermediate 2- sulfydryl -4- methyl -6- phenyl -1,6- dilzydro-pyrimidine -5- carboxylic acid, ethyl ester 1(7 mmol)
20 ml dehydrated alcohols are dissolved in, is added dropwise pyridine (14 mmol), then bromoacetate (14 mmol) is added dropwise, stirs evenly
Afterwards, it is heated to reflux, TCL tracks reaction process.End of reaction obtains crude product 7- methyl -3- oxo -5- phenyl -3,5- dihydro -2H-
Thiazole simultaneously [3,2-a] pyrimidine -6- carboxylic acid, ethyl ester 2.Intermediate 2 is not post-treated, is directly used in and reacts in next step, toward original reactant
It is added dropwise in system piperidines (7 mmol), benzaldehyde (7 mmol), continues back flow reaction, TCL tracks reaction process.End of reaction
Afterwards, it is cooled to room temperature, filters, sufficiently wash, column chromatography for separation purifies to obtain 2- benzylidene -7- methyl -3- oxo -5- phenyl -
2,3- dihydro -5H- thiazole simultaneously [3,2-a] pyrimidine -6- carboxylic acid, ethyl ester 3.
2,5- dihydroxy-Isosorbide-5-Nitrae-dithiane (1.5 mmol) is dissolved in 10 ml dehydrated alcohols, triethylamine is added dropwise dropwise
Then intermediate 2- benzylidene -7- methyl -3- oxo -5- phenyl -2,3- dihydro -5H- thiazole is added simultaneously in (0.45 mmol)
[3,2-a] pyrimidine -6- carboxylic acid, ethyl ester 3(3 mmol), it is reacted at 25 DEG C, TCL tracks reaction process.To after reaction, column
Chromatography purifies to obtain target product 5- phenyl -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetrahydro -
2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester, chemical structural formula as shown in formula (Ia), produce
Rate: 75%.
1H NMR (500 MHz, CDCl3)δ: 7.39 (d, J = 3.5 Hz, 1H), 7.38 (d, J = 1.5
Hz, 1H), 7.36 – 7.34 (m, 1H), 7.33 – 7.32 (m, 2H), 7.30 (s, 2H), 7.28 (s,
1H), 7.27 – 7.24 (m, 2H), 5.88 (s, 1H), 5.22 (s, 1H), 4.68 (dd, J = 16.5, 8.0
Hz, 1H), 4.08 – 4.02 (m, 2H), 3.18 (dd, J = 11.0, 7.5 Hz, 1H), 2.82 (t, J =
10.5 Hz, 1H), 2.31 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3)δ: 172.00 , 165.37, 157.45, 151.43, 140.17, 133.80, 129.35, 128.97, 128.67,
128.52, 128.48, 127.84, 108.91, 79.80, 76.58, 60.54, 55.85, 51.75, 33.56,
22.61, 14.06; ESI MS m/z: 481 (M+H)+。
Embodiment 2:5- (2- aminomethyl phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetrahydro -
The synthesis of 2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ib).
The preparation method of the present embodiment in addition to replacing benzaldehyde with o-tolualdehyde in the synthesis in intermediate 1, remaining
With embodiment 1, light yellow crystal 5- (2- aminomethyl phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4' is finally obtained,
5,5'- tetrahydro -2'H- spiral shells [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester, chemical structural formula such as formula (Ib)
It is shown, yield: 59%.
1H NMR (500 MHz, CDCl3) δ: 7.39 (s, 2H), 7.34 (d, J = 4.0 Hz, 3H),
7.17 (d, J = 7.0 Hz, 1H), 7.12 (dd, J = 14.0, 7.0 Hz, 3H), 6.03 (s, 1H), 5.21
(s, 1H), 4.62 (q, J = 9.0 Hz, 1H), 4.05 (q, J =7.0 Hz, 2H), 3.16 (t, J =9.5
Hz, 1H), 2.81 (t, J = 10.5 Hz, 1H), 2.65 (s, 3H), 2.31 (s, 3H), 2.17 (s, 1H),
1.15 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 172.10, 165.65, 157.13,
150.94, 139.34, 136.79, 133.93, 130.24, 129.39, 128.94, 128.53, 127.98,
126.62, 109.63, 79.78, 76.11, 60.57, 52.31, 51.62, 33.45, 22.83, 19.25,
14.16; ESI MS m/z: 495 (M+H)+。
Embodiment 3:5- (2- chlorphenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetrahydro -2'
The synthesis of H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ic).
For the preparation method of the present embodiment in addition to replacing benzaldehyde with o-chlorobenzaldehyde in the synthesis in intermediate 1, remaining is same
Embodiment 1, finally light yellow crystal 5- (2- chlorphenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'-
Tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester, shown in chemical structural formula such as formula (Ic),
Yield: 56%.
1H NMR (500 MHz, CDCl3) δ: 7.41 (d, J = 4.0 Hz, 1H), 7.40 (d, J = 1.5 Hz,
1H), 7.37 – 7.35 (m, 1H), 7.35-7.34 (m, 2H), 7.33 (d, J = 3.0Hz, 1H), 7.32 –
7.31 (m, 1H), 7.19 (dd, J = 7.5, 4.5 Hz, 2H), 6.25 (s, 1H), 5.22 (s, 1H),
4.69-4.64 (m, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.20 (dd, J= 10.5, 7.0 Hz, 1H),
2.81 (t, J = 10.5 Hz, 1H), 2.31 (s, 3H), 2.29 (d, J = 9.5 Hz, 1H), 1.16 (t, J
= 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 171.74, 165.22, 156.96, 151.66,
137.58, 133.76, 133.57, 130.71, 129.82, 129.38, 129.01, 128.56, 127.14,
108.03, 79.76, 76.11, 60.60, 53.59, 51.70, 33.66, 22.67, 14.10; ESI MS m/z:
515 (M+H)+。
Embodiment 4:5- (4- aminomethyl phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetrahydro -
The synthesis of 2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Id).
The preparation method of the present embodiment in addition to replacing benzaldehyde with p-tolyl aldehyde in the synthesis in intermediate 1, remaining
With embodiment 1, light yellow crystal 5- (4- aminomethyl phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4' is finally obtained,
5,5'- tetrahydro -2'H- spiral shells [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester, chemical structural formula such as formula (Id)
It is shown, yield: 57%.
1H NMR (500 MHz, CDCl3) δ: 7.39 (d, J = 3.5 Hz, 1H), 7.38 (d, J = 1.5
Hz, 1H), 7.35 – 7.32 (m, 3H), 7.19 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz,
2H), 5.85 (s, 1H), 5.22 (s, 1H), 4.72 – 4.66 (m, 1H), 4.07–4.03 (m, 2H), 3.19
(dd, J = 10.5, 7.5 Hz, 1H), 2.83 (t, J = 10.5 Hz, 1H), 2.30 (s, 3H), 2.28 (s,
4H), 1.18 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 172.02, 165.43,
157.35, 151.17, 138.47, 137.39, 133.80, 129.35, 129.16, 128.96, 128.51,
127.70, 109.08, 79.79, 76.59, 60.52, 55.59, 51.76, 33.52, 22.60, 21.22, 14.09
; ESI MS m/z: 495 (M+H)+。
Embodiment 5:5- (4- chlorphenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetrahydro -2'
The synthesis of H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ie).
For the preparation method of the present embodiment in addition to replacing benzaldehyde with p-chlorobenzaldehyde in the synthesis in intermediate 1, remaining is same
Embodiment 1, finally light yellow crystal 5- (4- chlorphenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'-
Tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester.Shown in its chemical structural formula such as formula (Ie),
Yield: 49%.
1H NMR (500 MHz, CDCl3) δ: 7.39 (d, J = 3.5 Hz, 1H), 7.37 (s, 1H),
7.33 (d, J = 5.0 Hz, 3H), 7.24 (s, 4H), 5.85 (s, 1H), 5.22 (s, 1H), 4.70 (dd,J = 17.0, 9.5 Hz, 1H), 4.08 – 4.03 (m, 2H), 3.21 (dd, J = 10.5, 7.5 Hz, 1H),
2.83 (t, J = 10.5 Hz, 1H), 2.42 (dd, J = 17.5, 7.5 Hz, 1H), 2.30 (s, 3H),
1.17 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)δ: 171.97, 165.22, 157.50,
151.62, 138.61, 134.45, 133.68, 129.34, 129.32, 129.02, 128.65, 128.56,
108.57, 79.81, 76.60, 60.65, 55.21, 51.73, 33.68, 22.68, 14.09; ESI MS m/z:
515 (M+H)+。
Embodiment 6:5- (3- aminomethyl phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetrahydro -
The synthesis of 2'H- spiral shell simultaneously [thiazole [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (If).
The preparation method of the present embodiment in addition to tolyl aldehyde replaces benzaldehyde between in the synthesis in intermediate 1, remaining
With embodiment 1, light yellow crystal 5- (3- aminomethyl phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4' is finally obtained,
5,5'- tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester.Its chemical structural formula such as formula (If)
It is shown, yield: 50%.
1H NMR (500 MHz, CDCl3) δ: 7.39 (d, J = 4.0 Hz, 1H), 7.38 (d, J = 1.5
Hz, 1H), 7.33 (dd, J = 9.0, 4.0 Hz, 3H), 7.16 (t, J = 7.5 Hz, 1H), 7.10 (d, J
= 1.5 Hz, 2H), 7.05 (d, J = 7.5 Hz, 1H), 5.85 (s, 1H), 5.22 (s, 1H), 4.69
(dd, J = 17.0, 8.0 Hz, 1H), 4.09 – 4.03 (m, 2H), 3.19 (dd, J = 11.0, 7.5 Hz,
1H), 2.83 (t, J = 10.0 Hz, 1H), 2.41 (dd, J = 14.5, 3.5 Hz, 1H), 2.30 (d, J =
1.0 Hz, 3H), 2.30 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)δ: 171.96, 165.40, 157.63, 151.01, 140.16, 138.14, 133.80, 129.42, 129.35,
128.96, 128.52, 128.40, 128.34, 124.83, 109.06, 79.84, 76.66, 60.53, 55.89,
51.78, 33.54, 22.55, 21.42, 14.07;ESI MS m/z: 495 (M+H)+。
Embodiment 7:5- (4- fluorophenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetrahydro -2'
The synthesis of H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ig).
For the preparation method of the present embodiment in addition to replacing benzaldehyde with 4-Fluorobenzaldehyde in the synthesis in intermediate 1, remaining is same
Embodiment 1, finally light yellow crystal 5- (4- fluorophenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'-
Tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester.Shown in its chemical structural formula such as formula (Ig),
Yield: 46%.
1H NMR (500 MHz, CDCl3)δ: 7.39 (d, J = 4.0 Hz, 1H), 7.37 (s, 1H), 7.34
– 7.33 (m, 3H), 7.28 (dd, J = 8.5, 5.5 Hz, 2H), 6.96 (t, J = 8.5 Hz, 2H),
5.87 (s, 1H), 5.22 (s, 1H), 4.69 (dd, J = 16.5, 8.0 Hz, 1H), 4.08 – 4.02 (m,
2H), 3.20 (dd, J = 11.0, 7.5 Hz, 1H), 2.82 (t, J = 10.0 Hz, 1H), 2.42 (s,
1H), 2.30 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ:
171.95, 165.27, 161.62, 157.28, 151.52, 135.99, 133.70, 129.79, 129.72,
129.33, 129.01, 128.55, 115.48, 115.30, 108.80, 79.84, 76.59, 60.60, 55.13,
51.71, 33.70, 22.65, 14.07; ESI MS m/z: 499 (M+H)+。
Embodiment 8:5- (4- methoxyphenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,5'- tetra-
The synthesis of hydrogen -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ih).
The preparation method of the present embodiment in addition to replacing benzaldehyde with anisaldehyde in the synthesis in intermediate 1, remaining
With embodiment 1, finally light yellow crystal 5- (4- fluorophenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,
5'- tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester.Its chemical structural formula such as formula (Ih) institute
Show, yield: 47%.
1H NMR (500 MHz, CDCl3) δ: 7.10 (t, J = 6.5 Hz, 1H), 7.00 (s, 1H),
6.98 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 7.0 Hz, 3H), 6.71 (s,
1H), 6.69 (s, 1H), 5.90 (s, 1H), 5.13 (s, 1H), 4.97 (dd, J = 17.5, 10.0 Hz,
1H), 4.06 –4.02 (m, 2H), 3.83 (s, 3H), 3.35 (dd, J = 11.0, 7.5 Hz, 1H), 2.91
(d, J = 10.5 Hz, 1H), 2.82 (t, J = 10.5 Hz, 1H), 2.36 (s, 3H), 1.14 (t, J =
7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 172.14, 165.23, 159.43, 156.90,
151.28, 133.32, 132.14, 129.19, 128.63, 128.42, 128.11, 113.87, 109.02,
79.54, 60.51, 55.29, 55.03, 52.47, 34.28, 22.40, 14.03; ESI MS m/z: 511 (M+H)+。
Embodiment 9:5- (3- methoxyl group -4- hydroxy phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- phenyl -3,4', 5,
The synthesis of 5'- tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ii).
The preparation method of the present embodiment is removed and replaces benzene first with Vanillin in the synthesis of intermediate 1
Outside aldehyde, remaining finally obtains light yellow crystal 5- (3- methoxyl group -4- hydroxy phenyl) -4'- hydroxyl -7- methyl -3- with embodiment 1
Oxo -2'- phenyl -3,4', 5,5'- tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester.Its
Shown in chemical structural formula such as formula (Ii), yield: 48%.
Embodiment 10:5- (2- aminomethyl phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- (2- aminomethyl phenyl) -3,4', 5,
The synthesis of 5'- tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ij).
The preparation method of the present embodiment, which is removed, with o-tolualdehyde replaces benzaldehyde in the synthesis of intermediate 1 and in centre
It is replaced outside benzaldehyde in the synthesis of body 3 with o-tolualdehyde, remaining finally obtains light yellow crystal 5- (2- methyl with embodiment 1
Phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- (2- aminomethyl phenyl) -3,4', 5,5'- tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-
A] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester.Shown in its chemical structural formula such as formula (Ij), yield: 58%.
1H NMR (500 MHz, CDCl3) δ: 7.11 (t, J = 7.0 Hz, 1H), 6.92 (d, J = 8.0
Hz, 1H), 6.90 (s, 1H), 6.88 (d, J = 7.0 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H),
6.65 (dd, J = 8.5, 2.0 Hz, 1H), 6.42 (d, J = 1.5 Hz, 1H), 5.86 (s, 1H), 5.70
(s, 1H), 5.12 (s, 1H), 4.98 (dd, J = 17.5, 10.0 Hz, 1H), 4.07-4.02 (m, 2H),
3.65 (s, 3H), 3.35 (dd, J = 10.5, 7.5 Hz, 1H), 2.99 (d, J = 10.5 Hz, 1H),
2.83 (t, J = 10.5 Hz, 1H), 2.36 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H); 13C NMR
(125 MHz, DMSO)δ: 171.96, 164.80, 157.22, 150.88, 147.32, 146.80, 133.84,
130.64, 128.12, 127.94, 127.80, 120.08, 115.12, 110.88, 107.98, 78.85, 76.52,
60.00, 55.25, 54.45, 51.54, 33.01, 22.10, 13.89; ESI MS m/z: 527 (M+H)+。
Embodiment 11:5- (2- aminomethyl phenyl) -4'- hydroxyl -7- methyl -3- oxo -2'- (4- chlorphenyl) -3,4', 5,
The synthesis of 5'- tetrahydro -2'H- spiral shell [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester (Ik).
The preparation method of the present embodiment, which is removed, with o-tolualdehyde replaces benzaldehyde in the synthesis of intermediate 1 and in centre
It is replaced outside benzaldehyde in the synthesis of body 3 with p-chlorobenzaldehyde, remaining finally obtains light yellow crystal 5- (2- methylbenzene with embodiment 1
Base) [thiazole is simultaneously [3,2-a] phonetic for -4'- hydroxyl -7- methyl -3- oxo -2'- (4- chlorphenyl) -3,4', 5,5'- tetrahydro -2'H- spiral shell
Pyridine -2,3'- thiophene] -6- carboxylic acid, ethyl ester.Shown in its chemical structural formula such as formula (Ik), yield: 54%.
1H NMR (500 MHz, CDCl3)δ: 7.34 – 7.30 (m, 4H), 7.17 (d, J = 7.5 Hz,
1H), 7.14 – 7.08 (m, 3H), 6.04 (s, 1H), 5.16 (s, 1H), 4.60 (dd, J = 17.5, 9.0
Hz, 1H), 4.06 (q, J = 7.5 Hz, 2H), 3.15 (dd, J = 10.5, 7.0 Hz, 1H), 2.81 (t,J = 10.5 Hz, 1H), 2.64 (s, 3H), 2.33 (s, 3H), 2.05 (d, J = 8.5 Hz, 1H), 1.16
(t, J = 7.0 Hz, 3H);13C NMR (125 MHz, CDCl3)δ: 171.88, 165.59, 156.63, 150.84,
139.26, 136.79, 134.85, 132.49, 130.73, 130.26, 128.75, 128.56, 127.95,
126.63, 109.78, 79.70, 75.94, 60.61, 52.40, 50.91, 33.47, 22.84, 19.22,
14.15; ESI MS m/z: 529 (M+H)+。
Below by compound experiment example and activity experiment example, the present invention is described in further detail.
Using mtt assay, to synthesized 11 kinds of target product 5- aryl -4'- hydroxyl -7- methyl -3- oxo -2'- aryl -
It is living that 3,4', 5,5'- tetrahydro -2'H- spiral shell [thiazole [3,2-a] pyrimidine -2,3'- thiophene] -6- acid ethyl ester derivatives have carried out anticancer
The experiment of property.With the MGC803(gastric cancer of people), PC-3(prostate cancer), EC109(esophageal squamous cell carcinoma), be material to be tested.Collection pair
Number phase cell adjusts concentration of cell suspension to 2 × 10 with trypsin digestion cell4A/mL is dispensed into 96 orifice plates, and every hole is added
200 μL;In 5%CO2, the sample of various concentration is added until cell monolayer is paved with bottom hole 37 DEG C of incubation half a day, every 100 μ l of hole,
If 3 parallel holes;Then at 5% CO2, 37 DEG C are incubated for four days, observe under inverted microscope;20 μ l MTT solution (5 are added in every hole
Mg/ml, i.e. 0.5%MTT), continuing 4 h of culture can first be centrifuged if drug can be reacted with MTT and discard culture solution afterwards, careful to use
PBS rushes 2-3 after, adds the culture solution containing MTT, terminates culture, carefully sucks culture solution in hole;180 μ l bis- are added in every hole
Methyl sulfoxide sets 10 min of low-speed oscillation on shaking table, dissolves crystal sufficiently.In enzyme-linked immunosorbent assay instrument in 550 nm of wavelength
Place measures the light absorption value in each hole.(sample is free of, sample is replaced with the solvent for dissolving it, other conditions complete one referring to control
Sample), calculate inhibiting rate IC50, test result is shown in Table 1.
1 5- aryl -4'- hydroxyl -7- methyl -3- oxo -2'- aryl -3,4', 5,5'- tetrahydro -2'H- spiral shell [thiazole of table
[3,2-a] pyrimidine -2,3'- thiophene] -6- acid ethyl ester derivatives anti-tumor activity
As it can be seen from table 1 5- aryl -4'- hydroxyl -7- methyl -3- oxo -2'- aryl -3,4', 5,5'- tetrahydro -2'H- spiral shells
[thiazole [3,2-a] pyrimidine -2,3'- thiophene] -6- Ethyl formate derivative is to MGC803(gastric cancer), PC-3(prostate cancer) have
Good inhibitory activity, wherein compound Ib, Id and Ik is best to the tumor promotion inhibitory effect of MGC803, PC-3, they are right
In the IC of above-mentioned cell50Value is respectively less than positive control 5-Fu (5 FU 5 fluorouracil).
Claims (8)
1. a kind of dihydropyrimidine derivatives containing spiral shell, which is characterized in that its chemical structural formula is shown in formula I:
In formula (I), substituent R1It is H, F, Cl, Br, C1-4Alkyl, alkoxy, hydroxyl, itrile group, nitro, carboxyl or/and sulfonic acid
Base.
2. dihydropyrimidine derivatives containing spiral shell according to claim 1, which is characterized in that in formula (I), substituent R2Be H, F,
Cl、Br、C1-4Alkyl, alkoxy, hydroxyl, itrile group, acetyl group, carboxyl or/and sulfonic group.
3. a kind of preparation method of dihydropyrimidine derivatives containing spiral shell, which comprises the steps of:
(1) aromatic aldehyde, ethyl acetoacetate, thiocarbamide and catalyst are dissolved in reaction dissolvent, under reflux condition instead
It answers, it is after the reaction was completed, cooling that solid is precipitated, filter to obtain intermediate 2- sulfydryl -4- methyl -6- substituted-phenyl -1,6- dihydro-pyrimidin -
5- carboxylic acid, ethyl ester;
(2) by above-mentioned intermediate 2- sulfydryl -4- methyl -6- substituted-phenyl -1,6- dilzydro-pyrimidine -5- carboxylic acid, ethyl ester, alkali, bromine second
Acetoacetic ester is dissolved in reaction dissolvent, is heated to reflux, after the reaction was completed, cooling intermediate product 7- methyl -3- oxo -5- substituted benzene
Base -3,5- dihydro -2H- thiazole simultaneously [3,2-a] pyrimidine -6- carboxylic acid, ethyl ester, this intermediate is not post-treated to be directly used in next step
Reaction, is added substituted benzaldehyde in former reaction system and piperidines continues back flow reaction, after completion of the reaction, cooling that solid is precipitated,
Column chromatography for separation purifies to obtain intermediate 2- substitution benzylidene -7- methyl -3- oxo -5- substituted-phenyl -2,3- dihydro -5H- thiophene
Azoles simultaneously [3,2-a] pyrimidine -6- carboxylic acid, ethyl ester;
(3) above-mentioned intermediate 2- is replaced into benzylidene -7- methyl -3- oxo -5- substituted-phenyl -2,3- dihydro -5H- thiazole
And [3,2-a] pyrimidine -6- carboxylic acid, ethyl ester, 2,5- dihydroxy-Isosorbide-5-Nitrae-dithiane and alkali soluble are in reaction dissolvent, it is anti-at 25 DEG C
It answers, to which after reaction, column chromatography for separation purifies to obtain product 5- substituted-phenyl -4'- hydroxyl -7- methyl -3- oxo -2'- substitution
Phenyl -3,4', 5,5'- tetrahydro -2'H- spiral shells [thiazole simultaneously [3,2-a] pyrimidine -2,3'- thiophene] -6- carboxylic acid, ethyl ester, i.e. dihydro containing spiral shell
Pyrimidine derivatives.
4. the preparation method of the dihydropyrimidine derivatives containing spiral shell as claimed in claim 3, which is characterized in that condensation in step (1)
Reaction catalyst used is sulfamic acid, and whipping temp is 70-78 DEG C, and reaction dissolvent is dehydrated alcohol.
5. the preparation method of the dihydropyrimidine derivatives containing spiral shell as claimed in claim 3, which is characterized in that cyclisation in step (2)
It is pyridine that reaction, which generates alkali used in thiazole, and alkali used in aldol reaction is piperidines, and reaction temperature is 70-78 DEG C, instead
Answering solvent is dehydrated alcohol.
6. the preparation method of the dihydropyrimidine derivatives containing spiral shell as claimed in claim 3, which is characterized in that condensation in step (3)
Reaction alkali used is triethylamine, and reaction temperature is 25 DEG C, and reaction dissolvent is dehydrated alcohol.
7. the application in preparation of anti-tumor drugs of dihydropyrimidine derivatives containing spiral shell as claimed in claim 1 or 2.
8. the application in preparation of anti-tumor drugs of dihydropyrimidine derivatives containing spiral shell according to claim 7, feature exist
In the dosage form of the anti-tumor drug is tablet, pill, capsule, injection, suspending agent or emulsion.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910408220.0A CN110041349B (en) | 2019-05-15 | 2019-05-15 | Spiro-containing dihydropyrimidine derivative and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910408220.0A CN110041349B (en) | 2019-05-15 | 2019-05-15 | Spiro-containing dihydropyrimidine derivative and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110041349A true CN110041349A (en) | 2019-07-23 |
CN110041349B CN110041349B (en) | 2021-06-01 |
Family
ID=67282182
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910408220.0A Active CN110041349B (en) | 2019-05-15 | 2019-05-15 | Spiro-containing dihydropyrimidine derivative and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110041349B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117180122A (en) * | 2023-11-02 | 2023-12-08 | 杭州湃肽生化科技有限公司 | Composition for relaxing and repairing allergy and application thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB734842A (en) * | 1952-03-25 | 1955-08-10 | Wellcome Found | Improvements in derivatives of pyrimidine and methods of making the same |
WO2012051410A2 (en) * | 2010-10-13 | 2012-04-19 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
CN103694258A (en) * | 2007-10-19 | 2014-04-02 | 默沙东公司 | Spiro-condensed 1, 3, 4-thiadiazole derivatives for inhibiting ksp kinesin activity |
WO2018187630A1 (en) * | 2017-04-05 | 2018-10-11 | The Broad Institute, Inc. | Tricyclic compounds as glycogen synthase kinase 3 (gsk3) inhibitors and uses thereof |
-
2019
- 2019-05-15 CN CN201910408220.0A patent/CN110041349B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB734842A (en) * | 1952-03-25 | 1955-08-10 | Wellcome Found | Improvements in derivatives of pyrimidine and methods of making the same |
CN103694258A (en) * | 2007-10-19 | 2014-04-02 | 默沙东公司 | Spiro-condensed 1, 3, 4-thiadiazole derivatives for inhibiting ksp kinesin activity |
WO2012051410A2 (en) * | 2010-10-13 | 2012-04-19 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
WO2018187630A1 (en) * | 2017-04-05 | 2018-10-11 | The Broad Institute, Inc. | Tricyclic compounds as glycogen synthase kinase 3 (gsk3) inhibitors and uses thereof |
Non-Patent Citations (4)
Title |
---|
GEORGE C.ROVNYAK ET AL.: "Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators", 《J.MED.CHEM.》 * |
JINLONG YAN ET AL.: "Synthesis of spiro thiazolo[3,2-a]pyrimidine-tetrahydrothiophenes via sulfa Michael/aldol cascade reactions", 《JOURNAL OF CHEMICAL RESEARCH》 * |
STEPHEN J HAGGARTY ET AL.: "Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis", 《CHEMISTRY & BIOLOGY》 * |
吴乙强: "含螺二氢嘧啶类衍生物的合成及其生物活性研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117180122A (en) * | 2023-11-02 | 2023-12-08 | 杭州湃肽生化科技有限公司 | Composition for relaxing and repairing allergy and application thereof |
CN117180122B (en) * | 2023-11-02 | 2024-04-09 | 杭州湃肽生化科技有限公司 | Composition for relaxing and repairing allergy and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN110041349B (en) | 2021-06-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107056772A (en) | Bifunctional molecule and its preparation and the application of BET degradeds are induced based on cereblon parts | |
GB2449293A (en) | Compounds having Hsp90 inhibitory activity | |
WO2013013614A1 (en) | 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquinoline as hedgehog pathway inhibitor and use thereof | |
CN106749513A (en) | Bifunctional molecule and its preparation and application based on the induction BET degradeds of VHL parts | |
CN106674136B (en) | Pyrimidine anti-tumor compounds and preparation method thereof | |
Yakaiah et al. | Design, synthesis and biological evaluation of novel pyrazolo-oxothiazolidine derivatives as antiproliferative agents against human lung cancer cell line A549 | |
TW201103905A (en) | 5-alkynyl-pyridines | |
Mor et al. | Synthesis, biological evaluations and in silico studies on pyrimidine-appended fused pyrazolones as anticancer and antimicrobial agents | |
CN110041349A (en) | One kind dihydropyrimidine derivatives containing spiral shell and its preparation method and application | |
CN116354959B (en) | Beta-carboline derivative of N-N bridged thiazole unit, and preparation method and application thereof | |
CN110437156B (en) | Paeonol dihydropyrimidinone derivative, preparation method and application thereof | |
WO2017170765A1 (en) | Novel nitrogen-containing heterocyclic compound | |
CN105175377A (en) | Chrysin and substituent salicylate phenolic ether compound and preparation method and application thereof | |
CN112174958B (en) | Pyrido [2,3-d ] pyrimidine compound and preparation method and application thereof | |
CN112679409B (en) | 4-indole-substituted thiosemicarbazide derivative and preparation method and application thereof | |
US9643959B2 (en) | Tubulin polymerization inhibitor and method for synthesizing same | |
Zhang et al. | Discovery of [1, 2, 4] triazolo [4, 3-a] pyrazine derivatives bearing a 4-oxo-pyridazinone moiety as potential c-Met kinase inhibitors | |
CN111606888B (en) | Pyrrole derivative and preparation method and application thereof | |
CN109748871B (en) | Preparation and application of benzenesulfonyl dihydropyrazole derivatives | |
CN109232570B (en) | Pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
CN105541805A (en) | Preparation method and application of indole acetyl pyrazole derivatives | |
CN101407515A (en) | Chinoline polycyclic compounds as CDK inhibitors | |
CN111303195B (en) | Boron-containing micromolecule compound, preparation method and application thereof | |
CN115572247B (en) | Vitamin K 3 Derivatives and medical use thereof | |
Said et al. | Pharmacological activities of some synthesized substituted pyrazole, oxazole and triazolopyrimidine derivatives |
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 |