CN110041349B - Spiro-containing dihydropyrimidine derivative and preparation method and application thereof - Google Patents
Spiro-containing dihydropyrimidine derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN110041349B CN110041349B CN201910408220.0A CN201910408220A CN110041349B CN 110041349 B CN110041349 B CN 110041349B CN 201910408220 A CN201910408220 A CN 201910408220A CN 110041349 B CN110041349 B CN 110041349B
- Authority
- CN
- China
- Prior art keywords
- reaction
- methyl
- pyrimidine
- oxo
- spirodihydropyrimidine
- 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
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
Abstract
The invention provides a novel 5-aryl-4 ' -hydroxy-7-methyl-3-oxo-2 ' -aryl-3, 4',5,5' -tetrahydro-2 ' H-spiro [ thiazole [3,2-a ] shown as a formula (I)]Pyrimidine-2, 3' -thiophenes]-6-carboxylic acid ethyl ester derivative of formula (I) wherein the substituent R1Is H, F, Cl, Br, C1‑4Alkyl, alkoxy, hydroxyl, nitrile, nitro, carboxyl or/and sulfonic acid groups; r2Is H, F, Cl, Br, C1‑4Alkyl, alkoxy, hydroxyl, nitrile, acetyl, carboxyl or/and sulfonic acid groups. The 5-aryl-4 ' -hydroxy-7-methyl-3-oxo-2 ' -aryl-3, 4',5,5' -tetrahydro-2 ' H-spiro [ thiazole [3,2-a ] of the present invention]Pyrimidine-2, 3' -thiophenes]The (E) -6-carboxylic acid ethyl ester derivative has certain inhibitory activity on tumor cells, and the synthetic method is simple and the material is easy to obtain. Can be used for preparing antitumor drugs.
Description
Technical Field
The invention relates to a novel pharmaceutical compound, in particular to a 5-aryl-4 '-hydroxy-7-methyl-3-oxo-2' -aryl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazole [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester derivative, a preparation method thereof and application thereof as an anticancer drug.
Background
Cancer is one of the major diseases seriously threatening the development of human life and society at present, and in recent decades, with the transformation of diseases and the aging trend of population, the burden of cancer in China is increasing day by day, and the prevention and treatment of cancer faces a severe situation. Therefore, research and development of anticancer drugs have been a focus of attention by chemists and pharmacologists. The search for anticancer drugs with high efficiency, high selectivity and small toxic and side effects is one of the main directions of drug research and development.
Pyrimidine rings are widely found in nature and are essential molecular building blocks for living systems. The synthesis and transformation, biological activity and metabolism research of pyrimidine derivatives have attracted attention. Dihydropyrimidinones are important nitrogen-containing heterocyclic compounds, most of which have biological activity and important application in the aspects of medicine, biology and the like. Some 3, 4-dihydropyrimidine-2-one compounds (DHPMs) have remarkable pharmacological activity and are important medicaments for treating hypertension, coronary heart disease and cardiovascular and cerebrovascular diseases, such as calcium antagonists (J. Med. chem., 1995, 38, 119-1aAntagonists, also can be used as a lead (chem. biol., 2000, 7, 275-286) for developing anticancer drugs, and the like, and has wide application in the fields of antimicrobial, antiviral, bactericidal, anti-inflammatory and other drugs. Therefore, the synthesis of the dihydropyrimidinone parent nucleus becomes one of the hot spots of the research of the bioactive organic heterocyclic compounds in recent years.
In the last decade, further research into the therapeutic and pharmaceutical properties and biological activities of 3, 4-dihydropyrimidinone derivatives has been carried out. As a result, the derivative S-Monastrol has an inhibiting effect on mitosis (Eg 5) kinesin, which provides a new idea and method for treating tumor diseases. However, 3, 4-dihydropyrimidinone derivatives have disadvantages of low activity, poor selectivity, etc., and thus, clinical applications thereof are significantly limited. Therefore, the research of scientists at home and abroad in the field is important subject by taking the 3, 4-dihydropyrimidinone derivative as a lead compound to carry out structural modification and searching for novel, safe and efficient antitumor drugs.
Disclosure of Invention
The invention aims to provide a spirodihydropyrimidine-containing derivative, namely a novel 5-aryl-4 '-hydroxy-7-methyl-3-oxo-2' -aryl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazole [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester derivative.
The invention also aims to provide a preparation method of the spirodihydropyrimidine-containing derivative.
The invention also aims to provide application of the spirodihydropyrimidine-containing derivative in preparation of antitumor drugs.
The above object of the present invention is achieved by the following scheme: a spirodihydropyrimidine-containing derivative is characterized in that the chemical structural formula is shown as formula I:
in the formula (I), the substituent R1Is H, F, Cl, Br, C1-4Alkyl, alkoxy, hydroxyl, nitrile, nitro, carboxyl or/and sulfonic acid groups.
In the formula (I), the substituent R2Is H, F, Cl, Br, C1-4Alkyl, alkoxy, hydroxyl, nitrile, acetyl, carboxyl or/and sulfonic acid groups.
A preparation method of spirodihydropyrimidine-containing derivatives has the following reaction general formula:
the method comprises the following specific steps:
(1) dissolving aromatic aldehyde, ethyl acetoacetate, thiourea and a catalyst in a reaction solvent, reacting under the condition of heating reflux, cooling to separate out a solid after the reaction is finished, and filtering to obtain an intermediate 2-mercapto-4-methyl-6-substituted phenyl-1, 6-dihydropyrimidine-5-carboxylic acid ethyl ester;
(2) dissolving the intermediate 2-mercapto-4-methyl-6-substituted phenyl-1, 6-dihydro-pyrimidine-5-carboxylic acid ethyl ester, alkali and ethyl bromoacetate in a reaction solvent, heating and refluxing, cooling after the reaction is finished to obtain an intermediate product 7-methyl-3-oxo-5-substituted phenyl-3, 5-dihydro-2H-thiazolo [3,2-a ] pyrimidine-6-carboxylic acid ethyl ester, directly using the intermediate in the next reaction without post-treatment, adding substituted benzaldehyde and piperidine in an original reaction system for continuous reflux reaction, cooling to separate out a solid after the reaction is finished, separating and purifying by column chromatography to obtain an intermediate 2-substituted benzylidene-7-methyl-3-oxo-5-substituted phenyl-2, 3-dihydro-5H-thiazolo [3,2-a ] pyrimidine-6-carboxylic acid ethyl ester;
(3) dissolving the intermediate 2-substituted benzylidene-7-methyl-3-oxo-5-substituted phenyl-2, 3-dihydro-5H-thiazolo [3,2-a ] pyrimidine-6-carboxylic acid ethyl ester, 2, 5-dihydroxy-1, 4-dithiane and alkali in a reaction solvent, reacting at 25 ℃, after the reaction is finished, carrying out column chromatography separation and purification to obtain a product 5-substituted phenyl-4 '-hydroxy-7-methyl-3-oxo-2' -substituted phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester, namely spirodihydropyrimidine-containing derivatives.
Experiments prove that the spirodihydropyrimidine-containing derivative has good inhibitory activity on tumor cells, can be used for preparing medicines for inhibiting the tumor cells, has a simple synthesis method and easily-obtained materials, and provides a new development approach for solving the problem of antitumor medicines.
Detailed Description
For a better understanding of the present invention, examples of the preparation of 5-aryl-4 '-hydroxy-7-methyl-3-oxo-2' -aryl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester derivatives (i.e., spiro dihydropyrimidine-containing derivatives) are now given, and the present invention includes but is not limited to this preparation method.
Example 1: synthesis of ethyl 5-phenyl-4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ia).
And dissolving benzaldehyde (20 mmol), ethyl acetoacetate (24 mmol), thiourea (30 mmol) and sulfamic acid (16 mmol) in 20 ml of absolute ethyl alcohol, heating and refluxing, tracking the reaction process by TCL, cooling to room temperature after the reaction is finished, filtering, washing with water, and drying to obtain an intermediate 2-mercapto-4-methyl-6-substituted phenyl-1, 6-dihydropyrimidine-5-carboxylic acid ethyl ester 1.
Dissolving the intermediate 2-mercapto-4-methyl-6-phenyl-1, 6-dihydro-pyrimidine-5-carboxylic acid ethyl ester 1 (7 mmol) in 20 ml of absolute ethanol, dropwise adding pyridine (14 mmol), dropwise adding ethyl bromoacetate (14 mmol), stirring uniformly, heating for refluxing, and tracking the reaction progress by TCL. After the reaction is finished, a crude product, namely 7-methyl-3-oxo-5-phenyl-3, 5-dihydro-2H-thiazolo [3,2-a ] pyrimidine-6-carboxylic acid ethyl ester 2 is obtained. The intermediate 2 is directly used for the next reaction without post-treatment, piperidine (7 mmol) and benzaldehyde (7 mmol) are added into the original reaction system drop by drop, reflux reaction is continued, and the reaction progress is tracked by TCL. After the reaction is finished, cooling to room temperature, filtering, fully washing with water, and carrying out column chromatography separation and purification to obtain 2-benzylidene-7-methyl-3-oxo-5-phenyl-2, 3-dihydro-5H-thiazolo [3,2-a ] pyrimidine-6-carboxylic acid ethyl ester 3.
2, 5-dihydroxy-1, 4-dithiane (1.5 mmol) was dissolved in 10 ml of anhydrous ethanol, triethylamine (0.45 mmol) was added dropwise, and then the intermediate ethyl 2-benzylidene-7-methyl-3-oxo-5-phenyl-2, 3-dihydro-5H-thiazolo [3,2-a ] pyrimidine-6-carboxylate 3 (3 mmol) was added and reacted at 25 ℃ with TCL following the progress of the reaction. After the reaction is finished, the target product 5-phenyl-4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester is obtained by column chromatography separation and purification, the chemical structural formula is shown as formula (Ia), and the yield is as follows: 75 percent.
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)+。
Example 2: synthesis of ethyl 5- (2-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ib).
The preparation method of this example is the same as example 1 except that o-methylbenzaldehyde is used to replace benzaldehyde in the synthesis of intermediate 1, and light yellow crystal ethyl 5- (2-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate is finally obtained, the chemical structural formula of which is shown in formula (Ib), and the yield is: 59 percent.
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)+。
Example 3: synthesis of ethyl 5- (2-chlorophenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ic).
The preparation method of this example is the same as example 1 except that o-chlorobenzaldehyde is used to replace benzaldehyde in the synthesis of intermediate 1, and a light yellow crystal of ethyl 5- (2-chlorophenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate is finally obtained, the chemical structural formula of which is shown in formula (Ic), and the yield is: 56 percent.
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)+。
Example 4: synthesis of ethyl 5- (4-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Id).
The preparation method of this example is the same as example 1 except that p-methylbenzaldehyde is used to replace benzaldehyde in the synthesis of intermediate 1, and a light yellow crystal of ethyl 5- (4-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate is finally obtained, the chemical structural formula of which is shown in formula (Id), and the yield is: 57 percent.
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)+。
Example 5: synthesis of ethyl 5- (4-chlorophenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ie).
The procedure of this example was followed, except that p-chlorobenzaldehyde was used instead of benzaldehyde in the synthesis of intermediate 1, in the same manner as in example 1, to finally obtain pale yellow crystalline ethyl 5- (4-chlorophenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate. The chemical structural formula is shown as a formula (Ie), and the yield is as follows: 49 percent.
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)+。
Example 6: synthesis of ethyl 5- (3-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazole [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (If).
The procedure of this example was followed, except that m-methylbenzaldehyde was used instead of benzaldehyde in the synthesis of intermediate 1, in the same manner as in example 1, to finally obtain pale yellow crystalline ethyl 5- (3-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate. The chemical structural formula is shown as a formula (If), and the yield is as follows: 50 percent.
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)+。
Example 7: synthesis of ethyl 5- (4-fluorophenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ig).
The procedure of this example was followed, except that p-fluorobenzaldehyde was used instead of benzaldehyde in the synthesis of intermediate 1, in the same manner as in example 1, to give 5- (4-fluorophenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester as pale yellow crystals. The chemical structural formula is shown as a formula (Ig), and the yield is as follows: 46 percent.
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)+。
Example 8: synthesis of ethyl 5- (4-methoxyphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ih).
The procedure of this example was followed, except that p-methoxybenzaldehyde was used instead of benzaldehyde in the synthesis of intermediate 1, in the same manner as in example 1, to give pale yellow crystalline ethyl 5- (4-fluorophenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate. The chemical structural formula is shown as a formula (Ih), and the yield is as follows: and 47 percent.
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)+。
Example 9: synthesis of ethyl 5- (3-methoxy-4-hydroxyphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ii).
The procedure of this example was followed, except that 3-methoxy-4-hydroxybenzaldehyde was used instead of benzaldehyde in the synthesis of intermediate 1, in the same manner as in example 1, to give 5- (3-methoxy-4-hydroxyphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' -phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester as pale yellow crystals. The chemical structural formula is shown as a formula (Ii), and the yield is as follows: 48 percent.
Example 10: synthesis of ethyl 5- (2-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' - (2-methylphenyl) -3,4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ij).
The procedure of this example was followed, except that o-methylbenzaldehyde was used in the synthesis of intermediate 1 instead of benzaldehyde and that o-methylbenzaldehyde was used in the synthesis of intermediate 3 instead of benzaldehyde, in example 1, to give 5- (2-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' - (2-methylphenyl) -3,4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester as pale yellow crystals. The chemical structural formula is shown as a formula (Ij), and the yield is as follows: 58 percent.
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)+。
Example 11: synthesis of ethyl 5- (2-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' - (4-chlorophenyl) -3,4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylate (Ik).
The procedure of this example was followed, except that o-methylbenzaldehyde was used instead of benzaldehyde in the synthesis of intermediate 1 and p-chlorobenzaldehyde was used instead of benzaldehyde in the synthesis of intermediate 3, in the same manner as in example 1, to give 5- (2-methylphenyl) -4 '-hydroxy-7-methyl-3-oxo-2' - (4-chlorophenyl) -3,4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester as pale yellow crystals. The chemical structural formula is shown as a formula (Ik), and the yield is as follows: 54 percent.
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)+。
The present invention is described in further detail below by way of synthesis experimental examples and activity experimental examples.
Adopting MTT method to synthesize 11 target products 5-aryl-4 ' -hydroxy-7-methyl-3-oxo-2 ' -aryl-3, 4',5,5' -tetrahydro-2 ' H-spiro [ thiazole [3,2-a ]]Pyrimidine-2, 3' -thiophenes]Experiments on anticancer activity were carried out on ethyl-6-carboxylate derivatives. Human MGC803 (gastric cancer), PC-3 (prostate cancer), EC109 (esophageal squamous carcinoma) were used as test materials. Collecting logarithmic phase cells, digesting the cells with pancreatin, adjusting the cell suspension concentration to 2X 104each/mL, dispensing into a 96-well plate, and adding 200 mu L of the solution into each well; at 5% CO2Incubating at 37 ℃ for half a day until cell monolayers are fully spread at the bottom of the wells, adding samples with different concentrations, wherein each well is 100 mu l, and 3 parallel wells are arranged; then 5% CO2Incubating for four days at 37 ℃, and observing under an inverted microscope; adding 20 μ l MTT solution (5 mg/ml, namely 0.5% MTT) into each well, continuously culturing for 4 h, if the drug can react with MTT, centrifuging and then discarding the culture solution, carefully flushing with PBS for 2-3 times, then adding the culture solution containing MTT, terminating the culture, and carefully sucking off the culture solution in the wells; add 180 μ l dimethyl sulfoxide into each well, and shake for 10 min at low speed on a shaking bed to dissolve the crystals sufficiently. The absorbance of each well was measured at a wavelength of 550 nm in an enzyme linked immunosorbent assay. The inhibition IC was calculated with reference to a control (without sample, with the sample replaced by the solvent which dissolves it, and with the other conditions being identical)50The test results are shown in Table 1.
TABLE 15 antitumor Activity of aryl-4 '-hydroxy-7-methyl-3-oxo-2' -aryl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester derivatives
As can be seen from Table 1, 5-aryl-4 ' -hydroxy-7-methyl-3-oxo-2 ' -aryl-3, 4',5,5' -tetrahydro-2 ' H-spiro [ thiazole [3,2-a ]]Pyrimidine-2, 3' -thiophenes]The ethyl-6-carboxylate derivative has excellent inhibitory activity on MGC803 (gastric cancer) and PC-3 (prostate cancer), wherein the compounds Ib, Id and Ik have the best inhibitory effect on the tumor activity of MGC803 and PC-3, and the IC of the cells is shown to be50Values were all less than the positive control 5-Fu (5-fluorouracil).
Claims (7)
1. A spirodihydropyrimidine-containing derivative is characterized in that the chemical structural formula is shown as the formula (I):
in the formula (I), the substituent R1Is H, F, Cl, Br, C1-4Alkyl, alkoxy, hydroxyl, nitrile, nitro, carboxyl or sulfonic acid groups;
in the formula (I), the substituent R2Is H, F, Cl, Br, C1-4Alkyl, alkoxy, hydroxyl, nitrile, acetyl, carboxyl or sulfonic acid groups.
2. A process for the preparation of spirodihydropyrimidine containing derivatives as claimed in claim 1, characterized by the following steps:
(1) r is to be1Dissolving substituted benzaldehyde, ethyl acetoacetate, thiourea and a catalyst in a reaction solvent, reacting under the condition of heating reflux, cooling to separate out a solid after the reaction is finished, and filtering to obtain an intermediate 2-mercapto-4-methyl-6-substituted phenyl-1, 6-dihydropyrimidine-5-carboxylic acid ethyl ester;
(2) dissolving the intermediate 2-mercapto-4-methyl-6-substituted phenyl-1, 6-dihydro-pyrimidine-5-carboxylic acid ethyl ester, alkali and ethyl bromoacetate in a reaction solvent, heating and refluxing, and cooling to obtain an intermediate product 7-methyl-3-oxo-5-substituted phenyl-3, 5-dihydro-2H-thiazolo [3,2-a ] after the reaction is finished]Pyrimidine-6-carboxylic acidEthyl ester, the intermediate is directly used for the next reaction without post-treatment, and R is added into the original reaction system2The substituted benzaldehyde and piperidine continue to carry out reflux reaction, after the reaction is finished, solid is separated out by cooling, and the intermediate 2-substituted benzylidene-7-methyl-3-oxo-5-substituted phenyl-2, 3-dihydro-5H-thiazolo [3,2-a ] is obtained by column chromatography separation and purification]Pyrimidine-6-carboxylic acid ethyl ester;
(3) dissolving the intermediate 2-substituted benzylidene-7-methyl-3-oxo-5-substituted phenyl-2, 3-dihydro-5H-thiazolo [3,2-a ] pyrimidine-6-carboxylic acid ethyl ester, 2, 5-dihydroxy-1, 4-dithiane and alkali in a reaction solvent, reacting at 25 ℃, after the reaction is finished, carrying out column chromatography separation and purification to obtain a product 5-substituted phenyl-4 '-hydroxy-7-methyl-3-oxo-2' -substituted phenyl-3, 4',5,5' -tetrahydro-2 'H-spiro [ thiazolo [3,2-a ] pyrimidine-2, 3' -thiophene ] -6-carboxylic acid ethyl ester, namely the spirodihydropyrimidine-containing derivative;
wherein R is1And R2Is as defined in claim 1.
3. The process for preparing spirodihydropyrimidine derivative as claimed in claim 2, characterized in that the catalyst used in the condensation reaction in step (1) is sulfamic acid and the reaction solvent is absolute ethanol.
4. The process for preparing spirodihydropyrimidine derivative as claimed in claim 2, characterized in that the base used in the cyclization reaction to form thiazole in step (2) is pyridine, the base used in the aldol condensation reaction is piperidine, and the reaction solvent is absolute ethanol.
5. The process for preparing spirodihydropyrimidine derivative as claimed in claim 2, characterized in that the base used in the condensation reaction in step (3) is triethylamine, the reaction temperature is 25 ℃ and the reaction solvent is absolute ethanol.
6. The spirodihydropyrimidine-containing derivative as defined in claim 1 for use in the preparation of antitumor drugs.
7. The application of spirodihydropyrimidine containing derivatives in the preparation of antitumor drugs as claimed in claim 6, characterized in that the antitumor drugs are in the dosage form of tablets, pills, capsules, injections, suspensions or emulsions.
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 CN110041349A (en) | 2019-07-23 |
| CN110041349B true 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) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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 |
|---|
| Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators;George C.Rovnyak et al.;《J.Med.Chem.》;19951231;第38卷(第1期);第119-129页 * |
| Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis;Stephen J Haggarty et al.;《Chemistry & Biology》;20000320;第7卷(第4期);第275-286页 * |
| Synthesis of spiro thiazolo[3,2-a]pyrimidine-tetrahydrothiophenes via sulfa Michael/aldol cascade reactions;Jinlong Yan et al.;《JOURNAL OF CHEMICAL RESEARCH》;20171218;第41卷;第722-724页 * |
| 含螺二氢嘧啶类衍生物的合成及其生物活性研究;吴乙强;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20200615(第06期);第B014-189页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110041349A (en) | 2019-07-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2121620B1 (en) | Inhibitors of mek | |
| CN108864057B (en) | JAK and HDAC double-target-point inhibitor containing 4-aminopyrazole structure and preparation method and application thereof | |
| RU2485116C2 (en) | 4-pyrimidinesulphamide derivative | |
| GB2449293A (en) | Compounds having Hsp90 inhibitory activity | |
| CN108610348A (en) | A kind of simultaneously [2,3-b] pyridine -3- carbonitrile derivatives and its preparation and application of the 5H- chromenes containing imidazole substituent | |
| EP1542978B1 (en) | Novel bio-active molecules | |
| CN110041349B (en) | Spiro-containing dihydropyrimidine derivative and preparation method and application thereof | |
| CN107235917A (en) | The licochalcone A Dihydropyrimidines and its synthetic method of one class tool antitumor activity | |
| CN110437156B (en) | Paeonol dihydropyrimidinone derivative, preparation method and application thereof | |
| CN111153889B (en) | 2-indolone-triazole anti-tumor compound and preparation method and application thereof | |
| CN111518104A (en) | 1,2, 4-triazolo [1,5-a ] pyrimidine compound containing thiourea pyrimidine and preparation method and application thereof | |
| CN107200731B (en) | Thiazole ring-containing pyridone derivative and preparation method and application thereof | |
| Soliman et al. | Synthesis, biological and anti-tumor evaluation of some new nucleosides incorporating heterocyclic moieties | |
| US10047071B1 (en) | Dihydropyrimidinone derivatives | |
| CN110156672B (en) | Preparation method of semicarbazide compound and application of prepared compound | |
| CN106008458A (en) | Azobenzene compound and preparation method thereof | |
| CN112225733B (en) | Preparation method of 1,3, 4-thiadiazole pyridine-2-ketone derivative and application of derivative as anti-cancer drug | |
| CN108467363B (en) | Benzo [ h ] quinoline substituted Schiff base derivative with biological activity and synthesis method and application thereof | |
| CN103709146B (en) | One class is containing the quinolin-4-amines derivative of benzimidazole structure, its method for making and medicinal use | |
| KR100542325B1 (en) | 2,2-Dimethyl-3-ester-4-alkoxy-6-alkyl amino benzopyran derivatives and parallel synthesis of the derivatives on solid-phase | |
| CN114560813B (en) | Benzimidazole MK2 allosteric inhibitor and preparation method and application thereof | |
| CN115105503B (en) | TRPV1 antagonism/COX inhibition double-target drug or pharmaceutically acceptable salt thereof, pharmaceutical preparation and application | |
| CN115322192B (en) | Pyrrolo [3,4-b ] pyridine derivative and synthetic method and application thereof | |
| CN108484606B (en) | Pyrimido [4,5-f ] quinazoline compound and application thereof | |
| CN115109019A (en) | Dehydrocostuslactone derivative, preparation method and application 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 |