CN102180849A - Diaryl diene cyclic ketone derivatives, and preparation method and application thereof - Google Patents
Diaryl diene cyclic ketone derivatives, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses diaryl diene cyclic ketone derivatives, and a preparation method and application thereof. The chemical formula of the derivatives is shown as the formula (I). The diaryl diene cyclic ketone derivatives have a structure similar to that of natural curcumin, are more stable than the curumin, easy to synthesize and suitable for expanded production. The diaryl diene cyclic ketone derivatives have good inhibition effects on the proliferation growth of various tumor cells such as humanized prostatic cancer cells, pancreatic cancer cells, colon cancer cells and the like, low toxic and side effects and a prospect of being developed into a novel anti-tumor medicament.
Description
Technical field
The present invention relates to a kind of diaryl diene cyclic ketone derivative and preparation method thereof and application.
Background technology
Cancer is one of principal disease that jeopardizes human survival and health.PTS is the focus of various countries medicine scholar research always, and the cancer therapy drug of high-efficiency low-toxicity is one of main direction of antitumor drug research.
The natural product representative of diaryl dienone derivative is a curcumine, and curcumine is the main component of plant turmeric (Curcuma longa Linn), has nontoxic and multiple biological action.Because curcumine has the obvious suppression effect to the propagation of kinds of tumor cells, curcumine receives great concern as the research of antitumor drug.But because the bioavailability of curcumine is lower, poor stability, the inhibition activity of tumour cell is still waiting factors such as raising, application clinically is restricted.For stability and the anti-tumor biological that improves curcumin chemical compounds, studying its similar structures is one of main strategy.
The constitutional features of diaryl dienone compounds mainly partly is connected with two being good for intermediary ketone by the symmetric aromatic portion in both sides.Be that acetone or C6 and following alicyclic ketone and both sides are the aryl substituent in the middle of this compounds of report mainly concentrates at present.Contain assorted macrocyclic ketone itself and have certain antitumor action.The centre contains O, heteroatomic C6 of S and above macrocyclic ketone, or C7 and above undersaturated alicyclic ketone, simultaneously the both sides phenyl contains alkyl or the alkoxyl group more than 2, or on one side or both sides be that this compounds that contains N heteroaryl etc. yet there are no report; This compounds yet there are no report to the research of function of tumor.
Summary of the invention
The object of the present invention is to provide a kind of diaryl diene cyclic ketone derivative with antitumour activity.
Another object of the present invention is to provide a kind of preparation method of above-mentioned diaryl diene cyclic ketone derivative.
Another object of the present invention is to provide the application of a kind of above-mentioned diaryl diene cyclic ketone derivative in the preparation antitumor drug.
Above-mentioned purpose of the present invention is achieved by following scheme:
The present invention designs the synthetic assorted diaryl diene cyclic ketone derivative that contains of the present invention that obtains according to the structure of the small molecules hexichol dienone compounds (as curcumine) with antitumor action.Its chemical structure is suc as formula shown in (I):
Wherein:
M=0～4, n=0～4, m+n
2; And X=O, S, OCH
2CH
2O, OC (CH
3)
2, CO
2CH
2, CONH, CH=CH or C ≡ C;
Y and Z are compound shown in compound, the formula V shown in compound, the formula (IV) shown in compound shown in the formula (II), the formula (III) at the same time or separately:
R in the formula (II)
1, R
2, R
3, R
4, R
5There are three or above substituting group to be C at the same time or separately
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Contain alkane fat base, C
1-6Contain F alkyl, C
1-6Contain the F alkoxyl group, C
1-6Contain F alkane fat base ,-F,
, all the other are H, R
3Can be OH.
R in formula (III), formula (IV), the formula V
6Be C
1-6Alkyl;
R in formula (III), formula (IV), the formula V
7Be C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Contain F alkyl, C
1-6Contain the F alkoxyl group.
The preparation method that the present invention contains assorted diaryl diene cyclic ketone derivative is identical and different according to Y shown in the formula (I) and Z's, mainly contains two kinds of preparation methods:
In the formula (I) Y and Z be formula (II), formula (III), formula (IV), when formula V is identical, this method comprises the steps:
With aromatic aldehyde with contain O or S heterocyclic ketone or C
7-12Big ring grease ketone carries out bilateral aldol reaction, obtains diaryl diene cyclic ketone derivative shown in the formula (I).
In the above-mentioned steps aromatic aldehyde with contain O or S heterocyclic ketone or C
7-12The molar ratio of big ring grease ketone is 2～3:1, preferred 2:1.
Adopting mass percent in the above-mentioned steps is that 5～40% NaOH solution is made catalyzer, and the preferred mass mark is 15%.
Can adopt ethanol or the acetic acid solution of saturated HCl (g) to make catalyzer in the above-mentioned steps.
Above-mentioned steps is determined the reaction times according to the reactive behavior of aromatic aldehyde and ketone, and the general reaction times is 1～2 hour.
Temperature of reaction generally is controlled at room temperature in the above-mentioned steps, according to aromatic aldehyde and reactive ketone activity, can suitably be heated to 50 ℃ Celsius.
In the formula (I) Y and Z be formula (II), formula (III), formula (IV), when formula V is incomplete same, this method comprises the steps:
Earlier with aromatic aldehyde with contain O or the monolateral aldol reaction of S heterocyclic ketone prepares monolateral ketenes intermediate, with another aromatic aldehyde reaction, obtain the asymmetric diaryl diene cyclic ketone derivative shown in the formula (I) again.
In the above-mentioned steps aromatic aldehyde with contain O or S heterocyclic ketone or C
7-12The molar ratio of the big monolateral aldol reaction of ring grease ketone is 1:3～10, preferred 1:3.
To adopt mass percent be that 5～40% NaOH solution is made catalyzer for monolateral aldol reaction in the above-mentioned steps, and the preferred mass mark is 10%.
Monolateral aldol reaction prepares monolateral ketenes intermediate in the above-mentioned steps, and aromatic aldehyde is dissolved in the THF(tetrahydrofuran (THF)) or ethanol in, be added drop-wise among the THF or ethanolic soln of ketone, slowly stir.Reactive behavior according to aromatic aldehyde and ketone is determined the reaction times, and the general reaction times is 1～2 hour.
When carrying out second aromatic aldehyde aldol condensation in the above-mentioned steps, the molar ratio of the monolateral ketenes intermediate of aromatic aldehyde and preparation is 1～2:1, preferred 1:1.
Adopting mass percent when carrying out second aromatic aldehyde aldol condensation in the above-mentioned steps is that 5～40% NaOH solution is made catalyzer, and the preferred mass mark is 10%.
Can adopt ethanol or the acetic acid solution of saturated HCl (g) to make catalyzer when carrying out second aromatic aldehyde aldol condensation in the above-mentioned steps.
Diaryl diene cyclic ketone derivative of the present invention is through experiment confirm, and the growth of various human JEG-3 is had significant inhibitory effect, therefore can be used for preparing cancer therapy drug.
Diaryl diene cyclic ketone derivative of the present invention and the auxiliary agent combined preparation cancer therapy drug that pharmaceutically can receive, cancer therapy drug is tablet, capsule, pill, injection liquid, emulsion or suspension liquid etc.
Compared with prior art, the present invention has following beneficial effect:
Diaryl diene cyclic ketone derivative of the present invention and natural product curcumine similar are more stable than curcumine; Simultaneously, synthetic simple, be easy to enlarge and produce; Growth to the various human JEG-3 has significant inhibitory effect and lower toxic side effect, has the prospect that develops into new type antineoplastic medicine.
Embodiment
Below the present invention will be further described by specific embodiment, but specific embodiment is not done any qualification to the present invention.
Embodiment 1: compound 1 synthetic
(VI)
The preparation process of the process of present embodiment comprises the steps:
With 3,4 of 0.01 mol, the tetrahydro pyrone of 5-TMB and 0.005 mol places round-bottomed flask, adds the glacial acetic acid solution of the saturated HCl of 20 mL (g), places 2 days after room temperature (25-30 ℃) stirs 30 min.React completely, add 20 mL water in reaction flask, filtering-depositing obtains thick product, uses ethyl alcohol recrystallization, and vacuum-drying gets yellow powder, and promptly compound 1, and this example productive rate is 90.0%.
Fusing point: 248-250 ℃.
1H NMR (CDCl
3,300 MHz) δ ppm:7.76 (s, 2H ， – CH=), 6.55 (s, 4H, arom), 4.97 (s, 4H ， – CH
2-O – CH
2–) 3.90 (s, 18H ,-OCH
3). ESI-MS(m/z): 457 (M+1)
+.
Embodiment 2: compound 2 synthetic
(VII)
The preparation process of the process of present embodiment comprises the steps:
With 3,4 of 0.01 mol, the tetrahydric thiapyran ketone of 5-TMB and 0.005 mol places round-bottomed flask, adds the glacial acetic acid solution of the saturated HCl of 20 mL (g), places 2 days after room temperature (25-30 ℃) stirs 30 min.React completely, add 20 mL water in reaction flask, filtering-depositing obtains thick product, uses ethyl alcohol recrystallization, and vacuum-drying gets yellow powder, and promptly compound 2, and this example productive rate is 85.0%.
Fusing point: 220-222 ℃.
1H NMR (CDCl3,300 MHz) δ (ppm): 7.71 (s, 2H, – CH=), 6.63 (s, 4H, arom), 3.96 (s, 4H, – CH2-S – CH2 –), 3.89 (s, 18H ,-OCH3). and ESI-MS(m/z): 473 (M+1)+.
Embodiment 3: compound 3 synthetic
(VIII)
The preparation process of the process of present embodiment comprises the steps:
With 3 of 0.01 mol, the tetrahydro pyrone of 5-dimethoxy-4 '-hydroxyl-phenyl aldehyde and 0.005 mol places round-bottomed flask, adds the dissolving of 20 mLTHF solution, adds the 5mL20%NaOH aqueous solution, places 2 days after room temperature (25-30 ℃) stirs 30 min.After reacting completely, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets orange-yellow powder, and promptly compound 3, and this example productive rate is 78.0%.
Fusing point: 228 ℃ of 226 –. 1H NMR (DMSO-d6,300 MHz) δ (ppm): 9.03 (brs, 2H, – OH), 7.58 (s, 2H, – CH=), 6.70 (s, 4H, arom), 4.95 (s, 4H, – CH
2-S – CH
2–), 3.81 (s, 12H ,-OCH
3). ESI-MS (m/z): 427 (M-1)
+.
Embodiment 4: compound 4 synthetic
(VIV)
The preparation process of the process of present embodiment comprises the steps:
With 3 of 0.01 mol, the tetrahydric thiapyran ketone of 5-dimethoxy-4 '-hydroxyl-phenyl aldehyde and 0.005 mol places round-bottomed flask, adds the dissolving of 20 mLTHF solution, and the Dropwise 5 mL20%NaOH aqueous solution was placed 2 days after room temperature (25-30 ℃) stirs 30 min.After reacting completely, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets the glassy yellow powder, and promptly compound 4, and this example productive rate is 82.0%.
Fusing point: 149-152 ℃.
1H NMR (DMSO-d6,300 MHz) δ (ppm): 8.93 (brs, 2H ， – OH), 7.53 (s, 2H ， – CH=), 6.80 (s, 4H, arom), 4.03 (s, 4H ， – CH
2– S – CH
2–), 3.80 (s, 12H ,-OCH
3). ESI-MS (m/z): 443 (M-1)
+.
Embodiment 5: compound 5 synthetic
(X)
The preparation process of the process of present embodiment comprises the steps:
The 2,4 difluorobenzene formaldehyde of 0.01 mol and the tetrahydro pyrone of 0.005 mol are placed round-bottomed flask, add the dissolving of 40 mLTHF solution, the Dropwise 5 mL10%NaOH aqueous solution was placed 1 day after room temperature (25-30 ℃) stirs 30 min.After reacting completely, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets buff powder, and promptly compound 5, and this example productive rate is 72.0%.
Fusing point: 130-132 ℃.
1H NMR (CDCl
3, 300 MHz) and δ (ppm): 7.93 (s, 2H ， – CH=), 7.13 (s, 2H, arom), 6.69-6.63 (m, 4H, arom), 3.90 (s, 4H ， – CH
2-O – CH
2–). ESI-MS(m/z): 349 (M+1)
+.
Embodiment 6: compound 6 synthetic
(XI)
The preparation process of the process of present embodiment comprises the steps:
With 2 of 0.01 mol, the tetrahydro pyrone of 4-trifluoro-methoxybenzaldehyde and 0.005 mol places round-bottomed flask, adds the dissolving of 40 mLTHF solution, and the Dropwise 5 mL15%NaOH aqueous solution was placed 1 day after room temperature (25-30 ℃) stirs 30 min.After reacting completely, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets buff powder, and promptly compound 6, and this example productive rate is 86.0%.
Fusing point: 180-182 ℃.
1H NMR (CDCl
3, 300 MHz) and δ (ppm): 7.91 (s, 2H ， – CH=), 6.93 (s, 2H, arom), 6.28-6.23 (m, 4H, arom), 3.91 (s, 4H ， – CH
2-O – CH
2–), 3.89 (s, 18H ,-OCH
3). ESI-MS(m/z): 613 (M+1)
+.
Embodiment 7: compound 7 synthetic
(XII)
The preparation process of the process of present embodiment comprises the steps:
The 2-pyridylaldehyde of 0.01 mol and the tetrahydro pyrone of 0.005 mol are placed round-bottomed flask, add 20 mL dissolve with ethanol solution, drip the 2mL15%NaOH aqueous solution, after room temperature (25-30 ℃) stirs 30 min, place 6 h.After reacting completely, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets buff powder, and promptly compound 7, and this example productive rate is 63.0%.
Fusing point: 200-202 ° C.
1H NMR (CDCl
3, 300 MHz) and δ (ppm): 8.73-8.63 (m, 2H, arom), and 7.75-7.65(m, 2H, arom), 7.63 (s, 2H ， – CH=), 7.49-7.41 (m, 2H, arom), 7.23-7.15 (m, 2H, arom), 5.31 (s, 4H ， – H
2C – O-CH
2–). ESI-MS (m/z): 279 (M+1)
+.
Embodiment 8: compound 8 synthetic
(XIII)
The preparation process of the process of present embodiment comprises the steps:
The 2-pyridylaldehyde of 0.01 mol and the tetrahydric thiapyran ketone of 0.005 mol are placed round-bottomed flask, add 20 mL dissolve with ethanol solution, drip the 2mL15%NaOH aqueous solution, after room temperature (25-30 ℃) stirs 30 min, place 6 h.After reacting completely, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets yellow powder, and promptly compound 8, and this example productive rate is 68.0%.
Fusing point: 153-156 C.
1H NMR (CDCl
3, 300 MHz) and δ (ppm): 8.94-8.83 (m, 2H arom), 8.70-8.58 (m, 2H arom), 7.96-7.87 (m, 2H, arom), 7.62 (s, 2H ,-CH=), 7.48-7.39 (m, 2H, arom), 3.80 (s, 4H ， – H
2C – S-CH
2–). ESI-MS (m/z): 295 (M+1)
+.
Embodiment 9: compound 9 synthetic
(XIV)
The preparation process of the process of present embodiment comprises the steps:
With 3 of 0.01 mol, 4, the 5-oxa-cyclooctanone of 5-TMB and 0.005 mol places round-bottomed flask, adds the glacial acetic acid solution of the saturated HCl of 30 mL (g), with a small amount of THF dissolving raw material, after stirring 30 min, room temperature (25-30 ℃) placed 5 days.React completely, add 5 mL water in reaction flask, filtering-depositing obtains thick product, heats recrystallization with ethanol, and vacuum-drying gets yellow powder, and promptly compound 9, and this example productive rate is 63.0%.
Fusing point: 236-238 ° C.
1H NMR (CDCl
3,300 MHz) δ ppm:7.74 (s, 2H ， – CH=), 6.50 (s, 4H, arom), 4.95 (s, 4H ， – CH
2-O – CH
2–) 3.81 (s, 18H ,-OCH
3), 2.24 (t, 4H ,-CH
2-). ESI-MS(m/z): 485 (M+1)
+.
Embodiment 10: compound 10 synthetic
(X)
The preparation process of the process of present embodiment comprises the steps:
(1) with 3,4 of 0.01 mol, 5-TMB and place round-bottomed flask with 0.04 mol tetrahydric thiapyran ketone, be dissolved among 20 mLTHF, evenly stir and make its dissolving, slowly drip concentration and be 10% aqueous sodium hydroxide solution 10 mL, it is 2 d/s that speed is dripped in control, drip complete stirring at room and react 15 h, separate out solid, suction filtration, ethyl alcohol recrystallization, gained solid vacuum-drying to weight remains unchanged, and gets pale yellow powder;
(2) the above-mentioned pale yellow powder and the 4-trifluoromethoxy-2-methoxybenzaldehyde 0.005mol that will get 0.005 mol joins in the glacial acetic acid solution of the saturated HCl of 10mL (g), with the DMSO dissolving, places 2 days after room temperature (25-30 ℃) stirs 30 min.React completely, add 10 mL water in reaction flask, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets the glassy yellow powder, and promptly compound 10, and this example overall yield is 52.0%.
Fusing point: 226-228 ℃.
1H NMR (CDCl
3, 300 MHz) and δ (ppm): 7.76 (s, 2H ， – CH=), 6.68 (s, 1H, arom), 6.60 (s, 1H, arom), 6.20 (s. 2H, arom), 3.90 (s, 4H ， – CH
2-S – CH
2–), 3.89-3.93 (s, 12H ,-OCH
3). ESI-MS(m/z): 497 (M+1)
+.
Embodiment 11: compound 11 synthetic
(XI)
The preparation process of the process of present embodiment comprises the steps:
(1) with 3,4 of 0.01 mol, 5-TMB and place round-bottomed flask with 0.04 mol 5-thia cyclooctanone, be dissolved among 20 mLTHF, evenly stir and make its dissolving, slowly drip massfraction concentration and be 20% aqueous sodium hydroxide solution 10 mL, it is 2 d/s that speed is dripped in control, drip complete stirring at room and react 15 h, separate out solid, suction filtration, ethyl alcohol recrystallization, gained solid vacuum-drying to weight remains unchanged, and gets pale yellow powder;
(2) will get the above-mentioned pale yellow powder and 2 of 0.005 mol, 4-two (trifluoromethoxy) phenyl aldehyde 0.005mol joins in the NaOH solution of 10mL15% massfraction, dissolve fully with 5mL DMSO, after room temperature (25-30 ℃) stirs 30 min, placed 2 days.React completely, add 10 mL water in reaction flask, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets the glassy yellow powder, and promptly compound 10, and this example overall yield is 59.0%.
Fusing point: 208 ° of C. of 206 –
1H NMR (DMSO-
d 6, 300 MHz) and δ (ppm): 7.38 (s, 2H ， – CH=), 6.23-6.28 (m, 5H, arom), 3.95 (s, 4H ， – CH
2-S – CH
2–), 3.81 (s, 9H ,-OCH
3), 2.33-2.40 (m, 4H ,-CH
2-). ESI-MS (m/z): 579 (M-1)
+.
Embodiment 12: compound 12 synthetic
(XV)
The preparation process of the process of present embodiment comprises the steps:
(1) with 3,4 of 0.01 mol, 5-TMB and place round-bottomed flask with 0.04 mol tetrahydro pyrone, be dissolved among 20 mLTHF, evenly stir and make its dissolving, slowly drip concentration and be 10% aqueous sodium hydroxide solution 10 mL, it is 2 d/s that speed is dripped in control, drip complete stirring at room and react 15 h, separate out solid, suction filtration, ethyl alcohol recrystallization, gained solid vacuum-drying to weight remains unchanged, and gets pale yellow powder;
(2) will get the above-mentioned pale yellow powder and 3 of 0.005 mol, 5-two (trifluoromethoxy) phenyl aldehyde 0.005mol joins in the NaOH solution of 10 mL10% massfractions, dissolve fully with 5mL DMSO, after room temperature (25-30 ℃) stirs 30 min, placed 2 days.React completely, add 10 mL water in reaction flask, filtering-depositing obtains thick product, uses washing with alcohol, and vacuum-drying gets the glassy yellow powder, and promptly compound 12, and this example overall yield is 56.0%.
Fusing point: 204 ° of C. of 202 –
1H NMR (DMSO-
d 6, 300 MHz) and δ (ppm): 7.58 (s, 2H ， – CH=), 6.36 (s, 2H, arom), 6.23 (s, 2H, arom), 6.15 (s, 1H, arom), 4.05 (s, 4H ， – CH
2-S – CH
2–), 3.81 (s, 9H ,-OCH
3). ESI-MS (m/z): 535 (M-1)
+.
Embodiment 13: derivative is to the restraining effect of growth of tumour cell
The implementation case is selected Human Prostate Cancer Cells strain (PC-3), human pancreas cancer cell strain (Panc-1), human large intestine cancer cell strain (HT-29), contains the growth experiment that assorted diaryl diene cyclic ketone derivative suppresses tumour cell to what embodiment prepared.
Adopting mtt assay to carry out vitro cytotoxicity measures: on 96 orifice plates tumour cell planted and contain 0.2 X 10
5Cells/mL (0.2 mL/ hole) was hatched 24 hours.Each specimen effect cancer cells of different concns 72 hours.Calculate the compound concentration that cell growth inhibiting reaches at 50% o'clock respectively, with IC
50Expression the results are shown in Table 1:
As can be seen from Table 1, embodiment gained compound 1-12 all has very strong restraining effect to external three kinds of JEG-3, illustrates that diaryl diene cyclic ketone derivative of the present invention has the prospect that can be used for cancer therapy drug.
Claims (8)
1. what the present invention relates to contains heteroatomic a kind of diaryl diene cyclic ketone derivative, and its chemical structure is suc as formula shown in (I):
Wherein:
M=0～4, n=0～4, m+n
2; And X=O, S, OCH
2CH
2O, OC (CH
3)
2, CO
2CH
2, CONH, CH=CH or C ≡ C;
Y and Z are compound shown in compound, the formula V shown in compound, the formula (IV) shown in compound shown in the formula (II), the formula (III) at the same time or separately:
R in the formula (II)
1, R
2, R
3, R
4, R
5There are three or above substituting group to be C at the same time or separately
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Contain alkane fat base, C
1-6Contain F alkyl, C
1-6Contain F alkoxyl group, C
1-6Contain F alkane fat base or-F,
, all the other are H, R
3Can be OH;
R in formula (III), formula (IV), the formula V
6Be C
1-6Alkyl;
R in formula (III), formula (IV), the formula V
7Be C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Contain F alkyl or C
1-6Contain the F alkoxyl group.
2. the preparation method of the described diaryl diene of claim 1 cyclic ketone derivative is characterized in that
During Y in the formula (I)=Z, this method comprises the steps:
With aromatic aldehyde with contain O or S heterocyclic ketone or C
7-12Big ring grease ketone carries out bilateral aldol reaction, obtains diaryl diene cyclic ketone derivative shown in the formula (I).
3. preparation method according to claim 2 is characterized in that: above-mentioned aromatic aldehyde with contain O or S heterocyclic ketone or C
7-12The mol ratio of big ring grease ketone is 2～3:1.
4. preparation method according to claim 2 is characterized in that: it is that 5～40% NaOH solution is made catalyzer that mass percent is adopted in above-mentioned reaction, or adopts ethanol or the acetic acid solution of saturated HCl (g) to make catalyzer.
5. the preparation method of the described diaryl diene of claim 1 cyclic ketone derivative is characterized in that
During Y in the formula (I) ≠ Z, this method comprises the steps:
Elder generation is with aromatic aldehyde and contain O or the monolateral aldol reaction of S heterocyclic ketone, with another aromatic aldehyde reaction, obtains the asymmetric diaryl diene cyclic ketone derivative shown in the formula (I) again.
6. preparation method according to claim 5 is characterized in that: above-mentioned aromatic aldehyde with contain O or S heterocyclic ketone or C
7-12The mol ratio of the big monolateral aldol reaction of ring grease ketone is 1:3～10.
7. preparation method according to claim 5, it is characterized in that: it is that 5～40% NaOH solution is made catalyzer that mass percent is adopted in the reaction of the above-mentioned the first step, and it is that 5～40% NaOH solution is made catalyzer or adopted ethanol or the acetic acid solution of saturated HCl (g) to make catalyzer that mass percent is adopted in the reaction of second step.
8. the application of the described diaryl diene of claim 1 cyclic ketone derivative in the preparation antitumor drug.
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| US4128648A (en) * | 1978-03-24 | 1978-12-05 | E. R. Squibb & Sons, Inc. | Substituted pyrano[4,3-d]-thiazolo[3,2-a]pyrimidines |
| WO2000047205A1 (en) * | 1999-02-10 | 2000-08-17 | The Trustees Of The University Of Pennsylvania | Tyrosine kinase inhibitors and methods of using the same |
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|---|
| 《Journal of Heterocyclic Chemistry》 19810331 Rovnyak, George; Shu, Virginia; Schwartz, Joseph Tricyclic thiazolo[3,2-a]thiapyrano[4,3-d]pyrimidines and related analogs as potential antiinflammatory agents 327-31页 1,2-4,8 第18卷, 第2期 * |
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