CN101337928A - Quinoline compounds, synthesizing method, applications in synthesis of alkaloid of camptothecins - Google Patents
Quinoline compounds, synthesizing method, applications in synthesis of alkaloid of camptothecins Download PDFInfo
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Abstract
The invention relates to quinoline compound, a synthesis method and the application for preparing medicines of camptothecin alkaloid. The syntheticroute is concise, high-efficient and economical, and can play a great role in promoting the later industrialized production of camptothecin alkaloid.
Description
Technical field
This patent relates to the organic synthesis field.In particular, relate to the synthetic alkaloidal intermediate quinolines of camptothecin of a class, can obtain the different quinolines that replace from the raw material that simply is easy to get is synthetic, and it is applied to prepare in camptothecin alkaloidal drug synthetic as synthetic intermediate.
Background technology
Quinoline is a main type in the heterogeneous ring compound, and its a lot of preparation methods are grown up from 19 th century later.Wherein skeleton quinoline ring is prevalent in some natural products, medicine, the functional materials, especially be present in the alkaloid, thereby the construction process of quinoline ring is significant for the synthetic design of many bioactive molecules.
All contain the quinoline structure in the multiple natural product, and the camptothecin alkaloid is exactly a class wherein.Camptothecine (Camptothecin, CPT) be to separate (the J.Am.Chem.Soc.1966 that obtains by U.S. scientist Wani and the camplotheca acuminata (Camptotheca acuminata) that Wall etc. introduces a fine variety from China first in 1966,88,3888), structural formula is as follows, and it has condensed hexa-atomic lactone, pyrrolidone successively, tetramethyleneimine and quinoline are wherein at 20 chiral centres that contain a S configuration.
Camptothecine has good anti-cancer activity, and is especially stronger to digestive tract tumor, leukemia, bladder cancer isoreactivity, thereby caused people's extensive concern.1985, discovery camptothecine such as Hsiang were specific inhibitor (Hsiang, the Y.H. of topoisomerase I; Hertzberg, R.; Hecht, S.M.; Liu, L.F.J.Biol.Chem.1985,260,14873), can combine, form CPTs-Topo I-DNA ternary complex with this cleavable mixture of Topo I-DNA, thereby stablized this cleavable mixture of Topo I-DNA, finally cause irreversible dna replication dna to be stagnated, show its cytotoxicity, make death of neoplastic cells.
Active high in order to obtain, the camptothecin derivative that toxicity is little, people have carried out a large amount of structure of modification.Synthesized hundreds of camptothecin derivatives by semi-synthetic or total synthesis method, have or be about to enter clinical study.Wherein, the semi-synthetic derivative irinotecan of camptothecin (Irinotecan) is researched and developed by Japanese first drugmaker, at first went on the market in 1994 in Japan, be that first is used for clinical camptothecine, FDA ratified it in 1996 and goes on the market in the U.S., was used for the treatment of colorectal carcinoma, was produced respectively by Japanese first pharmaceutical factory and U.S. Pharmacia-Upjion company at present, Irinotecan belongs to a kind of prodrug, is converted into 7-ethyl-10-hydroxycamptothecine in vivo and plays a role.Topotecan (Topotecan) is an another one by the camptothecine of U.S. FDA in approval listing in 1996, is used for the treatment of ovarian cancer, is produced by SmithKline-Beecham company.Camptothecine becomes second cancer therapy drug that extracts after taxol from plant, the confirmation of camptothecine, taxol and the effect of Vitamin A compounds anticancer therapy is described as three great discoveries of the cancer therapy drug nineties.
At present, that is that all right is ripe for the method for chemosynthesis camptothecine and analogue thereof, and the cancer therapy drug of above-mentioned camptothecine utilizes mainly that natural CPT is semi-synthetic to be obtained.But the amount of the camptothecine that is obtained as starting material by natural materialss such as camplotheca acuminatas is few, and very big as the demand of useful non-natural camptothecin derivative, realizes that by plant raw-material method is greatly limited.In addition, when the complete synthesis preparation method of research, owing to often face problems such as equipment, yield and cost, practicability not as yet at present.
Patent of the present invention is in line with high-level efficiency, low cost, theory simple to operate has designed and has completed successfully the synthetic of quinolines, and be applied to the synthetic of camptothecine and derivative thereof, can support the amplification preparation and the suitability for industrialized production in camptothecine and derivative drug research later stage thereof.
Summary of the invention
One of the object of the invention is to provide the quinolines of a class different substituents;
Purpose of the present invention also provides a kind of raw material from simply being easy to get, the method for the quinolines of synthetic above-mentioned different substituents.
Another object of the present invention is to utilize above-mentioned quinolines as intermediate, is used to prepare camptothecine and derivative cancer therapy drug thereof.
The quinolines of the different substituents that the present invention relates to have a following structural formula:
Wherein, R
1The alkyl of=hydrogen, alkoxyl group, C1-C10, the phenyl of replacement;
R
2=carbonyl, oximido, first oximido or methylamino;
R
3The alkyl of=hydrogen, acyl group or C1-C10;
R
4The alkyl of=hydroxyl or C1-C10;
R
5=hydrogen or acyl group;
R
6The alkoxyl group of=hydrogen or C1-C10;
Described carbonyl is the ketone group of aldehyde radical or C1-C10; Described acyl group is alkyloyl, enoyl-or the alkynes acyl group of C1-C10.
In particular, said structure can be expressed as for example:
The synthetic schemes of the quinolines that the present invention relates to is from compound 4 and 5, can synthesis of quinoline compounds 6～14, and again by 14 synthetic camptothecin alkaloids..Having synthesized target compound from compound 4 and 5s by the reaction of 11 steps is camptothecin alkaloid, wherein R
1, R
2As mentioned above.Typical reaction formula is as follows:
Wherein pyrrolidine is a tetramethyleneimine, and benzoic acid is a phenylformic acid, and MS is a molecular sieve, and NaOAc is a sodium acetate, DMF is N, and dinethylformamide, DMAP are 4-N, the N-lutidine, mesitylene is a trimethylbenzene, and DDQ is 2,3-two chloro-5,6-dicyano benzoquinone.
When obtaining compound 16a, i.e. R
1=OMe, R
2During=H, just can slough oxygen methyl (Chem.Eur.J.1998,4,67), obtain 10-hydroxycamptothecine according to the method for bibliographical information.
The concrete scheme of the present invention is from compound 4 and 5, by following stepwise compound 6～14, and target compound:
1) in the organic solution of compound 5, adds molecular sieve and catalyzer tetramethyleneimine and phenylformic acid, stir adding compound 4 after 1～10 minute, react 1～10 hour acquisition compound 6 under the room temperature, add silica gel and stirred 1～10 hour; Described compound 5, catalyzer tetramethyleneimine and benzoic mol ratio are 1: 0.1: 0.1; Every mmole compound 5 adds the silica gel of 1g;
2) at room temperature with organic solution in, add the reaction of compound 6 and Manganse Dioxide and obtained compound 7 in 1～10 hour, the mol ratio of described adding compound 6 and Manganse Dioxide is 1: 2;
3) in organic solution and under the room temperature, compound 7 and hydroxylamine hydrochloride and acetic acid sodium reaction obtained compound 8 in 1～10 minute, and wherein compound 7, and the mol ratio of hydroxylamine hydrochloride and sodium acetate is 1: 1.5: 1.5;
4) add salt of wormwood in the muddy liquid of the methyl alcohol of compound 8, react 0.1～1 hour acquisition compound 9 under the room temperature; Described compound 8 is 1: 2 with the mol ratio of salt of wormwood;
5) the palladium carbon of catalytic amount adds in the organic solution of compound 9, is placed on room temperature reaction acquisition in 12 hours compound 10 in the normal pressure atmosphere of hydrogen; Described every mole compound 9 adopts 0.1 normal palladium carbon;
6) in the organic solution of compound 10, add triethylamine and acyl chlorides, room temperature reaction obtained 11 in 2 hours; Wherein compound 10, and the mol ratio of triethylamine and acyl chlorides is 1: 1.5: 1.1;
7) compound 11 is dissolved in the organic solvent, adds oxygenant Manganse Dioxide, reaction obtained compound 12 in 3 hours under the room temperature; The mol ratio of described compound 11 and oxygenant is 1: 4;
8) compound 12 is in organic solvent, compound 12 and acetic anhydride, and 4-N, N-lutidine and triethylamine reaction 0.5 hour remove and desolvate and triethylamine, add methylene dichloride then, are chilled to-78 ℃, add BF
3.Et
2The O reaction adds silyl enol ether and obtains compound 13 after 1～5 hour; Described compound 12, acetic anhydride, 4-N, N-lutidine, triethylamine, BF
3.Et
2The mol ratio of O and silyl enol ether is 1: 1.1: 0.05: 1.5: 3: 4; Described silyl enol ether is 2-ethyl-1,3-butadiene-1-alcohol trimethylsilyl ethers;
9) under inert gas conditions, compound 13 is heated 120～160 ℃ of tube sealing reactions obtained compound 14 in 7 hours in high boiling solvent;
10) under the room temperature condition, compound 14 is dissolved in the organic solvent, adds oxygenant 2.2-two chloro-5, and 6-dicyano benzoquinone reacted 1.5 hours, and the product that will get is dissolved in the organic solvent, and room temperature condition adds BF down
3.Et
2O and Et
3SiH obtains compound 15, wherein, and compound 14, oxygenant, BF
3.Et
2O and Et
3The SiH mol ratio is 1: 2: 2.2: 2.6;
In sum, count the cancer therapy drug that totally 11 steps just can obtain above-mentioned camptothecine and derivative thereof from compound 4 and 5.(Chavan, S.P. on the basis of Chavan research group work; Venkatraman, M.S.ARKIVOC 2005,165), carry out compound 15 bishydroxies are used I then with the asymmetric bishydroxy reaction conditions of Sharpless earlier
2-CaCO
3Oxidation obtains camptothecine and derivative thereof.
1) with (DHQD)
2-PYR, K
3Fe (CN)
6, K
2CO
3, K
2OsO
2(OH)
4And CH
3SO
2NH
2Be dissolved in H
2O and t-BuOH volume ratio are in 1: 1 the mixed solvent, and the gained mixed system is chilled to 0 ℃ after at room temperature being stirred to the two-phase clarification; Compound 15b joins above-mentioned reaction system, keeps 0 ℃ of reaction 40h acquisition dihydroxyl compound intermediate 16b down, uses Na under this temperature
2SO
3(0.5g) cancellation reaction, the compound 15b of every mmole adopts the above-mentioned mixed solvent of 3mL; Compound 15b and Na
2SO
3Mol ratio be 1: 2; Rise to room temperature restir 30min, wherein, (DHQD)
2-PYR, K
3Fe (CN)
6, K
2CO
3, K
2OsO
2(OH)
4And CH
3SO
2NH
2With the mol ratio of compound 15b be 0.02: 3: 3: 0.004: 1: 1; The structural formula of described (DHQD) 2-PYR is:
2) the gained solid being dissolved in volume is 2: 1 MeOH and H
2In the O mixed solvent, add I
2And CaCO
3, the gained reaction mixture stirs 15h at 40 ℃, wherein, and the dihydroxyl compound intermediate of gained, I
2And CaCO
3Mol ratio be 1: 15: 3, the compound 16b of every mmole adopts the above-mentioned mixed solvent of 3mL;
Described compound 14,15 and 16 structural formulas are as follows:
More known other routes of the cancer therapy drug synthetic schemes of above-mentioned camptothecine and derivative thereof have had very big improvement.Specifically, route is shorter, and productive rate is greatly improved, and has avoided the use of the metal reagent of air and water sensitive, and the operation that relates to is simple, relatively is fit to a large amount of preparations and industrialization demands.
Embodiment
The present invention will be helped to understand by following embodiment, but content of the present invention can not be limited.
Embodiment 1
(5g 39mmol) in the dichloromethane solution, adds molecular sieve at compound 5, the tetramethyleneimine of catalytic amount (0.32mL, 3.9mmol) with phenylformic acid (0.32mL, 3.9mmol), stir after five minutes add compound 4 (7.09g, 58.57mmol), stir about half an hour under the room temperature.After reaction finished, the elimination molecular sieve added silica gel in filtrate, stirred under the room temperature and spent the night.Elimination silica gel concentrates, and column chromatography gets product 6a (R
1=H, 8.44g, 82%).
1H?NMR(CDCl3，300MHz)：δ9.52(s，1H)，7.28(d，1H，J＝4.8Hz)，7.15(t，1H，J＝7.9Hz)，7.10(d，1H，J＝7.5Hz)，6.67(t，1H，J＝7.4Hz)，6.52(d，1H，J＝8.1Hz)，4，82(m，1H)，4.67(s，1H)，4.04(m，2H)，1.94(s，3H)，
According to same operation, get compound 6b (R
1=OMe, 84%).
1H?NMR(CDCl3，300MHz)：δ9.53(s，1H)，7.25(s，1H)，6.81(dd，1H，J＝8.7，3.0Hz)，6.66(d，1H，J＝3.3Hz)，6.50(d，1H，J＝9.0Hz)，4.76(dd，1H，J＝6.6，3.6Hz)，4.32(s，1H)，4.03-3.96(m，2H)，3.75(s，3H)，1.96(s，3H)，
Embodiment 2
At room temperature, (13.2g, 151.5mmol) (7.0g, in dichloromethane solution 30.3mmol), stirring at room disappears until raw material disposable adding compound 6 with the Manganse Dioxide after the activation.Filter, concentrate, column chromatography gets product 7a (R
1=H, 6.2g, 89%).
1H?NMR(300MHz，CDCl
3)：δ10.31(s，1H)，8.69(s，1H)，8.16(d，1H，J＝8.7Hz)，8.00(d，1H，J＝7.8Hz)，7.90(m，1H)，7.67(m，1H)，5.75(s，2H)，4，82(m，1H)，2.24(s，3H).
According to same operation, get compound 7b (R
1=OMe, 87%).
1H?NMR(300MHz，CDCl
3)：δ10.31(s，1H)，8.69(s，1H)，8.45(d，1H，J＝9.3Hz)，7.52(dd，1H，J＝7.8，2.7Hz)，7.22(d，1H，J＝2.1Hz)，5.70(s，2H)，3.97(s，3H)，2.20(s，3H).
Embodiment 3
(5.57g, (2.54g, 36.5mmol), (2.99g, 36.5mmol), stir about is ten minutes under the room temperature for sodium-acetate to add hydroxylamine hydrochloride in ethanolic soln 24.3mmol) successively to compound 7.After revolving most of ethanol, add entry, dichloromethane extraction, anhydrous sodium sulfate drying concentrates, and directly drops into next step.
Embodiment 4
(6.7g, (7.58g 54.9mmol), stirred 45 minutes under the room temperature to add salt of wormwood in methyl alcohol 27.4mmol) (100mL) suspension liquid to compound 8.Revolve most methyl alcohol, add entry and methylene dichloride, extraction, anhydrous sodium sulfate drying concentrates, and directly drops into next step.
Embodiment 5
(4.4g, (8.4g in methyl alcohol 41.6mmol) (200mL) solution, feeds hydrogen, normal pressure hydrogenation to 10% palladium carbon 4.2mmol) to add compound 9.After question response is complete, filter, concentrate, column chromatography gets product 10a (R
1=H, 3.6g), for compound 7, three step overall yields are 79%.
1H?NMR(DMSO-d
6，300MHz)：δ8.28(s，1H)，7.95(m，2H)，7.70(m，1H)，7.57(m，1H)，4.77(s，1H)，3.98(s，1H).
According to same operation, get compound 10b (R
1=OMe, three step productive rates are 84%).
1H?NMR(DMSO-d
6，300MHz)：δ8.17(s，1H)，7.89-7.86(m，2H)，7.35-7.32(m，2H)，4.73(s，2H)，3.97(s，2H)，3.89(s，3H).
Embodiment 6
Compound 10 is dissolved in N, in the dinethylformamide (50mL), adds the 3.3mL triethylamine, reduces under the ice bath temperature, (2.4g 17.5mmol), after reaction finishes, adds water slowly to drip acyl chlorides, ethyl acetate extraction repeatedly, anhydrous sodium sulfate drying concentrates, column chromatography gets product 11a (R
1=H, 3.9g, 85%).
1H?NMR(DMSO-d
6，300MHz)：δ8.21(t，1H，J＝5.7Hz)，8.10(s，1H)，7.98(m，2H)，7.72(m，1H)，7.57(m，1H)，7.40(d，1H，J＝12.6Hz)，5.45(d，1H，J＝12.0Hz)，5.35(t，1H，J＝5.4Hz)，4.80(d，2H，J＝5.7Hz)，4.59(d，2H，J＝5.7Hz)，3.90(q，2H，J＝6.6Hz)，1.25(t，3H，J＝6.9Hz).
According to same operation, get compound 11b (R
1=OMe, 86%).
1H?NMR(DMSO-d
6，300MHz)：δ8.21(t，1H，J＝5.7Hz)，7.99(s，1H)，7.88(d，1H，J＝8.7Hz)，7.42-7.32(m，3H)，5.46(d，1H，J＝12.3Hz)，5.29(t，1H，J＝5.4Hz)，4.75(d，1H，J＝5.4Hz)，4.57(d，1H，J＝6.0Hz)，3.94-3.87(m，5H)，1.25(t，3H，J＝6.9Hz).
Embodiment 7
At room temperature, (0.5g, 5.77mmol) add compound 11 (0.55g, in dichloromethane solution 1.9mmol), stirring at room disappears until raw material in batches with the Manganse Dioxide after the activation.Filter, add silica gel in filtrate, stirring is spent the night.Filter, concentrate, column chromatography gets product 12a (R
1=H, 0.46g, 84%).
1H?NMR(DMSO-d
6，300MHz)：δ8.38(s，1H)，8.04(m，2H)，7.77(m，1H)，7.63(m，1H)，7.54(d，2H，J＝12.0Hz)，6.89(d，1H，J＝8.7Hz)，6.41(d，1H，J＝9.0Hz)，6.01(d，1H，J＝12.3Hz)，4.77(AB，2H，J＝17.4Hz)，4.03(q，2H，J＝7.2Hz)，1.29(t，3H，J＝7.2Hz).
According to same operation, get compound 12b (R
1=OMe, 82%).
1H?NMR(DMSO-d
6，300MHz)：δ8.25(s，1H)，7.95(d，1H，J＝10.2Hz)，7.54(d，1H，J＝12.0Hz)，7.43-7.40(m，2H)，6.82(d，1H，J＝9.0Hz)，6.37(d，1H，J＝9.0Hz)，6.00(d，1H，J＝12.0Hz)，4.77(AB，2H，J＝16.8Hz)，4.02(q，2H，J＝6.97.2Hz)，3.91(s，3H)，1.29(t，3H，J＝7.2Hz).
Embodiment 8
(1.03g, (0.76mL, 5.4mmol), (0.38mL, 4.0mmol) and 4-N, (13mg 0.1mmol), is stirred under the room temperature and reacts completely the N-lutidine aceticanhydride to add triethylamine in methylene dichloride 3.6mmol) (70mL) suspension liquid to compound 12.Reaction solution is spin-dried for, and oil pump is taken out, and adds methylene dichloride, is placed in ethanol the dry ice bath, add boron trifluoride ether solution (1.4mL, 5.4mmol), stir half an hour after, add the compound silyl enol ether (2.5g, 14.5mmol), stir about 2 hours.Add the reaction of going out of saturated sodium bicarbonate collection, extraction, anhydrous sodium sulfate drying concentrates, and column chromatography must product 13a (R
1=H, 0.95g,, 72%).
1H?NMR(CDCl
3，300MHz)：δ9.14(s，1H)，7.81(d，1H，J＝8.1Hz)，7.65-7.73(m，2H)，7.54(t，1H，J＝7.5Hz)，6.23(t，1H，J＝7.5Hz)，5.57-5.72(m，2H)，4.70-5.20(m，2H)，4.00(q，2H，J＝6.6Hz)，3.20-3.56(m，2H)，2.15(m，2H)，1.36(t，3H，J＝5.4Hz)，0.81(t，3H，J＝7.5Hz).
According to same operation, get compound 13b (R
1=OMe, 69%).
1H?NMR(CDCl
3，300MHz)：δ9.15(s，1H)，7.98-7.89(m，2H)，7.69(t，1H，J＝11.2Hz)，7.36(dd，1H，J＝9.3，2.7Hz)，7.07(s，1H)，6.22(t，1H，J＝7.5Hz)5.72-5.29(m，2H)，4.97-4.74(m，2H)，4.02-3.97(m，2H)，3.92(s，3H)，3.51-3.21(m，2H)，2.19-2.07(m，2H)，1.37(t，3H，J＝6.6Hz)，0.79(t，3H，J＝7.5Hz).
Embodiment 9
Add the compound 13 of 100mg in the trimethylbenzene (15mL), tube sealing is heated to 160 ℃, after question response finishes, concentrates, and column chromatography gets product 14a (R
1=H, 83mg, 85%).
1H?NMR(CDCl3，300MHz)：δ8.12(m，2H)，7.85(d，1H，J＝8.1Hz)，7.74(t，1H，J＝7.1Hz)，7.58(t，1H，J＝7.4Hz)，6.17(s，1H)，5.16-5.08(m，3H)，4.74(d，1H，J＝16.2Hz)，4.09-3.90(m，2H)，2.62-2.43(m，4H)，2.03(q，2H，J＝7.8Hz)，1.36(t，3H，J＝6.9Hz)，0.96(t，3H，J＝7.2Hz).
According to same operation, get compound 14b (R
1=OMe, 92%).
1H?NMR(CDCl
3，300MHz)：δ8.00-7.98(m，2H)，7.38(dd，1H，J＝9.0，2.7Hz)，7.09(d，1H，J＝3.0Hz)，6.17(s，1H)，5.14(d，1H，J＝7.8Hz)，5.07(t，1H，J＝7.8Hz)，4.08-3.89(m，5H)，2.57-2.39(m，3H)，2.02(q，2H，J＝7.2Hz)，1.35(t，3H，J＝7.2Hz)，0.96(t，3H，J＝7.2Hz).
Embodiment 10
The mixture (100mg) of compound 14 is dissolved in the dioxane (10mL), adds the glacial acetic acid of catalytic amount, stirring at room is complete to raw material reaction, and the compound that will get behind the rapid column chromatography is dissolved in the methylene dichloride, adds Et successively
3SiH and BF
3.Et
2O, stir about is 2 hours under the room temperature.Concentrate, column chromatography gets product 15a (R
1=H, 66mg, 76%).
1H?NMR(CDCl
3，300MHz)：δ8.33(s，1H)，8.21(d，1H，J＝8.4Hz)，7.90(d，1H，J＝7.8Hz)，7.81(t，1H，J＝7.5Hz)，7.63(t，1H，J＝7.6Hz)，7.20(s，1H)，6.66(s，1H)，5.25(s，2H)，5.17(s，2H)，2.45(q，2H，J＝7.8Hz)，1.22(t，3H，J＝7.2Hz).
According to same operation, get compound 15b (R
1=OMe, 81%).
1H?NMR(CDCl
3，300MHz)：δ8.17(s，1H)，8.07(d，1H，J＝9.3Hz)，7.43(dd，1H，J＝9.3，3.3Hz)，7.12-7.11(m，2H)，6.65(s，1H)，5.18(s，2H)，5.16(s，2H)，3.97(s，3H)，2.43(q，2H，J＝7.8Hz)，1.21(t，3H，J＝7.2Hz).
Embodiment 11
(DHQD)
2-PYR (5.6mg, 0.0064mmol, 2mol%), K
3Fe (CN)
6(312mg, 0.95mmol), K
2CO
3(131mg, 0.95mmol), K
2OsO
2(OH)
4(0.5mg, 0.0014mmol, 0.4mol%) and CH
3SO
2NH
2(30mg 0.32mmol) is dissolved in H
2In the mixed solvent of O and t-BuOH (4mL, 1: 1), the gained mixed system is chilled to 0C after at room temperature being stirred to the two-phase clarification.It is disposable that (100mg 0.32mmol) joins above-mentioned reaction system, keeps 0 ℃ of reaction 40h down, uses Na under this temperature with compound 15b
2SO
3(0.5g) cancellation reaction rises to room temperature restir 30min, adds CH in reaction mixture
2Cl
2(10mL), CH
3OH (1mL) and H
2O (10mL), water CH
2Cl
2And CH
3The mixed extractant solvent of OH (2 * 10mL, 10: 1) merges organic phase, uses anhydrous Na
2SO
4Drying, filtering and concentrating is through column chromatography (CH
2Cl
2-CH
3OH=25: 1) separation and purification gets a white solid (92mg).
The gained solid is dissolved in MeOH and H
2In O (60mL, 2: the 1) mixed solvent, add I
2(1.0g, 3.9mmol) and CaCO
3(79mg, 0.79mmol), the gained reaction mixture adds Na behind 40 ℃ of stirring 15h
2SO
3(1.3g) cancellation reaction, rotary evaporation add CH after removing methyl alcohol in the mixed solvent
2Cl
2(10mL), CH
3OH (1mL) and H
2O (10mL), water CH
2Cl
2And CH
3The mixed extractant solvent of OH (2 * 10mL, 10: 1) merges organic phase, uses anhydrous sodium sulfate drying, filtering and concentrating, column chromatography (CH
2Cl
2-CH
3OH=30: 1) separation obtains camptothecine (16a) (R
1=OMe, 91mg, 83%), it is 95% that chirality HPLC measures its ee value.
1H?NMR(DMSO，300MHz)：δ8.69(1H，s)，8.17(1H，d，J＝8.7Hz)，8.13(1H，d，J＝8.1Hz)，7.89-7.84(1H，m)，7.74-7.68(1H，m)，7.35(1H，s)，6.53(1H，s)，5.43(2H，s)，5.29(1H，s)，1.86(2H，q，J＝6.6Hz)，0.88(3H，t，J＝6.6Hz)
According to same operation, get compound 15b (R
1=OMe, 82%, 99%ee).
1H?NMR(DMSO-d
6，300MHz)：δ8.53(1H，s)，8.06(1H，d，J＝10.2Hz)，7.51-7.47(2H，m)，7.27(1H，s)，6.49(1H，s)，5.40(2H，s)，5.25(2H，s)，3.93(3H，s)，1.85(2H，q，J＝7.5Hz)，0.86(3H，t，J＝7.8Hz)。
Claims (8)
1, one class quinolines has following structural formula:
Wherein, R
1The alkyl of=hydrogen, alkoxyl group, C1-C10, the phenyl of replacement;
R
2=carbonyl, oximido, first oximido or methylamino;
R
3The alkyl of=hydrogen, acyl group or C1-C10;
R
4The alkyl of=hydroxyl or C1-C10;
R
5=hydrogen or acyl group;
R
6The alkoxyl group of=hydrogen or C1-C10;
Described carbonyl is the ketone group of aldehyde radical or C1-C10; Described acyl group is alkyloyl, enoyl-or the alkynes acyl group of C1-C10.
2, a class quinolines as claimed in claim 1 is characterized in that having following structural formula:
3, a kind of synthetic method of a class quinolines as claimed in claim 1 is characterized in that synthetic as follows:
1) in the organic solution of compound 5, adds molecular sieve and catalyzer tetramethyleneimine and phenylformic acid, stir adding compound 4 after 1～10 minute, react 1～10 hour acquisition compound 6 under the room temperature, add silica gel and stirred 1～10 hour; Described compound 5, catalyzer tetramethyleneimine and benzoic mol ratio are 1: 0.1: 0.1; Every mmole compound 5 adds the silica gel of 1g;
2) at room temperature with organic solution in, add the reaction of compound 6 and Manganse Dioxide and obtained compound 7 in 1～10 hour, the mol ratio of described adding compound 6 and Manganse Dioxide is 1: 2;
3) in organic solution and under the room temperature, compound 7 and hydroxylamine hydrochloride and acetic acid sodium reaction obtained compound 8 in 1～10 minute, and wherein compound 7, and the mol ratio of hydroxylamine hydrochloride and sodium acetate is 1: 1.5: 1.5;
4) add salt of wormwood in the muddy liquid of the methyl alcohol of compound 8, react 0.1～1 hour acquisition compound 9 under the room temperature; Described compound 8 is 1: 2 with the mol ratio of salt of wormwood;
5) the palladium carbon of catalytic amount adds in the organic solution of compound 9, is placed on room temperature reaction acquisition in 12 hours compound 10 in the normal pressure atmosphere of hydrogen; Described every mole compound 9 adopts 0.1 normal palladium carbon;
6) in the organic solution of compound 10, add triethylamine and acyl chlorides, room temperature reaction obtained 11 in 2 hours; Wherein compound 10, and the mol ratio of triethylamine and acyl chlorides is 1: 1.5: 1.1;
7) compound 11 is dissolved in the organic solvent, adds oxygenant Manganse Dioxide, reaction obtained compound 12 in 3 hours under the room temperature; The mol ratio of described compound 11 and oxygenant is 1: 4;
8) compound 12 is in organic solvent, compound 12 and acetic anhydride, and 4-N, N-lutidine and triethylamine reaction 0.5 hour remove and desolvate and triethylamine, add methylene dichloride then, are chilled to-78 ℃, add BF
3.Et
2The O reaction adds silyl enol ether and obtains compound 13 after 1～5 hour; Described compound 12, acetic anhydride, 4-N, N-lutidine, triethylamine, BF
3.Et
2The mol ratio of O and silyl enol ether is 1: 1.1: 0.05: 1.5: 3: 4; Described silyl enol ether is 2-ethyl-1,3-butadiene-1-alcohol trimethylsilyl ethers;
9) under inert gas conditions, compound 13 is heated 120～160 ℃ of tube sealing reactions obtained compound 14 in 7 hours in high boiling solvent;
Above-claimed cpd 6～14 structural formulas are as follows:
, R wherein
1, R
6According to claim 1.
4, method as claimed in claim 3 is characterized in that step 2) described Manganse Dioxide is new system.
5. method as claimed in claim 3 is characterized in that step 6) and 8) described reaction is to carry out under inert gas conditions.
6. a quinolines as claimed in claim 1 is used to prepare camptothecine and derivative cancer therapy drug thereof.
7. quinolines as claimed in claim 6 is used to prepare camptothecine and derivative cancer therapy drug thereof.
8. the purposes of quinolines as claimed in claim 7, its feature comprises the steps:
1) with (DHQD)
2-PYR, K
3Fe (CN)
6, K
2CO
3, K
2OsO
2(OH)
4And CH
3SO
2NH
2Be dissolved in H
2O and t-BuOH volume ratio are in 1: 1 the mixed solvent, and the gained mixed system is chilled to 0 ℃ after at room temperature being stirred to the two-phase clarification; Compound 15b joins above-mentioned reaction system, keeps 0 ℃ of reaction 40h acquisition dihydroxyl compound intermediate 16b down, uses Na under this temperature
2SO
3(0.5g) cancellation reaction, the compound 15b of every mmole adopts the above-mentioned mixed solvent of 3mL; Compound 15b and Na
2SO
3Mol ratio be 1: 2; Rise to room temperature restir 30min, wherein, (DHQD)
2-PYR, K
3Fe (CN)
6, K
2CO
3, K
2OsO
2(OH)
4And CH
3SO
2NH
2With the mol ratio of compound 15b be 0.02: 3: 3: 0.004: 1: 1; The structural formula of described (DHQD) 2-PYR is:
2) the gained solid being dissolved in volume is 2: 1 MeOH and H
2In the O mixed solvent, add I
2And CaCO
3, the gained reaction mixture stirs 15h at 40 ℃, wherein, and the dihydroxyl compound intermediate of gained, I
2And CaCO
3Mol ratio be 1: 15: 3, the compound 15b of every mmole adopts the above-mentioned mixed solvent of 3mL; Described compound 15b and 16b structural formula are as follows:
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| CN102250104A (en) * | 2011-05-20 | 2011-11-23 | 南京大学 | Camptothecin derivative, and its synthetic method and application |
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| CN114835720A (en) * | 2021-02-02 | 2022-08-02 | 四川大学 | Quinolinone compound, synthesis method and application thereof in camptothecin alkaloid synthesis |
| CN114292231A (en) * | 2021-12-17 | 2022-04-08 | 江苏广域化学有限公司 | 2-methyl-8-substituent-quinoline and preparation method thereof |
| CN114292231B (en) * | 2021-12-17 | 2023-09-22 | 江苏广域化学有限公司 | 2-methyl-8-substituent-quinoline and preparation method thereof |
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