CN1101819C - 4-beta-carbonsubstituted-4-deoxy-4'-demethylepi podophyllotoxin derivative with antineoplastic activity and its synthesis method - Google Patents
4-beta-carbonsubstituted-4-deoxy-4'-demethylepi podophyllotoxin derivative with antineoplastic activity and its synthesis method Download PDFInfo
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Abstract
The present invention relates to pharmaceutical synthesis, more specifically to a 4-beta-carbon substituted-4-deoxy-4'-deepipodophyllotoxin derivative and a preparing method thereof. The present invention also describes the stereospecificity synthesis of key intermediates, namely 4-beta-cyano-4-deoxy-4-deepipodophyllotoxin (B) and 4-beta-carboxyl-4-deoxy-4'-deepipodophyllotoxin (C).
Description
It is synthetic to the present invention relates to medicine, is specifically related to a kind of 4-β-carbon with anti-tumor activity and replaces 4-deoxidation-4 '-demethylated podophyllotoxin derivative and synthetic method.
Podophyllotoxin (Podophyllotoxin) is the main aryl-tetralin Lignanoids compounds in Himalaya Podophyllum emodi var chinense and the America podophylli,rhizoma.It has antimitotic and to the destruction of cancer cells.Sixties Switzerland Sandoz company has found VP-16-213 (Etoposide) and VM-26 (Teniposide) in the further chemical structure of podophyllotoxin is modified, the both has the intensive anti-tumor activity.The seventies enters clinical study, finally becomes two to the most successful up to now podophyllotoxin series antineoplastic medicament.But the antitumor spectrum of Etoposide is still narrower, and action intensity is also not enough, and certain toxic side effect is arranged.
The objective of the invention is to overcome above-mentioned shortcoming, seek the Podophyllum emodi var chinense series antineoplastic medicament of more effective and low toxicity.
The inventor carries out structure activity study and structural modification to podophyllotoxin, and the C4 position of podophyllotoxin is one of most important decorating site.
Character such as this position substituting group and corresponding spatial orientation are very big to the biological activity influence of compound.Wherein best with the derivatives active of beta comfiguration nitrogen replacement.But the activity research of the derivative that 4 β carbon are replaced is less.
The present invention goes into have highly active C
4Insert carbon atom between C-N key in the molecule that position N, O and S replace or the C-O key, synthetic new derivative;
The invention provides a kind of 4-β with anti-tumor activity-carbon replacement-4-deoxidation-4 '-demethylated podophyllotoxin derivative as shown in the formula A.
Working as X in the formula is NR
1R
2The time (R
1, R
2Be C1-C6 straight or branched alkyl; Allyl group; Methoxyl group, halogen, nitro, hydroxyl etc. are single to be replaced or polysubstituted phenyl, phenmethyl etc.) be acid amides I analog derivative of the present invention; When X is that (R is a C1-C6 straight or branched alkyl to OR; Allyl group; Methoxyl group, halogen, nitro, hydroxyl etc. are single to be replaced or polysubstituted phenyl, phenmethyl etc.) be ester II analog derivative of the present invention; When X is that (R is a C1-C6 straight or branched alkyl to SR; Allyl group; Methoxyl group, halogen, nitro, hydroxyl etc. are single to be replaced or polysubstituted phenyl, phenmethyl etc.) be thioesters III analog derivative of the present invention.
Another object of the present invention has provided the compound of 4-β-carboxyl-4-deoxidation-4 '-demethylated podophyllotoxin of 4-beta-cyano-4-deoxidation-the 4 '-demethylated podophyllotoxin of following formula B and formula C, these two key intermediates that compound is synthesis type A.
Another purpose of the present invention has provided the synthetic method of above-mentioned formula A 4-β-carbon replacement-4-deoxidation-4 '-demethylated podophyllotoxin acid amides I class, ester II class and thioesters III analog derivative and key intermediate formula B and formula C compound.
Method of the present invention comprises draws together the following step: (1) is starting raw material with 4 '-demethyl epipodophyllotoxin, make catalyzer with boron trifluoride ethyl ether complex, in halogen-containing lower paraffin hydrocarbons, benzene or substituted benzene solvent, under 0～40 ℃ and Lewis acid catalysis condition, with potassium cyanide or front three cyano group silane reaction, main selectivity synthesizes 4-beta-cyano-4-deoxidation-4 '-demethylated podophyllotoxin B; (2) 4-beta-cyano-4-deoxidation-4 '-demethylated podophyllotoxin B reacts more than 0.5 hour down in 20～100 ℃ in containing hydrochloric acid or vitriolic acetic acid or acetone solvent, obtains Compound C; (3) in the triethylamine solvent, Compound C is prepared the acyl chlorides intermediate with thionyl chloride, need not separate, solvent evaporated adds the required amine NHR of reaction then respectively at normal temperatures
1R
2(R
1, R
2Replace or polysubstituted phenyl, phenmethyl etc. for C1-C6 straight or branched alkyl, allyl group, methoxyl group, halogen, nitro, hydroxyl etc. are single); (R is a C1-C6 straight or branched alkyl for alcohol or phenol ROH; Allyl group; Methoxyl group, halogen, nitro, hydroxyl etc. are single to be replaced or polysubstituted phenyl, phenmethyl etc.); Mercaptan or thiophenol RSH (R is single replacement such as C1-C6 straight or branched alkyl, allyl group, methoxyl group, halogen, nitro, hydroxyl or polysubstituted phenyl, phenmethyl etc.) and Et
3N or Pyridine make compound.The physical data of derivative I, II, III compounds sees Table 1 respectively, table 3 and table 5.
Reaction formula:
The physical data of table 1:I analog derivative:
The The pharmacological results of table 2:I analog derivative:
The physical data of table 3:II analog derivative:
The The pharmacological results of table 4:II analog derivative:
The physical data of table 5:III analog derivative:
The The pharmacological results of table 6:III analog derivative:
The pharmacological results is summed up:
With Etoposide is contrast, and the I among the A, II, III compounds have been carried out external L
1210The growth inhibition test of leukemia cell and KB cell the results are shown in Table 2, table 4 and table 6.
The activity of individual compound and Etoposide are suitable in the I compounds, but the activity of majority of compounds is weaker than Etoposide.
The activity of fatty ester is better than the activity of aromatic ester in the II compounds, and wherein the activity with II-10 is the strongest, surpasses 2 orders of magnitude of Etoposide.Main chain is no more than active better (II-1,2,3,4) of 3 carbon atoms in the fatty ester, and the activity of carbonatoms＞3 is decline (II-5,6,7,8) to some extent all.In aromatic ester, the activity that connects the compound (II-26,30,31,32,34,38) of electron withdrawing group on the phenyl ring is better than the compound (II-23,28,29,35,36,37) that is connected with electron-donating group slightly.
The III compounds all shows certain antitumor activity, but all is weaker than Etoposide.Similar with the compound that ester replaces, the activity of fatty thioesters is better than the activity of fragrant thioesters.But the length of aliphatic chain is to not influence of activity.In aromatic ester, the activity of the substituting group compound on the phenyl ring does not have obvious influence.
Embodiment 1:
4-beta-cyano 4-deoxidation-4 '-demethylated podophyllotoxin 1 (synthetic method 1):
4 '-demethylated podophyllotoxin 10g (25mmol) joins the 350ml trichloromethane, and vigorous stirring becomes suspension.Add potassium cyanide 3.2g (49mmol).Be cooled to below-15 ℃ with the cryosel bath, drip boron trifluoride diethyl etherate 5ml (about 1 hour).Keeping cryosel to bathe after 4 hours removes.Allow it heat up naturally and reach room temperature.Continue to stir about five hours.Add the pyridine of 5ml, stirred 30 minutes.Adding 70ml water again stirs.Tell organic layer, respectively water, 5% sodium bicarbonate, dilute sulphuric acid ferrous iron solution, 5% hydrochloric acid, washing.Behind anhydrous sodium sulfate drying, after the solvent evaporated, be that eluent separates with silica gel column chromatography with ethyl acetate/hexanaphthene=1/1, get the white solid product, productive rate is 8%.Mp＝246-248℃；[a]
25 D＝66.7(C＝0.5，DMF)。EI-MS：409(M
+)，382(M
+-CN)。HR-MS：C
22H
19NO
7?calcd409.116140，obsd409.11572。
1H-NMR(400MHz，DMSO-d
6)：δ
ppm?3.00(m，1H，H-3)，3.13(m，1H，H-2)，3.63(s，6H，2xOCH
3)，4.08(t，1H，H-1)，4.57(m，2H，H-11)，4.69(d，1H，H-4)，6.05(d，2H，OCH
2O)，6.20(s，2H，H-2′，6′)，6.59(s，1H，H-8)，7.10(s，1H，H-5).
Embodiment 2:
4-beta-cyano-4-deoxidation-4 '-demethylated podophyllotoxin 1 (synthetic method 2):
4 '-demethylated podophyllotoxin 10g (10mmol) joins the 350ml trichloromethane, adds Me
3SiCN 4ml (30mmol).Cryosel is bathed and is cooled to-15 ℃, drips boron trifluoride diethyl etherate 4.5ml (about 1 hour).Dropwise the back and continue to stir 1～2 hour, add the 4.5ml pyridine.Use 5% sodium hydrogen carbonate solution, 5% hydrochloric acid, water, saturated common salt water washing respectively.Behind anhydrous sodium sulfate drying, be that eluent post silica gel column chromatography separates with ethyl acetate/hexanaphthene=1/1, get the white solid product, productive rate is 76.3%.Mp＝246～248℃。[α]
D 25＝66.4(C＝0.5，DMF)。EI-MS：409(M
+)，382(M
+-CN)。HR-MS：C
22H
19NO
7?calcd409.116140，obsd409.11572。
1H-NMR(400MHz，DMSO-d
6)：δ
ppm?3.00(m，1H，H-3)，3.13(m，1H，H-2)，3.63(s，6H，2xOCH
3)，4.08(t，1H，H-1)，4.57(m，2H，H-11)，4.69(d，1H，H-4)，6.05(d，2H，OCH
2O)，6.20(s，2H，H-2′，6′)，6.59(s，1H，H-8)，7.10(s，1H，H-5).
Embodiment 3:
4-β-carboxyl-4-deoxidation-4 '-demethylated podophyllotoxin 2:
Compound (1) 1g is dissolved in the Glacial acetic acid of 60ml, adds the distilled water of 10ml concentrated hydrochloric acid and 10ml.75 ℃ of following stirring reaction to solution of oil bath are clarified.The pressure reducing and steaming solvent.Acetic acid ethyl dissolution with 100ml.Washing repeatedly.Anhydrous sodium sulfate drying.With acetone/methylene dichloride/Glacial acetic acid=75/25/0.8 is the eluent column chromatography for separation, gets the white solid product.Productive rate is 47.8%.Mp＝254～256℃。[α]
D 25＝-70(C＝0.2，DMF)。EI-MS：428(M
+)，382(M
+-COOH-H)。HR-MS：C
22H
20O
9?calcd428.110719，obsd428.11037。H
1-NMR(400MHz，CDCl
3)：3.03-3.12(m，2H，H-2，3)，3.65(s，6H，2
*CH
3)，3.88(d，1H，H-1)，4.19(d，1H，H-4)，4.45(m，2H，H-11)，5.92(d，2H，H-2’，6’)，6.12(s，2H，OCH
2O)，6.47(s，1H，H-8)，7.10(s，1H，H-5).
Embodiment 4:
4-β-acid amides-4-deoxidation-4 '-demethylated podophyllotoxin I:
Compound (2) 100mg (0.234mmol) is dissolved in the methylene dichloride of 5ml, adds 5～6 triethylamines.Dropwise 5～6 thionyl chloride slowly under the room temperature.Stirring reaction is after half an hour, is being lower than solvent evaporated under 30 ℃ the temperature.Add the methylene dichloride of 5ml and 5～6 triethylamine again.Add the amine 1ml that needs reaction under the condition of stirring.Continue stirring reaction after 4～10 hours, with the methylene dichloride dilution of 50ml.Use cold saturated sodium bicarbonate solution, saturated common salt water washing respectively.Anhydrous sodium sulfate drying.Silica gel column chromatography separate white solid.Productive rate 30～50%.
4-β-normal hexyl Amine formyl radical-4-deoxidation-4 '-demethylated podophyllotoxin:
δ
ppm?0.85(t，3H，NH(CH
2)
6CH
3)，1.25(m，10H，NHCH
2(CH
2)
5CH
3，2.72(m，1H，H-2)，2.88～3.10(m，2H，NHCH
2(CH
2)
5CH
3)，3.23(m，1H，H-3)，3.78(d，1H，H-1)，3.80(s，6H，2
*OCH
3)，4.18(d，1H，H-4)，4.61(m，2H，H-11)，5.90(d，2H，OCH
2O)，6.27(s，1H，H-8)，6.29(s，2H，H-2’，6’)，7.18(s，1H，H-5)
Embodiment 5:
4-β-ester group-4-deoxidation-4 '-demethylated podophyllotoxin II:
Compound (2) 100mg (0.234mmol) is dissolved in the methylene dichloride of 5ml, adds 5～6 triethylamines.Dropwise 5～6 thionyl chloride slowly under the room temperature.Stirring reaction is after half an hour, is being lower than solvent evaporated under 30 ℃ the temperature.Add the methylene dichloride of 5ml and 5～6 pyridine again.Add alcohol or phenol 1ml under the condition of stirring.Continue stirring reaction after 4～10 hours, with the methylene dichloride dilution of 50ml.Use cold saturated sodium bicarbonate solution, saturated common salt water washing respectively.Anhydrous sodium sulfate drying.Silica gel column chromatography separate white solid.Productive rate 20～40%.
4-ethoxycarbonyl-4-deoxidation-4 '-demethylated podophyllotoxin:
Yield: 40.6%; Mp=162-165 ℃; [α]
25 D=-71 (C=0.2, DMF); EI-MS (m/z): 456 (M
+), 382;
1H-NMR (CDCl
3) δ
Ppm: 1.27 (t, 3H, COOCH
2CH
3), 3.00 (m, 1H, H-3), 3.10 (m, 1H, H-2), 3.68～3.88 (m, 8H, 2
*OCH
3, COOCH
2CH
3), 4.08～4.19 (m, 2H, H-1,4), 4.45 (m, 2H, H-11), 5.93 (d, 2H, OCH
2O), 6.08 (s, 2H, H-2 ', 6 '), 6.48 (s, 1H, H-8), 7.10 (s, 1H, H-5).
Embodiment 6:
4-β-thioesters-4-deoxidation-4 '-demethylated podophyllotoxin:
Compound (2) 100mg (0.234mmol) is dissolved in the methylene dichloride of 5ml, adds 5～6 triethylamines.Dropwise 5～6 thionyl chloride slowly under the room temperature.Stirring reaction is after half an hour, is being lower than solvent evaporated under 30 ℃ the temperature.Add the methylene dichloride of 5ml and 5～6 pyridine again.Add propylmercaptan 1ml under the condition of stirring.Continue stirring reaction after 4～10 hours, with the methylene dichloride dilution of 50ml.Use cold saturated sodium bicarbonate solution, saturated common salt water washing respectively.Anhydrous sodium sulfate drying.Silica gel column chromatography separate white solid.Productive rate 20～40%.
4-second thiocarbonyl group-4-deoxidation-4 '-demethylated podophyllotoxin:
Yield: 21.6%; Mp=210-212 ℃; [α]
25 D=-23.5 (C=0.2, DMF); EI-MS (m/z): 472 (M
+), 382 (M
+-COSCH
2CH
3);
1H-NMR (CDCl
3) δ
Ppm: 1.25～1.30 (t, 3H, CH
2CH
3), 2.89～2.95 (m, 2H, CH
2CH
3), 3.27～3.30 (m, 2H, H-2,3), 3.79 (s, 6H, 2
*OCH
3), 3.86 (d, 1H, H-11
α), 4.07 (d, 1H, H-11
β), 4.39～4.46 (m, 2H, H-1,4), 5.95 (d, 2H, OCH
2O), 6.13 (s, 2H, H-2 ', 6 '), 6.49 (s, 1H, H-8), 7.12 (s, 1H, H-5).
Claims (3)
1, a kind of 4-β-carbon replacement-4-deoxidation-4 '-demethylated podophyllotoxin derivative with anti-tumor activity is characterized in that representing with formula A:
Working as X in the formula is NR
1R
2The time (R
1, R
2Be C1-C6 straight or branched alkyl; Allyl group; Methoxyl group, halogen, nitro, the replacement of hydroxyl list or polysubstituted phenyl, benzyl) be acid amides I analog derivative of the present invention; When X is that (R is a C1-C6 straight or branched alkyl to OR; Allyl group; Methoxyl group, halogen, nitro, the replacement of hydroxyl list or polysubstituted phenyl, benzyl) be ester II analog derivative of the present invention; When X is that (R is a C1-C6 straight or branched alkyl to SR; Allyl group; Methoxyl group, halogen, nitro, the replacement of hydroxyl list or polysubstituted phenyl, benzyl) be thioesters III analog derivative of the present invention.
2, a kind of synthetic key intermediate with 4-β-carbon replacement-4-deoxidation-4 '-demethylated podophyllotoxin derivative of the anti-tumor activity of formula A as claimed in claim 1 is characterized in that representing with formula C:
3, a kind of synthetic method with 4-β-carbon replacement-4-deoxidation-4 '-demethylated podophyllotoxin derivative of the anti-tumor activity of formula A as claimed in claim 1, it is characterized in that this method comprises the following steps: that (1) is starting raw material with 4 '-demethyl epipodophyllotoxin, make catalyzer with boron trifluoride ethyl ether complex, in halogen-containing lower paraffin hydrocarbons, benzene or substituted benzene solvent, under 0～40 ℃ and Lewis acid catalysis condition, with potassium cyanide or front three cyano group silane reaction, main selectivity synthesizes 4-beta-cyano-4-deoxidation-4 '-demethylated podophyllotoxin B; (2) 4-beta-cyano-4-deoxidation-4 '-demethylated podophyllotoxin B reacted 0.5 hour down in 20～100 ℃ in containing hydrochloric acid or vitriolic acetic acid or acetone solvent, obtained Compound C; (3) in the triethylamine solvent, Compound C is prepared the acyl chlorides intermediate with thionyl chloride, need not separate, solvent evaporated adds the required amine NHR of reaction then respectively at normal temperatures
1R
2(R
1, R
2Be C1-C6 straight or branched alkyl, allyl group, methoxyl group, halogen, nitro, the replacement of hydroxyl list or polysubstituted phenyl, benzyl); (R is a C1-C6 straight or branched alkyl for alcohol or phenol ROH; Allyl group; Methoxyl group, halogen, nitro, the replacement of hydroxyl list or polysubstituted phenyl, benzyl); Mercaptan or thiophenol RSH (R is C1-C6 straight or branched alkyl, allyl group, methoxyl group, halogen, nitro, the replacement of hydroxyl list or polysubstituted phenyl, benzyl) and Et
3N or pyridine make compound.Reaction formula:
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|---|---|---|---|
| CN99119806A CN1101819C (en) | 1999-10-21 | 1999-10-21 | 4-beta-carbonsubstituted-4-deoxy-4'-demethylepi podophyllotoxin derivative with antineoplastic activity and its synthesis method |
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|---|---|---|---|
| CN99119806A CN1101819C (en) | 1999-10-21 | 1999-10-21 | 4-beta-carbonsubstituted-4-deoxy-4'-demethylepi podophyllotoxin derivative with antineoplastic activity and its synthesis method |
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|---|---|
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| CN1101819C true CN1101819C (en) | 2003-02-19 |
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ID=5281101
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| CN99119806A Expired - Fee Related CN1101819C (en) | 1999-10-21 | 1999-10-21 | 4-beta-carbonsubstituted-4-deoxy-4'-demethylepi podophyllotoxin derivative with antineoplastic activity and its synthesis method |
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|---|---|---|---|---|
| CN101314043B (en) * | 2007-05-29 | 2011-09-14 | 宁波大学 | Preparation method of podophyllinic acid lactone derivant |
| CN101314042B (en) * | 2007-05-29 | 2010-05-26 | 宁波大学 | Water-soluble 4'-nor-epipodophyllotoxin derivant and preparation method thereof |
| CN103351395B (en) * | 2013-07-12 | 2016-06-22 | 湖北工业大学 | Esterification podophyllum derivative with anti-tumor activity and its production and use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1059526A (en) * | 1990-08-27 | 1992-03-18 | 国家医药管理局上海医药工业研究院 | 4-sulphur replacement-4-deoxidation-4 '-demethylated podophyllotoxin derivative is synthetic |
| CN1064278A (en) * | 1991-01-25 | 1992-09-09 | 大鹏药品工业株式会社 | The salt that 4-deoxy-4-epipodophyllotoxin derivatives or its pharmaceutically allow |
| CN1154968A (en) * | 1995-12-04 | 1997-07-23 | 日本化药株式会社 | Process for prepn. of podophyllo ethylidene glucoside |
-
1999
- 1999-10-21 CN CN99119806A patent/CN1101819C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1059526A (en) * | 1990-08-27 | 1992-03-18 | 国家医药管理局上海医药工业研究院 | 4-sulphur replacement-4-deoxidation-4 '-demethylated podophyllotoxin derivative is synthetic |
| CN1064278A (en) * | 1991-01-25 | 1992-09-09 | 大鹏药品工业株式会社 | The salt that 4-deoxy-4-epipodophyllotoxin derivatives or its pharmaceutically allow |
| CN1154968A (en) * | 1995-12-04 | 1997-07-23 | 日本化药株式会社 | Process for prepn. of podophyllo ethylidene glucoside |
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