CN1781923A - Method for preparing 9-nitro-20(s)-camptothecine - Google Patents
Method for preparing 9-nitro-20(s)-camptothecine Download PDFInfo
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- CN1781923A CN1781923A CN 200410081350 CN200410081350A CN1781923A CN 1781923 A CN1781923 A CN 1781923A CN 200410081350 CN200410081350 CN 200410081350 CN 200410081350 A CN200410081350 A CN 200410081350A CN 1781923 A CN1781923 A CN 1781923A
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Abstract
The present invention provides a practical method of preparing 9-nitro camtothecine and the method has high selectivity and no need of chromatographic separation. The new anticancer medicine 9-nitro camtothecine is obtained in high selectivity by means of controlling the amount of the reductant, the reaction time, the reaction temperature and material feeding mode. The present invention also provides the intermediate and the destination product purifying method.
Description
Affiliated field
The invention relates to the method for preparing 9-nitro-20 (S)-camptothecine, belong to the organic synthesis field.
Background technology
Camptothecine is the micro-anti-cancer alkaloid that obtains from the peculiar Nyssaceae plant camptotheca acuminata of China.Because itself toxicity is too big, has limited its clinical application.Semisynthetic subsequently a series of camptothecin derivatives are because its unique biological active mechanism and good medicinal property become the PTS of having gone on the market or being in different development then.Camptothecin derivative has formed the very active chemicals of a big class.
New camptothecin derivative comprises water-insoluble derivative 9-amino-20 (S)-camptothecine and 9-nitro-20 (S)-camptothecine.Regrettably, although 9-amino-20 (S)-camptothecine shows anti-tumor activity in preclinical test, clinical test results is disappointing.Though 9-nitro-20 (S)-camptothecine has tangible toxic action, carcinoma of the pancreas there is good curative effect but still estimated.Carried out in the body and experiment in vitro to this water-insoluble 9-nitro-20 (S)-camptothecine, and the 9-nitrocamptothecin has been used for the clinical study of some cancer.European Union is used for the specifics of clinical treatment carcinoma of the pancreas with 9-nitro-20 (S)-camptothecine approval for Orphan drug, 9-nitro-20 (S)-camptothecine is expected to go on the market in the U.S. end of this year, and China also has producer to obtain the clinical official written reply of 9-nitro-20 (S)-camptothecine at present.
The preparation method of 9-nitro-20 (S)-camptothecine has total synthesis method and semisynthesis.(patent No. US4894456 US4981968) provides the method for complete synthesis 9-nitro-20 (S)-camptothecine to United States Patent (USP).But complete synthesis step is too many, and route is oversize, and synthetic cost is higher, and does not have economic advantages from semi-synthetic the comparing of camptothecine.1984 Japanese Patent (patent No. JP5951298) semisynthesis for preparing 9-nitro-20 (S)-camptothecine with the vitriol oil and the direct nitrated camptothecine of concentrated nitric acid is provided.The amount that this directly nitrated 20 (S)-camptothecine obtain activated 9-nitro-20 (S)-camptothecine seldom, the yield of target product has only 3%-7%, the nitration product major part is that another does not have active isomer 12-nitro-20 (S)-camptothecine.Although U.S. The Stehlin Foundation for Cancer Research was in the Chinese patents (patent No.: CN 1266435A) provide with the method for blended nitrate direct nitrated 20 (S)-camptothecine in the vitriol oil and the yield of 9-nitro-20 (S)-camptothecine can have been brought up to 20% in 2000, but, therefore still generate 12-nitro-20 (the S)-camptothecine of a large amount of non-activities because 9 activity of 12 ratios of camptothecine are higher.The existence of a large amount of 12-nitro-20 (S)-camptothecine brings sizable difficulty not only for separation and purifying, and the camptothecine that will waste a large amount of costlinesses simultaneously obtains isomeric compound 12-nitro-20 (the S)-camptothecine of another non-activity.The separation and purification process of this complexity and lower yield can not adapt to the industrial requirement that will obtain 9-nitro-20 (the S)-camptothecine of a great deal of.Therefore need a kind ofly can either improve 9-nitro-20 (S)-camptothecine preparation method that yield can be simplified treating processes again.
Gondola W. Ka Buli (Tetrahedron Letters 1995,36,9197) introduces activating group hydroxyl location, the product that obtains 9 nitrated in position that the position is single-minded when nitrated 10 of camptothecine.The inspiration that worked by they, (Tetrahedron Letters 1986,27,5541 simultaneously bibliographical information also; When Synthesis1995,1348) having nitro to exist on the aromatic ring, under palladium catalysis, hydroxyl can be removed optionally and nitro can not be reduced.We wish with this optionally method of reducing be used for the preparation of 9-nitro-20 (S)-camptothecine.The result proves that we have found a kind of simple and convenient while yield to prepare the method for 9-nitro-20 (S)-camptothecine preferably.
Summary of the invention
The purpose of this invention is to provide a kind of fast, high yield, be fit to the method for industrial synthesizing antitumor new drug 9-nitro-20 (S)-camptothecine.
The present invention is a starting raw material with natural 20 (S)-camptothecine, by introduce the electron distributions on the hydroxyl change camptothecine phenyl ring 10 of 20 (S)-camptothecine, thereby make when nitrated can the position single-minded 9 nitrated in position products that obtain, introduce the sulphonate of easily leaving away then on hydroxyl, the selective reduction dehydroxylation obtains target molecule 9-nitro-20 (S)-camptothecine under the palladium catalysis.
The objective of the invention is to realize by the following technical solutions:
Synthetic route of the present invention is as follows:
(1) 10 of camptothecine 9 of introducing hydroxyl activation camptothecine, thus realized that the position is incorporated into nitro 9 single-mindedly when nitration reaction takes place.Thereby solved when direct nitrated camptothecine not optionally problem.
(2) in nitration reaction, promptly when 9 introducing nitros of III, the present invention has adopted multiple nitrated system.(a): nitrate and sulfuric acid share, and used nitrate has saltpetre, SODIUMNITRATE, nitric acid ammonia, magnesium nitrate, cupric nitrate, iron nitrate etc.; Used sulfuric acid concentration is that 20% sulphuric acid soln is to the vitriol oil.(b): nitrosonitric acid and solvent share, and comprise that nitrosonitric acid and glacial acetic acid share, and nitrosonitric acid and chloroform, DMF share.(c): salpeter solution comprises that concentration is 15% to 65% salpeter solution.
The nitration product IV that obtains handles through simple, does not need purifying just can carry out next step reaction.Experimental results show that this step not purifying not only can not influence next step reaction, and simplified entire test.
(3) the easy leavings group of Cai Yonging is the sulphonate of various replacements, and promptly the XO-on the formula V is a sulphonate.The X group is R-SO
2-, wherein R comprises perfluor or polyfluoro or the floride-free C that replaces
1-C
4Alkyl and the phenyl or naphthyl of replacement.
Used organic bases comprises C when introducing sulphonate
1-C
4Alkylamine or DMAP in a kind of or in them any both use with.
The crude product V that obtains directly uses ethyl acetate and sherwood oil recrystallization purifying.
(4) the catalytic reduction decarboxylation reaction of palladium is the important organic reaction of a class.The present invention has studied this reaction in great detail, has obtained gratifying result.
(a) solvent that adopted of reduction is DMF or glycol dimethyl ether or ethylene glycol diethyl ether or dioxane, wherein with dioxane the best.
(b) hydrogen source used of reduction reaction is the ammonia salt of formic acid and formic acid.The feed way of reductive agent is for dripping.The dropping time is 1 hour to 5 hours.
(c) consumption of reductive agent be 1 equivalent to 2 equivalents, wherein optimum amount is 1.1 equivalents.
(d) temperature of reaction has very big influence to reduction reaction.The reduction reaction selectivity is fine in the time of 70 ℃, reacts very complete, only is reduced less than 1% nitro simultaneously.
(e) the used palladium of reduction reaction is a palladium, and part is DPPF.
After reacting completely through simple extraction, washing, drying, the thick product that obtains after concentrating obtains pure product 9-nitro-20 (S)-camptothecine with ethyl acetate and sherwood oil recrystallization.
Embodiment
Be embodiments of the invention below:
Embodiment one:
10-hydroxyl-20 (S)-camptothecine
With 2 grams, 20 (S)-camptothecine, 20ml glacial acetic acid, 0.2 gram PtO
2And the autoclave of 2 dimethyl sulfoxide (DMSO) adding 100ml.6 kilograms of pressure of hydrogen, 60 ℃ were reacted 12 hours.Filter, add the 20ml deionized water in the filtrate, disposable adding iodobenzene diacetate 4.8 grams, room temperature reaction spends the night.Filter, solid drying obtains 10-hydroxyl-20 (S)-camptothecine 1.43 grams, yield 70%.
H
1NMR(DMSO-d
6)，δppm：0.86(3H，t)；1.84(2H，q)；5.21(2H，s)；5.40(2H，s)；6.54(1H，s)；7.25(1H，s)；7.26(1H，d)；7.41(1H，q)；8.00(1H，d)；8.43(1H，s)；10.42(1H，s).
Embodiment two:
10-hydroxyl-9-nitro-20 (S)-camptothecine
(method A)
0.365 gram 10-hydroxyl-20 (S)-camptothecine is suspended in the glacial acetic acid of 10ml, is added dropwise to the nitrosonitric acid of 80ul, room temperature reaction spends the night.Add 100ml water, have a large amount of solids to separate out, filter, dry that 10-hydroxyl-9-nitro-20 (S)-camptothecine 0.342 restrains yield 83.4%, HPLC, 93%.
(method B)
0.365 gram 10-hydroxyl-20 (S)-camptothecine is dissolved in 30% the dilute sulphuric acid, adds saltpetre 0.5 gram, room temperature reaction spends the night, and chloroform extraction gets 10-hydroxyl-9-nitro-20 (S)-camptothecine 0.3 gram, yield 73%.
H
1NMR(CDCl
3)，δppm：1.05(3H，t)；1.89(2H，q)；3.74(1H，s)；5.36(2H，s)；5.50(2H，dd)；7.61(1H，s)；7.65(1H，s)；8.40(1H，d)；9.54(1H，s)；12.20(1H，s).
Embodiment three:
9-nitro-10-(tolysulfonyl oxygen base)-20 (S)-camptothecine
0.409 gram 9-nitro-10-hydroxyl-20 (S)-camptothecine is suspended in the methylene dichloride of 50ml, adds 0.21 gram triethylamine, the solid dissolving, room temperature adds Tosyl chloride 0.2 gram.Room temperature reaction 24 hours, dichloromethane extraction is used 0.5 normal hydrochloric acid respectively, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, distillation removes desolvates to such an extent that 9-nitro-10-(tolysulfonyl oxygen base)-20 (S)-camptothecine 0.48 restrain yield 83%.
H
1NMR(CDCl
3)，δppm：1.05(3H，t)；1.90(2H，q)；2.48(3H，s)；3.87(3H，s)；5.30(2H，s)；5.50(2H，dd)；7.38(2H，d)；7.68(1H，s)；7.81(2H，d)；7.95(1H，d)；8.31(1H，s)；8.41(1H，d).
Embodiment four:
9-nitro-10-(mesyloxy)-20 (S)-camptothecine
As described in embodiment three, react, replace Tosyl chloride to react, obtain 9-nitro-10-(mesyloxy)-20 (S)-camptothecine yield 59% with methylsulfonyl chloride.
H
1NMR(CDCl
3)，δppm：1.05(3H，t)；1.92(2H，q)；3.39(3H，s)；3.75(2H，s)；5.36(2H，s)；5.50(2H，dd)；7.70(1H，s)；8.02(1H，d)；8.46(2H，d).
Same method obtains
9-nitro-10-(p-nitrophenyl sulfonyloxy)-20 (S)-camptothecine;
H
1NMR(CDCl
3)，δppm：1.04(3H，t)；1.89(2H，q)；3.74(1H，s)；5.31(2H，s)；5.50(2H，dd)；7.69(1H，s)；8.05(1H，d)；8.15(2H，d)；8.25(1H，s)；8.43(2H，d)；8.49(1H，s).
9-nitro-10-(to the methoxyl group sulfonyloxy)-20 (S)-camptothecine;
H
1NMR(CDCl
3)，δppm：1.04(3H，t)；1.92(2H，q)；3.85(1H，s)；3.91(3H，s)；5.31(2H，s)；5.50(2H，dd)；7.02(2H，d)；7.66(1H，s)；7.86(2H，d)；7.98(1H，d)；8.32(1H，s)；8.41(1H，d).
9-nitro-10-(phenylsulfonyloxy)-20 (S)-camptothecine,
H
1NMR(CDCl
3)，δppm：1.04(3H，t)；1.93(2H，q)；3.79(1H，s)；5.31(2H，s)；5.50(2H，dd)；7.60(2H，t)；7.69(1H，s)；7.76(1H，t)；7.99-7.92(3H，m)；8.31(1H，s)；8.41(1H，d).
9-nitro-10-(brosyl oxygen base)-20 (S)-camptothecine,
H
1NMR(CDCl
3)，δppm：1.04(3H，t)；1.89(2H，q)；3.77(1H，s)；5.31(2H，s)；5.50(2H，dd)；7.69(1H，s)；7.81-7.72(4H，m)；7.99(1H，d)；8.32(1H，s)；8.43(1H，d).
9-nitro-10-(to the fluorine sulfonyloxy)-20 (S)-camptothecine;
H
1NMR(CDCl
3)，δppm：1.12(3H，t)；1.87(2H，q)；3.77(1H，s)；5.31(2H，s)；5.50(2H，dd)；7.28(2H，s)；7.69(1H，s)；8.02-7.94(3H，m)；8.31(1H，s)；8.43(1H，d).
9-nitro-10-(naphthalene sulfonyl oxygen base)-20 (S)-camptothecine.
H
1NMR(CDCl
3)，δppm：1.03(3H，t)；1.90(2H，q)；3.75(1H，s)；5.27(2H，s)；5.50(2H，dd)；7.52(1H，t)；7.65(1H，s)；7.78-7.57(3H，m)；8.03(1H，d)；8.23(3H，t)；8.32(1H，d)；8.74(1H，d).
Embodiment five:
9-nitro happiness-20 (S)-tree alkali
With 9-nitro-10-(tolysulfonyl oxygen base)-20 (S)-irinotecan .2mg, Pd (AcO)
20.46mg DPPF1.24mg, 2mlDMF add in the 5ml single necked round bottom flask, the Ar gas shiled, and 70 ℃ of mixed liquid that drip triethylamine 6.1mg and formic acid 2.76mg react 1 hour raw material and disappear.Entire reaction is very complicated from TLC, does not further handle.
Embodiment six:
9-nitro-20 (S)-camptothecine
With 9-nitro-10-(mesyloxy)-20 (S)-camptothecine 98mg, Pd (AcO)
24.6mg DPPF12.4mg, 20ml dioxane add in the 50ml single necked round bottom flask, the Ar gas shiled, and 70 ℃ of mixed liquid that drip triethylamine 61mg and formic acid 27.6mg react after 2 hours.Distill dioxane, ethyl acetate extraction is used the hydrochloric acid of 0.5eq respectively, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, distillation is removed solvent and is got thick product, thick product with an amount of must ethyl acetate and the sherwood oil recrystallization get pure product 9-nitro-20 (S)-camptothecine 63mg, yield 82%
H
1NMR(CDCl
3)，δppm：1.04(3H，t)；1.91(2H，q)；3.97(1H，s)；5.37(2H，s)；5.56(2H，dd)；7.71(1H，s)；7.90(1H，t)；7.45(1H，d)；8.54(1H，d)；9.25(1H，s).
Embodiment seven:
9-nitro-20 (S)-camptothecine
With 9-nitro-10-(phenylsulfonyloxy)-20 (S)-irinotecan 0mg, Pd (AcO)
24.6mg DPPF12.4mg, 20ml dioxane add in the 50ml single necked round bottom flask, the Ar gas shiled, and 70 ℃ of mixed liquid that drip triethylamine 61mg and formic acid 27.6mg react after 2 hours.Distill dioxane, ethyl acetate extraction is used the hydrochloric acid of 0.5eq respectively, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, distillation is removed solvent and is got thick product, thick product with an amount of must ethyl acetate and the sherwood oil recrystallization get pure product 9-nitro-20 (S)-camptothecine 66mg, yield 85%.
Embodiment eight:
9-nitro-20 (S)-camptothecine
With 9-nitro-10-(tolysulfonyl oxygen base)-20 (S)-irinotecan 0mg, Pd (AcO)
24.6mg DPPF12.4mg, 20ml dioxane add in the 50ml single necked round bottom flask, the Ar gas shiled, and 70 ℃ of mixed liquid that drip triethylamine 61mg and formic acid 27.6mg react after 2 hours.Distill dioxane, ethyl acetate extraction is used the hydrochloric acid of 0.5eq respectively, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, distillation is removed solvent and is got thick product, thick product with an amount of must ethyl acetate and the sherwood oil recrystallization get pure product 9-nitro-20 (S)-camptothecine 68mg, yield 88%.
Embodiment nine:
9-nitro-20 (S)-camptothecine
With 9-nitro-10-(p-nitrophenyl sulfonyloxy)-20 (S)-irinotecan 8mg, Pd (AcO)
24.6mg DPPF12.4mg, 20ml dioxane add in the 50ml single necked round bottom flask, the Ar gas shiled, and 70 ℃ of mixed liquid that drip triethylamine 61mg and formic acid 27.6mg react after 2 hours.Distill dioxane, ethyl acetate extraction is used the hydrochloric acid of 0.5eq respectively, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, distillation is removed solvent and is got thick product, thick product with an amount of must ethyl acetate and the sherwood oil recrystallization get pure product 9-nitro-20 (S)-camptothecine 67mg, yield 87%.
Embodiment ten:
9-nitro-20 (S)-camptothecine
With 9-nitro-10-(to the anisole sulfonyloxy)-20 (S)-irinotecan 6mg, Pd (AcO)
24.6mg DPPF12.4mg, 20ml dioxane add in the 50ml single necked round bottom flask, the Ar gas shiled, and 70 ℃ of mixed liquid that drip triethylamine 61mg and formic acid 27.6mg react after 2 hours.Distill dioxane, ethyl acetate extraction is used the hydrochloric acid of 0.5eq respectively, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, distillation is removed solvent and is got thick product, thick product with an amount of must ethyl acetate and the sherwood oil recrystallization get pure product 9-nitro-20 (S)-camptothecine 65mg, yield 84%.
Embodiment 11:
9-nitro-20 (S)-camptothecine
With 9-nitro-10-(1-naphthalene sulfonyl oxygen base)-20 (S)-camptothecine 120mg, Pd (AcO)
24.6mg DPPF12.4mg, 20ml dioxane add in the 50ml single necked round bottom flask, the Ar gas shiled, and 70 ℃ of mixed liquid that drip triethylamine 61mg and formic acid 27.6mg react after 2 hours.Distill dioxane, ethyl acetate extraction is used the hydrochloric acid of 0.5eq respectively, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, distillation is removed solvent and is got thick product, thick product with an amount of must ethyl acetate and the sherwood oil recrystallization get pure product 9-nitro-20 (S)-camptothecine 68mg, yield 88%.
Claims (7)
1. method for preparing 9-nitro-20 (S)-camptothecine, it is characterized in that: with natural camptothecine is raw material, synthetic through following step:
A) with the pyridine ring of the natural camptothecine of platinum dioxide catalytic hydrogenation, after the iodobenzene diacetate oxidation, obtain 10-hydroxycamptothecine;
B) nitrated 10-hydroxycamptothecine obtains 9-nitro-10-hydroxycamptothecine;
C) 9-nitro-10-hydroxycamptothecine and SULPHURYL CHLORIDE are reflected on 10 hydroxyls of camptothecine and introduce alkylsulfonyl;
D) sulfonyloxy on the selective reduction camptothecine obtains target molecule 9-nitrocamptothecin.
2. the synthetic method of 9-nitro-10-hydroxycamptothecine according to claim 1 is characterized in that with 10-hydroxycamptothecine in room temperature and one of following nitrated system: a) nitrate and 20% sulphuric acid soln are to the mixed solution of the vitriol oil; B) mixed solution of nitrosonitric acid and glacial acetic acid; C) mixed solution of nitrosonitric acid and chloroform or DMF; D) 10%～65% salpeter solution; Reaction obtains 9-nitro-10-hydroxycamptothecine.
3. the alkylsulfonyl synthetic method of introducing on 10 hydroxyls of camptothecine according to claim 1, it is characterized in that: 9-nitro-10-hydroxycamptothecine is at C
1-C
4Alkylamine or a kind of or any two kinds of mixed catalytics in them among the DMAP under, be solvent with the methylene dichloride, obtain with the SULPHURYL CHLORIDE reaction.
4. the alkylsulfonyl of introducing on 10 hydroxyls of camptothecine according to claim 3, it is characterized in that: alkylsulfonyl is R-SO for containing various substituent sulfonic groups
2-, wherein R comprises perfluor or polyfluoro or the floride-free C that replaces
1-C
4Alkyl and the aryl or the naphthyl of replacement.
5. according to the described crude product 9-nitro of claim 3-10-sulfonyloxy-camptothecine ethyl acetate and sherwood oil recrystallization purifying.
6. the synthetic method of 9-nitrocamptothecin according to claim 1 is characterized in that when selective reduction 9-nitro-10-sulfonyloxy-camptothecine obtained target molecule 9-nitrocamptothecin, the catalyzer of reduction reaction was a palladium, and part is DPPF; The hydrogen source that reduction reaction is used is formic acid and formic acid ammonium salt; The amount of used reductive agent is that 1 equivalent is to 2 equivalents; The adding mode of reductive agent is for dropwising; Reaction times is 1 hour to 5 hours; Corresponding temperature of reaction is 20 ℃ to 80 ℃; Select a kind of for solvent in DMF or glycol dimethyl ether or ethylene glycol diethyl ether or the dioxane for use.
7. the target molecule 9-nitrocamptothecin that obtains according to claim 6 obtains pure product with ethyl acetate and sherwood oil recrystallization.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046634A (en) * | 2008-05-29 | 2011-05-04 | 美露香株式会社 | Production method for camptothecin derivative |
| CN103130814A (en) * | 2011-11-25 | 2013-06-05 | 上海医药工业研究院 | Two types of 9-nitro comptothecin novel crystal forms and preparation method thereof |
| CN104628737A (en) * | 2015-01-28 | 2015-05-20 | 华南理工大学 | Two novel crystal forms of 9-nitrocamptothecin and preparation methods thereof |
-
2004
- 2004-11-29 CN CN 200410081350 patent/CN1781923A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102046634A (en) * | 2008-05-29 | 2011-05-04 | 美露香株式会社 | Production method for camptothecin derivative |
| CN102046634B (en) * | 2008-05-29 | 2013-04-24 | 日本迈科洛生物制药有限公司 | Production method for camptothecin derivative |
| CN103130814A (en) * | 2011-11-25 | 2013-06-05 | 上海医药工业研究院 | Two types of 9-nitro comptothecin novel crystal forms and preparation method thereof |
| CN104628737A (en) * | 2015-01-28 | 2015-05-20 | 华南理工大学 | Two novel crystal forms of 9-nitrocamptothecin and preparation methods thereof |
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