CN1222523A - Process for preparation of 9-amino camptothecin - Google Patents
Process for preparation of 9-amino camptothecin Download PDFInfo
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Abstract
9-Amino-20(S)-camptothecin is prepared by reducing 12-nitro-20(S)-camptothecin (II); converting the resulting 12-amino-20(S)-camptothecin (III) into a compound of formula (IV)whereinX is a group which can be reductively removed; reacting the compound of formula (IV) with a nitrating agent, to obtain thereby the corresponding 9-nitro-20(S)-camptothecin compound of formula (V) substituted at the 12-position by the group X; reducing in a single step the compound of formula (V), so obtaining the 9-amino-20(S)-camptothecin of formula (I); or reducing the compound of formula (V), so obtaining the corresponding 9-amino-20(S)-camptothecin compound of formula (VI) substituted at the 12-position by the group X and reductively removing the X group from the compound of formula (VI), so obtaining 9-amino-20(S)-camptothecin.
Description
The present invention relates to intermediate that is used for production formula (1) 9-amino-20-(s)-camptothecine and preparation method thereof:
It is a kind of known anticarcinogen: Wani etc., J, Med.Chem.1987,30,1774-1779; Hsiang etc., Cancer, Rew.49,4385-4389, August 15,1989; Can-cer Res.49,1465-1469, March 15,1989.
Total synthesis method for 9-aminocamptothecin is extensively described (US-A-4,894,456 and US-A-5,053,512).Yet this product complete synthesis not only undesirable but also be not suitable for scale operation because it comprises too many intermediate steps, not only makes synthetic oversizely, and especially makes synthetic expensive.
Semi-synthetic 9-aminocamptothecin is existing to be described, for example in disclosed JP-A-59-51289 in 1984, initial from the natural product camptothecine: Cancer ChemotherapyReports part 1,54 volume, the 6th phase, in December, 1970,461-470; J.Med.Chem.,, 1980,23,554-560; Science, 246 volumes, in November, 1989,1046-1048.This semisynthesis comprises the nitrated of natural product camptothecine, reduces the 9-nitro-derivative subsequently.Yet, 70/30 mixture of this nitrated camptothecin derivative (30%) that originally produces unwanted 12-nitro base tree alkali derivant (70%) and need.Therefore only generate a spot of 9-nitro-derivative.
After separating two kinds of nitration products, the active 12-nitro-derivative of own lifeless matter (seeing: Wani C. for example, Nicholas A.W., Wall M.E., J.Med.Chem., 1986,29,2358) then must discharging, and this will cause waste disposal problem.About the critical defect of removing unwanted 12-nitro-derivative byproduct especially relevant with scale operation because need to collect and remove a large amount of useless 12-nitro-derivatives.
And, after the semisynthesis, need the natural camptothecine of mass expensive so that produce a small amount of required anticarcinogen 9-aminocamptothecin.The low overall yield of this method makes a large amount of required compound of generation become difficult.Therefore need a kind of method that improves productive rate than the semi-synthetic 9-aminocamptothecin method of above-mentioned summary.
We have developed a kind of novel method that satisfies this purpose, and the waste product that the 12-nitrocamptothecin that having solved is not simultaneously needed by continuous generation constant causes is handled problems.According to the present invention, this 12-nitro-derivative is recycled and enters present method by being transformed into 9-aminocamptothecin under easy and mild reaction conditions, obtains high yield and the reaction product that cleans.
Therefore, the invention provides and a kind ofly prepare the novel method of the 9-aminocamptothecin of formula I from the 12-nitrocamptothecin of formula II, its step is scheme I illustrated below: the scheme I
Wherein X is a kind of reducible group of removing.
This method comprises the 12-aminoderivative that the 12-nitro-derivative reduction of formula II is changed into formula III.This intermediate is transformed into corresponding diazo compound derivative successively, and it is transformed into the compound of formula IV on the spot, and wherein X is a kind of reducible group of removing such as a kind of halogen atom.
Getting of the 12-derivative of nitrated formula IV has highly selective, and produces corresponding formula (V) 9-nitro-12-substitutive derivative.The compound of reduction-type (V) subsequently, obtain the 9-aminocamptothecin of formula I, can directly obtain the compound of formula I a step, or also can obtain the formula I compound in two steps, at first the compound of a kind of formula (V) is reduced into a kind of compound of formula VI, then, a kind of compound of formula VI is reduced into a kind of compound of formula I.The compound of formula VI can separate.
(for example see Chem.pharm among the JP-A-59-51289 that quotes and at the document of publishing in the above, Bull.1991,39, a lot of Chemical Problem about camptothecin molecule are disclosed 3183), comprise 12-amino is transformed into corresponding 12-halo derivatives, but it only is used for being used on the synthetic biology purpose of the compound estimated.Biologically useless (for example the seeing Crow, R.T., Crothers, D.M.J.Med.Chem.1992,35,4160) of 12 substitution compounds and chemical difficulty have stoped other any effort that may change to 12-substituted camptothecin derivative.
Especially, it is not known introducing nitro on this molecule 1 2-substitutive derivative, and seems to be a problem, because it may cause the mixture of derivative: in fact, the different positions of member ring systems may react.
And, for the X base of removing compound (V) or (VI), must emphasize: though halogen atom is removed in the quinoline in reduction is well-knownly (for example to see Jones, G. chemistry of heterocyclic compound, 32, I.P.604-611), wherein in general exist alkali to be considered to favourable, so that obtain gentle reaction conditions, on the contrary, although the camptothecine Chemical Problem has been carried out the effort in several years, also do not know how to remove the group (for example removing halogen group) of camptothecin derivative, say nothing of and know that camptothecin derivative is extremely responsive to alkali, it will be debatable therefore relying on alkali.
Surprisingly, we find now: can remove for example halogen atom in the presence of the organic or inorganic non-nucleophilic base from camptothecine.The present invention includes this respect and also based on the utmost point weakly alkaline of observing 9-amino in the camptothecin molecule and nucleophilic character.Really, the 9-nitro in reduction-type (V) 9-nitro-12-substitutive derivative will produce 9-amino functional degree, and so the 9-amino that forms can be used as the weak non-nucleophilic base that the original place produces then, and promote reduction to remove the X base in principle, and not decompose.
On the other hand, in formula (V) compound, exist two substituting groups can expect that undesirable influence will be arranged in the contraposition each other, hinder two recovery steps or make it become difficult; Can expect the low-yield or the decomposition of required product.In any case, above the complete synthesis signal scheme of association reaction order never reported, be not familiar with in the past yet or develop its potential application.
The invention provides a kind of method for preparing the formula I 9-aminocamptothecin,
This method comprises: the compound of (1) reduction formula II
So obtain the compound of formula III
(2) compound of formula III is transformed into a kind of compound of formula IV
Wherein X is the reducible group of removing; (3) a kind of compound of formula IV and a kind of nitrating agent react, and obtain the compound of a kind of formula (V)
The compound of X such as top definition and a kind of formulas of (4) one step reduction (V) wherein obtains the 9-aminocamptothecin of formula I, or also can (5) reduces the compound of a kind of formula (V), obtains the compound of formula VI
Wherein the X base in the formula VI compound is removed in X such as top definition and (6) reduction, obtains the 9-aminocamptothecin of formula I.
The X base is preferably a kind of halogen, as Cl, and I, Br or F, more preferably Cl or Br.
For example available suitable reductive agent or in the presence of suitable reductive agent, by catalytic reduction the compound of formula II is reduced into the compound of formula III with suitable catalyzer.For example, can be according to J.March, Advanced Organic Chemistry, is described in 1103 and is carried out by the 3rd edition.For example, approximately-20 ℃ to about 60 ℃ at appropriate solvent such as rare or dense moisture HCl, rare moisture protonic acid, water, ethanol, methyl alcohol, or in its mixture with reductive agent such as SnCl
2, or other metal or metal-salt and Zn or Fe and salt thereof can reduce several minutes to for some time of several days as from about 5 minutes to about 3 days, as from 4 hours to 24 hours; Or about 0 ℃ under about 100 ℃ a certain temperature about 1atm under the pressure of about 100atm at appropriate solvent such as dimethyl formamide (DMF), MeOH, acetate, CHCl
3In ， diox or its mixture at hydrogen molecule or hydrogen source such as formic acid triethyl ammonium, formic acid, three times basic stannic hydrides, cyclohexadiene etc. exist down, by using the catalytic amount metal such as the palladium of reduction nitro, platinum oxide, platinum, rhodium or ruthenium reduce for some time, as from several minutes as 5 minutes to H
2Stop to consume as about 3 days.
With a kind of suitable reagent such as a kind of copper halide (I) by generating the compound that does not need from reaction mixture isolating a kind of diazo compound derivative the compound of formula III can be transformed into a kind of formula IV, in approximately-20 ℃ under about 100 ℃ temperature with suitable diazo reagent such as NaNO
2Or moisture rare protonic acid such as HCl, HBr or H
2SO
4In or the organic nitrite acidizing thing in organic solvent can carry out diazotization reaction for some time, can be from several minutes by several hours, as from about 5 minutes to about 24 hours.Then the about 0 ℃ solution of choosing gained in the presence of the corresponding haloid acid that can be used for solvent under about 100 ℃ a certain temperature wantonly can with from stoichiometric quantity to a large amount of excessive as excessive nearly 10-doubly the copper halides (I) of mole as CuCl or CrBr reaction, or with iodide ion reaction for some time, can be from several minutes to 1 day for example from about 5 minutes to about 1 day.
Can approximately-20 ℃ under about 100 ℃ a certain temperature with nitrating agent such as nitric acid, nitric acid and vitriolic mixture or other nitrating agent such as saltpetre or nitric acid and boron trifluoride such as boron trifluoride monohydrate (are for example seen Olah, G.A. wait Synthesis 1085,1992), or nitric acid/trifluoromethanesulfanhydride anhydride (ibid, 1087,1992) nitrated formula IV compound for some time obtains the compound of formula (V), time can be from several minutes by several days, as from about 5 minutes to about 3 days, as from about 4 hours to about 24 hours.
In about 0 ℃ under about 100 ℃ a certain temperature from 1atm under about 100atm pressure, choose any one kind of them mineral alkali or organic bases exist down at appropriate solvent such as DMF, MeOH, acetate, CHCl
3The ， diox, or in its mixture in the presence of the suitable catalyzer or under the homogeneous phase condition as in the presence of palladium or platinum salt and suitable phosphorus or nitrogen ligand or under heterogeneous conditions as at palladium, platinum oxide, platinum, existence such as rhodium or ruthenium descend or are suspended on the suitable medium as on carbon, at CaCO
3On, at BaSO
4On, on aluminum oxide or the like with suitable reductive agent such as hydrogen molecule or triethylammonium formate, formic acid, tri-butyl tin hydride, cyclohexadiene, or the like can be reduced into the compound of formula I a kind of compound one step of formula (V), the recovery time can be from about 1 hour to about 3 days.
When with two steps the compound of formula (V) being reduced into the formula I compound in addition, can carry out the first step short period with those reductive agents of a suitable reductive agent such as above-mentioned step reduction-type (V) compound, as from several minutes by several hours, for example from about 5 minutes to about 24 hours, if desired, the intermediate that separates formula VI carries out second step reduction formula VI compound according to the identical reduction step of above-mentioned step reduction-type (V) compound then; Perhaps at appropriate solvent such as benzene, toluene, CHCl
3, propionitrile, DMF, or in its mixture radical initiator as 2,2 '-Diisopropyl azodicarboxylate (AIBN) or three (trimethylammonium) silane (tristrimethyl-silane) or the like exist the reagent that utilizes free radical to eliminate halogen atom down as just-Bu
3SnH carry out second the step, temperature can be from room temperature to the solvent refluxing temperature, the time from several minutes by several hours, for example from about 5 minutes to about 24 hours.
The reductive agent that preferably compound of formula II is reduced into the formula III compound for example is the SnCl in rare or dense moisture HCl
2, temperature is from about 0 ℃ to about 60 ℃, and the time was from about 1 hour to about 2 days; Perhaps by catalytic reduction, 5% or 10%Pd/C and DMF in molecular hydrogen, or PtO
2And molecular hydrogen, to about 60 ℃, the time is from about 1 hour to about 24 hours from room temperature for temperature, hydrogen pressure from about 1atm to about 10atm.
The reagent that preferably the formula III compound is transformed into the formula IV compound for example is NaNO
2, amyl nitrite, nitrite tert-butyl, or organic nitrite acidizing thing are at moisture or organic solvent such as dense HCl or HBr, rare HCl or HBr, DMF ， diox or CH
2Cl
2In, to about 60 ℃, the time was from about 10 minutes to about 12 hours from approximately-20 ℃ for temperature.The solution of gained then can with from the normal copper halide of stoichiometric quantity to 10 (I) as CuCl or CrBr reaction, or react with iodide ion, preferably can be used as in the presence of the corresponding aqueous solution of halogen acid of solvent, temperature from room temperature to about 80 ℃, time can be from several minutes by several hours, as from about 5 minutes to about 12 hours.
The reagent that preferably the formula IV compound is changed an accepted way of doing sth (V) compound is nitric acid, or nitric acid and vitriolic mixture, or saltpetre, or nitric acid and boron trifluoride monohydrate, or nitric acid/trifluoromethanesulfanhydride anhydride, temperature from approximately-20 ℃ to about 60 ℃, the time from several minutes by several hours, for example from about 5 minutes to about 24 hours.
The reductive agent that one step of preferred formula (V) compound is reduced into the formula I compound is a molecular hydrogen, triethylammonium formate, and formic acid, or cyclohexadiene, at suitable catalyzer such as palladium, platinum oxide, platinum and rhodium or the like exist following or are supported in carbon, CaCO
3, BaSO
4, in silica or the aluminum oxide, at appropriate solvent such as DMF, MeOH, acetate, CHCl
3The diox, or in its mixture, choose wantonly in suitable organic bases such as pyridine or 2,6-alkyl disubstituted pyridines is as 2,6-lutidine etc., or existence such as mineral alkali such as yellow soda ash or lime carbonate down, and to about 80 ℃, the time was from about 1 hour to about 2 days from about room temperature for temperature, pressure from about 1atm to about 50atm, more preferably from about 1atm to about 10atm.
When using alternative method, when going on foot reduction-type (V) compound with two, preferred the first step reagent is identical with those reductive agents of above-mentioned step reduction-type (V) compound, the reduction short period, as from several minutes as 5 minutes to about 6 hours, if desired, separate the formula VI midbody derivant, the identical also step the second according to above-mentioned step reduction-type (V) compound goes on foot reduction formula VI compound then.
The reagent that preferred free radical is eliminated halogen for just-Bu
3SnH, at radical initiator such as AIBN, or three (trimethylammonium) silane etc. exists down, at appropriate solvent such as benzene, toluene, CHCl
3, propionitrile, DMF, or its mixture exists down, temperature is from room temperature to the solvent refluxing temperature, the time from several minutes by several hours, as from 5 minutes to 24 hours.
Gentle reaction conditions is the feature of the inventive method, makes the formula II Compound C
20(s) configuration on the position is retained on the 9-aminocamptothecin of final compound formula I.
The starting compound of formula II is a known compound, can prepare with currently known methods.
The present invention also comprises the method for preparing the formula I 9-aminocamptothecin in its scope, comprising: (a) camptothecine of nitration (VII)
Obtain 9-nitro-20-(s)-camptothecine and 12-nitro-2-(s)-camptothecine; (b) from 12-nitro-20-(s)-camptothecine, separate 9-nitro-2-(s)-camptothecine; (c) therefore reduction isolating 9-nitro-20 (s)-camptothecine generates 9-amino-20 (s)-camptothecine; (d) isolating 12-nitro-20 (s)-camptothecine is recycled to this method steps (1) in (4) or method steps (1) to (3), in (5) and (6), so generate 9-aminocamptothecin.
Another object of the present invention is the method for preparing following formula (VII) camptothecine, and it comprises that the X base is removed in reduction from last formula IV compound.
Can be by the suitable reductive agent of use such as molecular hydrogen or triethylammonium formate, formic acid, cyclohexadiene etc., at suitable catalyzer such as palladium, platinum oxide, platinum, rhodium or ruthenium etc. exist down, or are supported in suitable medium such as carbon, CaCO
3, BaSO
4, on the aluminum oxide etc., at appropriate solvent such as DMF, MeOH, acetate, CHCl
3The diox, or in its mixture, suitably organic three as pyridine or 2,6-alkyl disubstituted pyridines is as 2, and 6-lutidine etc. exist down, from about 0 ℃ under about 100 ℃ temperature, eliminated about 1 hour to about 3 days in the reduction of following the X of formula IV compound base of the pressure from about 1atm to about 100atm, obtain the camptothecine of formula (V II).
When X was halogen in the formula IV compound, preferred reductive agent was a molecular hydrogen, triethylammonium formate, and formic acid or cyclohexadiene, at suitable catalyzer such as palladium, platinum oxide, platinum and ruthenium etc. exist down, or are supported in carbon, CaCO
3, BaSO
4, on silica or the aluminum oxide, at DMF, MeOH, acetate, CHCl
3The ， diox, or in its mixture, arrive under about 80 ℃ temperature in about room temperature, recovery time from about 1 hour by about 24 hours, at organic bases, preferred pyridine, 2, the 6-lutidine exists down, arrives about 50atm at about 1atm, more preferably under about pressure of 1 to about 10atm.
The camptothecine of the 9-aminocamptothecin of formula I and formula (VII) is useful as the inhibitor of topoisomerase I (topoisomerate I).It is used for the treatment of cancer, especially leukemia, colorectal carcinoma and the rectum cancer.Therefore this compounds can be used for improving patient's state of an illness of suffering from this certain cancer of class.They also can be used to alleviate this class cancer.
Therefore can need be to the host by it, typical people feeds the 9-oxygen base camptothecine or the camptothecine of significant quantity.Can feed active compound by suitable approach such as oral or parenteral such as intravenously, can be to 0.1 to 60mg active compound by these approach to the patient of every kg body weight.The preferred dosage scope is every kg body weight 1 to 40mg.
Be the administration purpose, the camptothecine of the 9-aminocamptothecin of formula I or formula (VII) can be mixed with pharmaceutical composition with pharmaceutical carrier or thinner.According to the administration route, can use any appropriate carriers or thinner.Suitably the composition of type is recorded among US-A-5106742 and the WO91/05556.
Following embodiment illustrates The compounds of this invention and intermediates preparation, does not limit the scope of the invention.Embodiment 112-amino-20 (s)-camptothecine
In 12-nitro-20 (s)-stirred solution/suspension of camptothecine (20g) in dense HCl (300ml), add anhydrous SnCl in 0-5 ℃
2(41.9 gram), the gained mixture continues stirring and spends the night under room temperature then.Cross filter solid, wash with a small amount of dense HCl.Yellow solid is suspended in the water, with the sodium bicarbonate solid that adds in batches pH is transferred to and is approximately 2.Solid collected by filtration washes with water to neutrality, washes with ethanol and ether then.Obtain 10.5 gram title compounds after the drying.
1NMR(DMSO-d
6),δppm:0.88(3H,t,J=7.2?Hz)；1.83
(2H,m)；5.22(2H,s)；5.40(2H,
s)；6.19(2H,bs)；6.50(1H,s)
6.9-7.4 (3H, m); 8.44 (1H, s). embodiment 212-amino-20 (s)-camptothecine
Under normal atmosphere and the room temperature in the presence of 10%Pd/C (0.25 gram) solution of hydrogenation 12-nitro-20 (s)-camptothecine (1 restrains) in DMF (100ml), up to H
2Consume and end.With equivalent DMF dilution gained suspension, filter then.The vacuum concentration solvent filters the solid of collecting precipitation to small volume, washes with ethanol and ether.Obtain being the title compound (0.8 gram) of yellow solid.It has identical physical properties with the compound of embodiment 1.Embodiment 3
12-chloro-20 (s)-camptothecine
Sodium Nitrite in the 30ml water (2.4 gram) adds when 0-5 ℃ is being stirred in the solution of 12-amino camptothecin (9 gram) in 18%HCl (650ml).After 30 minutes, drip in the flask that contains CuCl (12.2 gram) and 18%HCl (250ml) in 70 ℃ of reaction mixtures.Heating is 1.5 hours continuously.Reaction mixture is poured in the frozen water then, uses the dichloromethane extraction aqueous mixture.Solvent removed in vacuo is used the ether dissolution solid, refilters, and obtains 5.5 gram title compounds.
1NMR(DMSO-d
6),δppm:0.89(3H,t,J=7.3?Hz)；1.86
(2H,m)；5.29(2H,s)；5.42(2H,
s)；6.57(1H,s)；7.3?6(1H,s)；
7.66(1H,t,J=7.9?Hz)8.0-8.1
(2H, m); 8.75 (1H, s). embodiment 412-bromo-20 (s)-camptothecine
Under 0-5 ℃ is stirred simultaneously, the Sodium Nitrite in the 30ml water (2.4 gram) is added in the solution of 12-amino-20 (s)-camptothecine (9 gram) in 15%HBr (650ml).After 30 minutes, reaction mixture splashes in the flask that contains CuBr (21.3 gram) and 16%HBr (250ml) in 70 ℃.Continue heating 1.5 hours.Reaction mixture is poured in the frozen water, uses the ethyl acetate extraction aqueous mixture.Behind the evaporating solvent,, obtain being the title product (6.1 gram) of yellow solid by separating pure products with ether sedimentation.
1NMR(DMSO-d
6),δppm:0.88(3H,t,J=7.3?Hz)；1.86
(2H,m)；5.31(2H,s)；5.43(2H,
s)；6.58(1H,s)；7.37(1H,s)；
7.60(1H,t,J=7.9Hz)；8.1-8.2
(2H, m); 8.74 (1H, s). embodiment 59-nitro-12-chloro-20 (s)-camptothecine
12-chloro-20 (s)-camptothecine (5 gram) dissolves/is suspended in dense H
2SO
4(70ml), be as cold as 0-5 ℃, simultaneously mechanical stirring.In reaction mixture, splash into 70%HNO in 20 minutes
3(2.7ml), reaction flask is warming to room temperature then.At room temperature continue to stir to spend the night.Reaction mixture is poured in the frozen water, and filter and collect yellow solid, water, ethanol, ether is washed.Obtain 4 gram title product after the drying.
1NMR(DMSO-d
6),δppm:0.89(3H,t,J=7.2Hz)；1.86
(2H,m)；5.34(2H,s)；5.44(2H,
s)；6.61(1H,s)；7.39(1H,s)；
8.24(1H,d,J=8.3Hz)；8.48
(1H,d,J=8.3Hz)；9.22
(1H, s). embodiment 69-nitro-12-bromine 20 (s)-camptothecine
12-bromo-20 (s)-camptothecine (5.5 gram) dissolves/is suspended in dense H
2SO
4(80ml), be cooled to 0-5 ℃, simultaneously mechanical stirring.70%HNO
3(3.1ml) splash in the reaction mixture, last 20 minutes, reaction flask is warming to room temperature then.At room temperature continue to stir to spend the night.Reaction mixture is poured in the frozen water, and filter and collect yellow solid, water, ethanol, ether is washed.Obtain 4.2 gram title product after the drying.
1NMR(DMSO-d
6),δppm:0.88(3H,t,J=7.3Hz)；1.87
(2H,m)；5.35(2H,s)；5.44(2H,
s)；6.61(1H,s)；7.40(1H,s)；
8.39(1H,d,J=8.4Hz)；8.45
(1H,d,J=8.4Hz)；9.20
(1H, s). embodiment 79-amino-12-chloro-20 (s)-camptothecine
Under normal atmosphere and the room temperature in the presence of 10%Pd/C (0.1 gram) solution of hydrogenation 9-nitro-12-chloro-20 (s)-camptothecine (3 restrain) in DMF (50ml) 2 hours.Filter reaction mixture, vacuum concentrated solution.Residue of chromatography on silicagel column obtains title compound (2.5 gram).
1NMR(DMSO-d
6),δppm:0.87(3H,t,J=7.2Hz)；1.86
(2H,m)；5.28(2H,s)；5.42(2H,
s)；6.30(2H,bs)；6.56(1H,s)；
6.75(1H,d,J=8.4Hz)；7.31
(1H,s)；7.66(1H,d,J=8.4
Hz); 8.89 (1H, s). embodiment 89-amino-20 (s)-camptothecine
Under normal atmosphere and the room temperature in the presence of 10%Pd/C (0.1 gram) solution of hydrogenation 9-nitro-12-chloro-20 (s)-camptothecine (3 restrain) in DMF (50ml) 48 hours.Filter reaction mixture, vacuum concentrated solution.Residue of chromatography on silicagel column gets title compound (1.5 gram).
1NMR(DMSO-d
6),δppm:0.87(3H,t,J=7.3Hz)；1.85
(2H,m)；5.26(2H,s)；5.41(2H,
s)；6.11(2H,s)；6.50(1H,s)；
6.79(1H,m)；7.28(1H,s)；7.3-
7.5 (2H, m); 8.83 (1H, s). embodiment 99-amino-20 (s)-camptothecine
Under normal atmosphere and the room temperature in the presence of 10%Pd/C (0.1 gram) solution of hydrogenation 9-nitro-12-bromo-20 (s)-camptothecine (3 restrain) in DMF (50ml) 6 hours.Filter reaction mixture, vacuum concentrated solution.Residue of chromatography on silicagel column obtains title compound (2.0 gram).The compound that obtains among this compound and the embodiment 8 has identical characteristics.9-amino-20 (s)-camptothecine that embodiment 10 obtains from 9-amino-12-chloro-20 (s)-camptothecine
React according to embodiment 8, obtain being the purpose product of yellow solid, it is identical with real product.20 (s)-camptothecine that embodiment 11 obtains from 12-chloro-20 (s)-camptothecine
React according to embodiment 8, just in the presence of pyridine, react reaction mixture hydrogenation 12 hours.Separate title product by column chromatography.It is identical with the sample of genuine products.20 (s)-camptothecine that embodiment 12 obtains from 12-bromo-20 (s)-camptothecine
React according to embodiment 11, just reaction was carried out 6 hours, obtained title compound, and it is identical with real material sample.
Claims (4)
1. the compound of a formula (V):
Wherein X is a halogen atom.
2. method for preparing the formula described in the claim 1 (V) compound, this method comprise makes formula IV compound and the reaction of a kind of nitrating agent,
Wherein X is a halogen atom.
3. formula VI compound
Wherein X is a halogen atom.
4. method for preparing the formula VI compound described in the claim 3, this method are included in and obtain formula (V) compound described in the reduction claim 1 under the formula VI compound condition.
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| CN 98125302 CN1222523A (en) | 1993-08-06 | 1998-12-11 | Process for preparation of 9-amino camptothecin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1312155C (en) * | 2005-01-21 | 2007-04-25 | 华东理工大学 | Method for separating and purifying 9-nitro camptothecin |
| CN100334089C (en) * | 2004-07-21 | 2007-08-29 | 王洋 | Production method of 9-nitro camptothecin |
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1998
- 1998-12-11 CN CN 98125302 patent/CN1222523A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100334089C (en) * | 2004-07-21 | 2007-08-29 | 王洋 | Production method of 9-nitro camptothecin |
| CN1312155C (en) * | 2005-01-21 | 2007-04-25 | 华东理工大学 | Method for separating and purifying 9-nitro camptothecin |
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