CN1300147C - Camptothecin derivatives preparing process - Google Patents

Camptothecin derivatives preparing process Download PDF

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CN1300147C
CN1300147C CNB2004100650025A CN200410065002A CN1300147C CN 1300147 C CN1300147 C CN 1300147C CN B2004100650025 A CNB2004100650025 A CN B2004100650025A CN 200410065002 A CN200410065002 A CN 200410065002A CN 1300147 C CN1300147 C CN 1300147C
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compound
preparation
formula
nitro
alkane
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CN1634928A (en
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李玉艳
尤启冬
王磊
陈晟
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The present invention relates to the field of pharmaceutical synthesis, more specifically to a new method for preparing an oxazolo camptothecin derivative (I) used as a compound with antitumor activity. In the preparing method of the present invention, a compound II reacts with an amine-group compound to generate the compound I. The product prepared by the preparing method of the present invention is high in yield and simple is post treatment.

Description

The preparation method of camptothecin derivative
Technical field
The present invention relates to new preparation method as tool active compound for anti tumor De oxazole and camptothecin derivative.
Background technology
Camptothecine is from the distinctive a kind of jade of China
Figure C20041006500200041
Isolated alkaloid in leaf of section drought Nelumbo deciduous plant camplotheca acuminata and the bark with anti-tumor activity.Camptothecine has special curative effect by suppressing the activity of topoisomerase I, demonstrating to tumour.(Wall ME et.al..J.Am.Chem.Soc., 1966,88:3888-3890) existing two new camptothecin semisynthetic drug irinotecans and topotecan go through to go on the market, and a plurality of active compounds are in the clinical study stage.The research of camptothecin derivative has been become the focus of antitumour drug research.
Oxazole and camptothecin derivative have good antitumor activity, adopt semisynthetic method preparation, and the existing report of synthetic method (Angelo B.et.al., W097/25332).In this synthetic method, used expensive palladium catalyst, cost is very high.Then cyclization generates target compound, needs through column chromatographic isolation and purification.Yield can only reach 40%.It can't suitablely be produced on a large scale.
Oxazole and camptothecin derivative (I) semi-synthetic, according to known method, at first synthetic 9-nitro-10 hydroxycamptothecine and analogue (II) thereof.(Wani，M.C.et.al.，J.Med.Chem.，1986，29，2358-2363)。With camptothecine and derivative thereof such as 7-ethyl-camptothecin is raw material, hydrogen peroxide is the oxynitride that oxidant reaction obtains camptothecine and derivative thereof, obtain 10-hydroxycamptothecine and derivative thereof through photochmeical reaction again, then with the vitriol oil and synthetic 9-nitro-10 hydroxycamptothecine of nitric acid nitrating and analogue (II) thereof.Make catalyzer with palladium carbon then, under catalytic condition, formula (II) compound is reduced to formula (III) compound, obtains 9-amino-10 hydroxycamptothecine and analogue thereof (III), then add group with imine moiety, as ethyl formate imines (ethylformimidate), obtain formula (I) compound.Synthetic route is as follows:
In by formula (II) compound formula (III) compound step, adopt palladium carbon to make catalyzer.This catalyzer costs an arm and a leg, and production cost is improved.Owing to will also make to have certain danger in the building-up process with hydrogen as reductive agent.During Zai oxazole and camptothecin derivative are synthetic,, cause raw material impure, formula (II) compound can be brought in the target compound because formula (III) compound instability can not must directly feed intake by purifying.Because reaction is not thorough, also makes and contain a large amount of by products in the final product in addition.Can't obtain formula (I) compound by recrystallization, must adopt silica gel column chromatography separating purification, yield is low, and about 40%.
Adopt this synthetic method, need the expensive catalysts palladium, production cost is increased.The more important thing is intermediate formula (III) compound instability, and contain more impurity in the target product of reaction, cause final product must adopt silica gel column chromatography separating purification.Formula (I) compound in a large number by silica gel adsorption, descends yield in the column chromatography purification process.
Summary of the invention
The invention provides the novel method of a kind of Zhi Bei oxazole and camptothecin derivative, shortened reaction scheme, avoided using expensive metal catalyst and column chromatography for separation, yield reaches more than 60%.
Preparation method of the present invention is as follows:
ArNL 1L 2Be aminated compounds.Can obtain formula (I) compound by ring-closure reaction and formula (II) compound effects.
Present method makes formula (I) compound synthetic with high yield and high productivity.The method is characterized in that:, guarantee that high yield and reaction product are clear with easy reaction conditions.Especially in the method, only need single step reaction just formula (II) compound can be converted into formula (I) compound.Avoided generating unsettled formula (III) compound.Say that more specifically because the high-level efficiency of reaction transforms, making in the reaction solution after reaction finishes seldom has other by products except formula (I) compound.Can obtain formula (I) compound by recrystallization purifying easily, compare with chromatography purification, provide cost savings and the labour, the product that is obtained by present method is also pure than what obtained by chromatography.
Wherein, R 1For:
Hydrogen, contain 0-5 substituent C 1-C 6Alkane, C 3-C 7Naphthenic hydrocarbon, hydroxyl, halogen, C 1-C 6Alkoxyl group, C 1-C 6Itrile group, nitro, amino, NR 3R 4, aldehyde radical, ketone group, C 1-C 6Carboxylic acid and carboxylicesters, C 1-C 6Trialkyl silyl, diazanyl or oximido, above-mentioned substituting group is hydroxyl, halogen, C 1-C 6Alkoxyl group, C 1-C 6Itrile group, nitro or amino;
R 2For:
Hydrogen, contain 0-5 substituent C 1-C 6Alkane or C 3-C 7Naphthenic hydrocarbon, hydroxyl, halogen, C 1-C 6Alkoxyl group, itrile group, nitro, amino, NR 3R 4, aldehyde radical, ketone group, C 1-C 6Carboxylic acid and carboxylicesters, acyloxy and amide group, C 1-C 6Trialkyl silyl, diazanyl or oximido, above-mentioned substituting group is hydroxyl, halogen, C 1-C 6Alkoxyl group, C 1-C 6Itrile group, nitro or amino;
R 3And R 4Be respectively:
Hydrogen, contain 0-5 substituent C 1-C 6Alkane, substituting group is hydroxyl, halogen, C 1-C 6Alkoxyl group, C 1-C 6Itrile group, nitro or amino;
C 3-C 7Naphthenic hydrocarbon;
1-5 substituent phenyl ring or benzyl are arranged, and substituting group is C 1-C 6Alkane, hydroxyl, halogen, C 1-C 6Alkoxyl group, C 1-C 6Itrile group, nitro or amino;
Five yuan and hexa-member heterocycle containing one or two nitrogen or Sauerstoffatom;
Also can be R 3And R 4Form the saturated or unsaturated ring that 3-7 atom formed with nitrogen-atoms; ArNL 1L 2For:
Ar is for there being 1-5 substituent phenyl ring, and substituting group is C 1-C 6Alkane, hydroxyl, halogen, C 1-C 6Alkoxyl group, C 1-C 6Itrile group, nitro or amino; Or contain one or two nitrogen or Sauerstoffatom five yuan and hexa-atomic fragrant heterocycle,
L wherein 1And L 2Identical or be respectively:
Contain 0-5 substituent C 1-C 6Alkane or C 3-C 7Naphthenic hydrocarbon, substituting group are hydroxyl, halogen, C 1-C 6Alkoxyl group, C 1-C 6Itrile group, nitro or amino;
1-5 substituent phenyl ring or benzyl are arranged, and substituting group is C 1-C 6Alkane, hydroxyl, halogen, C 1-C 6Alkoxyl group, C 1-C 6Itrile group, nitro or amino;
Five yuan and hexa-member heterocycle containing one or two nitrogen or Sauerstoffatom.
Further finding in the test, work as R 1During for the alkane of hydrogen or C1～6, R 2Reaction is carried out more fully during for hydrogen, and yield is higher, reaches about 60～70%.
More excellent, be at R 1Be hydrogen, CNCH 2Or CH 3, R 2During for hydrogen, reaction yield is higher, reaches about 70～80%.
In addition, aminated compounds ArNL 1L 2Be preferably N, N-disubstituted benzene amine.
Preparation method's reaction conditions gentleness of the present invention, simple to operate, formula (II) compound and ArNL 1L 2Reaction can be carried out formula (II) compound and ArNL at temperature 0-250 ℃ 1L 2Molar ratio be 1: 1-5000, reaction times is 5 minutes to 48 hours, reaction is generally carried out in organic solvent as dimethylbenzene, tetrahydrofuran (THF), phenyl ether, dimethyl formamide, N,N-DIMETHYLACETAMIDE, one condensed ethandiol, whiteruss etc. or do not use any solvent and adopt excessive ArNL 1L 2Solvent as reaction.
By formula (I) compound that aforesaid method obtains, can use the organic solvent recrystallization, organic solvent comprises as chloroform, methylene dichloride, low-molecular-weight alcohol such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone, acetate, tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE.
In a series of compounds with present method preparation, reaction, yield compound preferably are:
With
Also obtain a new compound IV with present method:
Figure C20041006500200073
R 2For H or-CH 2CH 3.
Formula (I) compound is the inhibitor of topoisomerase I (Topoisomerase I).Can be used as the treatment cancer, improve the medicinal substance of cancer patients's symptom or alleviation cancer.
The compounds of this invention nitrile first base oxazole and camptothecine (IV) in human oral cavity epithelial cancer cells, liver cancer cell 7402 be, lung becomes when experimentizing on inocarcinoma cell and the colon cancer cell, finds to have cytotoxic activity.To liver cancer cell 7402 is IC 50Value (cell growth produces 50% concentration that suppresses) is 50ng/ml, to the IC of all the other cancer cells 50Value is all less than 100ng/ml.Can be used for these treatment for cancer.
The compounds of this invention can various formulation administrations, as oral dosage form: tablet, capsule, lozenge, liquor or suspension;
Rectum formulation such as suppository; Parenteral route such as intramuscular, vein, intracutaneous or subcutaneous administration.
The following examples have illustrated the preparation of compound of the present invention, but do not limit the scope of the invention.
Embodiment
Embodiment 1
The preparation of oxazole and camptothecine
With N, accelerine 15ml drops into 50ml two neck bottles, is heated to 80 ℃, adds 9-nitro-10-hydroxycamptothecine 150mg (0.37mmol) again, is heated to 150 ℃, continues reaction 20min, stopped reaction.Reactant is poured in the ether, filters filter cake chloroform recrystallization.Get product 95mg.Yield: 63% Mp.232-234 ℃.
Embodiment 2
The preparation of Jia Ji oxazole and camptothecine
With N, N-Diethyl Aniline 20ml (0.13mol) drops into 50ml two neck bottles, drops into 9-nitro-10-hydroxycamptothecine 200mg (0.49mmol) again, is heated to 150 ℃, reacts about 20min.Reactant is poured in the distilled water, and the upper strata is red-brown.With chloroform extraction, add anhydrous Na again 2SO 4Dry.The concentrating under reduced pressure chloroform obtains the target compound crude product, again with ethyl alcohol recrystallization, gets product 142mg, productive rate: 71%.Mp.253-256℃。
Embodiment 3
The preparation of Yi Ji oxazole and camptothecine
With N, N-dipropyl aniline 20ml drops into 50ml two neck bottles, drops into 9-nitro-10-hydroxycamptothecine 200mg (0.49mmol) again, is heated to 130 ℃, reacts about 25min.Pour reactant into distilled water, the upper strata is red-brown.With chloroform extraction, add anhydrous Na again 2SO 4Dry.The concentrating under reduced pressure chloroform obtains the target compound crude product, again with the methylene dichloride recrystallization, gets product 145mg, productive rate: 70%.Mp.261-264℃。
Embodiment 4
The preparation of Qing Jia Ji oxazole and camptothecine
With N, the two cyanoethyl aniline 1g (0.05mol) of N-drop into 50ml two neck bottles, are heated to 80 ℃, and solid is molten into red liquid.Add 9-nitro-10-hydroxycamptothecine 100mg (0.24mmol) again, be warming up to 150 ℃, react about 20min.Add chloroform, the unreacted N of filtering, the two cyanoethyl aniline solids of N-.Obtain product 78mg with the ether recrystallization.Yield: 76%, Formula:C 23H 16N 4O 5, MS:M-1=427,
1HNMR (TFA+CDCl 3) δ: 0.97 (t, 3H, 20-CH 3), 1.92 (m, 2H, 20-CH 2), 2.95 (d, 1H, CH), 3.97 (d, 1H, second cyanogen CH), 5.38-5.72 (m, 4H, 5-CH 2, 17-CH 2), 8.19-9.69 (m, 4H, fragrant hydrogen) ppm
IR:3392 (water peak), 2970 (alkane C-H stretching vibrations), 2300 (CN), 1748 (ester carbonyl groups), 1660 (amidocarbonylations), 1603,1519 (phenyl ring skeletal vibrations), 1157 (C-O stretching vibration) cm -1
Embodiment 5
The preparation of oxazole and 7-ethyl-camptothecin
With N, accelerine 15ml drops into 50ml two neck bottles, is heated to 80 ℃, adds 9-nitro-10-hydroxyl-7-ethyl-camptothecine 150mg (0.36mmol) again, is heated to 150 ℃, continues reaction 20min, stopped reaction.Reactant is poured in the ether, filters filter cake chloroform recrystallization.Get product 97mg.Yield: 64%.Mp.241-243℃。

Claims (6)

  1. Oxazole shown in the formula (I) and camptothecin derivative the preparation method:
    Figure C2004100650020002C1
    Comprise and make compound shown in the formula (II) and aminated compounds ArNL 1L 2Reaction obtains De oxazole and camptothecin derivative shown in the formula (I):
    Figure C2004100650020002C2
    Wherein, R 1For:
    Hydrogen, contain 0-5 substituent C 1-C 6Alkane, halogen, hydroxyl, nitro, amino; Described substituting group is hydroxyl, halogen, C 1-C 6Itrile group, nitro or amino;
    R 2For:
    Hydrogen, C 1-C 6Alkane;
    ArNL 1L 2For: Ar is for there being 1-5 substituent phenyl ring, and substituting group is C 1-C 6Alkane;
    L 1And L 2Identical or be respectively:
    Contain 0-5 substituent C 1-C 6Alkane, described substituting group is hydroxyl, halogen, C 1-C 6Itrile group, nitro or amino.
  2. 2, the preparation method of claim 1, wherein Compound I is:
  3. 3, the preparation method of claim 1, wherein Compound I is:
  4. 4, the preparation method of claim 1, wherein Compound I is:
    Figure C2004100650020003C2
  5. 5, the preparation method of claim 1, wherein Compound I is:
  6. 6, the preparation method of claim 1 further comprises the recrystallization of product, and the used solvent of recrystallization is: chloroform, methylene dichloride, methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone, acetate, tetrahydrofuran (THF), dimethyl formamide or N,N-DIMETHYLACETAMIDE.
CNB2004100650025A 2004-10-18 2004-10-18 Camptothecin derivatives preparing process Expired - Fee Related CN1300147C (en)

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CN100586952C (en) * 2006-11-10 2010-02-03 中国药科大学 Derivative of oxazolocamptothecin ester, preparation method and application
CN101407524B (en) * 2007-10-09 2012-07-18 江苏先声药物研究有限公司 Oxazino camptothecin derivative, preparation and use thereof
CN102659800B (en) * 2012-05-11 2014-09-03 中国药科大学 Hypoxia-activated antitumor compounds and application thereof
CN108017656B (en) * 2016-11-03 2020-01-07 深圳瀜新生物科技有限公司 Camptothecin derivative and application thereof in preparation of antitumor drugs
CN109467563B (en) * 2018-06-08 2021-08-03 浙江大学 Camptothecin derivative and application thereof in preparation of anti-inflammatory drugs

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1997025332A1 (en) * 1996-01-10 1997-07-17 Pharmacia & Upjohn S.P.A. Hexacyclic camptothecin analogues, and process for preparing them

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025332A1 (en) * 1996-01-10 1997-07-17 Pharmacia & Upjohn S.P.A. Hexacyclic camptothecin analogues, and process for preparing them

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