CN104341429A - (S)-camptothecin intermediate preparation method and (S)-camptothecin preparation method - Google Patents
(S)-camptothecin intermediate preparation method and (S)-camptothecin preparation method Download PDFInfo
- Publication number
- CN104341429A CN104341429A CN201310322465.4A CN201310322465A CN104341429A CN 104341429 A CN104341429 A CN 104341429A CN 201310322465 A CN201310322465 A CN 201310322465A CN 104341429 A CN104341429 A CN 104341429A
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- preparation
- bromo
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- DKBIFNHJWRSNJH-UHFFFAOYSA-N CCOC(C(C(C=C(C1(CC2)OCCO1)N2C1=O)=C1C#N)Br)=O Chemical compound CCOC(C(C(C=C(C1(CC2)OCCO1)N2C1=O)=C1C#N)Br)=O DKBIFNHJWRSNJH-UHFFFAOYSA-N 0.000 description 2
- FQVVPISPHQOPFC-UHFFFAOYSA-N CCOC(CC(C=C(C1(CC2)OCCO1)N2C1=O)=C1C#N)=O Chemical compound CCOC(CC(C=C(C1(CC2)OCCO1)N2C1=O)=C1C#N)=O FQVVPISPHQOPFC-UHFFFAOYSA-N 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N CC[C@](C(C=C1N2Cc3cc(cccc4)c4nc13)=C(CO1)C2=O)(C1=O)O Chemical compound CC[C@](C(C=C1N2Cc3cc(cccc4)c4nc13)=C(CO1)C2=O)(C1=O)O VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a (S)-camptothecin intermediate preparation method and a (S)-camptothecin preparation method. The method comprises the following steps: in an inertia solvent, under effect of an initiator, under illumination condition, a compound 6-cyan-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydro nitrogen indenes-7-ethyl acetate shown in a formula I and a solid bromination reagent are subjected to a bromination reaction, so that a compound shown in a formula II can be obtained. The method has the following advantages and active effects that usage of unstable sodium hydrogen and bromine with strong corrosivity and easy volatility can be avoided, and the method has the characteristics of high security and high maneuverability. The method has the advantages of mild reaction condition, simple post-treatment and high reaction yield, and is adapted to industrial production.
Description
Technical field
The invention belongs to pharmacy field, in particular to a kind of preparation method of (S)-camptothecine intermediate and the preparation method of (S)-camptothecine.
Background technology
(S)-camptothecine (Camptothecin, be called for short (S)-CPT) be from China endemic plant Nyssaceae camplotheca acuminata, be separated in 1966 a kind of alkaloid obtained by Wall with Wani of National Cancer Institute etc. people first, its content is about 0.01%.First professor Hsiang of John Hopkins University finds that camptothecin analogues suppresses copying of DNA and transcribe to play anti-tumor activity by acting on topoisomerase I (TopoI), secondly find again that CPT lactone form is its activity form, and only have the enantiomer of (S) configuration just to have activity.Through going deep into of clinical pharmacology research, with (S)-CPT for lead compound, exploitation high reactivity, the upsurge of the Me-Too medicine of hypotoxicity and good water solubility.
(S) shown in the following formula III of structural formula of-camptothecine:
Formula III
The preparation method of (S)-camptothecine is disclosed in US Patent No. 4778891A1 and U.S. scientific and technical literature Antitumour Agents.Part2.Asymmetric Synthesis of (S)-Camptothecin.J.CHEM.SOC.PERKIN TRANS.11990.Wherein, an important intermediate in (S)-camptothecine building-up process is α-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate, and its chemical formula is as shown in the formula shown in II:
Important intermediate α in (S)-camptothecine building-up process that first US Patent No. 4778891A1 discloses-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3, the synthetic method of 5-tetrahydrochysene benzazole-7-ethyl acetate: by 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate is dissolved in organic solvent, adds sodium hydrogen, is heated to 80 DEG C of reactions 10 minutes, then room temperature is down to, add bromine, react 2 hours, then carry out aftertreatment, obtain product through recrystallization, yield is 97%.Method in the method disclosed in U.S. scientific and technical literature Antitumour Agents.Part2.Asymmetric Synthesis of (S)-Camptothecin.J.CHEM.SOC.PERKIN TRANS.11990 and US4778891A1 is basically identical, and it is 85.1% that its crude product crosses the yield after silicagel column.
The present inventor is studied the method that above-mentioned two sections of documents disclose and has done a large amount of revision tests, found that: aforesaid method all adopts the bromine and the synthesis of more unstable sodium hydrogen that toxicity is larger, its reaction is more violent, wayward, make reaction system become black if control bad meeting, make product not drop into next step reaction by simple aftertreatment; Secondly, harsh to the requirement of reaction system, this is because sodium hydrogen removing benzyl position hydrogen generates as lively as a cricket benzyl negative ion, it not only can react with bromine, and can react with water, so reaction solvent and reaction vessel as far as possible anhydrous, reaction solvent will dewater in advance if desired; Finally, although the yield of products therefrom is higher unstable, and product all needs further recrystallization or crosses silicagel column process just to enter next step reaction, and complex steps, is unfavorable for suitability for industrialized production.
Therefore, the higher and synthetic method of the α of applicable suitability for industrialized production-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate of a kind of yield is needed at present badly.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides the preparation method of one (S)-camptothecine intermediate and the preparation method of (S)-camptothecine.
Specifically, the invention provides:
(1) a kind of preparation method of (S)-camptothecine intermediate, described (S)-camptothecine intermediate is the compound α shown in formula II-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate:
Described method comprises:
In inert solvent, under the existence of initiator, under illumination condition, make the compound 6-cyano group-1 shown in formula I, 1-(ethylenedioxy)-5-oxygen-1,2,3, there is following bromo-reaction in 5-tetrahydrochysene benzazole-7-ethyl acetate and solid brominated reagent, thus obtains the compound shown in formula II:
(2) method Gen Ju (1), wherein, described initiator is selected from dibenzoyl peroxide, metachloroperbenzoic acid or Diisopropyl azodicarboxylate; Be preferably metachloroperbenzoic acid.
(3) method Gen Ju (1), wherein, the mol ratio of the compound shown in formula I and described initiator is 1:(0.01-0.2); Be preferably 1:(0.05-0.1).
(4) method Gen Ju (1), wherein, described solid brominated reagent is selected from bromo-5, the 5-dimethyl hydantion of 1,3-bis-or N-bromosuccinimide; Be preferably N-bromosuccinimide.
(5) method Gen Ju (1), wherein, the mol ratio of the compound shown in formula I and described solid brominated reagent is 1:(0.9-1.2); Be preferably 1:1.1.
(6) method Gen Ju (1), wherein, described inert solvent is selected from one or more in hexanaphthene, toluene, tetracol phenixin, trichloromethane and DMF; Be preferably tetracol phenixin.
(7) method Gen Ju (1), wherein, the weightmeasurement ratio of the compound shown in formula I and described inert solvent is 1:(10-50), be preferably 1:(20-30).
(8) method Gen Ju (1), wherein, the temperature of reaction of described bromo-reaction is 0 DEG C-100 DEG C; Be preferably 15 DEG C-80 DEG C.
(9) method Gen Ju (1), wherein, the light source of described illumination is selected from one or more in infrared lamp, incandescent light, natural light; Be more preferably incandescent light.
(10) method Gen Ju (1), wherein, the reaction times of described bromo-reaction is 1-10 hour; Be preferably 4-8 hour; Be more preferably 6-7 hour.
(11) a kind of preparation method of (S)-camptothecine, it comprises:
1) according to the compound shown in method preparation formula II in (1)-(10) described in any one; And
2) compound preparation (the S)-camptothecine shown in the formula II obtained by step 1).
The present invention compared with prior art has the following advantages and positively effect:
1. present invention, avoiding the bromine of the more unstable sodium hydrogen of use and severe corrosive and easy volatile, but use and compare the solid brominated reagent be easy to get and add initiator and complete bromo-reaction, have the advantages that security is high and operability is high.
2. reaction conditions of the present invention is gentle, is suitable for suitability for industrialized production.
First, reaction of the present invention does not need complicated temperature to control, such as, and 0 DEG C-100 DEG C.Secondly, the bromo-reaction mechanism that the solid brominated reagent that the present invention uses adds initiator is free radical mechanism, and react more single, there is water in reaction solvent can not have an impact to reaction, does not therefore relate to solvent water removal, is suitable for suitability for industrialized production.
3. aftertreatment of the present invention is simple, and the crude product obtained does not need recrystallization or crosses silicagel column, and can put in next step reaction, reaction yield is higher, can reach more than 85%.
In sum, method of the present invention can obtain α-bromo-6-cyano group-1 under relatively mild condition, 1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate, has the advantages that security is good, easy and simple to handle, yield is high, do not need purifying directly to may be used for next step synthesizes, and is more suitable for the large production of industry.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic spectrum of the compound α shown in formula II-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate.
Embodiment
Below by way of embodiment description and the invention will be further described with reference to accompanying drawing, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
In the present invention, described " initiator " English is initiator, refer to the compound that a class easily resolves into free radical (i.e. primary group of free radicals), can be used for causing alkene class, the radical polymerization of two vinyl monomer and copolymerization, also can be used for crosslinking curing and the high molecular crosslink reaction of unsaturated polyester.Initiator generally includes peralcohol initiator and azo-initiator and redox initiator etc., and peroxide initiator is divided into again organic peroxide evocating agent and inorganic peroxide initiator.
In the present invention, described " solid brominated reagent ", also referred to as solid brominating reagent, for bromine, specifically refers to the brominated reagent for solid under room temperature (room temperature herein refers to 10-35 DEG C).
The synthesis technique of the present inventor to (S)-camptothecine intermediate has carried out studying in large quantities, have been surprisingly found that: under initiator effect, 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate can be reacted with solid brominated reagent, thus synthesis α-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate.Above-mentioned steps does not need to use bromine and sodium hydrogen, thus overcomes the defects such as poor stability of the prior art and severe reaction conditions.The present inventor, on the basis that this finds, obtains technical scheme of the present invention further.
Specifically, the invention provides:
(1) preparation method of (S)-camptothecine intermediate
The present invention provide firstly the preparation method of one (S)-camptothecine intermediate, described (S)-camptothecine intermediate is the compound α shown in formula II-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate:
Described method comprises:
In inert solvent, under the existence of initiator, under illumination condition, make the compound 6-cyano group-1 shown in formula I, 1-(ethylenedioxy)-5-oxygen-1,2,3, there is following bromo-reaction in 5-tetrahydrochysene benzazole-7-ethyl acetate and solid brominated reagent, thus obtains the compound shown in formula II:
Preferably, described initiator is selected from dibenzoyl peroxide, metachloroperbenzoic acid or Diisopropyl azodicarboxylate; Be preferably metachloroperbenzoic acid.
Preferably, the mol ratio of the compound shown in formula I and described initiator is 1:(0.01-0.2); Be preferably 1:(0.05-0.1).
Preferably, described solid brominated reagent is selected from bromo-5, the 5-dimethyl hydantion of 1,3-bis-or N-bromosuccinimide; Be preferably N-bromosuccinimide.
Preferably, the mol ratio of the compound shown in formula I and described solid brominated reagent is 1:(0.9-1.2); Be preferably 1:1.1.
Preferably, described inert solvent is selected from one or more in hexanaphthene, toluene, tetracol phenixin, trichloromethane and DMF; Be preferably tetracol phenixin.
Preferably, the weightmeasurement ratio of the compound shown in formula I and described inert solvent is 1:(10-50), be preferably 1:(20-30).
Preferably, the temperature of reaction of described bromo-reaction is 0 DEG C-100 DEG C; Be preferably 15 DEG C-80 DEG C.
Preferably, the light source of described illumination is selected from one or more in infrared lamp, incandescent light, natural light; Be more preferably incandescent light.
Preferably, the reaction times of described bromo-reaction is for being 1-10 hour; Be preferably 4-8 hour; Be more preferably 6-7 hour.
(2) preparation method of (S)-camptothecine
A kind of preparation method of (S)-camptothecine, described method comprises:
1) compound shown in method preparation formula II Gen Ju (); And
2) compound preparation (the S)-camptothecine shown in through type II.
Wherein, step 2) described in the method for the preparation of the compound shown in through type II (S)-camptothecine be well-known to those skilled in the art, such as, see US Patent No. 4778891A1, but can the present invention is not limited thereto.
In one embodiment of the invention, in order to overcome the defect existed in prior art, bromine is changed to solid brominated reagent, to 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3, add initiator in 5-tetrahydrochysene benzazole-7-ethyl acetate (I), react under illumination condition.After thin-layer chromatography detection reaction terminal, carry out aftertreatment.Wherein, add methylene dichloride solubilizing reaction product solid, this solution is successively after sodium thiosulfate solution, washing, anhydrous sodium sulfate drying organic layer, concentrates and obtains α-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate, can be directly used in next step reaction.
In another embodiment of the invention, by 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate (I) is dissolved in inert solvent, add initiator, solid brominating reagent, illumination, stirring reaction, point plate confirms reaction end, generate α-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate (II).Its synthetic route is as follows:
Wherein, described inert solvent is selected from hexanaphthene, toluene, tetracol phenixin, trichloromethane, DMF; Preferably, described inert solvent is tetracol phenixin.
Wherein, described initiator is selected from dibenzoyl peroxide, metachloroperbenzoic acid, Diisopropyl azodicarboxylate; Preferably, described initiator is metachloroperbenzoic acid.
Wherein, described brominated reagent is selected from bromo-5, the 5-dimethyl hydantion of 1,3-bis-, N-bromosuccinimide; Preferably, described brominated reagent is N-bromosuccinimide.
Wherein, the light source of described illumination is selected from infrared lamp, incandescent light, natural light; Preferably, described illumination is incandescent light.
Wherein, temperature of reaction is 0 DEG C-100 DEG C; Preferably, temperature of reaction is 15 DEG C-80 DEG C.
Wherein, described 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate and the mol ratio of described initiator are 1:0.01-1:0.2; Preferably, described 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate and the mol ratio of described initiator are 1:0.05-1:0.1.
Wherein, described 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate and the mol ratio of described bromide reagent are 1:0.9-1:1.2; Preferably, described 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate and the mol ratio of described bromide reagent are 1:1.1.
Wherein, the reaction times of described bromo-reaction is for being 1-10 hour; Be preferably 4-8 hour; Be more preferably 6-7 hour.
In a preferred embodiment of the invention, the synthetic route of α of the present invention-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate is as follows:
By 6-cyano group-1, 1-(ethylenedioxy)-5-oxygen-1, 2, 3, 5-tetrahydrochysene benzazole-7-ethyl acetate (I) is dissolved in tetracol phenixin, add metachloroperbenzoic acid, N-bromosuccinimide, incandescent light adds natural lighting, stirred at ambient temperature reacts, thin-layer chromatography determination reaction end, add methylene dichloride dissolved solids, solution is washed 2-3 time with 10% sodium thiosulfate solution successively, wash 2 times, finally wash 1 time with saturated common salt, anhydrous sodium sulfate drying organic layer, be spin-dried for and namely obtain α-bromo-6-cyano group-1, 1-(ethylenedioxy)-5-oxygen-1, 2, 3, 5-tetrahydrochysene benzazole-7-ethyl acetate.
Mode by the following examples further explains and describes content of the present invention, but these embodiments are not to be construed as limiting the scope of the invention.
In the examples below, the preparation method of 6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate can see (such as) U.S. Patent Publication No.US4778891A1.
In the examples below, if no special instructions, each reagent all commercially, such as, can derive from Sigma company.
In the examples below, thin-layer chromatography testing conditions is as follows: silica-gel plate is GF254; Light source INSTRUMENT MODEL is ZF-1 tri-ultraviolet lamp; Moving phase adopts: (sherwood oil: ethyl acetate)=(1:8).
In the examples below, the determination methods of reaction end is as follows: with the product (obtaining according to the method in US Patent No. 4778891A1) by structural identification and raw material product in contrast, the disappearance of product point generation and raw material point in control reaction liquid, and not having obvious impure point to generate, proved response terminates.Wherein the reference substance of product is correct through nucleus magnetic hydrogen spectrum and mass spectrum determination structure, and with U.S. scientific and technical literature Antitumour Agents.Part2.Asymmetric Synthesis of (S)-Camptothecin.J.CHEM.SOC.PERKIN TRANS.11990 in disclose nuclear-magnetism and mass-spectrometric data is coincide.
In the examples below, α-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2, the nuclear-magnetism of 3,5-tetrahydrochysene benzazole-7-ethyl acetate (II) and Mass Spectrometry detection method can see U.S. scientific and technical literature Antitumour Agents.Part2.Asymmetric Synthesis of (S)-Camptothecin.J.CHEM.SOC.PERKIN TRANS.11990.
In the examples below, the calculation formula of the yield in embodiment 1-3 is: [(m
iI× 304)/(m
i× 382)] × 100%; Wherein, m
iI, m
irepresent respectively: the quality that feeds intake of the quality that formula II obtains through aftertreatment, formula I.
Embodiment 1
6-cyano group-1 is added successively in the 1000mL there-necked flask that mechanical stirring and drying tube be housed, 1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate 20.7g(0.068mol), tetracol phenixin 450ml, N-bromosuccinimide 13.33g(0.075mol), metachloroperbenzoic acid 0.6g(0.0034mol), open the incandescent light stirring 50W and shine, room temperature reaction 4-5h, reaction solution becomes off-white color aaerosol solution from tawny.Thin-layer chromatography detects and confirms reaction end, add methylene dichloride 400ml dissolved solids, use 10%(w/v successively, down together) sodium thiosulfate solution is washed 3 times, is washed 2 times, finally washes 1 time by saturated salt, use anhydrous sodium sulfate drying organic layer, be spin-dried for obtain faint yellow solid 25.75g, yield is 98%, and product can be directly used in next step reaction.
The nuclear magnetic spectrum of the α-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate (II) of gained is shown in Fig. 1.
Embodiment 2
6-cyano group-1 is added successively in the 250mL there-necked flask that mechanical stirring and drying tube be housed, 1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate 3.04g(0.01mol), trichloromethane 80ml, bromo-5, the 5-dimethyl hydantion 3.43g(0.012mol of 1,3-bis-), dibenzoyl peroxide 0.024g(0.1mmol), open stirring.The infrared lamp illumination of 100W, be heated to 80 DEG C of reaction 6h, reaction solution becomes off-white color aaerosol solution from tawny.Thin-layer chromatography detects and confirms reaction end.Add methylene dichloride 50ml dissolved solids, wash 2 times with 10% sodium thiosulfate solution successively, wash 2 times, finally wash 1 time by saturated salt, use anhydrous sodium sulfate drying organic layer, be spin-dried for obtain faint yellow solid 3.32g, yield is 87%, and product can be directly used in next step reaction.
The nuclear magnetic spectrum of the α-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate (II) of gained is identical with Fig. 1.
Embodiment 3
6-cyano group-1 is added successively in the 100mL there-necked flask that mechanical stirring and drying tube be housed, 1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate 1.52g(5mmol), toluene 35ml, N-bromosuccinimide 8.0g(4.5mmol), Diisopropyl azodicarboxylate 0.16g(1mmol), open stirring.Natural lighting, be heated to 50 DEG C of reaction 8h, reaction solution becomes off-white color aaerosol solution from tawny, and thin-layer chromatography detects and confirms reaction end, add methylene dichloride 20ml dissolved solids, wash 2 times with 10% sodium thiosulfate solution successively, wash 2 times, finally wash 1 time by saturated salt, use anhydrous sodium sulfate drying organic layer, be spin-dried for obtain faint yellow solid 3.4g, yield is 88%, and product can be directly used in next step reaction.
The nuclear magnetic spectrum of the α-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate (II) of gained is identical with Fig. 1.
Embodiment 4
By the α-bromo-6-cyano group-1 of embodiment 1 gained, 1-(ethylenedioxy)-5-oxygen-1, the concrete steps of 2,3,5-tetrahydrochysene benzazole-7-ethyl acetate (II) preparation (S)-camptothecine can see (such as) US Patent No. 4778891A1.Final obtained (S)-camptothecine 1.54g, mole total recovery is 17.6%.
The nuclear magnetic data of (the S)-camptothecine of gained is:
1hNMR (300MHz, DMSO-d6): δ 0.9 (3H, t, J=7.5Hz, CCH
2cH
3), 1.89 (2H, q, J=7.5Hz, CCH
2cH
3) .5.32 (2H, s, CH
2), 5.45 (2H, s, CH
2), 6.54 (1H, s, OH), 7.40 (1H, s, ArH), 7.6-8.3 (4H, m, ArH), and8.74 (1H, s, ArH); M/z348 (M+).
Embodiment 5
By the α-bromo-6-cyano group-1 of embodiment 2 gained, 1-(ethylenedioxy)-5-oxygen-1, the concrete steps of 2,3,5-tetrahydrochysene benzazole-7-ethyl acetate (II) preparation (S)-camptothecine can see (such as) US Patent No. 4778891A1.Final obtained (S)-camptothecine 0.19g, mole total recovery is 16.5%.
The nuclear magnetic data of (the S)-camptothecine of gained is identical with embodiment 4.
Embodiment 6
By the α-bromo-6-cyano group-1 of embodiment 3 gained, 1-(ethylenedioxy)-5-oxygen-1, the concrete steps of 2,3,5-tetrahydrochysene benzazole-7-ethyl acetate (II) preparation (S)-camptothecine can see (such as) US Patent No. 4778891A1.Final obtained (S)-camptothecine 0.17g, mole total recovery is 15.2%.
The nuclear magnetic data of (the S)-camptothecine of gained is identical with embodiment 4.
Claims (11)
1. the preparation method of (S)-camptothecine intermediate, described (S)-camptothecine intermediate is the compound α shown in formula II-bromo-6-cyano group-1,1-(ethylenedioxy)-5-oxygen-1,2,3,5-tetrahydrochysene benzazole-7-ethyl acetate:
Described method comprises:
In inert solvent, under the existence of initiator, under illumination condition, make the compound 6-cyano group-1 shown in formula I, 1-(ethylenedioxy)-5-oxygen-1,2,3, there is following bromo-reaction in 5-tetrahydrochysene benzazole-7-ethyl acetate and solid brominated reagent, thus obtains the compound shown in formula II:
2. method according to claim 1, wherein, described initiator is selected from dibenzoyl peroxide, metachloroperbenzoic acid or Diisopropyl azodicarboxylate; Be preferably metachloroperbenzoic acid.
3. method according to claim 1, wherein, the mol ratio of the compound shown in formula I and described initiator is 1:(0.01-0.2); Be preferably 1:(0.05-0.1).
4. method according to claim 1, wherein, described solid brominated reagent is selected from bromo-5, the 5-dimethyl hydantion of 1,3-bis-or N-bromosuccinimide; Be preferably N-bromosuccinimide.
5. method according to claim 1, wherein, the mol ratio of the compound shown in formula I and described solid brominated reagent is 1:(0.9-1.2); Be preferably 1:1.1.
6. method according to claim 1, wherein, described inert solvent is selected from one or more in hexanaphthene, toluene, tetracol phenixin, trichloromethane and DMF; Be preferably tetracol phenixin.
7. method according to claim 1, wherein, the weightmeasurement ratio of the compound shown in formula I and described inert solvent is 1:(10-50), be preferably 1:(20-30).
8. method according to claim 1, wherein, the temperature of reaction of described bromo-reaction is 0 DEG C-100 DEG C; Be preferably 15 DEG C-80 DEG C.
9. method according to claim 1, wherein, the light source of described illumination is selected from one or more in infrared lamp, incandescent light, natural light; Be more preferably incandescent light.
10. method according to claim 1, wherein, the reaction times of described bromo-reaction is 1-10 hour; Be preferably 4-8 hour; Be more preferably 6-7 hour.
The preparation method of 11. 1 kinds of (S)-camptothecine, it comprises:
1) compound according to the method preparation formula II in claim 1-10 described in any one; And
2) compound preparation (the S)-camptothecine shown in the formula II obtained by step 1).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310322465.4A CN104341429B (en) | 2013-07-29 | 2013-07-29 | (S) preparation method of-camptothecine intermediate and the preparation method of (S)-camptothecine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310322465.4A CN104341429B (en) | 2013-07-29 | 2013-07-29 | (S) preparation method of-camptothecine intermediate and the preparation method of (S)-camptothecine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104341429A true CN104341429A (en) | 2015-02-11 |
| CN104341429B CN104341429B (en) | 2016-08-10 |
Family
ID=52497953
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310322465.4A Expired - Fee Related CN104341429B (en) | 2013-07-29 | 2013-07-29 | (S) preparation method of-camptothecine intermediate and the preparation method of (S)-camptothecine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104341429B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4778891A (en) * | 1985-10-21 | 1988-10-18 | Daiichi Seiyaku Co., Ltd. | Certain pyrano (3,4-f)-indolizine derivatives |
| CN1183414A (en) * | 1996-10-30 | 1998-06-03 | 田边制药株式会社 | S type 2 -substituted hydroxy-2 -indolidinylbutyric ester compounds and process for preparation thereof |
-
2013
- 2013-07-29 CN CN201310322465.4A patent/CN104341429B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4778891A (en) * | 1985-10-21 | 1988-10-18 | Daiichi Seiyaku Co., Ltd. | Certain pyrano (3,4-f)-indolizine derivatives |
| CN1183414A (en) * | 1996-10-30 | 1998-06-03 | 田边制药株式会社 | S type 2 -substituted hydroxy-2 -indolidinylbutyric ester compounds and process for preparation thereof |
Non-Patent Citations (3)
| Title |
|---|
| JOSEPH W. EPSTEIN ET AL.: ""l-Aryl-3-azabicyclo[3.l.0]hexanes, a New Series of Nonnarcotic Analgesic Agents"", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| TATSUYA WATANABE ET AL.: ""Practical Synthesis of (20S)-10-(3-Aminopropyloxy)-7-ethylcamptothecin, a Water-Soluble Analogue of Camptothecin"", 《CHEMISTRY AN ASIAN JOURNAL》 * |
| YUN-YAN KUANG ET AL.: ""Synthesis and Molecular Structure of Ethyl [N-tosyl-(R)-prolyloxy]-2(S)-[4-cyano-8,8-ethylenedioxy-5-oxo-5,6,7,8-tetrahydroindolizin-3-yl] Acetate, a Key Intermediate in the Total Synthesis of (20S)-Camptothecins"", 《MOLECULES》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104341429B (en) | 2016-08-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Bao et al. | A fluorescent conjugated polymer for trace detection of diamines and biogenic polyamines | |
| CN110283169B (en) | N heterocyclic benzophenone derivative containing substituted hydrogenated acridine group and preparation method thereof | |
| CN103666452B (en) | A kind of bioprobe of methyl benzofuran quinolines and its preparation method and application | |
| CN108088828B (en) | Double-column aromatic mercury ion fluorescent sensor and preparation and application thereof | |
| CN113666966B (en) | Synthesis and application of fluorescent probe for detecting trace water in dimethyl sulfoxide | |
| CN112574739B (en) | Hydrogel sensor based on modified fluorescein derivative and preparation method thereof | |
| CN104341429A (en) | (S)-camptothecin intermediate preparation method and (S)-camptothecin preparation method | |
| US11203573B2 (en) | N-alkylation of acridans | |
| CN104151533A (en) | Fluorescent conjugated polymer containing phenothiazine group, and synthesis method and application thereof | |
| CN113999218B (en) | Flavonol compound, preparation method and application thereof in detection of biological mercaptan | |
| CN113045576B (en) | Construction method of pyrimido [1,2-b ] indazole parent nucleus | |
| CN111057066B (en) | Red solid fluorescent luminescent material and preparation method thereof | |
| Wu et al. | A [2+ 3] fragment coupling approach to N, O-bridged calix [1] arene [4] pyridines and their complexation with C60 | |
| CN104262250A (en) | Triiodothyroxin hapten luminous marker and synthetic method thereof | |
| CN114573512A (en) | Method for synthesizing C2-difluoroalkyl benzimidazole derivative | |
| CN108047291B (en) | Synthetic method of houttuynine sodium bisulfite heterozygosis flavonoid compound | |
| CN108003157B (en) | Perylene diimide compound, synthesis method thereof and Fe thereof 3+ Application in detection | |
| CN117362239B (en) | Luminol etherified derivative and preparation method and application thereof | |
| JP2003518084A (en) | Excited complex | |
| AU777784B2 (en) | Nucleic acid sequencing method | |
| CN111233905A (en) | Fluorescent probe for selectively detecting singlet oxygen in solution phase and application | |
| CN110078772A (en) | Fluorescence probe based on complex of iridium and preparation method thereof and the application in hypochlorous acid detects | |
| CN108976394A (en) | Conjugated polymer, synthetic method and the method for detecting Etimicin concentration with it | |
| CN107955156A (en) | One kind enhancing fluorescence probe intermediate and preparation method thereof | |
| CN106831816B (en) | A kind of gulf position embedding hexa-atomic thia ring and hexa-atomic oxa- ring -3,4,9,10- tetracarboxylic acid diimide and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee after: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee after: PKUCARE PHARMACEUTICAL R&D CENTER Patentee after: PKU HEALTHCARE INDUSTRY Group Address before: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: PKUCARE PHARMACEUTICAL R&D CENTER Patentee before: Pku Healthcare Industry Group Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221011 Address after: 3007, Hengqin international financial center building, No. 58, Huajin street, Hengqin new area, Zhuhai, Guangdong 519031 Patentee after: New founder holdings development Co.,Ltd. Patentee after: PKUCARE PHARMACEUTICAL R&D CENTER Patentee after: Peking University Medical Management Co.,Ltd. Address before: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: PKUCARE PHARMACEUTICAL R&D CENTER Patentee before: PKU HEALTHCARE INDUSTRY Group |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160810 |