CN104650107A - Preparation method of 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I) - Google Patents

Preparation method of 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I) Download PDF

Info

Publication number
CN104650107A
CN104650107A CN201510072600.3A CN201510072600A CN104650107A CN 104650107 A CN104650107 A CN 104650107A CN 201510072600 A CN201510072600 A CN 201510072600A CN 104650107 A CN104650107 A CN 104650107A
Authority
CN
China
Prior art keywords
preparation
dihydro
ethyl
indolizine
pyrans
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.)
Pending
Application number
CN201510072600.3A
Other languages
Chinese (zh)
Inventor
陈芬儿
牛新文
吴妍
王新龙
许灵君
熊方均
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fudan University
Original Assignee
Fudan University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Fudan University filed Critical Fudan University
Priority to CN201510072600.3A priority Critical patent/CN104650107A/en
Publication of CN104650107A publication Critical patent/CN104650107A/en
Pending legal-status Critical Current

Links

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
    • C07D491/22—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

Abstract

The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I). The method comprises the following step: in the presence of Lewis acid, carrying out ketalization on 4-ethyl-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,6,10(4H)-trione (II) and glycol compounds (III) in an organic solvent and a polar non-proton cosolvent to obtain the 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I). The method is mild in conditions and simple to operate, does not have special requirements for reactors, and is convenient for industrial production.

Description

A kind of preparation method of 4-ethyl-6,6-disubstituted alkoxy base-7,8-dihydro-1H-pyrans [3,4-f] indolizine-3,10 (4H)-diketone (I)
Technical field
The invention belongs to technical field of organic chemistry, be specifically related to a kind of 4-ethyl-6,6-disubstituted alkoxy base-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,10 (4 hthe preparation method of)-diketone (I).
Background technology
4-ethyl-6,6-disubstituted alkoxy base-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,10 (4 h)-diketone (I) is that synthesis camptothecin antitumour drug is as the important intermediate of irinotecan, topotecan, Belotecan, 10-hydroxycamptothecine etc.
US Patent No. 4894456) and European patent EP 0220601 successively describe with 7-methyl-6-cyano group-1,5-dioxo-1,2,3,5-indolizine is starting raw material, through reaction preparation 4-ethyls-6,6-(1 such as ethylene ketal, ethoxycarbonyl, cyano reduction, cyclizations, 2-ethylenedioxy)-7,8-dihydros-1 h-pyrans [3,4- f] indolizine-3,10 (4 hthe method of)-diketone (I).
This processing step is tediously long, and potassium hydride KH is expensive and without industrialization product supply, be unfavorable for scale operation.
Chen Fener etc. ( helv. Chim. Acta 200891,2057-2061, CN101121719) describe with 7-methyl-6-cyano group-1,5-dioxo-1,2,3,5-indolizine is starting raw material, through reaction preparation 4-ethyls-6 such as ethylene ketal, ethoxycarbonyl, cyano group selective reduction, cyclizations, 6-(ethylenedioxy)-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,10 (4 hthe method of)-diketone (I).
This technique is not still avoided using expensive potassium hydride KH, causes industrial production cost high.
4-ethyl-6,6-(2,2-dimethyl-trimethylenedioxy)-7,8-dihydros-1 h-pyrans [3,4- f] indolizine-3,10 (4 h)-diketone (I) obtains by the step such as, ethoxycarbonyl ketalization through neopentyl glycol with the similar approach that describes in above-mentioned two lines, reduction.
Summary of the invention
The object of the present invention is to provide 4-ethyl-6,6-disubstituted alkoxy base-7, the 8-dihydro-1 that a kind of step is simple, cost is low h-pyrans [3,4- f] indolizine-3,10 (4 hthe preparation method of)-diketone (I), is applicable to suitability for industrialized production.
4-ethyl-6,6-disubstituted alkoxy base-7,8-dihydro-1 of the present invention h-pyrans [3,4- f] indolizine-3,10 (4 h)-diketone (I), its chemical formula is as follows:
R in formula 1, R 2be respectively hydrogen, halogen, be connected or disjunct straight or branched C1-C5 alkyl, n is 0-1.
4-ethyl-6,6-disubstituted alkoxy base-7,8-dihydro-1 provided by the present invention h-pyrans [3,4- f] indolizine-3,10 (4 hthe preparation method of)-diketone (I), it is by 4-ethyl-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,6,10 (4 h)-triketone (II) and glycol compound (III) in the presence of a lewis acid, carry out ketal reaction, prepare 4-ethyl-6,6-disubstituted alkoxy base-7,8-dihydro-1 in organic solvent and aprotic, polar solubility promoter h-pyrans [3,4- f] indolizine-3,10 (4 h)-diketone (I);
Its synthetic route is as follows:
In formula, R 1, R 2be respectively halogen, be connected or disjunct straight or branched C1-C5 alkyl, n is 0-1.
In the present invention, described glycol compound (III) is ethylene glycol, 1,3-PD, 2-single substitution propanediol, 2,2-two replace propylene glycol; Preferred ethylene glycol, 1,3-PD or neopentyl glycol.
In the present invention, described halogenated silanes class Lewis acid is trimethylchlorosilane.
In the present invention, described organic solvent be halohydrocarbon, single-substituted, disubstituted benzene, tetrahydrofuran (THF), dioxane, C2-C5 nitrile, C2-C5 ethers one or more; Preferred methylene dichloride, 1,2-ethylene dichloride, tetrahydrofuran (THF) or acetonitrile.
In the present invention, described aprotic, polar solubility promoter is n,N-dimethyl formamide, n,N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) or hexamethylphosphoramide; Be preferably n,N-dimethyl formamide.
In the present invention, 4-ethyl-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,6,10 (4 h)-triketone (II): glycol compound (III): the mol ratio of halogenated silanes is 1:(1 ~ 10): (1 ~ 5), preferably 1: (1 ~ 4): (1 ~ 5); Temperature of reaction is 0 ~ 100 DEG C, preferably 0 ~ 80 DEG C, and the reaction times is 1 ~ 24h, preferably 5 ~ 24h.
In the present invention, described 4-ethyl-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,6,10 (4 h)-triketone (II) by with j. Org. Chem. 1993, the similar approach described in 58,611-617 obtains.
The invention has the advantages that raw material is easy to get, the features such as reaction conditions is gentle, easy and simple to handle, be applicable to suitability for industrialized production.
Embodiment
Following examples illustrate content of the present invention better.But the invention is not restricted to following embodiment.
Embodiment 1
By compound (II) (10g, 0.04mol), ethylene glycol (8.3g, 0.13mol), methylene dichloride (360mL) and n,Nwhole dissolving is stirred to after-dimethyl formamide (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.18mol), 25 DEG C of reactions 20 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separate organic phase through anhydrous anhydrous sodium sulfate drying, reclaim methylene dichloride and obtain compound (I) 10.8g, yield 92%.
Embodiment 2
By compound (II) (10g, 0.04mol), neopentyl glycol (9.7g, 0.09mol), 1,2-ethylene dichloride (360mL) and n,Nwhole dissolving is stirred to after-dimethyl formamide (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.18mol), 25 DEG C of reactions 20 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separates organic phase through anhydrous anhydrous sodium sulfate drying, reclaims 1,2-ethylene dichloride obtains compound (I) 12.7g, yield 94%.
Embodiment 3
By compound (II) (10g, 0.04mol), 1,3-PD (6.8g, 0.09mol), methylene dichloride (360mL) and n,Nwhole dissolving is stirred to after-dimethyl formamide (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.18mol), 25 DEG C of reactions 20 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separate organic phase through anhydrous anhydrous sodium sulfate drying, reclaim methylene dichloride and obtain compound (I) 11.2g, yield 93%.
Embodiment 4
By compound (II) (10g, 0.04mol), 2-methyl isophthalic acid, ammediol (14.4g, 0.16mol), methylene dichloride (360mL) and n,Nwhole dissolving is stirred to after-dimethyl formamide (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.18mol), 25 DEG C of reactions 24 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separate organic phase through anhydrous anhydrous sodium sulfate drying, reclaim methylene dichloride and obtain compound (I) 11.6g, yield 91%.
Embodiment 5
By compound (II) (10g, 0.04mol), ethylene glycol (8.3g, 0.13mol), methylene dichloride (360mL) and n,Nwhole dissolving is stirred to after-N,N-DIMETHYLACETAMIDE (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.18mol), 25 DEG C of reactions 20 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separate organic phase through anhydrous anhydrous sodium sulfate drying, reclaim methylene dichloride and obtain compound (I) 10.7g, yield 91%.
Embodiment 6
By compound (II) (10g, 0.04mol), ethylene glycol (8.3g, 0.13mol), whole dissolving is stirred to after methylene dichloride (360mL) and dimethyl sulfoxide (DMSO) (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.18mol), 25 DEG C of reactions 20 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separate organic phase through anhydrous anhydrous sodium sulfate drying, reclaim methylene dichloride and obtain compound (I) 10.6g, yield 90%.
Embodiment 7
By compound (II) (10g, 0.04mol), ethylene glycol (8.3g, 0.13mol), acetonitrile (360mL) and n,Nwhole dissolving is stirred to after-dimethyl formamide (10ml) mixing, temperature control 0-5 DEG C drips methyl chlorosilane (19.3g, 0.18mol), 25 DEG C of reactions 7 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separate organic phase through anhydrous anhydrous sodium sulfate drying, reclaim acetonitrile and obtain compound (I) 9.7g, yield 82%.
Embodiment 8
By compound (II) (10g, 0.04mol), ethylene glycol (8.3g, 0.13mol), tetrahydrofuran (THF) (360mL) and n,Nwhole dissolving is stirred to after-dimethyl formamide (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.18mol), 25 DEG C of reactions 7 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separate organic phase through anhydrous anhydrous sodium sulfate drying, reclaim tetrahydrofuran (THF) and obtain compound (I) 10.8g, yield 92%.
Embodiment 9
By compound (II) (10g, 0.04mol), neopentyl glycol (9.7g, 0.04mol), methylene dichloride (360mL) and n,Nwhole dissolving is stirred to after-dimethyl formamide (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.04mol), 40 DEG C of back flow reaction 24 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separate organic phase through anhydrous anhydrous sodium sulfate drying, reclaim methylene dichloride and obtain compound (I) 7.47g, yield 56%.
Embodiment 10
By compound (II) (10g, 0.04mol), ethylene glycol (8.20g, 0.132mol), 1,2-ethylene dichloride (360mL) and n,Nwhole dissolving is stirred to after-dimethyl formamide (10ml) mixing, temperature control 0-5 DEG C drips trimethylchlorosilane (19.3g, 0.04mol), 80 DEG C of reactions 5 hours are risen to after dropwising, reaction terminates the washing of rear use 10% sodium carbonate solution (100ml × 3), separates organic phase through anhydrous anhydrous sodium sulfate drying, reclaims 1,2-ethylene dichloride obtains compound (I) 11.2g, yield 96%.

Claims (9)

1. 4-ethyl-6,6-disubstituted alkoxy base-7, a 8-dihydro-1 h-pyrans [3,4- f] indolizine-3,10 (4 hthe preparation method of)-diketone (I), this compound chemistry formula is:
R in formula 1, R 2be respectively hydrogen, halogen, be connected or disjunct straight or branched C1-C5 alkyl, n is 0-1;
It is characterized in that concrete steps are as follows:
By 4-ethyl-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,6,10 (4 h)-triketone (II) and glycol compound (III) in the presence of a lewis acid, carry out ketal reaction, prepare 4-ethyl-6,6-disubstituted alkoxy base-7,8-dihydro-1 in organic solvent and aprotic, polar solubility promoter h-pyrans [3,4- f] indolizine-3,10 (4 h)-diketone (I).
2. preparation method as claimed in claim 1, is characterized in that described glycol compound (III) is ethylene glycol, 1,3-PD, 2-single substitution propanediol or 2,2-are two and replaces propylene glycol.
3. preparation method as claimed in claim 1 or 2, is characterized in that described halogenated silanes class Lewis acid is trimethylchlorosilane.
4. preparation method as claimed in claim 1, is characterized in that described organic solvent is the one in halohydrocarbon, single-substituted, disubstituted benzene, tetrahydrofuran (THF), dioxane, C2-C5 nitrile, C2-C5 ethers, or wherein several.
5. preparation method as claimed in claim 1, is characterized in that described aprotic, polar solubility promoter is n,N-dimethyl formamide, n,N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) or hexamethylphosphoramide.
6. preparation method as claimed in claim 1, is characterized in that described 4-ethyl-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,6,10 (4 h)-triketone (II): glycol compound (III): the mol ratio of halogenated silanes is 1:(1 ~ 10): (1 ~ 5), temperature of reaction is 0 ~ 100 DEG C, and the reaction times is 1 ~ 24h.
7. preparation method as claimed in claim 2, it is characterized in that described 2,2-, two to replace propylene glycol be neopentyl glycol.
8. preparation method as claimed in claim 4, is characterized in that described organic solvent is methylene dichloride, 1,2-ethylene dichloride, tetrahydrofuran (THF) or acetonitrile.
9. preparation method as claimed in claim 6, is characterized in that described 4-ethyl-7,8-dihydro-1 h-pyrans [3,4- f] indolizine-3,6,10 (4 h)-triketone (II): glycol compound (III): the mol ratio of halogenated silanes is 1: (1 ~ 4): (1 ~ 5), and temperature of reaction is 0 ~ 80 DEG C, and the reaction times is 5 ~ 24h.
CN201510072600.3A 2015-02-12 2015-02-12 Preparation method of 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I) Pending CN104650107A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510072600.3A CN104650107A (en) 2015-02-12 2015-02-12 Preparation method of 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510072600.3A CN104650107A (en) 2015-02-12 2015-02-12 Preparation method of 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I)

Publications (1)

Publication Number Publication Date
CN104650107A true CN104650107A (en) 2015-05-27

Family

ID=53241801

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510072600.3A Pending CN104650107A (en) 2015-02-12 2015-02-12 Preparation method of 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I)

Country Status (1)

Country Link
CN (1) CN104650107A (en)

Citations (3)

* Cited by examiner, † Cited by third party
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
US4894456A (en) * 1987-03-31 1990-01-16 Research Triangle Institute Synthesis of camptothecin and analogs thereof
CN101121719A (en) * 2007-09-06 2008-02-13 复旦大学 Method for preparing (S)-4-ethyl-6,6-disubstituted alkoxy(thio)-7,8-dihydro-4-hydroxy-1H-pyran[3,4-f]indoleridine-3,10-(4H)-dione compounds (I)

Patent Citations (3)

* Cited by examiner, † Cited by third party
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
US4894456A (en) * 1987-03-31 1990-01-16 Research Triangle Institute Synthesis of camptothecin and analogs thereof
CN101121719A (en) * 2007-09-06 2008-02-13 复旦大学 Method for preparing (S)-4-ethyl-6,6-disubstituted alkoxy(thio)-7,8-dihydro-4-hydroxy-1H-pyran[3,4-f]indoleridine-3,10-(4H)-dione compounds (I)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KEIKO TAGAMI，等: "Asymmetric syntheses of (+)-camptothecin and (+)-7-ethyl-10-methoxycamptothecin", 《HETEROCYCLES》 *

Similar Documents

Publication Publication Date Title
Mori et al. Expeditious Construction of Quinazolines via Brønsted Acid-induced C–H Activation: Further Extension of “tert-Amino Effect”
CN105111205B (en) A kind of preparation method of Pa Boxini
Zheng et al. A highly efficient way to capture CX 2 (O, S) mildly in reusable ReILs at atmospheric pressure
CN104744303A (en) 2-R-4'-bromomethyl biphenyl and preparation method thereof
CN105384788A (en) Tildipirosin preparation method
CN102993205B (en) High-yield purification method for preparation of high-purity sildenafil freebases
CN101486753A (en) Novel method for synthesizing finasteroid
Mori et al. Open-shell singlet diradicaloid difluoreno [4, 3-b: 3′, 4′-d] furan and its radical cation and dianion
CN107540678B (en) Method for preparing coumarin heteroaromatic ring compound and derivative thereof through intramolecular cross dehydrogenation coupling
CN104650107A (en) Preparation method of 4-ethyl-6,6-bis-substituted-alkoxy-7,8-dihydro-1H-pyranyl[3,4-f]indolizinyl-3,10(4H)-dione (I)
CN102250016B (en) Method for preparing 4,5,6-trichloropyrimidine
CN102070679B (en) 1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose and application
CN102229561B (en) Method for preparing 2, 2-disubstituted 1, 2-dihydro quinoline derivative
CN103664952A (en) Preparation method of zopiclone
CN102372707B (en) The synthetic method of 6-methyl-4-bromo-1,6-pyrrolin [2,3-c] pyridin-7-one
CN103396371A (en) Preparation method of erlotinib hydrochloride crystal form A
CN106008336A (en) Preparation method of 4-chloro-6,7-dimethoxyquinoline
CN104370962B (en) Lamellar triphenylphosphine and production method thereof and application
CN103896903A (en) Method for preparing and purifying 2,3-O-isopropylidene threitol
CN103373963B (en) Intermediate of pazopanib hydrochloride and preparation method of intermediate of pazopanib hydrochloride
CN111518148A (en) Synthetic method of gastrodin intermediate
CN107629049B (en) Synthesis method of pyridine [2,1-a ] isoindole compound
CN107235837B (en) Preparation method of fenofibric acid
CN107011362B (en) A kind of synthetic method of lavo-ofloxacin isomeric compound
CN104016900A (en) Preparation method of 3, 3'-diindolylmethane

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20150527