+

WO1994005672A1 - PROCEDE DE PREPARATION DE CERTAINES PYRROLO[3,4-b]QUINOLINES, DE CERTAINES |H-PYRANO[3'4':6,7]INDOLIZINO[1,2-b]QUINOLIN-3,14(4H,12H)-DIONES, ET DE CERTAINES 8-METHYLE-7-(OXOPROPYLE)-INDOLIZINO[1,2-b]QUINOLIN-9(11H)-ONES - Google Patents

PROCEDE DE PREPARATION DE CERTAINES PYRROLO[3,4-b]QUINOLINES, DE CERTAINES |H-PYRANO[3'4':6,7]INDOLIZINO[1,2-b]QUINOLIN-3,14(4H,12H)-DIONES, ET DE CERTAINES 8-METHYLE-7-(OXOPROPYLE)-INDOLIZINO[1,2-b]QUINOLIN-9(11H)-ONES Download PDF

Info

Publication number
WO1994005672A1
WO1994005672A1 PCT/US1993/008434 US9308434W WO9405672A1 WO 1994005672 A1 WO1994005672 A1 WO 1994005672A1 US 9308434 W US9308434 W US 9308434W WO 9405672 A1 WO9405672 A1 WO 9405672A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinolin
process according
indolizino
compound
group
Prior art date
Application number
PCT/US1993/008434
Other languages
English (en)
Inventor
Joseph M. Fortunak
Zhiping Zhuang
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to KR1019950700883A priority Critical patent/KR950702987A/ko
Priority to AU51023/93A priority patent/AU5102393A/en
Priority to EP93920496A priority patent/EP0660835A4/en
Priority to JP6507518A priority patent/JPH08501104A/ja
Publication of WO1994005672A1 publication Critical patent/WO1994005672A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for preparing certain pyrrolo-[3,4-b]quinolines, certain 1H-pyrano[3',4':6,7] indolizino[3,4-b]quinolin-3,14(4H,12H)-diones, specifically camptothecin and its analogs, and certain 8-methyl-7-(oxopropyl)-indolizino[3,2-b]quinolin-9(11H)-ones, specifically mappicine ketones and mappicines.
  • camptothecin itself is known to be cytotoxic at levels which inhibit tumor growth
  • certain water-soluble camptothecin analogs which exhibit litde or no cytotoxicity are efficacious against solid tumor types normally refractory to known treatments.
  • (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione commonly known as topotecan (Formula lb), which is disclosed in U.S. Pat No.5,004,758, issued to Boehm et al.
  • tumors include, but are not limited to, ovarian, esophageal, non-small cell lung and colorectal carcinomas.
  • topotecan is also useful for the preparation of a combination chemotherapeutic pharmaceutical composition which also comprises a platinum coordination compound, most preferably cis-platin.
  • a platinum coordination compound most preferably cis-platin.
  • the 4-(piperidino)-piperidinyl carbamate analogue of 7-ethyl-10-hydroxycamptothecin, commonly known as irinotecan (or CPT- 11) (Formula Ic) has also been shown to be efficacious against certain tumors. Both compounds are presently undergoing human clinical testing in refractory tumor types. Additionally, the 9-amino and 10,11-methylenedioxy analogs: of camptothecin (Formula Id) have shown promising antitumor activity in preclinical testing.
  • camptothecin molecule results in compounds possessing antiviral activity while exhibiting little or no cytotoxicity.
  • examples of such compounds include derivatives in which the E ring lactone has been replaced by some other functionality, i.e., two broad classes of compounds commonly called mappicine ketones and mappicines, of Formulas IIa and IIb respectively.
  • mappicine ketones and mappicines of Formulas IIa and IIb respectively.
  • These compounds which are useful in treating infections in humans and animals caused by a variety of viruses, (for example, Herpes simplex virus types 1 and 2, cytomegalovirus, and Varicella zoster virus) are disclosed in U.S. Ser. No. 07/606,216, filed by S. Petteway et al. on October 31,1990; U.S. Ser. No.
  • Camptothecins have also been recently shown to possess antiretroviral activity, specifically the ability to inhibit the replication of Human
  • HTV-1 Immunodeficiency Virus
  • HTV-1 at dosages non-cytotoxic to mammalian cells, and thus may be useful in the treatment of patients suffering from Acquired Immune Deficiency Syndrome (AIDS, see AIDS Res. Hum. Retr., 1991, 7, 65).
  • topoisomerase I is a monomeric enzyme with a molecular weight of approximately 100,000.
  • Camptothecin is known to exert its antitumor activity by stabilization of the covalently bound topoisomerase I - DNA complex. As a result, progression of the DNA replication sequence proceeds only as far as induction of a single strand break. The ultimate result of this inhibition of the DNA transcription/replication process is cell death. Camptothecin and a few of its close congeners are the only agents in clinical drug development which inhibit topoisomerase I.
  • Topoisomerase II consists of two identical subunits of molecular weight 170,000. Topoisomerase II induces transient breaks of both strands of the DNA helix and passes another double-stranded segment through the break.
  • Several commercially important oncolytic agents e.g., etoposide, doxorubicin and mitoxantrone
  • camptothecin does not inhibit topoisomerase ⁇
  • mappicines and mappicine ketones are known to inhibit topoisomerase II As such these compounds are of interest both as potential antineoplastic and antiviral agents.
  • camptothecin discloses a semisynthetic method of preparing certain water-soluble camptothecin analogs from camptothecin.
  • the only practical method for obtaining preparative- and commercial-scale quantities of camptothecin is by extraction of the tissues of the Camptotheca acuminata tree indigenous to the People's Republic of China or the Nothapodytes foetida shrub indigenous to India.
  • reliance on such natural sources has certain inherent disadvantages, including very high starting material cost (about $28,000/kg) and lack of a dependable source. Camptothecin has also been prepared from readily available materials by various totally synthetic approaches.
  • strategy A a tricyclic CDE ring system is prepared by known methods and is coupled with ortho-aminobenzaldehyde via a Friedlander quinoline synthesis.
  • the critical bond disconnection strategy is shown by the dashed line labelled A.
  • strategy B tricyclic ABC and bicyclic DE ring components are prepared separately by known methods and are coupled using a two-step, standard procedure to form the D ring pyridone.
  • the critical bond disconnection strategy is shown by the dashed line labelled B.
  • the tricyclic ABC ring fragment for strategy B is ultimately prepared via a Friedlander quinoline synthesis requiring several steps. The Friedlander quinoline synthesis is therefore a basic component of many of the known approaches.
  • the present invention provides an efficient general route for the facile synthesis of pyrrolo[3,4-b]quinolines, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones and 1H-pyrano[3',4':6,7]indolizmo[1,2-b]qumolin-3,14(4H,12H)-diones, preferably camptothecin analogs.
  • the present invention provides a process for preparing pyrrolo[3,4-b]quinolines, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs , more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the step of intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV with the unactivated acetylene portion of said compound, the compound of Formula IV being generated from compounds of Formula III (shown in Scheme 2 below and having the same substitutions as compounds of Formula IV), which are derived from generally available compounds.
  • R 1 H, OH, or OR, where R is an ester protecting group
  • R 2 H, NO 2 , or a protected amine function
  • R 3 H, C 2 H 5 , or a trialkylsilyl
  • R 4 H or CH 2 COOEt
  • R 5 COOMe or tosyl
  • R 4 and R 5 are joined together to form a substituted pyridone IIa:
  • A H, COOR, or a functionality for preparation of the hydroxymethyl (C-17) portion of an E ring lactone
  • B H, OH, an appropriate leaving group such as halide or
  • the present invention also provides a process for the preparation of 7-(1,1-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-ones, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and 1H- pyrano[3 , ,4 , :6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the step of coupling a vinyl triflate derived from a 7-hydroxy-5,6-dihydroindolizino[1,2-b]quinolin-9(11
  • the resulting 7-(1,1-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one may be conveniently elaborated into a 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-dione or a 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one as disclosed elsewhere in the present application.
  • the present invention also provides a process for the preparation of pyrrolo[3,4-b]quinolines, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the steps of:
  • the present invention also provides a process for the preparation of camptothecin analogs which lack the lactone E ring, preferably 8-methyl-7-(oxopropyl)-indolizino[1,2-b]quinolin-9(11H)-ones, most preferably mappicines and mappicine ketones, said process comprising the steps of:
  • the present invention provides a process for the total synthesis of, depending upon choice of termination step, 4-ethyl-4-hydroxy-9-methoxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H, 12H)-dione, more commonly known as 10-methoxycamptothecin, 4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione, more commonly known as 10-hydroxycamptothecin, as well as of 10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4 , :6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-dione, more commonly known as topotecan, said process comprising the
  • tetrahydrofuran N,N-dimethylformamide, acetonitrile, acetone or N-methylpyrrolidinone, most preferably acetonitrile;at a temperature of about 20 -85°C, preferably about 60 - 85°C, most preferably at about the reflux temperature of acetonitrile; in the presence of a strong alkylatmg agent or such agent as is capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, imidoyl halide, or a strong acid (such as aluminum chloride) capable of initiating a cyclodehydration, preferably trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromid
  • a camptothecin includes camptothecin and and any derivative thereof the structure of which is based on the 1H-pyrano[3',4':6,7] indolizino-[1,2-b]quinolin-3,14(4H,12H)-dione ring system.
  • pyrrolo[3,4-b]quinoline refers generally to compounds based on these ring systems.
  • camptothecin analog includes camptothecins as defined above and also includes derivatives of camptothecin wherein the E ring has been replaced with another functionality.
  • esteer protecting group is defined to include C 1 -C 6 alkyl groups as well as allyl, benzyl, phenyl and ⁇ , ⁇ , ⁇ -trichloroethyl.
  • amine protecting group is defined to include alkyl and arylsulfonate esters, carbamates of common alkyl groups such as methyl, ethyl, ⁇ , ⁇ , ⁇ -trichloroethyl, allyl, tert-butyl and phenyl, amides such as acetamido and propionamido, as well as common alkyl groups such as methyl and benzyl.
  • trimerkylsilyl is defined to include trimethyl, triethyl, triisopropyl and tripropylsilyl, as well as phenyldimethylsilyl and tert-butyldimethylsilyl.
  • the present invention provides a process for preparing pyrrolo[3,4-b]quinolines, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, the process comprising the step of intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV, generated from a starting material of Formula III, with the unactivated acetylene portion of said compound.
  • Scheme 2 illustrates one embodiment of the present process wherein R 4 and R 5 of the compound of Formula IV are not joined together to form a pyridone
  • X, R 1 -R 5 and Y are as defined for Formula IV;
  • the starting material of Formula III is heated in a polar solvent, preferably methylene chloride, 1,2-dichloroethane, 1,2-dimethoxyethane tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone or N-methylpy ⁇ olidinone, most preferably acetonitrile; at a temperature of about 20 - 85 °C, preferably 60 - 85 °C, most preferably at the reflux temperature of acetonitrile; in the presence of a strong alkylating agent or such agent as is capable of producing either an O-alkylimidate or imidate ester, imidoyl halide, or such imide derivative as is capable of
  • cyclodehydration preferably trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromide, most preferably trimethyloxonium tetrafluoroborate, thereby generating the compound of Formula IV which then undergoes [4 + 2] cycloaddition to yield a pyrrolo[3,4-b]quinoline.
  • Compounds of Formula IV have not been isolated, but have been detected.
  • the products of the present process are either pharmaceutically useful themselves, e.g. topotecan, or are intermediates, e.g. 10-methoxycamptothecin, useful for elaboration into pharmaceutically useful compounds, particularly camptothecin analogs.
  • the present invention also provides a process for the preparation of 7-(1,1-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-ones, 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones; and1H-pyrano [3',4': 6,7] indolizino [1,2-b] quinolin - 3,14 (4H, 12H - diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, yet more preferably topotecan and irinotecan, most preferably topotecan, said process, referring to Scheme 3, comprising the step of coupling a vinyl triflate dervived from a 7-hydroxy-5,6-dihydroindoli
  • the resulting 7-(1,1-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one may be conveniently elaborated into a 1H-pyrano[3',4':6,7]indolizino-[1,2-b]quinolin-3,14(4H,12H)-dione or a 8-methyl-7-(oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one as disclosed elsewhere in the present application.
  • R 4 H or CH 2 COOEt
  • R 5 COOMe, toluenesulfonyl, benzyl, COCH 3 ; or COCH 2 CH 3
  • Y M.
  • this embodiment of the present process may be conveniently used to provide a variety of useful
  • the compounds of Formula IV are readily prepared by known methods, for example as shown in Scheme 5 and Steps 1-3 of Scheme 7, below, and as is exemplified in me Example (Steps 1-3 ).
  • a polar solvent such as methylene chloride, 1,2-dichl ⁇ roethane, 1,2-dimethoxyethane tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone or N-methylpyrrolidinone, but preferably acetonitrile; at a temperature of about 20 - 85 °C, preferably at 60 - 85 °C, most preferably at the reflux temperature of acetonitrile; in the presence of a strong alkylating agent or an agent capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, or an imidoyl halide, e.g.
  • trifluoromethanesulfonic anhydride dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or
  • triphenylphosphine/carbon tetrabromide preferably trimethyloxonium
  • step (b) the substituted pyrrolo[3,4-b]quinoline resulting from step (a) is cyclized to a 7-hydroxy-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one as follows.
  • the carbamate function protecting the C-ring nitrogen is hydrolytically cleaved, preferably with acetic acid saturated with HBr, to give the resulting tricyclic amine.
  • the amine is then coupled at the C-ring nitrogen with a monoalkyl malonyl chloride, preferably monomethyl malonyl chloride, to give the resulting malonate half-amide.
  • the D ring is formed when the malonate half-amide undergoes a Dieckmann condensation in the presence of base, preferably methoxide, to give a 7-hydroxy-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one.
  • step (c) the vinyl triflate of the 7-hydroxy-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one is coupled with a tertiary malonate anion to form a 7-(1,1-di-tert-butoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[1,2-b]quinolin-9(11H)-one.
  • step (d) the diester is cyclized to form the lactone E ring of an indolizino[1,2-b]quinolinone, preferably a camptothecin analog.
  • 1,2 elimination of the tertiary hydrogen ⁇ to the quinolino nitrogen by oxidation in the presence of sodium nitrite or other oxidizing agents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gives the analogous indolizino[1,2-b]quinolin-9(11H)-one, followed by reduction of the carbomethoxy group at C-8 to a hydroxymemyl function and hydrolysis/decarboxylation of the malonate diester to give the resulting 4-ethyl- 1H- pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione.
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • the 4-ethyl-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione may be further reacted to form a tertiary alcohol ⁇ to the E ring carbonyl by air-oxidation, thus giving a camptothecin.
  • camptothecin may be further elaborated to give a variety of
  • camptothecin analogs For instance, cleavage of the methoxy group of 4-ethyl-4-hydroxy-9-methoxy-1H-pyrano[3',4 , :6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione (10-methoxycamptothecin) with HBr yields 10-hydroxycamptothecin, which is itself pharmaceutically useful. 10-Hydroxycamptothecin may be conveniently converted to topotecan by reaction with N.N.N'.N'-tetramethyldiaminomemane (BDAM).
  • BDAM N.N.N'.N'-tetramethyldiaminomemane
  • camptothecin products of the present process may further be converted to camptothecin analogs in which the E ring has been replaced by some other functionality, e.g., mappicines and mappicine ketones, for instance by the process described in our recently allowed U.S. Ser. No. 07/589,848, which discloses a semisynthetic method of preparing certain 8-methyl-7-(-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-ones from camptothecin or derivitized camptothecins.
  • some other functionality e.g., mappicines and mappicine ketones
  • the starting material is a compound of Formula in wherein R 4 and R 5 are joined together to form a substituted pyridone.
  • the present invention provides a process for the preparation of camptothecin analogs which lack the lactone E ring, preferably 8-methyl-7-(oxopropyl)-indolizino [1,2-b]quinolin-9(11H)-ones, most preferably mappicines (1ib) and mappicine ketone (11a), said process comprising the steps of:
  • camptothecin analog which lacks the lactone E ring, preferably a 8-methyl-7-(oxopropyl)-indolizino[1,2-b]quinolin-9(11H)-one, most preferably a mappicine or mappicine ketone.
  • the present invention provides a process, as shown in Scheme 7, for the total synthesis of, depending upon choice of termination step, 4-ethyl-4-hydroxy-9-memoxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinolin-3,14(4H, 12H)-dione, more commonly known as 10-methoxycamptothecin, 4-ethyl-4,9-dihydroxy-1H-pyrano[3',4 , :6,7] indolizino[1,2-b]quinolin-3,14(4H,12H)-dione, more commonly known as 10-hydroxycamptothecin, as well as of 10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-3,14(4H,12H)-dione, more commonly known as topotecan, said
  • tetrahydrofuran N,N-dimeti ⁇ ylformamide, acetonitrile, acetone or N-methylpyrrolidinone, most preferably acetonitrile;at a temperature of about 20 -85°C, preferably about 60 - 85°C, most preferably at about the reflux temperature of acetonitrile; in the presence of a strong alkylating agent or such agent as is capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, imidoyl halide, or a strong acid (such as aluminum chloride) capable of initiating a cyclodehydration, preferably trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetra
  • step (b) hydrolyzing the carbamate function of the C-2 substituted pyrrolo[3,4-b]quinoline from step (a) with acetic acid saturated with HBr to give a tricyclic amine (X);
  • Soduim borohydride (200 mg, 3 eq.) was added in small portions to this stirred solution and the resulting mixture was stirred for 15 minutes after addition was complete.
  • the solvent was removed on a rotavapor and dilute hydrochloric acid (50 ml of 0.4% solution) was added to the residue.
  • the mixture was extracted with 3 ⁇ 100 ml of methylene chloride.
  • the combined organic layers were dried over magnesium sulfate and concentrated to give a dark solid to which trifluoroacetic acid (20 ml) was added.
  • the mixture was stirred at ambient temperature for 1 h. Trifluoroacetic acid was removed on a rotavapor and water (50 ml) was added to the residue.
  • the overall yield of topotecan for the total synthesis in 13 steps was about 5- 6%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de certaines pyrrolo-[3,4-b]quinolines, de certaines 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-diones, spécifiquement de la camptothécine et ses analogues, et de certaines 8-méthyl-7-(oxopropyle)-indolizino[1,2-b]quinolin-9(11H)-ones, spécifiquement des cétones de mappicines, et des mappicines. Ledit procédé comprend l'étape consistant en la cycloaddition intramoléculaire [4+2]de la partie N-arylimidate d'un composé de formule (IV), dans laquelle X=OH, OAlCl2, Cl, Br, I, F, OR, OSO2CF3 ou n'importe quel groupe labile satisfaisant ou H, R1=H, ou OR, où R représente un groupe protecteur d'ester; R2=H, NO2 ou une fonction amine protégée; R3=H, C2H5, ou un trialkylsilyle; R4=H ou CH2COOEt; R5=COOMe ou tosyle; ou R4 ainsi que R5 sont joints pour former une pyridone substituée de formule (IVa): Y=H ou Y,R1=-OCH2O-, formule dans laquelle A=H, COOR, ou une fonctionnalité de préparation de la partie hydroxyméthyle (C-17) d'une lactone à cycle E; B=H, OH, un groupe labile approprié tel que halogénure ou O(trifluorométhanesulfonate), ou une fonctionnalité de préparation de C-(18-21) de la partie lactone à cycle E de camptothécine, avec la partie acétylène non activée dudit composé.
PCT/US1993/008434 1992-09-08 1993-09-08 PROCEDE DE PREPARATION DE CERTAINES PYRROLO[3,4-b]QUINOLINES, DE CERTAINES |H-PYRANO[3'4':6,7]INDOLIZINO[1,2-b]QUINOLIN-3,14(4H,12H)-DIONES, ET DE CERTAINES 8-METHYLE-7-(OXOPROPYLE)-INDOLIZINO[1,2-b]QUINOLIN-9(11H)-ONES WO1994005672A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1019950700883A KR950702987A (ko) 1992-09-08 1993-09-08 특정 피롤로[3,4-b] 퀴놀린, 특정 1H-피라노[3′,4′: 6,7]인돌리지노[1,2-b] 퀴놀린-3,14(4H,12H)-디온, 및 특정 8-메틸-7-(옥소프로필)-인돌리지노[1,2-b] 퀴놀린-9-(11H)-온을 제조하는 방법(PROCESS FOR PREPARING CERTAIN PYRROLO[3,4-b]QUINOLINES, CERTAIN 1H-PYRANO[3′,4′: 6,7] INDOLIZINO[1,2-b]QUINOLIN-3,14(4H,12H)-DIONES, AND CERTAIN 8-METHYL-7-(OXOPROPYL)-INDOLIZINO[1,2-b]QUINOLIN-9(11H)-ONES
AU51023/93A AU5102393A (en) 1992-09-08 1993-09-08 Process for preparing certain pyrrolo(3,4- b)quinolines, certain 1H-pyrano(3',4':6,7)indolizino(1,2-b)quinolin-3,14(4H,12H) -diones, and certain
EP93920496A EP0660835A4 (en) 1992-09-08 1993-09-08 Process for preparing certain pyrrolo 3,4- -i(b))quinolines, certain 1h-pyrano 3',4':6,7)indolizino 1,2--i(b))quinolin-3,14(4h,12h)-diones, and certain 8-methyl-7-(oxopropyl)-indolizino 1,2--i(b))quinolin-9(11h)-ones.
JP6507518A JPH08501104A (ja) 1992-09-08 1993-09-08 ある種のピロロ［３，４−ｂキノリン類、ある種の１Ｈ−ピラノ［３’，４’：６，７インドリジノ［１，２−ｂキノリン−３，１４（４Ｈ，１２Ｈ）−ジオン類およびある種の８−メチル−７−（オキソプロピル）−インドリジノ［１，２−ｂキノリン−９（１１Ｈ）−オン類の製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US94149692A 1992-09-08 1992-09-08
US07/941,496 1992-09-08

Publications (1)

Publication Number Publication Date
WO1994005672A1 true WO1994005672A1 (fr) 1994-03-17

Family

ID=25476581

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/008434 WO1994005672A1 (fr) 1992-09-08 1993-09-08 PROCEDE DE PREPARATION DE CERTAINES PYRROLO[3,4-b]QUINOLINES, DE CERTAINES |H-PYRANO[3'4':6,7]INDOLIZINO[1,2-b]QUINOLIN-3,14(4H,12H)-DIONES, ET DE CERTAINES 8-METHYLE-7-(OXOPROPYLE)-INDOLIZINO[1,2-b]QUINOLIN-9(11H)-ONES

Country Status (11)

Country Link
EP (1) EP0660835A4 (fr)
JP (1) JPH08501104A (fr)
KR (1) KR950702987A (fr)
CN (1) CN1096297A (fr)
AU (2) AU5102393A (fr)
CA (1) CA2144048A1 (fr)
MX (1) MX9305517A (fr)
NZ (1) NZ255942A (fr)
TW (1) TW246674B (fr)
WO (1) WO1994005672A1 (fr)
ZA (1) ZA936580B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660861B1 (en) * 2003-03-27 2003-12-09 Council Of Scientific And Industrial Research Process for preparing Topotecan from 10-hydroxy-4-(S) camptothecin

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN2757510Y (zh) 2004-12-06 2006-02-08 鸿富锦精密工业（深圳）有限公司 散热器扣具
US7520313B2 (en) 2006-03-16 2009-04-21 Fu Zhun Precision Industry (Shen Zhen) Co., Ltd. Locking device for heat sink
CN105859716B (zh) * 2016-05-06 2018-03-09 华东师范大学 一种合成喜树碱类化合物中5‑6并环结构的方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS49117491A (fr) * 1973-03-26 1974-11-09
JPS5217499A (en) * 1975-07-31 1977-02-09 Nippon Chemiphar Co Ltd Preparation of mappicine
DE2534601A1 (de) * 1975-08-02 1977-02-17 Basf Ag Verfahren zur herstellung von camptothecin-aehnlichen verbindungen
US4914205A (en) * 1987-06-25 1990-04-03 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives
JPH0383986A (ja) * 1989-08-29 1991-04-09 Yakult Honsha Co Ltd 新規キノリン誘導体およびその製造法
US5155225A (en) * 1990-09-28 1992-10-13 Smithkline Beecham Corporation Method for making certain pyrano[3',4':6,7]indolizino-[1,2-B]quinolinones

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS49117491A (fr) * 1973-03-26 1974-11-09
JPS5217499A (en) * 1975-07-31 1977-02-09 Nippon Chemiphar Co Ltd Preparation of mappicine
DE2534601A1 (de) * 1975-08-02 1977-02-17 Basf Ag Verfahren zur herstellung von camptothecin-aehnlichen verbindungen
US4914205A (en) * 1987-06-25 1990-04-03 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives
JPH0383986A (ja) * 1989-08-29 1991-04-09 Yakult Honsha Co Ltd 新規キノリン誘導体およびその製造法
US5155225A (en) * 1990-09-28 1992-10-13 Smithkline Beecham Corporation Method for making certain pyrano[3',4':6,7]indolizino-[1,2-B]quinolinones

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Jour. Am. Chem. Soc., Vol. 111, issued 1989, HAYAKAWA et al., "Competitive Intramolecular (4+2) Cycloaddition and Tandem (2+2) Cycloaddition (3,3)-Sigma-Tropic Rearrangement Sequence of Allenyl3-Vinyl-2-Cyclohexene Ethers: Evidence for Switching of the Reactive Pathway by the Substituent Effects", see *
Jour. Am. Chem. Soc., Vol. 114, issued July 1992, CURRAN et al., "New 4+1 Radical Annulations. A Formal Total Synthesis of (+) Camptothecin", pages 5863-4, see entire document. *
See also references of EP0660835A4 *
Tetrahedron Letters, Vol. 27, No. 40, issued 1986, K.J. SHEA et al., "The Intramolecular Diels-Alder Cycloaddition of N Dienoyl Acrylimidates. New Methodology for the Construction of Nitrogen Heterocycles", pages 4837-40, see Scheme 1, page 4839. *
Tetrahedron Letters, Vol. 32, No. 52, issued 1991, D.L. BOGER et al., "Studies on the Synthesis of Rubrolone; 4 Pi Participation of O-AlkylAlpha, Beta, Unsaturated Oximesin Intramolecular (4+2) Cycloaddition Reactions", pages 7643-46, see page 7643, Scheme 1 and page 7645. *
Tetrahedron, Vol. 44, No. 13, issued 1985, C. CLARKE et al., "An Approach to the Synthesis of Gelsemine: The Intramolecular Reaction of an Allylsilane with an Acyliminium Ion for the Synthesis of the Quaternary Centres", pages 3931-44. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660861B1 (en) * 2003-03-27 2003-12-09 Council Of Scientific And Industrial Research Process for preparing Topotecan from 10-hydroxy-4-(S) camptothecin

Also Published As

Publication number Publication date
AU5102393A (en) 1994-03-29
AU2859197A (en) 1997-10-23
ZA936580B (en) 1994-08-01
NZ255942A (en) 1996-11-26
CA2144048A1 (fr) 1994-03-17
KR950702987A (ko) 1995-08-23
TW246674B (fr) 1995-05-01
CN1096297A (zh) 1994-12-14
MX9305517A (es) 1994-05-31
EP0660835A4 (en) 1995-08-16
EP0660835A1 (fr) 1995-07-05
JPH08501104A (ja) 1996-02-06

Similar Documents

Publication Publication Date Title
US5244903A (en) Camptothecin analogs as potent inhibitors of topoisomerase I
FI91872C (fi) Menetelmä terapeuttisesti aktiivisten pyranoindolitsinokinoliinijohdannaisten valmistamiseksi
Wani et al. Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogs
US5106742A (en) Camptothecin analogs as potent inhibitors of topoisomerase I
US4981968A (en) Synthesis of camptothecin and analogs thereof
ES2254600T3 (es) Nuevos analogos de la camptotecina, procedimientos de preparacion, su aplicacion como medicamentos y las composiciones farmaceuticas que los contienen.
WO1998035940A1 (fr) Derives de camptothecine hautement lipophile
US5364858A (en) Camptothecin analogs as potent inhibitors of topoisomerase I
US5405963A (en) Process for asymmetric total synthesis of camptothecin analogues
NZ520835A (en) Alkylated imidazopyridine derivatives
EP0555347A1 (fr) INDOLIZINO 1,2-b]QUINOLINONES SUBSTITUEES
WO1996021666A1 (fr) Derives de camptothecine et leur procede de fabrication
JP2003528879A (ja) 三環式イミダゾピリジン
WO1994005672A1 (fr) PROCEDE DE PREPARATION DE CERTAINES PYRROLO[3,4-b]QUINOLINES, DE CERTAINES |H-PYRANO[3'4':6,7]INDOLIZINO[1,2-b]QUINOLIN-3,14(4H,12H)-DIONES, ET DE CERTAINES 8-METHYLE-7-(OXOPROPYLE)-INDOLIZINO[1,2-b]QUINOLIN-9(11H)-ONES
NZ248841A (en) Pyrido[4,3-b]carbazole derivatives (or ellipticines) and medicaments
MXPA04011682A (es) Camptotecinas con un anillo lactona modificado.
Albright et al. Synthesis of 1, 4, 5, 6‐tetrahydropyrazolo [3, 4‐d] pyrido [3, 2‐b] azepine
CA2161318A1 (fr) Nouveaux derives anthraquinoniques ayant une activite antitumorale, et leurs applications
US6169080B1 (en) Highly lipophilic camptothecin derivatives
IL144987A (en) History of homocamptocin and medicinal products containing them
US6500953B1 (en) Preparation of camptothecin and nothapodytine derivatives
Groundwater et al. Synthesis of pyrido [2, 3-c] acridines
Hepburn et al. A concise synthesis of further thiophene analogues of kuanoniamine a
Hermecz et al. A ring transformation of 6, 7-dihydro-4H-pyrido [1, 2-a] pyrimidin-4-ones
MXPA01000767A (en) Preparation of camptothecin and nothapodytine derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR BY CA CZ FI HU JP KP KR KZ LK LV MG MN MW NO NZ PL RO RU SD SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 255942

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2144048

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1993920496

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 1995 397214

Country of ref document: US

Date of ref document: 19950407

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 1993920496

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1993920496

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载