EP0660835A1 - PROCEDE DE PREPARATION DE CERTAINES PYRROLO 3,4-$i(b)]QUINOLINES, DE CERTAINES H-PYRANO 3'4':6,7]INDOLIZINO 1,2-$i(b)]QUINOLIN-3,14(4H,12H)-DIONES, ET DE CERTAINES 8-METHYLE-7-(OXOPROPYLE)-INDOLIZINO 1,2-$i(b)]QUINOLIN-9(11H)-ONES - Google Patents

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

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Publication number
EP0660835A1
EP0660835A1 EP93920496A EP93920496A EP0660835A1 EP 0660835 A1 EP0660835 A1 EP 0660835A1 EP 93920496 A EP93920496 A EP 93920496A EP 93920496 A EP93920496 A EP 93920496A EP 0660835 A1 EP0660835 A1 EP 0660835A1
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Prior art keywords
quinolin
process according
indolizino
compound
group
Prior art date
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EP93920496A
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German (de)
English (en)
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EP0660835A4 (en
Inventor
Joseph M. Fortunak
Zhiping Zhuang
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0660835A1 publication Critical patent/EP0660835A1/fr
Publication of EP0660835A4 publication Critical patent/EP0660835A4/en
Withdrawn legal-status Critical Current

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    • 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-&]quinolines, certain lH-pyrano[3',4':6,7] indolizino[l,2-&]quinolin- 3,14(4H,12H)-diones, specifically camptothecin and its analogs, and certain 8- methyl-7-(oxopropyl)-indolizino[l,2-i>]quinolin-9(l lH)-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- lH-pyTano[3',4':6,7] indolizino[l,2- ?]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-lO-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 Ha and lib respectively.
  • mappicine ketones and mappicines of Formulas Ha and lib 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. 07/783,063, filed by H.
  • Camptothecins have also been recently shown to possess antiretroviral activity, specifically the ability to inhibit the replication of Human 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).
  • HTV-1 Human Immunodeficiency Virus
  • 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 ⁇ 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 IL As such these compounds are of interest both as potential antineoplastic and antiviral agents.
  • a tricyclic CDE ring system is prepared by known methods and is coupled with ort r ⁇ -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-Z>]quinolines, 8-methyl-7-(oxopropyl)indolizino[l,2- fc]quinolin-9(HH)-ones and lH-pyrano[3',4':6,7]indoUzmo[l,2- ⁇ ]qumo ⁇ n- 3,14(4H,12H)-diones, preferably camptothecin analogs.
  • the present invention provides a process for preparing pyrrolo[3,4- ?]quinolines, 8-methyl-7-(oxopropyl)indolizino[l,2-b]quinolin-9(llH)- ones; and lH-pyrano[3',4':6,7]indolizino[l,2- ?]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 IH (shown in Scheme 2 below and having the same substitutions as compounds of Formula IV), which are derived from generally
  • R-l H, OH, or OR, where R is an ester protecting group
  • R2 H, NO2, or a protected amine function
  • R3 H, C2H5, or a trialkylsilyl
  • R4 H or CH 2 COOEt
  • R5 COOMe or tosyl
  • 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 O(trifluoromethanesulfonate) or a functionality for preparation of C-(18-21) of the E ring lactone portion of camptothecin.
  • the present invention also provides a process for the preparation of 7-(l,l-_t ⁇ s-alkoxycarbonyl)propyl-8-me ⁇ oxycarbonyl-5,6- dihydroindolizino[ 1 ,2-6]quinolin-9( 1 lH)-ones, 8-methyl-7- (oxopropyl)indolizino[l,2-6]quinolin-9(l lH)-ones; and 1H- pyrano[3 , ,4 , :6,7]indolizino[l,2- >]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[
  • the resulting 7-( 1,1 -bis- alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[l,2-b]quinolin- 9(1 lH)-one may be conveniently elaborated into a 1H- pyrano[3',4':6,7]indolizino[l,2-b]quinolin-3,14(4H,12H)-dione or a 8-methyl-7- (oxopropyl)indolizino[l,2-b]quinolin-9(llH)-one as disclosed elsewhere in the present application.
  • the present invention also provides a process for the preparation of pyrrolo[3,4- ⁇ ]quinolines, 8-methyl-7-(oxopropyl)indolizino[l,2- 6]quinolin-9(l lH)-ones; and lH-pyrano[3',4':6,7]indolizino[l,2-fc]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[l,2-fc]quinolin-9(l lH)-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-lH-pyrano[3',4':6,7] indolizino[l,2-6]quinolin-3,14(4H, 12H)-dione, more commonly known as 10-methoxycamptothecin, 4-ethyl-4,9-dihydroxy-lH- indolizino[l,2-fe]quinolin-3,14(4H,12H)-dione, more commonly known as 10-hydroxycamptothecin, as well as of 10-[(dimethylamino)methyl]-4- ethyl-4,9-dihydroxy-lH-pyrano[3',4 , :6,7]indoUzino[l,2-Z>]quinolin-3,14(4H,12H)- dione, more commonly known as topotecan, said process comprising the steps of: (
  • a polar solvent preferably methylene chloride, 1,2-dichloroethane, 1,2-dimethoxyethane 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-benzyltrichloroacet
  • a camptothecin includes camptothecin and and any derivative thereof the structure of which is based on the lH-pyrano[3',4':6,7] indolizino-[l,2-6]quinolin-3,14(4H,12H)-dione ring system.
  • pyrrolo[3,4-fc]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 C1-C6 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, re/T-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 pre ides a process for preparing pyrrolo[3,4-
  • X, Rl - R5 and Y are as defined for Formula IV;
  • Table I illustrates representative compounds and intermediates made by the present process.
  • the starting material of Formula HI is heated in a polar solvent, preferably methylene chloride, 1,1 ⁇ ichloroethane, 1,2-dimethoxyethane tetrahydrofuran, N,N- dimethylformamide, 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 alkylatmg 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, 0-benzyltrichloroacetimidate, triphenylphosine/carbon
  • 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-(l,l- 6w-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[l,2- 6]quinolin-9(l lH)-ones, 8-methyl-7-(oxopropyl)indolizino[l,2-Z>]quinolin-9(l 1H)- ones; andlH-pyrano [3',4': 6,7] indolizino [l,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,
  • the resulting 7-(l,l-6 «- alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin- 9(1 lH)-one may be conveniently elaborated into a lH-pyrano[3 * ,4':6,7]indolizino- [l,2-6]quinolin-3,14(4H,12H)-dione or a 8-methyl-7-(oxopropyl)indolizino[l,2- 6]quinolin-9(llH)-one as disclosed elsewhere in die present application.
  • this embodiment of the present process may be conveniently used to provide a variety of useful intermediates (pyrrolo[3,4-b]quinolines, indolizino[l,2-b]quinolin-9(l lH)-ones and lH-pvrano[3 ⁇ 4':6,7]indolizino[l,2-b]quinolin-3,14(4H, 12H)-diones) and products, preferably camptothecin analogs, by the selection of appropriately substituted starting materials and of the appropriate terminating step.
  • This process comprises the steps of:
  • 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- dimemylformamide, 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 tetrafluoroborate, thereby generating a compound of Formula IV which then undergoes [4 + 2] cycloaddition to yield a substituted pyrrolo[3,4-6]quinoline.
  • solvents, temperature ranges, and alkylating agents applies to all embodiments disclosed in the present application.
  • step (b) the substituted pyrrolo[3,4-b]quinoline resulting from step (a) is cyclized to a 7-hydroxy-5,6-dihydroindolizino[l,2-b]quinolin-9(l lH)-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[l,2-b]quinolin- 9(llH)-one.
  • step (c) the vinyl triflate of the 7-hydroxy-8- methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin-9(HH)-one is coupled witii a tertiary malonate anion to form a 7-(l,l-di-rerr-butoxycarbonyl)propyl-8- methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin-9(llH)-one.
  • step (d) the diester is cyclized to form the lactone E ring of an indolizino[l,2-6]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-l,4-benzoquinone (DDQ) gives the analogous indolizino[l,2-b]quinolin-9(llH)-one, followed by reduction of d e 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[l,2-6]quinolin-3,14(4H,12H)-dione.
  • DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
  • the 4-ethyl- 1H- pyrano[3',4':6,7] indolizino[l,2-6]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.
  • the camptothecin may be further elaborated to give a variety of camptothecin analogs.
  • 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[l,2- b]quinolin-9(l lH)-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 R4 and R5 are joined togetiier to form a substituted pyridone.
  • the present invention provides a process for die preparation of camptothecin analogs which lack the lactone E ring, preferably 8-methyl-7-(oxopropyl)-indolizino [l,2-b]quinolin-9(HH)-ones, most preferably mappicines (lib) 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[l,2-6]quinolin-9(llH)-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-lH-pyrano[3',4':6,7] indolizino[l,2-6]quinolin- 3,14(4H, 12H)-dione, more commonly known as 10-methoxycamptothecin, 4-ethyl- 4,9-dihydroxy-lH-pyrano[3',4 , :6,7] indolizino[l,2-6]quinolin-3,14(4H,12H)-dione, more commonly known as 10-hydroxycamptothecin, as well as of 10- [(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH-pyrano[3',4':6,7]indolizino[l,2- 6]quinolin-3,14(4H,12H)-dione, more commonly known
  • a compound of Formula in (e.g. VII) in a polar solvent preferably methylene chloride, 1,2-dichloroethane, 1,2-dimethoxyethane 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, dimetiiylsulfate, alkyloxonium tetra
  • the starting material of Formula HI (e.g. V ⁇ i) may be prepared from a variety of readily available starting materials using well-known methods.
  • a mixture of fumaric acid mono p-memoxy phenyl amide mono etiiyl ester (50g, 0.2 mol) and propargyl amine (40 ml, 3 eq.) in t ⁇ uOH (700 ml) was stirred under reflux at 100 °C for 24 h.
  • the reaction mixture was cooled to 20 °C and solvent was removed on a rotavapor.
  • Ethyl acetate (1500 ml) was added to the remaining thick oil.
  • the resulting solution was washed widi hydrochloric acid (10%, 3 x 500 ml).
  • the aqueous phase was then made basic to a pH of approximately 8 by the slow addition of solid sodium bicarbonate.
  • the white grey solid obtained as a byproduct from the initial filtration from hexane:ethyl acetate was N-propargyl aspartic N-p-methoxy phenyla ide, mp 165- 166 °C.
  • Step 8 To a suspension of the tetracyclic enol (lg, 2.9 mmol) in methylene chloride (50 ml) was added triethylamine (0.5 ml, 1.2 eq.). The resulting brown solution was cooled to -78 °C using a dry ice-acetone batii. Trifluoromethanesulfonic anhydride (0.6 ml, 1.2 eq.) was added dropwise, neat. After me addition was complete, d e dry ice-acetone bath was replaced by an ice batii and d e reaction mixture was stirred at 0 °C for anotiier hour, then poured into ice water (100 ml). The mixture was extracted with 3 x 100 ml of methylene chloride. The combined organic phases were washed with water (100 ml) dried, and evaporated to give a brown solid which was used directly in the next reaction.
  • Soduim borohydride (200 mg, 3 eq.) was added in small portions to this stirred solution and die 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 die residue.
  • the mixture was extracted with 3 x 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%.

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  • 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.
EP93920496A 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. Withdrawn EP0660835A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US94149692A 1992-09-08 1992-09-08
US941496 1992-09-08
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

Publications (2)

Publication Number Publication Date
EP0660835A1 true EP0660835A1 (fr) 1995-07-05
EP0660835A4 EP0660835A4 (en) 1995-08-16

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP93920496A Withdrawn 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.

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)

Families Citing this family (4)

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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
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

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5626677B2 (fr) * 1973-03-26 1981-06-19
JPS5217499A (en) * 1975-07-31 1977-02-09 Nippon Chemiphar Co Ltd Preparation of mappicine
DE2534601C2 (de) * 1975-08-02 1987-01-22 Basf Ag, 6700 Ludwigshafen Verfahren zur Herstellung von Camptothecin und Camptothecin-Derivaten
CA1332413C (fr) * 1987-06-25 1994-10-11 Kabushiki Kaisha Yakult Honsha Derives de la campothecine et methode de preparation
JP2711728B2 (ja) * 1989-08-29 1998-02-10 株式会社ヤクルト本社 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 (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9405672A1 *

Also Published As

Publication number Publication date
TW246674B (fr) 1995-05-01
ZA936580B (en) 1994-08-01
WO1994005672A1 (fr) 1994-03-17
EP0660835A4 (en) 1995-08-16
CA2144048A1 (fr) 1994-03-17
CN1096297A (zh) 1994-12-14
MX9305517A (es) 1994-05-31
JPH08501104A (ja) 1996-02-06
KR950702987A (ko) 1995-08-23
NZ255942A (en) 1996-11-26
AU2859197A (en) 1997-10-23
AU5102393A (en) 1994-03-29

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