EP1192126A1 - Esters actives de c-2 hydroxyl protege-n-acyl(2r,3s)-3-phenylisoserine et methodes de production de ces derniers - Google Patents

Esters actives de c-2 hydroxyl protege-n-acyl(2r,3s)-3-phenylisoserine et methodes de production de ces derniers

Info

Publication number
EP1192126A1
EP1192126A1 EP00946816A EP00946816A EP1192126A1 EP 1192126 A1 EP1192126 A1 EP 1192126A1 EP 00946816 A EP00946816 A EP 00946816A EP 00946816 A EP00946816 A EP 00946816A EP 1192126 A1 EP1192126 A1 EP 1192126A1
Authority
EP
European Patent Office
Prior art keywords
group
formula
compound according
chemical compound
moiety
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.)
Withdrawn
Application number
EP00946816A
Other languages
German (de)
English (en)
Inventor
Jan Zygmunt
James D. Mcchesney
Madhavi C. Chander
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.)
Tapestry Pharmaceuticals Inc
Original Assignee
Tapestry Pharmaceuticals Inc
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
Priority claimed from US09/336,962 external-priority patent/US6143902A/en
Priority claimed from US09/336,961 external-priority patent/US6136999A/en
Application filed by Tapestry Pharmaceuticals Inc filed Critical Tapestry Pharmaceuticals Inc
Publication of EP1192126A1 publication Critical patent/EP1192126A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/72—4,7-Endo-alkylene-iso-indoles
    • C07D209/76—4,7-Endo-alkylene-iso-indoles with oxygen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • This invention generally relates to the synthesis of paclitaxel from precursor compounds. More particularly, though, this invention concerns the semi-synthesis of paclitaxel using a protected baccatin III backbone which is esterified with suitably protected side chain activated esters to produce an intermediate that may be converted to paclitaxel.
  • paclitaxel The chemical compound referred to in the literature as taxol, and more recently "paclitaxel", has received increasing attention in the scientific and medical community due to its demonstration of anti-tumor activity.
  • Paclitaxel has been approved for the chemotherapeutic treatment of several different varieties of tumors, and the clinical trials indicate that paclitaxel promises a broad range of potent anti-leukemic and tumor-inhibiting activity.
  • paclitaxel is a naturally occurring taxane diterpenoid having the formula and numbering system as follows:
  • paclitaxel is found in several species of yew (genus Taxus, family Taxaceae), the concentration of this compound is very low. Moreover, these evergreens are slow-growing. Thus, a danger exists that the increasing use of paclitaxel as an effective anti-cancer agent will deplete natural resources in the form of the yew trees. Indeed, while the bark of the yew trees typically exhibit the highest concentration of paclitaxel, the production of 1 kilogram of paclitaxel requires approximately 16,000 pounds of bark. Thus, the long term prospects for the availability of paclitaxel through isolation is discouraging.
  • the paclitaxel compound is built upon the baccatin III backbone, and there are a variety of other taxane compounds, such as baccatin III, cephalommanine, 10-deacetyl baccatin III, etc., some of which are more readily extracted in higher yields from the yew tree. Indeed, a relatively high concentration of 10-deacetyl baccatin III can be extracted from the leaves of the yew as a renewable resource. Typically, however, these other taxane compounds present in the yew tree do not exhibit the degree of anti-tumor activity shown by the paclitaxel compound.
  • paclitaxel compound Since the paclitaxel compound appears so promising as a chemotherapeutic agent, organic chemists have spent substantial time and resources in attempting to synthesize the paclitaxel molecule.
  • a more promising route to the creation of significant quantities of the paclitaxel compound has been proposed by the semi-synthesis of paclitaxel by the attachment of the A-ring side chain to the C-13 position of the naturally occurring baccatin III backbone derived from the various taxanes present in the yew. See, Denis et al, "Highly Efficient, Practical Approach to Natural Taxol", Journal of the American Chemical Society, page 5917 (1988). In that article, the partial synthesis of paclitaxel from 10-deacetylbaccatin III is described.
  • the side chain in Swindell et al is distinct from the side chain attachment used in Denis et al, above, in that the nitrogen is protected as a carbamate.
  • the A-ring side chain is benzyloxycarbonyl (CBZ) protected. After esterification, the CBZ protecting group is removed and replaced by PhCO to lead to paclitaxel. This process generated higher yields than that described in Denis et al.
  • the preferred masking groups were selected to be trichloroethoxymethyl or trichloroethoxycarbonyl.
  • BOM Benzyloxymethyl
  • U.S. Patent No. 4,924,012 issued May 8, 1990 to Colin et al discloses a process for preparing derivatives of baccatin III and of 10- deacetylbaccatin III, by condensation of an acid with a derivative of a baccatin III or of 10-deacetyl baccatin III, with the subsequent removal of protecting groups by acid hydrolysis.
  • Another object of the present invention is to provide a new and useful process for the production of an hydrogenatable benzyl-type protected side chain which may be readily attached to a protected baccatin III backbone during the semi-synthesis of paclitaxel.
  • Ri may be an alkyl group, an olefinic group, an aromatic group, an O-alkyl group, an O-olefinic group, or an O-aromatic group, and Z may be a substituted phenyl moiety or an N- imido moiety.
  • Ri is preferably Ph, PhCH 2 , O-Ph or 0-CH 2 Ph, and Pi is preferably benzyl, benzyloxymethy! or benzoyl.
  • Z may be a phenyl moiety having the formula:
  • each of R2 to Re is H or an electron withdrawing group.
  • electron withdrawing groups include NO2 or halogens, such as F. It is preferred that at least one of R2 to Re is a halogen or NO2.
  • a preferred embodiment is where Pi is benzyloxymethyl; R 2 , R 3 , Rs, and Re are H; R 4 is NO2; and Ri is OCH 2 Ph. Also preferred is where Pi is benzyloxymethyl; R2, R 3 , R , Rs and Re are F; and Ri is OCH2Ph. It is further preferred where Pi is benzyloxymethyl; R2 and R are N0 2 ; R 3 , Rs, and Re
  • Z may alternatively be a heterocyclic N-imido moiety, preferably having 5 to 7 atoms in the ring, and alternatively substituted with at least one electron withdrawing group, such as a nitro or a halogen group.
  • the N-imido moiety may be substituted with a plurality of the same or different electron withdrawing groups.
  • Z may be succinimido, phthalimido, 5- norbornene-2,3-dicarboxyimido, and maleimido moieties and substituted derivatives thereof.
  • the present invention is also directed to a process for producing an ester derivative useful in the production of paclitaxel, paclitaxel analogues and their intermediates.
  • the process comprises the step of reacting a first compound of the general formula:
  • Ri is an alkyl group, an olefinic group, an aromatic group, an O-alkyl group, an O-olefinic group, or an O-aromatic group
  • Pi is a hydroxyl protecting group
  • R10 is H or CO2X, where X is an alkyl group, an olefinic group or an aromatic group, with a second compound of the general formula:
  • Ri is an alkyl group, an olefinic group, an aromatic group, an O-alkyl group, an O-olefinic group, or an O-aromatic group
  • Pi is a hydroxyl protecting group
  • Z is selected from the group consisting of a substituted phenyl moiety and an N-imido moiety.
  • R10 is H
  • the step of reacting may be conducted in the presence of THF and a carbodiimide, such as dicyclohexylcarbodiimide.
  • X may particularly be — CH2CH(CH 3 )2, and the step of reacting may be conducted in the presence of N-methyl morpholine and THF.
  • the first compound may be formed by reacting a compound having the formula:
  • the second compound may be one having the formula: wherein each of R2 to Re is selected from the group consisting of H and an electron withdrawing group.
  • each of R2 to Re may be H, halogen or NO2 with at least one of R2 to Re being halogen or NO2.
  • Ri may particularly be Ph, PhCH , O-Ph or 0-CH Ph, and Pi may be benzyl, benzyloxymethyl or benzoyl.
  • the second compound may be one where Z may be a heterocyclic N-imido moiety, such as one having 5 to 7 atoms in the ring.
  • Z may be succinimido, phthalimido, 5- norbornene-2,3-dicarboxyimido, or maleimido moieties and substituted derivatives thereof.
  • the present disclosure is broadly directed to a chemical process for the efficient production of paclitaxel, intermediates and precursors therefor. More specifically, the present invention concerns the semi-synthesis of paclitaxel by esterifying suitably protected 3-phenylisoserine activated esters having protecting groups at C-2 to the C-13 hydroxyl of 7-O-protected baccatin III. More particularly, the present invention preferably utilizes CBZ protection at the C-7 site of the baccatin III.
  • the general process described herein involves the production of C-7 CBZ baccatin III, the production of a suitably protected 3-phenylisoserine activated ester having a suitable protecting group at C-2, the condensation of the two compounds, and the subsequent deprotection, acylation, deprotection of the condensation product to form paclitaxel.
  • baccatin III can be protected at the C-7 site to yield C-7 CBZ baccatin III.
  • 10-deacetylbaccatin III (10-DAB) can be directly converted to C-7 CBZ baccatin III without going through a baccatin III intermediate. Production from baccatin III is advantageous for its yield and simplicity.
  • the method using 10- deacetylbaccatin III has an advantage since 10-deacetylbaccatin III is much more naturally abundant, and thus less expensive, than baccatin III; however, this alternative method has a reduced yield.
  • Baccatin III is dissolved in THF (tetrahydrofuran) to form a first solution, which is cooled under a nitrogen atmosphere to a reduced temperature of less than -20°C.
  • n-Butyl lithium 1.6 M in hexane
  • CBZ-CI Benzyl chloroformate
  • the third solution is quenched with cold saturated ammonium chloride to eliminate any excess n- butyl lithium and CBZ-CI, and the mixture is concentrated under vacuum to yield a first residue.
  • This first residue is next taken up in ethyl acetate and washed once with water to remove unwanted salts.
  • the organic layer is washed with brine.
  • the organic layer is then dried and concentrated under vacuum to yield a second residue.
  • the second residue is recrystallized or column chromatographed with ethyl acetate: hexane to give C-7 CBZ baccatin III as a white solid.
  • alkali bases may be used, especially potassium hydride and sodium hydride, to form the C-7 metal alkoxide of baccatin III, to the extent understood by the ordinarily skilled artisan.
  • C-7 CBZ baccatin III can be synthesized directly from 10-deacetylbaccatin III as follows:
  • 10-DAB III is dissolved in THF to form a first solution which is cooled to a reduced temperature of less than -20°C, and preferably to -40°C, under a nitrogen atmosphere.
  • At least two equivalents of n-butyl lithium 1.6 M in hexane
  • acetyl chloride one equivalent
  • acetic anhydride one equivalent may possibly be used in place of the acetyl chloride to acylate the 10-DAB III.
  • benzyl chloroformate (one equivalent) is next added, and this fourth solution is stirred for an additional thirty minutes at the reduced temperature and then warmed to 0°C over thirty minutes.
  • the fourth solution is then quenched with cold saturated ammonium chloride at the reduced temperature to remove any excess n- butyl lithium, acetyl chloride and CBZ-CI; this mixture is then warmed to room temperature.
  • the solvent is removed under vacuum to yield an initial residue, which is taken up in ethyl acetate and washed with water to remove unwanted salts.
  • the organic layer is then washed with brine, dried and concentrated under vacuum to yield a final residue.
  • both Route 1 and Route 2 to the production of C-7 CBZ baccatin III can be expressed as a generalized method.
  • This method starts with a step of dissolving a starting compound selected from the group consisting of baccatin III and 10-deacetylbaccatin III in a first solvent to form a first solution.
  • the first solution is then cooled to a temperature of -20°C or less.
  • an alkyl lithium base is added to the first solution thereby to form an intermediate compound having a lithium alkoxide at the C-7 position thereof.
  • the method includes selectively acylating, at the C-10 position, any of the first intermediate compound present in the first solution where the intermediate compound does not already have an acetyl group at the C-10 position thereby to produce a second solution of C-7 lithium alkoxide of baccatin III.
  • the starting compound is baccatin III
  • the C-10 position already has an acetyl group.
  • the method includes a step of thereafter adding CBZ-CI to the second solution to form a third solution of C-7 CBZ baccatin III.
  • Ri is an alkyl group, an olefinic group, an aromatic group, Ph, PhCH2, an O-alkyl group, an O-olefinic group, an O-aromatic group, O-Ph, or 0-CH 2 Ph.
  • Pi is a hydroxyl protecting group and R2 can be an N-imido group or a phenyl ring substituted with one or more electron withdrawing groups.
  • Imido groups contemplated by the present invention include such groups as succinimido, phthalimido, 5-norbornene-2,3-dicarboxyimido, or derivatives thereof such as a maleimido group or succinimido group substituted at the 3 and/or 4 positions, or other heterocyclic imido groups, preferably having 5 to 7 atoms in the ring, alternatively substituted with chloro, fluoro, nitro or other groups.
  • the preferred hydroxyl protecting group is a benzyloxymethyl (BOM) protecting group.
  • BOM benzyloxymethyl
  • Benzyl has also been demonstrated to be suitable as has benzoyl, and other protecting groups are believed suitable as well.
  • the preferred N-Acyl group is benzyl oxycarbonyl (CBZ).
  • Other protecting groups and acyl groups (having alkyl, olefinic, and aromatic substituents and variations thereon) may be substituted, to the extent understood by the ordinarily skilled artisan.
  • the starting compound to produce the desired side chain is (2R,3S)- 3-phenylisoserine ethyl ester to produce the preferred N-CBZ protected (2R,3S)-3-phenylisoserine ethyl ester according to the reaction:
  • (2R,3S)-3-phenylisoserine ethyl ester was alternatively dissolved in either equal parts diethyl etherwater or equal parts methyl t-butyl etherwater and the solution was cooled to 0°C.
  • the sodium carbonate was then added to the solution and benzylchloroformate was added dropwise over an interval of about five minutes and the resulting mixture stirred at 0°C for approximately one hour.
  • the solution was then poured into water and extracted with methylene chloride or ethyl acetate, as desired.
  • the organic layer is separated, dried and reduced under vacuum to residue.
  • the residue was then recrystallized from ethyl acetate: hexane to result in N-CBZ (2R,3S)-3-phenylisoserine ethyl ester having the formula:
  • the N-CBZ (2R,3S)-3-phenylisoserine ethyl ester was next protected by the hydrogenatable benzyl-type protecting group, in several ways.
  • the hydrogenatable benzyl-type protecting group in several ways.
  • one route to the desired hydrogenatable benzyl protected side chain is as follows:
  • the CBZ (2R,3S)-3-phenylisoserine ethyl ester is dissolved in anhydrous THF under a nitrogen atmosphere and cooled to a reduced temperature such as -40°C or -78°C, for example, in a dry ice/acetone bath followed by the dropwise addition of an alkylithium agent, such as n-butyl lithium, although it is desirable that the alkylithium agent be a straight chain alkyl.
  • an alkylithium agent such as n-butyl lithium
  • the reaction is best done at a temperature no greater than 0°C.
  • the resulting mixture was stirred for about ten minutes.
  • Benzyloxymethyl chloride (BOM-CI) was then added dropwise over an interval of about five minutes and the mixture stirred for approximately two to five hours at the reduced temperature. Thereafter, the solution was warmed to 0°C and quenched with water. The resulting mixture is reduced under vacuum to residue, and this residue is thereafter taken up in ethyl acetate and washed with water and brine. The organic layer may then be dried and reduced under vacuum and the residue recrystallized from ethyl acetate:hexane or chromatographed with ethyl acetate: hexane to give the compound:
  • the resulting protected (2R,3S)-3-phenylisoserine ethyl ester compound of formula 6 may simply be converted to the N-CBZ C- 2 O-BOM-protected (2R,3S) phenylisoserine intermediate by the reaction:
  • Benzyl itself is another example of a hydrogenatable benzyl protecting group that may be used instead of BOM.
  • the CBZ protected (2R,3S)-3-phenylisoserine ethyl ester is dissolved in anhydrous THF under a nitrogen atmosphere and cooled to a reduced temperature such as -40°C or -78°C, for example, in a dry ice/acetone bath followed by the dropwise addition of an alkylithium agent, such as n-butyl lithium, although it is desirable that the alkylithium agent be a straight chain alkyl.
  • an alkylithium agent such as n-butyl lithium
  • BnBr Benzyl bromide
  • the compound of Formula 8 may be obtained according to the reaction:
  • N-CBZ C-2-OBOM protected (2R,3S)-3-phenylisoserine (Formula 7) may be converted into its corresponding activated esters by one of two routes, although it should be appreciated that other este fication methods known in scientific literature may be used to produce the activated ester, to the extent understood by the ordinarily skilled artisan. Further, it should be appreciated that the methods are applicable to C-2 and C-3N variations of Formula 7, to the extent understood by the ordinarily skilled artisan.
  • N-CBZ-C-2-OBOM protected (2R,3S)-3- phenylisose ne is mixed with 1.2 equivalents of dicyclohexylcarbodiimide or other suitable carbodiimide and 1.2 equivalents of either p-nitrophenol, pentaflurophenol, 2,4-dinitrophenol (or other substituted phenols, to the extent understood by the ordinarily skilled artisan) or N-hydroxy succinimide (or other N-hydroxy imides, to the extent understood by the ordinarily skilled artisan) in THF and stirred for several hours at room temperature.
  • the preferred substituted phenol is p-nitrophenol.
  • the preferred N-hydroxy imide is N-hydroxy succinimide. It should be appreciated that the substituted phenols and N-hydroxy imides contemplated by the present invention are either readily available or may be synthesized from readily available starting materials according to procedures known in the art.
  • the resulting mixture is diluted with ethyl acetate, cooled to 0°C for several hours, stirred for an additional several minutes and filtered.
  • the filtrate is then washed with 1 N HCI, water, 20% aqueous NaHC0 3 , water, brine, dried over sodium sulfate and reduced in vacuo to a residue.
  • the residue may then be column chromatographed and/or recrystallized from ethyl acetate: heptane.
  • a mixed anhydride of N-CBZ-C-2-OBOM 3- phenylisoserine may be reacted with either p-nitrophenol, pentaflurophenol, 2,4-dinitrophenol (or other substituted phenols, to the extent understood by the ordinarily skilled artisan) or N-hydroxy succinimide (or other N-hydroxy imides, to the extent understood by the ordinarily skilled artisan) to afford the corresponding activated esters. It is contemplated that mixed anhydrides having alkyl, olefinic, aromatic or other appropriate radicals might be used, to the extent understood by the ordinarily skilled artisan.
  • N-CBZ-C-2-OBOM-3-phenylisoserine in THF cooled to -15° to -20°C under nitrogen was added 1.5 equivalents of i-butyl chloroformate followed by 1.5 equivalents of N-methyl morpholine.
  • the resulting mixture was stirred for several minutes followed by addition of 1.5 equivalents of either p-nitrophenol, pentaflurophenol, 2,4-dinitrophenol (or other substituted phenols, to the extent understood by the ordinarily skilled artisan) or N-hydroxy succinimide (or other N-hydroxy imides, to the extent understood by the ordinarily skilled artisan).
  • the mixture was then stirred for several minutes between -15° to 0°C then one hour at between 0°C to 25°C. After which time the mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and reduced in vacuo to a residue. The residue was then purified by column chromatography and/or recrystallization from heptane:ethyl acetate.
  • Reaction XII Reactions VIII, IX, X, XI and XII may be generalized by the following reaction XIII:
  • Pi is a hydroxyl protecting group such as BOM or benzyl
  • Ri is an alkyl group, an olefinic group, an aromatic group (such as Ph, PhCH2), an 0- alkyl group, an O-olefinic group, or an O-aromatic group (such as O-Ph or O- CHaPh);
  • Rio is H or CO2X, where X is an alkyl group, an olefinic group, or an aromatic group; and Z is either a substituted phenyl moiety such as:
  • each of R2 to Re is selected from the group consisting of H and an electron withdrawing group (such as a halogen or NO2), or Z is an N-imido moiety, including but not limited to succinimido, phthalimido, 5-norbornene- 2,3-dicarboxyimido, maleimido or derivatives thereof such as a maleimido group or succinimido group substituted at the 3 and/or 4 positions, or other heterocyclic imido groups, preferably having 5 to 7 atoms in the ring, alternatively substituted with chloro, fluoro, nitro or other groups.
  • the side chain activated esters (Formulas 10, 11 , 12 or 13, or other variations to the extent understood by the ordinarily skilled artisan) as well as the C-7 CBZ baccatin III may now be condensed. This condensation may proceed in the presence of an appropriate lithium base (e.g., lithium hexamethyl disalizane or n-Bu ⁇ ) in THF at 0°C according to the reaction:
  • an appropriate lithium base e.g., lithium hexamethyl disalizane or n-Bu ⁇
  • C-7 CBZ baccatin III (1.0 equivalent) and the activated ester (Formula 10, 11 , 12, 13 or others as discussed, 1.5 equivalents) are dissolved in anhydrous THF under nitrogen and brought to 0°C. It should be noted that other temperatures, including ambient temperature, have been shown to be suitable as well. To this is then added a suitable lithium base- in this case lithium hexamethyl disalizane, but n-butyl lithium can also be employed. This presumably generates the C-13 lithium alkoxide of C-7 CBZ baccatin III in analogous fashion to the C-13 lithium alkoxide of C-7 TES baccatin III as described by Holton (U.S. Patent No. 5,229,526 and U.S.
  • Patent No. 5,274,124 The mixture is then stirred for a period of time, preferably several hours, although time periods as short as thirty minutes have been employed.
  • the mixture is then diluted with a 1 :1 mixture of ethyl acetate and 1 N HCI, the organic phase collected and washed with water and brine, dried over sodium sulfate and reduced in vacuo to a residue.
  • the residue could then be purified by column chromatography (ethyl acetate/heptane) or recrystallization (diethyl ether or methyl t-butyl ether or ethyl acetate/heptane) to afford the coupled product of Formula 14.
  • C-7 TES baccatin III can also be used in place of C-7-CBZ baccatin to yield Formula 15.
  • the compound according to Formula 14 may now be converted into paclitaxel by removing the nitrogen and C-7 CBZ groups, putting the benzoyl group onto the nitrogen, and finally removing the C-2' benzyl-type protecting group. Removal of the CBZ groups, and subsequent addition of the benzoyl group to the nitrogen are accomplished as follows (BOM is shown as the protecting group at the C-2' hydroxyl site, although benzyl could also be used):
  • the coupled product of Formula 14 is dissolved in isopropanol to which the Pearlman's catalyst is added.
  • the resulting mixture is hydrogenated at 40 psi for twenty-four hours, although alternatively, the mixture can be stirred under one atmosphere of hydrogen for twenty-four hours.
  • the mixture can be hydrogenated at 1 atm of hydrogen in the presence of at least one equivalent of tri-fluroacetic acid resulting in the TFA salt of the resultant amine.
  • the mixture is filtered through diatomaceous earth and reduced under vacuum to residue.
  • the residue is taken up in toluene and anhydrous potassium carbonate added.
  • the residue may be taken up in ethyl acetate or toluene and a tertiary amine base, such as triethylamine, is added.
  • a tertiary amine base such as triethylamine
  • benzoyl chloride is then added dropwise, and the mixture stirred for two hours.
  • the resulting mixture is then washed with water and finally brine.
  • the resulting organic phase is then separated, dried, and concentrated under vacuum to yield C-2'-BOM paclitaxel (Formula 16).
  • the BOM protected paclitaxel is dissolved in isopropanol to which Pearlman's catalyst is added. This mixture is hydrogenated for twenty-four hours under 40 psi hydrogen or twenty-four hours under one atmosphere of hydrogen in the presence of tri-fluroacetic acid to yield paclitaxel.
  • the compound according to Formula 15 may now be converted into paclitaxel by removing the CBZ protecting group and acylating the side chain, removing the TES protecting group and removing the hydrogenatable benzyl protecting group.
  • CBZ protecting group removing the CBZ protecting group and acylating the side chain
  • removing the TES protecting group removing the hydrogenatable benzyl protecting group.
  • several convenient routes have been found although in general, it is necessary to deprotect the C-7 site by removing the TES protecting group prior to deprotecting the C-2' site with the hydrogenatable benzyl protecting group. If the TES protecting group is not removed first, it is believed difficult at best to remove the hydrogenatable protecting group in a later processing step.
  • the preferred route of producing paclitaxel is to first remove the CBZ protecting group according to the reaction:
  • the coupled product of Formula 15 is dissolved in isopropanol to which the Pearlman's catalyst is added.
  • the resulting mixture is stirred under one atmosphere of hydrogen for twenty-four hours. Thereafter, the mixture is filtered through diatomaceous earth and reduced under vacuum to residue. The residue may then be taken up in ethyl acetate or toluene and a tertiary amine base, such as triethylamine is added.
  • Benzoyl chloride was added dropwise, and the mixture stirred for two hours.
  • the resulting mixture was then washed with dilute aqueous solution of NaHC0 3 , water, and finally brine.
  • the resulting organic phase was then separated, dried and reduced under vacuum to yield the CBZ deprotected/acylated compound:
  • the compound of Formula 17 was dissolved in acetonitrile (CH 3 CN) at 0°C. Hydrofluoric acid (40% aqueous) was then added and the mixture stirred for ten hours while being held at 0°C. Thereafter, the mixture is diluted with ethyl acetate, saturated aqueous solution of NaHC0 3 , water and finally brine. The organic phase was separated, dried and reduced under vacuum to produce a deprotected product at the C-7 position according to the formula:
  • the compound of Formula 15 may first be dissolved in CH 3 CN at 0°C and hydrofluoric acid (40% aqueous) added to deprotect the compound at the C-7 site by removing the TES protecting group. This results in a compound according to the Formula 19:
  • the CBZ protecting group may be removed in a manner similar to that described above.
  • the compound of Formula 19 is dissolved in isopropanol and Pearlman's catalyst was added along with trifluoroacetic acid (TFA) (one equivalent).
  • TFA trifluoroacetic acid
  • the mixture was held at 40 psi of hydrogen at room temperature for approximately four days. This removes the CBZ protecting group and forms the C-2' BOM protected paclitaxel compound as a TFA salt.
  • the mixture was filtered through diatomaceous earth and reduced under vacuum.
  • a base plus an acylating agent was added to the residue.
  • the TFA salt of the C-2' BOM protected compound was dissolved in pyridine and either benzoyl chloride or benzoic anhydride was added. The resulting product is:
  • the compound of Formula 16 is dissolved in isopropyl alcohol and placed in a Parr bottle and Pearlman's catalyst was added. The mixture was hydrogenated for twenty-four hours at 40 psi of hydrogen. Thereafter, the mixture was filtered through diatomaceous earth and the eluent reduced under vacuum. The residue may then be column chromatographed according to any desired technique or recrystallized from ethyl acetate: hexane for the final paclitaxel product.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne de nouveaux esters activés de C-2 hydroxyl protégé-N-Acyl (2R,3S)-3-phénylisosérine ainsi qu'une méthode de production de ces derniers qui sont utiles pour la semi-synthèse de paclitaxel.
EP00946816A 1999-06-21 2000-06-16 Esters actives de c-2 hydroxyl protege-n-acyl(2r,3s)-3-phenylisoserine et methodes de production de ces derniers Withdrawn EP1192126A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US09/336,962 US6143902A (en) 1999-06-21 1999-06-21 C-2 hydroxyl protected-N-acyl (2R,3S)-3-phenylisoserine N-imido activated esters and method for production thereof
US336962 1999-06-21
US09/336,961 US6136999A (en) 1999-06-21 1999-06-21 C-2 hydroxyl protected-n-acyl (2R,3S)-3-phenylisoserine substituted phenyl activated esters and method for production thereof
US336961 1999-06-21
PCT/US2000/016617 WO2000078707A1 (fr) 1999-06-21 2000-06-16 Esters actives de c-2 hydroxyl protege-n-acyl(2r,3s)-3-phenylisoserine et methodes de production de ces derniers

Publications (1)

Publication Number Publication Date
EP1192126A1 true EP1192126A1 (fr) 2002-04-03

Family

ID=26990473

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00946816A Withdrawn EP1192126A1 (fr) 1999-06-21 2000-06-16 Esters actives de c-2 hydroxyl protege-n-acyl(2r,3s)-3-phenylisoserine et methodes de production de ces derniers

Country Status (7)

Country Link
EP (1) EP1192126A1 (fr)
JP (1) JP2003502401A (fr)
AU (1) AU6051500A (fr)
CA (1) CA2375343A1 (fr)
NO (1) NO20016165L (fr)
TR (1) TR200103747T2 (fr)
WO (1) WO2000078707A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CO5280224A1 (es) 2000-02-02 2003-05-30 Univ Florida State Res Found Taxanos sustituidos con ester en c7, utiles como agentes antitumorales y composiciones farmaceuticas que los contienen
JP2007527432A (ja) 2004-03-05 2007-09-27 フロリダ・ステイト・ユニバーシティ・リサーチ・ファウンデイション・インコーポレイテッド Ｃ７ラクチルオキシ置換タキサン

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5948919A (en) * 1993-02-05 1999-09-07 Napro Biotherapeutics, Inc. Paclitaxel synthesis from precursor compounds and methods of producing the same
US5750737A (en) * 1996-09-25 1998-05-12 Sisti; Nicholas J. Method for paclitaxel synthesis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0078707A1 *

Also Published As

Publication number Publication date
TR200103747T2 (tr) 2002-04-22
CA2375343A1 (fr) 2000-12-28
NO20016165D0 (no) 2001-12-17
WO2000078707A1 (fr) 2000-12-28
AU6051500A (en) 2001-01-09
JP2003502401A (ja) 2003-01-21
NO20016165L (no) 2002-02-14

Similar Documents

Publication Publication Date Title
WO1997034866A1 (fr) Procede de synthese du docetaxel
AU706406B2 (en) Paclitaxel synthesis from precursor compounds and methods of producing the same
US5948919A (en) Paclitaxel synthesis from precursor compounds and methods of producing the same
US5684175A (en) C-2' hydroxyl-benzyl protected, N-carbamate protected (2R, 3S)- 3-phenylisoserine and production process therefor
US6107497A (en) Intermediate for use in docetaxel synthesis and production method therefor
US6048990A (en) Method for selective acylation of C-2'-O-protected-10-hydroxy-taxol at the C-10 position
US5973170A (en) C-7 metal alkoxides of baccatin III
US6136999A (en) C-2 hydroxyl protected-n-acyl (2R,3S)-3-phenylisoserine substituted phenyl activated esters and method for production thereof
US6143902A (en) C-2 hydroxyl protected-N-acyl (2R,3S)-3-phenylisoserine N-imido activated esters and method for production thereof
EP1192126A1 (fr) Esters actives de c-2 hydroxyl protege-n-acyl(2r,3s)-3-phenylisoserine et methodes de production de ces derniers
AU745731B2 (en) Methods and useful intermediates for paclitaxel synthesis from C-7, C-10 di-CBZ baccatin III

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020116

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: CHANDER, MADHAVI, C.

Inventor name: MCCHESNEY, JAMES, D.

Inventor name: ZYGMUNT, JAN

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NAPRO BIOTHERAPEUTICS, INC.

18D Application deemed to be withdrawn

Effective date: 20040305

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: TAPESTRY PHARMACEUTICALS, INC.

18RA Request filed for re-establishment of rights before grant

Effective date: 20050126

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060103