AU726730B2 - Delta 12,13-iso-taxol analogs, antineoplastic use and pharmaceutical compositions containing them - Google Patents
Delta 12,13-iso-taxol analogs, antineoplastic use and pharmaceutical compositions containing them Download PDFInfo
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- AU726730B2 AU726730B2 AU80860/98A AU8086098A AU726730B2 AU 726730 B2 AU726730 B2 AU 726730B2 AU 80860/98 A AU80860/98 A AU 80860/98A AU 8086098 A AU8086098 A AU 8086098A AU 726730 B2 AU726730 B2 AU 726730B2
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- 0 CC(C)([C@@](C1)([C@@](*)C([C@]2(C(CC3OCOC)OC2)OC(C)=O)[C@]3(C)C([C@@]2OC(C)=O)=O)O)C2=C(C)[C@]1O Chemical compound CC(C)([C@@](C1)([C@@](*)C([C@]2(C(CC3OCOC)OC2)OC(C)=O)[C@]3(C)C([C@@]2OC(C)=O)=O)O)C2=C(C)[C@]1O 0.000 description 2
- BOYULKKSLKOLLJ-SBHLBFIGSA-N CC(C)([C@@](C1)([C@H](C([C@]2(C(CC3OCOC)OC2)OC(C)=O)[C@]3(C)C([C@@H]2O)=O)OC(c3ccccc3)=O)O)C2=C(C)[C@H]1O Chemical compound CC(C)([C@@](C1)([C@H](C([C@]2(C(CC3OCOC)OC2)OC(C)=O)[C@]3(C)C([C@@H]2O)=O)OC(c3ccccc3)=O)O)C2=C(C)[C@H]1O BOYULKKSLKOLLJ-SBHLBFIGSA-N 0.000 description 1
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Description
AUSTRALIA
Patents Act COMPLETE
SPECIFICATION
(ORIGINAL)
Application Number: Class Int. Class Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: a a a.
a a a. a a Name of Applicant: Pharmacia Upjohn Company Actual Inventor(s): Robert C. Kelly Peter G. M. Wuts Nancy Anne Wicnienski Address for Service: PHILLIPS ORMONDE
FITZPATRICK
Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA a a Invention Title: DELTA 12,13-ISO-TAXOL ANALOGS,
ANTINEOPLASTIC
PHARMACEUTICAL COMPOSITIONS CONTAINING
THEM
USE AND Our Ref: 540508 POF Code: 1459/285890 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- -1a- A'23-ISO-TAXOL ANALOGS, ANTINEOPLASTIC USE AND PHARMACEUTICAL COMPOSITIONS CONTAINING
THEM
BACKGROUND OF THE INVENTION This application is a divisional from parent application 16806/95 (691575) the entire content of which is herein incorporated by reference.
The invention relates to intermediate compounds and processes utilising these intermediates to prepare taxol analogs and in particular some of the taxol analogs disclosed in parent application 16806/95.
Taxol is a member of the taxane family of diterpenes, having the structure shown below: Y3 C 0 0 H3
OH
0 NH 0 H 3
C
p CE 3 1 13 C 3 3 The numbering system shown for taxol is that recommended by IUPAC (IUPAC, Commission on the Nomenclature of Organic Chemistry, 1978).
The chemistry of the potent anticancer diterpenoid taxol and analogs thereof is reviewed, with an emphasis on isolation and analysis, structural modifications, partial synthesis, and structure-activity relationships by David G.I.
Kingston, The Chemistry of Taxol, Pharmac. Ther., Vol 52, pp 1-34, 1991.
The clinical pharmacology of taxol is reviewed by Eric K. Rowinsky and Ross C. Donehower, The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics, Pharmac. Ther., Vol 52, pp 35-84, 1991.
Clinical and preclinical studies with taxol are reviewed by William J.
Slichenmyer and Daniel D. Von Hoff, Taxol: A New and Effective Anti-cancer Drug, Anti-Cancer Drugs, Vol. 2, pp 519-530, 1991.
C:kV41NWORDUENNYM\SPECNMI\I8061V.DOC -lb- Taxol and analogs thereof are the subject of various patents including, for example, U.S. Patent Nos. 4,814,470; 4,857,653; 4,942,184; 4,924,011; 4,924,012; 4,960,790; 5,015,744; 5,157,049; 5,059,699; 5,136,060; 4,876,399; 5,227,400, 5,248,796 as well as PCT Publication No. WO 92/09589, European Patent Application 90305845.1 (Publication No. A2 0 400 971), 90312366.9 (Publication No. Al 428 376), 89400935.6 (Publication No. Al 0 366 841) and 90402333.0 (Publication No. 0 414 610 Al), 87401669.4 (A1 0 253 739), 92308608.6 (Al 0 534 708), 92308609.4 (Al 534 709) and PCT Publication Nos. WO 91/17977, WO 91/17976, WO 91/13066, WO 91/13053.
Various processes for the preparation of taxol (and intermediates and analogs thereof) are described in Tetrahedron Letters, 1992, 33, 5185; J. Org.
Chem., 1991, 56, 1681 and J. Org. Chem., 1991, 56, 5114 as well as WO 94/07876, WO 94/07877, WO 94/07878 and WO 94/07879. See also US Patent 4,924,011 (and Reissue Patent 34,277, dated 8 June 1993) as well as 15 Tetrahedron Letters 35, 4483 (1994).
C* hen et al., Serendipitous Synthesis of a Cyclopropane-Containing Taxol Analog via Anchimeric Participation of an Unactivated Angular Methyl Group, Advance ACS Abstracts, Vol 1, No. July 15, 1993 reported the treatment of a 7-epi taxol derivative with DAST in dichloromethane led to an unexpected reaction involving participation of the C-19 methyl group and clean S. formation of a cyclopropane ring. See also J. Org. Chem., 1993, 58, 4520 (August 13, 1993) and U.S. Patent 5,254,580 (granted 19 October 1993).
U.S. Patent 5,248,796 (granted 28 September 1993) relates to desacetoxy-11,12-dihydroxtaxol-l 0,12(18)-diene derivatives and the preparation of EP Application 0 558 959 Al discloses various phosphonooxy and carbonate 2' taxol derivatives of taxol with increased water solubility: Water-soluble pro-taxol analogs are disclosed in Nicolaou, Riemer, Kerr, Rideout, Wrasidlo, Nature 364:464-66 (1993).
C-2 substituted benzoate analogs of taxol and their synthesis is described in J. Am. Chem. Soc. 1994, 116, 4097-98 and Bioorganic Medical Chemistry Letters, Vol. 4, No. 3, 479-82, 1994.
C:\WINWORDUENNYM\SPECNKI\1 6 8
O
6
D]VDOC
-1c- SUMMARY OF THE INVENTION This invention provides A12, 13 -iso-taxol analogs of Formula I:
R
R
4
R
COCH
3 a. a.
The compounds of Formula I are useful for the treatment of the same cancers for which taxol has been shown active, including human ovarian cancer, breast cancer, and malignant melanoma as well as lung cancer, gastric cancer, colon cancer, head and neck cancer, and leukemia.
The present invention also provides a compound of the formula
COCB
wherein X 2 is selected from the group consisting of
-H,
-C,-C
4 alkyl,
-C
1
-C
3 alkoxy, halo, C:AWNWOROUENNYM
SECNKRI
8
NOIV.DOC
-2- -Cl-C 3 alkyithia, -trifluoromethyl,
-C
2
-C
6 dialkylamino, benzyloxymethyl, cya no, azide or nitro; and wherein R 30 and R 3 1, being the same or different, are selected from the group consisting of -OC(O)0 1 -C~alkyI, -OC(O)0C 1 -C~alkyl, -OC(O)OCH 2
OX
3 where X is Halo, -OC(O)OCH 2
CH
2 SiR 20 (wherein R 20 is 0 1 -C~alkyI), or -OSi(R, 6 3 [where
R
1 being the same or different, is selected from C,-C~alkyI or CYClo(C 5
-C
8 )alkyl]; with the overall proviso that at least one R 20 is secondary alkyl or cycloalkyl, and further wherein when R 3 1 is -OSi(C 2
H
5 3 then R 3 1 cannot be -OC(O)CH 3 and when R 34 is -OCOOCH 2
CC
3 then R 30 cannot be either 15 OC(O)CH 3 or -O-(2,2,2-trichloroethoxy carbonyl).
The present invention further provides a process of preparing :H 0 3
CH
H
0which comprises reacting an oxazolidine free acid of Formula 7 W:\tiona\Species\1 8O6div.do c -2awith a baccatin compound of Formula 8'
COOCHA
U I.
group consisting of -OC(O)C,-C~alkyl, -OC(O)0C 1
-C
6 alkyl, -OO(O)OCH 2
CX
3 where X is Halo, -OC(O)OCH 2
OH
2 SiR 2 0 (where
R
20 is C 1
-C
6 alkyl), or -OSi(Rl 6 3 [where R 1 6 being the same or different, is selected from C 1
-C
6 alkyl or cyclo(0 5 10 0 8 )alkyl];
X
2 is selected from the group consisting of
-H,
-01-C, alkyl, -Cl-C3 alkoxy, 15 halo, -01-03 alkylthio, -trifluoromethyl,
-C
2
-C
6 dialkylamino, benzyloxymethyl, cyano, azide
(N
3 or nitro; R, is selected from the group consisting of
-OH
3 W;\fiona\SpecIes\I 806D IV.oOC -2b-
-C
6
H
5 or phenyl substituted with one, 2 or 3 cl-c 4 alkyl, Cl-C 3 alkoxy, halo, 0 1
-C
3 alkylthio, trifluoromethyl,
C
2 -0 6 dialkylamino, hydroxy or nitro, 2furyl, 2-thienyl, 1 -naphthyl, 2-naphthyl or 3 4 -methylenedioxyphenyl;
R
1 1 is phenyl substituted with -(OCI-C 2 alkyl)n where n is 1 to 3; and
R
12 is selected from the group consisting of -C(O)Ci-Cl 0 alkyl, -C(O)phenyl, -C(O)phenyl substituted with one, 2 or 3 Cl-C 4 alkyl, C 1
-C
3 alkoxy, halo, Cl-C 3 alkylthio, trifluromethyl,
C
2
-C
6 dialkylamino, hydroxy or nitro,
C(O)C(CH
3
)=CHCH
3
-C(O)OC(CH
3 3
-C(O)OCH
2 phenyl,
-SO
2 -4-methylphenyl,
-C(O)(CH
2 3 000H, -C(O)-4-(SO 3 H)phenyl, -C(O)-1-adamantyl, -C(O)O-3-tetrahyd rofuranyl,
-C(O)O-
4 -tetrahydropyranyl,
-C(O)CH
2
C(CH
3 3 *0 -C(O)C(CH 3 3 -C(O)0C-Clalkyl, -C(O)NHC,-Clalkyl, -C(O)NHPh substituted with one, 2 or 3 Cl-C 4 alkyl, Cl-0 3 alkoxy, halo, CI-C 3 alkylthio, trifluoromethyl,
C
2
-C
6 dialkylamino, or nitro, or -C(O)C 3
-C
8 cycloalkyl,
-C(O)C(CH
2
CH
3 2
CH
3 -C(o)C(CH) 2 CI, -cocc 3 2
CH
2
CH
3 -C 1 -p he nyl- 1-cyclopentyl, -C -1 -methyl- 1-cyclo hexyl, -C(s)NHC(CH 3 3 -C(o)NHCC(CH 3 3 or -C(o)NHPh.
The present invention further provides a process of preparing be.
20R0 3 be, C
HF
0 0N
R'
HO
I
25 O-c 6-x 2 which comprises reacting an oxazoline free acid of Formula 7' H R N1 R"
H
C:IWNVIORD JENNY"PECNXnl6SO6DlV.DOC -2cwith a baccatin compound of Formula 8'
OC
100 in the presence of a dehydrating agent; wherein R 30 and R34, being the same or different, are selected from the :z.group consisting of -OC(O)Cl-C 6 alkyl, -OC(O)00 1
-C
6 alkyl, -OC(O)OCH 2
CX
3 where X is Halo, -OC(O)OCH 2
CH
2 SiR 20 (where R 20 is Cl-C 6 alkyl), or -OSi(Rl 6 3 a [where R 16 being the same or different, is selected from C 1
-C
6 alkyl or cyclO(C 5 C,)alkyl];
X
2 is selected from the group consisting of
-H,
0 -cl-c 4 alkyl, -Cl-C 3 alkoxy, halo, 600*0:-0 1
-C
3 alkylthio, a. -trifluoromethyl,
-C
2
-C
6 dialkylamino, benzyloxymethyl, cyano, azide
(N
3 or nitro; R, is selected from the group consisting of
-CH
3 C:kWNMRO JFNNYMSPECNK[11680601V.DOC -2dor phenyl substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C3 alkoxy, halo, Cl-C3 alkylthio, trifluoromethyl, C2-C6 dialkylamino, hydroxy or nitro, 2furyl, 2-thienyl, 1 -naphthyl, 2-naphthyl or 3,4-methylenedioxyphenyl; and R'll is selected from the group consisting of -Cl-Cloalkyl, -phenyl, -phenyl substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C3 alkoxy, halo, Cl-C3 alkylthio, trifluoromethyl, C2-C6 dialkylamino, hydroxy or nitro -1-adamantyl, -3-tetrahydrofuranyl, -4-tetrahydropyranyl, or -CH2C(CH3)3.
too.
so 069 C:\WINWORD\.JENNYM\SPECNKI\16806D]V.DOC -3- CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, or where is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z, would represent a bivalent variable if attached to the formula CH 3
-C(-Z
1 Groups R, and R, would represent monovalent variable substituents if attached to the formula CH 3 When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R, and R, are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as taxol, these carbon atoms are designated as where is the integer corresponding to the carbon atom number. For example, C, represents the 6 position or carbon atom number in the nucleus as traditionally designated by those skilled in the art.
Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol in general represents a bond between two atoms in the chain.
Thus CH,-O-CH,-CH(R)-CH 3 represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol represents a double bond, CH 2
-C(R)-O-CH
3 and the symbol represents a triple bond, HC=C-CH(R)-CH,-CH 3 Carbonyl groups are represented in either one of two ways: -CO- or with the former being preferred for 25 simplicity.
Chemical formulas of cyclic (ring) compounds or molecular fragments can be S represented in a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be represented in linear fashion by N-C(CH)-CH-CCI-CH-C'H with the convention that the atoms marked with an asterisk are bonded to each other resulting in the formation of a ring.
30 Likewise, the cyclic molecular fragment, 4-(ethyl)-l-piperazinyl can be represented by -N-(CHz)2-N(C2H,)-CH 2 -CH2. Similarly, 2-furyl can be represented by -C*-O-CH-CH-C*H- 4744.P -4and 2-thienyl represented by -C*-S-CH-CH-C*H-.
A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent which is "below" another substituent (X 2 will be r identified as being in the alpha configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, by the symbol or The corresponding substituent attached "above" (X 2 the other is identified as being in the beta configuration and is indicated by an unbroken line attachment to the carbon atom.
When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable Ri attached to a carbon atom as might be bivalent and be defined as oxo or keto (thus forming a carbonyl group or as two separately attached monovalent variable substituents ct-R,. and B-R. When a bivalent variable, R, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form or some variant thereof. In such a case both ct-R,.j and B-R,k are attached to the carbon atom to give For example, when the bivalent variable is defined to consist of d two monovalent variable substituents, the two monovalent variable substituents are a-R,:B-Ro, etc, giving etc.
25 Likewise, for the bivalent variable two monovalent variable substituents are a-RI. 2 For a ring substituent for which separate a and B orientations do not exist (e.g.
due to the presence of a carbon double bond in the ring), and for a substituent bonded to a 0* carbon atom which is not part of a ring the above convention is still used, but the a and 8 designations are omitted.
30 Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula (Ci and C, define arbitrarily a first and second carbon atom, respectively) R, and R, may be defined to be taken together to form a second bond between C, and C or a bivalent group such as oxa 35 and the formula thereby describes an epoxide. When R 1 and R, are taken together to form a more complex entity, such as the group then the orientation of the entity is such that C, 4744.P in the above formula is bonded to X and C, is bonded to Y. Thus, by convention the designation R, and Rj are taken together to form -CH,-CHI-O-CO- means a lactone in which the carbonyl is bonded to C2. However, when designated R, and R, are taken together to form
-CO-O-CH,-CH
2 -the convention means a lactone in which the carbonyl is bonded to C,.
The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as "C,-C 4 where both and are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C'-C alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix H indicates the entire carbon atom content of the variable being defined. Thus C2-C alkoxycarbonyl describes a group CH3-(CH 2 where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C,-C 3 )alkoxycarbonyl has the same meaning as C-C alkoxycarbonyl because the "C,-C 3 refers only to the carbon atom content of the alkoxy group. Similarly while both C-C 6 alkoxyalkyl and (C,-C 3 )alkoxy(C,-C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the 25 chemical structural formula of that particular substituent.
The term "Boc" refers to C(O)O-t-butyl, 'Troc" refers to C(O))CHCCI 3 TES refers to Si(Et) 3 Ph refers to phenyl, Ac refers to C(O)CH 3 and Bz refers to C(O)Ph.
S 4744.P -6- DETAILED DESCRIPTION OF THE INVENTION More specifically, this invention provides 7-deoxy-A' 2 '-iso-taxol analogs of general Formula 1
R
3 0 R R7 N. 0C1 CC3
L
-H,
hal (pefraby -l)
-C
1 -C3 alkylthio, -trifluoromethyl, *25 -qCC dialkylanino, benzyloxymethiyl, cyano, azide (NO), or nitro; ;:30 R, is selected from the group consisting of -CJ~s or phenyl substituted with one, 2 or 3 alikyl. C,-C 3 alkoxy, halo, C,-C, alkylthio, trifluoromethyl, C 2 -C6 dilkylainino, nydroxy or itro, -2-fwryl, 2-diienyl, l-Wapthyl. 2-naphthyl or 3,4-methylcoedioxyphenyL; R, is selected from the group consisting of -NHC(O)H,-NHC(O)C-C 10 alkyI (preferably -NHC(O)C,-Calkyl), -NHC(O)phenyl, -NHC(O)pbenyl substituted with one, 2 or 3 4744.P -7-
C
1
-C
4 alkyl, C,-C 1 alkoxy, halo, C,-C 3 alkyltho, trifluoromethyl. C 2 dialkylamino, hydroxy or nitro, -NHC(O)C(CH 3
)-,CHCH
3
-NH-C(O)OC(CH
3 3 -NHC(O)OCHphenyl, -NHl,,
-NHSO
2 -4-mechylphenyl, -NHC(O)(CH 2 3 COOH. -NHC(O)-4-(SO 3 H)phenyl, -OH, -NHC(O)-1 -adamantyl, -NHC(O)O-3-tetrahydrofuranyl. -NHC(O)O-4-tetrahydropyranyl,
-NHC(O)CH
2
C(CH
3 3
-NHC(O)C(CH
3 3 -NHC(O)0C-C 0 allcyI -NH-C(O)NI-C 10 alkYl, -N-HC(O)NHPh, -Nl-C(O)NHPh substituted with one, 2 or 3 CI-C 4 alkyl, CI-C alkoxy, halo,
CX-
3 allclthio, trilluoromethyl, C 2
-C
6 dialkylamino, or nitro, -NH(2(O)C3-Cscycloaikyl,
-NHC(O)OC(CH
2
CH
3 2
CH
3
-NHC(O)OC(CH
3 2
CH
2 Cl, -NHc(O)OQCcH 3 2
CH
2
CH
3 phthalimnido.
-NE-C(O)-i1-phenyl-lI-cyclopentyl, -NHC(O)- 1-methyl-I -cyclohexyl,
-NHC(S)NHC(CH
3 3 or -NHc(O)NlCC(CH 3;
R
3 is selected from the group consisting of -NH(2(O)phenyl or -NHC(O)OC(CH 3 3 with the overall proviso that one of R, and R 3 is -H but R, and R, are not both -H; R, is -H or selected from the group consisting of -OH, -OAc (-OC(O)2H 3
-OC(O)OCH
2
C(C)
3
-OCOCH
2
CH
2
NH
3 HCOO-, -NHC(O)phenyl, -NHC(O)OC(CH 3 3
-OCOCH
2
CH
2 COOH and pharmaceutically acceptable salts thereof, -OCO(CHI) 3 COOH and pharmnaceutically acceptable salts thereof, and (where Z is ethylene propylene (-CH 2
CH
2 -CH-CH-, 1,2-cyclohexane or 1,2-phenylene, R' is -OH. -OH base, 3
-OR'
3
-SR'
3
-OCH.C(O)NR'
4
R'
5 where R' 2 is -H or -CH3, is or 8 X~ where n is 1-3. is -H or -C,-C~alkyl, is -H, -C,-C~alkyl. benzyl. hydroxyethyl, -CH 2
CO
2 H or dimethylarninoethyl, R' 6 and are C3 -CHzCH 3 benzyl or R' 6 and together with the nitrogen of NR',R' 7 form a pyrrolidino, piperidino, morpholino, or N-methylpiperizino group; is -CH3, -CH 2
CH
3 or benzyl X- is halide, and base is NH 3 (110CH 4 )3N, N(CH3)3, CH 3 N(CqHj)NH, NH 2 (CH06NH 2 N-methylglucamine, NaOH or KOHI, _OC(O)(CH2)NRR 3 [where n is 1-3, R 2 is -H or
-C
1
-C
3 alkYl and R 3 -H or -C,-qalkyl], -OC(O)CH(R")NH 2 [where R" is selected from the group consisting of -CH 3
-CH
3
CH(CH-
3 2
-CH(CH
3
)CH
2
CH
3
-CH(CH
3 2 -CHzphenyl,
-(CH
2 )NH-1, -CH 2 CI-ICOOH. -(CH 2 3 NHC(-N-)N-1 2 the residue of the amino acid proline, 9*-OC(O)CH-CH 2
-C(O)CH
2
CH
2
C(O)NIICH
2
CH
2 SQ3 Y.1
-OC(O)CH
2
CH
2
C(O)NHCH
2
CH
2
CH
2
SO
3 wherein is Na* or N(u, 30 -OC(O)CH- 2
CH
2 C(O)OCH, CH 2
OH;
9 R 5 is -H or -OH, with the overall proviso that when R5 is -OH. R, is -H and with the **fuirther proviso that when R, is R, is other than -H;
R
4 is when R. is a-R, 1 -R72 where one of R, and Rn is -H and the other of R 7 and Rnis AX where X, ishao orazido(-No)afdR$ is-CH 3 R is when R.7 is ct-H: -R, 4 where R 74 and are taken together to form a **cyclopropyl ring-, 4744.P
R
6 4 is R 4
,:R
6 when R7 is R 75 where one of RO and P.6 is taken together with one of R.,s and to form a second bond between the carbon atoms to which they are attached and the other of and R.6 is and the other of R,3 and R,4 is -H and where Re is -CH,; R. is when R 7 is a-R, 1 :f -Rn where one of Re, and is -H and the other of R,, and Ris -OH or -Hand Reis -CH,; Ft. is when R 7 is 2 where one of R 9 and is -H and the other of R.9, and Rn is -W where W is selected from the group consisting of -OC(O)H, -O-C 1 -Calkyl, -0-
C
3 -CIcycloallcyl, -0-(CH 2 ).phenyl where n is 1-6, -O-C(O)C 1 -Cl 0 alkyl, -O-C(O)phenyl, -0- C(O)phenyl substituted with one, 2 or 3 CX- 4 alkyl, alkoxy, halo, C 1 -q alkylthio, trifluoromethyl, C 2
-C
6 dialkylamino, or nitro, -O-C(O)naphthyl, -O-C(O)naphthyl. substituted with one, 2 or 3 cl-c 4 alkyl, C,-C 3 alkoxy, halo, C,-Cq alicyithia, trifluoromethyl, C 2
-C
6 dialkylamino, or nitro, -O-C(O)Ophenyl, -0-C(O)Ophenyl substituted with one, 2 or 3 alkyl, CI-C 3 alkoxy, halo, C,-C 3 alkylthio, trifluoromethyl, Cq-C 6 dialkylamino, or nitro, O-C(O)Onaphthyl, -0-C(O)Onaphthyl substituted with one, 2 or 3 cl-c 4 alkcyl, CI-C3 alkoxy, halo, C,-q3 alkylthio, trifluoromethyl, (2 2
-C
6 dialkylamino, or nitro, -O-C(O)OC-C 2 alkyl, -0- C(O)NHC,-C,,alkyl, -O-C(O)NHphenyl, -O-C(O)NHphenyl substituted with one, 2 or 3 C 1
-C,
alkyl, C,-C 3 alkoxy, halo, CX- 3 alkylthio, ti-ifluoromethyl, C,--C 6 dialkylamino, or nitro, -O-C(O)NIHnaphthyl, -O-C(O)NHnaphthyl substituted with one, 2 or 3 cl-c 4 akl, ca-C3 alkoxy, halo, CX- 3 alkylthio, trifluoromethyl, C 2
-C
6 dialkylamino, or nitro.
-o-C(o)ocH,CHCI,, -O-C(O)OCHICC1 3 -OSi(R 6 3 [where R" 6 being the same or different, is slected from C, -C 6 alkyl or cyclo(C 5 -(2)alkyl], -O-CH 2
-C
6 alkyl.
-O-CH
2 -O-(CH9,,,henyl where .is 1-3, -O-CH 2 -O-(CH2),,Phenyl substituted with one, 2 or 3 Cl- C, alkyl, CX- 3 alkoxy, halo, C,-q alkylthio, trifluoromethyl, c-C 6 dialkylamino, or nitro and where is 1-3, -O-CH 2
-O-CH
2 -CX,I-1q where q-0-3 and X is 25 halogen, and Re is -CH,; R30 is OH, or -OC(O)CH 3 and .pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic 999 functional group, A preferred embodiment of the subject invention is compounds of Formula I where R, is phenyl or phenyl substituted with halo, R 2 is -NHC(Q)CjH 5
R
3 and R3 are R, is -OH, and 9 R~v is -OH or -OC(O)CH 3 Another preferred embodiment of the subject invention is compounds of Formula I where R, is preferably phenyl or phenyl substituted with halo, R, is
-NHC(O)OC(CH
3 3 R3 and R, are R, is -OH. and is -H or -COCH 3 A preferred embodiment of the subject invention is compounds of Formula I where R, is preferably phenyl or phenyl substituted with halo, R 2 is -N11C(O)NHC(CH 3 3
R
3 and R 5 are R, is -OH, and R0 is-OH or -OCOCH 3 4744,P An embodiment of the subject invention are compounds of Formula I where R, is selected from the group consisting of -CH- 3 -Cji 3 or phenyl substituted with one, 2 or 3 ailkyl, C,-C 3 alkoxy, halo, C 1 -Cq alkylthio, trifluoromethyl, C 2
-C
6 dialkylamnino, hydroxy or nitro and R, is selected from the group consisting of -NHC(O)H, -NHC(O)C,-C 10 alkyl (preferably -NHC(O)C 4
-C
6 allcyl), -NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 ailkyl, C,-C 3 alkoxy, halo, CI-C 1 alkylthio, trifluoromethyl, (2 2
-C
6 dialkylamino, hydroxy or nitro, -N'HC(O)C(CH 3
)-CHCH
3
-NHC(O)OC(CH)
3
-NHC(O)OCH
2 phenyl,
-NH
2 -NH-S0 2 -4-methylphenyl, -NHC(CH 2 3 COOH, -NHC(O)-4-(SO 3 H)phenyl, -OH, -NHC(O)-lI-adamantyl, -NI-IC()O-3-tetrahydrofuranyl, -NH-C(O)O-4-tetrahydropyranyl,
-NH-C(O)CH
2 C(CH3) 3
-NHC(O)C(C{
3 3 -NHC(O)0C-C 1 0 alkyl, -NHC(O)NHCI-C 10 Alkyl, -NTIC(O)NHPh substituted with one, 2 or 3 alkyl, CX- 3 alkoxy, halo, C,-C 3 aikyithio, trifluoromethyl, 2
-C
6 dialkylamino, or nitro.
An embodiment of the subject invention are compounds of Formula I where X' is
-H.
An embodiment of the subject invention are compounds of Formula I where X' is
-H,
R, is selected from the group consisting of -CH, or phenyl substituted with one, 2 or 3 alkyl, C,-C 3 alcoxy, halo, C,-C 3 alkylthio, trifluoromethyl, dialkylamino, hydroxy or nitro, -2-ftuyl, 2-thienyl, 1 -naphthyl, 2-naphthyl or 3,4-methylenedioxyphenyl;
R
2 is selected from the group consisting of -NH-C(O)H,-NHC(O)C 1
-C
10 alkyl (preferably -NHC(O)C,-C 6 alkl), -NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3
C,-C
4 ailkyl, C 1 alkoxy, halo, C 1
-C
1 alkylthio, trifluoromethyl, C 2 dialkylamino, hydroxy or nitro, -NHC(O)C(CH 3
)-CHCH
3
-NHC(O)OC(CH
3 -NHC(O)OCHphenyl, -NH,
-NHSO
2 -4-methylphenyl, -NI-ICO)(C-1) 3 COOH, -NHC(O)-4-(SO 3 H)phenyl, -OH, -NHC(O)-lI-adamantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-teb-ahydropyranyl,
-N;HC(O)CH
2 C(CH0 3
-NHC(O)C(CH
3 3 -NHC(O)0C-C 10 lk -N}IC(O)N1CI-C 4 ,allyl, -NIIC(O)NHPh, -NH-C(O)NHPh substituted with one, 2 or 3 C 1 alkyl, C,-Cq alkoxy, halo,
CI-C
1 alkylthio, trifluoromethyl, (2 2
-C
6 dialkylamnino, or nitro, -NHC(O)C 3 -Ccycloalkyl, Woo-NHC(O)oc(CH 2
CH
3 2 C11,, -NHC(O)OC(CH 3 2
CH
2 CI, -NHC(O)OC(CHA)CH 2
CH
3 phthalimnido, 9 9. -NHC(O)-i1-phenytl1-cyclopentyl, -NHC(O)- 1-methyl-i -cyclobexyl,
-NHC(S)NHC(CH)
3 or -NHC(O)NHCC(CH) 3 R3 is selected from the group consisting of -HL -NHC(O)pbenyl or -NHC(O)OC(CH) 3 999935 with the oveall prov iso tha on of R2 and R3 i -Hbut R ad R, are not boh H; R, is -H or selected fromn the group consisting of -OH, -OAc (-OC(O)CH 3 4744.P
-OC(O)OCIC(C)
3
-OCOCH
2
CH
2
NH
3 HCOO', -NHC(O)phenyl. -NHC(O)OC(CH 3 -OCOCH2CH 2 COOH and pharmaceutically acceptable salts thereof, -OC(CH 2 3 COOH and pharmaceutically acceptable salts thereof, and (where Z is ethylene (-CH2CH 2 propylene (-CH 2
CH
2
CH
2 -CHinCH-, 1,2-cyclohexane or 1,2-phenylene, R' is -OH, -OH base, -NR' 2
R'
3
-OR'
3
-SR'
3
-OCH
2
C(O)NR'
4 R's where is -H or R' 3 is or (CH0,N*R'R'R', X where n is 1-3, is -H or -C 1
-C
4 allcyl, is -H,
-C,-C
4 alkyl, beazyl, hydroxyethyl, -CH 2
CO
2 H or diznethylaminoethyl, and are-H,
-CH
2
CH
3 benzyl or R' 6 and R'7 together with the nitrogen of NR' 6 form a pyi-rolidino, piperidino, morpholino, or N-mediylpiperizino group; is -CH 3
-CH
2
CH
3 or benzyl X* is halide, and base is NH 3
(HOC
2 H, N, N(CH 3 3 CH_,N(qHA)zNH, NII 2
(C-I)
6
NH
2 *N-methylglucamine, NaOH or KOH], -OC(O)(CH 2
).NR~R
3 (where n is 1-3, R 2 is -H or
-CI-C
3 alkyl and R' -H or -C 1
-C
3 a~k-yl], -OC(O)CH(R")NH, [where R" is selected from the group consisting of -CH 3
-CH
2
CH(CH
3 2
-CH(CH
3
)CH
2
CH
3
-CH(CH
3 2
-CH
2 phenyl,
-(CH,),NH
2
-CH
2
CH
2 COOH, -(CH 2 3 NHC(-NH)N-1 2 the residue of the amino acid proline,
-OC(O)CH-CH
2
-C(O)CH
2
CH
2
C(O)N}ICH
2
CH
2 SQ, Y-,
-OC(O)CH
2 CHC(O)NHCl- 2
CH
2
CH
2 SQ3Y* wherein Y* is Na* or N*(Bu) 4 -OC(O)CH2CH 2 C(O)OCH, CH 2
OH;
R
5 is -H or -OH, with the overall proviso that when R 5 is -OH, R, is -H and with the further proviso that when R 5 is R, is other than -H; R6 is when R, is ct-R 7 :P-R,2 where one of R 7 and R,2 is -H and the other of R 7 and R, is A, 7 where X7 is halo or azido (-N 3 and Rs is -CH 3
R
6 is when R, is ct-H:f-R,, where R1 4 and R. are taken together to form a cyclopropyl mig;
R.
6 is Rk:R. when R 7 is R, 5
:R
76 where one of k~ and R.66 is taken together with one of
R,
5 and R 76 to form a second bond between the carbon atoms to which they are attached and the other of Rk and R, is and the other of R 75 and is -H and where R, is -CH 3
~R,
6 is when R 7 i -RJ 1 where one of and R 1 2 is-H adthe otheroR 1 7 isai*n.o ro *and R, 2 is -OH or -H and R, is -CH 3 is when R, is a-R 91 2 where one of and Rk is -H and the other of and is -W where W is selected from the group consisting of -OC(O)H, -O-C 1 -Calkyl, -0-
C
3 -Ccycloalkyl, -O-(CH .phenyI where n is 1-6, -O-C(O)C,-C 10 alkyl, -O-C(O)phenyl, -0- C(O)ph-enyl substituted with one, 2 or 3 CX- 4 alkyl, C,-C 3 alkoxy, halo, C,-C 1 alkylthio, trifluoromethyl, C 2
-C
6 dialkylamino, or nitro, -O-C(O)naphthyl, -O-C(O)naphthyi substituted with one, 2 or 3 C 1 alkyl. C,-C 3 alkoxy, halo, C,-C 3 alkylthio. trifluoromthyL C-CS diaklamnino, or nitro, -O-C(O)Ophenyl, -O-C(O)Opbenyl substituted with one, 2 or 3
C
1 alkyl. C,-C 1 alkoxy, halo, alkylthio, trifluoromethyl, C 2
-C
4 dialkylamino, or nitro, 4744.P -11- O-C(O)Onaphthyl, -O-C(O)Onaphthyl substituted with one, 2 or 3 C,-C 4 alkyl, C,-C 3 alkoxy, halo, C,-C 3 alkylthio, trifluoromethyl,
C
2 dialkylamino, or nitro, -O-C(O)OCI-C 0 alkyl, -0- C(O)NHqC-Calkyl, -O-C(O)NI-phenyl, -O-C(O)NI-phenyl substituted with one, 2 or 3 CI-C, alkcyl, CX- 3 alkoxy, halo, C,-C 1 alkylthio, trifluoromethyl,
C
2
-C
6 dialkylamino, or nitro, -0-C(O)NHnaphthyl, -O-C(O)NI~naplnhyl substituted with one, 2 or 3 alkyl,
CX-
3 alkoxy, halo, C 1
-C
3 alikylthio, trifluoromfethyl, (2 2
-C
6 dialkylamino, or nitro,
-O-C(O)OCH
2
CHC
2
-O.-C(O)OCH
2 CCI,, -OSi(R' 6 3 [where R" 6 is C,-C~alkyll,
-O-CH
2
-O-CI-C
6 alcYl, -O-CH 2 -O-(CH ,phenyl where ,is 1-3, -O-CH 2 -O-(CH2)phenyl substituted with one, 2 or 3 C 1
-C
4 alkyl, C,-C 3 alkoxy, halo, CI-Cq alkylthio, trifluoromethyl,
C
2 -Cs dialkylarnino, or nitro and where is 1-3, -0-CH 2
-O&HM
2 -CXH3- where q 0-3 and Xis halogen, and R,is -CH 3 is OH, or -OC(O)CH 3 and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group.
A further embodiment of the subject invention are compounds of Formula I where X 2 is ui the ortho, meta or para-position (preferably meta or para, more preferably the meta position) and is selected from the group consisting of alkyl, -C,-C3 ailcoxy (preferably
-OCH
3 halo (preferably alkylthio, trifluoromethyl,
-C--C
6 dialkylamino, benzyloxymethyl.
cyano. azide (N 3 or nitro.
A still further embodiment of the subject invention are compounds of Formula I where X' is in the ortho, meta or para-position (preferably meta or para, more preferably the meta position) and is selected from the group consisting of -N 3 -CN, -OCH 3 or -Cl. A sti further embodiment of the subject invention are compounds of Formula I where X' is in the ortho, meta or para-position (preferably meta or para, more preferably the mets position) and is selected from the group consisting of -N 3 -CN, -OCH 3 or -Cl and R, is phenyl or phenyl 9* substituted with halo, R 2 is -NIIC(O)C 6 H5, R 3 and R 5 are R, is -OH, and R3. is -OH or
-OC(O)CH
3 fuirther embodiment of the subject invention are compounds of Formula I where X' is in the ortho, mets or para-position (preferably mets or para, more preferably the meta position) 30 and is selected from the group consisting of -N 3 -CN, -OCH, or -al and R, is preferably phenyl 9. or phenyl substituted with halo, R 2 is -NHC(O)O(CH 3
R
3 and R 5 are R 4 is -OH, and R~o is -H or -COCH 3 99*A preferred embodirnent of the subject invention is compounds of Formula I where X2 is -H and R, is phenyl or phenyl substituted with halo, R 2 is -NHQCO)CH 5 s, R 3 and Its are -H, :9.:35 R, is -OH, and is -OH or -OC(O)CH 3 Another preferred embodiment of the subject 9 invention is compounds of Formula I where X' is -H and R, is prefesibly phenyI or phenyl 4744.P -12.
substituted with halo, R2 is -NHC(O)OC(CH 3 3
R
3 and R3 are R 4 is -OH, and R3 is -H or -COCH3. A preferred embodiment of the subject invention is compounds of Formula I where
X
2 is -H and R, is preferably phenyl or phenyl substituted with halo, R 2 is -NHC(O)NHC(CH 3
R
3 and R, are R, is -OH, and R3 is -OH or -OCOCH 3 An embodiment of the subject invention are compounds of Formula I where X 2 is -H and R, is selected from the group consisting of -CH 3
-CH
5 or phenyl substituted with one, 2 or 3 C 1
-C
4 alkyl, C,-C 3 alkoxy, halo, C 1
-C
3 alkylthio, trifluoromethyl,
C
2 dialkylamino, hydroxy or nitro and R, is selected from the group consisting of -H, -NHC(O)H, -NHC(O)CI-Cl 0 alkyl (preferably -NHC(O)C 4 -Caalkyl), -NHC(O)phenyl, -N-C(O)phenyl substituted with one, 2 or 3 CI-C 4 alkyl, alkoxy, halo, C,-C3 aikylthio, trifluoromethyl, C 2 -4 dialkylanino, hydroxy or nitro,
-NHC(O)C(CH
3
)-CHCH
3
-NHC(O)OC(CH)
3 -NHC(O)OCHgphenyl, -Ni 2
-NHSO
2 -4-methylphenyl, -NHC(OXCH) 3 COOH, -NHC(O)-4-(SO 3 H)phenyl, -OH, -NHC(O)-l -adamantyl, -NHC(O)O-3-tetrahydrofuranyl, -N-C(O)O-4-tetrahydropyranyl,
-NHC(O)CHC(CH
3 3
-NHC(O)C(CH,)
3
-NIC(O)OCI-C
0 alkyl, -NHC(O)N-HC 1
-C
1 0 alky, NHC(O)NHPh substituted with one, 2 or 3 C 1 alkyl, C 1
-C
3 alkoxy, halo,
C
1
-C
3 alkythia. trifluoromethyl, C2-C 6 dialkylamino, or nitro.
This invention also provides A '"-iso-taxol analogs of general Formula a
R
3 0
R
2 R 3
H
0 H3C
CH
F.,H
II t
C
0 1 13 C3 Ji 2 0O R R
HO
3OH
O=C
X2 00.
0.0*0.
09* 6C 4744.P -13and Formula lia 0=0 6-x and Formula IVa
R
4
R
COCH 3 Formula Va
S
S.
S
S.
S S
S.
9 5* S S
S.
5555
S.
S. S S S *5
*,SS
S R 4 Rs COCH3 4744.P -14and Formula VI& R 4 R C0CH 3 wherein X, is selected from the group consisting of -Br, -Cl, or -N 3 and wherein W, RI,
R
2
R
3
R
5 R3. and X 2 are as defined above.
This invention also provides 3 -iso-taxol analogs of general Formula II 'ewe
S
S.
C S 0we@ 5* C C
C.
C
S.
C
S.
C.
C
C.
SC..
CC
SC 0 *5 C. *5
*CCC
and Formula I 0oca
COCOHS
4744.P and Formula IV Formula V and Formula VI wherein X7 isslced from the gup cosisting of -Br, or and wherein W, R1, P-2.Rj R 4 ,nd r3dinedabve.
An embodiment of the present invention ame 7-deoxy-70,8P.methahAIZ)L4o-taxoI 4744.P -16analogs of general Formula 11 (or Ia) wherein: R, is selected from the group consisting of -C,H5 or phenyl substituted with one, 2 or 3 C 1 alkyl, C,-C3 aikoxy, halo, aikylthio, trifluoromethyl, C 2
-C
6 dialkcylarnino, hydroxy or nitro; R, is selected from the group consisting of -NI-C(O)C 1 -Cloalkyl (preferably
-NHC(O)C
4 -4a'kYI), -NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 CI-C, alkyl,
C,-C
3 alkoxy, halo, C,-q alkylthio, trifluoromethyl, (2 2
-C
6 dialkylamino, hydroxy or nitro, -NHC(O)CCH,)-CHCH3, -NI{C(O)OC(CH3)3, -NH 2
-NHSO
2 -4-methylphenyl,
-NHC(OXCH
2 )3COOH, -NHC(O)-4-(SO3H)phenyl, -OH, -NHC(O)- 1 -adamnantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl,
-NHC(O)CH
2
C(CH,,
-NHC(O)C(CHI)3, -NHC(O)0C-C 1 0 alkYl, -NH-C(O)NHC 1
-C
10 alkyl, -NHC(O)NHPh substituted with one, 2 or 3 ailcl, alkoxy, halo, CIC, alkylthio, trifluoromethyl,
C
2
-C
6 dialkylamino, or nitro, -NHC(O)C,-Cqcycloalkyl; R, is selected from the group consisting of -NI-C(O)phenyl or -N}{C(O)OC(CH 3 with the overall proviso that one of R, and R 3 is -H but R, and R3 are not both -H; R, is -H or selected from the group consisting of -OH, -OAc (-OC(O)CH3),
-OC(O)OCH
2
C(C)
3
-OCOCH
2
CH
2 NH3- HCOO, -INHC(O)phenyl, -,NHC(O)OC(CH,) 3 -OCOCH,CHCOOH and pharmaceutically acceptable salts thereof, -OCO(C-1 2 )3COOH and pharmaceutically acceptable salts thereof, and (where Z is ethylene propylene (-CH 2
CH
2
CH
2 -CH-CH-, 1,2-cyclohexane or 1,2-phenylene, R' is -OH, -OH base, -NR',R' 3
-OR'
3 -SR'3, -OCI-1C(O)NR' 4 R%5 where R' 2 is -H or R'3 is -(CH).NRj ',or (CH,).N'R'X 7 X where n is 1-3, R' 4 is -H or -C,-C 4 alkyl, is -H,
-C,-C
4 alkyl, beuzyl, hydroxyethyl, -CH 2
CO
2 H or dixnethylaminoethyl, R' 6 and arm -C-I,
-CH
2 CH3, benzyl or R' 6 and R'7 together with the nitrogen of form a pyrrolidino, ~~25 pipenidino, morpholino, or N-methylpiperizino group; R's is -C3I, -CH 2 CH or3 nylX halide, and base is NH,, (HOC 2 H,)3N, N(CH 3
CHN(CH)
2 NH, NH 2 (CH2)6NH 2 ***N-methylglucainine, NaOH or KOH], -OC(O) (CH2).NR 2 R' (where n is 1-3, R 2 is -H or
-C
1
-C
3 alkyl and R 3 -H or -CI-CqallcylI, -OC(O)CH(R)NH,1 (where R" is selected from the group consisting of -Cl-I, -CH 2 CH- (Cl-I) 2 -CH(CH3)CH 2 CH3. -CH(CH3)2, -CH 2 phenyl, 30 -(CH2)NH 2
-CH
2
CH
2 COOH, NHC(-NH)NHJ], the residue of the amino acid proline,
OC(O)CH-CH
2
-C(O)CHCH
2
C(O)NHCH
2
CH
2 SO3; Y,1
-OC(O)CH
2
CH
2
C(O)NHCH
2
CH
2 CHrSO3'Y* wherein Y* is Na* or N*(Bu) 4
-OC(OCH
2
CH
2
C(O)OCH
2
CH
2
OH;
It -H or -OK ith te ora rovisohath henRjis OH, Ris -Hand with te further proviso that when 1 is 4 is other than -H; is -OH, or and 4744.P -17pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group.
A preferred embodiment of the subject invention is compounds of Formula II (or Ha) where R, is phenyl or phenyl substituted with halo, R, is -NHC(O)CH,, R, and R, are and R3 is Another preferred embodiment of the subject invention is compounds of Formula II (or IIa) where R, is preferably phenyl or phenyl substituted with halo, R, is
-NHC(O)OC(CH
33 and R 3 R, and R30 are -OH. A further preferred embodiment of the subject invention is compounds of Formula II (or HIla) where R, is preferably phenyl or phenyl substituted with halo, R, is -NHC(O)OC(CH03, and R, and R, are and R3, is -OC(O)CH 3 Another preferred embodiment of the subject invention is compounds of Formula I where R, is preferably phenyl or phenyl substituted with halo, R, is -NHC(O)NHC(CH 3
R
3 and R, are -H, R, is -OH, and R30 is -OH or -OCOCH 3 Additional preferred embodiments of Formula II include: The compound according to Formula II, namely 7-deoxy- 7 0,8-methano-A&2.1 3 -iSo-taXol; The compound according to Formula II, namely 2'-[{(2,2,2-trichloroethyl)oxy)carbonyl]-7deoxy-70,8i-methano-A'-'"-iso-taxol; The compound according to Formula II, namely 10-acetyl- 7 -deoxy-70,8-methano-A' 3 -isotaxotere; and The compound according to Formula II, namely N-debenzoyl-a-(t-butyl)aminocarbonyl-7deoxy-70,80-methano-A' 2 "-iso-taxol.
A preferred embodiment of the subject invention are compounds of Formula II (or IIa) where R, is preferably phenyl or phenyl substituted with halo, R, is -NHC(O)NHC(CH) 3
R,
and R, are R 4 is -OH, and R3 is -OH or -OCOCH.
Another embodiment of the present invention are 7-halo-A' 2 '"-iso-taxol analogs of general Formula m (or IIIa) wherein: X, is selected from the group consisting of -Br, -CL, or -N 3 R, is selected from the group consisting of -CH 3 -CH, or phenyl substituted with one, 2 or 3 alkyl, C 1
-C
3 alkoxy, halo, C,-C alkylthio, trifluoromethyl, C-C, dialkylamino, hydroxy or nitro; *30 R, is selected from the group consisting of -NHC(O)phenyl, -NHC(O)pbenyl substituted with one, 2 or 3 C 1
-C
4 alkyl, CI-C alkoxy, halo, alkylthio, trifluoromethyl, C- C, dialkylamino, hydroxy or nitro,-NHC(O)C(CH 3 )-CHCH,, -NHC(O)OC(CH 3
-NH,,
-NHSO-4-methylphenyl, -NHC(OXCH) 3 COOH, -NHC(O)-4-(SO]H)phenyl, -OH, NHC(O)-1-adamantyl, -NHC(O)O-3-tetrahydrofurnyl, -NHC(O)O-4-tetrahydropyranyl, -NHC(O)CHC(CH0 3
-NHC(O)C(CH,)
3 -NHC(O)OC-Coa*lkyl, -NHC(O)NHC -Ctalkyl, ~-NHC(O)NHPh substituted with one, 2 or 3 CI-C, alkyl, alkoxy, halo, C,-C alkylthio, 4744TP -18trifluoromethyl,
C
2
-C
6 dialkylainino, or nitro, -NHC(O)C 3 -C~cycloalcyl; R, is selected from the group consisting of -NHC(O)phenyl or -NHC(O)OC(CH) 3 with the overall proviso that one of R, and R, is -H but R 2 and R, are not both -H; R, is -H or selected from the group consisting of -OH, -OAc
-OC(O)OCH
2
C(C)
3
-OCOCH
2
CH
2
NH
3 HCOC), -NHC(O)phenyl,
-NHC(O)OC(CH)
3 -OCOCH2CH 2 COOH and pharmaceutically acceptable salts thereof, -CO(CH 2 3 COOH and pharmaceutically acceptable salts thereof, and (where Z is ethylene
(-CH
2
CH
2 propylene (-CH 2
CH
2
CH
2 -CH-CH-, 1,2-cyclohexane or 1,2-phenylene, R' is -OH, -OH base, -NR'2R' 3
-OR'
3
-SR'
3 -OCH2C(O)NR'.R' 5 where R' 2 is -H or -CH 3
R'
3 is -(CH2)NR' 6 ,R'7 or (CH- N*R',R'R' 8 X where n is 1-3, is -H or -C,-Cakl, R'5 is -H, -C,-C~alkyl, benzyl, hydroxyethyl,
-CH
2
CO
2 H or diinethylaniinoethyl,
R'
6 and are C3 -CH2CH 3 benzyl or and R'.1 together with the nitrogen of NR' 6
R'
7 form a pyrrolidino, piperidino, morpholino, or N-methylpiperizino group; is -CH 3
-CH
2
CH
3 or benzy X- is halide, and base is NH3, (HOq2H 3 N, N(CH3)3, CH3N(q2Hj 2 NH, NH 2 (CH2)NH 2 N-methylglucamine, NaOH or KOH], -OC(O)(CH 2 [where n is 1-3, R' is -H or -C,-C~akyl and R 3 -H or -C 1 -C~alkylJ, -OC(O)CH(R")NH 2 [where R" is selected from the group consisting of -CH3, -CH 2
CH(CH
3 2
-CH(CH
3
)CH
2
CH
3 -CH(CI-i)2, -CHzPhenyl,
-(CH,N-
2
-CH
2
CH
2 COOH, -(CH 2 the residue of the amino acid praline, -OC(O)CH-CH2,
-C(O)CH
2
CH
2
C(O)NHCIA
2 CH,SO,- Y,1 -OC(O)CH, CH 2
C(O)NHCH
2 CHgCH,S0 3 Wherein Y* is Na* or N*(Bu) 4
-OC(O)CH
2
CH
2
C(O)OCH
2
CH
2
OH;
R, is -H or -OH, with the overall proviso that when R, is -OH, R, is -H and with the further proviso that when R, is R, is other than -H; R3 0 is -OH or -OC(O)CI-l; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group.
The compounds of Formula Ill (or m1a) include both the 7-at and 7-0 configurtion of the 7-halo substitution. Halo refers to -Br, -Cl, or NP.
In compounds of Formula [M (or Mfa): X 7 is preferably and R 3 and R, are preferably and R, is preferably phenyl or phenyl substituted with halo.
A preferred embodiment of the subject invention are compounds of Formula DII (or Mla) where R, is preferably phenyl or phenyl substituted with halo, R, is -NHC(O)NHC(CH 3 3
R
3 andR1; are -H R, is -OHand R. i -H r xOCOCH ~Additional preferred embodiments of Formula [M (or Mil) include: A compound according to Formula III (or 111a) wherein k 4 is -H and is -OH; A compound according to Formula H11 (or (Mia) wherein R, is other than -H and It, is-H 4744.P -19- A compound according to Formula III (or La) wherein R, is and R, is Ph or substituted phenyl; A compound according to Formula III (or ia) wherein X is -F; A compound according to Formula M (or Ma) wherein X, is -c-F; A compound according to Formula III (or Ila) wherein X, is -F and R 4 is other than -H and R, is -H; -A compound according to Formula M (or Ma) wherein X is R3 is and R, is Ph or substituted phenyl; A compound according to Formula M selected from the group consisting of 7 -deoxy-7-fluoro 12 -iso-taxol and 2 2 2 -trichloroethyl)oxy )carbonyl]-7-deoxy-7-fluoro-
A'
2 -isotaxol and A compound according to Formula III, namely N-debenzoyi-N-(t-butyl)aminocarbonyl-7deoxy-7-fluoro- 2 "-iso-taxol.
An additional preferred embodiment of Formula M are compounds selected from the group consisting of 7 -deoxy-7-fluoro-A'"-iso-taxol, 7 -deoxy-7fluoroA '1iso-tx.ol, 2'-f 2 ,2, 2 -trichloroethyl).oxy carbonyl]-7-deoxy-7c-fuoroAtl-isol and trichloroethyl)-oxy }carbonyl 7 -deoxy-78 fluoro-A 'Z iso-tiol.
Another embodiment of the present invention are 7 2 -iSo-taxol analogs of general Formula IV (or IVa) wherein: R, is selected from the group consisting of -CH, -C6H or phenyl substituted with one, 2 or 3 alkyl, alioxy, halo, C 1
-C
3 alkylrhio, trifluoromethyl,
C
2
-C
6 dialkylamino, hydroxy or nitro;
R
2 is selected from the group consisting of -NHC(O)H,
-NHC(O)C
1
-C
10 alyl NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 alkyl, C 1
-C
3 alkoxy, halo, alkylthio, trifluoromethyl, Cq-C 6 dialkylarino, hydroxy or nitro,
-NHC(O)C(CH)-CHCH
3
-NHC(O)OC(CH
3 -NHSOz-4-methylphenyl, .:..-NHC()(CH')3CooHI -NHQ(O)-4(SOH)henI -OH, -NHC(O)-l-adarnantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl, -NHC(O)CH2C-(CH3)3 -NC(O)C(CH03 -NHC(O)OC1-CI) 3 ylI -NHC(O)NHC,-CIalrkyl -NHC(O)NH h substituted with one, 2 or 3 alkyl, C-C 3 alkoxy, halo, CC- alkylthio, trifluoromethyl, 2 dialkylanino, or nitro or -NHC(Q)C 3 -C cycloalkyl; and R 4 R, and R3.are as defined above.
A preferred embodiment of the present invention are A4-A' 2 I'-iso-taxol analogs of general Formula IV (or IV&) where R, is phenyl or phenyl nibstibned with halo, R2 is NHC(O)QIA,
R
3 and Rt ae and is -OC(O)CH,. Another prefered embodiment of the subject invention is compounds of Formula IV (or IVa) where R, is pefeably phenyl or phenyl substituted with halo, R is -NHC(O)OQCH,) and R 3 ad R, ar -H and Rx is -OH.
4744.P Another preferred embodiment of the subject invention are compounds of Formula [V (or IVa) where R, is preferably phenyl or phenyl substituted with halo, R, is
NHC(O)NHC(CH)
3
R
3 and R, are R 4 is -OH, and R)O is -OH or -OCOCH 3 Preferred embodiments of Formula TV include: A compound according to Formula WV, namely 7-deoxy-A-' 2 J3-iso-tAXoI; A compound according to Formula IV, namely 2'-({(2,2,2-trichloroethyl)oxy~carbonyl]-7deoxy-A"',-a1 2 '1 3 -iSo-taXol; and A compound according to Formula IV, namely l0-acetyI-7-deoxy-Ac 7 2 .1 3 -iso-taXotere; and A compound according to Formula IV, namely N-debenzoyl-N-(t-butylI)aminocarbonyl-7-deoxy- &6.
7 _-A12 13 _iSO-t&XoJ.
A preferred embodiment of the subject invention is compounds of Formula V (or Va) where R, is phenyl or phenyl substituted with halo, R 2 is -NHC(O)C~H 5
R
3 and R 5 are and
R
3 0, is -C(O)CH 3 Another preferred embodiment of the subject invention is compounds of Formula V (or Va) where R, is preferably phenyl or phenyl substituted with halo, R, is -N}IC(O)OC(CH 3 3 and
R
3 R, and R30 are A fur-ther preferred embodiment of the subject invention is compounds of Formula LI where R, is preferably phenyl or phenyl substituted with halo, R, is
-NHC(O)OC(CH)
3 and R 3 and are and R3. is -C(O)CH 3 Another preferred embodiment of the subject invention is compounds of Formula I where R, is preferably phenyl or phenyl substituted with halo, R, is NHC(O)NH-C(C-1) 3 R, and R, are R, is -OH, and R3.is -OH or -OCOCH 3 A further embodiment of the present invention are iso-taxol analogs of general Formula V (or Va) wherein: R, is selected from the group consisting of -CHI, -C 6 H, or phenyl substituted with one, 2 or 3 cl-c 4 ailkyl, C,-q alkoxy, halo, C,-C 3 alkylthio, trifluoromethyl, C 2
-C
6 dialkylamino, .:..hydroxy or nitro;
R
2 is selected from the group consisting of -NHC(O)phenyl, -NH-C(O)pbenyl substituted with one, 2 or 3 alkyl, C,-Cq atkoxy, halo, C,-C 1 alkylthio, trifluoromethyl, C 2 Cs dialkylarnino, hydroxy or nitro, -NIIC(O)C-(CH,)--CHCH 3
-NHC(O)OC(CH)
3
-NH
2 30 -NH-S0 2 -4-miethylphenyl, -NHC(O)(CH 2 3 COOH, -NHC(O)-4-(SO 3 H)pbenyl, -OH, -NHC(O)-lI-adaniantyl, -NHC(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl,
-NHC(O)CH
2
C(CH,)
3 -NHC(O)C(CHO., -NHC(O)OCI 1
C
0 Alkyl, -NHC(O)NHC,-C 0 Alkl, -NHC(O)NHPh substituted with one, 2 or 3 C 1
-C
4 alkyl. Ci-C alkoxy, halo, Wlkylthio, trifluoroinethyl, C 2 dialkylamnino, or nitro, -NHC(O)C 3 -C~cycloalkyl; and R 3 R. R 5 and are as defined above.
The compounds of Formula V (or Va) include both the 7-a and 7-0 configuration of the 4744.P -21- 7-hydroxy substitution.
An embodiment of the present invention are 7-deoxy-7-W-A 11" -is-taxol analogs of general Formula VI (and Via) wherein: R, is selected from the group consisting of -CH3I, -C Hs or phenyl substituted with one, 2 or 3 C 1
-C
4 alicyl, C,-C3 alkoxy, halo, C,-C3 alkylthio, trifluoromethyl, C 2
-C
6 dialkylamino, hydroxy or nitro;
R
2 is selected from the group consisting of -NHC(O)C 1 -Cl 0 alkyl (preferably
-NHC(O)C-C
6 aJkyl), -NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 CX- 4 alkyl, CX3C alkoxy, halo, alkylthio, trifluoromethyl, C 2 -C diaklamino, hydroxy or nitro, -NHC(O)C(CH,)-CHCH3, -N}{C(O)OC(CH3)3, -NH2, -NHSO,-4-axthylphenyl,
-NHC(O)(CH
2 )3COOH, -NHC(O)-4-(SO3H)phenyl, -OH, -NHC(O)-l-adamantyl, -NH-C(O)O-3-tetrahydrofur-anyl, -NHC(O)O-4-tetahydropyranyl,
-NHC(O)CH
2
-NHC(O)C(CH
3 3 -NHC(O)0CI-CI 0 alkYI, -NHC(O)NHC-ClalkyI, -NHC(O)NI-IPh substituted with one, 2 or 3 CX- 4 alkyl, C,-C3 alkoxy, halo, alkylthio, hrifluoromethyl, (2 2
-C
6 dialkylamino, or nitro, -NH-C(O)C3,-Cscycloalkyl;
R
3 is selected from the group consisting of -NHC(O)phenyl or -NHC(O)OC(CH 3 with the overall proviso that one of R 2 and R, is -H but R 2 and R 3 are not both -H; R, is -H or selected from the group consisting of -OH, -OAc (-OC(O)CH3),
-OC(O)OCH
2 C(Cl) 3
-OCOCH
2
CH
2
NH
3 HCO(Y, -NHC(O)phenyl, -NHC(O)OC(CH,),,
-OCOCH
2
CH
2 COOH and pharmaceutically acceptable salts thereof, -OCO(CH 2 3 COOH and pharmaceutically acceptable salts thereof, and [where Z is ethylene
CH
2
CH
2 propylene (-CH 2
CH
2
CH
2 -CH-CH-, 1,2-cyclohexane or 1,2-phenylene, R' is -OH, -OH base, -NR' 2
R'
3
-OR'
3 -SRi,, -OCH 2
C(O)NR'
4 where is -H or -CH3, R'3 is-
(CH).NR'XR
7 or X' where n is 1-3, R' 4 is -H or -C,-C 4 aIlcyI R'5 is -H, -C,-Calkyl, benzyl, hydroxyethyl, -CH 2
CO
2 H or dirnethylaminoethyl, R' 6 and are -Cl-I,
-CH
2
CH
3 benzyl or and R' 7 together with the nitrogen of NR' 6 R' form a pyrrolidino, piperidino, morpholino, or N-methylpiperizino group; is -CH 3
-CH
2 CH, or benzyl X is :4::halide, and base is NH3, (HCCqHj,3N, CHN(C 2
H
4 )2NH, NH 2 (CH2)NH., Nmethyiglucamine, NaOH or KOH], -OC(O) (CH,)NR 2 R3 (where n is 1-3, R 2 is -H or -C,-Cqalkyl and R 3 -H or -C 1 -C~alkyl], -OC(O)CH(R")NH2 [where R" is selected from the group consisting of-H, -CH3I, -CH 2 CH -CH(CHX)H2CH3, -CH(CH) 2
-CH
2 pbenyl,
-(CH
2 XNH2, -CHzCHzCOOH, -(CH2)3 NHC(-NH)NH 2 J, the residue of the amino acid proline, -OC(O)CH-CH2, C(O)CH 2
CH
2
C(O)NIICHCH
2 SQ3 Y, -OC(O)CH2 CHC(O)NHCH2CHCH 2 SO.-Y wherein Y* is Na* orN(B -OC(O)CH2CHC(O)OCH 2
CH
2 0H Rs -H or -OH, whhe ovralprovso that when R,i -OH. R4~ is -H andlwith the 4744.P -22further proviso that when R, is P, is other tha -H; is -OH or -OC(O)CH 3 and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group.
Another embodiment of the present invention are 7-deoxy-7-W-A'12' 3 -iso-taxol analogs of general Formula VI (and Via) wherein: R, is selected from the group consisting of -41Ij or phenyl substituted with one, 2 or 3 C 1 -CI alkYl, CI-C 3 aikoxy, halo, CI-C 3 allcylthio, trifluoromethyl, C 2 -Cq dialkylamino, hydroxy or nitro-,
R
2 iS selected from the group consisting of -NH-C(O)C,-Cl 0 akyl (preferably
-NIIC(O)C
4 -Cqalkyl), -NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 CX- 4 alkyl,
C,-C
3 alkoxy, halo, C -C alkylthio, tiifluoromethyl, (2 2 dialkylamino, hydroxy or nitro,
-NHC(O)C(CH
3 )u.CHCH 3
-NHC(O)OC(CH
3 3 -Nil 2
-NHSO
2 -4-methylphenyl,
-NH[C(O)(CH
2 3 COOH, -NHC(O)-4-(SO 3 H)phenyl, -OH, I-adainantyl, -NHC(0)O-3-tetrahydrofuranyl, -NHC(0)-4-tetrahydropyranyl, -NIIC(0)CH 2
C(CH
3 3
-NIIC(O)C(CH
3 3 -NI{C(O)0CI-C 10 AlkYl, -NHC(O)NI-C 0 aIlcyl, -NH-C(O)NHPh substituted with one, 2 or 3 alkyl, CX- 3 alkoxy, halo, C,-C 3 alkylthio, trifluoromethyl, diaklam-ino, or nitro, -NHC(0)C 3 -C8CYCloalkyl; and W is selected from the group consisting of propionyl; O-(2,2-dichloroethyl)carbonate; 0-(2-chloroethyl)carbonate; 0-methyl; 0-propyl; 0-allyl; 0-rnethoxymethyl; O-ethoxyrnethyl; O-rethoxyethoxymethyl; O-benzyloxymrethyl; O-(2,2,2-trichloroethoxy)miethyl; 0-(2,2,2-trichloroethoxy)me~thoxynmethyl; and
R
3 R5 and R30 are as defined above.
A further preferred emimxlzent of the present invention arm 7-deoxy-7-W-AZI 3 -iso-taxoI analogs of general Formula VI wherein: R, is selected from the group consisting of -CII,, -4CHj1 or phenyl substituted with one, 2 or 3 C 1
-C
4 alkyl, CI-C, alkoxy, halo, C,-C 1 alkylthio, trifluoromethyL, C 2 diaklamino, 47 44. P -23hydroxy or nitro;
R
2 is selected from the group consisting of -NHC(0)C-CI 0 alkyl (preferably NHC(0)C 4
-C
6 alkyl), -NHC(0)phenyl, -NHC(O)phenyl substituted with ome 2 or 3 C 1 alkyl,
CX-
3 alkoxy, halo, C 1
-C-
1 alkylthio, trilluoroniethyl, C-C dialkylamino, hydroxy or nitro, -NHC(0)C(CH,)-CHCHl 3
-NHC(O)OC(CH
3 3
-NH
2
-NHSO
2 -4-medhylphenyl, -NHC(O)(CH03COOH, -NHC(0)-4-(SO 3 H)phenyl, -OH, -NHC(0)- 1 -adamantyl, -NHC(0)O-3-tetrahydrofuranyl, -NHC(O)O-4-tebrahydropyrayl,
-NHC(O)CH
2
C(C
3 -NHC(0)C(CH 3 3 -NHC(0)0C-CIalkYL, -NHC(0)NHC-CJ 0 alky1, -NI4C(O)NHPh substituted with one, 2 or 3 CI-C 4 alkyl, C,-C 3 alkoxy, halo, C 1 -Cq allcylthio, trifluoromethyl, (2 2 -Cs dialklcyamino, or nitro, -NHC(O)C 3 -CcYCloa~kyl; W is selected from the group consisting of 0-ethoxymetbyl; O-methoxyethoxymethyl; O-benzyloxymethyl;
O-(
2 ,2,2-trichloroethoxy)methyl;
O-(
2 2 2 -richloroethoxy)methoxymethyl; and
R
3 R5 and R 3 4 are as defined above.
A preferred embodiment of the subject invention is compounds of Formula VI where R, is phenyl or phenyl substituted with halo, R, is -NH-C(O)C 6
H
5 R, and R, are and is C(0)CH 3 Another preferred embodiment of the subject invention is compounds of Formula VI where R, is preferably phenyl or phenyl substituted with halo, R 2 is -NHC(O)O(CH 3 3 and R 3 R, and R3. are A further preferred embodiment of the subject invention is compounds of Formula VI where R, is preferably phenyl or phenyl substituted with halo, R 2 is
NH-C(O)OC(CH
3 3 and R 3 and R 5 are and R 3 0, is -OC(O)CH 3 Another preferred embodiment of the subject invention is compounds of Formula VI where R, is preferably phenyl or phenyl substituted with halo, R. is -N1-C(0)N1-C(CH0 3
R
3 and R, are R, is -OH, and
R
3 is -OH or -OCOCH 3 In compounds of Formula VI, W is preferably selected from the group consisting of propionyl; 30
O-(
2 ,2-dicbloroethyl)carbonate; O-(2-chloroethyl)carbonate; 0-methyl; 0-propyl; 0-allyl; 0-methoxyrnethyl; O-ethoxymedsyl; 4744.P .24.
0-methoxyethoxymethyl; O-benzyloxymethyl; O-(2,2,2-trichloroethoxy)methyl; O-(2,2,2-trichloroethoxy)methoxymethyl; and more preferably 0-methoxymethyl; 0-ethoxymethyl; O-znethoxyethoxymethyl; O-benzyloxyrnethyl; O-(2,2,2-trichloroethoxy)methyl; and O-(2,2,2-tricbloroethoxy)methoxymethyl.
Examples of -NHC(O)C,-COalkyl include -NHC(Q)-n-pentyl and
-NHC(O)CH(C-H
3
)CHCH
3 Examples of C 1
-C
6 alkyl include straight and branched alkyl chains, including for example methyl, ethyl, isopropyl. t-butyl, isobutyl and 2-methyl-pentyl.
Examples of C 1
-C
3 alkoxy are methoxy, ethoxy, propoxy and isomeric form thereof Halo refers to -Br, -Cl or 1, or NP.
Examples of Formula UI compounds of this invention include: 2 {(2,2,2-trichloroethyl)oxy )carbonyl]-7-deoxy-70,f8-methano-A 3 -iso-taol; 7-deoxy-70,8f--methano-tV'-sotxl 2' -succinyl-7-deoxy-70,8 -methano-A" 3 -iso-taxol; 2'-(f-alany1)-7-deoxy-70,8f3-methano-A 1 2 3 _iso-ta.Xol formate; 2 '-glutaryl-7-deoxy-70,8f -methano-A 1- 3 iso-taxol; 2 -sulfopropionyl)-7-deoxy-70,8f-methano-A'2- 3 -iso-taxol; 2' -(2-sulfoethylamido)succinyl-7-deoxy-7fr8f -mtho-A'"' 3 -iso-taxol; 2' -(3-sulfopropylan ido)succinyl-7-deoxy-70,8f -methano-Al' -iso-taxol; 2' -(tiethylslyl)-7-deoxy-7,*mthano-A 3 iotaxol; 2 '-(t-butyldimethylsilyl)-7-deoxy-70,8f-methano-&"-"-iso-taxol; 2'(Ndehlmnpoinl--ex-0* ehn-'--s>txi 2 '-(NN-dimethylglycyl)-7-deoxy-7,8f-methano-A' 2 -iso-taxol; 2 '-(glycyl).7-deoxy-70,8 -rnethano-AtWL'3iao-txol; .*~'2'-(L-alanyl)-7-deoxy.7,gP-methano-A2-iijo-taxol; *.be 2'-(L-lcucyl)-7-deoxy-70,8*methano-4'"'-iso-taXOI- 2'-(L-ioleucyl)-7-deoxy-7,oq-metiao-A'2"-isL-o-taxol; 2' -(L-valyl)-7-deoxy-7f,8o.-tnehno-A' 2 "iao-_aol; 47 44.
2' -(L-phenylaianyl)-7-dcoxy-70,81-methano-A' 2 3 -iso-taxol; 2' -(L-proly)-7-eoxy-70,8f-methano-A'""-iso-taxoI; 2' -(L-gluysyl)-7-deoxy-7,8-meano-A' 3 -iso-taxo; 2' -(L-arginmy)-7-deoxy-7,8 -ethano-A"-iso-taxo; 2-(-ainl)7-deoxy-70,an-A 2 "-ieto-LAotere; txo 1 0-acetyI-7-deoxy-70,8f -mediano-A' -is-aoe N-cbenzoyl-N-tewAhydroftan-3-yoxycarbony-7-doxy-7,8f-methno-a'"'-iso-taxo; N-debenzoyl-N-( 1-ada nantoyl)-7-doxy-70,8f-methano-A'2' 3 -iso-taxoI N-debenzoyl-N-( I-methyl-I -cyclobexylanoy1)-7-deoxy-7A,8f -methano-A" 3 "-iso-taxol; N-debeazoyl-N-( 1-phenyl- 1 cyclopentanoyI)-7-deoxy-70,8f-mthano-A'" 3 -iso-taxol; N-debenzoyl-N-phthalirnido-7-deoxy-70,8f-methano-& 2 3 -iso-taxol; N-debenzoy1-N-t-butylaniinothiocabonyl-7-deoxy-7,8-ehno-A"-iso-taxo1; N-debenzoyI.N-t-amyloxycarbony-7-deoxy-7,8-methano-A- 3 -iso--taxoI; N-debenzoyi-N-neopentyloxycarbony-7-deoxy-7r8f-methano-A' 21 -iso-taxol; N-debenzoyl-N-(2-chloro- 1,1-diincthylethyl)oxycarbonyl-7-deoxy-70,8f -methano-& 2 iso-taxoI; N-debenzoyl-N-(3-methyl-3-pentyl)oxycarbonyl-7-deoxy-7r8P-methao-A 2 3 -iso-taxol; 3' -desphenyl-3 '-(2-furyl)-7-deoxy-7,*methano-A 2 3 -iso-taxo; 3' -desphenyl-3 '-(2-thieny1)-7-deoxy-7,8f-nethano-A 2 13 -iso-taxoI; 3' -desphenyl-3 -naphthyl)-7-deoxy-7fr8f-methano-A'2. 3 -iso-taxol; 3' -desphenyl-3 '-(2-naphthy1)-7-eoxy-7,8f-methano-A" 3 -iso-taxol; 3 '-despbeny1-3'-(4-methoxyphenyl)-7-deoxy-7,8-cthano-' 2 "-iso-taxol; 3'-dephy-3 '-(4-chlorophenyI)-7-deoxy-70,8f-metano-A' 2 "-iSotaxo1 3' -desphenyl-3 '-(4-bromphenyI)-7-deoxy-7,8-methano-A 2 3 -iso-taxoi 3'-desphenyl-3 ,4-methylenedioxyphenyl)-7-deoxy-7,8-rrmethano-A'2- 3 -iso-taxo; -desphenyl-3 drtoyhnl--ex-0, mtaoA-'Lotxl .30 3'-dcesphenyl-3 '-(4-niopbeay1)-7-deoxy-70,8f -nwmet o-A2 3 -LsO-taxol; *3'-despbenyl-3 '-(4-fluorophey)-7-deoxy-7,8frmethan&'2.-isotaXol; N-debenzoyl-N-(4-bromobenzoyI-7-dcoxy-7,8 -meano-A2' 3 -iso-taxo1- N-dcbenzoyl-N-(4-nethylbenzoyI)--dexy-7,*-ehano-A' "-io-taxoi; 35N-debenzoy.N-(4-nhoxtylboyl)-7-deoxy-7o,8d~aflno-A 1 13 i3O-WaXO N-debeuzoyl-N-(4-fluorobeuzoyl)-3'-despheayl-3 '-(4-ftuorophmy)-7doxy-7f,8f 4744.P -26methao-A~ M, -iso-taxol; N-ebenzoy-N(4-fluorobezy)-7-deoxy-7,8-mehmo-'"' 3 -iso-tUxo1; N-debenzoyl-N-(4-methylbenzoyl)-3 '-desphenyl-3 '-(4-chlorophenyl)-7-deoxy-70,8- MethOAno-& 2 3 _iSo-t&Xol; N-debenzoyl-N-(4-chlorobenzoyl)-3 '-desphenyl-3 '-fluoropheny)-7-deoxy-7,8f methano-A" 3 -iso,-taxoI; N-debenzoyl-N-(4-brornobenzoyl)-3 '-desphenyl-3 '-(4-fluoropheny)-7-deoxy-70,8 methano,-AI1i~SO~taxO1; N-debenzoyl-N-(4-methylbenzoyl)-3 '-dspbenyl-3 '-(4-fluoropheny1)-7-deoxy-70,8flmethano-Al"l)-iso-taxol; N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphcnyl-3 '-(4-methoxyphenyI)-7-deoxy-70,8f methano-A Ui-iso-taxoI; N-debenzoyl-N-(4-methylbenzoyl)-3 '-desphenyl-3 '-(4-methoxypheny1)-7-deoxy-70,8* methao-A 1 -iso-taxol; N-debenzoyl-N-(4-fluorobenwoyl)-3 '-desphenyl-3 '-(4-chlorophenyl)-7-deoxy-70,8f methano-A 1 2 .1 3 -iSo-taXol; N-debenzoyl-N-(4-chlorobenzoyl)-3 '-desphenyl-3 '-(4--choropheny)-7-&eoxy-7fr8f methano-& 2 3 -iso-taxot; N-debenzoyl-N-(4-bromobenzoyl)-3'-desphenyl-3 '-(4-chlorophenyI)-7-deoxy-70,8methano-A 2 3 -iSo-taxol; N-debenzoyl-N-(4-t-butylbenzoyl)-3 '-desphenyl-3 '-(4-oropheny)-7-oxy-7,8rnethano-A'" 3 -iso-taxol; N-debenzoyl-N-(4-t-butylbenzoyl)-3 '-desphenyl-3 '-(4-fluoropbeny1)-7-deoxy-70,8f methao-A'" -iso--taol; N-debenwoyl-N-(4-clilorobenzoyl)-3 '-desphenyl-3 '-(4-mebhoxyphenyI)-7-deoxy-70,8f methano-&A' 3 -iso-taol;, N-debenzoyl-N-(4-bromobenzoyl)-3 '-desphenyl-3 '-(4-methoxyphenyl)-7-deoxy-70,8P methao-A" 3 -iso,-taxoI; N-dehenzoyl-N-(4-t-butylbeazoyl)-3 '-despbenyl-3 '-(4-miethoxyphenyl)-7-deoxy-70,8P 30 methano-A'-"-iso-taxoI; *N-debenoyl.NhoxybfethxynoyI)-3-sph speyI-3'-(4-ithoxypeyl7deoxy-70, 8
P
methano-A' 2 '"-iso-taxol; N-eezolN ncabnl7-ex-7,f-mtao-""is-ao and pharmaceutically acceptable salts theeof when the compound contains either an acidic or basic functional group.
Examples of Formula Ill compounds of this invention include: 4744-P ((2,2,2-trichloraethy1)oxy)carbony].7-deoxy-7-fluoro-,A'2 1 iso-taxoI; 7-deoxy-7-fluoro-A'12"-iso-taxol; 2'sciy--ex--looA2"Lotxl 2 -(O-alanyl)-7-deoxy-7-fluoro-A 3 -iso-taxol formate; 2'-glutaryI-7-deoxy-7-fluoro-A2-"-iso-taxo; 2'[CO(H3()HC)NC3j7doy7fur-&2"iotxl 2' .(f-sulfopropiony1)-7-deoxy-7-fluoro-A 2 -"-iso-taxol; 2' -(2-sulfoethylamido)succinyl-7-deoxy-7-fluoro-A' 2 "1 3 _isoaOL.
2'-(3-sulfopropylamido)succinyl7-deoxy-7-fluoro-A 2 3 -io-taxol; 102'-(t-bethyisimeyls-7y-7-ex7fuoro-A"is -so-txl 2'-(N,N-diethylaninopropiony)-7-deoxy-7-fluoro-A 12 -"-iso-taxo; 2'-(,-iehllcl--ex--loo, 121_~ot~ 2' -(glycyI)-7-deoxy-7-fluoro-A&"' 3 -iso-taxol; 2' -(L-alanyl)-7-deoxy-7-fluoro-A 1 "-iso-taxol; 2' -(L-leucyl)-7-deoxy-7-fluoro-A&" 3 "-iso-taxol; 2' -(L-isoleucyl)-7-deoxy-7-fluoro-A& 2 3 -iso-taxol; 2 '-(L-valyl)-7-deoxy-7-fluoro-A"- 3 -iso-taxo; 2 '-(L-phenylalanyl)-7-deoxy-7-fluoro-AI 1 QiSotaXo: 2'-(L-prolyl)-7-deoxy-7-fluoro-A" 3 -iso-taxol; 2 '-(L-lysyl)-7-deoxy-7-fluoro-A' 2 3 -iso-taxol; 2 '-(L-glutamyl)-7-deoxy-7-fluoro-A 12 -iso-taxol; 2'-(L-arginyl)-7-deoxy-7-fluoro-A"- 3 -iso-taxol; 7-deoxy-7-fluoro-,& 2 3 -iso-taxotere; 10-acetyl-7-deoxy-7-fluoro-A' 2 '-iso>-taxotere; eezy--ttayrpra--lxcrbnl7doy-- ooA-"iotxl N-debenzoy-N-pivaloyl-7-deoxy-7-fluoro-' 2 3 -iso-taxo; N-ebezoy-N-n-hexylaminocarbonyI-7-deoxy-7-fluoro-A'2' 3 -iso-taxol; N-debenzoyl-N-( I -methyl- I ccoeyaol--ex-7fur-&2'-s>txl N-debenzoyl-N-( I -phenyl- 1 -cyclopentanoyl-7-deoxy-7-fluoro-A'2' 3 -io-taxoI; N-debenzoyl-N-phthalimido-7-doxy-7-floro-A' 2 3 -iso-taxoI; N-debenzoyI-N-t-butylaminothiocarbouyI-7-deoxy-7-fluoro-A'&" -iso-xo; N-debenzoyl-N-t-amyloxycarouyl-7-deoxy-7-fluor- 2 "-iso-ULaxo N-debenzoyl-N-neopentyloxycarbooyl-7-deoxy-7-fluoro-A' 2 "-iso-taXOI; N-debenzoyt-N-(2-cbloro- 1, 1 -dim thylIthy)oxycabcyI-7-deoxy-7-ftuoro-A'13-iSo- 4744.P -28taxol; N-debenzoyl-N-(3 -methyI-3-penty)oxycarbonyI.7-deoxy7fluoro.A 2 '_iSa.&ol; 3' -desphenyl-3 -(2-furyl)-7-dcoxy-7-fluoro-A II 43 taol 3 '-desphenyl-3 '-(2-thienyI)-7-deoxy-7-fluoro-A& 2 11 3 -iSo-t&aXol; 3' -desphenyl-3 -naphthyI)-7-deoxy-7-fluoro-A' 2 1 3 iso-axol; 3 '-desphcnyI-3'-(2-naphthy)-7doxy7fuoro-' 2 13 .iso.taxo; 3 -desphenyl-3 4 -methoxyphcnyl)-7-deoxy7-fluoro-& 2 *'1 3 _iSo-taxol; 3 '-desphenyl-3 '-(4-chloropheayl)-7-deoxy-7-fluoro-A 2 1 -iso-taxol; 3 '-desphenyl-3'-4omopheny)-7deoxy7fuorA' 2 -isotaxo; 3 '-desphenyl-3 -(3,4-methylenedioxypbenyl)-7.deoxy-7.fluoro-,A' 2 4 k1iSo..Xo; 3 '-desphcnyl-3 '-(3,4methoxyphenyl)-7-doxy7-fluoro-A' 2 -iso-taxol; 3' -desphenyl-3 '-(4-nitrophenyl)-7-deoxy-7-fluoro-A -iso-taxoi; 3 '-desphenyl-3 '-(4-fluoropbenyl)-7-deoxy-7-fluoro-A' 2 1 3 -iso-taxol; N-debenzoyl-N-(4-bromobenzoyl)-7-deoxy7-fluoro-' 2
J
3 iso-.uo; N-debenzoyl-N-(4-methylbe-nzoyl)-7..deoxy-7-luoro-AZ' 3 .iso.taxol; N-debenzoyl-N-(4-t-butylbenzoy1)-7-deoxy..7.fluoro..& 2 3iso-taxol; N-debenzoyl-N-(4-methoxybenzoyl)-7-deoxy-7-fluoro-& 2 "-iso.taxol; N-debenzoyl -N-(4-fluorobenzoyl)-3'-desphenyl-3 '-(4-fluorophenyl)-7-deoxy-7-fluoro- A" -so-taxoI; N-debenzoyI-N-(4-fluorobenoy)-7deoxy74iuoro-A'"kiso-taxo; N-debenzoyl-N-(4-methylbenzoyl)-3 '-desphenyl-3 '-(4-chlorophenyl)-7-deoxy-7-fluoro-
A'
2 -"-iso-taxol; N-debenzoy!-N-(4-chlorobenzoyl)-3 '-desphenyl-3 '-(4-fluoropbenyl)-7-,deoxy-7-fiuoro-
A'
2 3 l-iso-zaxol; N-1ebenzoy-N-(4-bromobenzoy).3'-desphenyl-3 '-(4-fluoropbenyl)-7-deoxy-7-fluoro- 3 -iso-taxol; N-debenzoyl-N-(4-methylbenzoyl)-3 '-desphenyl-3 '-(4-fluorophenyl)-7-deoxy-7-fluoro- 2 1 -iso-taxol; N-debenzoyl-N-(4-fluorobenzoyl)-3 '-despbenyi-3 '-(4-methoxyphenyl) -7-deooxy-7-fluoro- *30 &1 2 13 _iSO--taXOj; N-debenzoyl-N-(4-methylbenzoyl)-3 '-despbenyl-3 '-(4-methoxyphenyl)-7-dcoxy-7-fluoro- A1 2 .1 3 -iso-taxol; N-debenzoyl-N-(4-fluorobenzyl)-3 '-despbenyl-3 '-(4-chlorophczyl)-7-deoxy-7-fluoro- A1 2 1 3 _iSO-taXOj; N-dcben2zoyl.N-(4-chlorobenzoyl)-3 '-despbenyl-3 '-(4-chloropltnyl)-7-deoxy-7-fluoro- 4744.P "29- N-debenzoyl-N..(4-bromobenzoyl).3' -dsphenyl-3 '-(4-chlorophenyl)-7.deoxy-7-fluoro- N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3 '-(4-chlorophenyl)-7-deoxy-7-fluoro- 2 -"-iso-taxol; N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3 '-(4-fluorophenyl)-7-deoxy-7-fluoro.
N-debenzoyl-N-(4-chlorobenzoyl)-3 '-desphenyl-3 '-(4-methoxyphenyl)47-deoxy-7-fluoro- A 12, 3 -iso-taxol; N-debeazoyl-N-(4-bromobenzoyl)-3 '-desphenyl-3 '-(4-mietboxyphenyl)-7-deoxy-7-fluoro,- 3 -iso-taxol; N-debenzoyl-N-(4-t-butylbenzoyl)-3 '-desphenyl-3 '-(4-mrethoxyphenyl)-7-deoxy-7-fluoro- A 2 3 _iso--taXol; N-debenzoyl-N-(4-methoxybenzoyl)-3 '-desphenyl-3 '-(4-methoxyphenyl)-7-deoxy-7fluoroAlI.
3 _iso.-taxol; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group.
Examples of Formula IV compounds of this invention include: -trichloroethyl)oxy]carbonyl }-7-deoxy-A&6'--' 3 -iso-taxol; 7-deoxy-A& 7
-AI
2 I 1- 3 -iso-taxoI; N-desbenzoyl-N-benzyloxycarbonyl-2 ((2,2,2-trichloroethyl)oxy]carbonyl }-7-deoxy- N-desbenzoylN-benzyloxycarbonyl-7-deoxy-A6-A- 1' 2 3 -iso-taXol; 2'-succinyl-7-deoxy-A'-i'1." 3 _iso-taxol; 2' alanyl)-7-deoyA'-A 2 1 -sao frmate; 2' guay--ex-6--""iotxl
-[C(OXCH
2 3 C(O)N}1(CH 2 3 N(CH)I-7-deoxy-A"-A'_,&12 3 -iso-taxol; 2' -(f-sulfopropionyl)-7deoXyA67_-' 2 1 3 -iSo-taXol; -(3-sulfopropylaxnido)succinyl-7-deoxy-A' 7 11' 3 iSotaXo; *30 2'-(zriethysilyl)-7-deoxy-Ak-A' 2 ,"iso-taxol; 2'-(N.N-ethyaminopropionyl)-7-deoxy-A'-A''-io-taxol; '-(NN--dmeylyc-deoxy-A" -AA"'-iso-axo 2'-(L-alanyl)-7-deoxy-A'-A' 3 -iso-axol; -uy)7-ex-6A""io=i 4744.P 2' -(L-isoleucy I)-7-coxy-&6--A 11.1 -iso-taxo; 2' -(L-valy1)-7-deoxy-A'l'-A 2 3 iso-taxol; 2 '-(L-phenylalanyl)-7-deoxy-A&"-A iso-taxol; L-lysyl)-7-deoXyA6 7 3 _iSotXol; 2'-(L-glutmyl)-7-eoxy-A 7 -A 3 _jSota~Xol; 27-argixyl)' 7 -de" 3 iox-Axoiere;3_sotao N-debenzoyl-N-( 1 -methyl- I ccoeyaol--exyA"A1.3iotxl N-debenzoyl-N-( 1 -phenyl- 1 -cyclopentanoyl)-7-deoxy-eA' 7 '1 3 _iSo-taXol; N-debenzoyl-N-phtbado-7-deoxy-Ac-A 2 "'-iso-taxol; N-debenzoyl-N-t-amyloxycarbonyl-7-deoxy-M6 7 3 _isotaxo; N-debenzoyl-N-neopentyloxycarbonyl-7-deoxy-A" *-A2'1 3 _iSo-taXol; N-debenzoyl-N-(2-chloro- 1,1 I diethylethyl)oxycarbonyl-7-deoxy-A 7 -A1 2 3 _ise..taxol; N-debenzoyl-N-(3-iehyl-3-pentyl)oxycarbonyl-7-eoxy-A 6 A" 3 _iso-taxol; 3' -desphenyl-3 '-(2_furyl)_7_deoXyA6 7
_A"
1 3 -iso-taxol; 3 '-desphenyl-3 '-(2-thienyl-7-deoxy_M' 7 _A2.
3 _isoaXo; 3' -desphenyl-3 -naphthyl)-7-deoxy-A 7 2 ,1 3 -iso-taxol; 3' -desphenyl-3 '-(2-naphthyl)-7-deoxy-MA' 2 .1 3 _iS&a.Xol; 3' -desphenyl-3 -4mtoyhnl)7doy,67AI,1iotxl 3 '-desphenyl-3 '-(4-chloropheny)-7-eoxy-A'-A 2 3 -iso-taxol; 3 '-desphenyl-3'(-ompey)7dx-A'A 111_sot~l .25 3 '-desphenyl-3 '-(3.4nehlndoyhnl--ex-&- 121_~~aO -desphenyl-3 '-(3,-iehxpey)7do_6. -A1.3iot~l .93 '-despbenyl-3'-4ntohnl--ex-',- 121_sotx *993'-dephy-3 '-{4-fluoropheny1)-7-deoxy-A&'.A'2 1 -iso-taxo; N-debenzoyi-N-(4-bwmobenzoy)-7-doxy-A 7 3 iso-aXo; N-ebezoy-N-(4--butylbenoy)-7-eoxy-'6'-A'12.
3 _iSotaXol; N-debenzoyl-N-(4-methoxybenzy)-7-deoxy-A 7 12.
3 _iso-taxol; N-debeazoyl-N-(4-fluorobenzoyl)-3 '-dcspbenyi-3'-4furpey)7doyA 1213 9 iso-taxol; .999.9N-debenzoyl-N-(4-mthybcazy)-3 '-despheuyl-3 hk pbcnyl)-7-deoxy-A"-A&'"- 4744.P -31.
iso-taxol; N-debenzoyl-N-(4-chlorobenzoyl)-3 '-desphcnyl-3 '-(4-fluoropbenyl)-7-deoxy-A'6 7 12.3 iso-taxol; N-debenzoyl-N-(4..bromobenzoyl)-3 '-desphenyl-3 '-(4-fluorophenyl)-7-deoxy.A'-A'12 13 iso-taxol; N-debenzoyl-N-(4-imthylbenzoyl)-3 '-desphenyl-3 '-(fluoropheny)-7-deoxy-A 7 -A 12.
3 iso-taxol; N-debenzoyl-N-(4-fluorobenzoyl)-3 '-desphenyl-3 '.(4-methoxyphenyl)7-deoxy-A&l.A,& 1.3_ iso-taxol; N-debenzoyl-N-(4-inethylbenzoyl)-3'-desphenyl-3 '-(4-metboxypbenyl)-7-deoXy_-' 7 N-debenzoyl-N-(4-fluorobenzoyl)-3 '-despbenyl-3 '-(4-chloropheny)7-deoxy-A'kA' 1213 iso-taxol; N-debenzoyl-N-(4-chlorobenzoyl)-3'-despbenyl-3' -(4-chlorophenyl)-7-deoxy-A' 7 -A 'L' 3 iso-taxol; N-debenzoyl-N-(4-bromobenzoyl).3 '-desphenyl-3 -(4-chlorophenyl)-7-deoxyA'- A 12.
3 iso-taxol; N-debenzoyl-N-(4-t..butylbenzoyl)-3 '-desphenyl-3 '-(4-chlorophenyl)-7-deoxy-A"-A 2 .1 3 iso-taxol; N-debenzoyl-N-(4-t-butylbenzoyl)-3 '-desphenyl-3 '-(4-fluorophenyl)-7-deoXYA' 7
_A'
2 1 3_ iso-taxol; N-debenzoyl-N-(4--chlorobenzoyl)-3'-desphenyl-3 '-(4-methoxyphenyl)-7-deoXYA 6 7 _A1 2 3 iso-taxol; N-debenzoyl-N-(4-bromobenzoyl).3 '-desphenyl-3 thoxypheny)-7-de oXyA* 7 3 iso-taxol; *~.N-debenzoyl-N-(4-t-butylbeazoyl)-3 '-desphenyl-3 '-(4-rnethoxyphenyl)-7- eoXy-& 6 1 2,3 iso-taxol; N-debenzoyl-N-(4-rnetboxybenzoyl)-3 '-desphenyl-3 '-(4-m-ethoxyphenyl)-7-deoxyA 6 7 A &""-iso-taxol-, N-debenzoyI-N-(t-butyl)amiinocarbonyI.7_dcoxy_.A,'2-' 3 -iso-taxo; and *.*pharmaceutically acceptable salts thereof whn the comundonaisiteranacdi or basic functional group.
Examples of Formula V componunds of this invention include: {(2,2,2-trichloroethyl)oxy )cabocyUl-A'-ibo.4axID &12. l-iso-taxol; *2'succinyl-&'2- 3 .iso-taxoJ; 4744.P -32- 2' -(0-aIanyl)-A&'2'-iso-tuxol formate; 2 '-(-C(OXCH 2 3 C(O)NH(CH)N(CH~]-Al'-"-iso-taxol; 2' -(f-suifopropionyl)-A'"-' 3 -iso-taxoI; 2'-(2-sulfoethylamido)succinyl-A'2".iso-taxol; 2 '-(3-sulfopropylamido)succinyl-A' 2 3 -iso-taxoL 2' -(triethylsilyl)-A&''-iso-taxo1; 102' -(t,-budimethyiyy)-A&'2 1 -iso-taxol;.
2' -{L,-danyan 2 3 -isopinl&--s-taxol; to -(L-ie lyy1) l)'-iso-taxoi;otx 2'(-vyl)-A 12 1 3 isotaXol; 2 -(L-pelanyl)A 12 -iso-aol; 2' -(L-leucyl)-A 1 '2 3 -iso-waol; 2' -(L-isolucyl)-,&Ll]-3iSo~taXol; 2'-(L-agyl)-A"-iso-taxol;
A
2 13 hntlay)A--iso-taxotere I 0-acetryl-A'-iso-taxor; 2 "-oy-axo."L;,tx ~.N-debenzoyl-N.( I -methyl- I -cyclohexylanoyl) -A' 2 .1 3 -iso-taxol; N-debenzoyl-N-( 1-phenyl- I cyclopentanoyl)-AlZI 3 -iso-taxol; .*N-debenzoy1-N-t-butylaininothiocarbonyl-A 12.
3 _iso-taxol; N-debenzoyl-N-t-amyloxycabonyl-A' 2 -"-iso-taxol; N-debenzoyl-N-neopentyloxycarbony-A2' 3 -iso-taxo.
S N-debenzyl-N-(2-chloro- 1, 1 -dimethylethyl)oxycarboylI2Il)iso-taxoI.
3 '-despbeyl-3 '-(2-fuzyl)-A&' 2 '"-iso-axo1; 3 '-desphenyl-3 '-(2-thieny)-A'&" 3 -iso-taxol; 3 -despbenyt-3'-(I -naphthyl)-A'& 2 13_iSO~taXOl; 4744.P -33- 3'.desphenyl-3'(2-naphhyl)-A'&"--iso-taxol; 3 '-desphenyl-3 '-(4-nmethoxyphenyl)-.& 1 '-i-so-taxol; 3 '-desphenyl-3 .(4-chlorophenyI)-AtiisaxI 3' -desphenyl-3 -(4-bromopheny)-AI' 3 _iSo~ao; 3' .desphenyl-3 -(3,4-methylenedioxyphenyl)I'2l 3 isotaxoI, 3'-desphenyl-3 '-(3,4-dixnethoxypbenyl)-A'2' 3 .iso-taxol; 3 '-desphenyl-3 '-(4-nitrophenyl)-A'z' 3 -iso-taxol; 3 '-despbenyI-3'-(4-fluoropheny)-'& 1 3 -3i~o-taXOL.
N-debenoy-N(4bromobenzoyl)-' 1.
3 _iSo-taXO N-debenoy-N-(4-methybenzoy)-A'&'-is-taxoL; N-debenzoy-N-(4-t-butylenzoy)-A 12 3 -iso-taxol N-debenzoy-N-(4-methoxybenzoyl)-A' 2 -iso-taxol; N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphelyl- 3 '-(4-fluorophenyl)-A'&, 3 iso-taxol; N-debenoy-N-(4-fluorobnzoy)-'' 3 -iso-taxol; N-debenzoyl-N-(4-methylbenzoyl)-3 '-desphenyl-3 '-(4-chlorophenyl)-A' 2 3 _iSo-taxol; N-debenzoyl-N-(4.-chlorobenzoyl)-3~1 1-epey- -4furpey)A 2 3 _iSo-t 1.l N-debenzoyl-N-(4-bromrobenzoyl)-3 '-desphenyl-3 '-(4-fluorophenyl)-A' 2 1 -io-taxol; N-debenzoyl-N-(4.-methybenzoyl)-3 '-desphenyl-3 '-(4-fluorophenyl)-A'" 3 -iso-taxol, N-debenzoyl-N-(4-fluorobenzoyl)-3 '-desphenyl-3 '-(4-metophenyl)_A' 2 -iSo-taxo; N-debenzoyl-N-(4-fluorobenzoyl)-3 '-desphenyl-3 '-(4-meboopheny)-''-iso-taxo; N-debenzoyl-N-(4-chlbenzoyl)-3 '-desphenyl-3 '-(4-mhoxphenyl)-'12 3 iso-taxol; N-debenzoyl-N-(4-bromrobenzoyl)-3 '-desphenyl-3' o~aX N-debenzoyl-N-(4-t-butylbenzoyl)-3 '-despbenyl-3 '-(4-cbloropbeny1)-A&'2. 3 -iSo>-taxol; N-debenzoyl-N-(4-tbutylbenzoyl)-3 '-dsphenyl-3 '-(4-loropheny1)-A"' 3 -iso-taxol; N-debenzoyl-N-(4-chlorobenzoyl)-3 '-despbenyl-3 '-(4-methoxyphenyl)-A'2' 3 -is-taxol; N-deberizoyl-N-(4-bromobenzoyl)-3 -desphenyl-3 '-(4_MethoXypheny)A 1 2.
3 iSoLaxol; N-debenzoyl-N-(4-methoxybeflzoyl)-3 '-desphenyl-3 -4mtoybnl_,1.3iotxl N-bnolN(-uy~mncroy-&1-3iot~l and phannaccutically acceptable salts thereof when the compound contains either an acidic or basic functional group.
Additional preferred embodments of the invention include: em-&"iotx~ N-de,-(t-byloxyCafly)-N-t-btyl)amuflocabonl- 7-deoxy-7,8f-MehUano_& 2 iso-axotere; 7.dcoxy-7-fluro-,AIU)-so-taxotere; N-de-(t- ***:butyloxycarbonyl)-N-(t-butyl)*miflocabonyl7deoxy-74Uiwmo-lz"iso-taxoteve; 7_doXy_-A' 7 4744.P -34.
1-iso-taxotere; and N-de.(t-butyloxycarbonyl)-N-(tbutyl)anoc~arbooyl-7-deoxy.alkA 21 iso-taxotere.
Examples of Formula [Ila compounds of the invention include: 2 -debenzoyl-2(mcyanobewyl)7deoxy7,8-methao-AI-iiso-axo; 2 -debenzoyI-2-(m-cyanobenzoyl)-2'-({(2,2,2.trichloroethyl)oxy )carbonylJ-7-deoxy-7,8f..
methao-A' 2 "k3iso-taxol; 2-debenzoyl-2-(m-cyanobenzoyl)- 10 ctl7doy-08~taoAz--s-aoe methano-A 12 3 -iso-taXoL; 2-debenzoyl-2-(m-methoxybenzoyl)-2 '-4(2,2,2-trichloroethyI)oxy)cartxInyl]-7.
4 jexy..70,8p.
methano-A"~-iso-taxo1; 2-dekbenzoyl-2-(m-methoxybenzoyl.. 1 0-ctl7doy7,f-ehn-'--s-aoee is methano-A"-lkiso-taxol; 2-debenzoyl-2-(ni-chlorobenzoyl)-2 '4 {(2,2,2-trichloroethyl)oxy )carbonylI-7-deoxy-70,8f methano-A 2 3 iso-taxol; 2-debenzoyl-2-4m-chlorobenzoyl)- I -ctl7doy7,f-ehn-"-s-aoee 2 -debenzoyl2mchorobenzoyl).NdebbenolN-(tbuylNamiutylbony17dexy- 7 0, 8 methano-Al 1- 13 -iso-.taxol; 2 -debenzoyl2(midbazdoyl)oyI)oxy.7f ,8ehaA 1.Q3iSoaxo; 2-debenzoyl-2-(m-azidobenzoyl)-2'4 {(2,2,2-trichloroethyl)oxy )carbonyl]-7-deoxy-70,8 methano-AU-"iso-taxol; 2-debenzoyl-2-(nl-azidobenzoyl)- I aey--ex-7,f-ehn-I21-s-aoee *methano-A 12 1 3 iso-taxol;
*.C
2 .debenzoyl-24-cyanobenzoyl)7deoxy70,8nethafoA 3io l; 2 -ebenzoyl-2-(p-cyanobenzoyl)-2'-( ((2,2,2-trichloroethyl)oxy )carbouylI-7-deoxy-7,8P MethaoAIZ2.3iso~taXol; C. 2 -&dezoyl-2-4pcyanobenzoyl)- 1 O-acetyl- 7 -deoxy-7,80-.metano-' 2 3 .iso.taxotere; methano-A' 2 3 -io-taxoL 4 2 -debcnzoyl-24J-mtboxybenzyl)7deoxy7,ph,.dx.-A '"-io-taoL 35 2 -&benzoyl-2-(,p-rmthoxybenzoyl).2 '4 (2,2,2-trichloroethyl)oxy )cabonyl]-7-dsox-70,g8 CCraedhano-,&M1.iso-=aoL 4744.P 2-&denzoyl1-2-(p-mcthoxybenzoyl)- I 0-ctl7doy7,fmtan.&I- _s-aoee 2-<debenzoyI.
2 -(pmethoxybenzoyl)Ndebeazoyl.N-(t-butyl)aminocarbony[-7deoxy. 70,8flmethano-AIZ3i4so-taxoI; 2-eezy--pcooezy)7dox-08 mtaoA2"iotxl 2-debenzoyl-2-(p-chlorobenzoyl)-2 {(2,2,2-trichloroethyl),oxy }carbonyl]-7-deoxy-7,8f..
methano-A 2 '"-iso.-taxol; 2-debenzoyl-2-(p-chlorobenzoyI)- I -acty-7-deoxy-70,8f -mfetno-A 1"'-isotaxotere; methano-A' 3 -iso-taxol; 2-bnol2(-zdbnol--ex-08 mtao, 1 3iotxl 2-debenzoyl-2-(p-azidobenzoyl)-2'-( ((2,2,2-trichloroethyl)oxy )earbouyl]-7-deoxy-70,8f MedhaOAlI.
3 _iso..taxol; 2-debenzoyl-2-(p -azidobenzoyly. lO-acetyl-7-deoxy-7p,8 _Methano_A' 2 3 _iso-taxotcem; and 2-ee~y--paioezy)N&ezy--tbtlaincroy--ex-08 methano-&A's-iso-taxol.
Examples of Formula lIIa compounds of the invention include: 2 -debenoyl-2-(m-cyanobenzoyl)-7-eoxy-7-fluoro-A' 2 4 3 .iso-taxol; 2-debenzoyl-2-(m-cyanobenzoyl)-2' {(2,2,2-trichloroethyl)oxy )carbonyl]-7-deoxy-7-fluoro- A 1 2 .1'-iso-taxol; 2 -debenzoyl2-(m-cyanobezoy)-N-ebenzoy-N.(t-butyl)aminocarbonyl.7.deoxy-7. fluoro- 3 -iso--taxol; 2-debenzoyl-2-(m-methoxybenzoyl)-7deoxy.7fluor-'2.4so.taxoL- 2-dcbenzoyl-2-(m-methoxybenzoyl)-2 '-((2,2,2-trichloroethyl)oxy lcarbonyll-7-deoxy-7fluoro_,&2"'-iso-taxoI; 2 -debenzoyI-2-(m-methoxybenzoyl)-N-debenzoyIN-(tbutyl)ahinocarbonyl.7.dexy.7 fluoro- A","-iso-taxol; 2 -dcbenzoyI-2-(m-chlorobenzoyl)-7-deoxy-7-fluoro-" 3 isozxol; 2-debenzoyl-2-(m-chlorobcnzoyl)-2 {(2,2,2-trichloroethyl)oxy )carbonyl]-7-dcoxy-7-fluoro- 30A12.' 3 -iso-taxol; 2 -debcnzoyl-2-(morziobeoyl)-N-dbnzoy-N-(t-butyl)amnocarbonyl.7..dcoxy.7.. fluoro- 4744.P -36- ,&"'-iso-taxol; 2-debenzoyl-2-(p-cyanobenzoyl)-2 '4 ((2,2,2-trichloroethyl)oxy )carboayl]-7-deoxy-7-fluoro- At 2 -'ISiso-taxol; 2-debenzoyl-2-(cyanobenzoyl)-N-ebenzoyl-N--butyl)aninocarbonyl-7-deoxy-7- fluoro- 2-denzoyl-2-(p-methoxybenzoyl)-2'-( {(2,2,2-trichloroethyl)oxy)carbonyl]-7-deoxy-7- fluoro-
AIZI
3 .iso-taxol; 2-dcbenzyl-2-(pmehoxybzoyl)-N-debenzoyl-N-(t-butyl)aminocabonyl-7-deoxy-7- fluoro- &11,"1-iso-taxol; 2-debenzoyl-2-(p-chlorobenzoyl)-7-deoxy-7-fluoro-' 2 3 -iso-taxol; 2-debenzoyl-2-(p-chlorobenzoyl)-2 '4 {(2,2,2-tirichloroethyl)oxy)carbonyl]-7-deoxy-7-fluoro-
A'
2 3 1-iso-taxoi; 2-debenzoyl-2-(p-cblorobenzoyl)-N-debenzoyl-N-(-butyl)aminocarbonyl-7-deoxy-7- fluoro- A 2 3 -iso-taxol; 2-debenzoyl-2-(p-azidobenzoyl)-7-deoxy-7-fluoro-A 2 3 -so-taxol; 2-debenzoyl-2-(p-azidobenzoyl)-2 {(2,2,2-trichloroethyl)oxy )carbonyl]-7-deoxy-7-fluoro- 2-debenzoyl-2-(p-azidobenzoyl)-N-debenzoyl-N-(-butyl)aninocarbonyl-7-deoxy-7- fluoro-
A
1 3 -iso-taxol; 2-ebezoyl-2-(n-cyanobenzoyl)- 10aey--ex--lor-&2"i(-aoee 2-debenzoyl-2-(rn-methoxybenzoyl)- 1 0-acetyl-7-deoxy-7-fluoro-A' 2 3 -iso-taxotere; 2-debenzoyl-2-(m-chlorobenzoyl)- I O-acetyl-7-deoxy-7-fluoro-A"-i-so-taxotere; 2-debenzoyl-2-(p-chlorobenzoyl)- 1 0-ctl7doy7fuoo-&,-s-aom ~2-debenzoyl-2-(p-cyanobenzoyl)-1I0-acetyl-7-deoxy-7-fluoro- 3 -iso-taxotere; 2-debenzoyl-2-(p-azidobenzoyl)- 1 0acetyl-7-doy7fuoo "io-aoee and 2-debenzoyl-2-(m-azidobenzoyl)- 1 0-acetyl-7-deoxy-7-fluoro_,A' 2 -iso-ta~Xotere.
Examples of Formula IV& conyounds of the invention include: 2-debenzoyl-2-(m-cyanobenzoyl)-2'-({(2,2,2-trichtoroethyl)oxy)carbonyl]-7-deoXy-A"- 7 ~&1 2 .11_iSo-taXol; 2-debcuzoyl-2(m-cyanobenzoyl)-1 0-a etyl-7-deoxy-A'-A 2 1 -iso-taxoem; 2-denzoyl-2-(m-cyanobenzoyl)-N-dezoy-N-Q-buyl)aminocarbonyl-7-deoxy-t5' 7 A1 2 .13- :i3o-t&XOl; 474-4.P .37- 2-debenzoyl2(m-methoxybenzoyl)-7-deoxyA"' 2 ".isozaxol; 2-debenzyl-2-(m-nmethoxybenzoyl)-2'-({(2,2,2-trichloroethyl)oxy }carbonyl]-7-deoxy-A&'- 2-dcbenzoyl-2-(m-methoxybenzoyl). I 0-acety1.7-deoxyA*- 7 .AIL-i-iso-taxotere; 2 -debenzoy-2(mmehoxybenzoy)NdebenzoyN-buty)aoanhlDyI7.xy.Ae-' ,412.1_iSo-iaXol; 2.debenoy.2(m-chorobenzoy) 7dexy.
6 7 _At 2 3iso.taxo; 2-debeazoyl-2-(m-chlorobcazoyl)-2'-({(2,2,2-trichloroethyl)oxy )carbonyl]-7-deoxy-A'6 7 A1 2 .1 3 -iSo-taXol; taxol; 2.debenzoyl-2(mazidobenzoy)7deoXy_11?7A2.1iSotaXo; 2-debenzoyl-2-(m-azidobenzoyl)-2 '-[(2Z2-trichloroethyl)oxy )carbonyIJ-7-deoXy_-' 7 A1 2 .1 3 -iSo_ taxol; 2-debenzoyl-2-(m-azidobenzoyl)- l0-acetyl-7-deoxy-A'-A' 2 "-iso..taxotere; 2 -debenzoyI.2-(1mazidobenzoyI).N-debenzoyl1N.(t-butyl)anminocarbony1-7dexyA.7 A 111 iso-taxol; 2-ebenzoyl2(pcyanobenzoy)7-doxy-Al'- 7 .A2ZI 3 _iSo~taXol; 2-debenzoyl-2-(p-cyanobenzoyl)-2 ((2,2,2-tirichloroethyl)oxy }carbonyl]-7-deoxy-AM 7
A'
2 iso-taxol; 2-debenzoyl-2-(p-cyanobenzoyl). 1 O-acetyI-7-deoxy-A--A 3 -iso.taxotere; 2 -debenzoyl-24pcyanobenzoy)-N-debenzoylN(tbuty)amocarbony.7deoxy-A'. Alliso-taxol; 2-debenzoyl-2-(p-methoxybenzoyl)-2' (2,22-trichloroethyl)oxy )carbouyl]-7-deoxy-A' 7 ***2-debenzoyl-2-{p-methoxybenzoyl)-10 -acetyl-7-deoxy-A&'-A 'L"-iso-taxotere; 2 -ebenzoy-2-(-ethoxybenzoy)-NdebenzoyNtbuty)anocbonyl7-.xy-e"-.
30 A12.1 3 -iSo-&Xol; 2-ebenzoyI.24pchorobenzoyl)-7doXy.AI2-jo-tWOI 2-&benzoy-24{p-ch~orobenzoyl)-2 '-[((2,2,2-trichloroethyl)oxy )carbonyl]-7-deox-yA 17_ A 111 3 -iso- 0 0 000. 2-debczazoyl-2-(p-chlorobmwzyl)- I 0-acety-7-deoxy-4-'2 3 iotXotere 00 35 2-dcbenzoyI-2-4pchlorobeazoyt)-N-debenzoy-N-Qt-u tyI ami y-7dx-4 e_ &2*1io4mxok 0 0.
4744.P -38- 2-debenzoyl.2-(p.azidobeazoyl).2'-.( 2 ,2,2-trichloroethyl)oxy }carbonyI]-7-deoxy.A&6'- A12.1iso-taxol; 2-debenzoyl-2-(p-azidobenzoyl)- 1 -aietyl.7-deoxy-.A 47 AI"t).isotaxoer; and 2-bnol2paioezy)N&ezy--t-uy~mncfnl7cex---&1.3 iso-taxol.
Examles-of Formula Va compvounds of the invention include: 2 dbenzoyl-2-(m..cyanobenzoyI}.7-deoxy-.AzI 3 _iso.taXoI; 2-debenzoyl-2-(m-cyanobenzoyl)-2-.({(2,2,2-trichloroethyl)oxy )carbonyl]-7..deoxy-..lWkj-s 0 taxol; 2-debenzoyl-2-(m-cyanobenzoyl)- lO-actyl-7-deoxyAZ" 3 .iso.taxotere; 2 .dbnz-2.m.benzoy--mcaoenzoyl)NnzoaylNq(butyl)ainocfly1..7-de~xy.2s 3 iso-taxol; 2 debenzoyl.2-(m-methoxybenzoyl)7deoxy-A&2.13iso.taxol; 2-debenzoyl-2-(m-methoxybenzoyl)-2'-I {(2,2,2-trichloroethyl)oxy )carbonyll-7.deoxy-AZI 3 iso-taxol; 2-debenzoyl-2-(m-mehoxybenzoyly. 1 -acetyl-7-deoxy-A'.i-taxotere; 2 -&eoyl 2 -(mrthoxybenzoyl)N-benzoy.N(buty)aminocarboyl.7.deoy. 2 4 iso-taxol; 2 -debenzoyl.2-<m-chlorobenzoyi)-7doxyA2.Iiso-taxol; 2-debenzoyl-2-(m-cblorobenzoyl)y2'-[{( 2 ,2,2-trichloroethyl)oxy }carbonyl]-7-deoxy-A 12, 3 iso-taxol; 2-debenzoyl-2-(m-chlorobenzoyl)- I O-acetyI.7..deoxy-A 1 2 1 3 _jSo..taXotere; iso-taxol; 2 -debenzoyl-2-(mazidobeazy)2'.[((2,2,2ricbJroetyloxy )carbonyl]7deoxy2.I- 3 iso taxol; 2 -debenzoyI.2-(rn4..aibezoy)Nd'benzoyIN:blotyl)iocalcmbony,..7-doxyA'_sotaxol; 2 -debenzoyI-2-(p-cyanobmnzoyl)- lO..aetyl-7..dozy-A"4iiso.taxoter; 47 44. P -39- 2.debenzoyl-2-(p-cyanobenzoyl)N-debenzoy.N-(qbutyl)aminocabony.7deoxyAI-n..iso taxol; 2-debenzoyl-2-(p -methoxybenzoyl).7-deoxy.A'l.".isotaxo; 2-debenzoy1-2-(p-mezhoxybenzoyl)-2' ((2,2,2-trichloroethyl)oxy }carbonyl]-7-deoxy.A'" k iso-Laxol; 2-debeazoyl-2-(p-methoxybenzoyl)- 1 0-waetyl7deoxy_AIZI 3 _isotaXotere; 2 -debenzoyl.
2 -(p-methoxybenzoyl).N-debenzoyl-N.Q-butyl)aminocarbony1..7-eoxy-AI2.13.
iso-taxol; 2-debenzo-2-(p-chlorbenzoyl)-7-deoxy-A' 2 -isa-taxol; 2-debenzoyl-2-(p-chlorobenzoyl)-2'-({(2,2,2-trichloroethyl)oxy)carbonyl]-7doxy-A 2 3 so.
taxol; 2-debenzoyl-2-(p-chlorobenzoyl)- 1 0-acetyl-7-deoxy-A'2-' 3 -iso-taxotere; 2-debenzoyl-2(chlorobenzoyI).N-debenzoy-N(t.buty)anioabonyl.7-dexy.AtzQ' iso-taxol; 2 -debenzoyl-2-(p-azidobenzoyl)-7-deoxy-&"'-iso-taxol; 2-debenzoyl-2-(p-azidobenzoyl)-2 '-[({(2,2,2-trichloroethbyl)oxy )carbonyl]-7-deoxy-A' 2. 3isotaxol;, 2-debenzoyl- 2-(p-azidobenzoyl)- 1 0-acetyl-7-deoxy-A 1' 2 "'-iSo-taxotere; and 2 -debenzoyI- 2 -(p-azidobenzoyl)-N&benzoy1.N-.:-butyl)aminocarbonyI..7-deoxy-' 2.1 '-isotaxol.
The present invention also provides a process for preparing oxazolidines of Formula R, 25R1
R-R
in which R, is as defined above; R, is selected fromi C,-Cal; RI, is phenyl substituted with -(OC,-C2ly). where n is I to 3; is selected rj om the group consisting of -c(O)C 1 -COaryl (preferably -C(O)Cc-4alkyl), -C(O)pbeuyL. -C(OMphyl substituted with one, 2 at 3 Cj-C alkyl.
:0 -cQO)C(cH)-MCH -C(o)OC(ai,)3. -C(OPCHphenyI -S0r4ethylphenyl 4744.P
-C(O)(CH)
3 COOH. .C(O)-4-(SO 3 H)phenyl, -C(O)-l1-adamnantyl, -C(0)O-3-tetrahydrofuranyl.
*C(O)O-4-tetrahydropyranyl, -C(O)CH 2 1C(CH 3, -C(O)C(CH 3 3 -C(O)OCI-Cl 0 alkyl,
*C(O)NHC
1
-C,
0 alkyI, -C(O)NHPh substituted with one, 2 or 3 C 1 alkyl. C,.Cq alkoxy, halo,
C,-C
3 alkylthio, trifluoromethyl, (2 2
-C
1 dialkylamino, or nitro, or -C(O)C 3 .Cscycloall, -C(O)C(CH2CH 3 2
CH
3 -C(O)C(CHA)CHPC, -C(O)C(CH 3 2
CH
2
CH
3 -C(O)-l1-phenyl- 1-cyclopentyl, 1-methyl-i -cyclobexyl, -C(S)NHC(CH3),
-C(O)NHCC(CH
3 3 or -C(O)NHPh.
which comprises reacting a hydroxy-amine of Formula 3
OR
in which R, and R, are as defined above and R 2 is selected from the group consisting of -NHC(O)H,-NHC()C-Cj 0 a~kyI (preferably -NHC(O)C 4 -C,,alkyl), -NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 alkyl, C,-Cq alkoxy, halo, C 1 -C alkylthio, trifluoromethyl, (2 2
-C
6 dialkylaniino. hydroxy or nitro, -NHC(O)C(CH 3
)-CHCH
3
-NHC(O)O)C(CH
3 3 -NHC(O)OCHzphenyI, -NHSO 2 -4-methylphenyl, -NHC(OXCHz) 3
COOH,
-NHC(OY-4-(SO 3 H)phenyl, -NI{C(O)-l1-adaniantyl, -NI{C(O)O-3-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl,
-NIIC(O)CH
2
C(CH
3 3
-NI-C(O)C(CH)
3 -NHC(O)OC,-Cjalkyl, -NHC(O)NHC,-C 0 alkyl, -NHC(O)NHPh substituted with one, 2 or 3 alkyl, C,-C 3 ailcoxy, halo, C,-Cq aikylthio, trifluoromethyl, C 2
-C
6 dialkylamnino, or nitro, or
*NHC(O)C
3 -Ccycloalyl, -NHC(O)C(CH2CH3)CH 3
-NHC(O)C(CH
3 2
CH
2
CI,
25 -NHC(O)C(CH 3 2
CH
2
CH
3 -NHC(O)- 1-phenyl- I-cyclo-pentyl, -NHC(O)- 1-methyl-i -cyclohexyl, -NHC(S)NH-C(CH0 3
-NH-C(O)NHCC(CH
3 3 or -N}IC(O)NHPh, *..*with an electron rich benzaldehyde of Formula 4A
CHO
(0Cj-C 2 a1ky1 -n 4744.P -41.
or an electron rich acetal of Formula 4
~(OCI-C
2 1ky1) where n is 1-3.
In addition, the present invention provides a process of preparing 0 COC H which comprises reacting an oxazolidine free acid of Formula 7 R H RI 0
H
S
0* 47 44. P -42with a baccatin compound of Formula 8 COCK 3 S0 in the presence of a dehydrating agent. Wherein R30 and R34, being the same or different, are selected from the group consisting of -OC(O)CI-C 6 alcyl, -OC(O)0C,-Ca~ci,
-OC(O)OCH
2
CX
3 where X is Halo, -OC(OOH 2
CH
2 SiR20, (where R2, is CI-Calkyl, or -OSi(R 6 3 (where being the same or different, is selected from C,-C~alkyl or cyclo(C 5 -C)akylj* and X 2 and R 1 2 are as defined above.
The present invention also provides a process of preparing foe.
0 9 0 4744.P .43.
which comprises reacting an oxazolidine free acid of Formula 7
R
11 with a baccatin compound of Formula 8' a a 9**a a.
a a a.
a a.
a a a.
a.
a a a.
a a a. a a.
a a a.
a a a. a a.
a.
in the presence of a dehydrating agent. Wherein R30, and R34, being the same or different, are selected from the group consisting of -OC(O)C,..C 6 alkyl, -OC(O)OC,-CqalkyI, 25 -OC(O)OCH 2
CX
3 where X is Halo, -OC(O)OCH 2
CH
2 SiRw (where R2 is C,-C~alkyI or -OSi(R,) 3 (where being the same or different, is selected from CI-C 6 alkyl or cyclo(C 5 Ct)alkylJ; and X 2 and R, 2 are as defined above.
4744.P .44- A fturher embodiment of the subject invention are the novel compounds of Formula 8 '3
R
3 4 9.9.
.9.9 9* S @049 .9 9 0@ 9 995* *9 9 9 9* 9* 9 9 .9 9.
99 9
S.
I. 4 99 9999 9909 9 990999 9 99 9 S S
S.
where R. is selected from 2 3 -methylbutyl)dirnethylsilyl.O., (n-bUtYl) 3 S'IYl-O.., 2 -(2-methylethyl)diethylsilyl..0, cyclohexyldinethylsilyl-O-, cycloheptyldimethylsily[O.
A further embodiment of the subject invention are the novel compounds of Formnula 8' 20R30H HOCe 250 /OC 3 o=c 6x wher R3. is selected from 2-(3-methylbutyl)ditnedylsilyl-o.., (n-butyl) 3 sily!-O-, 2 2 -methylethyl)diethylsilylitj., cyciohexyldlimethylsilyl.O., cyclohepcylinmethylsilyI.O.
35 Mwe comnpounds of the present inva~kjm am prepared by the Inedhd(s) as shown in Cats I through 7 sad 46. Generally the compounds of this invention am prquzd from a 4744.P' protected baccatin analog with a free 1 3-hydroxyl such as compound III of Charts 1 2 or compound xvii of Chart 7 by oxidation to give the 13 keto-baccatins v or xviii. The respective enones are then reduced with activated zinc or by electrolytic reduction, or by other metal reductions such as sodium or aluminum amalgam, chronium(1) salts or other reductions of the correct reducing potential. The resulting enols vi of Chart 3 and xix of Chart 7 are coupled to a protected side chain precursor by one of several methods. Most favorably the coupling of the enols vi or xix may be accomplishe by the method descibed in PCT/US93/11827 (Case 4809.1 CP); see page 24, line 14 as well as Preparation Nos. 8, 11, 13, 16, 22, 28 and Thus, the enols vi or xix ae condensed with a protected isoserinyl carboxylic acid such as vii in the presence of a dehydrating agent such as dicyclohexyl carbodimide, or other cajrbodiimide, carbonyl diimidazole, 2,2-dipyridyl carbonate, alkyl or aryl sulfonyl chloride or sulfonic anhydride or other dehydrating agent known in the art for the preparaioi of esters to give the protected taxol analog viii or xi. Thle enols vi or xix may be also condensed with a side chain precursor by methods described in the literature (see: Kingston. D. G. 1. Phannac.
Ther., 1991, 52, 1-34; Commerron, B&zard, Bernard, Bourzat, J. D. Tetrahedron Lett., 1992, 33, 5185; Georg, G. Cheruvallath, Z. Himzes, R. Mejillano, MA R.
BioMed. Chem. Lett. 1992, 2, 295; Kingston, D. G. Molinero, A. Rimoldi, J. MA Prog.
Chem. Org. Na. Prod., 1993, pp 1-206 The resultant protected taxol analog viii or xi may then be deprotected to taxol analogs such as ix and xii.
More specifically, the compounds of this invention may be prepared as shown in Charts 1, 2 and 3. Thus, lO-deacetyl baccatin HI Chauviere, Guenard, Picot, Senih.l, V.; Potier, P. CAR. Acad. Sc. Paris, Serie 11, 1981, 93, 501.) may be selectively protected at the 7position, for example with a carbonate, ester or silyl protecting group to give a protected baccatin The 7 protected baccatin (Hi) may then be protected at the 10 position with a cabnt oretrgopt0ieii If the 10 protecting group is acetate then the copund ii is a 7 protected derivative of baccatin HI. The same 10 acetyl derivative is available as shown *in Chart 2. Thus, a 10 protected baccatin, particularly where the 10 protecting group is acetyl, is baccatin III Protection of iv in the same manner as protection of ii from Chart 1, gives 30 compound iii, particularly where, R' is acetate. The I 3-hydroxyl group of compound HLi. may 0* be oxidized to the give the ketone v. The oxidation may be accomplished with manganese dioxide in aprotic solvents such us methylene chloride, tetrahydrofuran, dioxane, chloroform, tolene or aixanes such as exane, peatanie, or ncptane. AU maioa may berun at 0T to TC, £o zmost meadly at mmon Iealeramme 7be oxidation may be carie out with other oxiditing agents, such u chromium tuioxide in pyridla, pyndinuu dichuniate, pyridinium ch o o k o s e .o m m p r a p s .ilet r pp r u h e 1f r 474.4.P -46periodinane, or other oxidant known in the art. As shown in Chart 3, the ketone v may be reduced to the enol vi. This reduction is readily accomplished with zinc metal activated by washing successively with 1 N hydrochloric acid, water, ethanol and ether. The reduction is carried out in acetic acid at 25*C, and is over in 2to 4hours. The reaction may be run at ooc for 24 to4husor at upto 7 0 CT for 10 to20 minutes. The reaction may also be run in aqueous acetic acid, methanol containing ammnonium chloride, or in water miscible solvents such as tetrahydrofuran or dioxane containing acetic acid, formic acid, or other carboxylic acid, or aqueous acid such as hydrochloric, sodium bisulfate, or phosphoric acid. The reduction also may be carried out electrolytically in solvents such as methanol, pyridine, tetrahydrofurun, or dioxane with a carbon or platinum electrode and with the ekectrolytic potential set just high enough to carry out the reduction. The reduction may also be accomplished with other metals such as sodium or aluminum amalgam, or with chromium (HI) salts. The enol vi is readily coupled with an oxazolidinecarboxylic acid vii in a solvent such as toluene, xylene, tetrahydrofur-an, dioxane, or the like in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, or other carbodihmide, carbonyl diimnidazole, 2,2-dipyridyl carbonate, alkcyl or aryl sulfonyl chloride or sulfonic anhydride or other dehydrating agent known in the aut for the preparation of esters in the presence of a catalyst such as 4-dimethylarninopy-ridine or trin-butyl phosphine to give the protected enol ester viii. When the R 1 protecting group on position 7 has a different selectivity from R"o and is removable by id acid or by hydrogenolysis then the protected enol ester viii may be converted to the deprotected A12-1 3 _isotaxol analog ix. For example if R" is a silyl group such as trimethyl or triethyl silyl and R" 0 is acetate; then treatment of protected enol ester viii with mild acid such as 80 acetic acid-water for 4 to 1 10 hours at 10 0 C to 60 0 C gives the AIZ- 3 -isotaxol analog Ix. Alternatively, the deprotection may be accomplished with mild acid such as 0.1 N hydrochloric aci in *2.5 methanol or ethanol, or with other acids such as trifluoroacetic, methanesulfonic or other acid in alcoholic and mixed alcoholic and aqueous solvents. If the protecting group is removable by hydrogenation, such as a benzyloxymethyl ether, then conversion of protected enol ester viii *to the deprotected A'" 3 -isotaxol analog ix may be accomplished by hydrogenation in solvents such as methanol, ethanol, ethyl acetate, tetrahydrofuran, or the like in the presence of a hydrogenolysis catalyst such as palladium metal, palladium on carbon, Raney nickel, or the like.
Theu compounds of this invention include A'2--iso taxol analogs with modificaton on the and 7,8- positions as shown in Charts 4 throgh 7. Thus, selective deproection of Rofsntredigvsthe 7-hydroxy cmpound x. If R" ncqom iii for example trichiroethyl carbonate and R* is =n ester or ether, then reduction with zinc in a mikdly acid medium such as acetic acid-weer, methaol, ethanol, or other alcoholic solvent aciclifiud with :,:hydrochloric aci or anunosbhi loride gives the 7-hydroxy compound x. If R"1 in Compound 4744.P -47, vii is for example a silyl ether such trunethyl or triethyl silyl and R 0 is an ester or ethier or carbonate, then treatment with tetra-n-butyl ammonium fluoride or pyridine-hydrofluoride or triethyl ammonium hydrofluoride in solvents such as tetrahydrofuran, dioxane, or alcoholic solvents such as methanol or ethanol gives the 7-hydroxy compound x.
Compound if where W'and R' taken together are a double bond and R is methyl a protected 7-deoxy-A'" 7 -A&'-isotaxol analog, is most favorably prepared from x by conversion of the 7-hydroxyl group of compound z to the trillate followed by elimination. Thus, treatment of 7-hydroxy compound x with trilluoromethanesulfonic anhydride in rmethylene chloride, I ,2-dichloroethane, chloroform, or other suitable aprotic solvent, in the presence of a base such as pyridline, 2-me-thyl pyridine, 2,6-dimethyl pyridine or 2,4,6-tirnethyl pyridine or other AN ~suitable bas at a temperature of -20 T to 60 C for 10 mntsto 1 our gives the trifluoromethanesulfonate of alcohol x. Treatment of this tilluoronmethanesulfonate with 1,8-diazabicyclo(5.4.Olundec-7.ene, l,5-diazabicyclo[4.3.Olnon-5-ene or other strong amine base in tetahydrofuran, dioxane, or other suitable aprotic solvent at 0 OC to 90 0 C for 10 minutes to 10 hours gives the AtV -compound of structure id. T7he elimination of the trifluoromethanesulfonate of compound x can also be accomplished with other strong bases such lithium, potassium, or sodium hexamethyl disilazane, lithium diethyl, or di-isopropyl amide, sodium or potassium t-butoxide or other strong base in a suitable solvent such as tetrahydrofuran, dioxane, t-butyl alcohol or the like at -80 TC to 90 TC for 10 minutes to 5 hours.
Compound xi where R6 is hydrogen and W'and R taken together are 7 0,8 -methano, a protected 7 -deoxy-70,8-methano-A"- 3 -isotaxoI analog, can also be prepared from the trifluoromethanesulfonate of alcohol x. Thus, treatment of trifluoromethanesulfonate of compound x with sodium azide, sodium chloride, sodium sulfate, potassium azide, potassium chloride, potassium sulfate or other salt, in aqueous tetrahydrofuran, aqueous dioxane, aqueous methanol, or aqueous ethanol, or other water and water miscible solvent combinations at 0 *C *to 9 0 Cfor 20 minutes to48 hours. Altrnvely, atriflate xmay betreated with 10to fold weight excess of silica gel either by slow elution on chromatography or in a batch mode in a solvent such as toluene, THF, dioxane, methylene chloride, ethyl acetate, DMF, DMA. or other solvent for I hour to 200 hours at room temperature.
7 -deoxy-7_fluoro-A 2
I
1 3 _isotaxol analog, is most favorably prepared from alcohol z by reaction with a reagent such as diethylaminotulfur trifluoride (DAST), dimethylarninosulfur trifluoride ,*(methyIDAST), bi~intylmn~du dfuriux, bis(diethylamim)sulffr dfuon5AM, or 00..(diediylaninoXdnethylamo)sulfur difluoride The preferrd method for this conversion is -000 35 with DAST or 'nedqyIAST. The reaction with DAST or methylDAST is carried ou in an .poi sovn mc as metln clorid jn2.s lrom CC 4744-P -48fluorotrichioromethane (Freon ethylene glycol dimethyl ether (glynie), 2-methoxyethyl ether (diglyme), pyridine, hydrocarbons such as pentane, hexane, or isooctane, teftrahydrofuran (THF), benzene, toluene, xylene. The preferred solvent is methylene chloride. The reaction may be performed in a range of temperature from -100T to 100 0 C or above. Generally, the reaction is begun under conditions of low temperature, -78*C, and then is allowed to proceed at a higher temperature, 25*C. The reaction is quenched with water. the crude product is isolated by standard extraction methods, and is purified by standard chromatographic methods and/or by crystallization.
Compound Ai where R' and R 7 taken together are a double bond and W is methyl a protected 7_deoXy_-A' 7 2 3 -isotaxol analog, may also be prepared by reaction of alcohol x with a reagent such as diethylaminosulfur trilluoride (DAST), dirnethylaininosulfur trifluofide (rnethylDAST), bis(dimethylamino)sulfur difluoride, bis(diethylamino)sulfizr difluoride, or (diethylamino)(dimethylamnino)suwur difluoride as described above.
Compound Ai where R'is hydrogen and W 7 and R' taken together are 70,8f -methano, a protected 7-ex-08-ehn-&"ioao analog, may also be prepared by reaction of alcohol x with a reagent such as diethylaminosulfur trifluoride (DASI), dimethylaminosulfur trifluoride (methylDAST), bis(dirnethylamiino)sulfur difluoride, bis(diethylamino)sulfur difluoride, or (diethylamino)(dimethylamino)sulfur difluoride as described above.
A protected 3 -isotaxol analog 3d of Chart 4 may be converted to a A12.1 3 _isotaxol analog xii by deprotection. Thus, reaction of oxazolidine 3l with a mild acid in an aqueous or alcoholic solvent gives the l 3 -isoserinyl-A' t1 -baccatin III (AlZI 3 -isotaxol analog xl. More specifically, treatmnent of oxazolidine xi with mild acid such as 80 acetic acid-water for 4 to 110 hours at 10 TC to 60 C gives the A'"-sotaxol analog l. Alternatively, the deprotection may be accomplished with mild acid such as 0.1 N hydrochloric acid in methanol or ethanol, or with other acids such as trifluoroacetic, methanesulfonic or other acid in alcoholic and mixed alcoholic and aqueous solvents. Also the oxazolidine of i is removable by hydrogenation.
Thus, hydrogenation of oxazolidine Al in solvents such as methanol, ethanol, ethyl acetate, tetrahydrofuran, or the like in the presence of a hydrogenolysis catalyst such as pefladiurn metal, palladium on carbon, Raney nickel, or the lik gives A' 2 -"-isotaol analog xI&
_L'
3 stao analogs xWi of Chart 5 where R" is a carbonate, carbnrnate, ether, ester or silyl ether may be prepared by selective cleavage of the oxazolidine of YE. Thus, as described above, reaction of oxazolidine vii with a mild acid in an aqueous or alcoholic solvuat gives the 1 3 4sofonyl-A 1."-baccain (A'W'-i"oaol analog AlL More specifically, treatownt Of IC Sime the AW3SocaXOl analog ALi Alternatively, the deprotection may be acmlse with mild acid such as 0. 1 N hydochloric acid in methemnl or etbmol, or with other acids such 4744.P .49as trifluoroacetic, methanesulfonic or other acid in alcoholic and mixed Alcoholic and aqueous solvents. Also the oxazolidine of viii is removable by hydrogenation. Thus, hydrogenation of oxazolidine vii in solvents such as methanol, ethanol, ethyl acetate, tetrahydrofuran, or the like in the presence of a hydrogenolysis catalyst such as palladium, metal, palladium on carbon, Raney nickel, or the like gives 3 isotaxol analog zxl.
T'he A'"'-isotaxol analog xv with R" as an ester, carbonate, carbamnate, or ether of Chart 6 may be made from an oxazolidinyl 7-hydroxy-&' 2 "'-isotaxol x by conversion to 7-substituted oxazolidine ilv followed by cleavage of the oxazolidine ring. Oxazolidine xlv, as a 7-ester, may be produced from oxazolidinyl 7-hydroxy-A'2ZI 3 -isotaol x by esterification with an acyl halide, acyl anhydride or carboxylic acid and a dehydrating agent as is known in the rt Oxazolidine xlv, as a 7-carbonate, may be produced from an oxazolidinyl 7-hydroxy-,A' 2 .1 3 isotaxol x by reaction with an alkoxy chloroformate or alkoxy carbonate anhydride as is known in the art. Qxazolidine xiv, as a 7-carbonate, may also be prepared from an oxazolidinyl 7-hydroxy-A"' 3 -isotaxol x by reaction with phosgene, diphosgene, triphosgene or p-nitrophenyt chloroformate followed by reaction of the intermediate chioroformate or p-nitrophenyl carbonate with an alcohol as is known in the art Oxazolidine xlv, as a 7-carbaniate, may be prepared from an oxazolidinyl 7-hydroxy-A 1 "'-isotaxol x by reaction with a alkyl or aryl isocyanate as is known in the art. Oxazolidine xiv, as a 7-carbamate, may also be prepared from a 7 -hydroxy-A""'-isotaxol x by reaction of a carbonate as prepared above with an amine as is known in the art. Oxazolidine xiv, as a 7-carbamate, may also be prepared from a 7-hydroxy-A 12.
3 -isotaxol x by reaction with phosgene, diphosgene, triphosgene or p-nitrophenyl chloroformate and reaction of the intermediate chioroformate or p-nitropbenyl carbonate with an amine as is known in the art. Oxazolidine xl'i, as a 7-alkoxymethyl or aryloxymethyl ether, may be prepared from a 7-hydroxy-A'2' 3 -isotaxoI x by reaction with a chloromethyl alkyl or cbloromethylaryl ether as is known in the ait Oxazolidine ilv, as a 7-alkyl or aryl ether may be prepared from a 7-hydroxy-A 12.1-isotaxol x by reaction with a base such as sodium hydride, potassium hydride or lithium diethyl, or diisopropyl amide, sodium or potassium hexarnethyldisilazane or other strong base in a solvent such as tetrahydrofuran, dioxane, dimethoxy ethane, or other such solvent at -78 OC to 60 OC in the presence of an alkyl *30 halide such as methyl iodide, ethyl iodide, benzyl chloride, allyl chloride or bromide of the like for 10 minutes to 48 hours to give oxazolidine xlv as a 7-alkoxy or aryloxyinethyl ether.
Oxazolidine xlv, as a 7-alkyl or aryl ether may also be prepared from a 7-hydroxy-A""-isoaxoI 1@ by reaction with a diazo alkane or aryl diazo compound in the pxmmmc of a transition meta cauayst such as rhodium. ntlizium or palladium in an apcofic solvent suacHFdaTP,dor MFata ao rs o -20 C to 10 A 7-substitutied oxazolihu i, As a 7 ester, carbonate, carbarnage, or edue of Cbiart 6 4744.P as prepared above may be deprotected to a 2 3 -isotaxol analog xv by the deprotection procedures as described for the conversion of oxazolidine viii to A 2 3 -isotaxol analog xli of Chart A baccatin III analog xvI of Chart 7 may be converted to a baccatin MI analog of structure xvii where W'and R' when taken together are a double bond and R'is methyl, or where R' is hydrogen and R' and R' when taken together are 7 0,80-rnethano, or where R' is hydrogen, R'is fluoro and R'is methyl may be prepared as described above and shown in Chart 4 for the conversion of 7-hydroxy compound x to the respective 7-ex-6'A ioao analog, 7dex-08 nehaoA2"ioao analog, or the 7-deoxy-fluoroA'2J.isotaxol analog A. A 13-hydroxy baccatin analog xvii may be oxidized to the 13 keto baccatin analog xvffi in the same manner as described above and shown in Chart 2 for the oxidation of a 13-hydroxy baccatin analog II to a 13-keto-baccatin analog v. A 13-keto baccatin analog xviii may be reduced to a A,2.13iiso~baCCatin analog xi as described above and shown in Chart 3 for the reduction of a 13-keto baccatin analog v to a A 1 3 soaatnanalog vi. A A 7 3 isobaccatin analog xix may be converted to a protected
A'
2 3 -isotaxol analog Al as described above and shown in Chart 3 for the conversion of a A12, "-isobaccatin analog vi to a protected A12.1 3 -isotaxoI analog viii. A protected
A'
2 3 -isotaxol analog xf of Chant 7 may be converted to a A' 2 ,13iSotaxol analog xli as described above and shown in Chart 4.
T'he compounds of Formula I where Xis other ta can be prepared by the methods disclosed in J. Am. Chem. Soc. 1994, 116, 4097-98 and Bloorganic Medical Chemnistry Letters, Vol. 4, No. 3, 479-82, 1994; and Tetrahedron Lett. 1994, 35, 8931 which are incorporatedi herein by reference.
Alternatively, the compounds of this Invention (Formula
I)
H3 0 R 0.
HO 0 30 N
.*C
35 4744.P -51which comprises reacting an oxazoline bee acid of Formula 7' H FRi 0 N 6o~ 6 O with a baccatin compound of Formula 8 H3 H3Cj
H
HO
COCH 3 O=c &X2 in the presence of a dehydrating agent; wherein R. and R3, being the same or different, are selected from the group consisting of -OC(O)CI-Calkyl, -OC(O)OCj-C 6 aIyl, -OC(O)OCHCX 3 where X Is Halo,
OC(O)OCH
2 CHJSiR. (where R is C 1 -CaIkyI), or -OSI(R, 1 I [where R, being the same or different, Is selected from C,-Calkyl or cyclo(Cs-CS)alkyl]; SX is selected from the group consisting of
-H,
-C
1
C'
4 alkY, alkoxy, S* halo, 35
-C
2
-C
4 dlalkyh 000 *i 0cZbPL 4744.P -52.
cyano, azd. (Na), or nitro; III Is selected from the group consisting of -Cli, -Aor phenyl substituted with one, 2 or 3 C 1
-C
4 alkyl, C 1
-C
3 alkoxy, halo,
C
1 -C3 alkylthlo, trifluoromethyl, C2-Cd dialkylamino, hydroxy or nitro, UkIiryI, 2-thienyl, I-napbthyl, 2-naphthyl or 3,4-methylenedioxyphenyl; and R'l 1 is selected from the group consisting of -CI-Clealkyl, -phenyl, -phenyl substituted with one, 2 or 3 CI-C. all, CI-C3 alkoxy, halo, C 1
-C
alkyitlo, trifinoromethyl, dialkylamno, hydroxy or nitro, -1-adamantyl, -3-tetrahydrofuranyl, -4-tetrahydropyranyl, or
-HC(CH
3 Another aspect of this invention is the process of preparing 20R30H
N
@600 HO 0 Re..
CeC X2
'H
*o RC i- 4744.P -53with a baccatin compound of Formula 8' H3 HO CH3 H 6O COCH3 0= C in the presence of a dehydrating agent; wherein R3. and R3, being the same or different, are selected from the group consisting of -OC(O)Cj-C 6 alky, -OC(O)OC,-C~alkyl, -OC(O)OCHCX where X is Halo, OC(O)OCHCHSMIR (where R, is C,-CpalkyI), or [where R being the same or different, Is selected from Cl-Calkyl or cyclo(C,-Cdalkyl];
X
2 Is selected from the group consting of
-H,
-C
1
-C
4 alyl,
-C
1 -C3 aikoxy, halo, -CI-C, lkYlktho, -triftuoromnthyl, -qC6 dlkylauno, benzyklotyfat azide (NA~ or trM
R
1 b &M fo a. o M wuf of 474.4Y -54- -Aor phenyl substituted with one, 2 or 3 alkyl, CX- 3 alkoxy, halo,
CX-
3 alkyithio, trifluoromethyl,
C
4 dialkyamlno bydroXY or nitro, 2-Faryl, 2-tbjenyi, 1.
naphthyl, 2-naphthyl or 3,4-methylenedioxyphenyl; arid R'll Is selected from the group consisting of
-C
1 'en~yl, -phenyl substituted with one, 2 or 3 CX- 4 alkyl, C 1
-C
3 alkoxy, halo, Cl-C 3 alkylthlo, trifuoromethyl,
C
2
-C
6 dlhkaio bydroxy or nitro, -1-adamantyl, 0 tetrahydro furanyl, -4-tetrahydropyranyl, or
-CH
2 C(CH3).
General procedure for the coupling of oxazoline acid to silyl protected Baccatin III followed by deprotection is provided: Part A: The oxazoline acid slurried in toluene is treated with 0.5 -1 equivalents of a dehydrating agent such as a carbodiimide and allowed to react. The resulting solution is then treated wiith a catalytic amount of dimethylaminopyridine or a similar catalyst and the protected baccatin 111. When TLC shows the reaction to be complete. The slurry is filtered to remove the urea, poured into aqueous sodium bicarbonate solution and extracted with methyl tbutyl ether. Concentration and purification by chromatography affords the coupled ester.
Part B: The ester from above is combined with methanol and treated with HC.
0The solution is refluxed until TLC shows the reaction to be complete. The reaction mixture is quenched with sodium bicarbonate solution and stirred at rt to effect 0 to N acyl migration.
Isolation with Ethyl acetate and chromatography affords taxol.
Silylation of 10-DAB (79).
10-DAB (79) and pyridine are combined in a ratio of 3 niL pyridine to 1 g 10-DAB and treate with 5 equivalents of the silyl chloride at room tenperature. The solution is stirred at roo wmeratmr until indC icates tereaction is complete. Upon conpletion of the %e*reaction the solution is poured into wate asS the product is isolated with a suible solvent, usually ethyl acetate or methyl :-butyl ether. 71k organic layers are dried over magnesium sulfat and concentrated to afford the AMy derivative 4744.P EXamDIC 1 Preparation of 1 3 -keto-7-TES-baccatin 111 (2) A 5 g (7.13 mM) quantity of 7-TES-baccatin 111 Denis, J. Greene, A. E. J. Am.
Chem. Soc. 1988, 110, 5917) is dissolved in 75 rnL of methylene chloride and the resultant solution is treated with 5 g (57.5 mM) of manganese dioxide. The m-ixtur is sdtred with a magnetic stirrer for 19 hr at which time TLC indicates no starting material left The reaction is then filtered through celite and the filtrate concentrated under vacuum giving 1 3 -keto-7-TES-baccatin
III.
TLC(silica gel GF): SM Rf 0.,24 product Rf 0.50, in ethyl acewae-hexane.
Proton NMR(CDCI 3 ,TMS): 8 8.08(d, 2H), 7 47 7 .63(m, 3H), 6.59(s, 18), 5.70(d, 118), 4.93(d, IH), 4.48(m, 1H), 4.31(d, 18), 4.12(d, 18), 3.91(d, 18), 2.95(d, 18f), 2.65(d, 18), 2 .55(m, 1H), 2 .23(s, 3H), 2.19(s, 381), 2.18(s, 3H), 1.88(m, 1H), 1.67(s, 3H), 1.28(s, 3H), 1.19(s, 3H), 0.92(m, 9H), 0.58(ra, 68).
Carbon NMER(CDCI 3 ,TMS): 8 199.95, 198.07, 169.85, 16.8.64, 166.53, 152.75, 139.96, 133.67, 129.76, 128.46, 83.65, 80.25, 78.20, 75.89, 75.77, 72.59, 71.98, 59.16. 45.94, 43.15, 42.18, 36.90, 32.74, 21-44, 20.56, 17.94, 13.25, 9.30, 6.46, 4.96.
Example IA. l 3 -Keto-7-TE-S-baccatin III (2) A slurry of activated manganese (IV) oxide (14.7 g, Aldrich) in CH 2 C14 (80 rnL) is treated with a solution of 7-TES-baccatin (7.14 g) in CH 2
C
2 (320 mL) added from a dropping funnel over a 5 minute period. The reaction is stirred at room temperature for 4 hours. TLC acetone./hexane and 50% EtOAc/hexane) indicates that the reaction is complete. The mixture is filtered to remove the solids and further rinsed with CHCI 2 The combined filtrates are evaporated to dryness and subjected to high vacuum to yield 1 3 -Keto-7-TES-baccai M11 as a white solid (6.81 g, 96% yield): Tic: Silica gel; 50% EtOAc/hexane; starting material Rf .25 0.41, ketone 2Rf 0-59.
'H NMR (CDCI 3 TMS), 8 8.07 (in, 28), 7.63 (in, 18), 7.50 (mn, 2H), 6.59 18), 5.70 J 6.8 ME, 18H), 4.93 1-9.5 Hz, 18H), 4.48 (mn, 18H), 4.33 J 18), 4.12 J 8.4 Hz, I 3.92 J 6.7 Hz, 18H), 2.96 J 19.9 Hz, I18), 2.66 J 20.0 Hz, 18H), 2.55 (mn, 18), 2.23 3H), 2.194 38), 2.188 3H), 1.88 (in, 18), 1.85 18), 1.67 (s, 3H), 1.28 3H), 1. 19 38), 0.92 J 7.8 Hz, 981), 0.59 J 7.6 Hz, 6H).
Exuy11e12 Preparaioa of 7TAZiso-acat El (3) Zinc dust (2.82 S. 43.1 mgatm is sequentially -ahe with diueHC ate (6z), vieuto nd thr ecntig te iqud echtime. The zinc is dried udrvacutmi.
A solution of l3-keto-7-TES-wcfnj LU 0.498 g, 0.71 MK in acetic acid (4 mQL is treate *with the activated zinc. Mwreectio I stirred untrogen at room temeature 4 ho~u. e 4744TP -56reaction is diluted with ethyl acetate, filtered through diatomaceous earth. Evaporation of the filtrate followed by dilution with toluene and re-evaporation 7-TES-l'l 3 -iSo-baccatin II.
Proton NMIR (CDC1 3 TMS): 8 0.53 (mn, 6H); 0.89 (in, 9H); 1.11I 3H); 1. 14 3H); 1.61 3H); 1.82 3H); 1.87 (mn, 1H); 2.09 (di, IH, J-18.0 Hz); 2.18 3H); 2.33 3H); 2.30-2.58 (mn, 2H); 2.74 1H, J-18.0 Hz); 4.14 1H, J-5.3 Hz); 4.25 IH, J-8.4 Hz); 4.37 (mn. 1H); 4.39 (di, IH, J-8.4 Hz); 4.37 11H); 4.93 (cid, 114); 5.48 (dci, IH); 5.91 IH); 7.48 (mn, 2H); 7.61 (mn, 1H); 8.08 (mn, 2H).
Carbon NMR (CDCI 3 TMS): 5.36, 6.69, 9.08, 12.75, 18.75, 21.18, 23.14, 29.89, 32.43, 37.17, 38.59, 39.66. 56.52, 59.09, 73.05, 73.36, 75.56, 76.82, 80.92, 84.50, 102.44, 128.53, 129.03, 129.90, 133.57, 146.02, 166.57, 168.83, 170.82, 205.52.
Elenm. Anal Calc'd for C 3 7 H 52 Oil Si 1 63.41% C, 7.48% H.
Found.' 63.31%C, 7.45% H.
IR(Nujol): 981, 1112, 1241, 1281, 1375, 1454, 1687, 1716, 1725, 1741, 3402, 3508 -1 Example 2A. 7-Triethylsilyl-1I2,13-isobaccatin MI (3) A solution of 13-keto-7-TES-baccatin 11 (7.90 g, 11.3 nunol) in degassed HOAc m.L, argon) is placed in a 250 mL three neck round bottom flask equipped with an air powered stirrer. The solution is purged with nitrogen and then activated zinc dust (82 g) added in one portion as a dry powder. The reaction is stirred vigorously. The starting material is consumed after two hours by tlc evidence (50% EtOAc/hexane). The reaction is worked up by dilution with EtOAc (degassed with argon). The reaction mixture is filtered through Celite under a nitrogen atmosphere. The flask and filter cake are rinsed well with degassed EtOAc. The combined filtrates are evaporated at a reduced pressure. Degassed toluene is added to the residue and re-evaporated. The addition and evaporation of toluene is repeated uintil the HOAc is gone (two more times). The vacuum on the evaporator is released and replaced each time with nitrogen. A white solid is obtained which is placed under high vacuum (0.02 Toir) overnight to yield 7.57 g (96 of 7-Triethylsilyl-12,13-isobaccatin Ell.
'H4 NMR (CDC1 3 ,TMS), 8 8.08 (di, 2H, J 7.1 Hz), 7.61 1H, J 7.5, Hz), 7.49 (t, 2H, J 7.5 Hz), 5.92 IH), 5.49 1H, J 5.3 Hz), 4.93 (mn. IH), 4.40 111, J 8.1 Hz), ~4.37 (mn, 1H), 4.26 (di, IH, J 8.5 Hz), 4.14 (di, 111 J 5.3 Hz), 2.75 111, J 18.0 Hz), 2.54-2.46 1H), 2.41 (mn, IH), 2.33 3H), 2.17 3H), 2.07 1.89 (mn, 1H), 1.81 3H), 1. 14 3H), 1. 11 3H), 0.89 (mn 9K1) 0.52 (in, 6HM.
le Preparation of 7-TES-Auk-o-baccti III-1I3-(4S,SR)-N-Boc-2-(Z,4acid ester 4744YP .57.
(4S .SR)-N-Boc-2-(2,4-dimcthoxyphenyl)-4-phenyl-5-oxazolidinecarboxyic acid (4ab) is prepared from the side chain salt as follows. The (4SSR)--N-Boc-2-(2,4-dimrethoxyphenyl)-4phenyl-S-oxazolidinecarboxylic acid potassium salt (1.5 mM) is suspended in ethyl acetate, and the solution washed twice with 5% aqueous sodium bisulfate, once with brine, dried and evaporated. The carboxylic acid is treated with methylene chloride (2 mL), 4-dimethylaminopyridine (48 mg), a solution of the 7-TES-A'"' 3 -iso-baccafin EII 0.492 g, 0.702 m.M) in toluene (5 m.L) plus methylene chloride (8 and 1 ,3-dicyclobexylcarbodiimide (0.3 16 g, 1.53 mM). The solution is stirred under an inert atmosphere 2.5 IL The reaction is diluted with ethyl acetate and washed with aqueous sodium bisulfate and aqueous bicarbonate plus brine. The layers are filtered and separated, and the organic layer dried and evaporated.
The product is purified by silica gel chromatography in acetone-hexane m-ixtures 7-TES-A"-iso>-baccatin III- I 3-(4S,.5R)-N-Boc-2-(2,4-diniethoxyphenyl)-4-phenyl.5oxazolidinecarboxylic acid ester (Sab) is obtained.
Proton NMIR (CDCI 3 TMS): 8 0.54 0.89 1.05 1.57 1.87 2.15 2.16 2.19 2.50 3.82 3.86 3.89 4.35 4.88 5.30 5.50 5.88 5.99 6.50 7.35-7.65 8.02 (mn).
Separation of 5a The reaction is carried out as above with 7-TES-A"-iso-baccatin HI1 0.5 g, 0.71 mM) and the crude product obtained after aqueous extraction is chromatographed over an E. Merck size B medium pressure chromatography column eluted with (20-80) acetone-n-hexane (300 mnL), (25-75) acetone-n-hexane (300 inL), and (30-70) acetone-n-bexane (300 niL), collecting fractions of 15 m.L. Fractions 24-28 are found by TLC to contain a 50-50 mixture of less and more polar isomers of 7-TES-AI"l 3 iso-baccatin Hffl3-(4S,5R>-N-Boc-2-(2,4dimethoxypbenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (5a 5b, 355 mag). Fractions 1-4, 15-23, and 29 are combined. evaporated and found to contain impure 5a and 5b. This mixture is rechromatograpbed over an E Merck size B mediumn pressure chromatography columrn eluted with (25-75) ethyl acetate-n-hexane (200 mL), (30-70) ethyl acetate-n-hexane (500 rnL), and (40-60) ethyl acetate-n-hexane (500 collecting fractions of 15 niL The les polar isomer of 7-TES-A"'"-Lso-b~cati Ml-13-(4S,SR)-N-Boc-2-(2,4.dimetxypbeuyl)-4phenyl-5-oxazolldinecarboxylic acid ester (Sa) is found in fractions 25-30 and the mom polar isomer of 7-TE-A'"'-is-baccatin III-I 3-(4S,SR-N-BoDc-2-(2,4-dinehxypbenyl)-4-pheyl-5oxazohdikocarboxylic acid catm (Sb) is found in fractions 31-39.
LAes polar isomer 7-TES&'A' 3 so-baccatin uI-l3-(4S,5R)-NBoc2-(2Aetoypey)-4- ~phenyl-5-ox zldieabxylic ac" ester 4744.P -58- TLC (silica gel GF): (30-70) ethyl acetate-hexane; Rf: 0.50.
Proton NMJI (CDC1 3 TMS): 8 0.47-0.63 6H); 0.84-0.99 9H); 1.24 9H); 2.16 3H); 2.19 3H); 3.81 3H); 3.86 3H); 4.24-4.30 lH); 4.35-4.42 1H); 4.42-4.50 1H); 4.83-4.93 lH); 4.97 1H); 5.35-5.50 IH); 5.51-5.58 111); 6.00 IR); 6.39-6.46 (cid, 1H); 6.48-6.53 (di, lH); 6.72 IH); 7.10-7.19 1H); 7.29-7.65 (in, 8H); 8.00- 8.11 (di, 2H).
More polar isomer 7.TES-A2-' 3 -iso-baccatin II-I3(S5)NBc2(,-iehxpey)4 acid ester TLC (silica gel GF): (30-70) ethyl acetate-hexine; Rf: 0.37.
Proton NMR (CDCI 3 TMS): 8 0.45 -0.59 6H); 0.83-0.96 9H); 1.05 9H); 2.16 3H1); 3.69-3.75 3.82 3H); 3.90 3H); 4.18-4.25 (di, 114); 4.30-4.36 (di, If!); 4.27-4.43 (in, 4.56-4.64 (bd, IH); 4.80-4.86 lH); 5.25-5.33 5.45-5.51 (di, if4); 5.88 114); 6.36-6.45 (dci, i1H); 6.45-6.54 (di, 7.30-7.68 (mn, 9H); 8.00-8.06 (di, 2H), Example 4 Preparation of 7-TES-13-(N-Boc- phenyl isoserinyl)-A'" 3 .iso-baccatin MI (6) 12. 3 "--iso-baccatin III- Il 3 4 SS5R)-N-Boc-2-(2,Adimethoxyphenyl)..4.phnyl.5oxazolidinecarboxylic acid ester (Sa~b 355 mng 0.319mM) is stirred at room temperature and under nitrogen in 8 ml, acetic acid-2 ml, water. The reaction is followed by TL-C and after 24 hours the more polar isomer 5b has all reacted while there some of the less polar isomer 5a still remains. T1he reaction is diluted with 100 mL ethyl acetate and washed with 50 ml, IN sodium hydroxide and 3 times with 50 mL 5% sodium bicarbonate. The organic layer is dried over sodium sulfate and evaporated under vacuum. The crude product is chromatographed over an E.
Merck size B prepacked silica gel column. Fractions of 10 ml, are collected, analyzing them by TLC. The column is eluted with (20-80) acetone-n-bexane (800 mL), (30-70) acetone-n-bexane (300 mL), (40-60) acetone-n-hexane (300 mL). Fractions 22-36 are found to contain 7 -TES-13-(N-Boc-.-phenyl isoserinyl)-A'2- -iso-baccatin EIn as a mixture. Fractions 59-63 are found to contain 13-(N-Boc-f-phenyl soserinyl)_,&12.
3 -iso-baccatin DII 7he residue from evaporation of fractions 22-36 is rechromatograpbed over an E. Merck size B prepacked silica gel column eluted with (5-95) acetone-toluene. Fraction 30-60 are found to contain 7-TE-3-(N-Boc-f.-phenyl isoserinyl)-At l.isoWbaccatin MI (6) TLC (silica gel OF): (10-90) a etome-tolue- k- 0.31 Proton NMR (CDC1 1 TMS). 8 0.48-0.61 0.84-0.96 9H); 1.14 3W) 1.23 9H), 1.26 3W) 1.62 3W, 1.84-1.9 1W, 2.03-2.15 1H); 2.17 3H); 2.83-2.94 1H); 3.18-3.25 Kd 3.82-3389(d, 1H); 4.26-4.34 (di, 111); 4.38445 1H); 4-3"448 1H)j; 4.67A74i 1H); 4.89-497 1ts), 5.40 lit); 5.355 1W 5.7 a, Iii); 4744.P -59.
7.13-7.63 (in, 9H); 8.08-8.17 2H).
Mass spectrum: measured at 964.4547; theory for C5 1
HONO
1 5Si+H is 964.4514.
Example 5 Preparation of 13-(N-Boc--pheny1 isoserinyl)a' 2 3 so-baccatin MI (7) 7-TES-,A kso-baccatin II- I 3 4 S,5R)-N-Boc-2-(2,Adimethoxyphenyl)..4-phnyl.S oxzzolidinecarboxylic acid ester (5ab; 0.69 g, 0.62 mM) is stirred in a mixture of acetic acid (16 mL) and water (4 mL) at room temperature under an inert atmosphere 4 days. The reaction is diluted with ethyl acetate and washed multiple times with water and aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and evaporated. The product is chromatographed on silica gel 60 (230-400 mesh) in acetone-hexane mixtures and 13-(N-Boc-. -phenyl isoserinyl)-A' 2 1 -isobaccatin HII is obtained.
Proton NMIR (CDC1 3 TMS): 5 1.06 3M1; 1.22 9H); 1.30 3H1); 1.92 (in, 111); 2.08 IH, J1-19 Hz); 2.23 3H); 2.51 (in, IH); 2.57 3H1); 2.76 111); 2.92 111, J1-19 Hz); 3.21 (bs, I1H); 3.52 I H, J1-4 Hz); 3.71 I H, J-6 Hz); 4.33 I H, J-8 Hz); 4.36 (mn, 111); 4.42 I H, J-8 Hz); 4.70 11H); 4.94 (dd, IRH); 5.40 (mn, I 5.48 11H); 5.58 11H, J-6 Hz); 7.30-7.67 (in, 8H); 8.13 2H, J-7 Hz).
Carbon LNMR (CDC1 3 TMIS): 9.12, 14.38, 19.97, 21.07, 22.65, 28.13, 29.78, 32.73, 35.30, 38.78, 39.53. 55.72, 57.94, 71.54, 73.57, 73.71, 77.66, 77.77, 80.19, 81.05, 84.58, 121.90, 126.56, 128.04, 128.74,128.89, 128.95, 130.27, 133.67, 138.52, 143.33, 155.16, 166.77, 170.74, 170.90, 172.04, 206.64.
Mass Spectrum (TAB): Calc'd for C,5HsNO,5: 850.3650 Found, 850.3650 Major ions at 794, 594, 105.
Example 6 Preparation of 7 -TES-l3-(N-BocP-pbenyl isoserinyI)-A'2- 3 .sobaccatin M and l3-(N-Boc-f -phenyl isoseriny1)-A'2,1 3 .iso..baccafi InI (7) Less polar isomer 7
-TE-A'"
3 -iso-baccatin III-1I3-(4S,5R)-N-Boc-2-(2,4acid ester (5a, 50 mg, 0.045mM) is treated with 0.5 mL 0.1IN HCI in MCOH with stirring at room temperature under nitrogen. The reaction is followed by TLC, starting material being found to be consurned in 30 minutes. The reaction mixtr is partitioned between edhyl acetawe5% sodium bicarbonate. T1he organic layer is separated, dried over sodium acetat sod evaporated under vacum Mwe crude jrodnct is a ~chromakogaphed over a L. Mrck sim A prepackod silica gel column, chuting with a gradient of (10-90) acetone-toluene to (20-80) ameone-toluene. ractices of 5 ml ame collected, a naingJ them by TLC. Fmta 4-14 ame fouind to contain -WI(NBcAhy 4744TP isoserinyl)-& 2 ""-so..baccatin 111 and fractions 18-28 are found to contain 13-(N-Boc-fphenyl issrnl-1.3iObc~i HII The data for 6 and 7 are comparable to those described in examples 4 and Example 7 Preparation of lO-deacetyl-13-(N-Boc-13.phenyl issrnl- [U1.~~aCai 1 I 3-(N-Boc:-J-phenyl isoserinyl)-A 2 .'kiso.haccatin 25mg O.029mM) is stirred at room temperature under nitrogen in I mL 95% ethanol. To this is added 2 drops anhydrous hydrazine. Most of the starting material is reacted after 5 minutes, as indicated by TLC. After 1 hour, the reaction is partitioned between methylene chloride-water. The layers are separated and the water layer re-extracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaprated under vacuum. The crude product is purified by chromatography over an E. Merck size A prepacked silica gel column. The column is eluted with (40-60) acetone-hexane, collecting 3mL fractions. The fractions are analyzed by TLC and pure product found in fractions 1 6-23, which are combined and evaporated, leaving l0-dacetyl-13-(N-Boc-f.phenyl issrnl-&-"iobcai M1 as a solid.
TLC (silica gel GE): 40-60 acetone-hexane, RI: 0.28.
Proton NIMR (CDC1 3 TMS): d 1.02 3H); 1.23 9H); 1.25 3H); 1.68 311); 1.71 3H); 2.57 3H); 3.38 (bs, 11ff); 3.76-3.82 11-1); 4.16 (1s, 11H); 4.27-4.33
IH);
4.39-4.46 1ff1); 4.50-4.56 (bd, IH); 4.56-4.63 (lxi, 4.70 (bs. IH); 4.90-4.97 11H); 5.33-5.44 (bd, li-I); 5.44-5.54 (bd, 5.52-5.59 1Hf); 7.30-7.45 (in, 5H); 7.45-7.56 2H-); 7.56-7.66 lH); 8.09-8.18 211).
Example 8 2 '..Troc-13-(N-Bocf phenyl isoserinyl)-A"'-iso.baccatin [11 A solution of l 3 -(N-Boc-f phenyl isoserinyl)-A' 2 3 -L-o brctt 111 0.104 g, 99.25 0. 12 rmnole) and dry pyridine (0.6 mL) in mnethylene chloride (10 mL) is cooled to -20 *C under *a nitrogen atmosphere. 2 2 2 -Trichloroethyl chioroformate (20piL, 0.032 g, 0.015 rnnole) is added in one portion to the solution. The reaction is examined after I hr by mLC, which shows :9::that no reaction has occurred. Additional 2 ,2,2-trichloroethyl chloroformate (20 piL, 99 0.15 nmole) is added and the reaction stirred for an additional 1.75 hr. Although TLC indicats incomplete reaction (about 1: 1 starting material and product) at this point, the reaction is quenched and worked up by washing with ice cold 0.1IN HCI saturate NaHCO 3 and with H120. The organic layer is dried (NaSO 4 filtered, and evaporated to give a residual mixture (0.139 The mixture is chrOmatogapedJ Over silia gel (one E. Merck size B Lobar coln) 9 using CHp 2 3 to apply the maweial to the column and 50% BI)Ac-bexane to cluse the column.
Fractions of 8 mL volume are collected. Later frtfion (42-60) contain starting material while *99*99 earlier fractions (20-25) contained 2'-Troc-I3.(N-Boc-..phpnyl U serinyl)-A'ksobc aj [U 9. to 4744.P -61.
Proton NMR (CDC1 3 1 TMS): 8 8.13 (di, 2H, J 7.3 Hz), 7.59 I H, J 7.3 Hz), 7.30- 7.52 (in, 7H), 5.66 (di, 1H, J 10.0 Hz), 5.58 1H, J 5.7 Hz, H 2 5.45-5.53 (mn, 3H), 4.96 (dd, 1 H. J 3.2, 9.6 Hz, H 5 4.71 2H, troc-CH- 2 4.42 I H, J 8.8 Hz, 4.39 (in, 1 H, H4 7 4.34 I H. J 8.6 Hz, Hxb), 3.71 I H, J 5.7 Hz, H 3 2.94 (di, I1H. J 19.0 Hz, H14), 2.76 1H, H11), 2.61 3H. -CH3), 2.53 (7 lines, lH, JH47 6.2, JM 9.5, ,JIM M 15.0 Hz, Hu), 2.23 3H, -CH 3 2.17 1H, J1 19.3 Hz, 1.93 (7 lines, 1H, JH7 11.3, Jm, 3.3, M 14.6 Hz, 1.67 1.64 1.28 3H, -CH2) 1.22 9H, -CMe 1 1.05 3H, -CH3).
Example 9 Preparation of &12.' 3 -iso-baccatin M-13-(4S,5R)-N-Boc-2-(2,4-dinethoxyphenyl)-4acid ester The less polar isomer of 7-TESAlZI 3 _iso-baccatin Ell--I3-(4S,5R)-N-Boc-2-(2,4acid ester (5a, 45 mng, 0.041mM) is dissolved in 1 rnL dry THF with stirring at room temperature and under nitogen. To this is added tetrabutyl amnmonium fluoride trihydrate (15 mg, 0.041 mM). The reaction is followed by TLC and is mostly complete in one hour. The reaction mixture is partitioned between ethyl sodium bicarbonate. The organic layer is dried over sodium sulfate and evaporated under vacuum. The crude product is purified by chromatography over an E. Merck size A prepacked silica gel column. The column is eluted with (40-60) ethyl acetate-hexane and ethyl acetate-hexane. Fractions of 5 mL are collected, analyzing them by TLC. The major product spot is found in fractions 12-18, which upon combining and evaporating under vacuum leaves A' 2 "'-iso-baccatin [II-1I 3-(4S ,5R)-N-Boc-2-(2,4-diinethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid ester (10a) as a solid.
.2.5 TLC (silica gel GE): (40-60) ethyl acetate-hexane; Ri 0.44.
Proton NMR (CDCI 3 TMS): 8 1.07 3H); 1.25 9H); 1.33 3H); 1.62 3H); 1.70 3H); 2.17 3H); 2.24 3H); 3.51-3.56 (di, 1H); 3.68-3.75 1H); 3.82 3H); 3.88 3H); 4.28-4.36 (ci, 1H); 4.38-4.44 1W); 4-36-4.47 (mn, 1H); 4.86-4.96 (dci, 111); 4.99 (s, 0 *01W); 5.33-5.41 1H); 5.50 114); 5.56-5.63 1W); 6.40-6.46 (dci, 1W); 6.50-6.54 (di, 1W); 0 so30 6.72 114); 7.09-7.16 (di, 1H); 7.33-7.68 (mn, 8H); 8.01-8.10 (di, 2H).
Mans spectrum at 998. Ot1wr ions at 942, 898, 384, 284, 105, 57.
00*00 xame 1 Preparation of 7-Troc-A"'-Lso-bscatin UI-13-(4S,SR)-N-BoDc-2-(2,4- 0 medxoxypbenyl)-4-pbenyI-5-oxadihnecszboxylic acid ester (Ile) AlU 3 Jso-baccatifl 111-1 3-(4SSR)-N-Boc-2-<2,4-dimectxyplhfly1)-4-pheuyl-5- 0 0 oxazobdinecarboxylic acid cerw (16m, 81 rn. 0.081mM) is stirrd under nitrogen at room 9 9 9.
4744YP -62temperature in 1 mL dry pyridine. To this is added 140 ilL trichioroethyl chloroforrnate in 200 pL methylene chloride. The reaction is left to go overnight. TLC the next day shows no starting material left.
The reaction mixture is partitioned between methylene chloride-I N HCI. The layers are separated and the water layer re-extracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum. The crude product is chromatographed over an E. Merck size A prepacked silica gel column, eluting with (30-70) ethyl acetate-hexane. Fractions of 5 rnL are collected, analyzing them by TLC. 7-Troc-A' 2 3 -isobaccatin rn-i 3-(4S.5R)-N-Boc-2-(2,4-dirnethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (Ila) is found in fractions 9-15, which upon combining and evaporating under vacuum leaves a solid.
TLC (silica gel GF): (30-70) ethyl acetate-hexane; Rf: 0.14 Proton NMR (CDC 3 TMS): 8 1.10 3H); 1.26 9H); 1.32 3H); 1.77 3H); 2.16 3H); 2.19 3H); 3.82 3H); 3.86 3H); 3.92-3.98 18); 4.24-4.34 18); 4.36- 4.44 IR); 4.54-4.63 18); 4.85-4.94 lH); 4.85-4.94 (in, lH); 4.99 (bs, 1H); 5.26-5.36 (in, IH); 5.36-5.44 18); 5.54-5.60 1H); 5.63 lH); 6.38-6.46 (dd, 1H); 6.48-6.53 (dd, IH); a6.72 1H); 7.10-7.18 lH); 7.34-7.66 (in, 8H); 8.01-8.10 2H).
Example I1I Preparation of 7-Troc I 3-(N-Boc-f -phenyI isoserinyl)-A 121 -iso-baccatin H1l (12) 7-Troc-A' 1 -iso-baccatin 11-1 3-(4S ,5R)-N-Boc-2-(2,4-dimnethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid ester (11a, 82 mg, 0.07mM) is treated at room temperature with stirring under nitrogen with 800 pL 0.LN HCI in methanol. The reaction is followed by TLC 0 and is mostly complete after I hour. The reaction mixture is partitioned between ethyl acetatesodium bicarbonate. The layers are separated and the water layer re-extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum. The crude product is Chromatographed over an E. Merck size A prepacked silica gel column, eluting with a gradient of (30-70) ethyl acetate-hexane to (40-60) ethyl acetate-bexane.
Fractions of 5 mL are collected, analyzing them by TLC. The product is found in fractions I11- 17 which upon combining and evaporating under vacuum give 7-Troc-13-(N-Boc--pbeny1 isoserinyl)-A'-iso-baccatin HI1(12) as a solid.
TLC (silica gel OF): (30-70) ethyl acetate-bexane; R 0.14 Proton NMR (CDC1 3 TMS): 8 1.06 3H); 1.25 1.29 38); 1.77 3H); 1.90-2.03 2.14 3H); 2.59 3H); 3.30-3.36 (di, 1H); 3.90-3.99 (di, 18); 4.26-4.33 (di, 18); 4.39-4.47 1W); 45-4.63 (di, 1W,; 4.72 (be, 18); 4.8&-4.93 (di, 18); 4.90-4.98 1H); 5.23-5.33 5.34-5.51 18); 5.52-5.60 (di, 18); 5.62 18); 7-10-7.45 (in, 5M); 7.45- 7.55 2H); 7.53-7.65 18); 8.08-8.17 Kci 18).
4744TP -63.
Example 12 2'-Troc- 13-(N-Boc- -phenyl isoserinyl)-7-deoxy-7-fluoro-,&"' -iso-baccatin I 2' -Troc-1I3.(N-Boc-o-phenyl isoserinyl)-7-deoxy-7b,8b-methano-A'"'-3iso-baccatin 111(14), and 2'-Troc- 1 3(N-Boc-f -phenyl isoserinyl)-7-deoxy-A'-A' "'-iso-baccatin MI Dimethylamninosulfur trifluoride (methylDAST, 8 jiL, 0.011 g, 0.08 mrnol) is added to a cold (-78 *C bath) solution of 2'-Troc-13-(N-Boc-f-phenyl iSoserinyl)-A&1'"3iso-baccatin III (9, 0.050 g, 0.048 minol) in CH 2
CI
2 (4 mL) under a N, atmosphere. T'he cooling bath is removed and after 1.75 hr, TLC indicats; an incomplete reaction. The solution is again cooled to -78 *C and additional rnethylDAST (12 pL) is added. The cooling bath is removed and a TLC after 1.25 hr indicats complete reaction. The reaction is quenched with H 2 0 and diluted with CHC1 2 The layers are separated and the organic layer washed with water. The aqueous layers are comabined and back extracted with CH 2
CI
2 The combined CH 2
CI
2 extracts are dtried (Na 2
SO
4 filtered, and concentrated to give a white solid. This solid is chromatographed over silica gel (two E. Merck size A Lobar columns) using a solution in CH 2
CI
2 to apply the material to the column and using first 5% CH 3
CN-CH
2
C
2 (115 fractions) and then 10% CH 3
CN-CH
2
C
2 for elution of the column. Fractions of 3 mL, volume are collected through fraction 100 and fractions of 8 mL volume are collected thereafter. Fractions 56-98 contained 2'-Troc-13-(N-Boc-f -phenyl isoserinyl)-7-deoXyA 6 3 -iSo-baccatin 111 Proton NMNR (CDCII, TMS): 8 8.18 2H, J 7.1 Hz), 7.60 IlH, J1 7.3 Hz), 7.50 2H, J 7.5 Hz), 7.30-7.45 (in, 5H), 6.10 (dci, 1W, J 5.1, 9.9 Hz, HJ~, 6.04 (di, lH, J 9.8 Hz, 5.73 (di, IIH, J 5.6 Hz, Hi), 5.66 (ci, IH, J 10.1 Hz), 5.50 5.18 III, H, 0 5.14 lH, J 5.0 Hz, H 5 4.70 2H, troc-CH,-), 4.55 (ci, 1H, J 8.3 Hz, 4.35 (d, LH, J 8.3 Hz, 3.8(i H z 3 2.97 (ci, 1H, J 19.1 Hz, 2.75 (s, 1H, H 11 2.64 3H, -CH 3 2.19 3H, -CH 3 2.11 IH, J 19.3 Hz, 1.75 3H, 1.58 -CH- 3 1.30 3H, 1.20 9H, 1.04 3H, -CH3); Fractions 106-124 contain a mixture of which 2'-Troc- I3-(N-Boc-J -phenyl isoserinyl)- 7 deoxy-Th,8b-mey-thano-A'12"-iso-baccatin lfl (14) was the major component.
Proton NMR (CDCI,, TMS): 5 8.18 2H, 3 7.2 Hz), 7.58 ILH, J 7.3 Hz), 7.49 2H, J 7.4 H4z), 7.30-7.45 (in, 5.65 (in, 2H, H 2
H
2 5.48 (mn, 2H, H 3 5.22 (ci, IH, J 2.0 Hz, H 10 4.80 (ci, lH, J 3.2 Hz, Hs), 4.70 2H, troc-CH 2 4.43 (ci, lH, J 8.7 a .30 Hz, H..,4.11 (di, I H, J-8.6 Hz, Hwt), 3.87 (di, I H, J- 6.7 Hz, 2.96 1IH, J- 19.2HRz,
H
1 2.75 ILH H 11 2.58 3H, -CHO,, 2.46 (dt, 1H, J 4.4, 16.1 Hz., Hu,) 2.17 3H, CHO), 2.15 3K Hl, H 1 Hzb), 1.68 (mn, H 1 9b), 1.63 3H. 1.31 1.31 3K 1.13 9H, -CAe 1 1.12 3K, CWboU NMR (CDCI,, TMS). 203.5, 169.7, 167.3, 164.8, 134.7, 153.2, 144.4, 137. 1, 133.6, 130.3, 129.1, 129.0, 128.7, 128.3, 126.3, 123.1, 85.1, 80.4, 79.0, 78.6, 78.4, 77.2, 75.6, 55.0, 54.1, 39.7, 36.6, 32-. 32.4, 30.2, 28.9, 28.0, 25.8, 22-4, 21.1, 20.8, 14.2, 12.8.
4744YP The minor component in this mixture is compound 2'-Troc-13-(N-Boc.-phenyl isoseriny1)-7-deoxy-7-fluoro-A'"' 3 -iso-baccatin 111 which was identified in the following experiment after removal of the 2*-troc protecting group and separation from the 70,80-methano analog 1 3-(N-Boc-f -phenyl isoserinyl)-7-deoxy-7b,8b-rnethano-A'-"-iso-baccain 111 (17, in Example 13).
Example 13 1 3-(N-Boc-o-phenyl isoserinyl)-7-deoxy-7-fluoro-A'3-iso-baccatin m1 (16, and 1 3-(N-Boc-f-phenyl isoserinyl)-7-deoxy-7,8f-methano-A 1 2 .1 3 _iso-baccain Dm (17) A solution of the 1:9 mixture of 2'-Troc-l3-(N-Boc-f -pbenyl isoserinyl)-7-deoxy-7fluoro-A'-iso-baccatin Ell (13) and 2'-Troc-13-(N-Boc-f -phenyl isoserinyl)-7doxy-7,80methano-A'" 3 -iso-baccatin 11 (14) from the example 12 (0.029 g, 0.029 mmol) in
CH
3 OH-HOAc 1) is stirred with activated Zn dust (0.074 g) under a N 2 atmosphere at room temperature. After 4 hr, a small amount of starting material remains, additional Zn dust (0.025 g) is added and stirring continued for another hour. The mixture is filtered to remove solids and the filtrate evaporated under reduced pressure giving a residue which is dissolved in
CH
2 C1 2 and washed twice with H 2 0. The aqueous extracts are back extracted with CH 2
CI
2 and the combined organic extracts dried (Na 2
SO
4 filtered, and evaporated to yield a white solid residue (0.027 This residue is chromatographed over silica gel (two E. Merck size A Lobar columns, 3.5 mL fractions) by application to the column in CHl-C1 solution and elution of the column with 40% EtOAc-hexane. Fractions 41-58 contain pure 13-(N-Boc-f-phenyl isoserinyl)- 7-deoxy-70,8f -methano-A' 2 -"-iso-baccatin 111 66%); Proton NMR (CDC 3 TMS): 8 8.19 (di, 2H, J 7.2 Hz), 7.29-7.62 (in, 8H), 5.62 (di, 1 H, 6.7 Hz, H 2 5.41 2H, H 3 5.22 (di, ILH, J 2.0 Hz, H 1 0 4.79 I1H, J 3.1 Hz, 4.69 I1H, J 3.8 Hz, 4.42 (di, 11H, J1 8.7 Hz, 4.09 (di, I1H, J 8.8 Hz, Hxp), 3.87 (di, I1H, J 6.7 Hz, 2.96 (di, 11H, J 19.3 Hz, H jd, 2.75 I1H, H1) 2.56 3H, -CHO), 2.45 (dt, 1H, J 4.3, 16.1 Hz, 2.17 -CH2), 2.05-2.21 (in 3H,
H
1 b, H19.), 1.72 1H1, J 6.2 Hz, H1b) 1.58 3H, -CH3), 1.33 3H, 1.13 (s, 1211, -CMe 1 3, -CH3).
m spectrun found 832.3529, C,H 53
NO
1 4 H requires 832.3544, 776, 732, 551, 73, 0 SO 30 57 m/z.
Fractions 62-75 contained 13-(N-Boc-f -pbenyl isoserinyl)-7-deoxy-7-fluoro-A'"'-iso-baccatin III (16); Proton NMR (CDC1 3 TMS): 858.13 28J3- 7.2 Hz), 7.60 1H), 7.49 2H1), ~7-30-7.42 (wn, 58), 5.87 (di, IH. I 6.1 Hz, HN, 5.54 K 5.8 Hz, H 3 5.41 (mn, 2H, H10), 5.11 (di, 11LJ 7.2 Hz, 112), 4.71 l, 174 4M5 1K J3- 47 Hz, 4.49 6 (di, I1H. 3-8.4 Hz, 4.36 111J- .3-5 Hz, 4.11 (ci, IH. 1-5.6 Hz, H1), 2.92 (di, 4744TP 1H, J 19 Hz, 2.74 I1.8, H 1 2.59 3H, -CH- 3 2.20 3H, -CH3), 2.10 18 H. J 19 Hz, H 1 ,OJ, 1.64 3H, -CH3), 1.27 9H, *CMe 1 1.08 3H, -CH3).
mass spectrum: found 852.3597, C 4 sH5 4 FNOI, H requires 852.3606, 832, 796, 752, 692, 180, 105, 57 m/z.
Example 14 1 3-(N-Boc-f -phenyl isosernyl)-7-eoxy-A6 7 3 -iso-baccatil MI (18) A solution of 2'-Troc-13-(N-Boc-phenyl issrnl--ex.67,M3Lobcai
III
0.0080 g, 0.0079 mmol) in 9:1 CH 3 OH-HOAc (2 niL is stirred with activated Zn dust (0.020 g) under N, at room temperature for 3 hr after which additional Zn dust (0.050 g) is added and stirring continued another 1.25 hr. The mixture is filtered to remove solids, the filtrate is evaporated, the residue is dissolved in CH 2
CI
2 and the solution washed with saturated aq NaHCO 3 and twice with 820. 'flu combined aqueous washes are back extracted with CH2,C1,. The combined CH 2 C1 2 extracts are dried (Na 2
SO
4 filtered, and evaporated to give a white solid (0.008 The solid is chromatographed over silica gel (two E. Merck size A Lobar columns, 3 mL fractions) using a solution in CH 2
CI
2 for application to the column and EtOAc-hexane for elution of the column. Pure I 3-(N-Boc-f -phenyl isoserinyl)-7-deoxy-A"-7
A
1 "-iso-baccatin 111 (18) is eluted in fractions 31-51.
Proton LNMNR (CDCl 3 TMS): 8 8.18 2H, J 7.2 Hz), 7.61 IlH, J 7.3 Hz), 7.50 (mn, 2H), 7.30-7.44 (in, 5H), 6.09 (dd, 18H, J 5.1, 9.9 Hz, Hi), 6.05 I1H, J -9.8 Hz, H1 7 5.73 1 H, J 5.5 Hz, H 2 5.40 2H, H 3 5.18 I H, HI), 5.13 I H, J 5.1 Hz, 4,70 (in, 18, H 2 4.55 III, J 8.3 Hz, 4.34 1H, J -8.4 Hz, H20), 3.68 (d, I1H, J 5.4 Hz, 83), 2.97 18H, J 18.9 Hz, H 1 2.74 18H, H 1 1 2.61 38, -CHO), 2.20 3H, -CH3). 2.09 18H, J 18.0 Hz, 1.75 3H, -CHI 3 1.52 3H, 1.32 (s, IlH, -Cl- 3 1.20 98, -CMe3), 1.05 38, -CHOI 3 mass spectrum: found 832.3579, C4 5
H
53 N0 14 H requires 832.3544, 776, 732, 180, 57 m/z.
ft...Example 15 Baccatin-Tfl-7-O-triflate A solution of baccatin-TIT (5.25 g, 8.93 mmoles) in CH 2
CI
2 (21 mL) and pyridine (18.1 mL) is cooled in a -30 *C bath. Trifluoromnethanesulfonic anhydride (3.76 mL, 6.31 g, 22.3 mmoles) is added and the resulting mixture is stirred and allowed to warm to room temperature over a period of an hour. The reaction is complete after 4 brs; saturate aq NHi.C1 (50 niL) is added and the mixture is extracted with CH 2
CI
2 71e organic extract is washed successively with 1 M aq NaHSO 4 (30 mL), saturfat aq NaHCO 3 (2 x 50 mL), saturated aj Nsa and dried (Na 2
SO
4 filtered, and concentrated under reduced pressure. Carm is taken not oD warm the solution greater dma 40 T during removal of the solvent. A pole yellow solid is obtained 4744TP which is flash chromatographed over silica gel silica gel in a 75 mmn column, 125 mL fractions). The material is applied to the column in a CH2CI, solution and the column eluted with 5% CH 3
CN-CH
2
C
2 Fractions 19-35 contain the desired 7-0-triflate (20) which is a solid.
Proton NMifR (CDCI,, TMS): 8 8.10 2H, J 7.2 Hz), 7.63 IlH, I1 7.4 Hz), 7.49 2H, J 7.6 Hz), 6.63 IM, H 1 0 5.68 11H, J 7.0 Hz, H 1 5.52 (dd, 1H, J 7.5, 10.1 Hz, H7), 4.94 I1H, J 8.4 Hz, H43), 4.86 (mn, IlH, H 13 4.3 5 IlH, J 8.4 Hz, 4.15 (d, 1H, J 8.4 Hz, H20), 4.01 1H, J 7.0 Hz, HO), 2.87 (5 lines, 2.30 3H, -CH3), 2.20 3H, 2.10-2.30 (in, fie, 1 1.87 3H, 1.59 3H, 1.19 3H, 1.05 3M, -CH3).
Example 16 A1.7 -Baccatin-Jfl (21) A solution of baccatin-III-7-O-triflate (20, 0.97 S, 1.35 inmoles) and 1,8diazabicyclo[5.4.0]undec-7-ene (1.01 mL, 1.03 g, 6.76 inmoles) in THF (6 inL) is stirred at room temperature for 1 hr, at 50 *C for 2.5 hr, and at reflux temperature for 3 hr, after which reaction is complete. EtOAc is added and the solution washed with saturated aq NaHCO3 and with saturated aq NaCI. The organic layer is dried (Na 2
SO
4 filtered, and evaporated under reduced pressure. The residue (0.876 g) is flash chromatographed over silica gel silica gel in a 45 mim column) using a solution in CH 2
CI
2 (1 mL) for application to the column. The column is eluted with 10% CH-ICN-CH 2
C
2 (1 15% CH3CN-CH 2
C
2 (0.5 and with
CHJCN-CH
2
C
2 (0.5 Fractions containing the desired material are detected by TLC and are combined to give A"-Baccatin-mH (21).
Proton NM~R (CDCI,, TMS): 8 8.14 2H, J 7.2 Hz), 7.63 IMH, J 7.3 Hz), 7.50 2H, J 7.6 Hz), 6.24 (s I H, H 1 6.07 (dd, IMH, J 5.7, 9.9 Hz, 5.87 (di, I1H, J 9.9 Hz, 5.80 I H, J 6.6 Hz, H42), 5.12 ILH, J 5.5 Hz, Hs), 4.87 (Mn, I H. H 1 3), 4.43 I H, J 8.1 Hz, 4.29 IMH, J 8.1 Hz, 4. 10 I H, J 6.6 Hz, 2.31 3M, 2.20-2,31 (mn, 2H, H 1 2.24 3H, 1.97 3M, 1.85 3M,
CM
3 1.12 6H, 2 -CMH).
Carbon NMR (CDCI,, TMS): 8 205.6, 170.3, 169.7, 167.0, 145.5, 139.8, 133.7, 132.6, 130.1, 129.4, 128.6, 126.2, 81.2, 81.0, 78.7, 76.4, 75.5, 67.9, 5 5.5, 42.7, 41.7, 39.0, 30.9, 26.3, *30 22.7, 21.0, 20.9, 20.2, 15.0.
Exaple 17 Preparation of A 6-'-l1 3-keto-baccatin 111 (22) A'.'-Baccatin M11(100mg, 0.17 mM) is dissolved in 2 mnL CH 2 CI and 300 mng ativated MnO 2 added. TLC shows no tarting material left after I81r at which point the reactio is filtered through Celite uA concentraWe in vacuo leaVing A "-7_13 keto-baccaim Ml (22).
Proton NMR (CDC6, TMS): 1.19 (OM-H 1.24 (OR3); 1.81 (sM3); 2.03 2.19 47 44.
-67- 2.28 2.67 (dAM); 3.01 4.22 4.45 5.09 5.87 6.09 (ddI 6.32 IH). 7.50 7.64 (m,1IH); 8. 10 (d,2H) Mass Spectrum (FAB): Caic'd for C,,H 3 3
O
1 567.2230; Found: 567.216 Example 18 Preparation of A 6--A 2 '1 3 -iso-baccatin MI (23) A& "-13-keto-baccatinlfl (22. 90mg. 0.16 mM) is dissolved in 750 pl, HOAc arnd 560 mg activated Zn is added. TLC shows no starting material after 1 hr at which point the reaction is filtered through Celite and concentrated in vacuo leaving A 7 -A 12.1 3 _iso-baccatin MI (23).
Proton NN{R (CDC1 3 TMS): 8 1.02 1.14 1.56 1.72 2.18 2.35 3.83 4.32 4.52 5.09 5.14 5.66 6.05 7.49 7.62 8.11 (d,2H) Mass Spectrum: 569; C 3 ,H3,O 10 requires 569, other ions at rn/z 105 Example 19 ,Preparation of 7-deoxy-A"-A 1 2 1_iso-baCCatin HII- I 3-(4S ,5R)-N-Boc-2-(2,4- -oxazolidinecarboxylic acid ester (24ab) Crude (4S .5R)-N-Boc-2-(2,4 dimethoxyphenyl)-4-phenyl-5-oxazolidine carboxylic acid potassium salt (I116mg, 0.25mM\) is partitioned between CH 2
CI
2 and 5% NaHSO, solution. The layers are separated and the aqueous layer extracted with EtOAc. Thne combined organic layers are filtered through anhydrous sodium sulfate and concentrated in vacuo leaving 112 mg of (4S,5R)-N-Boc-2-(2,4 dimiethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (4ab).
A& 11.
7 _A "--iso-baccatin HI1 (23, 94mg, 0.16 mM) is dissolved in 1 niL toluene. All of the 9 (4S ,5R)-N-Boc-2-(2,4 dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid (4ab) is added in a solution of CH 2
CI
2 To the solution is added DCC (60mg, 0.29 mM) and DMAP 0.08mM). After stirring overnight the reaction is filtered through Celite. The filtrate is concentrated in vacuo and chromatographed over an E. Merck size A silica column in EtOAc:Toluenc. The column is eluted with 10% EtOAc:Toluene (25 mL), 15% EtOAc:Toluene mL), 20% EtOAc:Toluene (100 mnL, and 25% EtOAc:Toluene (50 ml.. collecting 3 ml, fractions. The less polar isomer 7-deoxy-A 11.7_& '2 3 -iso-baccatin lI-13-(4S,5R)-N-Boc-2-(2,4dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (24a) is found in fractions 27-37.
The more polar isomer 7-deoxy-A&"-A,' 2 -"-io-baccatin H[-13-(4S,5R)-N-Boc-2-(2,4dnihoxypbyl)-4-penyl--oxazolkincboxylic acid ester (24b) is found in fractions 44-54.
Dat for less polar isomer 7-deoxy-,&7-1.AI3liobecCAfin EI-13-(4S,SR)-N-Boc-2-(2,4acid ester (24&) Proton NMR (CDCI 3 TMS)r 8 1.00 1. 16 1. 18 1.26 1.66 (OH); ~~2.11 2.13 2.21 2.77 3.60 4d1H); 3.73 3.77 (O3H); 4.25 4744.P -68- (d,1IH); 4.46 (d,1IH); 4.90 (br s,1IH). 5.05 (br s,1IH); 5.11 (s,lIH); 5.27 (br s, IH); 5.65 (d,1IH); 5.99 6.33 (dd,ll1); 6.41 6.65 7.31 7.46 7.56 8.04 (d,2H) Data for more polar isomer 7-deoxy-A 1 2 .1 3 -iso-baccatin [II-1I3-(4S,5R)-N-Boc-2-(2,4dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (24b) Proton NMIR (CDCI 3 TMS): 8 1.04 1.27 1.69 2.17 2.67 3.56 3.80 3.84 3.88 4.26 (djlH); 4.47 4.59 (d,lH); 5.03 5.08 5.21 5.67 6.00 6.48 7.40 (br 7.50 7.64 8.06 (d,2H) Example 20 Preparation of 13-(N-Boc-o-phenyl isoseriny1)-7-deoxy-A 6 13 -iso-baccatin [HI 7_deoXy_-1A 6 .I-iso-baccatin rn-i3-(4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenylacid ester (24b, 36mg, .037mM) is dissolved in 800 p1. methanol and 200 pL acetic acid added. After stirring for 17 hrs. TLC shows the reaction is approximately complete and no further change is seen after 20 hrs. Thus, another 400 iL, methanol and 100 p1. acetic acid is added. An additional 150 ml,. acetic acid is added after 41 hrs. After 48 hrs. the reaction is partitioned between 5% NaHCO 3 brine, and EtOAc. The layers are separated and the aqueous re-extracted using EtOAc. The combined organic layers are filtered through Na 2 SO, and concentrated in vacuo. The residue is chromatographed over 4 gmn of silica gel packed in 2.5% EtOAc:Toluene. The column was eluted with EtOAc:Toluene (20 mL), 25% EtOAc:Toluene (40 mL), and 33% EtOAc:Toluene (24 niL) collecting 2 mL fractions. 13-(N-Boc-f -phenyl issrnl--ex-& -2"iobcai 11H (18) is found in fractions 19-33. Mixed fractions 14-18 are rechromatographed over I gmn of silica gel packed in 20% EtOAc:Toluene. The column was eluted with 20% EtOAc:Toluene mL), 33% EtOAc:Toluene (6 mnL), and 50% EtOAc:Toluene (6 mL) collecting 0.5 mL fractions. 13.{N-Boc- -phenyl isoserinyl)-7-deoxy-A 6 "'-A'"'-is-,o-baccatin [H1 (18) is found if fractions 25-34. The physical data are consistent with those from example 14.
E3HpJe 2 Preparation of N-(t-butylaininocarbonyl)-p-phenyI isoserine methyl ester (26) (2R,3S)- -pbenyl-isoserine methyl ester (4.35g. 22 mnM) is dissolved in 100 maL dry THF and the flask cooled to 0 *C To the solution is added t-butyl isocyanate (2.8 mL, mnM). TLC after 15 minutes shows some starting material left so another 0.5 mL. of the isocyanate is added. TLC after ihour shows no starting material so the solvent is concentrated in vacuo.
Proton NMR (CDCI), ThIS) 8 1.27 9H); 3.43 IH); 3.81 3H); 4.34 (br s, 4744.P -69- 1H); 4.48 I 5.27 I 5.32 I 7.29 2H); 7.34 3H) Mass spectrum (FAB-High Res.) Theory for CsHnN 2 295.1658 Found: 295.1663 Example 22 Preparation of (4S,5R)-N-(t-butylaminocarbony1)2-(2.4-dimethoxyphenyl)-4-phenyl.
acid methyl ester (28a b) N-t-butyl-f-phenyl-isoserine methyl ester (26, 68 ig, 0.23 mM) is dissolved in 5 mL dry THF and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal (70 ig, 0.33 mM) and pyridinium p-toluenesulfonate (6 mg, 0.02 mM) and the solution warmed to reflux. Approximately 2 mL solvent is boiled away 3 times in a 45 minute period replenishing with 2 mL of fresh THF at which time TLC shows no starting material. The solvent is concentrated in vacuo and chroiatographed over 7 gm of silica gel packed in 1:3 EtOAc:Hexane. The column is eluted with 80 mL 1:3 EtOAc:Hexane, 45 mL 1:2 EtOAc:Hexane, 30 mL 2:3 EtOAc:Hexane, and 30 mL 1:1 EtOAc:Hexane collecting 3 mL fractions.
A less polar isomer, (4S.SR)-N-(t-butylaminocarbonyl)2-(2,4-dirnethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid methyl ester (28a) was found in fractions 21-31.
A more polar isomer, (48,SR)-N-(t-butylaminocarbonyl)2-(2,4-dimedhoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid methyl ester (28b) was found in fractions 33-42.
Less Polar Product 28a Proton NMR (CDC 3 TMS): 8 1.19 9H); 3.82 3H); 3.85 3H); 3.89 3H); 4.68 (br s, 1H); 4.88 1H); 5.52 1H); 6.46 6.70 1H); 7.25-7.50 (m) Mass spectrum (FAB-High Res.): Theory for CH 3 1
,N
2
O
6 443.2182 Found: 443.2172 More Polar Product 28b Proton NMR (CDCI 3 TMS): 8 0.99 9H); 3.53 3H); 3.81 3H); 3.88 (m, 3H); 4.05 1H); 4.55 IH); 5.45 1H); 6.48 2H); 6.79 1H); 7.25-7.50 (m) Mass spectrum (FAB-High Res.): Theory for C,H 3 443.2182 Found: 443.2180 Examwk 23 Preparation of (4S.R)-N-(t-bumylinm yl)-2-(2,-dimethoxyphenyl)4acid potassium salt (29) 4744.P (4S ,SR)-N-(t-butylaminocarbonyl)-2-(2,4-dirnethoxyphenyl)-4-phenyl.5oxazolidinecarboxylic acid methyl ester (Example No. 22, 28a, 6.27 g, 14.2 mM) is stirred at room temperature under nitrogen in methanol (50 mL). To this is added a solution of potassium carbonate (2.50 g, 18.1 mM) in water (6 mL). After 6 hours the reaction is evaporated under reduced pressure to remove the methanol and the residue freeze dried. There is obtained a quantitative yield of (4S.5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylc acid potassium salt (29a) admixed with potassium carbonate salts as a powder.
Proton NMR (DMSOd, TMS): 8 1.10 9H); 3.77 3H); 4.17 1H, J-2.3 Hz); 4.70 (bs, lH); 5.16 1H, J-2.3 Hz); 6.50 2H); 6.60 1H); 7.14-7.42 (m, 6H);.
Example 23a Preparation of (4S.5R)-N-(t-butylaminocarbonyl)-2-(2,4-dimethoxyphenyi)# acid potassium salt (29b) (4S,5R)-N-(t-butylaminocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid methyl ester (Example No. 22, 28b, 0.98 g, 2.2 mM) is stirred at room temperature under nitrogen in methanol (50 mL). To this is added a solution of potassium carbonate (0.39 g, 2.5 mM) in water (1.1 mL). After 5 hours the reaction is evaporated under reduced pressure to remove the methanol and the residue freeze dried. There is obtained a quantitative yield of (4S.SR)-N-Boc-2-(2,4-dimethoxyphenyl)-4-pbenyl-5-oxazolidinecarboxylic acid potassium salt (29b) admixed with potassium carbonate salts as a powder.
Proton NMR (DMSO, TMS): 8 0.81 9H); 3.80 3H); 3.85 3); 3.92 IlH, J-6.4 Hz); 4.86 (bs, 1H); 5.16 IH, J-6.4 Hz); 6.43 1H); 6.56 2H); 7.30-7.47 (in, 6H);.
Example 24 Preparation of (4S,5R)-N-(t-butylami carbonyl)-2-(2,4-diethoxyphenyl)-4 acid (4S ,R)-N-Boc-2-(2,4-dimethoxypbenyl)-4-phenyl-5-oxazolidinecarboxylic acid potassium salt (29, example 23) is partitioned between methylene chloride and water containing 0.9 mL IN HCI. The layers are separated and the aqueous layer reextracted with methylene chloride. The organic layers are combined, dried over sodium sulfate and evaporated. This leaves (4SSR)-N-Boc-2-(2,4-dimthoxypheuyl)phenyl-5-oxazolidinecarboxylic acid (30a) as a solid Exmle 25 Ireperalmof 7-TES-i-ko4ccwin M-13-(4SjR)-N-(t yimmocrubonyrj-i- (2,4-diintboxyphenyl)-4-pheyl-5-oxzolidinecwboxyk acid eater (31a) (4S4R)-N-(t-butyminocrboiyl)-2(4,dizneoxyphny)-42nyl-5- 4744.P -71oxazolidinecarboxylic acid (3 mM, Preparation No. 24, 30a) is dissolved in 20 mL methylene chloride (11 mL)-toluene (5 mL). To this is added 7-TES-A'" 3 -iso-baccatin iM (1.0 g, 1.4 mM, 3, example 4-dimethylaminopyridine (93 mg, 0.76 mM), and 1,3-dicyclohexylcarbodiimide (0.63 g, 3.1 mM) and the reaction mixture stirred for 3 h under a nitrogen atmosphere. The reaction is diluted with toluene and filtered. The filtrate is washed with 1 N hydrochloric acid, aqueous sodium bicarbonate, and brine. The organic solution is dried over anhydrous sodium sulfate and evaporated. The product is purified by column chromatography on silica gel in acetone-bexane mixtures. Concentration of the fractions found to contain product by TLC give 7-TES-A"'"-iso-baccatin U-13-(4S,5R)-N-(t-butylaminocarbonyl)-2-(2,4-dimethoxyphenyl)- 4-phenyl-5-oxazolidinecarboxylic acid ester (31a) as a solid.
Proton NMR (CDC1 3 TMS): 8 0.54 6H); 0.90 (mn, 12H); 1.16 3H); 1.17 (s, 9H); 1.80 3H); 1.89 IH); 2.15 3H); 2.18 3H); 2.30 1H); 2.50 (inm, 2H); 2.78 (d, 1H); 3.83 3H); 3.85 1H); 3.91 3H); 4.28 1H); 4.38 1I); 4.43 11); 4.64 (bs, 1H); 4.88 1I); 5.04 5.55 1I); 5.65 1I); 5.99 1I); 6.49 2H); 6.74 1H); 7.22 1H); 7.34-7.68 8H); 8.07 2H).
Carbon NMR (CDCI 3 TMS): 8 5.27, 6.55, 8.99, 13.83, 14.11, 18.92, 20.90, 22.30, 28.79, 29.67, 32.86, 36.94, 38.75, 39.63, 50.59, 55.13, 55.28, 56.42, 58.40, 62.81, 72.50, 73.15, 74.10, 76.88, 80.58, 84.28, 85.81, 98.11, 104.94, 117.48, 122.28, 126.75, 127.66, 128.41, 128.49, 128.76, 129.76, 133.43, 139.81, 142.87, 154.95, 158.14, 161.68, 166.32, 168.33, 168.55, 170.12, 204.76.
Example 26 Preparation of 7-TES-13-(N-(t-butylaminocarbonyl)--penyl isoserinyl)-AiZso-isbaccatin El (32a) and 13-(N-(t-butylaminocarbonyl)-B-phenyl isoserinyl)-d' '-iso-baccatin m (32b) 7-TES-A' 2 1 -iso-baccatin E-1 3-(4S,SR)-N-(t-butylaminocarbonyl)-2-(2,4dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (31a, example 25, 0.102 g, 0.092 mM) is stirred in a mixture of acetic acid (4 mL) and water (1 mL) at room temperature under an inert atmosphere 65 h. The reaction is diluted with ethyl acetate and washed with **aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and 30 evaporated. The product is purified by column chromatography on silica gel 60 in (30-70) and (40-60) acetone-hexane. Fractions of 4 mL are collected. Concentration of fractions 13-22 gives 7-TES-13-(N-(t-butylaminocarbonyl)--phnyl isoserinyl)-& 2 "-iso-bccatin ill (32a).
Concentration of fractions 35-40 gives 13-(N-(t-butylamninocarboyl)--pbeny isowrinyl)-A'd" iso-bccatin (32b).
Data for 32a Proton NMR (CDC!, TMS) 8 0.53 6H); 0.89 9H); 1.13 12H); 1.24 (s, 4744.P -72- 4H); 1.57 (bs, lH); 1.62 3H); 1.68 3H); 1.89 1H); 2.07 1H); 2.16 3H); 2.50 2H); 2.58 3H); 2.86 1H); 3.84 1H, J-5.6 Hz); 4.34 4H); 4.71 1H, J-2.9Hz); 4.92 (dd, 1H); 5.03 IH, J-9.0 Hz); 5.53 2H); 5.97 1H); 7.28-7.68 8H); 8.11 2H).
Data for 32b Proton NMR (CDC 3 TMS): 8 1.05 3H); 1.13 9H); 1.29 3H); 1.55 (s, 3H);1.62 3H); 1.65 (bs, 11); 1.89 lH); 2.11 IH); 2.23 3H); 2.47 11); 2.54 (s, 3H); 2.72 (bs, 1H); 2.87 1H); 3.58 3.68 1H); 4.10 (bs, 11); 4.31(m, 2H); 4.39 11); 4.62 (bs, 1H); 4.71 4.90 (dd, 1H); 5.44 2H); 5.57 2H); 7.36(m, 5H); 7.49 2H); 7.59 11); 8.10 2H).
Carbon NMR (CDC1 3 TMS): 8 9.07, 14.41, 19.80. 21.03, 23.19, 29.30, 29.81, 32.87, 35.30, 38.66, 39.50, 50.47, 55.75, 57.93, 71.66, 73.50, 74.70, 77.21, 77.64, 77.73, 81.09, 84.47, 121.69, 126.66, 127.93, 128.75, 128.86, 130.22, 133.69, 138.88, 143.26, 156.52, 166.63, 170.69, 171.33, 171.99 206.71.
Mass spectrum (FAB-High Res.) Theory for COHmN 2 849.3809 Found- 849.3842 Example 27 Preparation of A'" 1 3 -iso-baccatin 1-13-(4S,5R)-N-(t-butylaminocarbonyl)-2-(2,4acid ester (33a) 7-TES-A'"'"-iso-baccatin II-1 3-(4S,SR)-N-(t-butylaminocarbonyl)-2-(2,4acid ester (31a, preparation 26, 460 mg, 0.413 mM) is dissolved in acetonitrile (0.5 mL) and the solution treated with triethyl amine hydrofluoride (0.5 mL). The reaction is stirred at room temperature for 6 b. The reaction is then diluted with ethyl acetate and washed with 5 aqueous sodium bicarbonate, 5 aqueous sodium bisulfate and saturated brine. The organic layer is dried over sodium sulfate and evaporated under vacuum. The crude product is purified by chromatography over 50 g of HPLC grade silica gel eluting with 30 and 40 acetone in hexane. Fractions of 10 mL are collected, analyzing them by TLC. The major product spot is found in fractions 24-30, which upon combining and evaporating under vacuum leave of A 2 '"-iso-baccatin UI-13-(4S,5R)-N-(t- 30 butylaminocarbonyl)-2-(2,4-dimethoxypbenyl)-4-phenyl-5-oxazoidinecarboxylic acid ester (33a).
Proton NMR (CDC 3 TMS): 8 1.07 3H); 1.17 9H); 1.32 3H); 1.62 3H); 1.67 3H); 1.91 1H); 2.16 3H); 2.24 3H); 2.31 1H); 2.49 IH); 2.81 2H); 1H) 3.71 1H); 3.83 3H); 3.92 3H); 4.35 3H); 4.65(bs, 11); 4.89 (m, 1H); 5.06 1H); 5.49 1H); 5.58 11); 5.67 6,47 11); 6.53 6.73 1H) 7.20(d, 1H): 734-7.65 8H); 8.01 2H).
Carbon NMR (CDC, TMS): 8 9.14, 13.83, 14.39, 19.85, 21.09, 22.50, 29.12, 4744.P -73- 29.93, 31.8, 33.2, 35.35, 38.69, 39.60, 50.92, 55.45, 55.82, 57.99, 63.16, 71.60, 73.68, 77.37, 77.72, 80.96, 84.62, 86.27, 98.43, 105.27, 117.5, 121.81, 127.02, 128.02, 128.76, 128.83, 130.09, 133.79, 140.2, 143.21, 155.4, 158.4, 162.1, 166.6, 168.7, 170.56, 172.0, 206.74.
Example 28 Preparation of 7-trifluoromethanesulfonyl-Il"-iso-baccatin III 13-(4S,5R)-N-(tbutylaminocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidnecarboxylic acid ester (34a) A solution of A'"'-iso-baccatin M 13-(4S,SR)-N-(t-butylaiinocarbonyl)-2-(2,4acid ester (33a, 63 mg, 0.063 mM) in CHIC1 2 (0.4 mL) and pyridine (0.15 rnL) is cooled in a -78 *C bath. Trifluoromethanesulfonic anhydride (33 jiL, 0.20 mM) is added resulting in the reaction solidifying. The reaction is warmed until it melts and then is re-cooled. After lh the reaction was warmed to room temperature and stirred 10 min. The reaction is poured into saturated aq NH1CI and the mixture is extracted with CHC1. The organic extract is washed with 1 M aq NaHSO 4 (50 mL), dried and concentrated under reduced pressure. The residue is chromatographed over silica gel (3 g), eluted with 30 acetone in hexane. Fractions of 1 mL are collected. Concentration of fractions 17,18 leaves 7-trifluoromethanesulfonyl-A''-iso-baccatin [H 13-(4SSR)-N-(tbutylanocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxyc acid ester (34a).
Proton NMR (CDCI 3 TMS): 8 1.11 3H); 1.17 9H); 1.77 68); 2.20 3H); 2.21 31); 2.34 18); 2.68 (1s, 18); 2.80 18); 2.95 18); 3.83 38); 3.88 (i, 18); 3.93 3H); 4.34 IH); 4.43 18); 4.67 (bs, 1H); 4.86 18); 5.05 18); 5.53 18); 5.60 1H); 5.88 1H); 6.47 18); 6.53 18); 6.72 18); 7.20 1H); 7.30-7.70 88); 8.07 2H).
Carbon NMR (CDCI 3 TMS): 5 10.17, 14.12, 14.42, 19.71, 20.71, 2236, 22.65, 29.10. 29.93, 31.59, 33.24, 38.75, 39.67, 50.93, 55.16, 55.44, 55.69, 57.57, 63.04, 72.95, 74.73, 77.20, 79.68, 80.87, 83.38, 85.86, 86.06, 98.38, 105.33, 117.61 122.78, 127.00, 127.98, 128.81, 130.09, 133.98, 140.17, 142.78, 155.29, 158.46, 162.06, 166.41, 168.91, 168.99, 170.90, 203.44.
Example 29 Preparation of 7-deoxy-70,*menthano-A' 3 -iso-baccatin IN 13-(4S,5R)-N-(tbutylamnnocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester A solution of 7-b fluoromethnesulfonyl-A'""-iso-bccatin M 13-(4SSR)-N-(tbutylamnxaboyyl)2-(2imhxypbyl)--penyl-5-oxaolidieabxylic acid eater (34a, Example 28) in distilled dioxine is treated with an aquow sodium azide solution. The reaction p refluxed under nitroen one hour. Te mixture is diluted with ethyl wacta and washed with 33 water and brine, dried over ah)ous som sulfate, and evaporated. The product is purified by column chromatography on dMle a 60 in ethyl acetae-methykne chloride mixuu&m 4744.P -74- Evaporation of the fractions found by TLC to contain the product gives 7-deoxy-7,80.methano- -iso-baccatin ELI 13-(4S ,5R)-N-(t-butylaminocarbonyl)-2-(2,4-dimethoxyphenyl)-4.phenyl-5oxazolidinecarboxylic acid ester Example 30 Preparation of 13-(N-(t-butylaminocarbonyl)-g-phenyl isoserinyl)-7-deoxy-70,8&methano-A' 2 .3kiso-baccatin 111 (36) Following the procedure of example 5, 7eoxy-7,80methano-A 111 -so-baccatin M 13- (4S,5R)-N-(t-butylaminocarbonyl)-2-(2,4-direthoxyphenyI)-4-phenyI-5-oxazolidinecarboxylic acid ester (35a) is stirred in a 4:1 mixture of acetic acid and water at room temperature under an inert atmosphere 4 days. The reaction is diluted with ethyl acetate and washed multiple times with water and aqueous sodium bicarbonate. Te organic layer is dried over anhydrous sodium sulfate and evaporated. The product is chromatographed on silica gel 60 (230-400 mesh) in acetone-hexane mixtures. Evaporation of the fractions found to contain product by TLC leaves 1 3-(N-(t-butylaminocarbonyl)- -pheny isoserinyl)-7-dmoxy-7,8methano- '""-iso-baccatin M (36).
Examvle 31 Preparation of 1 3-(N-(t-butylaminocarbonyl)-&phenylisoserinyl)-7-deoxy-7,8f..
methano-A"- 3 -iso-baccatin m (36) and 13-(N-(t-butylaminocarbonyl)-f-phenylisoserinyI)-7triflluoromethanesulfonyl-A'1 21 -iso-baccatin [I (37) A solution of A'""-iso-baccatin I-1 3-((4S,5R)-N-t-butylaminocarbonyl-(2,4acid ester]-7-triflate (0.20 g, 0.18 mM) in 2 ml of (80:20) acetic acidmethanol is stirred at room temperature for 1.3 hours. The reaction is diluted with ethyl acetate and washed with 5% aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and concentrated. The crude product is chronatographed on silica gel 60 in acetone-bexane mixtures, resulting in partial conversion to 7,19-methano-13- (N-t-butylaminocarbonyl- -pbenylisoseriny)-&' 3 "-iso-baccatin ll. The products eluting from this column are re-chromatographed in ethyl acetate-methylene chloride mixtures to give 13-{N- (t-butyxinocabony (-gphenylisosry u t l b an 37, mg) and 1 -(N-(t-buty lamiocarbonyl)-gphenylsserinyl)-7-doxy-7 ,8&miedino'f 1, 3sobaccatin 111 (36, 41 mg).
Da for 1 3-(N-(t-butymbwlrbonyl)-gp-piyisosriny)-7-tifluoromthatonyl-, ,2 L baccatin 1H (37) Proto NMR(CDaTMSY 8 1.09(s); 1.11 1.17(s); 1.24 1.76(S);2.1(m, 2.18 2.47 2.65 290 3.83 4.31(d); 4.43 4.73 4.88 5.32 (bs); 5.47(m) 5.58 5.85(s); 7.30-7.63 8.09 4744.P Carbon NMR (CDCI 3 TMS): 8 10.09, 14.36, 19.69, 20.68, 22.62, 23.00, 29.13, 29.22, 29.73, 31.54, 33.01, 33.53, 38.67, 39.57, 50.68, 55.13, 55.41, 57.50, 72.79, 74.24, 74.66, 79.59, 83.30, 85.89, 122.70, 126.72, 127.99, 128.61, 128.81, 128.86, 130.22, 133.88, 138.65, 142.85, 156.47, 166.41, 168.98, 170.68, 171.16, 203.40.
Data for 13 -(N-(t-butylaminocarbonyl)-g-phenylisoserinyl)-7-deoxy-7 ,8 -methano-A' 2 "k iso baccatin I1 (36) Proton NMR (CDCI 3 TMS): 8 1.04 9H); 1.12 1.31 1.55 1.73 2.17 2.41(m, lH); 2.55 3H); 2.73 (bs, 1H); 2.91 1H); 3.86 1H); 4.09 1H); 4.29 (bs, I1H); 4.41 IH); 4.70 1H); 4.78 1H); 5.08 1H); 5.21 IH); 5.50 (m, 1H); 5.62 1H); 7.27-7.65 10 8.18 2H).
Carbon NMR (CDC1 3 TMS): 8 12.80, 14.22, 20.86, 21.08, 22.44, 25.79, 28.77, 29.20, 30.09, 32.44, 32.81, 36.69, 39.70, 50.38, 55.03, 55.22, 74.39, 75.70, 78.29, 78.41, 78.87, 80.47, 85.15, 122.40, 126.65, 127.83, 128.77, 129.02, 130.38, 133.64, 139.15, 141.77, 156.19, 167.28, 169.76, 170.36, 171.02, 203.64.
Example 32 Preparation of 13-(N-(t-butylaminocarbonyi)- -pheny isoserinyl)-7-deoxy-A 6 7 -A 12,13 iso-baccatin 111 (38) Following the procedure of Example 16, a solution of 13-(N-(t-butylaminocarbonyl)phenyl isoserinyl)-7-trifuoromethanesuffonyl-A2li..isobaccatin HI(37) and 1,8-diazabicyclo[5.4.0]undec-7-ene in THF is stirred at room temperature for I hr, at 50 C for hr, and at reflux temperature for 3 hr, after which reaction is complete. EtOAc is added and the solution washed with saturated aq NaHCO 3 and with saturated aq NaCI. The organic layer is dried (Na 2 SQ), filtered, and evaporated under reduced pressure. The residue is flash chroiatographed over silica gel using a solution in CHCI 2 for application to the cohnnn. The column is eluted with acetonitrile-methyleae chloride nixture. Fractions containing the desired material are detected by TLC and are combined to give 13-(N-(t-butylaminocabonyl)-pheny1 isoserinyl)-7-deoxy-A"-A"'-'-iso-baccatin m (38).
Example 33 Preparation of 7-deoxy'--'2' 3 -iso-beccatin l 13-(4S,5R)-N-(tbutylaminocarbonyl)-2-(2,4diettboxypbyl)-4-phenyl-5-oxazolkdineca xylic acid ester (39a) Following the procedure of Example 16, a solution of 7uifiuoronetbaz=sulfonyl-AIZ Ii.
iso-bcctin 1 3-(4S,5R)-N-(t-bzylm ino oxaodinecarboxylic acid eaer and 1,8-di A bcyco(5.4.uaodac-7-aa in THF ae stirred at mom tmperture t1 hr.at 50 "C for 25 hr, and at wthmn tprmre for 3 hrafter which reaction is complete. E M Ib ddnd d hm e ution washed wb satuated q NAHO 3 and 4744.P with saturated aq NaCI. The organic layer is dried (Na 2 filtered, and evaporated under reduced pressure. T~he column is eluted with acetonitrile-miethylene chloride mixtures. Fractions containing the desired material are detected by TLC and are combined to give 7-deoxy-A-- A1'-11-iso-baccatin II 1 3-(4S ,5R)-N-(t-butylamidnocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid ester (39a).
ExaMple 34 Preparation of I 34 -(t-butylaminocarbonyl)-o-phenyl isoserinyl]-7-deoxy-A6 7 A1 2 1 3 _iso-bacctin In1(38) Following the procedure of Example 5, 7-deoxy-A 7 3 -iso-baccatin III 13-(4S.5R)-N- (t-butylaminocarbonyl)-2-(2,4-dinethoxypenyl)-4-phenyl-5-oxazolidilecarboxylic acid ester (39s) is stirred in a 4:1 mixture of acetic acid and water at room temperature under an inert atmosphere 4 days. The reaction is diluted with ethyl acetate and washed multiple times with water and aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and evaporated. The product is chromatographed on silica gel 60 (230-400 mesh) in acetone-hexane mixtures. Evaporation of the fractions found to contain product by TLC leaves 13 -[N-(t-butylaminocarbonyl)-f -phenyI isserinyl]-7-deoxy-A6-' "-iso-baccatin 11 (38).
Example 35 Preparation of 7-(O-ethoxymethyl)-A 12.1 3 -iso-baccatin [H-i3-(4S ,5R)-N-Boc-2-(2,4acid ester A 1 2 .1 3 -so.-baccafin [H1-13 (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid ester (10a) is stirred at room temperature under nitrogen in methylene chloride and the solution treated with chloroethyl ethyl ether and dilsopropylethyl S amine. The reaction is stirred for 2 days. when it is complete as shown by T*LC. The reaction is then partitioned between methylene chloride-water. The layers are separated and the water layer reextracted with mnethylene chloride. Mxe organic layers are dried over sodium sulfate, combined and evaporated under vacuum. The crude product is chromatographed over silica gel, eluting with acetone-hexane mixtures. Fractions contain the product are found by TLC and are combined and evaporated under vacuum leaving 7-(O-ethoxymethyl)_A 1 2 1 3 -b in~ m11-13- (4S,5R}-N-Boc-2-(2,4-dimethoxyphenyl)-4-pbenyl-5-oxazolidinecarboxylic acid ester Exml Preparaios of 7-(O-ethoxymethyl)-13-(N-Boc-f-phenyI isoserny)-A''-isObaccatin fijI (41) Following the procedure of exampl 5, 7-(O-etlhoxynm4byl)-A' 2 3 -iSo-bctin M1-13- (4,R-N-9c-2-(2,4dmetoxypeny-4-penyl--oxaOlidnecabOxyic ac" ester stiffed in a 4:1 mixamr of acetic acid and wa at room temperature under an budt atmospbere 4 days. The reactoe is diluted with ethyl acetae and washed multiple times wilu wowe and 4744.P -77aqueous sodium bicarbonate. The organic layer is dried over anhydrous sodium sulfate and evaporated. The product is chromatographed on silica gel 60 (230-400 mesh) in acetone-hexane mixtures. Evaporation of the fractions found to contain product by TLC leaves 7-(O-ethoxymethyl)-13-(N-Boc-f-phenyl isoserinyl)-& "-iso-baccatin 11I (41).
Example 37 Preparation of 7-(O-ethoxymethyl)-A'2"-iso-baccatin I-13-(4S,5R)-N-(tbutylaminocarbonyl)-2-(2,4-dimethoxypheny)-4-pbenyl-5-oxazoidinecarboxyl acid ester (42a) A"'"'-Iso-baccatin [-13 (4S,5R)-N-(t-butylaminocarbonyl)-2-(2,4dimethoxypbenyl)-4acid ester (33a, 70mg, 0.070 mM) is stirred at room temperature under nitrogen in 1 mL of methylene chloride and the solution treated with chloromethyl ethyl ether (3 2 pl, 0.35 mM) and diisopropylethyl amine (61 pil, 035 mM). After 1 hour the reaction is treated with addtional diisopropylethyl amine (5 pl). The reaction is stirred for 2 days, when it is still incomplete as shown by TLC. Additional chloromethyl ethyl ether (15 pl) and diisopropylethyl amine (30 pl) is added and the reaction stirred an additional 12 days. The reaction is then partitioned between methylene chloride-water. The layers are separated and the water layer reextracted with methylene chloride. The organic layers are dried over sodium sulfate, combined and evaporated under vacuum. The crude product is chromatographed over silica gel (10g), eluting with (10-90) acetone-toluene. Fractions of 3 mL are collected, analyzing them by TLC. Impure product is found in fractions 9-20. These are combined, evaporated under vacuum and the residue rechromatographed over an E Merck size A prepacked silica gel column eluting with (10-90) acetone-hexane. Fractions of 3 mL are collected. The product is found in fractions 10-15, which upon combining and evaporating under vacuum leave 7-ethoxymethyl-A,'2.-iso-baccatin II-1 3-(4S,5R)-N-(t-butylaminocarbonyl)-2-(2,4acid ester (42a).
25 TLC (silica gel GF): (20-80) acetone-hexane; Rf: 0.59.
Proton NMR (CDCI 3 TMS): 8 1.07-1.18 3H); 1.18 9H); 1.30 3H); 1.68 (s, 3H); 1.72 3H); 1.89-2.03 2.16 3H); 2.19 3H); 2.26-2.39 1H); 2.64 1H); 2.73-2.85 1H); 2.84-2.96 1H);330-3.43 1H); 3.61-3.75 3.83 3H); 3.86- 3.92 1H); 3.92 3H); 4.00-4.10 1H); 4.25-434 1H); 4.36-4.44 1H); 4.60-4.74 3H) 4.84-4.93 (dd, 1H); 5.04-5.09 1H); 5.50-5.58 1H); 5.64-5.70 1H); 6.44-6.51 (dd, 1H); 6.51-6.56 1H); 6.75 1H); 7.16-7.24 1H); 7.32-757 (m 757-7.65 (t, IH); 8.03-8.10 2H).
owe* g*a. gMn 3 Prparation of 7-(O-edoxymethyl)-1 3-(-byminb oboy1 1p-PI isoWrinyl-'" 2 3 -iso-bccati (43) 7(O-ethoxymethyl)-A'2"t obaccatin f-13(4S,5R)-N-(t-butylaminoryl- 2 4 4744.P -78acid ester (42 a, 45 mg. 0.043 mm) is stirred in a mixture of acetic acid (1.5 rnL) and water (0.5 mL) at room temperature. The reaction is followed by TLC and is complete in 3 hours. The reaction is then freeze-dried. The crude product is purified by HPLC over an E. Merck size A prepacked silica gel column, eluting with a gradient of (25-75) to (35-65) acetone-hexane. Fractions of 3 ml are collected, analyzing them by TL.C. Product is found in fractions 7-11, which are combined and evaporated under vacuum to give 7-(O-ethoxymethyl)-13-(N-(t-butylamino-carbonyl)--phenyI isoserinyl)-A'"' 3 iso-beccatin [11 (43) as a socld TLC(silica gel 60): (30-70) acetone-bexane; Rf: 0.24 Proton NMR (CDCI 3 TMS): 8 1.07-1.20 (in, 15H); 1.24 3H); 1.58 3H); 1.67 (s, 3ff); 1.87-2.02 1ff); 2.02-2.14 lH); 2.16 3Hf); 2.55 3Hf); 2.77-2.94 (in, 2ff); 3.27- 3.42 (mn, 1ff); 3.60-3.72 1H); 3.84-3.90 1ff); 3.97-4.06 (cld, 1H); 4.24-4.31 (di, 1ff); 4.37- 4.44 1H); 4.54 IH);4.57-4.64 1ff); 4.64-4.72 (mn, 2Hf); 4.87-4.95 (dci, 1ff); 5.27-5.35 1H); 5.42-5.49 (dd, 1H); 5.49-5.55 1ff); 5.75 1ff); 7.14-7.42 (in, 5ff); 7.44-7.55 (t, 2H); 7.55-7.63 1ff); 8.07-8.15 2Hf).
Example 39 Preparation of 7-deoxy-7p,80-methano-baccatin [11 (44) A solution of 7-trifluorornethanesulfonyl-baccatin 111 (87 ing, 0.12 mM) in distilled dioxane (1.5 mL) is treated with an aqueous sodium azide solution (0.10 g, 1.5 rnM NaN 3 in 0.30 ml water.) The reaction is refluxed under nitrogen one hour. The mixture is diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The product is purified by column chromatography on silica gel 60 in 25% ethyl acetate-inethylene chloride. Evaporation of the fractions found by TLC to contain the product gives 7-deoxy-70,8f -methano-baccatin M11(44) as crystals.
25 Proton NMR (CDCI 3 TMS): 8 1.10 3M); 1.22 3M); 1.35 (in, 1ff); 1.64 1ffI); 1.78 1ff); 2.03 4ff); 2-21 3M); 2.26 3ff); 2.20-2.55 (mn, 5H); 4.04 1ff, Hz); 4.18 (di, 1ff. J-7.5 Hz); 4.30 Iff, J-8.5 Hz); 4.74 (di, 1ff); 4.83 (mn, IMH); 5.63 (di, 1ffH, J-7.5 Hz); 6.35 IM); 7.49 (mn, 2M); 7.62 (in, IM); 8.13 (mn, 2ff).
Carbon NMR (=DC 3 TMS): 15.15, 15.28, 20.43, 20.82, 21.99, 25.90, 26.35, 31.63, 35.19, 38.57, 38.76, 42.20, 67.51, 75.30, 76.20, 76.49, 79.23, 79.91, 84.73, 128.50, 129.33, 129.99, 132.59, 133.54, 144.19, 167.20, 169.63, 170.00, 202.08.
too* 4744.P .79.
Example 40) Preparation of 7-ci-azido-baccatin M1 A mixture of 7-trifluoromethanesulfonyl-baccatin 111 (102 mg, 0.14 mM), sodium azide (13 mg, 0.20 mM), and 18-crown-6 (32 mg, 0. 12 mM) in l,3-dimethyl-3,4,5,6-tetrahydro-2(I H)pyrim-idinone (1.0 mL) is stirred at room temperature overnight under an inert atmosphere. The reaction is partitioned between ethyl acetate and water. The organic layer is dried over anhydrous sodium sulfate and evaporated. The crude product is purified by column chromatography on silica gel 60 in 15% ethyl acetate--methylene chloride. The product is further purified by crystallization from inethylene chioride-hexane giving 7-a-azido-baccatin III Proton NMR (CDCI 3 TMS): 8 0.96 6H); 1.59 38); 1.91(s, 3H); 2.13 3m); 2.25 3H); 2.10-2.35 (in, 4 2.47 (in, 18); 3.80 (mn, 2H); 4.07 1H, J-8.0 Hz); 4.33 (di, lH, J-8.0 Hz); 4.60 (s+mn, 2H); 4.99 (dci, 18); 5.35 (ci, 18); 5.48 (ci, IH, J-7.2 Hz); 6.79 (s, 7.59 (in, 2H); 7.69 (in, IH); 8.05 (mn, 2M.
Carbon NMR (=DC 3 TMS): 15.40, 17.31, 20.67, 22.20, 25.93, 29.81, 39.22, 40.63, 41.73, 55.57, 64.28, 65.91, 75.33, 76.91, 77.33, 78.22, 80.44, 80.94, 128.77, 129-58, 129.98, 130.28, 133.33, 145.43, 165.30, 168.75, 169.09, 207.11.
Example 41 Preparation of 13-(N-Boc-2'-TES--phenyl isoserinyl).& 2 "1, 3 _iso~baCCatin 111 (46) 13-(N-Boc-f -pheny1 isoserinyl)-A'" 3 -iso-baccatin m1 60 mg, 0.071mM)W is stirred at room temperature under nitrogen in freshly distilled pyridine (0.7inL). The solution is cooled in an ice bath and treated with triethylsilyl chloride (13 p1, 0.078mM). The reaction is followed by TLC. No reaction is seen after 1hr at 0*Candhr atroom temperature. Thus, TES cloride is repeatedly added in the portions above until a total of 12 equivalents are added, at which point the reaction in seen to go to completion. This requires a total reaction time of 18 hours.
The reaction is then partitioned between water-ethyl acetate. The layers are separated and the aqueous layer reextrac ted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum. Toluene is added and reevaporated. The crude product is chroinatographed over silica gel (l0g), eluting with (30-70) acetone-hexane. Fractions b* of 3 mL are collected, analyzing them by TLC. Fractions 7-1 1 are combined and evaporated 30 under vacuum to give 13-(N-Boc-2'-TE--penyl isoserinyl)-A'2 3-iso-baccatin M 1(46) as a solid.
TLC(silica gel 60): 30-70 acetone-hexane; RE: 0.43 Proton NMR (CI)CL; TMS): 8 0.2-0.49 (mn, 6H); 0.69-0.82 9H); 1.05 3H); 1.18 9H); 1.32 3H1); 1.62 3H); 1.63 3H); 1.87-2.02 (in. 111) 2.03-2.146(d, 18); 2.22 38); 2.46-2.60 1I); 2.64 3H); 2.79 111); 2.84-2.99 1W1, 3-50-3.57 (di, 1H1); 3.70-3.77 18); 4.324.46 (in, 3H)- 4,62 1H1); 4-92-5.00 (dd, 1H); 5-19-5.47 (bd, 111) 4744.P 5.49 IM); 5.53-5.63 2H); 7.24-7.43 SH); 7.44-7.53 2H); 7.53-7.62 1H); 8.07- 8.16 2H).
Exarnmple 42 Preparation of 7-(O-ethoxymethyl)-13-(N-Boc-2'-TES- -phenyl isoserinyl)-A 2 3 iso-baccatin i1 (47) 13-(N-Boc-2'-TES-phenyl isoserinyl)-A'' 3 -iso-baccatin 11 (46, 59mg, 0.061mM) is stirred at room temperature under nitrogen in methylene chloride (0.5mL) and the solution treated with diisopropylethyl amine (55pl, 031mM) and chloromethyl ethyl ether (28pl, 0.305mM). The reaction is followed by TLC and is found to be complete in 3.5 days. The crude reaction mixture is purified by HPLC over an E. Merck size A prepacked silica gel column, eluting with (20-80) acetone-hexane. Fractions of 3 mL are collected, analyzing them by TLC. The product is found in fractions 10-16, which are combined and evaporated under vacuum to give 7-(O-ethoxymethyl)-13-(N-Boc-2'-TES-f-phenyl isoserinyl)-A'""-iso-baccatin m (47) as a solid.
TLC (silica gel 60): (25-75) acetone-bexane; Rf: 0.50 Proton NMR (CDC 3 TMS): 8 0.22-0.49 6H); 0.70-0.80 9H); 1.08-1.16 (m, 3H); 1.20 9H); 1.27 3H); 1.30 3H); 1.66 3H); 1.69 3H); 1.90-2.04 1H); 2.04- 2.14 IH); 2.17 3H); 2.64 3H); 2.80-2.98 2H); 3.30-3.42 IH); 3.61-3.75 (m, 1H); 3.86-3.94 1H); 4.03-4.13 (dd, 1H); 4.27-4.36 18); 4.38-4.46 18); 4.56-4.65 (d, 1H); 4.62 18); 4.67-4.75 (md 1H); 4.90-4.98 (dd, 1H); 5.38-5.49 (bd, 18 5.51-5.60 (m, 2H); 5.80 18); 7.25-7.53 7H); 7.53-7.61 18); 8.08-8.16 2H).
Example 43 Preparation of 7-(O-ethoxymethyl)-13-(N-Boc-i-phenyl isoserinyl)-' 2 13 -isobaccatin E (41) 25 7-(O-ethoxymethyl)-1 3-(N-Boc-2'-TES--phbenyl isoserinyl)-AIu 3 '-iso-baccatin 111 (47, 62 mg, 0.061mM) is stirred at room temperature under nitrogen in (80-20) acetic acid-water (4 The reaction is followed by TLC and is found to be complete in 24 hours. The reaction is then freeze-dried. The crude product is purified by HPLC over an E. Merck size A prepacked silica gel column, eluting with (25-75) acetone-hexane. Fractions of 3 mL are collected, analyzing them by TLC. The product is found in fractions 17-24, which are combined and evaporated under vacuum to give 7-(O-ethoxymethyl)-13-(N-Boc--phenyl isoserinyl)-A'-u-isobaccatin n (41) as a solid.
TLC (silica gel 60): (25-75) acetonbe-hexane; Rf: 0.33 Proton NMR Cm,; TMS): 8 1.10-1.18 6H); 1.24 9H); 1.62 38); 1.68 (s, 3H) 1.88-2.04 18); 2.04-2.15 fL, 2.18 3H); 2.60 3H); 2.83-2.97 2H); 3.28- 3.42 18); 3.60-3.73 18); 3.84-3.90 18); 4.00-4.10(dd, 1H); 4.25-4.34 H18); 4744.P -81- 4.36-4.45 lH); 4.57-4.65 IH); 4.66-4.74 2H); 4.87-4.96 (dd, 1H); 5.36-5.50 2H); 5.50-5.57 1H); 5.77 IH); 730-7.55 7H); 7.55-7.64 1H); 8.07-8.17 2H).
Example 44 Preparation of 1 3-(N-(t-butylaminocarbonyl)-2 -TES- -phenyI isoserinyl)-,' 2 '-isobaccatin M (48) Following the procedure of Example 41 but starting with 13-(N-(t-butylaninocarbonyl)- &-phenyl isoserinyl)-A'"'-iso-baccatin IMl (32b) is prepared 1 3-(N-(t-butylaminocarbonyl)-2'- TES- hpbenyl isoserinyl)-A'2'-iso-baccatin I (48).
Example-45 Preparation of 7-(O-ethoxynethyl)-l 3-(N-(t-butylaminocarbonyl)-2'-TES--phenyI isoserinyl)-,&" 3 -iso-baccatin I (49) Following the procedure of Example 42 but starting with 13-(N-(t-butylaminocarbonyl)- 2'-TES-f-phenyI isoserinyl)-A' 2 ""-iso-baccatin III (48) is prepared 7-(O-ethoxymethyl)-1I3-(N-(tbutylaminocarbonyl)-2'-TES-Bphenyl isoserinyl)-A'l' 3 -iso-baccatin 111 (49) Example 46 Preparation of 7-(O-ethoxymethyl)-l3-(N-(t-butylaminocarbonyl)- Bpheny isoserinyl)-A' 2 3 -iso-baccatin 111 (43) Following the procedure of Example 43 but starting with 7-(O-ethoxymethyl)- butylaminocarbonyl)-2'-TES-f-pheny isoserinyl)-A' 2 "'-iso-baccatin IH (49) is prepared ethoxymethyl)-1 3-(N-(t-butylarinocarbonyl)- -pheny isoserinyl)-A"'"-iso-baccatin 1H (43).
Example 47. 7-Triethylsilyl-1 2,13-isobaccatin III, 13-(4S,5R}-N-carbobeazyloxy-2-(2,4acid ester (51 ab) A slurry of (48 ,5R)-N-carbobenzyloxy-2-(2,4-dimethoxypbenyl)-4-phenyl-5-oxazolidine carboxylic acid potassium salt (9.63 g 19.2 mmol) in EtOAc (1.2 L) is stirred vigorously during the addition of 5% NaHSO 4 solution until the pH is 2 The layers ae separated and the EtOAc is washed with more 5% NaHSO 4 solution. The EtOAc layers are combined, washed with half-saturated brine, dried Na 2
SO
4 filtered and evaporated at a reduced pressure. The residue is redissolved in EtOAc (50 mL), toluene is added and the solvent re-evaporated.
Toluene is added and evaporated two more times giving an oil (10.37 The oil is dissolved in CH2zC 2 (60 iL, purged with argon) plus toluene (75 mL, purged with argon) and then 4dimethylamiopyridine (0.965 g 7.91 mmol) added The solution is purged with argon and added to a solution of 7-TES-12,13-isobaccatiu il Q) (113 m201, purged with argon) in CH2CI6 (125 mL) plus olueae (65 mL). The acid is rinsed in with additional C]4 2
C
2 (2 x mL) and diem toluene (10 mediately after the solutioas me combined at room tempea*Iu,, 1,3-dicyclohexykabodfiime (4.66 SO 22.6 minol) is added Tic indicates conplet 4744.P -82reaction after one hour. The reaction is worked up after an addional 0.75 hour by dilution with toluene and chilling with an ice-water bath. The precipated solids (dicyclohexylurea, DCU) are removed by filtration. The filtrates are diluted with EtOAc and washed with 5% NaHSO, solution and 5% NaHCO, solution. More DCU precipitated during the NaHCO, wash which is removed by filtration through Celite. A half-saturated brine wash completes the workup. The organic layer is dried (Na 2 SOJ, filtered, and evaporated at a reduced pressure to yield an oil.
The oil is chromatographed on 790 g of 40-63 pm silica gel packed in two Michel-Miller (47 x 450 mm, Ace Glass) columns connected in series. The sample is applied in the minimum amount of acetone and eluted with 20% acetone/hexane (3 25% acetone/bexane (4 and 30% acetone/hexane collecting fractions of 50 mL each. Fractions 100-104 (050 g) contain an impurity which is removed by a second chromatography. Fractions 105-127 (14.31 g) contain DCU as an impurity which is removed by a second chromatography on 40-63 pm silica gel (two Michel-Miller 47 x 450 mm columns) using the minimum amount of EtOAc for application to the column. The product is eluted with 10% EtOAc/toluene collecting fractions of 50 mL each.
Eluted first in fractions 24-40 (1.30 g, is 7-Triethylsilyl-12,13-isobaccatin III, 13-(4S,5R)- N-carbobenzyloxy-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxyic acid ester, less polar isomer (51a) 'H NMR (CDC, 3 TMS) 5 8.05 2H), 7.63-7.37 8H), 7.22-6.99 (mn, 6H), 6.48,6.39 2H1), 5.97 1H), 5.54 1H, J 5.4 Hz), 5.45 1H, J 2.6 Hz), 5.01 3H, -OCH2Ph), 4.88 1H), 4.43 1H), 4.38 1H, J 8.5 Hz), 4.27 1H, J 8.5) 3.85 (m, 1H), 3.82 6H), 2.77 1H, J 18.1 Hz), 2.52 1H), 2.47 1H), 2.27 IH, J 17.4 Hz) 2.19 3H), 2.15 3H), 1.88 1H), 1.78, 1.61, 1.28, 1.16 (4s, 12H), 0.89 9H), 0.53 6H); mass spectrum: 1146.4927, C6H 7 ,NO,Si H requires 1146.4882, 1146, 1116, 1038, 1010, 418, 374, 284, 254, 151. 105, 91, 43 m/z; Fractions 41-62 (5.14 g, 28%) contain a mixture of isomers.
Fractions 63-130 (7.08 g, 38%) contain 7-Triethylsilyl-12,13-isobaccatin III, 13-(4S,5R)- N-carbobenzyloxy-2-(2,4-dimethoxypbenyl)4-pbenyl-5-oxazoidboxylic acid ester, more polar isomer (51b) 'H NMR (CDCITMS) 8 8.02 2H), 7.62 11), 7.48,7.40 8H), 7.24-7.14 (m, 6.74 2H), 6.44 (mn, 2H), 5.87 11), 5.48 1, J 4.7 Hz), 5.38 11, J 5.9 Hz), 4.88 d, 1H, 12.2 Hz), 4.81 1H), 4.73 1, J 11.8 Hz), 4.61 11, J 5.9 Hz), 4.34 11), 433 (dIH J- 8.6 Hz), 4.22 1, J 8.9 Hz), 3.82 3H), 3.72 (d IH J 2 Hz), 2.58 1H, J 17. 5 Hz), 2.43 (nm, 2H), 2.16 3H), 2.14 1H), 1.89(s, 3H), 1.82 (m, 1H), 1.56,1.42,111,1.10 (4s, 12), 0.88 031 W); ~mass spectnrun 1146.4904, C1,,NO, Si H requirs 1146.4S8, 1146, 1116, 1103, 4744.P -83- 1038, 1010, 446, 418, 374, 284, 254, 151, 105, 91, 43 m/z.
Tic: Rf (15% Ethyl Acetate/Toluene) 0.22, 0.33 for the two product isomers.
Example 48. N-Debenzoyl-N-benzyloxycarbonyl-12,13-isotaxol (52) A solution of 7-triethylsilyl-12,13-isobaccatin III, 13-(4S,5R)-N-carbobenzyloxy-2-(2,4acid ester (51ab; 646.5 mg, 0.564 mmole) in MeOH (35 mL) is cooled to 0-10C with an ice bath. Meanwhile, a 0.1 molar solution of HCI in MeOH is prepared by the slow addition of acetyl chloride (0.46 mL) to slightly cooled MeOH (30 mL). This solution is added to the solution of 51a,b in one portion. The resulting solution is allowed to warm to room temperature. The disappearance of the starting material and the appearance of the ortho-ester intermediate and the product is followed by TLC acetone/hexane and 5% CH 3
CN/CH
2 CI)1 and after 1.5 hours, water (6.2 mL) is added to the blue solution. The less polar ortho-ester intermediate is converted to the desired product within an additional hour. The reaction mixture is diluted with EtOAc (200 mL) and saturated aq. Na 2
CO
3 (200 mL) solution is added. About one half of the organic layer is removed by rotoevaporation to maximize recovery. The layers are separated, the aqueous layer back-extracted with EtOAc and the combined organic layers are washed with saturated aq. NaCl solution. The organic layer is filtered through Na 2 SO, and evaporated under vacuum. The crude solids (0.589 g) are flashchromatographed using 6 inches of silica gel in a 30 mm column. lThe elution solvent is 42.5% EtOAc/hexane (250 mL), 45% EtOAc/hexane(250 mL) and 50% EtOAc/hexane (250 mL) and mL fractions are collected. Fractions 13-16 are combined, the solvent is evaporated and replaced with acetone/hexane. Evaporation of the acetone-haxane under reduced pressure gives N-debenzoyl-N-benzyloxycarbonyl-12,13-isotaxol (0.434 g, 87%) as a white solid.
Tic: Silica gel; 40% acetone/hexane; starting material Rf 0.53, 52 Rf 0.33, orthoester Rf 0.39.
.I l NMR (CDC13, TMS), 8 8.18 J 7.2 Hz, 2H), 7.33-7.60 9H), 7.19 3H), 6.96 2H), 5.75 lH, J 10.0 Hz), 5.56 1H, J 5.9 Hz), 5.51 1H, J 10.0 Hz), 5.44 IH), 4.91 1H), 4.84 (dd, 2H, J 12.6 Hz), 4.74 1H), 4.33-4.42 3H, H7), 3.67 1H, J 3.7 Hz), 3.47 (bs, 1H), 3.26 (bs, 1H), 2.94 1H, J 19.0 Hz), 2.74 1H), S. 30 2.59 3H), 2.50 1H), 2.23 3H), 1.92 1H), 1.88 lH, J 19.0 Hz), 1.62 3H), 1.58 3H), 1.25 3H), 1.04 3H).
akExamle 49. N-Debenzoyl-N-benzyloxycarbonyl-2'-iethylsilyl- 12,13-iwtaxol (53) *A solution of the N-debezoyl-N-benzyloxycabonyl-12,13-IWtaxol (52; 6.61 S 7.48 mmol) in freshly distilled pyridine (WwL) aider a nitrogen atmosphere is cooled to 0 *C with an ice-water bath. Cho*triethylsila (5.0 mL, 30.6 mmol) is added dropwise from a syrins 4744.P -84over a three minute period. The temperature monitored internally does not rise above 1 OC. The cooling bath is removed after the addition is complete. TIc indicates complete reacton after one hour. Workup involves dilution with EtOAc (600 mL) and washing with half-saturated CuSO, (2 x 100 mL), saturated CuSO, (2 x 50 mL), water (2 x 100 niL), NaHCO 3 (1 XlOOinL), and brine (1 x lOOmL). All aqueous layers are back extracted. The organic layers are combined, dried (Na 2
SO
4 filtered and evaporated at a reduced pressure to yield 8.23 g (theory 7.47 g) of a greasy white solid. The solid is chroinatographed on 400 g of 40-63 PM silica gel in a Michel-Miller (47 x 450 mm) column. The sample is applied in the minimum amount of EtOAc and eluted with 30% EtOAclbexane collecting fractions of 50 niL eah. N-Debenzoyl- N-benzyloxycarbonyl-2'-triethylsilyl-12,13-isoIo is obtained in fractions 25-45 (6.45 g, 86%).
tic: silica gel; 1:1 EtOAc~hexane; starting material Rf 0.27, product Rf 0.62.
'H NMR (CDCI 3 ,TMS) 8 8.17 d, 2H, J 7.1 Hz), 7.55-6.97 (mn, 15H), 5.82 (di, 1H, J -9.8 Hz), 5.56 (di, IlH, J 5.51 (di, I1H, J 9.9 Hz), 5.46(s, IlH), 4.94 (in, I 4.80 (in, 2H), 4.64 IMH), 4.3 8 (mn, I 3.69 (di, 1IH, J 6.0 Hz), 3.49 (di, I H, J 2.92 (di, I H, J 18.5 Hz), 2.76 111), 2.64 3M), 2.50 mn, lH), 2.22 3M), 1.96 (in, IM), 1.88 (in, IH), 1.63, 1.59, 1.26, 1.04 (4s, 12H), 0.74 mn, 9H), 0.35 (mn, 6H).
Example 50. N-Debenzoyl-N-benzyloxycarbonyl- 12,1 3-isowaol-7-O-triflate (54) A solution of N-debenzoyl-N-benzyloxycarbonyl-2'-triethylsilyl- 12,1 3-isotaxol (53; g) in CH 2
CI
2 (12.2 inrL) and pyridine (4.12 niL) is cooled to -30'C in a 33% MeOlwater/cixy ice bath. Triflic anhydride (2.02 mL) is slowly added via a syringe over 5 minutes keeping the temperature below -14 0 C. At the end of the addition, the reaction mixture is allowed to warm to room temperature. Aliquots of the yellow-orange solution are taken over 6 hours and quenched into EtOAc and saturated aq. CuSO, solution. The organic layer is chocked by TLC (25% EtOAclhexane) and just a trace of starting material is noted after 6 hours The reaction mixtur is quenched into EtOAc (100 rnL) and saturated aq. CuSO, solution (100 mL). The layers are separated and the organic layer is washed separately with saturated aq. copper sulfate solution (100 mL) and water (100 rnL). The water wash is back-extracted with EtOAc (25 niL) and combined with the main organic layer and then washed with saturate aq. N&HC 3 and NaCI solutions respectively. The organic layer is dried throgh Na 2 SO, and the solvent is removed by rotoevaporazion. The~ residual oil is dissolved in a small amount of acetone and hexane is added until cloudbaes develops. 'The solvent is removed and the residue is subjected to high vacumi to give N-Debenzoyl-N-benzyloxycarbonyl-12,13-iwtaxol-7-O-Iriflate (54) as a yellow solid (2.20 St 97%.
Tic: Silia 8d;5 EzOAc/hexane; sdarting inateii RI 0.35, triflfte 54 Rf 0.57.
'H NMR (CDC1 3 TMS), 8 8.16 J 7.1 Hz, 211), 7.60-7.50 3H), 7.48-7.29 (in, 4744.P SH), 7.17 3H), 6.96 2H), 5.86 1H), 5.83 J 10.0 Hz, 11), 5.58 J 6.7 Hz, 1H), 5.54 1H), 5.50 J 8.1 Hz, 1H), 4.90 1H), 4.86 J 12.8 Hz, 1H), 4.79 J 12.5 Hz, 1H), 4.64 J 1.8 Hz, 1H), 4.43 J 8.7 Hz, 1H), 4.38 J 8.7 Hz, 1H), 3.83 J 5.7 Hz, 1H), 2.99 1H), 2.89 J 20.6 Hz, 1H), 2.66 3H), 2.22 1H), 2.19 3H, 1.87 J 19.2 Hz, 1H), 1.77 3H), 1.66 3H), 1.25 3H), 1.07 3H), 0.74 J 7.8 Hz, 9H), 0.33 6H).
Example 51. 2'-Triethylsilyl-N-debenzoyl-N-benzyloxycarbonyl-7-deoxy-70,8 -methano- 12,13-isotaxol (55) and 2'-triethylsilyl-N-debenzoyl-N-benzyloxycarbonyl-7-deoxy-A"-12,13isotaxol (56) A solution of N-debenzoyl-N-benzyloxycarbonyl-12,13-isotaxol-7-O-triflate (54; 1.02 g) in ethylene dichloride (95 mL) is stirred with silica gel (35 g, EM, 40-63 pM) at 55-65 0 C in an oil bath for 1.5 hours. An aliquot is filtered and a TLC CH 3
CN/CH
2 C1 2 of the filtrate shows the reaction to be complete. The reaction mixture is filtered through a medium sinteredglass funnel and acetone (600 mL) is used as a rinse. The solvent is removed under vacuum.
The crude solids (1.1 g) are flash-chromatographed using 6 inches of silica gel in a 55 mm column. The elution solvent is 6% CHCN/CH 2 CI, (750 mL), 8% (750 mL), 10% (750 mL) and 12% (750 mL) and 40 mL fractions are collected. The combined fractions are concentrated, acetone/hexane added and concentrated again to give white solids. Fractions 29-37 contain 2'-triethylsilyl-N-debenzoy-N-benzyloxycarbonyl-7-deoxy-A' -12,13-isotaxol (56; 0.174 g, 18%).
'H NMR spectrum is identical to the spectrum of 56 described in Example 57.
Fractions 41-64 contain 2'-Triethylsilyl-N-debenzoyl-N-benzyloxycarbonyl-7-deoxy-70,8methano-12,13-isotaxol (55; 0.659 g, 67%).
Tc: silica gel; 25% EtOAc/hexane; starting material Rf 0.63, cyclopropane 55 Rf 0.35, olefin 56 Rf 0.43.
'H NMR (CDCI 3 TMS), 8 8.21 J 6.6 Hz, 2H), 7.54-7.18 11H), 6.93 2H), 5.82 J 9.9 Hz, 1H), 5.60 J 6.5, 1H), 5.51 J 10.6 Hz, IH), 5.23 J 1.97 Hz, 1H), 4.79 1H), 4.67 2H), 4.63 J 1.8 Hz, 1H), 4.39 J 8.6 Hz, 1H), 4.13 J 8.7 Hz, 1H), 2.96 J 18.6 Hz, 1H), 2.75 1H), 2.62 3H), 2.47 (dt, J 16.0), 4.05 (Hz, IH), 2.17 4H, H7), 2.11 iH), 1.97 J 18.9 Hz), 1.73 1H), 1.59 3H), 131 (s, 3H), 1.11 3H), 0.73 J 7.9 Hz, 9H), 0.34 6H).
1C NMR (CDCI, TMS), 8 203.7, 170.1, 169.7, 168.8, 167.1, 155.6, 141.5, 138.7, 136.1, 133.6, 130.5, 129.2, 128.7, 128.6, 1283, 127.9, 127.4, 126.4, 122.5, 85.1, 80.5, 78.9, 78.7, 783, 75.6, 75.2. 66.8, 57.4, 54.9, 39.7, 36.6, 33.1, 32.3, 303, 29.7, 29.4, 25.9, 22.4, 213, 4744.P -86- 20.9, 14.1, 13.0, 6.5, 4.1.
Example 52. 2'-Triethylsiyl-N-debenzoyl-7-deoxy-70,8 -methano-12,13-isotaxol (57) 27548- PJD-152 Ammonium formate (0.96 g) and 10% Pd/C (0.44 g) are added to a solution of 2'triethylsilyl-N-debenzoyl-N-benzyloxycarbonyl-7-deoxy-70,8&-methano-12,13-isotaxol (55; 1.343 g) in MeOH (18 mL) and THF (12 mL). The mixture is stirred for 10 minutes at room temperature and then cooled to 0 0 C. The reaction mixture is monitored by TLC EtOAc/hexane) and is complete after 2 hours of stirring. The mixture is filtered through Celite and rinsed with EtOAc (150 mL). The filtrate is washed with saturated aq. NaHCO 3 solution (100 mL). 'The aqueous layer is back-extracted with EtOAc and the combined organic layers are washed with saturated aq. NaCI solution. The organic layer is dried through NaSO,, the solvent removed under vacuum and the solids subjected to high vacuum, giving 2'-triethylsilyl-Ndebenzoyl-7-deoxy-70,8 -methano-12,13-isotaxol (1.114 g).
TIc: silica gel; 50% EtOAc/hexane; starting material Rf 0.64, amine 57 Rf 0.42.
'H NMR (CDC 3 TMS), 8 8.09 2H), 7.65 1H), 7.53 2H), 7.34 4H), 7.17 IH), 5.59 J 6.65 Hz, 1H), 5.19 J 1.91 Hz, 1H), 4.76 J 3.1 Hz, 1H), 4.4 2H), 4.30 J 5.4, 1H), 4.08 J 8.6 Hz, 1H), 3.81 J 6.6 Hz, 1H), 2.72 (s, IH), 2.53-2.39 2H), 2.30 3H), 2.16 3H), 1.92 J 18.5 Hz, 1H), 1.69 3H), 1.28 3H), 1.10 3H), 0.90 J 8.0 Hz, 9H), 0.56 6H).
Example 53. 2'-Triethylsilyl-N-debenzoyl-N-(t-butyl)oxycarbonyl-7-deoxy-70,8,-methano- 12,13-isotaxol (58) A solution of 2'-triethylsilyl-N-debenzoyl-7-deoxy-70,8--methano-12,13-isotaxol (57; 0.438 triethylamine (88 pl) and di-t-butyldicarbonate (0.125 g) in THF (10 mL) is stirred at room temperature ovemrnight The reaction is determined to be complete by TLC EtOAc/hexane). The mixture is diluted with EtOAc (100 mL) and the resulting organic layer is washed with saturated aq. NaHCO and NaCI solutions. The organic layer is dried through NaSO, the solvent removed under vacuum and the crude solids subjected to high vacuum, giving 2'-triethylsilyl-N-debenzoyl-N-(t-butyl)oxycarbonyl-7-deoxy-70,8f-methano-12,13isotaxol (0.495 g).
TIc, silica gel, 50% EtOAc/hexane; starting materiIal Rf 0.45, 58 Rf 0.66 'H NMR (CDCI 3 TMS): 8 8.18 J 7.2 Hz, 2H), 7.59-7.24 8H), 5.62 J 6.8, S1H), 5.55 J 10.0 Hz, IH),6 3 J 10.0 Hz, 1H), 5.24 J 2.0 Hz, 1H), 4.81 IH), 4.60 1H), 4.42 J 8.6 Hz, 1H), 4.11 (d,J 8.6 Hz, 1H), 3.88 (d J 6.7 Hz, 1H), 2.93 J 183.5 Hz, 1H), 2.76 1H), 2.61 3H), 2.47 (dt, J 4.3 and 16.0 Hz, 4744.P -87- 1KH), 2.17 4H), 2.00 J 16.0 Hz, 1H), 1.71 1H), 1.52 3H), 1.26 1H), 1.12 3H), 1.10 3H), 0.74 J 3.4, 9H), 0.34 6H).
Examole 54. N-Debenzoy1-N-(t-butyl)oxycarbony1- oxy-7,81 .meao. 12,13-isotaxol (17) A solution of 2'-triethyls iyl-N debenzoy-N-(t-butyI)oxycarbonyl-7-deoxy-7,8 methano-12,13-isotaxol (58; 0.49 g) in CH 3 CN (2.45 mL) is treated with Et 3
N(I{F)
3 (1.47 mL.) and stirred at room temperature. The reaction is determined to be complete after 30 minutes by TLC (50% EtOAclhexane). The reaction mixture is diluted with EtOAc (100 niL) and the organic layer washed with saturated aq. NaHCO 3 and NaCI solutions. The organic layer is dried through NaSO,, the solvent removed under vacuum and the crude solids are subjected to high vacuum (0.422 The crude solids are flash-chromatographed using 6 inches of silica gel in a mm column. The elution solvent is 42.5% EtOAcohexane (300 mL), 45% (200 miL) and (200 mL) and 20 mL fractions are collected. Fractions 9-14 contained 0.308 g (71 of N-debenzoyl-N-(t-butyl)oxycarbonyl-7-deoxy-7,8 -iethano-12,13-isotaxol.
Tic: silica gel; 50% EtOAc/hexane; starting material Rf 0.70, 17 Rf 0.47.
'H NMR (CDCI 3 TMS): 8 8.19 J 7.3 Hz, 2H), 7.61-7.29 8H), 5.62 J 6.7 Hz, 1H), 5.42 2H), 5.22 J 2.0 Hz, 1H), 4.79 I 3.2 Hz, 1H), 4.69 J 3.4 Hz, I1H), 4.42 J 8.6 Hz, I1H), 4.09 J 8.6, 1H), 3.87 J 6.7 Hz, IH), 3.24 J 4.4 Hz, 1H), 2.96 J 19.1 Hz, 1H), 2.75 11), 2.56 3H), 2.45 (dt, J 4.3 and 16.1 Hz, 2.17 5H), 2.10 J 16.0 Hz, lH), 1.69 4H), 1.58 3H), 1.33 (m, 4H), 1.13 9H).
"C NMR (CDC 3 TMS), 8 203.5, 171.0, 170.1, 169.7, 167.3, 155.0, 141.8, 138.8, 133.6, 130.4, 129.1, 128.8, 128.7, 128.0, 126.5, 122.6, 85.2, 80.4, 80.0, 78.9, 78.6, 78.4, 75.7, 73.7, 55.6, 55.0, 39.8, 36.7, 32.9, 32.4, 30.1, 29.0, 28.0, 25.8, 22.4, 21.1, 20.9, 14.2, 12.9.
mass spectrum 832.3538 (COH 53
NO,
4 H requires 832.3544), 986, 832, 776, 758, 732, 551, 387, 180, 105, 77, 57, 43 m/z.
Examle 55, 2' -Triethylsily-N-benzoyl-N-Q-butyl)aminocarboyl-7-oxy-7 8 8-iethano- 12,13-isotaxol (59) (2aR-[2acL,40,4aS, ,7a,9,(czK$S), 112a 1 ZlcL,1214] butyl)aminocrbunylhninyl-a-trieyoyetlenepopanoic acid, 6,12-bis(actyloxy)-12- (benzoyloxy)-2a3,4,4,567,10, 11,12,12a, I 2b-dodecahydro- 1 -hydroxy-8,1 3,13-rimethyl-5-oxo- 4,4;7,1 1-bido-1H-cyckdeca3,4be~zl.2-bIoz-9-yI Eter)) A sohati of crude 2'yieyyl -Ndebenoy1-7ddxy- 7*8mhano- I12,13-Lotaxol a (57; 1.11 S) ad t-butylisocywante (0.6 mL, 525 mmol) in 46 (15 and EtN (18 pL) is 5 4744.P -88stirred overnight at rt. The solvent is removed under reduced pressure and the residue placed under high vacuum. 2'-Triethylsilyl-N-benzoyl-N-(t-butyl)amnocaronyl-7-deoxy-70,8methano-12,13-isotaxol (59: 1.225 g) is obtained: 'H NMR (CDCI 3 TMS) 8 8.18 2H, J 6.8 Hz), 7.57 1H), 7.49 2H), 7.35 (m, 2H), 7.27 3H), 5.64 1H, J 6.6Hz), 5.56 1H, J 9.3 Hz), 5.23 1H J 1.9 Hz), 5.18 1H, J 9.2 Hz), 4.82 1H), 4.60 1H, J 1.9 Hz), 4.42 1H, J 8.7 Hz), 4.12 1H, J 8.5 Hz), 3.90 1H, J 6.6 Hz), 2.95 1H, J 19.5 Hz), 2.76 1H), 2.64 3H), 2.44 (dt, 1H, J 16.2 Hz), 2.17 3H), 2.16 2H), 2.11(d, 1H, J 16.0 Hz), 1.34 3H), 1.13 3H), 1.00 9H), 0.74 9H), 0.30 6H).
Example 56. N-Debenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-7,8-methano-12,13-isotaxol (36) (2aR-[2aa,40,4aS,60,7a,9,(aR',KS),11a, 12a,12aa,12ba Butyl)aminocarbonylamino]--hydroxybenzenepropanoic acid, 6,12b-Bis(acetyloxy)-12- (benzoyloxy)-2a,3,4,4a,5,6,7,10,11,12,12a, 12b-dodecahydro-l 1 -hydroxy-8,13,13-trimethyl-5-oxo- 4,4a*7,11 -bismethano- I H-cyclodeca[3,4]benz[ 1,2-b]-oxet-9-yl Ester Using the procedure described for the preparation of 17, a solution of crude 2'-triethylsilyl-N-debenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-70,8.-methano- 12,13-isotaxol (59; 1.225 g) and triethylamine trihydrofluoride (3.66 mL) in CH 3 CN (6 mL) is prepared at OC, then allowed to warm to rt while stirring for 1 hr. Following workup and flash chromatography over silica gel, N-debenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-7,8n -methano-12,13-isotaxol (36; 0.919 g, 1.10 nmmols; 81% from 55) is obtained: 1H NMR (CDCl 3 TMS) 8 8.17 2H, J 7.0 Hz), 7.59 1H, J 7.3 Hz), 7.50 (t, 2H, J 7.6 Hz), 7.36 4H), 7.29 1H), 5.62 1H, J 6.5 Hz), 5.48 (dd, 18, J 2.7, 25 9.2 Hz), 5.26 1H, J 9.2 Hz), 5.20 1H, J 1.9 Hz), 4.77 1H), 4.69 1H), 4.41 1H), 4.09 18, 3 8.6 Hz), 3.85 1H, J 6.6 Hz), 2.91 18, J 19.0 Hz), 2.72 18), 2.53 3H), 2.40 (dt, 1H, J 16.1 Hz), 2.16 3H), 2.11 (mi, 2H), 2.07 1H, J 16.1 Hz), 1.71 18, J 6.1 Hz), 1.54 3H), 1.30 3H), 1.30 1H), 1.11 3H), 1.04 9H).
.C NMR (CDC,, TMS) 8 203.6, 171.0, 170.4, 169.8, 167.3, 156.2, 141.8, 139.2, 133.6, 130.4, 129.0, 128.78, 128.76, 127.8, 126.6, 122.4, 85.2, 80.5, 78.9, 78.4, 783, 75.7, 74.4, 55.2, 55.0, 50.4, 39.7, 36.7, 32.8, 32.5, 30.1, 29.2, 28.8, 25.8, 22.4, 21.1, 20.9, 14.2, 12.8.
mass spectrum (FAB), fomund: 831.3701 (COIHJ4 2 H requires 831.37.04), 732, 263, 235, 205, 179, 136, 119, 106, 105, 57 m/z.
4744.P -89- Example 57. 2'.Triethylsilyl-N-debenzoyl-N-benzyloxycarboyl-7-deoxy-A'7-12,13-isotaxo (56) A solution of N-debenzoyl-N-benzyloxycarbonyl- 12.1 3-isotaxol-7-O-triflate (54; 2.348 g) and DBU (3.11 mL) in toluene (180 mL) is heated with a 60 0 C oil bath for 4 hours. A trace of starting material is noted by TLC CHCN/CH2C1. The reaction mixture is diluted with EtOAc (100 mL) and the resulting organic layer is washed with saturated aq. CuSO, solution, water, saturated aq. NaHCO 3 and NaCI solutions. The organic layer is dried through Na 2
SO,
and the solvent removed under vacuum. The crude solids (2.07 g) ar flash-chronatographed using 6 inches of silica gel in a 55 mm column. The elution solvent is 4% CH 3
CN/CHCI
2 (1000 mL), 5% (1000 niL), 6% (1000 mL), 8% (1000 ML) and 15% (1000 mL) and 40 mL fractions are collected. Fractions 27-74 contained 2'-triethylsilyl-N-debenzoyl-Nbenzyloxycarbonyl-7-deoxy-A' 7 12,13-isotaxol (56- 1.43 g, 68%) as a white solid.
Tic: silica gel; 5% CH 3
CN/CH
2
CI
2 starting material Rf 0.64, olefin 56 Rf 0.47, cyclopropane 55 Rf 0.36.
1H NMR (CDC 3 TMS), 8 8.21 J 7.1 Hz, 2H), 7.60-7.47 3H), 7.41-7.26 (m, 611). 7.19-7.13 6.97 2H), 6.09 (dd, J 5.3 and 9.9 Hz, IR), 6.02 J 9.8, lH), 5.82 J 9.8, 1H), 5.72 J 5.8 Hz, 1H), 5.51 J 10.3, 1H), 5.18 1H), 5.12 I 5.3 Hz, IH), 4.83 J 12.5 Hz, 114), 4.76 J 12.4, 1H). 4.64 J 1.8, 1H), 4.52 J 8.4, 1H), 4.37 J 8.3 Hz, IH), 3.67 J 5.6 Hz, 1H), 2.95 J 18.6 Hz, lH), 2.75 1H), 2.67 3H), 2.18 3H), 1.90 J 18.5 Hz, 1H), 1.76 3H), 1.53 3H), 1.28 3H), 1.03 3H), 0.73 J 8.0, 9H), 0.35 6H).
'C NMR (CDCI TMS), 8 207.7, 169.9, 169.6, 168.8, 166.7, 155.7, 142.2, 138.8, 138.6, 136.1, 133.7, 130.3, 129.2, 128.7, 128.6, 128.4, 127.9, 127.9, 127.4, 126.4, 125.6, 122.1, 81.2. 80.8, 79.1, 77, 75.0, 73.7, 66.8, 57.3, 56.0, 54.1, 39.6, 36.5, 32.6, 29.9, 23.3, 21.0, 20.8, 18.5, 14.1, 6.4, 4.1.
Fractions 82-90 contained 2'-tiethylsilyl-N-z enzlxcroye-ex-l8x methano-12,13-isotaxol (55; 0.14 g, 'H NMR spectrum is identical to the spectrum of described in Example 51.
Examic 2'-Triethylyi-N-debenzoyl-7-deoxy-A't-123-iwtaxol (2&R-[2act, 446p,7u49(XKPS) Za12xa ,l22bCj -ammO trikthys~lybj L boi acid, 6,12b-bis(aeyeIoy)-12beaoxyloxy)- 2a,4a,6,7,10,I I,1212a,12b-dcahydro-1 1-hydroxy-4,8,13,13-tetaadiyt-5-oxo- 7 l 1-oxbmno- 1H-cyclodeca3,4be41-b-oxet-9-yl Easer))
*Z
4744.P Using the procedure described for the preparation of 57, a solution of 2'triethylsily-N debenzoyl-N-benzyloxycarbonyl-7-deoxy-A612,13-sotaoI (56; 1.721 g, 1.75 nmuols) and ammonium formae (1.07 g, 16.97 mmols) in MeOH (23 mL) and T-F (12.6 mL) is stirred at rt with 10% palladium on carbon for 10 min and then at 0 0 C for one hr. Following workup, 2'triethylsily-N-debnzoyl-7-eoxy-Al'.12,13-isoaxo (60; 1.47 g) is obtained.
'H NMR (CDCI, TMS 8 8.11 2H, J 8.0 Hz), 7.67 I, 1 -7.4 Hz), 7.54 2H), 7.35 4H), 7.18 1H), 6.05 2H), 5.68 1H, J 5.1 Hz), 5.13 1ff), 5.10 IH, J 4.5 Hz), 4.51 1f, J 8.2 Hz), 4.32 3f), 3.62 IH, J 5.3 Hz), 2.71 1f), 2.45 1H, I 17.9 Hz), 2.30 3f), 2.17 3H), 1.83 1H, J -17.9 Hz), 1.69 (s, 3H), 1.44 3H), 1.27 3H), 1.02 3H), 0.91 9H), 0.56 6H).
2'-Triethylsilyl-Nebo yl-oxycaoyl2,13-isotaxo {2aR-[2aar, 4aO,6,7(crx,9,(aRKS), I1 a, 12cr., 2act, 1 2ba] [(t-Buryl)oxycarbonylanino]-a-hydroxybenzenepropanoic acid, 6,1 2b-bis(acetyloxy)-1 2-(benzoyloxy)- 2a,4a,5,6,7,10,11,12,12a,2b-decahydro-1 -hydroxy-4a,8,13,1 3-terramethyl-5-oxo-7,11 -methano- 1 -cyclodecaf3 ,4]benz1 ,2-bl-oxet-9-y Ester Using the procedure described for the preparation of 58, a solution of crude 2'triethysilyl-N-debenzoy1 -7-deoxy- 647.. 12,13-isotaxol (60; 0.515 g) and di-i-butyl dicarbonate ("BOC anhydride," 0.147 g, 0.675 rmole) in THF (12 mL) and EtN (0.10 mL) is stirred overnight at RT. Additional di-t-butyl carbonate (0.013 g, 0.059 imole) is added and the solution stirred another 2 hr. Following workup, 2'-triethylsilyl-N-debenzoyl-N-tbutyl)oxycarbonyl-7-deoxy-_A6.712,13-isotaxol (61; 0546 g) is obtained.
'H NMR (CDCI 3 TMS) 8 8.17 2H, I 7.3 Hz), 7.58 1H, J 7.4 Hz), 7.49 (t, 2H), 7.38 2ff), 7.27 3f), 6.10 (dd, IH, J 5.2, 9.9 Hz), 6.04 1f, J 9.8 Hz), 5.73 1ff, J 4.3 Hz), 5.55 1ff, J 10.0 Hz), 5.44 1H, J 10.5 Hz), 5.19 1f), 5.14 (d, 1H, I 5.1 Hz), 4.62 1ff), 4.55 1ff, I 8.1 Hz), 4.35 1ff, J 8.3 Hz), 3.69 If, J 5.4 Hz), 2.94 1H, I 18.8 Hz), 2.77 11), 2.67 3H), 2.19 3f), 2.07 1ff, J 10.9 Hz), 1.76 3H), 1.28 31), 1.16 9H), 1.05 3H), 0.74 91), 0.37 6H).
E N-Debenzoy-N-(r-butyl)oxycarbonly-7-deoxy- 1 12,13-isotaxol. (18) {2aR-[24a, 4aP,6,7,9,(aR4S), 1c.,12c,12aa,12bJ )-P-((-Butyl)oxycrbonyl-amino)ahydroxybenzeepropanoic acid, 6,12b-bis(aceryloxy)- 12-(beIzoyoiny)- 2a,4a,,6,7,10,1 l,12,12,I12b-decahydr.o I I-bydroxy-4a8,13,13-searustdiyI.Sox.7,1 Ij 1-ncno- I Hcycoeca[3.41beol boxec-9-yI Flw Using the procedure described for the preparation of 17, a solution of 2'-riehylsilyl-N- 4744.P -91debenzoyl-N-(t-butyl)oxycarbonyl-7-deoxy-A"- 12,1 3-isotaxo (61, 0.546 g) from the preceding experiment and triethylamine trihydrofluoride (1.64 mL) in CH 3 CN (2.7 nL) is stirred at 0 for 1 hr. Following workup and chromatographic purification over flash silica gel, Ndebenzoyl-N-Qt-butyl)oxycarbonyl-7-deoxy-A' 7 12,13-iotaxol (18; 0.445 g, 0.547 mmole, 87% from 56) is obtained.
'H NMR (CDC1 3 TMS) 8 8.18 M J 7.2 Hz). 7.61 IH, J 7.3 Hz), 7.50 (t, 2H), 7.35 5H), 6.09 (dd, 1H, J 5.1, 9.9 Hz), 6.04 1H, J 9.8 Hz), 5.73 1H, J Hz), 5.40 2H), 5.18 1H), 5.13 (di, 11L J 5.1 Hz), 4.70 1H), 4.55( d, IH, J 8.3 Hz), 4.34 1H, J 8.4 Hz), 3.68 IH. J 5.4 Hz), 2.97 IH, J 18.9 Hz), 2.74 1H), 2.61 3H), 2.20 3H), 2.09 1H, J 18.0 Hz), 1.75 3H), 1.53 3H), 1.32 3H), 1.20 (s, 9H), 1.05 3H).
mass spectrum (FAB), found 832.3538 (COH 53
NO,
4 H requires 832.3544), 776, 732, 180, 150, 105, 57 miz.
Example 61. 2'-Triethylsilyl-N-debenzoyl-N-(t-butyl)a nocabonyl-7-deoxyA'.- 12,13-isotaxol (62) {2aR-[2aa, 4ao,6fr7a,9,(caR'S ll12c,12aa,2baI}P-([(t- Butyl)aminocarbonylamino]-t-triethylsilyloxybenzeepropaoic acid, 6, 12b-bis(acetyloxy)- 12- (benzoyloxy)-2a,4a,5 .6,7,10,11,12,12a, 12b-decahydro- I I-hydroxy-4a,8,13,1 3-tetramethyl-5 -oxo- 7,11 -methao- 1 H-cyclodeca[3 ,4]benz(1 ,2-bI-oxet-9-yI Ester Using the procedure described for the preparation of 59, a solution of 2'-triethylsilyl-Ndebenzoyl-7-deoxy-A''-12,13-isotaxo (60, 0.956 g) and t-butylisocyanate (0.52 mL, 4.52 mmols) in THF (19 m) andEtN (16 pL) is prepared at ice bath temperature and then allowed to warm and stir at rt overnighi Following workup, 2'-triethylsilyl-N-debenzoyl-N-(tbutyl)aninocarbonyl-7-deoxy-A' 7 -12,13-isotaxo (62; 1.027 g) is obtained.
'H NMR (CDCI 3 ,TMS) 8 8.17 21, J 7.0 Hz), 7.59 1I, J 7.3 Hz), 7.50 (t, 2H), 7.35 2H), 7.26 3H), 6.08 2H), 5.73 1H. J 5.4 Hz), 5.51 14, J 8.9 Hz), 5.18 3H), 4.60 14, J 1.1 Hz), 4.55 11), 4.37 1H, J 8.3 Hz), 3.70 1H, J 5.3 Hz), 2.95 11, J 19.0 Hz), 2.76 11), 2.70 3H), 2.19 3H), 2.11 LH, J 20.5 Hz), 1.76 31), 1.55 3H), 1.32 3H), 1.07 9H), 1.06 3H), 0.73 91), 0.30 6H).
Exaoe3 N-Debeazoyl-N--bAyr)ainOiDc=bo-yl-7-deoxy-'- 12,13-isotaxoL (38) (2R-[2aa 4aP,67a,9,(czrA S),1 1a,12a12w12bct }.f-[Q-Buty)amin-carboybmioJa-hydroxybaizenepropanoic a1 12k(acetyioxy)1 2-(benzoyXy)- 2aAe,,6,7, 10,11,12,12a, 12b-dcahydo-1 14-hyrqy-48,13,1 3tra3-tiimajW5-oxo-71 -mdthmno- .9 9d 4744.P -92- SH-cyclodeca(3,4]benz[ 1,2-b]-oxet-9-yl Ester Using the procedure described for the preparation of 17, a solution of crude 2'-triethylslyl-N-debenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-A"- 12,13-isotaxol (62; 1.02 g) and EtN HF) 3 in CH 3 CN (5 mL) is prepared at 0 0 C and then stirred while allowing to warm to rt for 1 hr. Following workup and flash chromatography over silica gel, N-debenzoyl-N-(-butyl)aminocarbonyl-7-dexyM6 7 12,13-isotaxol (38; 0.842 g, 1.01 mmols, 91% yield from 56) is obtained.
'H NMR (CDCI 3 TMS) 8 8.16 2H, J 7.1 Hz), 7.60 lH, J 7.3 Hz), 7.50 (r, 2H), 7.35 4H), 7.30 1H), 6.05 2H), 5.71 1H, J 5.2 Hz), 5.46 (dd, Ii, J 9.1 Hz), 5.39 1H, J 9.2 Hz), 5.12 2H), 4.69 (dd, 1H, J 2.5, 5.1 Hz), 4.53 1H), 4.33 IH, J 8.2 Hz), 3.77 IH, J 5.5 Hz), 3.65 IH, J 5.3 Hz), 2.92 LH, J 18.7 Hz), 2.71 1H), 2.58 3H), 2.19 3H), 2.10 IH, J 18.3 Hz), 1.74 3H), 1.47 3H), 1.30 3H), 1.10 9H), 1.04 3H); "C NMR (CDC 3 TMS) 8 206.7, 172.0, 171.3, 170.7, 166.6, 156.5, 143.3, 138.9, 133.7, 130.2, 128.9, 128.8, 127.9, 126.7, 121.7, 84.5, 81.1, 77.7, 77.6, 77.2, 74.7, 73.5, 71.7, 57.9, 55.7. 50.5, 39.5. 38.7, 35.3, 32.9, 29.8, 29.3, 23.2, 21.0, 19.8, 14.4. 9.1.
mass spectrum (FAR), found: 831.3701 (C 4 5H,,NO, 3 requires 831.3704). 732, 263, 235, 205, 136, 106, 105, 57 rniz.
Example 63 Preparation of (O-methoxymethyl)-13-(N-Cbz-2*-TES-B-phenyl isoserinyl)-A' 2 3 iso-baccatin 111 (63) Following the procedure of Example 45 but using as starting material 13-{N-Cbz-2-TES-f-phenyl isoserinyl)-A' 2 "--iso-baccatin 111 (53) and chloromethyl methyl ether in place of chioromethyl ethyl ether is prepared (O-methoxynethyl)-13-(N-Cbz-2*-OTSphenyl isoserinyl)-A l, 3 iso~baccatin 111 (63) Examle 64 Preparation of 7-(O-methoxymethyl)-13-(N-Cbz- -pheny isoserinyl)-A'2' 3 -isobaccatin 111(64) Following the procedure of Example 43 but using as starting material (0-methoxya: SO: 30 methyl)-I 3-(N-Cbz-2'-TES- -pheny isoserinyl)-A '2' 3 -iso-baccatin I (63) in place of etboxymethyI)-13-(N-Boc-2-TES-g-pbenyI isoserinyl) _'.i1 3 _iso-bWKacin Il is prepared 7-(O-mthoxymethyl)- 13-(N-z-f-pbeny1 isosiny)_AI2'.-iso-bccatin 111 (64).
*too @0000 47 44. P .93- Examp~le 65 Preparation of 7 -(O-methoxyrmthyl)-13-( -phenyl isoserinyl)-4' 2 3 .so-baccatin I 7-(O-Methoxymethyl)- 13-(N-Cbz-f -phenyI isoserinyl)-A" 3 -iso-baccatin m (64, 450 mg, 0.485mM) is stirred at RT under nitrogen in methanol (7.5 mL) and dry THF (5 ml). To this solution is added ammonium formate (225 mg) and 10% Pd/C (125 mg). The reaction is allowed to react at RT for 10 min and then cooled in ice bath, following the reaction by HPLC while maintaining the temperature at 00 C. After a total of 55 minutes reaction time, the catayst is filtered off and the filtrate diluted with ethyl acetate. The organic solution is washed with sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum, reevaporating the residue twice with ethyl acetate-toluene leaving 7 4-(O-ethoxyinethyl)-13-($-phenyI isoserinyl)- A'-iso-baccatin m TLC: silica gel; 40-60 ethyl acetate-hexane; RI': origin Proton NUvR (CDCl 3 TMS): 8 1.09 311); 1.25 3H1); 1.61 3H1); 1.66 (s, 3H); 2.16 3H1); 2.18 3H); 3.25 3H); 3.76-3.83 1H1); 3.93-4.05 (dd 1H1); 4.20- 4.40 (in, 411); 4.45-4.54(d, 1H1); 4.62-4.72 111); 4.80-4.90 (dd, 1H); 5.44-5.53 (d, 5.73 111); 7.26-7.40 (mn, 5H); 7.45-7.55 2H); 7.57-7.67 1H1); 7.99-8.09 (d, 2H1).
Example 66 Preparation of 7-(O-methoxyinethyl)-13-(N-Boc-P..phenyl isoserinyl)- Am"- 3 iso-baccatin 111 (66) 7-(O-Methoxyznethyl) -13..(-phenyl isoseriny)-Al 2 .U-iso-baccatin 111 (65, 0.194 mM) is stirred at RT under nitrogen in dry THF (1 nL) and the solution treated with di-tert-butyl dicarbonate (43 mng, 0. 197 niM) in dry THF (0.4 niL), followed by triethylamine (0.26 niL). The reaction is followed by HPLC and after 3.5 hours additional di-t-butyl dicarbonate (5 mg) is added. After 5.5 hours reaction the solvent is evaporated under vacuum. The crude product is purified by HIPLC over a size B E. Merck prepacked silica gel column, eluting with (50-50) ethyl acetate- ~*hexane. Fractions of 7 maL are collected, analyzing them by TLC. Fractions 39-46 are found to contained pure product and are combined and evaporated under vacuum to give 7-(O-inethoxymethyl)-13-(N-Boc-l..phenyI isoserinyl)-Al.Uiso-baccatin MI (66, 7 1% yield) as a white solid.
TLC: siica gel;,60-40 ethyl acetate-hexane; RE 0.69 Proton NMR (CDCl,; TMS): 8 1.11 3H1); 1.24 9H); 1.27 3H); 1.62 (a, 3H%) L69 3H) L87-2.15 (mi 3H) 2.17 3W); 2.56 3H1); 2.62 1H1); 2.76-2.94 (mn, 2H1); 3.26 3H% 8.42-3.50 1H1); 3.82-.89 1H); 3.98-4. 10 (dd, 1H); 4.24- 4.33 1H1); 4.36-4.44 lIM) 4.46-4.5.4 1H), 4.63-4.78 2H); 4.85-4.93 (dd, 4744.P -94iH); 5.34-5.45 1H); 5.50-5.59 2H); 5.77 1H); 7.27-7.43 5H); 7.43-7.53 (t, 2H); 7.54-7.63 1H); 8.04-8.16 2H).
Example 67 Preparation of 7 -(O-nethoxynethyl). 3-(N-t-butylaminocarbonyl. phenyl isoserinyl).AU 1 3 iso-baccatin III (67) 7-(O-Methoxymethyl)-13-$-pheny isoserinyl)-Ab'-iso-baccatin 1II (65, 0.485 mM) is stirred at 0* C under nitrogen in dry THF (5 mL) and the solution treated with t-butylisocyanate (75 After 5 minutes the reaction is allowed to warm to RT. The reaction is followed by HPLC and allowed to stand overnight. After 18 hr the solvent is evaporated under vacuum. The crude product is purified by silica gel chromatography, eluting with a gradient of (50-50) to (6040) ethyl acetate-hexane.
Fractions of 15 mL are collected, analyzing them by TLC. Fractions 44-66 are found to contained pure product and are combined and evaporated under vacuum to give 7- (0-methoxymethyl)-l 3 -(N-t-butylaninocarbonyl--phenyI isoserinyl).AiZ .iso baccatin III (67, 85% yield) as a white solid.
TLC: silica gel; (50-50) ethyl acetate-hexane; Rf: 0.33 Proton NMR (CDCl 3 TMS): 6 1.11 3H); 1.14 9H); 1.25 3H); 1.59 (s, 3H); 1.69 3H); 1.88-2.15 3H); 2.17 3H); 2.56 3H); 2.60 1H); 2.77-2.93 2H); 3.26 3H); 3.70-3.76 1H); 3.83-3.90 1H); 3.97-4.06 (dd, 1H); 4.24- 4.32 1H); 4.36-4.44 1H); 4.44-4.54 2H); 4.65-4.73 2H); 4.86-4.94 (dd, 1H); 5.19-5.26 1H); 5.44-5.51 (dd, 1H); 5.51-5.56 5.76 111); 7.27-7.43 5H); 7.44-7.55 2H); 7.55-7.63 1H); 8.07-8.14 2H).
Example 68 Preparation of 7-(O-ethoxymethyl)- 13-(N-Cbz-2'-TES..-phenyl *25 isoserinyl).Au"-iso-baccatin III (68) Following the procedure of Example 42 but using as starting material 13-(N- Cbz-2'-TESp-phenyl isoeerinyl)-.AIls-iso-baccatin 1II (53) in place of 13-(N-Boc-2'- TES-0-phenyl isoserinyl)-A' 3 .iso>-baccatin III (46) is prepared 7-(O-ethoxymethyl)l3-(N-Cbz-2'-TES-&phenyl isoserinyl)-Al'-iso-baccatin M (68) Eamprle 69 Preparation of 7 -(O-ethoxymethyl)-13(N-Cbz.pheny isoeiny)-A"'iso-baccatin 111 (69) Following the procedure d Example 43 but using as starting material ethoymethyl)-13-(NCbz-2.TES..phenyI ioseriny 1i "-iao-baccatin Ell(68) in 35 place of 7-(O-ethoxymethyl)- p-phenyl iesserinyl)-a"-iso-baccatin MiI (47) is prepared 7-(O-ethoxymethyl)-1a-(N-Cbz-pphenyl isoserinyi)-h"-iso- 4744.P baccatin III (69).
Example 70 Preparation of 7-(O-ethoxymethyl)-13-$-phenyl isoserinyl)-ad.1-isobaccatin III 7-(O-Ethoxymethyl)-13-(N-Cbz--phenyl isoserinyl)-A"s-iso-baccatin III (69, 99 mg, 0.105 mM) is stirred at RT under nitrogen in methanol (2 mL) and dry THF (1 mL). To this solution is added ammonium formate (50 mg) and 10% Pd/C mg). The mixture is allowed to react at RT for 10 minutes and then cooled in ice bath, following the reaction by HPLC. After a total of 35 minutes reaction time, the catalyst is filtered off. The reaction mixture is diluted with ethyl acetate, washed with 5% sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum. The residue is reevaporated twice with ethyl acetate-toluene leaving 7-(Oethoxymethyl)-13-(-phenyl isoserinyl)-A"* '-iso-baccatin III HPLC: Versapack 229 nm; Iml/min.; (25-75-.2) water-acetonitrile-TFA; retention time: 3.80 minutes.
Proton NMR (CDC1,; TMS): 8 1.07-1.18 6H); 1.26 3H); 1.63 3H); 1.66 3H); 1.34-2.00 1H); 2.00-2.15 1H); 2.17 3H); 2.22 3H); 2.80-2.94 1H); 3.26-3.40 1H); 3.59-3.70 1H); 3.79-3.86 LH); 3.94-4.07 (dd 1H); 4.22-4.44 3H); 4.56-4.64 1H); 4.64-4.74 1H); 4.83-4.94 11); 5.44-5.54 (d, 1H); 5.74 1H); 7.23-7.47 SH); 7.47-7.59 2H); 7.59-7.70 1H); 8.00-8.10 (d, 2H).
Example 71 Preparation of 7-(O-ethoxymethyl)-13-(N-Boc-W-phenyl isoserinyl)-A'"iso-baccatin III (41) S:25 7-(O-Ethoxymethyl)-13-($-phenyl isoserinyl)-,Al-i-iso-baccatin 1 (72, 0.531 *99* mM) is stirred at RT under nitrogen in dry THF (3 mL) and the solution treated with di-tert-butyl dicarbonate (116 mg) in dry THF (1 miL), followed by triethylamine (0.076 mL). The reaction is followed by HPLC and after 2 hours additional di-t-butyl dicarbonate (15 mg) is added. After 4.5 hours reaction time, methanol (0.05 mL) is added. The solvent is evaporated under vacuum and the residue twice reevaporated with methylene chloride-hexane. The crude product is purified by HPLC over a size B E. Merck prepacked silica gel column, eluting with (30-70) acetone-hexane. Fractions of 15 mL are collected, analysing them by TLC.
Fractions 18-22 are found to contained pure product and were cmbined and evaporated under vacuum to give 7-(O-ethoxymethyl)-13-(N-Boc--phnyl iserinyl)- .A -iso atin (41, 82%) as a white solid.
A"~-lsbctin 11 (41,82 a a white sohd.
4744Tp TLC: silica gel; 30-70 acetone-hexane; Rf: 0.33 Proton NMR (CDCl 3 TMS): 8 1.09-1.17 Ct, 3H1); 1.24 9H); 1.27 3H); 1.62 3H); 1.68 3H1); 1.90-2.02 Ct, 1H); 2.02-2.14 1H); 2.17 3H); 2.18 (a, 3H1); 2.57 3H); 2.62 Ca, 1H); 2.80-2.98 (in, 2H); 3.30-3.40 (in, 1H); 3.62-3.73 (m, 1H); 3.84-3.90 1H); 4.00-4. 10 (dd, 1H); 4.26-4.34 1H); 4.38-4.45 1H1); 4.57- 4.64 1H1); 4.65-4.74 (mn 2H); 4.87-4.95 1H1); 5.35-5.49 (mn, 2H1); 5.50-5.57 (d, 1H1); 5.77 Ca, 1H1); 7.30-7.44 (mn, 5H); 7.44-7.53 211); 7.55-7.64 1H); 8.07-8.18 (d, 2H1).
hx ve7 Preparation of 7-(O-ethoxyinethyl)-13-(N-t-butylaminocarbonyl-f -phenyl isoserinyl)-A'" 3 -iso-baccatin 111 (43) 7-(O-Ethoxymethyl)-13..( -phenyl isoserinyl)-A 1 2,' 3 -iso-baccatin 111 (70, 0.105 mMf) is stirred at 000 under nitrogen in dry THF C1 mL) and the solution treated with t-butylisocyanate C20 ilL). After 5 minutes the reaction is left to warm to RT.
The reaction is followed by HPLC and allowed to proceed for 50 mini. The solvent is then evaporated under vacuum and the residue purified by silica gel chromatography, eluting with (30-70) acetone-hexane. Fractions of 7 mL are collected, analyzing them by TLC. Fractions 50-67 are found to contain pure product and are combined and evaporated under vacuum to give 7-CO-ethoxyinethyl)- 13-(N-t-butylaminocarbonyl-f -phenyl isoserinyl)-A'" 3 -iso-baccatin 111 (43, 74%) as a white solid.
TLC: silica gel; (30-70) acetone-hexane; Rf: 0.22 Proton NMR (CDCl,; TMS): 8 1.04-1.18 Cm, 1511); 1.23 Cs, 3H); 1.57 311); 1.67 3H); 1.86-2.00 Ct, 1H1); 2.00-2.13 Cd, 1H1); 2.15 Cs, 311); 2.53 311); 2.58 (s, 1H1); 2.73-2.93 Cm, 2H); 3.26-3.39 1H1); 3.58-3.70 Cm, 1H1); 3.82-3.89 Cd, 1H1); 3.96- 4.05 Cdd, 1H); 4.21-4.30 Cd, 1H1); 4.34-4.43 Cd, 1H1); 4.55-4.64 Cd, 1H1); 4.64-4.73 Cm, 211); 4.84-4.94 1H); 5.37-5.53 Cm, 3H); 5.74 1H1); 7.25-7.40 Cm, 5H1); 7.43-7.53 2H); 7.54-7.63 1H1); 8.04-8.12 Cd, 2H1).
Exrnle 73 Preparation of 7-(O-inethylthioinethyl)-A"'---io-baccatin III-13-(4S,5R)- N-(t-butylmnocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxaolidinecarboxylic acid ester (71a,b) *AM-Io-bacatin III- 13-(4S,5R>-N-(t-butylammunocarbonyl)4-(2,4dimethaxypawmyl>4-,eyl6-oxazoldinecarbozylc acid ester 100 m. 0.10 'O in stre at O'C unde;*Mrogen in aoetonitrIle (1 xnL). To this solution is added dimethyl sulfide (0.000 rnL) by uyringe and then four tium bnzoyl peroxide 4744.P -97mg each) 5 min apart. By 30 min everything dissolves and after 2 hours the reaction is complete by TLC.
The reaction is partitioned between ethyl acetate-5% sodium bicarbonate.
After separation of the aqueous phase the organic layer is dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed over silica gel eluting with (40-60) and (50-50) ethyl acetate-hexane. Fractions of 4 mL are collected, analyzing them by TLC. Fractions 19-40 are found to contained pure product and are combined and evaporated under vacuum to give 7-(Omethylthiomethyl)-dA""-iso-baccatin III- 13-(48,5R)-N-(t-butylaminocarbonyl)-2-(2,4dimethoxyphenyl-phenyl-5-oxazolidinecarboxylic acid ester (71a,b, 72 mg, 68% Syield) product as a white solid.
TLC: silica gel; (50-50) ethyl acetate-hexane; RP0.47.
Proton NMR (CDCL; TMS): 8 1.06 3H); 1.10 9H); 1.22 3H); 1.61 (s, 3H); 1.69 3H); 2.03 3H); 2.08 3H); 2.12 3H); 3.74 3H); 3.78-3.85 (s, 311 m, 1H); 4.00-4.13 (dd, 1H); 4.13-4.24 1H); 4.26-4.36 1H); 4.42-4.52 (d, 1H); 4.52-4.61 1H); 4.62 1H); 4.78-4.86 1H); 4.99 1H); 5.42-5.50 1H); 5.56-5.63 1H); 5.81 111); 6.33-6.42 1H); 6.44 111); 6.68 1H); 7.03-7.13 1H); 7.23-7.49 6H); 7.49-7.58 1H); 7.93-8.03 2H).
Example 74 Preparation of 7-(O-methylthiomethyl)-13-(N-t-butylaminocarbonylphenyl isoserinyl)-A'"-iso-baccatin III (72) 7-(O-Methylthiomethyl)-A'-iso-baccatin III-13-(4S,5R)-N-(tbutylaminocarbonyl)-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (71a,b, 72 mg, 0.068mM) is stirred at RT under nitrogen in (80-20) acetic acid- *25 water (5 mL). TLC after 5 hours shows the reaction to be complete. The reaction is then freeze-dried. The residue is chromatographed over silica gel (13 eluting with (50-50) ethyl acetate-hexane. Fractions of 4 mL are collected, analyzing them by TLC. Fractions 11-24 are found to contained 7-(O-methylthiomethyl)-13-(N-tbutylaminocarbonyl--phenyl isoserinyl)-dA'-iso-baccatin M (72, 57 mg, 92%) as a white solid.
TLC: silica gel; 50-60 ethyl acetate-hexane; R1:0.39.
Proton NMR (CDCL,; TMS): 8 1.03 3H); 1.06 9H); 1.17 3H), L56 (a, S8H); 1.60 SH); 1.73-187 1H); 2.02 2.09 SH), 2.48 3H) 3.77-3.86 1K); 4.00-4.10 (dd, IH); 4.16-4.24 1H): 4.29-4.8 4.41-4.49 )pR 0* 35 4.49-4.56 1H); 4.57 4.61 1H); 4.804.88 1H); 6.31-5.41 2H); 6.41-5.48 1H); 5.80 1H), 7.20-7.34 511); 7.37-7.47 2H), 7.47-7.56 1H); 4744.P -98- 7.99-8.06 2H).
Mass Spec (FAB, m/z) measured at 909.3840; theory for C4 7 H6 1 0 1 4
NA
1 is 909.3843; 861, 847, 831, 263, 235, 205, 136, 119, 105, 61, 57.
Example 75 Preparation of 7-(O-methyl)-13-(N-t-butylaminocarbonyl-f-phenyl isoserinyl)-dA-Uiso-baccatin II (73) Raney Nickel (8 mL), prewashed with 5% sodium bicarbonate, water, and ethanol is stirred at 000 under nitrogen. To this is added by syringe 7-(Omethylthiomethyl)-13-(N-t-butylaminocarbonyl-fphenyl isoserinyl)-uIu-iso-baccatin m (72, 100 mg, 0.11 mM) in absolute ethanol (10 mL). The temperature is kept at 0 0 C throughout the reaction and the subsequent washing process described below.
The reaction is followed by TLC and allowed to proceed for 4 hr, when it judged to be complete. The Raney Nickel is then allowed to settle and the upper layer of liquid removed by suction. The residual Raney nickel is treated with THF (40 mL) and the mixture stirred for 2 minutes. After the nickel has settled the liquid is removed as above. This washing process is repeated 9 times. All the washings are combined and evaporated under vacuum, leaving 65 mg solid. The residue is chromatographed over silica gel (10 eluting with ethyl acetate-hexane (50-50, 100 mL) and (60-40, 200 mL). Fractions of 3 mL are collected, analyzing them by TLC.
Fractions 13-18 are found to contain recovered starting material, fractions 19-28 contain 7-(O-methyl)-13-(N-t-butylaminocarbonyl-f-phenyl isoserinyl)-A'-isobaccatin III (73, 43 mg, 43%) as a white solid.
TLC: silica gel; (50-50) ethyl acetate-hexane; R.0.33.
Proton NMR (CDCL 3 TMS): 8 1.03 311); 1.06 9H); 1.17 311); 1.52 (s, 311); 1.56 3H); 1.90-2.05 211); 2.10 3H); 2.48 3H); 2.56-2.68 1H);2.68- 2.83 2H); 3.13 311); 3.69-3.82 211); 4.14-4.24 1H); 4.27-4.36 111); 4.55 1H); 4.61 1H); 4.80-4.91 1H); 5.25-5.43 2H); 5.43-5.49 111); 5.76 1H); 7.16-7.35 511); 7.35-7.46 211); 7.46-7.57 1H); 7.96-8.07 211).
Mass Spec (FAB, m/z) measured at 863.3981; theory for CH,O,,N, is 863.3966; 563, 263, 235, 205, 179, 136, 119, 106, 106, 58, 57, 43.
Exanmple 76 Preparation of A"u-iso-baccatin I-13-(48,5R)-N-Cb-2-(2,4dimethozyphenyl)-4-phenyl a s lic acid ester (74ab) 7-TES-n.iso-baccatln I-18-(48,5R)Ji bs-2-(2,4-dimethozphenyl)-4- 35 phnyl-5-ozaoldinecarboxylic acid eater (51ab, 215 mg, 0.188mM) is stirred at RT under nitrogen in acetonitrile (0.75 mL) and 98% triethylamnine trihydroadmride 4744.P .99- (0.25 mL). The reaction is followed by TLC and is found to be complete after hours. The reaction mixture is then diluted with ethyl acetate and washed with sodium bicarbonate, 5% sodium bisulfate and brine. The organic layer is dried over sodium sulfate and evaporated under vacuum. The crude product is chromatographed over silica gel (20 eluting with (40-60) acetone-hexane.
Fractions of 7 mL are collected, analyzing them by TLC. Fractions 13-22 are combined and evaporated under vacuum to give A'".-iso-baccatin III-13-(4S,5R)-N- Cbz-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (74a,b, 182 mg, 94% yield) as a white solid.
TLC: silica gel; (40-60) ethyl acetate-hexane; Rf: 0.23 Proton NMR (CDCl 3 TMS): 8 1.16 12H); 1.28 3H); 1.66 3H); 1.90 (s, 3H); 1.98 3H); 2.26 3H); 2.43-2.55 2H); 3.73-3.81 lH); 3.84 3H); 3.91 3H); 4.11-4.16 1H); 4.21-4.27 1H); 4.36-4.47 1H); 4.50 (s IH); 4.82-4.92 (bd, 1H); 4.92-4.96 1H); 5.50-5.55 1H); 5.61-5.68 1H); 6.25-6.37 2H); 6.47-6.55 2H); 6.71 1H); 7.23-7.57 8H); 7.57-7.64 1H); 8.00-8.07 (d, 2H).
Example 77 Preparation of 7-(O-methoxymethyl)-A' 2 3 -iso-baccatin III-13-(4S,5R)-N- Cbz-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester A.1-Iso-baccatin III- 13-(4S,5R)-N-Cbz-2-(2,4-dimethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid ester (74a,b, 215 mg, 0.208mM) is stirred at RT under nitogen in methylene chloride (1 mL) and the solution treated with chloromethyl methyl ether (97 pL, 1.25 mM) and diisopropyl ethyl amine (225 gL,1.25 mM). The reaction is followed by TLC. After 21 hours the reaction is found to be incomplete.
25 Thus, additional chloromethyl methyl ether (48 pL, 0.62 mM) and diisopropyl ethyl amine (112 pL,0.62 mM) are added and the reaction continued for 24 hours, when it is found to be complete. The reaction is then diluted with methylene chloride and washed with 5% sodium bisulfate and 5% sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed over silica gel (20 eluting with (40-60) acetone-hexane. Fractions of 5 mL are collected, analyzing them by TLC. Fractions 17-26 are combined and evaporated under vacuum to give 7-(O-methoxymethyl)-A' 2 '-iao-baccatin IH-13-(48,5R)-N-Cbz-2-(2,4dimetaoxyphenyl)-4-phnyl--azazolldinearboxylic acid ester (75ab, 224 mg, 100% yield) as a white solid.
35 TLC: silica gel; (40-60) acetone-hexane; Rf: 0.44 Proton NMR (CDCI,; TMS) 8 L06 3H); 1.21 3H); 1.26 3H); 1.64 (a, 4744TP -100- 3H); 2. 11 3H); 2.16 3H); 2.44-2.69 2H); 2.70-2.88 Cm, 1H); 3.23 3H); 3.57-4.04 (in, 2H); 3.80 6H); 4.14-4.28 Cd, 1H); 4.28-4.38 Cd, 1H); 4.43-4.54 (d, 1H); 4.55-4.84 (mn, 4H); 4.84-4.96 1H); 5.34-5.44 1H); 5.44-5.53 Cd, 1H); 5.67 (a, 111); 6.30-6.58 (bd, 1H); 6.74 (bs, 3H); 7.04-7.29 (mn, 4H); 7.29-7.54 (in, 7H); 7.54-7.65 1H); 7.93-8.06 Cd, 2H).
Exampvle 78 Preparation of 7-(O-inethoxymethyl)-13-(N-Cbz-f -pheny isoserinyl)- AL"-so-baccatin 111 (64) 7-(O-Methoxyinethyl)-A 2 3 -iso-baccatin III- 13-(4S,5R)-N-Cbz-2-(2,4diniethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (75a,b, 224 mng, 0.208mM) is stirred at RT under nitrogen in (80-20) acetic acid-water (9 mLL). The reaction is followed by TLC and is found to be complete in 4.5 hours. The reaction is then freeze-dried. The residue is purified by chromatography over a silica gel column (25 eluting with a gradient of (40-60) to (60-40) ethyl acetate-hexane.
Fractions of 7 mL are collected, analyzing them by TLC. The product is found in fractions 38-60 which are combined and evaporated under vacuum to give 7-(Omethoxynethyl)- 13(N-Cbz-f-phenyl isoserinyl) Al! 2 l 3 -iso-baccatin 111 (64,180 mg 93% yield) as a white solid.
TLC: silica gel; (40-60) ethyl acetate-hexane; Rf: 0.19 Proton NMR (GDCI 3 TMS): 8 1.08 Cs, 3H); 1.21 3H); 1.59 Cs, 311); 1.68 Cs, 3H); 1.82-2.03 Cm, 2H1); 2.12 311); 2.16 3H); 2.74-2.94 211); 3.23 Cs, 3H); 3.66 (bs, 1H); 3.77-3.86 Cd, 111); 3.96-4.10 (dd 1H); 4.23-4.35 Cd, 1Hi); 4.35-4.42(d, 111); 4.44-4.52 111); 4.60-4.94 511); 5.40-5.56 2H); 5.75 111); 5.94-6.05 (d, 111); 6.94-7.04 (mn, 2H1); 7.10-7.23 (mn, 3H); 7.25-7.42 (mn, 9H); 7.42-7.53 2H); 7.53- *25 7.62 Ct, 1H); 8.08-8.20 Cd, 2H).
Mass Spec (FAB, mlz) CM+H)* measured at 928.3743; theory for C, 1
H,
7
N
1 0 1 is 928.3755; 928, 896, 866, 105, 91, 43.
Examle 7 Preparation of 7-(O-ethoxymethyl)- 13-(N-Cbz-f -phenyI isoaerinyl)-AL''iso-baccatin 111 (69) 9. 9 A 1 2--Lo-baccatin 11-13-(48,5R)-N-Cbz-2-(2,4-dixnethoxyphenyl)-4-phenyl-5oxazolidinecarboxy~c acid ester (740b, 1.9g, 1.84 mM) is dissolved in CH 1 CI, and the solution treated with chloromethylethyl ether (850 jiL, 9.2 mM) and diisopropyletbyl amnie (2 ad,, 11 mM). After stirring overnight 7Wh indicates reaction about 40% complete. Additional chloromethylethyl ether (850 n!4 9.2 mM) and dllsoropylethyl amie (2 tn! 4 11 mM) are 2 times at 24 hour intervals after 4744YP -101which the reaction is allowed to stir for two additional days. At this time TLC indicates no starting material left so the reaction is partitioned between EtOAc and 1N HCI. The organic layer is reextracted with 5% NaHCO, and then brine. The organic layer is filtered through Na 2 S0 4 and concentrated in vacuo. To the residue is added (80-20) acetic acid water (100 mL). After 4 hr TLC shows that no starting material remains and the reaction mixture is lyophilized. The residue is chroinatographed over silica gel (200 g) packed in ethyl acetate hexane and the product added using C112CI. The column was eluted with 1.5L ethyl acetate hexane (2-3,1.5 L; 1-1, 11,; and 2-1, 500 inL), collecting 50 mL fractions.
7-(O-ethxM ethyl)- 13-(N-Cbz-P-phenyl isoserinyl)-A&' 1 3 -iso-baccatin 111 (69, 1.45 g, 82% yield) was found in fractions 34-5 1.
MS: Theory 942.3912 Found 942.3901 Proton NM (CDCl 3 TMS): 8 1.13 1.27 1.60 1.68 3H1); 1.94 2H); 2.17 2.91 (mn, 2H1); 3.19 111); 3.35 (in, 1H1); 3.68 (mn, 1H1); 3.83 4.06 (in, 1H); 4.32 1Hi); 4.41 1H); 4.59 1H); 4.69 1H1); 4.75 (in, 1H); 4.89 (in, 3H); 5.52 (mn, 2H1); 5.69 1H); 5.76 1H1); 7.02 (mn, 2H1); 7.20 (mn, 3H); 7.41-7.61 (mn, 9H1); 8.15 1H).
Example 80 Preparation of 134-'TES- phenyl isoserinyl)-A 12" 13-iso-baeCatin 111 (76) 13-(N-Cbz-2'-TES-f -phenyl isoserinyl)-A'," 3 -iso-baccatin 111 (53, 100 mng, 0.1 m.M) is stirred at RT under nitrogen in dry THF (1 niL) and methanol (1 mnL) and the solution treated with ammnoniumn formnate (45 ing) and 10% PdIC (25 mng). After minutes the reaction is cooled in an ice bath and allowed to proceed for 60 min when TLC shows it to be complete. The reaction is then filtered through Celite, washing with ethyl acetate. The combined filtrate and wash are washed with .sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum. The too.
residue is reevaporated twice with toluene and once with ethyl acetate-hexane to give 13-(2'-TES-.$-phenyl isoserinyl)-AI 2 .U4so-baccatin 111 (76, 88 mg, 100%) as a white solid.
0 60 TLC: silica gel; (50-50) ethyl acetate-hexane; R,0.67.
to. 0Proton NMR (CDCL3; TMS): 8 0.40-0.58 6H); 0.76-0.90 9H1); 0.94 (s, 3H1); 1.17 (is, 3H); 1.45 3H1); 1.51 311); 2.13 3H); 2.70 3H1); 3.53-3.63 (d, 1H); 4.13-435 (in, 4M)~ 4.76-4.87 (dd, 111); 5.37 1H1); 5.40-5.48 1IM 7.06-7.37 (in, 7.38-7.50 2H), 7.50-7.63 1H1); 7.90-8.02 Kd 2H).
Ngv9 8 Prepara~o of 13-(N-t-butylarminocarbonyl-2'.TE8-f -phenyl iaoeerinyl)- 4744.P -102- A"'-iso-baccatin III (77) 13-(2'-TES- -phenyl isoserinyl)-Au,-iso-baccatin 111 (76, 88 mg, 0.1 mM) is stirred at 0*C under nitrogen in dry THF (1 mL). To this solution is added by syringe t-butyl isocyanate (0.02 mL). After 5 minutes, the reaction is warmed to RT, following it by TLC. After 1 hour the reaction is again cooled in ice bath and treated with t-butyl isocyanate (0.02 mL). The reaction is then warmed to RT and allowed to proceed overnight after which it is complete. The reaction is then evaporated under vaccum and the residue chromatographed over silica gel (10 g).
The column is eluted with ethyl acetate-hexane (30-70, 200 mL) and (40-60, 100 mL). Fractions of 3 mL are collected, analyzing them by TLC. Fractions 22-72 are found to contained pure product and are combined and evaporated under vacuum to give 13-(N-t-butylaminocarbonyl-2'-TES-B-phenyl isoserinyl)-A' 2 ,-iso-baccatin III (77, 87 mg, 92%) as a white solid.
TLC: silica gel; (40-60) ethyl acetate-hexane; Rf0.81.
Proton NMR (CDCL; TMS): 8 0.17-0.44 6H11); 0.64-0.80 9H); 1.03 (s, 3H11); 1.06 9H); 1.28 3H); 1.60 311); 1.61 3H); 1.77 1H); 1.84-1.99 (t, 1H); 2.00-2.15 1H); 2.19 3H); 2.40-2.57 1H); 2.65 3H); 2.76 1H); 2.82-2.96 1H); 3.52-3.59 1H); 3.67-3.76 1H); 4.26-4.43 3H); 4.46 (s, 1H); 4.59 1H); 4.894.99 1H); 5.15-5.25 1H); 5.47 1H); 5.47-5.60 2H); 7.18-7.38 5H); 7.40-7.50 2H); 7.50-7.58 1H); 8.04-8.14 211).
Example 82 Preparation of 7-(O-methylthiomethyl)-13-(N-t-butylaminocarbonyl-2'- TES-0-phenyl isoserinyl)-A'l'-iso-baccatin II (78) 13-(N-t-Butylaminocarbonyl-2-TES--phenyl isoeerinyl)-A'ul-iso-baccatin III SS 25 (77, 87 mg, 0.091 mM) is stirred at OC under nitrogen in acetonitrile (1 mL). To this 0 9. solution is added dimethyl sulfide (0.055 mL) by syringe followed by four additions of benzoyl peroxide (25 mg each portion) at 5 min intervals. After 4 hours the reaction is found to be complete by TLC. The reaction is then partitioned between ethyl acetate-5% sodium bicarbonate. The organic layer is dried over sodium sulfate a. 30 and evaporated under vacuum. The residue is chromatographed over silica gel eluting with ethyl acetate-hexane (30-70). Fractions of 4 mL are collected, analyzing them by TLC. Fractions 9-21 contain pure product and are combined and evaporated under vacuum to give t ylthiomethyl)-13-(N-tbutylaminocarbonyl-2'-TES-$-phenyl ioeriny)-A"-io-baccatn I (78, 73 mg, 78%) as a white solid.
T silica gel; (30-70) ethyl acetate-hexane; RP0.47.
s.: 4744.P -103- Proton NMR (CDCL; TMS): 8 0.12-0.37 6H); 0.61-0.74 9H); 1.04 (s, 911); 1.05 3H); 1.21 3H11); 1.63 3H); 1.64 311); 1.78-1.92 1H); 2.03 (a, 3H); 2.11 3H); 2.57 3H); 2.61 3H); 2.75-2.92 211); 3.83-3.90 1H); 4.04-4.14 (dd, 1H); 4.21-4.29 1H); 4.31-4.39 1H); 4.42-4.60 4H); 4.85-4.93 1H); 5.14-5.22 1H); 5.44-5.52 211); 5.84 1H); 7.15-7.35 511); 7.35- 7.45 2H); 7.45-7.55 1H); 8.00-8.08 2H).
Example 83 Preparation of 7 -(O-methylthiomethyl)-13-(N-t-butylaminocarbonylphenyl isoserinyl)-A"-iso-baccatin 1 (72) 7-(O-Methylthiomethyl)-13-(N-t-butylaminocarbonyl-2'-TES-i-phenyl isoserinyl)-Au 2 -Siso-baccatin II (78, 73 mg, 0.071mM) is stirred at RT under nitrogen in (80-20) acetic acid-water (7 mL). TLC after 1 hour shows the reaction to be complete after which the reaction is freeze-dried. The residue is chromatographed over silica gel (10 eluting with (50-50) ethyl acetate-hexane.
Fractions of 4 mL are collected, analyzing them by TLC. Fractions 12-30 are found to contain the pure product which upon evaporating leave 7-(O-methylthiomethyl)- 13-(N-t-butylaminocarbonyl-frphenyl isoserinyl)-A 2 U-iso-baccatin III (72, 50 mg, 77%) as a white solid.
TLC: silica gel; (50-50) ethyl acetate-hexane; R10.24.
Proton NMR (CDCL; TMS): 8 1.03 311); 1.06 911); 1.17 311); 1.56 (s, 311); 1.60 311); 1.73-1.87 1H); 2.02 3H); 2.09 3H); 2.48 3H); 2.52 (s, 1LH); 2.69-2.86 2H); 3.76-3.84 1H); 4.00-4.10 (dd, 111); 4.14-4.24 1H); 4.28- 4.36 111); 4.40-4.65 4H); 4.80-4.90 1H); 5.24-5.33 1H); 5.33-5.42 (m, 1H); 5.42-5.47 1H); 5.80 1H); 7.16-7.35 511); 7.37-7.47 2H); 7.47-7.56 (t, 1H); 7.99-8.06 211).
.Example 84 PART A: Preparation of 2 3 -methylbutyl)dimethylsilyl-10-desacetylbaccatin
III
I) 30 A solution of 1.04 g of 10-DAB in 3 mL of pyridine at room temperature is treated with 1.03 g of 2-(3-methylbutyl)diinethylilychloride (PDMSCl). The reaction mixture is stirred at room temperature for 7 hours at which point HPLC S.showed the reaction to be 99% complete. The mixture is poured into water and the product isolated with ethyl acetate. The ethyl acta solution is dried over MgSO, and concentrated to afford 1.34 g ofa foam after 4mn drying.
PART Preparation of 2-(3-metbylbutyl)dimethylsilyl-Baccatin H (81a).
4744.P -104- The crude material from Part A is dissolved in 8 mL of pyridine and cooled to 0°C. Acetyl chloride (0.736 mL) is then slowly added. The solution becomes a thick slurry and is stirred at 0°C for 6.5 hours and then placed in a -20°C freezer overnight. The next morning the reaction is quenched with methanol and the product isolated with ethyl acetate. The ethyl acetate solution is concentrated to an oil and the excess pyridine removed by azeotropic distillation with toluene. The crude product is chromatographed on silica gel with 40% ethyl acetate/cyclohexane to afford 1.14 g of 2-(3-methylbutyl)dimethylsilyl-Baccatin m.
Example 85 Preparation of cyclohexyldimethylsilyl-10-DAB O A solution of 182 mg of 10-DAB in 2 mL of pyridine is treated with 0.3 mL of cyclohexyldimethylsilyl chloride (CDMSC1) at room temperature. The solution is stirred at room temperature for 16 hours, quenched with ethanol, then poured into water and the product isolated with ethyl acetate. The crude product is chromatographed on silica gel with 40% ethyl acetate/cyclohexane to afford 131 mg of pure silyl derivative. (Note: extended stir time results in considerable over silylation and results in reduced yield of cyclohexyldimethylsilyl-10-DAB Example 86 As illustrated in Examples 84 and 85, silyl protective groups can be added by means well known to persons skilled in the art. See, for example, "Protective Groups in Organic Synthesis, 2ed.", Peter G. M. Wuts, pp 74-83, Wiley, New york, 1991 which is incorporated herein by reference.
It has been reported that tributyldimethylsilyl (TBDMS) could not be introduced cleanly onto baccatin III, see footnote 13 in the Journal of the American 25 Chemical Society (JACS), 110, 5917 (1988). Under reaction conditions tried to date, the introduction of TBDMS to baccatin II has not been successful. However, it is contemplated that TBDMS and triisopropylsilyl (TIPS) can be introduced onto baccatin III as well as iso-baccatin m under reaction conditions known in the art.
Example 87 Preparation of 10-Deacetylbaccatin-7-O-triflate (82) 30 A stirred solution of 10-deacetylbaccatin (10-DAB, 10.0 g, 0.0184 mole) in CHC,I (50 mL) and pyridine (50 mL) is cooled to -30C and triflic anhydride (3.85 mL, 6.42 g, 0.0229 mole) is added over a period of 20 minutes. The temperature of solution is held below -1*C during the addition and is kept at -20 to -25*C for min following the addition. A TLC (20% AcCN-CHLCL) at this time shows a ratio of about 1:3 produdk starting material. The reaction is then stirred at OC for two S* hours. A TLC at this tb shows three spots a which the most polar and the least o t 4744.P -105polar are smaller and the middle spot is major. At this point the reaction mixture may be acetylated as described in Example 88 or may be worked up as described below.
The reaction mixture is first diluted with CH 2 CL, (2.5 L) and this solution is washed successively with 1M NaHSO, (3 x 1L), sat'd NaHCO, (2 x 1L), and sat'd NaCI Each aqueous wash is back-extracted with CHCl, (100 mL each) and the combined organic layers are dried (NaSO 4 and filtered. Since the reaction components do not move on silica gel when CIH Cl is used as a solvent and because the 7-O-triflate is relatively insoluble, the entire extract (3 L) is applied directly to a flash silica gel column (28 cm in 72 mm diameter column packed in CH 2 Cl). The column is eluted with the following solvents: CHCI, (1.5 7.5% AcCN in CHlCl (2 10% AcCN in CIHC (2 20% AcCN in CHC, (3 and with AcCN (2 L).
Fractions (200 mL each) 20-22 contained 1.89 g (0.00233 mole, 12%) of bis-triflate.
Fractions 31-37 contained 7.57 g (0.0112 mole, 61%) of 82 and fractions 42-47 contained 1.18 of recovered Spectral data for 10-deacetylbaccatin-7-O-triflate (82): 'H NMR (CDC1,, TMS) 8 8.09 7.64, 7.49 5.65 5.46 5.43 4.94 4.37 4.18 4.00 2.31 2.10 1.91 1.10 Example 88 Preparation of Baccatin-III-7-O-triflate. (83=20) To the reaction mixture at 0°C from Example 87, acetic anhydride (43.5 mL, 47.1 g, 0.461 mole) is added. Following the addition, the reaction solution is warmed in an oil bath at 50"C for 15 minutes after which TLC indicates about conversion of the major triflation product to a new material. The reaction is cooled in an ice bath and quenched by the addition of water (50 mL) from an addition funnel over a period of 30 min while maintaining the temperature below EtOAc (50 mL) is stirred into the mixture with no additional release of heat. This mixture is added to EtOAc (500 mL) and the resulting mixture washed with NaHSO, (2 x 500 mL), with sat'd NaHCO, (3 x 500mL), and with sat'd NaCI (500 30 mL). Each aqueous layer is back-extracted with the same 50 mL of EtOAc. The combined organic extracts were dried (NasO), filtered, and concentrated. The crude product (14.5 g) is dissolved in CHC1, (150 mL plus two 50 mL rinses) and applied to a flash silica gel column (7 inches dry packed in an 80 mm diameter column). The column is eluted with CIH CI (500 mL), 5% AcCN in CHVl AcCN in CHC1, 10% AcCN in CH,Cl and AeN Baccatin m-7-Otriflate (83) is eluted in fractions 11-19 (7.36 g, 0.0102 mole, 55% frm 10-DAB); 1H 4744YP -106- NMR spectrum in CDC13 is identical to the spectrum described for 20 derived in Example 15 from baccatin III.
Example 89 Preparation of 13-ketobaccatin III 7-triflate (84) Baccatin III 7-triflate (83, 100 mg, 0.17 m.M) is dissolved in methylene chloride (2 mL) and the solution treated with manganese dioxide (300 mg, 3.45 m) and the solution stirred for 18 hr at which point TLC indicates the reaction is not yet completed. Addlitional manganese dioide (100 mg, 1. 15 nm) is add and the reaction stirred an additional 3 hr. The reaction is then filtered through celite and concentrated under vacuum leaving 13-ketobaccatin M1 7-triflate (84, 90 mg).
Proton NMR (CDCI,; TMSY 8 1.21 3H); 1.28 3H); 1.86(s, 3H); 2.22 (s, 311; 2.23 3H); 2.26 3H); 2.82 J=20 Hz, 1H); 2.80-2.89 (in, 1H); 2.95 (d, Hz, 1H); 4.02 J=8.6 Hz 1Hi); 4. 11 J=8.4, 4.38 J--8.4 Hz, 111); 4.91 J=7.8 Hz, 1H); 5.50 (dd, 1H); 5.74 J=6.6 Hz, 1H); 6.75 7.51 (t, 2H1); 7.65 1H); 8.06 2H1).
Example 91 Preparation of A ."-iso-baccatin III 7-trifiate As described for the preparation of 7-TES-Al"-Jiso-baccatin 1111(3) in Example 2 but starting with 13-ketobaccatin III 7-triflate (84) is prepared A12,-iso-baccatin 1117triflate Example 92 Preparation of 7-(O-trifluoroinethanesufonyl)-,AU.I 3 -isobaccatin 111, 13- *4,R--abbnyoy2(,-iehxpey)4pey--mzldneroyi Acid Ester (86 a,b) As described for the preparation of 7-TES-A"'-1-isobaccatin III, 13-(4S,5R)-N- Cbz-2-(2,4-.dimethoxyphenyl)-4-phenyl-5.oxazolidinecarboxylic acid ester (51a,b) in Example 47 but starting with &"-"-iso-baccatin III 7-triflate (85) is prepared 74-(O trifiuoroinethanesulfonyl)-A'--isobaccatin HII, 1344S,5R)-N-Cbz-2-(2,4- Acid Ester (86 a,b).
ExmDle 93 Preparation of 7-(O-trifluoromethanesuifonyl)- 13-N-Obz-f phenyl iaoerinyl)-A&m"-iso4*batan IR (87) As described for the preparation of 13-(N-Cbz-4.pbmsnAiwsoerinyl)-A"--isobaco*n 111(52) in Example 48 but startdW with U~ehnmoy) A U-isobacatin III, 13(4S,5R)-N-Cbs.(4,dimtoyhy)4phenyl-6- :.:oxazolidinecarboxylic Acid Ester (86 ab) is prepared 7-(O-trifluoromehneufny) 4744TP -107- 13-(N-Cbz-f -phenyl isoserinyl)-A"-iso-baccatin 111 (87).
Examvle-94 Preparation of 7.(O-trifluoromethanesulfonyl)- 13-(N-Cbz-2'-TES-f phenyl isoserinyl)-A"'-iso-baccatin 111 (54) As described for the preparation of 13-(N-Cbz-2'-TES-f -phenyl isoserinyl)Y
A'
2 3 '-iso-baccatin M11(53) in Example 49 is prepared 7-(O-trifluoromethanesulfonyl)- 13-(N-Cbz-2'-TE-phenyl isoserinyl)-,AISU-iso-baccatin M11(54). This material gives the same physical data on TLC and in the NMIR as compound 54 prepared in example Example 95 Preparation of 13-(N-Cbz-fr-phenyl isoserinyl)-7-deoxy-70,8Wmethano- A"--iso-baccatin 111 (88) As described for the preparation of 13-(N-Cbz-2'-TES-f -phenyl isoeerinyl)-7deoxy-70,8f -methano-A' 2 "'-iso-baccatin 1171 (55 in Example 51 but starting with 7-(Otrifluorornethanesulfonyl)- 13-(N-Cbz-f -phenyl isoserinyl)-,AlZU3 igo~baccatin 111 (87) in place of 7-(O-trifluoroinethanesufonyl)-13-(N-Cbz-2-TES-f -phenyl isoserinyl)-A',"iso-baccatin 111 (54) is prepared 13-(N-Cbz-f -phenyl isosernyl)-7-exy-7,8* mehn-l-iobcai 111 (88).
Example 96 Preparation of 13-( -phenyl issrnl--ex-0,mtaoA''io baccatin 111 (89) As described for the preparation of 13(2'-TES- -phenyl isoserinyl)-7-deoxy- 70,8*methano-A'-iso.-baccatin M11(57) in Example 52 but starting with starting with 13-(N-Cbz-f -phenyl isoserinyl)-7-dexy-70,8Pmethano-A&""-iso-baccatin 111 (88) in place of 13-(N-bz-2T-TES-f -phenyl isosny)-7y-dexy,8methano-A'-isobaccatin 111(55) is prepared 13-( -phenyl isoserinyl)-7-deoxy-70,8Wmethano-A'",-isobaccatin [11 (89).
Example 97 Preparation of l3-(N-Boc-f -phenyl isoserinyl)-7-deoxy-70,8Pmethano- A -iso-baccatin 111(17) *.30 As described for the preparation of 13-(N-Boc-2-TE-pheny1 iserinyl)-7deoxy-7Wmethano-A"'X'-iso-baccatin DI1(58) in Exrample 53 but starting with 13- (WIphenyI eewrinyI)-7-deoxy-7MP-maethano-A"'-iso-bacctin [11(89) in place of 13- (ZDTE8-11 pheny1 is em-Wmd .sb t [1H (57) is prepared 134(N-Boc-f-pheiyl Wwoernyl)-7-doy-7 mhano-Am'-io-baccatin 1I (17).
4744YP -108- Example 98 Preparation of 13-(N-(t-butylaminocarbonyl)-f -phenyl isoserinyl)-7dex-7, "ehn-A2'-iso-baccatin 111 (36) As described for the preparation of 13-(N-(t-butylaminocarbonyl)-2'-TES-f phenyl isoserinyl)-7-deoxy-70,8f-methano-A 1.
3 -iso-baccatin 111 (59) in Example but starting with 13-$f phenyl isosrnyl)-7-xy-70,8 -methano-"' 1 3 -iso-baccatin M1 (89) in place of 13-(2'-TES- -phenyl iseernyl)-7oxy-7,Wmethano-&Y"-isobaccatin 111 (57) is prepared 13-(N-(t-butylaminocarbonyl)$f phenyl isoserinyl)-7deoxy-70,8f-methano-A' 2 '-iso-baccatin 111 (36).
Example 99 Preparation of 13-(N-Cbz-0-phenyl iwrnl--ex-6'At3io baccatin 111 As described for the preparation of 13-(N-Cbz-2'.TES-j -phenyl isoserinyl)-7deoxy-,A6.l4ImU3iso-baccatin MI (56) in Example 57 but starting with 7-(Otrifluoroinethanesufonyl)-13-(N-Cbz-f-phenyl isoserinyl)-,Al iio~baccatin 111 (87) in place of 7-(O-trifluoromethanesulfonyl)-13-(N-Cbz-2'-TES-0-phenyl isoserinyl)A1 2 "1 3 iso-baccatin Mn (54) is prepared 13-(N-Obz-f -phenyl isoeerinyl-7-deoxy-A 6 7 ,Al2- 3 _isobaccatin 111 Example 100 Preparation of 134( -phenyl issrnl--e~_&',m3iobcai 111 (91) As described for the preparation of 13-(2'-TES-f -phenyl isoserinyl)-7-deoxy- CA'2,1z 3 -iso-baccatin 111 (60) in Example 58 but starting with starting with 13-(N- Cbz-j -phenyl isoserinyl)-7-deoxy-A&" 7 3 -iso -baccatin 111(90) in place of 13-(N-Cbz- *2'-TES--phenyl imwiy)7doy,67A%3iobcai 111 (56) is prepared 134( phenyl isoserinyl)-7-deoxy-6A4""'isobaCCatin MI (91).
*Example 101 Preparation of 13-(N-Boc-p-phenyl isoeerinyl-7-deoxy-,& AL, 1 '-iSo_ baccatin 111 (18) As described for the preparation of 13-(N-Boc-2'-TES-f -phenyl isoserinyl)-7- 30 deoxy-A"17A"-.U-iso-baccatin MI (61) in Exaimple 59 but dtarting with 134(1-pheny1 isoeerinyl)7-dq-A"&g 7 A'&I"igobaccatin III (91) in place of 13(2'-TE.S--phenyl iaoseriyl)-7-deoxzy-AG- 7 A'-io-bWatin 111 (56) iB prepared 13-(N-Boc-P-phenwl ieoerlnyl)-7-deoxy-& 7 4"-"'-iomeatin MU (18).
Eav10 Preparation of 13-(N-(t-butylaminocarbonyl)- -bey imew.inyl)-7deoxy-A4, 1 &13-iwo-ccatin M11(88) 4744Y -109- As described for the preparation of 13-(N-(t-butylaminocarbonyl)-.2'-TES-f phenyl isoserinyl)-7-deoxy-A' 7 4 12 1 "-iso-baccatin 11I (62) in Example 61 but starting with 13-(f -phenyl isoeinyl)-7-deoxy-,K' 1 2.
1 3-iso-baccatin 111 (91) in place of 13-(2'- TES-0-phenyl isoserinyl).7-deoxy-A6- 7 'AIt 3 iso-baccatin 111 (60) is prepared 13-(N-(tbutylaminocarbonyl)Pf-phenyl iwo~rinyl)-7-deoxy-.A 7 -,A"U-iso-baccatin 111 (38).
Example 103 Preparation of 10-deacetyl-iS-keto-baccatin M11(93) Jones reagent is prepared by dissolving chromium trioxide (10.3 g, 0. 103 mM) in a mixture of concentrated sulfuric acid (8.7 niL) and water (30 mL). A solution of 10-deacetylbaccatin 111(92, 23 mg, 0.043 mM) in acetone (1.6 maL) is cooled to -50 T.
To this is added the Jones reagent (11 p.L, 0.028 mM). The reaction is stirred minutes, then quenched with 2-propanol. The mixture is partitioned between ethyl acetate and 5% sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate and evaporated to give 25 mg of crude product. The product is purified by column chromatography on silica gel in acetone-hexane mixtures, giving 10-deacetyl-13-keto-baccatin 111(93, 5.3 mg 23% yield). Starting material (12 mg, 52%) is also recovered.
TLC (Silica Gel GF): Rr of product in (50-50) acetone-hexane 0.44; R, of starting material 0.31. Proton NMR (CDCI 3 TMS): 8 1.19 3H); 1.24 3H); 1.47 1H); 1.75 (s, 3H); 1.8,5 (in, 1H); 2.10 3H); 2.20 3H); 2.60 (mn, 111); 2.68 1H); 2.97 1Hi); 4.02 1H); 4.15 1H); 4.26 1H); 4.30 (mn, l1H); 4.35 4.95 (dd, 1H1); 5.42 1H1); 5.70 1H1); 7.51 (in, 2iH); 7.64 (mn, 8.07 2H).
Example 104 Preparation of 10-deacetyl-Am'3-iso-baccatin 111 (94) *As described for the preparation of 7-TES-AlU-iso-baccatin Ell in example 2 but starting with 10-deacetyl-13-keto-baccatin 111 (93) in place of 13-keto- 7-TES-baccatin 111 is prepared 10-deacetyl-Al'-iso-baccatin M (94).
Example 10 Preparation of 10-deaIe-7-(O-trifluoromethanesulfonyl)-A"-iso- .9..baccatin 1311(95) As described for the preparation of 10-deacetyl-74-(O triflucomnethanesulfonyl-baccatin 111 (82) in example 87 but starting with deacetyl.&UJ-iso-baccatin M11(94) in place of 10-deacetyl-baccatin [M1(79) is.
prepared 10-d"0ety-7-(O-tihcrowmethaneeulfonyI)-A&"-iso-bacctin Ell 4744TP -110- Example 106 Preparation of 7-(O-trifluoromethanesulfonyl)-A' 2 -iso-baccatin III (86) As described for the preparation of 7-(O-trifluoromethanesulfonyl)-baccatin 111 (83) in example 88 but starting with 10-deacetY14-(Otrifluoromethanesulfonyl)-
AL
213 -isobaccatin 111 (95) in place of lO-deacetyl..7-(-trifluoromethanesulfonyl).
baccatin II1 (82) is prepared 7.(O-trifluoromethanesulfonyl)-A&'-iso-baccatin 111 Example 107 Preparation of 10-deacetyl-7-(O-methoxymethyl) -baccatin 111 (96) As described for the preparation of 7-(O-methoxymethyl)-A 1 "-iao-baccatin III- 13-(4S,5R)-N-Cbz-2-(2,4-dimethoxyphenyl)y.4-phenyl-5-oxazoinamrboxylic acid ester (75a,b,) in example 77 but starting with lO-deacetyl-baccatin MI (92) in place of
A'
2 1 -iso-baccatin III-134S8,5R)-N-Cbz-2-(2,4-diinethoxyphenyl)-4-phenyl-5.
oxazolidinecarboxylic acid ester (74a,b) is prepared 1-deacetyl-74-miethoxymethyl)baccatin. 111 (96).
Example 108 Preparation of 7-(O-methoxyrnethyl)-baccatin HI (97) As described for the preparation of 7-(O-trifluoromethanesufonyl)-baccatin 111 (83) in example 8.8 but starting with 10-deacetyl-7-(O-methoxymethyl)-baccatin 111 (96) in place of 10-deacetyl-7-trifluoroxnethansulfonyl-baccatin 111 (82) is prepared 7-(O-methoxyinethyl)-baccatin ITI (97).
Example 109 Preparation of 13-keto-7-(O-methoxyinethyl)-baccatin 111 (98) As described for the preparation of 13-keto-7-TES-baccatin 111 in example 1 but starting with 7-(O-methoxymethyl)-baccatin 111 (97) in place of 7-TES-baccatin 111 is prepared 13-keto-7-(O-methoxymethyl)-baccatin 111 (98).
Example 110 Preparation of 7-(O-methoxymethyl)-A-''-iso-baccatin 111 (99) As described for the preparation of 7-TES-A""iso-baccatin M11(3) in example 2 but starting with 13-keto-7-(O-methoxymethyl) -baccatin 111 (98) in place of 13keto-7-TES-baocatin LU is prepared 7-(O-methoxymethyl)-A'"-iso-baccatin Ill 9**6 (99).
EXAM21e li'reparation of 7-(UmethoxymethyiM4"-iso-baccatin Ifl-13-(48,6R)- N-Boo-2-(2,4-dimethoxphenyl)-4-pbenyl-ozazoldinwcArboxyilc acid ester Am desar% for th. preparation of 8-"k-iobaccatin fl-13-(48,5R)-N- *0 ~Boc-2-(2,4-dimethoxypenl)-4-phenyl-6.ozaoidn araxl acid ester (5ab) in 4744Yp -Illexample 3 but starting with 7.(O-methoxymethyl).A12,U3iso-baccatin 111 (99) in place of 7-TES-Ai 1 2 "-iso-baccatin 111 is prepared 7-(O-methoxymethyl)-& 1 2 1 -iso-baccatin III- 13-(4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid eater Example 112 Preparation of 10-deacetyl-7-(O-methylthiomethyl)-baccatin 111 (100) As described for the preparation of 7-(O-methylthiomethyl)-A'%"-iso-baccatin In-13-(4S,5R)-N-(t-butylazninocarbonyl-2(2,4-dimethoxypheny)-4-phenyl-5oxazoldinecarboxylic acid ester (71a,b) in example 73 but starting with 1O-deacetylbaccatin Mn (92) in place ofA'~-iso-baccatin III-13-(4S,5R)-N-(tbutylaminocarbonyl) -2-(2,4-diniethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (33a,b) is prepared 10-deacetyl-7-(O-methylthiomethyl)-baccatin 111 (100).
Example 113 Preparation of 7-(O-methylthioinethyl)-baccatin M1 (101) As described for the preparation of 7-(O-trifluoromethanesulfonyl}-baccatin M11(83) in example 88 but starting with 1-deacetyl-7-(O-methyltbioinethyl)-baccatin 111 (100) in place of 10-deacetyl-7-(O-trifluoromethansulfonyl)-baccatin 111 (82) is prepared 74-Omethylthiomethyl)-baccatin Mn (101).
Example 114 Preparation of 13-keto-7-(O-methylthiomethyl)-baccatin 1II1 (102) As described for the preparation of 13-keto-7-TES-baccatin III in example 1 but starting with 7-(O-methylthiomethyl)-baccatin M (101) in place of 7-TESbaccatin II1 is prepared 13-keto-7-(O-methylthiomethyl)-baccatin M~ (102).
Example 115 Preparation of 7-(O-methylthiornethyl)-A&'%1-iso-baccatin InI (103) As described for the preparation of 7-TES-.&""-iso-baccatin 111 (3 in example 2 but starting with 13-keto-7-(O-methylthiomethyl)-baccatin Mf (102) in place of 13keto-7-TES-baccatin 111 is prepared 7-(O-methylthiomethyl) -A,"-iso-baccatin III (103).
.Example 116 Preparation of 7-Omtytlmty)A'iobcai Ifl-13- (4S,5R)-N-Cbz-2-(2,4-dimethoxypheny1)-4-pheny1-5-oxazoldinecarboxylic acid ester 4* **(104,b) 4. ~As described for the ptration of 7-TE8-A"-o-bacatn Ifl-1-4S,5R)-N- Cbz-2-(2,4-lehzpey)4piy--xzldncfo l acid ewtw (5lab) in ~example 47 but dtarting with 7-(O-m byithiotnethyt)-AP-O-o-baGU M- (103) in 4744YP -112place of 7-TES-&""-iso-baccatin, 111 is prepared 7.(O-methylthiomethy)-,& 11,13 baccatin III- 13-(4S,6R)-N-Cbz-2-(2,4-dimethoxyphenyl)-4-phenyl.5oxazolidinecarboxylic acid ester (104a,b).
'Exampwle 117 Preparation of 7 -(O-methylthiomethyl)-13-(N-Cbzp phenyl isoserinyl)- A" Ll-iso-baccatin 111 (105) As described for the preparation of 7-(O-methylthiomethyl)-13-(N.tbutylaminocarbonyipf-phenyl isoserinyl)-A"-iso-baccatin 111 (72) in example 74 but starting with 7.(O-methylthiomethy).A'XU2iso-baccatin MI- 13-(4S,5R)-N-Cbz-2-(2,4dimethoxypheny)-4-phenyl45 xaolidinecarboxylic acid ester (104ab) in place of 7- *(O-methylthiomethyl)-A"-"-iso-baccatin 111-4S5)N-tbylmocrnl)2 (2,4-dimethoxyphenyl)-4-phenyl-5-oxazohidiecarboxylic acid ester (71a,b) is prepared 7-(O-methylthiomethyl) -13-(N-Cbz-f -phenyl isoserinyl) Al 2 zlS-isobaccatin 111 (106) Example 118 Preparation of 7-(O-methylthiomethyl) -134( -phenyl isoserinyl)-A" 3 iso-baccatin 111 (106) As described for the preparation of 7-(O-methoxymethyl)-134-.$phenyI isoseriny1)-LA' 3 -iso-baccatin M (65) in example 65 but starting with 74-(O methylthioinethyl)43-(N-Cbz-p..phenyl isowerinyl)-A&2,-isqo-baccatin Iii (105) in place of 74-mxethoxymethyl)- 13-(N-Cbz-f -phenyI isoserinyl)-A '-'-iso-baccatin 111 (64) is prepared 7-(O-methylthiomethyl)-13-(f-phenyI isoserinyl)-A 2 ~'iso-baccatin 111 (106) Example 1.19 Preparation of 7-(O-methylthioznethyl)-134(N-Boc- phenyI isoserinyl)- A'34-so-baccatin 11 (107) dsrbdfor tepreparation of 7 -(O-methoxymethyl)- 13-(N-Boc-p..phenyl isoserinyl)-A""'-iso-baccatin MI (66) in example 66 but starting with 740- 0 00 0 methylthiornethyl)-13f-phenyl isoserinyl)-A"-',-iso-baccatin HII (106) in place of 7- S...(O-methoxymethyl)-13.(fphenyl isoserinyl)-A'"3-iso-baceatin m (65) is prepared 7- (O-methylthioinethyl) -13-(N-Boc-f -phenyI isoserinyI)-AlZU1-isobaccatin MI (107) Example M2 Preparation of 7-(O-methylthiomethyl)-13-(N-(t-butylaminocarbonyl p phenyl isoerinyl)-A" 4 1 3 -"*obaeatn M11(72) 0 0 As described for th. preparation o( 7-(0-Metpigthyl)-8-(N-(t- **wo*buqtyinocarbony)J -pheqyi IoerinyI)4A%-isobctin 111(67) in example 67 but starting wfet ?4<O-methythiomnedW)-13-($ phenyI isceernyi)-A12iso-Awwatin 0* SM (106) in piace of 7-(O-methozynwtby1)-WA4-phsny1 inoserinyl)-A"4'-ls-bacatin 60 0 4 a 06 4744TP 111 (65) is prepared 7-(O-methylthomethyl)-13(N(t-butylamnocabonyl)o-.
phenyl isoserinyl)-,' 2 1 3 .iao-baccatin 111 (72.) Example 121 Preparation of 10-deacetyl.7-(O-methyl)-baccatin 111 (108) As described for the preparation of 7 -(O-rnethyl)-13-(Nt-butylaminocarbonyl.
f -phenyl issrnl-t'iobcai 111 (73) in example 75 but starting with deacetyl-7-(O-methylthiomethyl)-baccatin 111(100) in place of 7- (0methyitbiomethyl)- 13-(N-t-butylaminocarbonyl.p..phenyl isoserinyl)-A"' 1 4iso-baccatin 111 (72) is prepared 10-deacetyl-7-(O-methyl).-baccatin 111 (108).
Example 122 Preparation of 7-(0-methyl)-baccatin 111 (109) As described for the preparation of 7.(O-trifluoromethanesulfonyl)-baccatin 11 (83) in example 88 but starting with 10-deacetyl-(0-methyl)-baccatin MI (108) in place of lO-deaceyl- 7 -(O-trifluoromethanesulfonyl)-baccatin MI (82) is prepared 7methyl)-baccatin 111 (109) Example 123 Preparation of 7-(O-methyl)-baccatin 111 (109) As described for the preparation of 7-(O-methyl)-13-(N-t-butylaminocarbonyl.
f -phenyl issrnl-&t-s-aai 111 (73) in example 75 but starting with methylthiomethyl)-baccatin M1 (101) in place of 7-(O-methylthiomethyl)-13-(N-tbutylaminocarbonyl-ii-phenyl isoserinyl),&-Aso-baccatin 111 (72) is prepared methyl)-baccatin 111 (109).
Example 124 Preparation of 13-keto-7-(O-methyl)-baccatin Il (110) 25 1btAs described for the preparation of 13-keto-7-TES-baccatin. M in example 1btstarting with 7-(0-methyl)-baccatin 111 (109) in place of 7-TES-baccatin In (1) is prepared 13-keto-7-(O-methyl)baccatin HI1(110).
a. Examiple 12 Preparation of 7.(0-methyl)-AI.U-iso-baccatin In (111) *.30 As described for the preparation of 7-TES-A"so-baccatin 111(3) in example 2 but starting with l3-keto-7-(0-methyl)-baccatin 111 (110) in place of 13-keto-7-TES baccatin In1 is prepared 7-(O-methyl)-A"l"-iso-baccatin 111 (111).
EumleINPreparatimo f 7-(O-mwthyl)-A"' 3 4ao-bccatin 1I-I*.4S,5R)-N-Cbs-2- (2,4-dimetboxpeny)4-phenyl4.owjjljdjW.crbnxyc acid eet(112ab) As dewibed for the preparation o( 7-TES-A"-io-bocatiz 111-134,5R).N- 4744TP Cbz-2-(2 ,4-dimethoxyphenyl)-4.phenyl.5-oxazolldnecarboxylic acid eater (5 la,b) in example 47 but starting with 7-(0-methyl)-A' 2 "1-iso-baccatin 111 (111) in place of 7- TES-,&m.iso-baccatin 111 is prepared 7.(0.methyl),U 3 ."iso-baccatin 111-13- -N-Cbz-2-(2,4-dlimethoxyphenyl) -4-phenyl.5.oxazolidinecarboxylic acid eater (1 12a,b).
Example 127 Preparation of 7-(0-niethy1)-134(N-Cbz-f -phenyl isoerny)-,' 2 3 -isobaccatin M (113) As described for the preparation of 7-(O-methylthiomethyl)-13-(N-tbutyiaminocarbonyl-f-phenyI isoserinyl)AIZ 1 S -iso-baeCatin 111(72) in example 74 but *starting with 7-(O-methyl).AU L23 isobaccatin II- 13-(4S,5R)-N-Cbz-2-(2,4acid ester (112a,b) in place of 74(0.methylthiomethy)-AlZU-iso-baccatin II- 13-(S,5R)-N-(t-butylaninocarbonyl)-2- (2,4-dimzethoxypheny1)-4-pheny1-5-oxazolidinecarboxylic acid ester (7 la,b) is prepared 7-(0-methyl)-13-(N-Cbz-f -phenyI isoserinyl)-A'2""-iso-baccatin 111 (113).
Example 128 Preparation of 7-(O-methyl)- 13-$ phenyl isoserinyl)-AlS-iso-baccatin 111(114) As described for the preparation of 7-(0-methoxymethyl)-13-( -pheny1 isoserinyl)-,&2 3 -iso-baccatin 111 (65) in example 65 but starting with 13-(N-Cbz-f -phenyl isoserinyl)-AIll 3 .iso..baccatin M11(113) in place of 7-(Ornethoxymethyl)-13-(N-Cbz-f -phenyl isoserinyl)-A'&",'-iso-baccatin 111 (64) is prepared 740-methyl)- 13-$f5phenyl isoserinyl)-A-'-iso-baccatin M (114).
Example 129, Preparation of 7-(0-methyD-13-(N-Boc-f-phenyl isoserinyl_12A'-iSo_ *.baccatin 111 (115) As described for the preparation of 7-(O-methoxyxnethyl) -13-(N-Boc-f-phenyI isoserinyl).,&M'iso-baccatin MI (66) in example 66 but starting with 740-methyl)- 13-(P-phenyl isoserinyl)-""-iso-baccatin 111 (114) in place of 1341 -phenyl isoserinyl)-A"-iso-baccatin I11(65) is prepared 7-(0-methyl)-13-(N-Boc-f -phenyl isoeerinyl)-&""-iso-baccatin m (115).
*W pe 3 Preparation of 740O-methyl I134N-(t-butylAminocarbonyl)-fr-phenyI ~iaosrny)4-lw-Io.baatin MI (78) As deowibed for the preparation of 7-(O-methoxymthyl)- 13-(N-(tbutylaminocrbny)-J-pheny120oe& yU-io-baccatin m[ (67) in azample 67 4744Yp -115but starting with 7.(O-methyl)-13-$ -phenyl isoserinyl)-P- 13 -iso-baccatin 111 (114) in place of 7-(O-methoxyznethyl)-13-(f -phenyl isoserinyl)-A 1.13-iso-baccatin 111 (65) is prepared 7-(O-methyl)- 134(N-(t-butylaminocarbonyl)-Boc- -phenyI isoserny)-,& 13 iso-baccatin 111 (73.) Example 131 Preparation of 10-deacetyl-7-(Omethoxymethyl)-, .AU3Siso-baccatin III (116) As described for the preparation of 7-Omtoyehl -&X3iobcai I- 13-(4S,5R)-N-Cbz-2-(2,4-dimethoxyphenyl)A4-phenyl-5-oxazolidinecarboxylic acid ester (75ab,) in example 77 but starting with lO-deacetyl-baccatin 111 (94) in place of Am -Sisobaccatin III- 13-S,5R)-N-Cbz-2-(2,4-diiethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid ester (74a,b) is prepared 10-deacetyl-7-(O-rnethoxymethyl)-
A'
2 '-iso-baccatin 111 (116).
Example 132 Preparation of 7-(Q-methoxymethyl)-,Al 2 U3iso-baccatin 111 (99) As described for the preparation of 7-(O-trifluoromethanesulfonyl)-baccatin 111 (83) in example 88 but starting with 10-deacetyl-7-(O-methoxymethy)-A9 21 3 _isobaccatin 111 (116) in place of 10-deacetyl-7-trifiuoromethansulfonyl-baccatin 111(82) is prepared 7-(O-methoxymethyl)_A"' 3 -iso-baccatin 111 (99).
Example 133 Preparation of 10-deacetyl-7-(O-methylthiomethyl)-A'"-iso-baccatin 111 (117) As described for the preparation of 7.(O-methylthiomethyl)-A'3-iso-baccatin mI- 13-(S,5R)-N-(t-butylamnocarbonyl)-2-(2,4-dinethoxyphenyl)-4-phenyl-5ozazolidinecarboxylic acid ester (7 la,b) in example 73 but starting with lO-deacetyl- A-t'lS.baccatin 111(94) in place of A'-iso-baccatin II-13-(48,5R)-N-(tbutylaminocarbonyl)-2-(2,4-dinethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (33a,b) is prepared 10-deacetyl-7-(O-xethylthioinethyl)-A'L-iso-baccatin MI a. (117).
*30 Example 134 Preparation of ethylthiomethy)-"-iso-baccatin 111 (103) As described for the preparation of 7-(O-trifiuoromethanesulfonyl)-baccatin 111(83) in example 88 but starting with 10-deaeyl-7-mthylthomethyl)-A"-io- ~~baccatin 111 (117) in place of 10-deacty-7.taifloroaiethansulfonyl-baeccatifl MI (82) is prepared 7-(O-methliomethyl)-6"41o-beatin 111 (103).
4744.P Examp~le 135 Preparation of 7 -(O-methyl)-4% 1 3io.baccatin 111 (111) As described for the preparation of 7-(O-methyl)- l34-(t-butylaniinocarbonyl.
f-phenyl isoserinyl)-Al 1 3 -iso-baccatin 111 (73) in example 75 but starting with 740O.
methylWomethy'1-iUobacti 111 (103) in place of 7- (O-methylthiomethyl)13.
(N-t-butylaxninocarbonyl.f..phenyI isos~erinyl)-A' 2 1 8 -iso-baccatin 111 (72) is prepared 7- (O-methyl)Au.U-iso-baccatin 111 (111).
Exampole 136 Part A Charge oxazoline acid (2.60 g, 9.73 mnmol) into a round bottom flask and slurry in toluene (20 ml). Atroom temperature add l, 3 -dlicyclohexylcarboduimide (960 mg, 4.65 mmol) and stir for 20 minutes. Add 7-2-(3-methylbutyl) dimethylsilyloxy baccatin 111 (1.0 g, 1.40 mmnol) in toluene (15 ml) followed by catalytic 4pyrrolidinopyridine. Stir the mixture at room temperature. After 1 hour, reaction is complete by TLC. Quench with 20% NaHCO 3 (50 ml) and stir at room temperature for 2 hours. Filter on a coarse frit to remove'th DCU and separate the phases.
Back extract the aqueous with methyl t-butylether (35 ml). Wash the combined organics with 50%7 NaHCO 3 (50 ml), brine (50 ml) and dry over Na 2
SO
4 Concentrate to solids. Purify by column chromatography with 3:1 cyclohexanes/ Ethyl acetate to afford coupled ester 118 as a white solid.
Part B Charge the coupled ester 16 g, 1.2 mmol) into a round bottom flask and dissolve in MeOH (11 ml). Add 1N H~l (1.25 ml, 1.25 mmol) at room temperature.
Heat the resultant mixture to reflux. After 2 hours at reflux, the reaction is done by TLC. Cool to room temperature. Add aq NaHCO, (535 mg/10 ml H120). Stir at broom temperature for 2 hours. Remove the MeOH under vacuum, then extract mixture with EtOAc (2 x 25 ml). Dry the organics over Na 2
SO
4 and concentrate to solids. By TLC the solids are a mixture of the O-benzoyl salt and taxol. Dissolve the solids in a small amount of EtOAc and add 2 drops of triethylamine. Leave overnight. After 16 hours, the migration is complete and the crude solids are :purified by column chromatography using 1.5:1 Ethyl acetate/cyclohexanes to afford taxol.
Follwing the general procedure of Exmple 1IN but substitutig 7-2-(3methYlutyl~lmethYlsIyloy A''-iao..bccti Ml for 7-2-(3-methylbutylgdhnety.
4744.P -117.
silyloxy baccatin III, A''-iso-taxol is prepared.
Example 138 Formation of 7-I0- 2 -(3-methylbutyl)dimethylsilyl-taxol (119) A solution of 1.02 g of the product of Example 136, Part A (Compound 118) in 12 mL of AcOH and 1.5 mL water is heated at 80C for one hour. The solution is cooled and the product isolated by chromatography after isolation with ethyl acetate to afford 680 mg of Compound 119.
Preparation A 2 2 ,2-trichloroethyl)oxlcarbonyll-A -iso-taxol is prepared as discribed for the preparation of 2 '-{[(2,2,2-trichloroethyl)oxy]carbonyljtaxol [Magri, N.
SF.; Kingston, D. G. I. J. Org. Chem., 1986,51, 7971 Preparation B 2 2 2 2 -Trichloroethyl)oxy)carbonyl]-lAII-iso-taxol, 7- Methanesulfonate Methanesulfonyl chloride (1.2 equivalents) is added dropwise to a solution of 2 '-[(2,2,2-Trichloroethyl)oxycarbonyl]-S.iso-taxol (1 equivalent) and pyridine equivalents) in CHC1 which is stirred at ice-bath temperature. The reaction mixture is allowed to warm and stirring is continued until tic evidence indicates that reaction is complete. The reaction mixture is quenched with ice water and is extracted with CH 2 C1, and these extracts are washed successively with dilute aqueous acid, dilute aqueous NaHCO 3 and water and then are dried, filtered, and concentrated to give the crude reaction product. Chromatography of the crude product over silica gel gives pure title compound.
Preparation C 2'-[{(2,2,2-Trichloroethyl)oxy)carbonyll-7-deoxy-7a-chloro-AM"-isotaxol A solution of 2'-((2,2,2-trichloroethyl)oxycarbonyll-d"-iso-taxol, 7-methanesulfonate (1 equiv.) in NN-dimethylformamide (DMF) is stirred with potassium chloride (10 equiv.). A phase transfer catalyst is added and the reaction 30 mixture is warmed to increase the rate of reaction. The course of the reaction is .followed by tic. The reaction mixture is worked up by the addition of water and extraction with CH 3 CI. The organic extracts are dried, filtered, and concentrated and the crude reaction product residue is chromatographed over silica gel, yielding the pure title compound.
Prenarago Preparation a( 7-deaoy-7achloro-A*s-iso-taxol 4744.P -118- A solution of 2'-[1(2,2,2-Trichloroethyl)oxycarbonyll-7-deoxy-7a-chloro-1 2 1 '-isotaxol in 9:1 methanol/acetic acid is stirred with activated zinc metal at room temperature After 90 min, the reaction is worked up by removal of the zinc by filtration and concentration of the filtrate under reduced pressure. The residue is dissolved in CHC1, and this solution washed with 0.1N aq. HCI, with 5% aq.
NaHCO,, and with water. The aqueous layer is back extracted with CHC1, and the combined organic extracts are dried (NaSO 4 filtered, and concentrated to give a residue. The residue is pruified by chromatography over silica gel and is obtained as a solid.
Preparation E 7-Deozy-70-chloro- '-iso-taxol Following the procedures of Examples AB,CD and E, but starting with 2'- [{(2,2,2-trichloroethyl)oxy)carbonyl]-7-epi-A'.l-iso-taxol, the title compound is prepared.
Following the general procedures of Examples 15 and 11 but using appropriate metal salts, such as sodium or potassium bromide and sodium or potassium iodide or sodium or potassium azide, in the procedure of Example 15, the following compounds are prepared: 7-Deoxy-7a-bromo-A'-iso-taxol; 7-Deoxy-73-bromo-,A-iso-taxol; 7-Deoxy-7a-iodo-A2'-iso-taxol; 7-Deoxy-7-iodo-A'--3iso-taxol; 7-Deoxy-7a-azido-, 2 .u-iso-taxol; and 7-Deoxy-7 azido-A "-iso-taxol.
Compounds of Formula xil wherein R is H, R' is methyl and R' is a chlorine, bromine or iodine atom can also prepared by reaction of an appropriately protected precursor I wherein R, R,2 -NHC(O)CAH; R, H; R4
OTROC;
Rs H; Ro -OCOCH 3 and X 7 OH) with (CH)P/X 2
(CH),P/CX
4 or 30 (CH0)P/X,) following, for example, the numerous examples and experimental conditions described in Castro, Organic Reactions. 1983, a, pp 1-162.
Derivatives of the 7-dey-7-halo-A U-iso-taxols in which the 2'-hydroxyl group is esterifled are prepared directly from the desired 7-deoa-7-ha o-A"-iso-taxol by methods which are given in Mathew, A. eal., J. Med. Chem., 199I 85, 145; U.S. Patent 4,960,790; U.S. I t 4,942,184; U.S. Patent 5,059,699.
Following the general procedures of Mathew et al. (see, U.S. Patent 4744.P -119- 4,960,790, 4,924,184 and 5,059,699) but substituting the appropriate 7-deoxy-7-halo.
a 1 213 -iso-taxol analog, the fMiowing compounds are prepared: -alanyl)-7-deoxy7-fluoroAl-"is~olx formnate; 2-ltrl7doy7fur-&,3iotxl 2 2 -sulfehyido)sunyl7deoxyfurflu,-ioaoj 0 2'(rehlfy)--ex-7fur- ,3iotxl 2 '-(N,N-diethylaminopropionyl) -7deoxy.7fluoro-A12 3 _iso-taxol; 2'-(L-alanyl)-7-deoxy-7fluoro-A 2 3 -iso-taxol; 2 '-(L-leucyl)-7-deoxy-7-fluoro.A
L
2 l 3 isotaxo1; 2 '-(L-isoleucyl-7-deoxy-7-fluoro-.A 2 3 -iso-taxol; 2 '4-valyl)-7-deoxy7-fluoroA 2 '-iso-t.xol; 2 1 Iphenyaanyl)7deoxy-7-fluoroA"- Uiso-taxol; 2 '-(L-prolyl)-7-deoxy-7-fluoro- 12 13 jSo.taol; 2 '-(L-lysyl)-7-deoxy-7-fluoro-A&'' -iso-taxol; 2 4arnyl)-7deoxy7fluoro-ZU..j-so-axol; 2-uenl7doy7chooA'iotxl 2 '.glutaryl7.deoxy.7chloro..2Z 1Bo-taXOLi f .0 30 s l o ro i n l -d o y 7 c lo o -i o t x l 3022olotyaiosciy-7doy7cooA"iotxl 2 N N 1 t y a h p o i r l 7 e y- -h r -i o L k a 4(gycyl)-7.-d zy. 2hI'ioaoL 4744.P -120- 2'-(Ialanyl)-7-deox-7-loro-A" 3 .iso-taxol; 2'l(eucy-7-deoxy-7-cloro-A 1 2 3 -iso-taxo; 2'-(L-isoleucy)-7-deoxy7chloro-&' U-iso-taxol; 2'-(L-valyl) -ex--JlroA"iotxl 2J-(L~arginyl)-7-deoxy-7-chloro-A'lS-iso-taxol; 7-deoxy-7-chloro-A"2,"-iso-taxotere; 2I-f anyl7dexy-7-bromo-A'2-iso-taxo1 formnate: slorpoy)7dox--rm-2'iotxl 2 '-(3-sulfopropylamido)succinyl-7-deoxy.7bromo.A 3 _iSo-taxol; tiethylsily1}-7-deoxy-7-bromno-A&'- ~iso-taxol; 2'-(t-butyldinethylilyl)-7-deoxy-7-bromoA-'-iso-taxol; 2'-(N,N-cdiethylaminopropiony)7deoxy7bronoAL 2 1 3 _iso-taxol; 2W(~ny)7-deoxy-7-bromo-..A-iso-taxol; 2'-(L-leucyl-7exy-7-bromo"4-iso-taxol; 99:25 2-(1B ioleucyl)-7-deoxy-7-bromo-A"','.iso-taxol; Lvalyl)-7-deoxcy-7-bromo-A'12--iso-taxol; 2'-L-phenylalanyl-7-deoxy-7-bromo-A1 2 ,"-iso-taxol; 2-proy)-7deoxy-7-bromo-A""-iso-taxol; .30 2-Lguay)--ex--rm-&t-wtxl 2'-(L-arginy1)-7-deoxy-7-bromo-Ak-iao-taxol; 7-dozy-7-brmo-A',1-iao-taxotere; 2'-ucdinyl7-deaoy-7-iodo-A' -io-taxo; X4aayl7-exy-7-odo.A" '-iso-tazoI formate; 2'lgiutaryI-7deoxy-741od4Ws-Ao-taoD; 2'-(-cOXCHX)WO)NH(CH),N(CH.))-deoxy7-iodoA4iotao1 47 44.
-121- 2'.(D-sulfopropionyl)-7-deoxy-7-iodo-A 1 2 1 3 .iso-taxol; 2'-(2sulfoethylamido)succnyl-7deoxy7iodo-.&12.U3isotazol; 2'-(3-sulfopropylamido)succinyl-7-deoxy-7-iodo-A"lxs18o-taxol; 2'-1ethylily)-7deoxy-7-iodo-" 3 iso-taxol; 2'-(t-butyldiraethylsil)-7-deoxy-7-iodo-A 13 io-t~ol; 2J-(N,N-diethylainopropiony)7deoxy7iodo-,A'lU8otxol; 2'-(N,Nmethylglycyl)7-deo xy-iodo-A&' 2 13 2'-(glycyl)7-deoxy-7iodo-,Al2-l3is-taxol; 2'-(L-alanyl)-7-deoxy-7iodo_' 13 _iSO-taXol; 2'4L-leucyl)-7deoxy-7-iodo- 12 13 _iSotX0 1 2'-(Lioeucy)-7-deoxy-7-iod0A 3 -iso-taxol; 2'(L~phenylalany)-7-deoxy-7-iodo-AL2' 3 4iso48xol; 152'lyspyl)-7-deoxy-7-iodo-A'2"-iso-taxol; 2'Iarinyl)-7-deoxy-7-iodo-a' 3 -iso-taxol 7-deoxy-7-iodo-A'"3-iso-taxotere; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group.
Examp~le 138 Emulsion Formulation of N-Debenzoyl-N-(t-butyl)aininocarbonyl-7deoxy-70,8Wmethano-12,13-iotaxol (0$d 36) A 14.5 mng sample of N-Debenzoy1-N-(t-butyl)amiflocarboflyl-7-deoxy-70, 8 f methano-12,13-isotaxol (Cpd 36) is weighed and added to 0.5 gm, of water with probe sonication. An aliquot of 0.5 gmn oil (Miglyol 810) is added with mixing for four hours. An aliquot of an aqueous phase containing phoepholipid (egg lecithin) and glycerine is then added to the oil-drug mixture to yield a 20% oil emulsion containing 12.5 mg/gm phoepholipid, 22.5 mg/gm glycerine, and 6 mg/gm drug. The mixture is prehomogemized by sonication prior to final emulsification with an EmulsiFlex B3. A physically stable emulsion with mean particle size of 240 nm (measured by light scattering) results.
RnmD MOEmulsion Formulation of N-Dabosai-N-(t-butyl~uiml boI-l4 deoxy- 7 -12,13-isotaxol (C$d 38) A 70 mg sample of N-eosy--tbtlmncroy-4w-l1,3 4744TP -122isotaxol (Opd 38) is weighed and added to 1 grn water with probe soflication. An aliquot of 4.0 gm of oil (Miglyol 810) is added with mixing for 36 hours. The oil/water/drug mixture is centrifuged and oil phase removed, assayed and split into three different aliquots, which are then diluted with oil to 3.4, 6.9 and 13.8 mg drug/gm, oil. Aliqouts of an aqueous phase containing phospholipid (egg lecithin) and glycerine are then added to the oil-drug mixtures to yield a 20% oil emulsion containing 12.5 mg/gmn phoepholipid, 22.5 mg/gm glycerine, and either 0.7, 1.4, or 2.8 mg/gmn drug. The mixture is prehomogenized by sonication prior to final emulsification with an EmulsiFlex B3. Physically stable emulsions with mean particle sizes of 200-215 n (measured by light scattering) is obtained.
Procedures for the preparation of AL 2 1 -iso-taxol 7-ethers.
Preparation 1: Preparation of 7-(O-methyl)-A&2"-iso-baccatin III- 13-(4S,5R)-N-Boc-2- (2,4-dinaethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester Sodium hydride (55% dispersion in mineral oil, 43 mg, 1 rmol) is washed three times, by decantation, with anhydrous n-hexane. A solution of A baccatin 111-13 (4S,5R)-N-Boc-2-(2,4-ditnethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid ester (10a, 1 mmol) in anhydrous DMF (6 mL) is add at 0* C and the resulting mixture stirred at rt for 30 min. The resulting mixture is then treated with methyl iodide (82 iiL, 1.3 mniol) and stirred for an additional 60 min.
The reaction is then quenched with 5% aqueous ammionium chloride solution and extracted with ether. The organic layer is dried (MgSO 4 and the solvent evaporated under vacuum. The residue is purified by chromatography over silica gel, leaving Chem 1984 4974 (OPreprtylAio 2:sPreaatin f70mtyDA4LaLti -34,5)NBc2 mtoxphny phenyl-5-oxazolidinecarboxylic acid ester PrevaAt-I2:Peaaino -Omtl)'so-baccatin E1I-13-(4S,5R)-N-Boc-2-2,-intoyhyl-pel& oxazolldnecarboxylic acid ester (10m, 1 mmnol), methyl iodide (1.2 mmol), silver ttaftuoroborat. (1.2 mmW~ and silver carbonate (2 mmol) are added toA~tOnitrle (5 iL) and the mixture stirred at rt fbr 48 hr. The reaction Is then diluted with 5 ethyl acetate (20 mL) and filtered. The filtrate to extracted with water, 5% aqueous 4744Tp -123bicarbonate and dried (MgSO 4 and the solvent evaporated under vacuum. The residue is purified by chromatography over silica gel, leaving 7-(O-methyl)-'& 2 '-iso.
baccatin III. 13-(4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid ester.
See: Bhatia, S. K; Hajdu, J. Tetrahedron Lett. 1987, 28, 27 1.
Preparation 3 Preparation of 7-(O-methyl)-A'-1-iso-baccatin I11-13-(4S,5R)-N-Boc-2- (2,4-dinaethoxyphenyl)-4-phenyl-5-oxazo~idinecarboxylic acid eater A .UIso-baccatin M1-13 (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl5oxazolidinecarboxylic acid ester (10a, 1 minol), 2,6-di-t-butyl pyridine (2.3 mmol) and mercuric cyanide (5.8 mg, 0.023 rnnol) is dissolved in methylene chloride (4.5 mL) and the solution treated with methyl trifluoromethane sulfonate (0.24 mL, 2.2 mmol). The solution is heated under reflux for 50 hr, then treated with methanol (0.2 ml). The reaction is then evaporated under vacuum and the residue purified by chromatography over silica gel, leaving 7-(O-methyl)-A"' 1 -iso-baccatin 11-13- (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxyic acid ester.
See: J. Carbohyd. Chem. 1986, 5, 115.
Deprotection of Methyl ethers Preparation 4 Preparation of 7-(O-methyl)-13-(N-Boc- -phenyl isoserinyl)-A' 2 3 _iSo_ baccatin. 111 (41) 7-(O-methyl)-A&2' 3 -iso-baccatin II- 13-(4S,5R)-N-Boc-2-(2,4-dinaethoxyphenyl)acid ester (1 rmnol) is stirred at RT under nitogen in (80-20) acetic acid-water (4 ml). The reaction is followed by TLC and is found to be complete in 24 hours. The reaction is then fze-dried. The crude product is purified by chromatography over silica gel to give 7-(O-methyl)-13-(N-Boc-f -phenyl isoserinyl)-A"'-iso-baccatin III.
Allyl ether Syntheses Prevaration 5 Preparation of 7.(O-allyl)-AlZU3-iso~baccatin III-134S8,5R)-N-Boc-2- (2,4-dimethoxyphenyl)-4-pheny-oxazolidinecarboxylic acid ester A solution of AL"-iso-ba~atn M1-13 (48,5R)-N-Boc-2-(2,4-dimethoxyphenyl)- 4-phenyl-6-ozolidinecarboxylic sad ser (10a, 1 mmol) in methylene chloride is treated with allyl trichloroaostlmidate (2 mtino) and trifluoromnethan. sulfonic acid (25 pL) and the reaction stirred 48 hours at roo, m tinuperatur. The reaction is fitered and the filtrate washed with 5% aqueous sodium bicarbonate solution. The 4744.P -124organic layer is then dried (MgSO) and the solvent evaporated under vacuum. The residue is purified by chromatography over silica gel, leaving 7(Oallyl).au, 1_isobaccatin III-13-(4S,5R)-N-Boc-2-(2,4dimethoxyphenyl)4-phenyl.5oxazolidinecarboxylic acid ester.
See: Wessel Iverson, Bundle, D. R J. Chem. Soc. Perkin Trans. I.
1986, 2247.
Preparation 6 Preparation of 74(O-ally1)-AlU.i"so-baccatin III-13-(4S,5R)-N-Boc-2- (2,4-dinethoxyphenyl)4-phenyl-5-oxazoidinecarboxylic acid ester Sodium hydride (55% dispersion in mineral oil, 43 mg, 1 mmol) is washed three times, by decantation, with anhydrous n-hexane. A solution of 4"'-isobaccatin -13 (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)4-phenyl-5oxazolidinecarboxylic acid ester (10a, 1 mmol) in anhydrous DMF (6 mLL) is add at 0' C and the resulting mixture stirred at rt for 30 min. The resulting mixture is then treated with allyl bromide (1.3 mrnol) and stirred for an additional 60 min. The reaction is then quenched with 5% aqueous amnonium chloride solution and extracted with ether. The organic layer is dried (MgSO) and the solvent evaporated under vacuum. The residue is purified by chromatography over silica gel, leaving 7-(O-allyl)-A '"2-iso-baccatin II-13-(4S,5R)-N-Bo-2-(2,4-diethoxyphenyl)-4-phenyl- 5-oxazolidinecarboxylic acid ester.
See: loosternan, de Nijs, M. van Boom, J. H. J. CarbohyL Chem.
1986,5, 2247.
Preparation 7 Preparation of 7(Oallyl)Alu"-iso-baccatin III-13-(4S,5R)-N-Boc-2- (2,4-dinethoxyphenyl)-4-phenyl-6-oxalidinecarboxylic acid ester Under an argon atmosphere, tris(dibenzylidineacetone)dipalladiur (0.025 mrnol), and 1,4-bis(biphenylphosphino)butane (0.1 mmol) are added to tetrahydrofuran (2 mL). This solution is treated with AllS-'iso-baccatin M-13 (4S,5R)-N-Boc-2-(2,4-dimethoxypbenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (10a, 1 mmol) and allyl ethyl carbonate in tetrahydrofuran (2 mL). After stirring at 650 C for 4 h, the solvent is evaporated under vacuum. The residue is purified by chromatography over silica gel, leaving 7all4yl)-A'-iso-baccatin [If-13-(4,R)- N-Boo-2(2,4-diiethoxyphmyl)4-phenyl-6-msoidinecarboxylic add ester.
Sm Lathmfri, R; Lhot., Sinom, D. Tehuhedron Let. I, 30, 4069.
Deprotection of 7-(O-aQy)-A"u-lso-beocar n Il- 13-(4s,5R)-N-Boo-2-2,4dlmethoxypbnyl)-4-phonyl4-5o alldinecrb acd ester 4744.P -125- The protected allyl ethers may be deprotected to 7-(O-allyl)- 13-(N-Boc-j phenyl isoeerinyl)-A&" 1 5 -iso-baccatin III in the same manner as 7-(O-methyl)-13-(N- Boc-f -phenyl isoserinyl)-A&" 1 -iso-baccatin III is deprotected in preparation 4.
Following the procedure described in Carboni, J. Farina, Srinivasa, R.; Hauck, S. Horowitz, S. Ringel, 1. J. Med. Chein. 1993, 36, 513 but using the appropriate starting material of examples 5, 7, 26 and A"'-iso-taxol the following 7ester 12 "-iso-taxol analogs are prepared: 7-acetyl.AU"lS-iso-taxol; 7-acetyl1A""3-iso-taxotere; 7, 10-diacetyl-A'3-iso-taxotere; N-debenzoyl-N-t-butylAminocrbnyl-7-acetyl-"--iBo-taxol; 7-propionyl-A 12 3 -iso-taxol; 7-propionyl-A"'-iso-taxotere; 7-propionyl- 10-acetyl-A' 2 3 iso-taxotere; 7-butyryl-A 1' 3 _iso-taXol; 7-butyryl-A1 2 .1 3 _iso-taxotere; 7-butyryl- 1-acetyl-A' -iso-taxotere; N-debenzoyl-Ntbutyliminocarbonyl-7-butyry1-&-iso-taxol; 7-benzoylA 1 2 13 -iso-taxol; 7-benzoyl-A'- 1 3_iso-taxotere; 7-benzoyl- 1-acetyl-A 2 '1 3 iSo-taXotere; N-debenzoyl-N-tbutylamiflocarbonyl-7-benzoyl-A'2,'-iso48xol; 7-(4methylbenzoyl)-'2--iso-taxol; 7-(4-methylbenzoyl)-A'"-iso-taxotere; .:..7-(4-methylbenzoyl)- 10-acety1-A'2"3-iso-taxotere; and 0 .NdbaolNtbtlmncroy--4mtybnol A3iotxl Following the procedure described in Denis, Greene, A- Guenard, D.; Gueritte-Vogelein, Mangatal, Potier, P. J. Am Chem. Soc. 1988, 110, 5917 but using the appropriate starting material of examples 5, 7, 26 and A'"-iso-taxol the followin 7-ailyl ether AL%'-iso-taxol analogs are prepared: 7m(-tethy yl)-A-I-taXOI; 7-(O-trimetysilyl)-AUISio-t*XterS 74(O-triniethylsWy-Ioetyl-A'-O-taxoteZ N4bnolNtb~a O-iefy~l-"iotzl 4744.P -126- S 7-(O-triesorylyl)- 2 "-iso-taxol; 7-(O-triethypropylsi)-.AIisotaxoter; 7-(O-triisorylsilyl)- 10-diacety-A 3 -iso-taotere; 7-(O-t-buiso etylyl)-A 1 2 "-io-taxotere 7-(O-thisoyhy) 21_isoetxer1-e -iobcanm n 7-O-ehomy)-1N-t-buyaiobylminOcaiorbony1)- yl)phey 3 iseeiy1taxl 2
;U
so-acctin tlciety II)I.1,3-s-txl taxol 94 theflloig 7-ilyl) te10'-distal aalsog arerepaed 74-2-(3neylbutyladiethylsilyl-7-diacetylA' 2 liyl-a2 13 -iso-taxotere 257-(O-ti-n-btyl)-3-(-so-btyl;qioabnl- pey ssrnl-&2 9.-acanII 7-(O-94thefli-ngtysilyl ethdieyAIZisotaxoenaog re; peard 7-Ocyclomhyldimtylieylsoyl-tA x,3oaol 307-[02c3-lohydImeuty~lmylsUil-13otaxotere; 7-[0243-mohyldtydimeylsO-isyl.A0-diasoy-L21_otaxotere; N-debenoy-N-tbutaminocrony..Oyclohezy-2- methytysimeyl-s~izl- S 9 t -ax ol txl 9 7-(O-cypropeyldimethylaiyl)-A--io-taxo 7-(O4.prloheyldimhy~lyS*Aso-io-otere; .9....hxkietyW-0-imy.AX3io-aoee N-eezy*--uy-m 9croy-4-ylhxldmtyy)-&%3io 0o 74*-rpkiehW -m SOm 35 .9--rpks M 4otmte 4744.P -127- N-eezy---uyaioabnl7(--rplityay)-&,3iotxl 7.(O-cycloheptyldimethylsilyl)-,&"'-iso-taxol; 7-(O-cycloheptyldimethylsilyl)-A"2' 3 -ieo-taxotere; 7-(O-cycloheptyldirnethylsilyl)- 10-diacetyl-A 12 iso-taxotere; N-eezy---uyaioabnl7(-ccoetliehl~l-&2 3io taxol.
Following the procedure described in Denis, Greene, A. Guenard, D.; Gueritte-Vogelein, Mangatal, Potier, P. J. Am Chem Soc., 1988, 110, 5917 but using the appropriate starting material of examples 84 and 85 and 94 the folowing 7-silyl ether taxol analogs are prepared: *-02(-ehluy~iehliyltxl 7-[O-2-(3-methylbutyl)diinethylsilyl]-taxotere; 7-[O-2-(3-znethylbutyl)dimethylsilyl]- N-debenoyl-N-t-butylaminocarbonyl-7-40-2-(3-methylbutyl)dimethyl-silyl]taxol; 7-(O-tri-n-butylsilyl)-taxol; 7-(O-tri-n-butylsilyl)-taxotere; 7-(O-tri-n-butylsilyl)- lO-diacetyl-taxotere; N-debezoyl-N-t-butylam i nocarbonyl-7-(O-tri-n-butylsilyl)taxol; 7-(O-cyclohexyldiinethylsilyl)-taxol; 7-(O-cyclohexyldixnethylsilyl)-taxotere; 7-(O-cyclohexyldixnethylsilyl)- 1O-diacetyl-taxotere; 9 N-debenzoyl-N-t-butylaminocarbonyl-7-(O-cyclohexyldimethyl-silyl)taxol 7-(O-i-propyldiethylsilyl)taxol; 7-(Q-i-propyldiethylsilyl)taxotere; 7-(O-i-propyldiethylsilyl)- N-debenzoyl-N-t-butylAminocarbonyl-7.(O-i-propyldiethylsilyl)taxol; 7-(Q-cycloheptyldimethylsilyl)taxole; 30 7-(O-cycloheptyldimethylsiyl)- lO-diacetyl-taxotere; 0* N-debenzoyl.N-t-butylaminocarbonyl-7-(O-ccloheptyldimethylsiyl)-taxol.
Following the procedure described in Magri, N. Kingston, D. G. I.; ~*JitzrangwLi Picaielk, T. J. Ort Qusm 19K6,51,3239 but using the appropriate drng material of examples 5, 7, 26 aqj A"-iao-taxid the following 7-carbonate AUml~1o-taxol analogs are prepare&- 7SOmdkroae-'4iotmL 4744.P -128- 7-(O-methylcarbonate)-, 12 -ia~io-tazotere; 7-(O-rnethylearbonate)- N-debenzoyl-N-t-butylanminocarbonyl-7(O-methylcarbonate)AU. 13 iSo-taXol; 7-(O-ethylcarbonate)-A&L' 3 _iSotaXo1; 7-(O-ethylearbonate)-A'2"-iso-taxotere; 7-(O-ethylcarbonate)-10aey a%3io-aoee N-eezy---uyaioabnl7(-tyeroae- 2-3iotxl 7-(O-propylcarbonate)-Am'-iso-taxol; 7-(O-Propylcarbonate)-A 12 1 3 -iso-taxotere; 7-(Q-propylcarbonate)- 10-acety1."U"iso-taxotere; N-debenzoyl-N-t-butylaminocarbonyl-7-(O-propylarbonate)-A'' 13 _iso-taxol; 7-[O-(2,2,2-trichloroethyl)carbonate.A",U3iso-taxol; 7-[O-(2,2,2-trichloroethyl)carbonate-A' 2 .1 3 -iso-taxotere; 7-(O-(2,2,2-trichloroethyl)carbonatei- 10-acetyl-A' '-iso-taxotere; N-debenzoyl-N-t-butylaminocarbonyl-7.[O-(2,2,2-trichloroethyl)carbonate]- A"12.13* aol 7-[O-(2,2-dichoroethy~crbonae-A'-iso-taxol; 7-[O-(2,2dichlorethyl)carbonate]-A'2,1-is-taxotere; 7-{2,2-dichloroethyl)carbonate]- 10-acetyl-A' 2 "1 3 _iSo-taxotere; N-deben-zoyl-N-t-butylaminocarbonyl-740O-(2,2-dichloroethyl)carbonate-AU, 13.
iso-taxol; 7-(O-(2-choroethyl)cabonate-A"'-iso-taxol; 740O42-chloroethyl~carbonate]-A L 2 1 3 -iso-taxotere; 7-(O-(2-chloroethyl)carbonate]- 10-acety-',-iso-taxotere; and N-debenzoy-Ntbutyniarbonyl-7-(O-(2-chloroethy)carbonate}.A&"-isotaxol.
Following the procedure described in EP 524 093 Al but using the 000. appropriate starting material of examples 5, 7, 26 and &2,'-iso-taxol the following 7- 0 0 0 carbarnate A 12, 3 _iso-taxol analogs are prepared: 74[O.{N-zethy1)carbamate-AULU3iso-taxotere; *00 740O-(N-methyl)carbate]- 10-ac tyl-A%"-iso-taxotere; N-debenzoy-Nbutarnoony-74 -N-methy)carbamate-Al' 1 -isoo .0 taxoLo 7.-J",Ndimthy~earbamat}.A 1 1 3 4ao..taxo-ta 47 44.
-129- N-eezy---uyaioabnl7[-NNdmty~abmtl,1-1io taxol; 74[O-(N-ethyl)carbamateJ-A"-"-iso-taxol; 74(O-(N-ethyl)carbamate-A"'-1 13 _i8O~aXotere; 7.(O.(N-etlyl)carbamate10-acetylA2"' 13 iSOtaxotere; N-debenzoyl-N-t-butylaminocarbonyl-7-(O N-thyl crbamate A t3iotaxol; 7.(O-morpholinocarbolyl)-A2 -s~1o-taxol; 7-(O-morpholnocrboflyl)-A"-iso-taxotee 7.(O-morpholinocarboflyl)- iO-acetyl-A'%-iso-taxotere; and N-eezy---uyaioabnl7(-opoioabnl_&2,1 iotxl Following the procedure described in examples 36 and 38 but using the appropriate starting material of examples 5, 7, 26 and &"-iso-taxol the following 7carbaniate &A' 2 13 -iso-taxol analogs are prepared: 7-(O-methyl)-13-(N-Boc-f -phelyl isoseriny)-Al 2 .U-iso-baccatifl
II;
7-(Q-methyl)- 13-(N-(t-butylaminocarbonyl)-f -phelyl isoserinyl)-A 1 2 "3-isobaccatin III; 7-(O-ethyl)- 134-NBocP-phenyl isoserinyl)-A'l'-iso-baccatifl
III;
7-(O-ethyl) -13-(N-(t-butylaminocarbonyl)-f-phelyl Lsosrinyl)-A,&12, 3 _-so-baccatin 111; 7-(O-propyl)- 13-(N-Boc-f -phelyI isoserinyl)-Am'iso-baccatifl Ill; 7-(O-propyl)- 13-(N-(t-butylaminocarboflyl)-f -phelyl isosernyl)_A 2 "1 3 _iso- 9 baccatin HII; 7-(O-allyl)- 13-(N-Boc-pheny1 isoserinyl)-A&""--iso-baccatil
LUI;
7-(O-aflyl)- 13-(N-(t-butylamiflocarboflyl)-P phelyl isoeriny)-A",-iso-baccatifl 7-(O-benzyl)- 13-(N-Boc-f-phefly1 isoserinyl)-Al-3iso-baccatifl
III;
**7-(O-benzyl) -13-(N-(tbutyaminocarbonyl)-phelyl isoseriny)-A 12 1 3_iSo_ baccatin Il; 7-(O-methoxymethy1)-13-(N-Boc- pheDyl isoserinyl)-A",-iso-baccatin
III;
7-(O-methoxymethyl) -13-(N-(t-butylaminocarbonl)- phelyI iwwerinyl)-A'l'iso-baccatin Ml; 7.<O.methoxyetholymethyl) i3-(N-Boo.i -phenyI WornV"siobcai 7-(O-methoxyethO~mth~i) 13-4N(tWb amIDocarbWYi*phlnYI I.WedYI)- 4744.P -130- 7-(O-benzyloxymethyl)-13-(N-Boc--phenyl isoserinyl)-Au'-iso-baccatin
III;
7(O-benzyloxymethyl)- 13-(N(t-butylaminocarbonyl)-phenyisoserinyl)-dAl iso-baccatin III; 7-[O-(2,2,2-trichloroethoxy)methyl)-13-(N-Boc.)-phenyl isoserinyl)-& 2 u-isobaccatin III; 7-[O-(2,2,2-trichloroethoxy)methyl)- 13-(N-(t-butylaminocarbonyl)phenylisoserinyl)-A'&"-iso-baccatin
III;
7-(O-(2,2,2-trichloroethoxy)methoxymethyl)-13-(N-Boc-f-phenyl isoserinyl)- A&'-iso-baccatin I; and 7-[O-(2,2,2trichloroethoxy)methoxymethyl)- 13-(N-(t-butylaminocarbonyl)phenyl isoserinyl)-dAu-iso-baccatin
III.
Taxol and the other starting taxol analogs are known or can be readily prepared by known methods. See The Chemistry of Taxol, Pharmac. Ther., Vol 52, pp 1-34, 1991 as well as: U.S. Patent Nos. 4,814,470; 4,857,653; 4,942,184; 4,924,011; 4,924,012; 4,960,790; 5,015,744; 5,059,699; 5,136,060; 5,157,049; 4,876,399; 5,227,400, 5,254,580 as well as PCT Publication No. WO 92/09589, European Patent Application 90305845.1 (Publication No. A2 0 400 971), 89400935.6 (Publication No. Al 0 366 841) and 90402333.0 (Publication No. 0 414 610 Al), 87401669.4 (Al 0 253 739), 92308608.6 (Al 0 534 708), 92308609.4 (Al 534 709), and PCT Publication Nos. WO 91/17977, WO 91/17976, WO 91/13066, WO 91/13053 all of which are incorporated herein by reference.
The compounds of the invention can be formulated per se in pharmaceutical preparations or formulated in the form of pharmaceutically acceptable salts thereof, particularly as nontoxic pharmaceutically acceptable addition salts or acceptable basic salts. These salts can be prepared from those compounds of the invention which contain acidic or basic groups according to conventional chemical methods.
Normally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess thereof of the desired salt forming inorganic or organic acid in a suitable solvent or various combination of solvents. As an example, the free base can be dissolved in an aqueous solution of the appropriate acid and the salt recovered by standard techniques, for example, by evaporation of the solution. Alternatively, the free base can be dissolved in an organic solvent such as a lower alkanoyl, an other, an alkyl ester, or mixdtures there, for example, methanol, ethanol, ether, ethylacetate, an ethylacetate-ether solution, and the like, whereafter it is treated with the appropriate acid to form the corresponding salt 4744.P -131- The salt is recovered by standard recovery techniques, for example, by filtration of the desired salt on spontaneous separation from the solution or it can be precipitated by the addition of a solvent in which the salt is insoluble and recovered therefrom.
The taxol derivatives of the invention can be utilized in the treatment of cancers, due to their cytotoxic, antitumor activity. In addition the taxol derivatives of the present invention can be utilized in the treatment of arthritis, in particular rheumatoid arthiritis, see Arthritis Rheumatism, 32, 839, 1994 and Nature, 368, 757 (1994) which are incorporated herein by reference. In addition the taxol derivatives of the present invention can be utilized in preventing the restenosis of arteries following angioplasty.
The new compounds are administrable in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable form. The pharmaceutical preparation which contains the compound is conveniently admixed with a nontoxic pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic carrier, usually about 0.01 mg up to 2500 mg, or higher per dosage unit, preferably 50-500 mg. Typical of pharmaceutically acceptable carriers are, for example, mannitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid, and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
Exemplary of a typical method for preparing a tablet containing the active agents is to first mix the agent with a nontoxic binder such as gelatin, acacia mucilage, ethyl cellulose, or the like. The mixing is suitably carried out in a 30 standard V-blender and usually under anhydrous conditions. Next, the just prepared mixture can be slugged through conventional tablet machines and the slugs fabricated into tablets. The freshly prepared tablets can be coated, or they can be left uncoated. Representative of suitable coatings are the nontoxic coatings including shellac, methylkelluloe, carnauba wax, styrene-maleic acid copolymers, and the like. For oral administration, compressed tablets containing 0.01 milligram, 5 mlligrams, 25 milligrams, 50 milligrams, 500 milligrams, etc., up to 2500 44 4744-P -132milligrams are manufactured in the light of the above disclosure and by art known fabrication techniques weUl known to the art and set forth in Remington's Pharmaceutical Science, Chapter 39, Mack Publishing Co., 1966.
To formulate the tablet, the active compound, cornstarch, lactose, dicalcium phosphate and calcium carbonate are uniformly blended under dry conditions in a conventional V-blender until all the ingredients are uniformly mixed together. Next, the cornstarch paste is prepared as a 10% paste and it is blended with the just prepared mixture until a uniform mixture is obtained. The mixture is then passed through a standard light mesh screen, dried in an anhydrous atmosphere and then blended with calcium stearate, and compressed into tablet., and coated if desired.
Other tablets containing 10, 50, 100, 150 mgs, etc., are prepared in a like fashion.
The following Formulation I is an example of a tablet formulation comprising a compound of the invention.
I FORMULATION I1 a a a a a.
a a.
a.
Ingredients: Per tablet, mg.
Active compound 50.0 Cornstarch 15.0 Cornstarch paste Calcium carbonate 15.0 Lactose 67.0 Calcium stearate Dicalcium phosphate 50.0 The manufacture of capsules containing 10 milligrams to 2500 milligrams for oral use consists essentially of mixing the active compound with a non toxic carrier and enclosing the mixture in a polymeric sheath, usually gelatin or the like. The capsules can be in the art known soft form of a capsule made by enclosing the compound in intimate dispersion within an edible, compatible carrier, or the capsule can be a hard capsule consisting essentially of the novel compound mixed with a nontoxic solid such as talc, calcium stearate, calcium carbonate, or the like.
Capsules containing 25 mg, 75 ing, 125 mg, and the Mie, of the novel compound, singularly or mitures of two or more of the novel compounds are prepared, for example, as follows: 4744.P -133- FORMULATION II Ingredients Per Capsule, mg.
Active compound 50.0 Calcium carbonate 100.0 Lactose, U.S.P. 200.0 Starch 130.0 Magnesium stearate a a. a The above ingredients are blended together in a standard blender and then discharged into commercially available capsules. When higher concentrations of the active agent is used, a corresponding reduction is made in the amount of lactose.
The compounds of the invention can also be freeze dried and, if desired, combined with other pharmaceutically acceptable excipients to prepare formulations suitable for parenteral, injectable administration. For such administration, the formulation can be reconstituted in water (normal, saline), or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like.
The dose administered, whether a single dose, multiple dose, or a daily dose, will of course, vary with the particular compound of the invention employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient and the nature of the patient's condition. The dosage administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects.
25 Typically the compounds of the invention can be administered by intravenous injection at doses of 1-500 mg per patient per course of cancer treatment, preferable with doses of 20-200 mg, the exact dosage being dependent on the age, weight, and condition of the patient An example of a suitable formulation for injection is using a solution of the compound of the invention in a mixture of polysorbate alcohol and dehydrated alcohol 1:1) followed by dilution with 5% dextrose in water prior to infusion or injection.
Typically the compounds of the invention can be administered by oral adminitration at doe of 1-600 mg per patient per course o cancer treatment, preferable with do of e000 mg, the exact dosag being dependent on the age, 35 weight, and condition of the patient 4744,P -134- The compounds of Formula I (including 11,, Ha, III, IIla, IV, [Va, V, Va, and VI) are useful for the same cancers for which taxol has been shown active, including human ovarian tumors, mammary tumors, and malignant melanoma, lung tumors, gastric tumors, colon tumors, head and neck tumors, and leukemia. See, the clinical pharmacology of taxol is reviewed by Eric K Rowinsky and Ross C.
Donehower, The Clinical Pharmacology and Use of Antixnicrotubule Agents in Cancer Chemotherapeutics, Pharmac. Ther., Vol 52, pp 35-84, 1991. Clinical and predlinical studies with taxol are reviewed by Wifllam. J. Slichenmyer and Daniel D.
Von Hoff', Taxol: A New and Effective Anti-cancer Drug, Anti-Cancer Drugs, Vol. 2, pp 619-530, 1991.
The biological activity of the 7-deoxy-70,W~methano-iso-taxol compounds (Formula II) of the invention has been confirmed using well known procedures. For example, comparison of the cytotoxicity of 0$d 17 with taxol itself in L1210 mouse leukemia carcinoma cells in culture indicated that the IC9 (90% growth inhibitory concentration) for 7-deoxy-70,8fr-methano-iso-taxoI was 0.017 micrograms/mi and for taxol was 0.0 18 micrograms/mi. In an in vitro tubulin polymerization assay, conducted after the manner of F. Gaskin, et aL, J. Mol. Biol.. 89:737, 1974, 7-deoxy- 70,8f -methano-taxol was able to induce tubulin polymerization in vitro at 2000 in a manner very similar to taxol.
The biological activity of 7-deoxy-7-halo-iso-taxol compounds (Formula MI) of the invention has been confirmed using well known procedures. For example, comparison of the cytotoxicity of Cpd 16 with taxol itself in A2780 (human ovarian carcinoma) cells in culture indicated that the ICE, (90% growth inhibitory concentration) for 7-deoxy-7-fluoro-A'"-iso-taxol was 0.0029 micrograms/mI and for taxol was 0.017 micrograms/mi.
The biological activity of the compounds of this invention has been further confirmed using well known procedures against A2780 human ovarian carcinoma ***and the results set forth in Table II. The results were obtained using standard well known procedure (Perez, O'Dwyer, Handel, Owols, Hamilton, T.C. It. J. Cancer 1991, 48, 266, Alley, Scudiero, DA; Monks, Hursey, ML; Czerwinski, Fine, D.L. et al.; Cancer Res. 1988, 48:68N).
The biological activity of the compounds of this invention has been further a. confirmed using well known procedures against L1210 leukemia and the results set forth in Table L The results were obtauWd using standard well known procedure (Li, Ksatsel, 8.L; Murch, L.L;~1ioa LXM; and W.C. Krueger, :S*"Compurativ biological and biochemica a(etso nogalamycin and its analog on 4744.P -135- L1210 leukemia," Cancer Res. 39:4816-4822 (1979)). The results are expressed as an IC, which is the drug concentration required to inhibit cell proliferation to of that of untreated control cells. Lower numbers indicated greater activity.
It is well known that many human tumors are resistant to chemotherapeutic agents due to a phenomenon called multidrug resistance (MDR). Cells that are multidrug resistant are resistant to a wide variety of drugs including taxol, taxotere and other chemotherapeutic agents such as doxorubicin, vinblastine and etoposide.
This multidrug resistance undoubtedly contributes to the limited success of some therapeutic agents including taxol and taxotere. Therefore, development of a taxol or taxotere analog that could circumvent this multidrug resistance, and could kill multidrug resistant (MDR) cells more efficiently than taxol or taxotere would be expected to provide a better efficacy against multidrug resistant tumors in the clinic.
Several of the compounds described in this patent have been tested for their ability to circumvent multidrug resistance and kill multidrug resistant cells.
An in vitro assay to compare the killing ability of taxol analogs on the nonmultidrug resistant (non-MDR) cell line, KB-3-1 as compared to the MDR cell line, KB-V1, by taxol analogs (Shen et al., 1986, J. Biol. Chem. 261:7762; Mossman, T. J., 1983, Immunol. Methods 65:55-63; Abraham et al., 1994, Cancer Res. 54:5889). KB- V1 expresses high levels of the drug efflux pump, P-glycoprotein (pl70XShen et al., 1986, ibid.) has been used. This overexpression of the P-glycoprotein pump is thought to be the major source of the drug resistance in these cells (Endicott and Ling, 1989, Ann. Rev. Biochem. 58:137). The assays were performed in order to e assess whether any of the analogs can bypass the P-glycoprotein drug efflux pump and can kill cells that are multidrug resistant. The IC50 (inhibiting dose) for KB-3- 25 1 and KB-V1 was determined and the ratio of the IC50 for KB-V1 to that of KB-3-1 was also presented. IC50 measures the amount of drug required to kill 50% of the cells. A large ratio (IC50 KB-V1/IC50 KB-3-1) shows that a high concentration of the test compound is required to kill resistant cells as compared to the amount required to kill the drug sensitive cells. Compounds with large ratios do not efficiently 30 circumvent the drug resistance mechanism in the resistant cells. On the other hand, compounds with small ratios are effective at killing both the resistant and sensitive cells and require much smaller increases in drug to kill the resistant cells, as compared to the sensitive calls.
o A compound with a lower ratio, therore, would present an advantage in cancer treatment by allowing the more effective killing of multidrug resistant cells.
The ratios obtained are indicated in the table below and ranged from 20 to *oa 4744.P -136- 6 The compounds with lower ratios that more effectively kill drug resistant cells include Compound 7, Compound 17, Compound 18, Compound 38, and Compound 6; ratios ranged from 34 to 300. As a comparison, taxol and taxotere are very ineffective at overcoming resistance, with an average ratio of 7,570. Several of the tested compounds were also more effective than taxol or taxotere in retarding growth of a multidrug resistant tumor implanted in mice. These results suggest that these new taxol analogs may be more effective in killing resistant tumor cells in cancer patients than taxotere and could establish a new therapeutic niche for these analogs.
In using compounds of Formula I for use in angioplasty, an oral route of administration is one method of their systemic administration. Alternatively, however, these compounds may be administered by other convenient routes of administration whereby systemic activity is obtained.
The patient or animal being treated must be given periodic doses of the drug in amounts effective in preventing arterial occlusion in vascular trauma associated with coronary by-pass grafts, vascular surgery, restenosis following successful percutaneous transluminal coronary angioplasty (PTCA) or organ transplantation.
Such effective dosages are readily determined by methods known in the art.
Dosages may be administered orally, parenterally, or by local administration to the site of vascular injury by a catheter. Daily dosing of drug (0.01-200 mg/kg) may be administered initially with higher succeeding doses as tolerated. While the preferred dosage regimen is with single daily dosing in patients either by the oral or parenteral route, smaller locally acting doses either by the oral or parenteral route, smaller locally acting doses (1 ng/kg-1 mg/kg) may be administered at the time of the vascular intervention via local catheter installation or infusion in proper formulation.
While the preferred dosage regimen is with single daily dosing of patients, also preferred for obtining more uniform serum levels of drug are multiple dosages per day up to 4-6 times daily). Accordingly, when 4 daily doses of drug are to be administered, each such dose may be about 50 mg/kg per patient per dose, or higher depending on tolerance.
Similar doom are employed in hon-human mammals, e.g. 0.01-200 mg/kg/day.
9• 4744.P -137- TABLE I Compound L1210 (IC 4 u/m1) taxol 0.017 taxotere 0.004 6 1 7 0.0046 8 005 120.1 140.1 006 16 0.0029 17 0.0018 18 0.0022 32a 0.070 32b 0.0053 41 0.0007 43 0.0014
S
B
*0 9 *9 *999
B
*9 9 9 9.
*9 9 B 9 9*
BSSB
9* 9* 9 9* 9 9 9* 9*9* 09S9
S
9*99*B .9 99 .9 TABLE 11 COMPOUNDA78 I j/n) taxol 0.002-0.003 taxoteze 0.001-0.0016 64 0.0029 66 0.00026 67 0.00042 72 0.0004 78 0.00089 4744.P -138- Table III. Ability of compounds to kill KB-V-i multidrug resistant cells and EM-3-1 drug sensitive cells cpd no. EB-3-1 KB-V1 Ratio: nM) (1C50;, nM) KBV-1/ B-3-1 taxol 1.3 15000 11,58 Taxotere 0.25 1700 7,570 Cpd 36 0.050 360 11,400 Cpd 67 0.00075 140 5.7x10 Cpd 7 0.20 40 228 Cpd 18 0.20 6.2 34 Cpd 17 0.22 13 61 Cpd 66 0.00014 0.046 300 Cpd 41 01011 0.77 170 Cpd 32b 0.081 1100 17,650 Cpd 38 0.078 360 4,80 Cpd 43 0.00067 120 2.5x10 0* 4744.P -139- CHART 1 H1-11' protection of position 7 HO6"4 protection of position
HO..
C.
C.
C
Where R' 0 is -C(O)0H 3 and R 1 4 jS -C(O)C 1 -Calkyl, _C(O)0C 1 -Calkyl (preferably t-butyl), -C(O)OCH,0X$ where X is Halo, -C(O)OCH2CH 2 SiR 1 0 (where R 1 is CI-Caalkyl), or -&i(R 16 4744.P -140- CHART 2 protection of position 7 iv R1 0 =Ac oxidation
C
Where R 10 is -C(O)CH$ and R" 4 is -C(O)C,-C~aikyl, Qo-C(O0-Colkyl (preferably t-butyl), -C(O)OCHCXs where X in Halo, C(O)OCH 2
CH
2 SiR20 (where R.
is Ci-Coalkyl), or 4744.P -141- CHART 3 0 Zn or other reduction H0 0. R14R12_
NKOH
k vii 0 DCC, DMAP or other dehydration
HO,
Deprotection 9 9 9.
9 R12H
~NY
H
OH
4744Tp -142- CHART 4 RII
H
Selective deprotection 1. DAST or 1. Tf 2
O
2. base Deprotection too.
to 4744.P -143- CHART Selective deprotection 4744Tp -144- CHART 6 R"I H
S
estenificadon, etherilication, carbonation, carbamnoylation, etc.
17 Selective deprotection
RI)II;O
R' HHO BzO A'cO Iriv 0 0 0* 0 0*00 ~0 Where R 1 7 is -0 1 -Ca~kYl, -C 3 -Csycloalkyl, -(CH44henyl where n is 1-6,
C(O)C,-C,
0 alkyl, -C(O)phenyl, .C(O)phenyl substituted with one, 2 or 3 CX-4 alkyl,
CIC
0 .alkoxy, halo, alkylthio, trifluoromethyl, C 2 -Cs dialkylamino, or nitro, *C(O)naphthyl, -C(O)naphthyl substituted with one, 2 or 3 C 1
-C
4 alkyl, alkoxy, halo, CI-C, alkyIthia, trilluoromethyl, C2-C. !ilyamino, or nitro, -C(O)Ophenyl, -C(O)Opli~nyl substituted with one, 2 or 8 C,-C 4 alkyL C 1 -Cs alkoxy, halo, 4744.P -145- CHART 6 (cont.)
C
1 -C3 alkylthio, trifluorornethyl, 02-06 dialklcyamino, or nitro, -C(O)Onaphthyl, -C(O)Onaphthyl substituted with one, 2 or 3 01-04 alkyl, CI-C3 alkoxy, halo, 01-03 alkylthio, trifluoromethyl, 0 2 -Cs dialkylamino, or nitro, -C(O)00 1 -Cl 0 alkyl, -C(O)NHC,-C 1 0 alkyl, -C(O)Nllphenyl, -C(O)NHphenyl substituted with one, 2 or 3 C 1
-C
4 alkyl, 0 1
-C
3 alkoxy, halo, C,-0 8 alkylthio, trifluoroinethyl, 02*C6, dialkylainino, or nitro, -C(O)NHnaphthyl, -O-C(O)NHnaphthyl substituted with one, 2 or 3 01-04 alkyl, 01-03 alkoxy, halo, CI-0 3 alkylthio, trifluoromethyl, 02-06 dialkyiamino, or nitro, -C(O))CH2CHCHC4,
-C(O)OCH
2 CC1, -SiR"6 [where R' is C,-Calkyl or cyclo alkyl, with the proviso that at least two moieties are CI-C,,alkylI, -0H 2 -O-,-C,,alyl,
-CH
2
-O-(CH
2 ).phenyl where .is 1-3, -CH 2
-O-(CH
2 ),,pheny1 substituted with one, 2 or 3 C 1
-C
4 alkyl, C1-C3 alkoxy, halo, 01-C3 alkylthio, trifluoromethyl, 02-06 dialkylaniino, or nitro and where .is 1-3, -C20C2-X where q 0-3 and X is halogen.
S
S
*5
S
*5
SS
S S S S. S
S.
S
*5*S
S
S S 47 44. P -146- CHART 7 HOeI..
1. DAST or Tf 2
O
I. base
HO"..
MnO 2 Of other oxidation S1 Zn, HOAc orother reduction xviii R1 2 \H RI 0 N' AOH R"1 H V" DCC, DMAP or other dehydration a a.
a a a
R
1
H
4744.P -147- CHART 8
.TES
TES
H
HO.
ex 1 ex 2 Ac..
0
J.ES
ex 3 4a,b *5 S S
S.
*.SS
S
S
S
S S S
S.
4744.P -148- CHART 9 Ac- 0 Ph 0 Boc-N'~ Hp OMe HOBzO ZNI.1 OMe a,b Iex 4 Ac-.
0 Ph 0 Boc-N H OH HOBz6 6 0 *000 0 0 A c0.
0*0* Ph 0 *.*..oBoc-N H OH 00~
HO
lizoA 97 .9 ex
S
kTES -S a 4744.P -149- CHART Boc-I I ex 6 Bo'c-N
H
Ph 0 Boc -N 0 H OH 0090 Owe ^ll- Y -I 4744.P -150- CHART 11 Ac,o Ph 0 Boc-N H OH HOBzO b 7 ex 7 HO g Ph 0 HO Boc-N H OH
HO
Bzo A, 8 Ac%. 0 Ph0 Boc-N a..H Troc
SHO~
BzO) AcC 9 a. a.
x 8 4744.P -151- CHART 12
TES
ex 9 ex 9 .9 9 9 9 9 9b Ph 0 H OH 4744.P -152- CHART 13 I ex 12 Ph 0 Boc- 11 6,Troc a 4744.P -153- CHART 14 Ac Ph 0 Boc-N 1 H 0 Troc 13 Ph 0 Boc-N'~ H 6H Iex 13 Ac-. 0 Ph 0 Boc- H OH zOAcd 17 a..
a a p a a a a a a 4744.P -154- CHART Ph 0 ).Ak Boc-N H 6,Troc ex 14 0 Ph 0 Boc-N j H~ OH BzO) Ac(is 0 0 0 0* .4 0* 0 0000 00 0000 4744.P -155- CHART 16 Ac,.
ex 15 HO a 411a ex 16 ex 17 ex 18 Ac,
HO
C
C.
CA
*CCC
CCC CC
C
C. C C C Ph 0 Boc-N~
OH
0
H
OMe OMe ex 19 4a,b 4744.P -156- CHART 17 Ac.
0 ex .OMe 24 a,b Ac, Ph 0 Boc -N H OH
C
C
4744.P -157- CHART 18 Ph 0
H
2 N~
OH
ex 21 0 Ph 0 2N N :O H H OH 26 CH(OMeh2 0 1OMe MeG 27 ex 22 a
S
a.
28a,b R=Me 29a,b R=K 30a,b R=H z'ex 23, 23a ex 24 4744.P -158- CHART 19
,TES
>iPh 0
HH
OMe ex
.TES
Ph 0 0 HH$OMe OMe ex 26 4 4 a.
a a. a a.
32a R =TES 32b R=H 4744.P -159- CHART 0H ex 27 ex 28 0 OMe 33a Ac..
0 a 9* a a a
HH,
34a 4744TP -160- CHART 21 0
CF
3
S
H
ex 29 Ph 0
HH
ex a.
a a.
a. a a.
a a a. a a a.
H
H
4744.P -16 1- CHART 22 0 o OCF 3 Lu ?O' Ac,.
ex 31
,CF
3
>%N
H
0
H
ex 32 9
S
S
S S
S.
S. S S S S 0 Ph 0 H H OH HOBzo AcO 38 4744.P -162- CHART 23 ex 33 H H ex 34 a a, a.
a.
a a a a a a a a.
a a H H 4744.P -163- CHART 24 ex Boc-
H
lEt ex 36 OMe *1CH 2 OEt Ott* Ott* 4744.P -164- CHART ex 37
H
:H
2 OEt ex 38 H H
,CH
2 OEt *0 0 0*0 6 *0 000 0 00 0 00
>~N
H
4744.P -165- CHART 26 ex 39 HO66 ex HO If *m Ac...
4744.P -16&- CHART 27 0 kN
H
Ac-.1 ex 41 ex 42
,,CH
2 OEt I ex 43 >o lkN
H
a. 9* 4744.P -167- CHART 28 N LIN H
H
ex 44 32b 0 NA"kN H H Ph0 Acd ex 0 Pb 0 H H 0
TES
ex 46 a.
a.
a a a.
a a a. a a.
a a. a a a a a a.
a.
CH
2 OEt H H 4744.P -168- CHART 29 Cbz-
H
ex 47 HO0 ex 48 Cbz-1 1a ,b 0 Me a.
a a a a a.
a a a. a a.
Cbz-N
H
4744.P -169- CHART Ph 0 c 0O Cbz-N H
OH
HOBzo Acd ex 49 Ph 0 Cbz-N H TESBzO AcO ex Ph 0 H 6,
TES
S.
S
S
S.
S
SS
S
S
S
S.
4744.P -170- CHART 31 Ph 0 JQ.Ao Cbz-N H 0,TES ex 51 Cbz-] 0 a.
a a.
a a a a a.
.a.a a a a. a a a a a a.
Cbz- 4744Tp -17 1- CHART 32 Ph 0 Cbz-N 0,TES ex S2 ex 53 ~0 0 Ac-00 Ph 0
H
2 N 0 TESBzO5 AcO Ph 0 Boc- H 0,
TES
ex 54 0 *0.
0*0* *e 4744Tp -172- CHART 33 ex 0
H
Ph 0 1
,TES
ex 56 N7-
H
0
F
Ph 0
OH
6* 4744.P -173- CHART 34 Ph 0 Cbz-N TES HOBzAc 54 Ph 0
O
Cbz-N 0,TES ex 57 V p
S.
e S S
S.
p
SS
p p.
55 S S Sb SS*p *6 PS r 5*
S
4 pp..
p @5
S
S. p S S
S.
4744.P -174- CHART Ac ex 58 Cbz-1,
S
H
2
N
ex 59 ex 0 *m
S.
Ac.-O 0 Ph 0 Boc-N H
OH
H BZ0 Acd 4744TP -175- CHART 36 Ph 0
H
2 N :BzO AcO 0 ex 61 0
H
Ph 0
N
H 0,
TES
ex 62 0
H
Ph 0 J-k
N
H OH 4744.P -176- CHART 37 Ac-., ex 63 0 Ph 0 Cbz-N H 0,
TES
ex 64 ex a a a.
a a.
a a.
a a a.
a.
a a a.
a a a. a a.
a a a.
a a a. a a a a a a.
Ph 0
A~
HNOH
0 4744.P -177- CHART 38 Ac-.
0 ~OMe Ph 0 Ac' 00
H
2 N O HO Bzo AcO 6S I ex 6 ex 67 a a.
a a a a a.
a a.
a a.
a.
a a a.
a a a. a a.
a a a a a. a a a a.
H H 4744.P -178- CHART 39 ex 68 Cbz OEt ex 69 ex a.
a a a.
a a a.
a.
a a a.
a a a. a a a.
a.
Ph 0
H
2 N O 4744.P -179- CHART OEt
H
2 N OH Ph 0 Boc -N 0 H OH 0 Ph 0 )N ~NE H H OH ex 71 ex 72 a a.
a.
a a a.
a *aa.
a a. a z a.
4744.P -180- CHART 41 ex 73 33a~b OMe Ph 0 0 H H ex 74 S Me ex 71a,b >N
H
H
0 0* 0* 0 a a.
000* 0 a a. a a a.
4744.P -18 1- CHART 42
~.TES
ex 76
OH
Ph 0 ex 77 )Me ex 78 74a,b
S.
S
S
S
S
S SS
S.
75a,b OMe Gbz 4744TP -182- CHART 43 ex 79 74a,b OEt 0 0) Ph 0 Cbz-N0 H OH 00.
6 **6 0.0.
4744.P -183- CHART 44 Ph 0 Cbz-N H 0, TES HI4 ex ex 81 >N0N H H off* 9 .0
S..
4744.P -184- CHART 0 H H ex 82 SMe ex 83 0 H H
S
4* '4 0
SS
S S 5* p 4 S 4S
S.
S S @5 4554 S S
S
90 44 5* 4@54 p 0946 *5e40.
4 4. 0 34 4744.P -185- CHART 46
HO
ex 84 ex
HO..
8 1a,b
S
S.
S
*5*t
S
S S 55 5*55
S
555* 555555
S
S.
CS
80a: TLC Silica gel; 50% ethyl acetate: heptane, rf .44 TLC Silica gel; 50% ethyl acetate: heptane, rf .44 81a: TLC Silica gel; 50% ethyl acetate: heptane, if a R 40
=R
4 R 42 =2-(3-methylbutyl) b R 40 =R 41 =Me, R 4=cyclohexyl 4744-P -186- CHART 47 H-114i ex 87 ex 88
HOIIIJ
S0 2
-CF
3 ex 89 9 9.
9 9 9* 9** .9 9 9 9* 9 9 99 9999 9a .9 9 9* o 9 9**9 0.O-
CF
3 9 9* 9.
47 44.T -187- CHART 48 Ac,.
S0O2- CF 3 ex 91
HO
ex 92 Bzo AcO ex 93 9 9 9*9* 999999 9 9. 9 9* a.
86a ,b OMe Ph 0 Cbz- H OH 4744.P -188- CHART 49 ex 94 ,%.S0 2
-CF
3
S
Ac,.
V
S
S.
V
.0
V
V V
V.
V
V.
V.
S
Vt e
V
a
V.
4744.P -189- CHART Ac, IS0 2
-CF
3 I ex 9S Aco Ph 0 Cbz-N H OH HOBzo Acd ex 96 Ph 0
H
2 N O a. a.
a.
a a a.
a a a. a 0s a a a.
aa *aa.
a a. a.
a a.
4744.P -1 CHART 51 ex 97 ex 98 Ph 0 Boc-N 0 H OH 17 a a a a.
a a.
a a a a.
a a.
a a e.
a a a a a. a pa a a.
0 Ph 0 H H BzC 0H 4744TP -191- CHART 52 Ac...
Ph 0 Cbz-N H OH HOBz( 87
A
Ph 0 Cbz-N 0 H OH
OSO
2
-CF
3 ex 99 ex 100
C.
C
C.
C
C.
C
C.
C C C CC
C.
C C
C.
C
C. p
C.
C
C.
C
CCC...
C
C. C C C
C.
4744.P -192- CHART 53 ex 101 Ph 0 Boc-N'~~ H OH 18 ex 102
C
S.
S S
S.
*Sae
S
eS..
9S S S S S
S.
S
S
*S
S
S
9*
N
H
0 Ph 0
N
H OH 38 BzOCO 0c 4744.P -193- CHART 54 ex 103 ex 104
HO
U.
*UQU
'U
U U
U.
U.
U.
0UUS
U
U.
U U
U.
U. S
U*
U.
4744.P -194- CHART ex 105
HO-
S4 ex 106 a a a.
a a a.
a a a.
a.
a. a a a.
a. a..
*aa.a.
a a. ac a.
4744.P -195- CHART 56 ex 107
HO..
ex 108
HOII
ex 109 4 9 a.
a a.
.9 a a 99 a a a.
~9 a.
a. 0*
S
*99 9*9t9.
9 9* S 99 a.
4744.P -196- CHART 57 ex 110 ex III.
HO-
-OMe O~fe O NI e a a S a *5 a a. a I
S.
a a a. a a a a.
47 44. P -197- CHART 58 ex 112
HOI$
ex 113 100 SMe
HOIM
ex 114 *a.
a a.
a a a a.
a a.
a a.
a a
S.
a.
a a.
a a a *a a a a a aa aaa.
a a SMe 102 aaaaa *a p a a 4744.P -198- CHART 59 ex 115 102 lb ex 116
HO
103 SMe Ac 0 *a A. 00..
*0 0 00 0 0o 00 0 0 a to 0 @0 0 a 00 at..
Ot 104a,b 00 0 00 0004 toot 00000 tt 0 a 00 4744TP -199- CHART Cbz-
H
ex 117 s Ph 0 Cbz- H OH ex 118 105 SMe 0999
S
4*9* 9 *9S* 99 9 9 9.
09*9 9 99** .9 9. 4 9.
9.
9 9 90 9099 *9 9 99 9 99 *999 O *999 9 9 9 99 9.
4744Tp -200- CHART 61 SMe 106 ex 119 ex 120 Ph 0 BocN 0 H OH
C
C.
a
C.
C C
C.
C
C.
C C a.
a a.
C
C.
C.
C C
OC
C..
C
C
C. C C C
C.
N0 H H 4744.P -201- CHART 62 100 ex 121 ex 122 H41-1 108 sme ex 123
B.
B
Be..
B.
B
B.
B.
B B
B.
B
B. B
B
B.
*OBB
B
B
B.
HO1.46.
4744TP -202- CHART 63 Ac.
ex 124 ex 125 109 110 Ph 0 C k OH ex 126
HO
Ac...
.Me C C
CC
C. C
S.C.
C*
C C
C.
CCC.
C
CC..
CC
C
C.
C.
C
CC
C.
9C C C CC C C C CC
SC..
C C
CCC.
C CCC CC C C CC C
C.
4744.P -203- CHART 64 Ph 0 Cbz-N'T0 OMe 0 HBz N 112a,b OMe Ph 0 CbzN: 0 H OH ex 127 ex 128 113 Ac-.
0
S
S
S*
S
S.
S S
S.
S p
U.
S S *5 5 S S a* 5*S*
S
*SSSU*
S
U. S Se Ph 0
H
2 N O 4744.P -204- CHART ex 129 Ph 0 B oc- H OH ex 130 115 0 *000 0 0@ 00 0 S0 0e 0 *0 0000 0 0000 *0 0 0 00 40 0 *0 0000 .0 0* 0 00 0 0 00 0000 0 0000 00000.
0 00 0 00 00 0
N
H H 4744.P -205- CHART 66 ex 131 OMe 0.)
HO-
ex 132 6 6660 4e .6 600@ 60 6 6@ 66..
6 6066 06 6 06 6* 6 6@ 6606 @6 OS 6
SS
@6 0 66 @666 0 0066 6 6600e 0 66 6 0@ 66 4744.P -206- CHART 67
HO
ex 133 ex 134 SMe
HO
ex 135 .0@ 9** 103 Ac
HO
4744.P .207- CHART 68 Ex 136 79 Part A Part B TaxoJ .4
Claims (3)
1. A compound of the formula 0-C3 R3 0 -H, -C 1 -C 4 alkyl, -C 1 -C 3 alkoxy, halo, 10 -Cl-C 3 alkylthio, -trifl uoromethyl, -C 2 -C 6 dialkylamino, benzyloxymethyl, cyano, 15 azide (N 3 S or nitro; and wherein R 3 and R. 4 being the same or different, are selected from the group consisting of -OC(O)Cl-C 6 alkyI, -OC(O)0C 1 -C 6 alkyl, -OC(O)OCH 2 CX 3 where X is Halo, -OC(O)OCH 2 CH 2 SiR 20 (wherein R 20 is Cl-C 6 alkyI), or -OSi(R 6 3 [where R, 6 being the same or different, is selected from Cl-C 6 alkyI or cyclo(C.-C,)alkyl]; with the overall proviso that at least one R 2 1 is secondary alkyl or cycloalkyl, and further wherein when R 3 1 is -OS(C 2 H 5 3 then R 3 1 cannot be -OC(O)CH 3 and when R 3 1 is -OCOOCH 2 CC 3 then R 30 cannot be either OC(O)CH 3 or -O-(2,2,2-trichloroethoxy carbonyl). 14 k (U W~fiona\Species\16806divdoc 44) -209-
2. A compound according to Claim 1 selected from the group consisting of
7-[O-2-(3-methylbutyl)dimethylsilyl]-baccatin III; 7-(O-tri-n-butylsilyl)-baccatin III; 7-(O-cyclohexyldimethylsilyl)-baccatin III; 7-(O-i-propyldiethylsilyl]-baccatin III; and 7-(O-cycloheptyld imethylsilyl]-baccatin III. 3. A process of preparing COCH 3 which comprises reacting an oxazolidine free acid of Formula 7 .4 25 with a baccatin compound of Formula 8' C:IMNWORDJENN4Y"PECNKfI~iNDIV DOC -2 H 3 q b COC-H 3 in the presence of a dehydrating agent; wherein and R 34 being the same or different, are selected from the group consisting of -OC(O)0 1 -CalkyI, -OC(O)0G 1 -C~alkyl, -OC(O)OCHCX where X is Halo, -OC(O)OCH 2 CH 2 SiR 20 (where R 20 is Cl-ClalkyI), or -OSi(Rl 6 3 [where R 1 6 being the same or different, is selected from Cl-C 6 alkyI or cyclo(C 5 C 8 )alkyl]; X 2 is selected from the group consisting of -H, -C 1 -C 4 alkyl, -Cl-C 3 alkoxy, halo, -trifluoromethyl, -C 2 -0 6 dialkylamino, benzyloxymethyl, cya no, azide (N 3 or nitro; R, is selected from the group consisting of Ws~f'0naSPecies16806D IV. DOC -211- -C 6 1- 5 or phenyl substituted with one, 2 or 3 cl-c 4 alkyl, Cl-C 3 alkoxy, halo, Cl-C 3 alkylthio, trifluoromethyl, C 2 -C 6 dialkylamino, hydroxy or nitro, 2- fury!, 2-th ienyl, 1 -naphthyl, 2-naphthyl or 3 4 -methylenedioxyphenyl; R 1 1 is phenyl substituted with -(OCI-C 2 alky)n where n is 1 to 3; and R1 2 is selected from the group consisting of -C(O)C 1 -Cl 0 alkyI, -C(O)phenyl, -C(O)phenyl substituted with one, 2 or 3 C1-C4 alkyl, 0,-C 3 alkoxy, halo, Cl-C3 alkylthio, trifluromethyl, C2-C6 dialkylamino, hydroxy or nitro, C(O)C(CH 3 )=CHCH 3 -C(O)OC(CH 3 3 -C(O)OCH 2 phenyl, -S0 2 -4-methylphenyl, -C(O)(CH 2 3 000H, -C(O)-4-(SO 3 H)phenyl, -C(O)-1-adamantyl, -C(O)O-3-tetrahydrofuranyl, -C(O)O-4-tetrahydropyranyl, -C(O)CH 2 C(C H 3 3 -C(O)C(CH 3 3 -C(O)0C-Cl 0 alkyl, -C(O)NHC,-Cl 0 alkyl, -C(O)NHPh substituted with one, 2 or 3 cl-c 4 alkyl, Cl-C 3 alkoxy, halo, Cl-C3 alkylthio, trifluoromethyl, 02-C6 dialkylamino, or nitro, or -C(O)C 3 -C 8 cycloalkyl, -C(O)C(CH 2 CH 3 2 CH 3 -C(O)C(CH 3 2 CH 2 C1, -C(O)C(0H 3 2 CH 2 CH 3 -phenyl-1 -cyclopentyl, -C(O)-1-methyl-1-cyclohexyl, -C(S)NHC(0H 3 3 -C(O)NHCC(CH 3 3 or -C(O)NHPh. 4. A process of preparing R1 11 H3C.C1 N y 0 ce, 25 O0 *0 H R 1 O *6 3 N* *Ia R*U- H CAWNWOROUENNYMZPECNKI%1MOSIV.DOC -212- with a baccatin compound of Formula 8' Hoo 0c X2 in the presence of a dehydrating agent; wherein R 30 and R34, being the same or different, are selected from the group consisting of -OC(O)C 1 -C 6 alkyl, -OC(O)0CI-C 6 alkyl, -OC(O)OCH 2 CX 3 where X is Halo, -OC(O)OCH 2 CH 2 SiR 20 (where R 20 is Cl-C 6 alkyl), or -OSi(R 1 6 3 [where R 16 being the same or different, is selected from Cj-C 6 alkyl or cyclO(C 5 0 8 )alkyl]; X 2 is selected from the group consisting of -H, -cl-c 4 alkyl, -0,-C 3 alkoxy, halo, 3 alkylthio, 9 9**-trifluoromethyl, -02-C6 dialkylamino, benzyloxymethyl, 0* cya no, azide (N 3 or nitro; R, is selected from the group consisting of -CH 3 C:XWNWORDUENNYMSPECNKIX16806orV.DOC -213- -0 6 H 5 or phenyl substituted with one, 2 or 3 cl-c 4 alkyl, 01-03 alkoxy, halo, Cj-C3 alkylthio, trifluoromethyl, 02-C6 dialkylamino, hydroxy or nitro, 2- furyl, 2-thienyl, 1 -naphthyl, 2-naphthyl or 3 4 -methylenedioxyphenyl; and 1 is selected from the group consisting of -Cl-Cl 0 alkyl, -phenyl, -phenyl substituted with one, 2 or 3 Cl-C4 alkyl, Cl-C3 alkoxy, halo, CI-C 3 alkylthio, trifluoromethyl, C2-C6 dialkylamino, hydroxy or n itro -1-adamantyl, (4 3 -tetrahydrofuranyl, -4-tetrahydropyranyl, or -CH 2 C(CH 3 3 A compound of the formula: 0 11 OH 3 2 0 NH H CH C 200 H2 0 H 0* GeV 6119 *00 0ep go DATED 20 August, 1998 PHILLIPS ORMONDE FITZPATRICK *p 30 Attorneys For: .See PHARMACIA UPJOHN COMPANY C:IV41NMROWENNYMISPECNKI 16606D[V.DOC
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU80860/98A AU726730B2 (en) | 1994-01-28 | 1998-08-21 | Delta 12,13-iso-taxol analogs, antineoplastic use and pharmaceutical compositions containing them |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US189235 | 1994-01-28 | ||
| AU16806/95A AU691575B2 (en) | 1994-01-28 | 1995-01-26 | Delta 12,13--iso-taxol analogs, antineoplastic use and pharmaceutical compositions containing them |
| AU80860/98A AU726730B2 (en) | 1994-01-28 | 1998-08-21 | Delta 12,13-iso-taxol analogs, antineoplastic use and pharmaceutical compositions containing them |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU16806/95A Division AU691575B2 (en) | 1994-01-28 | 1995-01-26 | Delta 12,13--iso-taxol analogs, antineoplastic use and pharmaceutical compositions containing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8086098A AU8086098A (en) | 1998-11-19 |
| AU726730B2 true AU726730B2 (en) | 2000-11-16 |
Family
ID=3706705
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU80860/98A Ceased AU726730B2 (en) | 1994-01-28 | 1998-08-21 | Delta 12,13-iso-taxol analogs, antineoplastic use and pharmaceutical compositions containing them |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU726730B2 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0534709A1 (en) * | 1991-09-23 | 1993-03-31 | Florida State University | Substituted taxanes as antitumour agents |
| EP0588959A1 (en) * | 1991-06-12 | 1994-03-30 | Thomas O Mcnamara | Nitinol stent system for hollow body conduits. |
| EP0814470A2 (en) * | 1996-06-19 | 1997-12-29 | Kao Corporation | Optical disk and process for producing the same |
-
1998
- 1998-08-21 AU AU80860/98A patent/AU726730B2/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0588959A1 (en) * | 1991-06-12 | 1994-03-30 | Thomas O Mcnamara | Nitinol stent system for hollow body conduits. |
| EP0534709A1 (en) * | 1991-09-23 | 1993-03-31 | Florida State University | Substituted taxanes as antitumour agents |
| EP0814470A2 (en) * | 1996-06-19 | 1997-12-29 | Kao Corporation | Optical disk and process for producing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| AU8086098A (en) | 1998-11-19 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) |