AU722920B2 - Delta 6,7-taxols antineoplastic use and pharmaceutical compositions containing them - Google Patents

Description

A

S F Ref: 322230DI

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Pharmacia &:Upjohn Company 301 Henrietta Street Kalamazoo Michigan 49001 UNITED STATES OF AMERICA Actual Inventor(s): Address for Service: Invention Title: Robert C. Kelly, Roy A. Johnson, Harvey I. Skulnick, Eldon G. Nidy Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia

A

6 ,7-taxols Antlneoplastic Use and Pharmaceutical Compositions Containing Them The following statement is a full description of this invention, including the best method of performing it known to me/us:oooooo .i 5845

A

6 .7-TAXOLS ANTINEOPLASTIC USE AND PHARMACEUTICAL COMPOSITIONS CONTAINING

THEM

BACKGROUND OF THE INVENTION Taxol is a member of the taxane family of diterpenes, having the structure shown below: 0 0

CE

10 H3 '0 0 CH3 Ho0 C/ 3 The numbering system shown for taxol is that recommended by ILU.AC (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.

25 The clinical pharmacology of taxcd is reviewed by Eric K. Rowinsky and Ross C.

Donehower, The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics, Pharma Ther., Vol 52, pp 35-84, 1991. Clinical and preclinical studies Swith taxol are reviewed by William J. Slichenmyer and Daniel D. Von Hoff, Taxol: A New and Effective Anti-cancer Drug, Anti-Cacer Drugs, Vol. 2, pp 519-530, 1991.

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; 4,876399; 5,227,400 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 0 428 376), 89400935.6 (Publication No. Al 0 366 841) and 35 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.

Various processes for the preparation of taxol (and intermediates and analogs thereof) are described in Tetrahedron Letters. 1992, 33, 5185; J. Org. Chemn., 1991, 56. 1681 and J. Org.

Chem., 1991, 56. 5114.

Chen et al., Seendipitous 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 dichioromethane led to an unexpected reaction. involving participation of the C- 19 methyl group and clean formation of a cyclopropane ring. See also J. Org. Chem., 1993, 58. 4520 (August 13, 1993).

Chen, et. at., Tetrahedron Letters. 1994. 35, 41-44, have reported that the reaction of 2'- O-Cbz-taxol with DAST gave 2'-O-Cbz-7-deoxy-7a-fluorotaxol and 2'-O-Cbz-7-deoxy-70.8 methanotaxol. Removal of the 2'-O-Cbz protecting groups from the latter two compounds gave 7-deoxy-7cz-fluorotaxol and 7 -deoxy-70,8[ -methanotaxol. 7 8 -Cyclopropataxanes are the subject of U.S. Patent 5,254,580. Klein-, el. aL. J. Org. Chem.. 1994. 59, 2370, report formation of 7 0,813-methaotaxols.

U.S. Patent 5,294,637 (granted 15 March 1994) relates 7-fluorotaxal derivatives.

U.S. Patent 5,248,796 (granted 28 September. 1993) relates to IlO-desacetoxy-l 11,12dihydrotaxol-1O,12(18)-diene derivatives and the preparation of lO-desacetoxytaxol.

Chaudhary, A. et.al., J. Am. Chem. Soc., 1994, 116, 4097-8 discloses several meta and para-substituted 2-benzoyl analogs of taxol.

Didier, E. et.al., Tetrahedron Lmt., 1994, 3, 2349-52 describe the use of 2-aryloxarylidines as protecting groups for the taxol side-chanin precursor fragment.

Ojima, et.aL. Bioorganic Med. Chem. Lett. 1993, 3. 2472-82 describe several side chain urea analogs (including a t-butyl urea analog).

SUMMARY OF THE INVENTION This invention provides 7-deoxy-taxol analogs of Formula 1:

OR

1

O

0 30H2 1C CRI 3 J33 13- -H

R

4

R

5 I2 0 *O 6R O 1 7

LCE

3 R, is selected from -CH 3

-C

6

H

5 phenyl substituted with one, 2 or 3 cl-c 4 alkyl,

C

1

-C

3 alkoxy, halo, C 1

-C

3 alkylthio, trifluoromethyl,

C

2

-C

6 dialkylamino, hydroxy or nitro, -2 -furyl, 2-thienyl, 1 -naphthyl, 2-naphthyl and 3 4 -methylenedioxyphenyl;

R

2 is selected from -NHC(O)H, -NHC(O)C-Cloalkyl, -NHC(O)phenyl, -NI-C(O)phenyl substituted with one, 2 or 3 cl-c 4 alyC 1

-C

3 akxhoC 1

-C

3 alkylthio, trifluoromethyl,

C

2

-C

6 dialkylamino, hydroxy or nitro, -NHC(O)C(CH 3

)=CHCH

3 -N HC(O)OCH 2 phenyl, -NH 2 -NHSO2-4-rnethyl-phenyl,

-NHC(O)(CH

2 3 COOH, -NHC(O)- 4-(SO 3 H)phenyl, -OH, -NHC(O)-lI-adamantyl, -NI-C(O)O-3 -tetrahydrofuranyl, -N U1C(O)O- 4 -tetrahydropyranyl, -NHC(O)0C 1

-C

1 oalkyl, -NHC(O)NHC 1

-C

1 oalkyl, 'U -NI-C(O)NHPh, -NHC(O)-NHPh substituted with one, 2 or 3cl-c 4 alkyl, C -C 3 alkoxy, ia lo'. CI-C 3 a! kylthio, trifluoroemethyl,

C

2

-C

6 di alkylamino, or niitro, -NHC(O)C 3 CNxcyc loalkyl, -NHC(O)C(CH 3 2

CH

2 CI, phthialirniido, -NHC(O)-l1-phienyl- I-cyclopentyl, -N lC(O)- I -methyl- 1 -cyclohexyl and -NHC(S)NHC(CH3) 3 is -NHC(O)phenyl or -NHC(O)OC(CH 3 3 with the proviso that one of R 2 and I R 3 is -IH but R? and R 3 are not both -H;

R

4 is selected from -OH, -QAc (-OC(O)CH 3 -Oc(O)OcH 2 c(cl) 3 -0OCH)ClLH 2

NH

3 +HCOO-, -NHC(O)phenyl, -NHC(o)OC(CH 3 3

-OCO-CH

2

CH

2

COOH,

:-OCO(CH

2 3 COOH, [where Z is ethylene (-CH 2

CH

2 propylene

(-CH

2 CI-1CH 2 -CH=CH-, l,2-cyclohexane or 1,2-phienylene and R' is -OH, -OH base,

-NR'

2

R'

3

-OR'

3

-SR'

3

-OCH

2

C(O)NR'

4

R'

5 where R' 2 is -H or -CH 3

R'

3 is -(CH 2 6

R'

7 or (CH- 2 6

R'

7 R'gX- where n is 1-3, R' 4 is -H or -Cl-C 4 alkyl, R' 5 is -CI-C 4 alkyl, beiizyl, hydroxyethyl,

-CH

2

CO

2 H or dimethylaminoethyl,

R'

6 and R' 7 are -EH 3

CH

2

CH

3 or benzyl or R' 6 and R'-7 together with the nitrogen of NR' 6

R

7 form a pyrrolidino, piperidino, morpholino or N-methylpiperizino group, and R'g is -CH 3

-EH

2

CH

3 or benzyl, X is halide, anid base is NH 3

(HOC

2

H

4 3 N, N(CH 3 3

CH

3

N(C

2

H

4 2

NH

2

NH

2

(CH

2 6

NH

2 N-mnethylglucamine, NaOH or KOH], -OC(O)(CH 2 1

,NR

2

R

3 [where n is 1-3, R 2 is or -CI-

C

3 alkyl and R 3 is -H or -Ci-C 3 alkyl], -OC(O)CH(R")NH 2 [where R" is selected from Cl- 3 -cH 2

CH(CH

3 2

-CH(CH

3

)CH

2

CH

3

-CH(CH

3 2

-CH(CH

3 2

-CH

2 phenyl,

(CH

2 4

NH

2

-CH

2 CH)COOH, -(CH 2 3

NHC(=NH)NH

2 the residue of the amino acid Ao proline,

-CO(O)CH=CH

2 -C(O)CH2CH 2

C(O)NHCH

2

CH

2

SO

3

-OC(O)CH

2

CH

2

C(O)NHCH

2

CH

2

SO

3 wherein Y+ is Na+ or Na+(BU) 4 and -Oc(O)cH 2

CH

2

C(O)OCH

2

CH

2

OH;

R

5 is -H or -OH, with the provisos that when R 5 is -OH, R 4 is and that when R 5 is R4 is other than -H; RI() is -H or C )H3 R AL~ ~f~(L1BXXIO22S(Jdoc:KWW 3a Ri 7 is -H or -C(O)phenyl optionally substituted with one, 2 or 3 azido, cyano, methoxy, or halo substituents; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group; with the overall proviso that the following combination is excluded: RI is -CH3, -C 6 1-1 5 or phenyl substituted with one to 3 alkyl, alkoxy, halo or CF 3 groups; R2 is -NHC(O)H, -NHC(O)Ci- 6 alkyl, -NHC(O)phenyl, -NHC(O)phenyl substituted with one to 3 alkyl, alkoxy, halo or CF 3 groups, -NHC(O)C(CH 3

)=CHCH

3

-NHC(O)OCI-

i 0 (,alkyl or -NHC(O)C 3 6 Cycloalkyl; R3 is H;

R

4 is OH; Rs is II; and RI7 is -C(O)phenyl.

1i The compounds of Formula I are useful for 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.

Conventions for Formulas and Definitions of Variables The Chemical formulas representing various compounds or molecular fragments in 20 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, "Zi" or "Ri" 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 ZI would 2s represent a bivalent variable if attached to the formula CH 3 Groups Ri and R i S would represent monovalent variable substituents if attached to the formula CH 3

-CH

2 C(Ri)(Ri)-lH. 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 parentheses. 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 Ri and Ri 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 Ci, where is the integer corresponding to the carbon atom I.\I11XX]02280.doc KW\V 3b number. For example, C 6 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.

SThus CH 3

-O-CH

2 -CH(Ri)-CH 3 represents a 2-substituted- I-methoxypropane compound. In a similar fashion, the symbol represents a double bond, CH 2 =C(Ri)-O-CH 3 and the symbol represents a triple bond, HC=-C-CH(Ri)-CH 2

-CH

3 Carbonyl groups are represented in either one of two ways: -CO- or with the former being preferred for simplicity.

mi Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Thus, the compound 4 -chloro-2-methylpyridine can be represented in linear fashion by N*=C(CH 3 )-CH-CC1-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. Likewise, the cyclic molecular fragment, 4 -(ethyl)-l-piperazinyl can be represented i1 by Similarly, 2-furyl can be represented by C H=C I-C*H= and 2-thienyl represented by -C*-S-CH=CH-C*H=

*C

II.IXXI02280.doc:KWW

I

-4- 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, -C(X 1

)(X

2 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 (X

I

which is "below" another substituent (X 2 will be 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 (XI) 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 R i attached to a carbon atom as might be bivalent and be defined as oxo or keto (thus forming a carbonyl group CO-) or as two separately attached monovalent variable substituents a-Ri j and B-Rik. When a bivalent variable, Ri, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "a-R-Rij:B-R or some variant thereof. In such a case both a-Ri, and B-Ri-k are attached to the carbon atom to give -C(a-Ri For example, when the bivalent variable R 6

-C(-R

6 is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are a-R6- :B-R 6 2 a-R6.

9 :B-R6.

10 etc, giving -C(a-R6_ 9 etc. Likewise, for the bivalent variable R 11 two monovalent variable substituents are a-Rl 1 i B-R, 1.2 25 For a ring substituent for which separate a and B orientations do not exist due to the presence of a carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still usd. but the a and B designations are omitted. Just as a bivalent variable may be defined as two separate monovalent variable 30 substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula -CI(Ri)H-C 2 (Cl and C 2 define arbitrarily a first and second carbon atom, respectively) R i and Rj may be defined to be taken together to form a second bond between C 1 and C 2 or a bivalent group such as oxa and the formula thereby describes an epoxide. When R i and Rj are taken together to form a more complex entity, such as the group then the orientation of the entity is such that C 3 in the above formula is bonded to X and C 2 is bonded to Y. Thus, by convention the designation R i and Rj are taken together to form -CH 2

-CH

2 -O-CO- means a lactone in which ,the carbonyl is bonded to C 2 However, when designated Rj and R, are taken together to form -CO-O-CH 2

-CH

2 -the convention means a lactone in which the carbonyl is bonded to C

I

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 "CI-C4". where both "1" 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. "CI-C 4 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 indicates the entire carbon atom content of the variable being defined. Thus C2-C 4 alkoxycarbonyl describes a group CH3-(CH 2 )n-O-CO- 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 "Ci-C designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (Ci-C 3 )alkoxycarbonyl has the same meaning as C2-C 4 alkoxycarbonyl because the "C 1

C

3 refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C 6 alkoxyalkyl and (Cl-C 3 )alkoxy(C 1

-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 chemical structural formula of that particular substituent.

DETAILED DESCRIFTION OF THE INVENTION More specifically, this invention provides 7-deoxy-A 6 7 -taxol analogs of general Formula OR 10 0 "30 ,0 H 3

C

n 3H3 13 CH3 R 2 0

R

4

R

5 2 0 6 17 0CB 3 R, is selected from -CH 3

-C

6

H

5 phenyl substituted with one, 2 or 3 Cl-C 4 alkyl,

CI-C

3 alkoxy, halo, C 1

-C

3 alkylthio, trifluoromethyl,

C

2

-C

6 dialkylamino, hydroxy or nitro, -2-furyl, 2-thienyl, I1-naphthyl, 2-naphthyl and 3 4 -methylenedioxyphenyl; R2 is selected from -NHC(O)FI, -NHC(O)CI-Cl 0 alkyl, -NHC(O)phenyl, -NI-C(O)phenyl substituted with one, 2 or 3cl-c 4 alkyl, C 1

-C

3 akxhlCI-C 3 a ikyl thio, trifluoromethyl,

C

2

-C

6 dialkylamino, hydroxy or nitro, -NHC(O)C(CH 3

)=CHCH

3 -N HC(O)OCH 2 phenyl, -NHSO 2 -4-mnethyl-phenyl,

-NHC(O)(CH

2 3 COOFI, -NHC(O)- 4-(503 l-l)phenyl, -OH, -NHC(O)-lI-adamantyl, -NHC(O)O-3-tetrahydrofuranyl, N HC(O)O-4-tetrahydropyranyl,

-NHC(O)OC

1

-C

1 oalkyl, -NHC(O)NHC I -C 1 0 alkyl, -Nl-lC(O)NH-Ph, -NHC(O)-NHPh substituted with one, 2 or 3 cl-c 4 alkyl, cI-c 3 alkoxy, halo, C 1

-C

3 alkylthio, trifluoroemethyl,

C

2

-C

6 dialkylamnino, or nitro, -NHC(O)c 3 Qxcycloalky I, -NHc(O)C(cH 3 2 CH,)Cl, phthalirnido, -NHC(O)-lI-phenyl- I-cyclopentyl, -N HC(O)- I-miethyl-I -cyclohexyl and -NHC(S)NHC(CH 3 3 RK, is -NHC(O)pheiiyl or -NHc(O)oc(CH 3 3 with the proviso that one of R 2 and Z is -11 but R 2 and R 3 are not both -H; R4 is selected from -OH, -QAc (-OC(O)cH 3 -OC(O)OcH 2 C(Cl) 3 -0cOcl-bcHNH 3 +HcOO-, -NHc(O)phenyl, -NHc(o)oc(cH 3 3 -OcO-cH 2 cH 2 cOOH, -OcO(CH 2 3 cOOH, [where Z is ethylene (-cH 2 cH 2 propylene -cH=cH-, 1,2-cyclohexane or 1,2-phenylene and R' is -OH, -OH base, ::21-NR',R' 3

-OR'

3

-SRW

3 -OcH 2 c(O)NR' 4

R'

5 where R' 2 is -H or -CH 3

R'

3 is -(cH 2 1

,NR'

6

R'

7 r(cl- 2 6

R'

7

R'

8 X- weeni1-3,

R'

4 is -H or -cI-c 4 akyl, R'5 is -cI-c 4 alkyl, hcnzyl, hydroxyethyl, -CH 2

CO

2 H or dimnethylamninoethyl,

R'

6 and R' 7 are -CH 3

CH

2

CH

3 or benzyl or R' 6 and R'-7 together with the nitrogen of NR 6

R'

7 form a pyrrolidino, piperidino, morholno r -methylpiperizino group, and R' 8 is -CH 3 2 H rbnyXis halide, 2 and base is NH 3 (HOc 2

H

4 3 N, N(cH 3 3

CH

3

N(C

2

H

4 2

NH

2

NH

2

(CH

2 6

NH

2 N -nethylglucam-ine, NaOH or KOH], -Oc(O)(cH 2

),,NR

2

R

3 [where n is 1-3, R 2 is -H or -CI- V. Csalkyl and R 3 is -H Or -cI-c 3 alkyl], -Oc(O)cH(R")NH 2 [where R" is selected from c11 3 -cH 2 cH(cH 3 2 -cH(cH 3 )cH 2 cH 3 -cH(CH 3 2 -cH(cH 3 2 -cH 2 phenyl, (Cl-1b) 4 H, -CH 2 cH 2 cOOH, -(cH 2 3 NHC(=NI)NI-1 2 the residue of the amino acid .1 rline, -cO(O)cH=cH-?, -C(O)cH 2

CH

2

C(O)NHCH

2 cH 2

SO

3 -Oc(O)cH 2 cH 2 c(O)NHcH 2 cH 2

SO

3 wherein Y is Na+ or Na+(Bu) 4 and -Oc(O)cH 2 cH 2 c(O)OCH 2 cH 2

OH;

is -H or -OH, with the provisos that when R 5 is -OH, R4 is and that when R 5 is R4 is other than -H; 3 RIO is -H or -C(O)CH 3 I\.11l3.X10f229) 1,,c.KWW

R

1 7 is -H or -C(O)phenyl optionally substituted with one, 2 or 3 azido, cyano, methoxy, or halo substituents; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group; with the overall proviso that the following combination is excluded: R, is -CH 3

-C

6

H

5 or phenyl substituted with one to 3 alkyl, alkoxy, halo or CF 3 groups; R, is -NHC(O)H, -NHC(O)CI-6alkyl, -NHC(O)phenyl, -NHC(O)phenyl substituted with one to 3 alkyl, alkoxy, halo or CF 3 groups, -NHC(O)C(CH 3 )=CHCH3, -NHC(0)OCI- 0 alkyl or -NHC(O)C3- 6 cycloalkyl; R" is H;

R

4 is OH; is Hi; and

R

17 is -C(O)phenyl.

is R,17 is preferably -C(O)C 6

H

5 or -C(O)phenyl substituted with one azido, cyano, methoxy, or halo; more preferably -C(O)C 6

H

5 or -C(O)phenyl substituted with one azido, cyano, methoxy, or chloro atom in meta position; most preferably -C(O)C 6 Hs.

preferred embodiment of the subject invention is compounds of Formula I where R, is phenyl or phenyl substituted with halo, R 2 is -NHC(O)C 6

H

5

R

3 and R 5 are R4 is -OH, N Rio is -H or -C(O)CH 3 and R 1 7 is -C(O)CsH. Another preferred embodiment of the subject invention is compounds of Formula I where R, is preferably phenyl or phenyl substituted with halo, R2 is -NHC(O)OC(CH 3 3

R

3 and R 5 are R 4 is -OH, and Rio is -H or -COCH 3 and R 1 7 is -C(O)C 6 1- 5 A further preferred embodiment of the subject invention is compounds of Formula I where RI is preferably phenyl or phenyl substituted with halo, R 2 3 is -NHC(O)NH-C(CH 3 3

R

3 and R 5 are R 4 is -OH, RI 1 o is -H or -COCH 3 and R 17 I is -C(0)C6Hi.

An embodiment of the subject invention are compounds of Formula I where Rj is selected from the group consisting of -CH 3

-C

6

H

5 or phenyl substituted with one, 2 or 3

CI-C

4 alkyl, C 1

-C

3 alkoxy, halo, C 1

-C

3 alkylthio, trifluoromethyl,

C

2

-C

6 dialkylamino, hydroxy or nitro and R 2 is selected from the group consisting of -NHC(O)H, -NHC(O)CI-Cloalkyl (preferably -NHC(O)C 4

-C

6 alkyl), -NHC(O)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 Cl-C 4 alkyl, C 1

-C

3 alkoxy, halo, CI-C 3 alkylthio, trilluoromethyl,

C

2

-C

6 dialkylamino, hydroxy or nitro, -NHC(O)C(CH 3

)=CHCH

3

-NHC(O)OC(CH

3 3

-NHC(O)OCH

2 phenfl, -NH 2

-NHSO

2 -4-methylphenyl,

-NHC()(CH

2 3 COOH, -NHC(O)-4-(SO 3 H)phenyl, -OH, -NHC(O)-1 -adamantyl, .IlXX)B1228.dc KWW a 7a -NHC(O)O-3)-tetrahydrofuranyl, -NHC(O)O-4-tetrahydropyranyl,

-NHC(O)CH

2

C(CH

3 3 -N I-C(O)C(CI-1 3 3 -NHC(O)0C 1

-C

1 oalkyl, -NHC(O)NHC 1

-C

1 ealkyl, -NFIC(O)NHPh substituted with one, 2 or 3 cl-c 4 alkyl, C 1

-C

3 alkoxy, halo, C 1

-C

3 alkylthio, tri fluoromethyl, C 2

-C

6 dialkylarnino, or nitro.

Another embodiment of the present invention are A 67-taxol analogs of general l'orniula I wherein: R, is selected from the group consisting of -CH 3

-C

6 1- 5 or phenyl substituted with Ofle.

R \LNI II XJ022S0.d KWc 2 or 3 cl-c 4 alkyl, C 1

-C

3 alkloxy, halo, C 1

-C

3 alkylthio, trifluoromethyl, C 2

-C

6 dialkylamino.

hydroxy or nitro;

R

2 is selected from the group consisting *of -NHC(O)H. -NHC(O)CI 1

-C

10 alkyl.

-NHC(O)phenyl, -NH-C(O)phenyl substituted with one. 2 or 3 C 1

-C

4 alkyl. C 1

-C

3 alkoxy. halo.

cl-c 3 alkylthio, trifluoromethyl. C 2

-C

6 dialicylamino. hydroxy or nitro, -NHc(o)c(CH 3 )-cHCH 3 -NHC(o)oC(CH 3 3

-NH

2

-NHSO

2 -4-methylphenyl, -NHC(o)(CH 2 3 CoOH. -NHC(O)-4-(SO 3 H)phenyl, -OH, .NHC(O)- 1 -adamantyl.

-NHC(o)o-3-tetraliydrofuranyl, -NHC(O)-4-tetrahydropyranyl. -NHC(O)CH 2

C-(CH

3 3

-NHC(Q)C(CH

3 3 -NMc(O)0C 1

-C

1 0 alkyl. -NHC(O)NHC 1

-C!

1 alkyl. -NHC(o)NHPh substituted with one, 2 or 3 C 1

-C

4 alkyl. C I-C 3 alkoxy. halo. C 1

-C

3 alicylthio. trifluoromethyl.

C2-C 6 dialkylamino, or nitro Or -NHC(o)C 3

-C

8 cycloalkyl; R 17 is -C(O)C 6

H

5 and R 3

R

4

RS

and Roare as defined above. A preferred embodiment of the present invention are A6.7 -zaxol analogs of genera Formula I where RIis phenyl or phenyl substituted with halo, R 2 is -NEC(o)C 6

H

5

R

3 and R 5 are RIO is -C(O)CH 3 and R 17 is -C(O)C 6 HS. Another preferred embodiment of the subject invention are compounds of Formula I where R1is preferably phenyl or phenyl substituted with halo, R 2 is -NHC(Q)OC(CH 3 3 R 17 is -C(O)C 6

H

5 and R 3

R

5 and ROare -H.

Preferred embodiments of Formula I include: A compound according to Formula L. namely 7-deoxy-A 6 7 -taxol (Compound 16E);, A compound according to Formula, 1, namely 2'-[{(2.2,2-trichloroethyl)oxy)carbonyl)-7- ***deoxy-& 6 7 -taxol; and 6.7 -A compound according to Formula 1, namely l0-acetyl-7-deoxy-A 'taxotere (Compound 16D).

A compound according to Formula L, namely N-Debenzoyl-N-t-butylaminocarbonyl-7-deoxy- 25 A 6 7 -taxol (Compound 16F).

Examples of -NHC(O)C 1

-CI

0 alk include -NHc(Q)-n-pentyl and 00 -NHC(Q)CH(CH 3

)CH

2

CH

3 Examples of c 1 -c 6 ailkyl 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 forms thereof Halo refers to -Br, -Cl or 4I.

Examples of Formula I compounds of this invention include: 67_ 2 -{[(2,2,2-trichloroethyl)oxylcarbonyl}-7-deoxy-A taxol (Compound 7-deoxy-A 6 7 -taxol (Compound 16A); N-Debenzoyl-N-benzyloxycarbonyl-2'-([(2,2.2-trichlor-oethyl)oxyjcarbonyl }-7-deoxy-

A

6 7 -taxol (Compound N-Debenzoyl-N-benzyloxycarbonyl-7-deoxyA 6 7 -taxoI (Compound 1 6B); 2-Debenzoyl-2-(m-azido)benzoyl-7-deoxy-A 67 -axol; 2'-succinyl,-7-deoxy-A 6 7 _taxol,; 2'-(f-alanyl)-7-deoxy-AO 6 7 -taxolforrnate; 2 '-gl'utarylW7 -doxy-A 6 7 -taxol;.

29 2 3

C(O)NH(CH

2 3

N(CH

3 2 ]-7_deoxy_A 6 7 _taxol; 2'-$f-sulfopropionyl)-7-deoxy-A 6 7 taxol; 2'-(2-sulfoethylamido)succin'yl-7-dcoxy-A 6 7 -taxol; 2'-(3-sulfopropylamido)succinyl-7-dcoxy-A& 6 7 .taxol;, 2'-(triethylsilyl)-7-deoxyA 6 7 -taxol;, 2'-(t-butyldimethylsilyl)-7-deoxy-A 6

I

7 4axohI 2'-(NN-diethylaminopropionyl)-7-deoxy-A 6 7 taxol; 2'-(N.N-diinthylglycyl)-7-deoxy-A 6 '.axol; 2'4glycyl)-7-deoxy-,A 6 7 -taxol; 2'-{L-alanyl)-7-deOxy-A 6 7 _taxol; 2'-(L-lcucyl)-7.deoxy-& 6 7 -taxol; 2'-(L-isoleucyl)-7-deoxyA 6 7 _taxol; 2'-(L-valyl)-7-deoxyA 6 7 -taxoh, 2'-(L-phenylalanyl)-7-deoxy-A& 6 7 -axol; 2'-(L-prolyl)-7-deoxy-A 6 7 -taxol; 2'-(L-Iysyl)-7-deoxy-A 6 7 _taxol; 2'-(L-glutaxnyl)-7-deoxy-A 6 7 -taxol; 2'-(L-arginyl)-7-deoxy-A 6 7 -taxoI; 7-ckoxy-,A 6 7 taxotmr (Compound 16E); 25 10-acetyl-7-deoxy_-A 6 7 _=taxoe(Compound16) N-Debenzoyl-N-t-butylaminocarbonyl-7-dcoxyA -taxol (Compound 16F); ~~N,2-Bisdezo1-2-(m-azido)benzoyI-7-deoxy-A6-xtcc ***N,2-Bisdebenzoyl-2-(m-azido)benzoyl-1O-acetyl-7-dcoxy-A& 6 7 _taxotere; Z A 6, N.2-Bisdebenzoyl-2-(m-azido)bcnzoyl-N-t-butylaminocarbonyl-7-deoxy -A 6 _taxol; N,2-Bisdbenzoyl-2-mho)bzoyl-7-oxy-A. -taxotre, N,2-Bisdcbenzyl-2-(m-chloro)benzoyl- I O-acetyl-7-deoxy-& 6 7 -taxotere; N,2-BisdebenzoyI-2-(m-chloro)beazoyl-N-t-butylaminocarbonyl-7-deoxy-A taxol; N,2-Bisdebenzoyl-2-(m-rnethoxy)benzoyl-7-deoxy-A 67 -taxotere; N,2-Bisdebenzoyl-2-(m-methoxy)benzoyl- 10Oacetyl-7-deoxy-A 6 7 _taxotrec N,2.Bisdebenzoyl-2-(m-niethoxy)bcnzoyl-N-t-butylaniinocarbonyl-7-doxy-A 6 -axol; N,2-Bisdebenzoyl-2-(m-cyano)benzoyl-7-dcoxy-A 6 7 -taxotere; N.2-Bisdebenzoyl-2-(m-cyano)tbcnzoyl-10-acetyl-7.deoxy-A 6 7 taxotcre.

N,2-Bisdcenzoyl-2-(m-cyano)benzoyl-N-t-butylanminocarbony1-7-deoxy-A 6 7 taxo; N-Debenzoyl-N-( 1 -phenyl- 1 -cyclopcntanoyl)-7-deoxy-A 6 7 _axol; N-Debenzoyl-N-phthalimido-7-deoxyA 6 7 -taxol; N-Dcenzoyl-N-t-butylaminothiocarbonyl-7-deoxy-A 6.7_axol; N-DebenzoyI-N-t-axnyloxycarbonyl-7-deoxy.A& 6 7 -taxol; N-DebenzoyI-N-neopentyoxycxbonyl7-deoxy- 6 7 _taxo; N-Debenzoyl-N-(2-chloro- 1.1 -dimethylcthyl)oxycarbonyl-7-deoxy-A 6 7 _uixol; N-ebnzoyl-N-(3-mthyl-3-pentyl)oxycarbonyl-7.deoxy-A 6 7 _raxol; 3'-dcsphcnyl.3'-(2-furyl)-7-deoxy-& 6 7 _taxol; 3 -desphenyl-3 '-(2-thi enyl)-7-deoxy-A 6 7 .axo1; 3'-desphenyl-3 -riaphthyl)-7-deoxy-A 6 7 _taxol; 3 -desphenyl-3'-(2-naphthyl)-7-deoxy-A 6 7 _taxoli; 3 '-desphenyl-3 '-(4-rnethoxyphenyl)-7-deoxy-A 67 -_taxol; 3 '-desphenyl-3 -{4-chloropbenyl)-7-deoxy-A 6 7 -taxol.

3'-desphenyl-3 '-(4-bromophenyl)-7-deoxy-A 6 7 taxol; 3 '-desphenyl-3 '-(3,4-miethylenedioxyphenyl)7-deoxy-A 6 7 -tol; 3 '-desphenyl-3 A-dixnedhoxyphenyl)-7-deoxy-A 6 7 -taxol; 3 '-desphenyl-3 '-(4-nitophenyl)-7-deoxy-A& 6 7 .taxol; 3 '-desphenyl-3 '-(4-fluorophenyl)-7-deoxy-A 67 taxol; N-debenzoyl-N-(4-bromobenzoyl)-7-deoxy-A 6 7 _taxol; N-debenzoyl-N-(4-nethylbenzoyl)-7-deoxy_,A 6 .'kaxo; ~~6.7 N-debenzoyl-N-t-fluybenzoy1)-7-deoxyA 6 7 -axol; 5N-debenzoyl-N-(4-n-ethoybenzoyl)-7-despey-3-4clrpey)7doxy-A 6 ,7-zaxol; *.N-debenzoy,-N-(4-lorobenzoy)-3'-despcyl-3 -(4-fluorophenyl)-7-deoxy-A 6 7 _taxol; ~N-debenoyl-N-(4-fluomobenzoy)-3-desphxyl3' 7 -xo1; hny)7-ex-A._tx N-debenzoyl-N-(4-rethylbenzoyl)-3 '-desphenyl-3 '-(4-lorophenyl)-7-deoxy-A 6 7 taxol; N-debenzoyl-N-(4-lorobenzoyl)-3'-desphenyl-3 '-(4-metuoophenyl)-7-deoxy-A 6 7 _xl 30Ndbnoy--4boobnol- -dshnl3 -4furphnl--exyA 7 txl N-debenzoyl-N-(4-fluorobenzoyl)-3-desphnyl-3 -(4-mthoxyphcnyl)-7-deoxy-A 7 taxol; N-debenzoyl-N-(4-fluorobenzoyl)-3 -desphenyl-3 '-(4--chdorophenyl)-7.-deoxy-A 6 7 taxol; N-debenzoyl-N-(4-chlorobenzoyl)-3 -desphenyl-3 '-(4-chloropheny)-7-deoxy- 6 7 .tzct: N-debenzoyl-N-(4-bromobenzoyl)-3 '-desphenyl-3'-(4-chlorophenyl)-7-deoxy-A 6 7 amajL N-debenzoyl-N-(4-t-butylbenzoyl)-3 '-desphenyl-3 -(4-chlorophenyl)-7-deoxy, 6 7 c 1 jc N-debenzoyl-N-(4-t-butylbenzoyl)-3 '-desphenyl-3 '-(4-fluoropheny1)-7-deoxy-A 6 N-debenzoyl-N-(4-chlorobenzoyl) 3 '-desphenyl-3 '-4-methoxypheny)-7-deoxy-,A 6 7 taxol; N-debenzoyl-N-(4-bromobenzoyl)-3 -desphenyl.3'-(4-methoxyphenyl)-7-deoxy-,A 6 taxol; N-debenzoyl-N-(4 -t-butylbenzoyl)-3 '-desphenyl-3 -(4-methoxypbeny1)-7-deoxy-.& 6 7 taxol; N-debenzoyl-N-(4-methoxybenzoyl)-3'-desphenyl-3 '-(4-methoxyphenyl)-7-deoxy..a 6 -7Ltaxol; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or bas functional group.

The present invention also provides a process for preparing oxazolidines of Formnjga

H

~.in which *R is as defined above;

R

9 is selected from C 1

-C

6 alkyl; R, I is phenyl substituted with -(QC 1

-C.

2 alkyl)n v'aw M islIto3-,

R

12 is selected from the group consisting of -C(O)CI-Cl 0 alkyl (preferably

-C(O)C

4 -4C 6 alkyl). -C(O)phenyl, -C(O)phenyl substituttd with one, 2 or 3 C 1

-C

4 alkyl,

CI-C

3 alkoxy, halo, CI-C 3 alkykhio, trifluoromethyl, C 2

-C

6 dialkylamino, hydroxy or nitroj.

-C()C(C

3 )-CHC1 3

-C(O)OC(CH)

3

-C(O)OCH

2 phenyl, S0-4-methylphenyl,

-C(Q)(CH

2 3 COOH, -C(O)-4-(SO 3 H)pbenyl, 1 -adamantyl, -C(O)O-3-tetrahydrofur=7p_ -C(Q)O-4-tetrahydropyranyl, -C(O)CH 2

C(CH

3 3

-C(O)C(C-

3 3 -C(O)0C 1

-C

1 alkyl,

-C(O)-NHC

1 -Cl 0 alkyl, -C(Q)NH-Ph substituted with one, 2 or 3 C 1

-C

4 alkyl, C 1

-C

3 alkoxj.

halo, C 1

-C

3 alkylthio, trifluoromethyl, C2 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(CH3!) 2

CH

2 CI, COCC 3 2 Clii I-phenyl-lI-cyclopentyl. I-methyl-i -cyclohexyl, -C(S)NHC(CH 3 3

-C(O)NHC(CH-

3 3 or -C(O)NHEh; -12which comprises reacting a hydroxy-amine of Formula 3 R O in which IIand R3are as defined above and R 2 is selected from the group consisting of

-NHC(O)H,-NHC(O)C

1 -Cj 0 alkylI (preferably -NHC(Q)C 4

-C

6 alkyl). -NM-C(Q)phenyl, -NHC(O)phenyl substituted with one, 2 or 3 C 1

:-C

4 alkyl. C 1

-C

3 alkoxy. halo,

C

1

-C

3 alkylthio, trifluoromethyl, C 2

-C

6 dialkylamnino, hydroxy or nitro.

-NHC(Q)C(CH

3

)-CHCII

3

-NH-C(O)OC(CH

3 3

-NHC(O)OCH

2 pbenyl.

-NHSO

2 -4-rnethylphenyl., -NHC(O)(CH 2 3 C0011, -NHC(Q)-4--(SO 3 H)phenyl, -NHC(O)-1 -adaxnantyl, -NHC(O)O-tetrahydrofuranyl, NHC(O)O-4-tetrahydropyranyl,

-NHC(Q)CH

2 C(CHi 3 3

-NE-C(O)C(CH

3 3 -NHC(Q)0C 1 -Cl 0 alkyl, -NH-C(Q.)NHC 1 -Cl 0 alkyl. -NI-C(O)NHPh substituted with one, 2, or 3

C

1

-C

4 alkyl, C 1

-C

3 alkoxy, halo, C 1

-C

3 alkylthia, trifluoromethyl, (2 2

-C

6 dialkylamino. or nitro, or -NHC(O)C 3 -Cgcycloalkyl. -NHC(O)C(C1 2

CH

3 2

C-

3

-NHC(O)C(CH

3 2

CH

2

CI,

-NH-C(O)C(CH

3 2

CH-

2

CH'

3 -NHC(O)-1-phenyl-1 -cyclo-pentyl.

-NHiC(O)- 1-methyl-i -cyclohexyl, -NH-C(S)NEC(CH 3 3

-NHC(O)NHC(CH-

3 3 or -NHC(O)N'HPh?; with an electron rich benzaldehyde of Formula 4A 630 (C-C~alkyl )a where n is 1-3.

-13- In acidition, the present invention provides a process of preparing which comprises reacting an oxazolidine free acid of Formula 7 with a baccatin compound of Formula 8

C..

*4 a.

in the presence of a dehydrating agent. Wherein R 10 and: R 1 4 being the same or different. are selected from the group consisting of -C(O)CI-C 6 alkyl, (preferably -C(O)CH 3 -C(O)0CI -C 6 alkyI, -C(O)OCH 2 C-XTj where X is Halo, -C(Q)OCH' 2 CH 2 SiR 20 (where R 20 is C 1

C

6 alkl), or -Si(Rr) 3 R 11 and R 12 are as defined above. 30 The compounds of the present invention are prepared b'y the method(s),as shown in Charts A, B. C and D.

-The starting point for the method shown in Chart A is a taxol or taxol analog derivative A-I. Reaction of the A-I compound with a reagent such as diethylarninosulfur trifluoride (DAST), dimethylamninosulfur trifluoride (methylDAST). bis(dimethylamaino)sulfur difluoride.

bis(diethylamino)sulfur difluoride, or (diethylamino)(dimethylamino)sulfur difluoridc. gives the 7-deoxy-A 6 7 analog A-2 (CHART A-1) as well as 7 -dcoxy-70,8-methano analog A'-2 (CHART A-II) as well as 7-deoxy-7-fluoro analog A"-2 (CHART A-III). The preferred method for this conversion is with DAST or methylDAST. The reaction with DAST or methylDAST is carried out in an aprotic solvent such as methylene chloride (CH 2

CI

2 chloroform (CHC1 3 fluorotrichloromethane (Freon ethylene glycol dimethyl ether (glyme). 2 -methoxyethyl ether (diglyme), pyridine, hydrocarbons such as pentane, hexane, or isooctane. tetrahydrofuran (THF), benzene, toluene, xylehe. The preferred solvent is methylene chloride. The reaction may be performed in a range of temperature from -100*C to 100 0 C or above. Generally, the reaction is begun under conditions of low temperature, -78 0 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. The product A-2 of this procedure is then submitted to conditions of reaction which will remove any protecting groups. For example, if a richlorocthyl)oxy]carbonyl (troc) group is used to mask a hydroxyl group of taxol or of a taxol analog, treatment of A-2 (CHART A-I) with activated zinc in methanol-acetic acid solution will serve to remove the protecting group and produce the desired 7-deoxy-A6.

7 -taxol or 7-deoxy-

A

6 7 -taxol analog A-3 (CHART [Treatment of A'-2 (CHART A-II) with activated zinc in methanol-acetic acid solution will serve to remove the protecting group and produce the desired 7-deoxy-70,p-methano-taxol or 7-deoxy-70,f-methano-taxol analog A'-3 (CHART A-II.

Treatment of A"-2 (CHART A-Il) with activated zinc in methanol-acetic acid solution will serve to remove the protecting group and produce the desired 7 -deoxy-7-fluorotaxol or 7-deoxy- 7-fluorotaxol analog A"-3 (CHART Methodologies for the addition of various protecting groups to taxol or to taxol analogs and for the removal of such groups are found in: Greene. T.W. and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd Ed., pages 142, Wiley, N.Y. 1991.

Alternatively, the compounds of this invention (Formula I) may be prepared treatment of a 7-epi taxol derivative with DAST in dichloromethane as disclosed in Chen et al., Serendipitous Synthesis of a Cyclopropane-Containing Taxol Analog via Anchimeric Participation of an Unactivated Angular Methyl Grodp, Advance ACS Abstracts, Vol 1, No. July 15, 1993 and J. Org. Chem., 1993, 56, 4520, (August 13, 1993).

30 The compounds of this invention (Formula I) may be prepared by a new, improved procedure as shown in Charts B, C and D. The preparation of 3 -azido-2-hydroxy-carboxylic acid esters 1 may be prepared as describ-d in the literature (see Denis, Correa, Greene, A. E. J. Org. Chem., 1990, 55, 1957). These materials are readily hydrogenated to the free amines 2, even though the literature intentionally avoids this intermediate by preparing the 35 hydroxy-acylated intermediate prior to the reduction of the azide. The amine 2 is sufficiently stable that no problem is encountered in isolating it and directly using it to prepare the Nacylated free hydroxy compounds 3. Compounds 3 have been utilized by protection of the hydroxy group, hydrolysis of the ester to the acid, and condensation directly with a baccatin III derivative or after conversion to the oxazinone (European Patent 0 428 376 AlI, US 436235).

These procedures are distinctly inferior because they require large excesses of the acylating agent and generally do not proceed beyond about 60% completion. Procedures have also been described using a beta-lactam intermediate but these also require large excesses of reagent or the introduction of very strong bases such as LDA which makes them more difficult to perform and unsuitable for certain analogs (Ojima. Habus, Zhao, George, G. Jayasinghe. L. R. J.

Org. Chem., 1991. 56, 1681, EP 0 400 971 A2). A very effective condensation procedure involving the conversion of the hydroxy-amine derivative 3 to an oxazolidine with 2 non hydrogen substituents at the 2 position was described by Commercon, Bezard, Bernard.

Bourzat, J. D. in Tetrahedron Len.. 1992, 33, 5185 and Patent WO 92/09589. The condensation proceeds in very high yield but the removal of the protecting group requires sufficiently strong acid that sensitive taxol analogs are destroyed under the deprotection conditions. We have modified and improved this procedure by formation of the oxazolidines not with a ketone, as the above workers have used but, with an electron rich benzaldehyde 4.

The oxazolidines derived from the benzaldehyde 4 are produced as a mixture of diastereomers but these have been separated in some cases and the diastereomers have been shown to be equally useful when carried on in the synthesis. The oxazolidines 5 are readily hydrolyzed to the salts 6 and the acids 7. The acid is labile and needs to be used shortly after preparation.

Both oxazolidine isomers are equally effective in the condensation reaction with theprotected baccatins 8 giving an excellent yield of the oxazolidine protected taxol analogs 9. More importantly, both oxazolidine isomers from these electron rich benzaldehydes are readily hydrolyzed under very mild acid conditions allowing deprotection without causing undesired transformations of highly acid sensitive taxol derivatives such as 10 or the A 6 7 -taxol analogs 16 which are the subject of this invention. There are references to the use of electron rich aldehydes for the protection of 1,2-diols as dioxolanes but no previous reference to the use of such aldehydes for the protection of 2-hydroxy protected amines. The deprotection may be carried out such that both the oxazolidine and the 7 protected hydroxyl of 9 are removed at the 30 same time or each may be removed independently. Additionally described is the deprotection of selected urethae analogs 10 to the free amine 11 (Chart These are then reconverted to a variety of amine acylated analogs The conversion of azide 1 to the amine 2 is effected by reduction as is known in the art.

Thus, the reaction may be carried out by hydrogenation in the presence of a variety of hydrogenation catalysts such as palladium, platinum, rhodium, or ruthenium. Alternatively, the azide may be reduced by treatment with a phosphine such as triphenyl or tributyl phosphine or by an acid such as hydrochloric, sulfuric, trifluoroacetic or hydrobromic in the presence of a metal such as zinc. iron, or tin. These reactions may be effected in a solvent such as ethanol.

methanol, ethyl acetate, methyl t-butyl ether or tetrahydrofuran and the like. The conversion of amine 2 to its acylated derivative 3 is effected by treatment of the amine in pyridine or a non basic solvent such as methylene chloride or tetrahydrofuran containing a tertiary amine such as triethyl amine or ethyl diisopropyl amine with an acylation agent. If 3 is a urethane, 2 is treated with an agent such as benzylchloroformate, 2,2,2-trichloroethoxycarbonyl chloride. di-tertbutyldicarbonate, or other urethane forming agent as is known in the art. If 3 is an amide, 2 is treated with an acylating agent such as an acyl halide, and acyl anhydride, or other acylating agent as is known in the art. If 3 is a urea or a thiourea, 2 is treated with an agent such as alkyl or aryl isocyanate, alkyl or aryl isothiocyanate, or other urea or thiourea forming agent as is known in the art.

The hydroxy amide or urethane 3 is converted to the oxazolidine 5 by treatment with an electron rich benzaldehyde or its acetal such as dimethyl or diethyl acetal 4 and an acid catalyst such as p-toluene sulfonic acid, pyridinium p-toluene sulfonate or other acid catalysts known in the art in a solvent such as tetrahydrofuran, toluene, methylene chloride, or other aprotic solvent Examples of electron rich benzaldehydes include but are not limited to 3-.

4-methoxybenzaldehyde; 2.5-dimethoxybenzaldehyde; 2.4.6-trimethoxybenzaldehyde; and 4-ethoxybenzaldehyde. The preferred benzaldehyde is 2,4-dimethoxybenzaldehyde. The oxazolidine formation is generally carried out by heating to reflux to distill both the solvent and to carry off the evolved water or alcohol. The ester of 5 is hydrolyzed to the salt 6 by treatment with an alkali or quaternerary amine hydroxide or by an alkali carbonate or other base as known in the art in a solvent such as water, methanol, ethanol, or other protic solvent. The reaction may by carried out from -78°C to 100 0 C. The product 6 is stable and may be isolated by evaporation of the solvents and stored as a solid or the reaction may be used directly to convert 6 to the acid 7 by treatment with acid. Generally, 7 is obtained by treating an aqueous solution of 6 in a separatory funnel with sufficient acid such as hydrochloric, sulfuric, potassium hydrogen sulfate, or the like, and partitioning the desired acid into an organic solvent such as ethyl acetate, methylene chloride, ether, or the like and evaporation of the solvent. The resultant .00: 30 acid 7 is sufficiently pure and stable for use in the next reaction but in generall is not sufficiently stable for long term storage. The acid 7 is condensed with the baccatin derivative 8 to form the ester 9 with a dehydrating agent Most preferred for this procedure is a carbodiimide such as dicyclohexyl carbodiimide, diisopropyl carbodiimide, di-p-tolyl carbodiimide, ethyl dimethylaminopropyl carbodiimide hydrochloride salt, or the like, and a basic catalyst.

preferably 4-dimethylaminopyridine. The reaction is generally carried out in an aprotic solvent such as toluene, benzene, tetrahydrofuran, dioxane, or the like at 25 0 C to 100 0 C. Other i dehydration procedures for the formation of 9 may be used such as conversion of 7 to its mixed ester with a sulfonic acid such as with toluenesulfonyl chloride or benzenesulfonyl chloride, or formation of the acid halide from the dried 6 in the presence of oxalyl chloride as is known in the art for acid sensitive carboxylic acids. The oxazolidines 9 may be deprotected so that the protecting oxazolidine and the groups blocking the hydroxyl at the baccatin 7 position are individually removed in either order or both removed together depending on the protecting group at the 7 position and on the reaction conditions. If RI4 is an acid labile group such as a silyl ether, then hydrolysis of the oxazolidine may be run under mild acid conditions and leads to the 7 position deprotection as well, giving 10MZ directly. Conditions for such conversions include hydrolysis in aqueous acetic acid, aqueous alcoholic acid of 0.01 to 0.1 N at 0°C to or alcoholic acid of 0.01 to 0.1 N at 0OC to 50 0 C. Alternatively, the protection at the 7 position could be removed at a second step if it is not acid labile. For example, the trichloroethoxycarbonyl group at position 7 could be removed from 10MY (Chart B) by reduction as is known in the art to give 10MZ. Depending on the nature of the protecting group on the nitrogen R 2 or R 3 of 10MZ (Chart B) the protecting group can be removed to give 11Z. For example, when R 2 is PhCH20C(O)NH, it may be removed by mild hydrogenolysis. Conditions for such conversions include reduction with hydrogen over a metal catalyst such as palladium in a solvent such as ethanol or ethyl acetate at room temperature and from one to three atmospheres of pressure. Other methods are known in the art. The resultant amine 11Z may be reconverted to a amide or urethane 10MZ (Chart B) by acylation procedures as described for the conversion of 2 to 3 above. The product 10MZ may be protected on the 2' hydroxyl to give 12MZ (Chart For example, the 2' hydroxyl may be acylated with trichloroethoxycarbonyl chloride in pyridine or other aromatic amine solvents, or in a non basic solvent such as toluene, methylene chloride, or tetrahydrofuran containing a tertiary amine base.

The reaction may be run at -50 0 C to 100 0 C. Other methods for such acylations are well known in the art.

The reaction of taxol, taxol analogs 10MZ (R 15 is acetate or other suitable acyl 'o *moiety), baccatin IM, or bacoatia I analogs 8 (R 6 is acetate or other suitable acyl moiety) with hydrazine comprises a particularly advantageous method for preparation of 10-deacetyl taxol, 30 10-deacyl taxol analogs (10MZ, R 15 10-deacetyl baccatin III, and 10-deacyl baccatin III analogs R 6 Whereas the reported method (Samaranayake, et. al., J. Org.

Chem.,1991, 56, 5114) for removal of the acyl group from this position of taxol and baccatin structures, zinc bromide in methanol, gives a number of other products in addition to the desired deacylation product, the reaction with hydrazine gives almost exclusively the desired deacylation product. The reaction may be performed at room temperature in an organic solvent and usually requires as little time as 15 min or as much as 24 hr, depending on the substrate.

S..

a a.

The preferred solvent for the reaction is 95% ethanol and 98% hydrazine is the preferred form of the reagent.

The compounds of this invention (Formula I) may also be prepared, from taxol or taxol analogs having a substituent at C-7 with the properties of a good leaving group, a methyl xanthate, -C(-S)SCH 3 a diazonium ion precursor such as -NH 2 a sulfonate ester, -OSO2R (where R is a group such as, for example. -CH3, -CF 3

C

6

H

4 -(p)-CH 3

-C

6

H

4

-C

6

H

4 -(p)-N0 2 or one of the halogens, iodine or bromine or A methyl xanthate upon warming (to approximately 100-200*C) undergoes an elimination reaction producing the olefmn. A C-7 amine substituent upon reaction with nitrous acid (HNO 2 is converted to a diazonium ion. The diazonium ion undergoes spontaneous loss of nitrogen resulting in formation of the 7-carbocation from which loss of the adjacent C-6 proton produces the desired

A

6 7-olefin. A C-7 sulfonate ester when dissolved in a polar solvent (such as methanol-water, ethanol-water, trifluoroacetic acid) undergoes ionization resulting in formation of the 7-carbocation with subsequent loss of the C-6 proton and formation of the desired A 6 7 -olefin.

The ionization of the C-7 sulfonate ester may be enhanced by the addition of a non-nucleophilic base [such as potassium carbonate, potassium bicarbonate, 1,4-diazabicyclo octane (DABCO)] to the reaction medium. A C-7 iodide or bromide undergoes ionization and formation of the 7-carbocation in a polar solvent in the presence of metal salts, particularly silver salts such as silver acetate, silver trifluoroacetate, silver tetrafluoro-borate.

The compounds Formula I of this nvention [whereR 17 is not equal to -C(O)C 6

H

5 can be prepared by the procedure shown in Chart D according to the method of Chaudhary. A. G.; et.al., J. Am. Chem. Soc., 1994, 116, 4097-8.

Preparation 1: Preparation of (2R,3S)--phenyl isoserine methyl ester (2) The (2R,3S)-3-azido-2-hydroxy-3-phenylpropionic acid methyl ester 0.5 g) is hydrogenated over 10% palladium on carbon (0.1 g) in ethanol at atmospheric pressure for 1 hour. The reaction is filtered and evaporated to yield the desired amine. Mp 106-108*C.

NMR(CDCj 3 TMS): 8 2.1 3.80 3H); 4.31 2H); 7.28-7.45 Preparation 2: Preparation of (4S,5R)-N-Benzoyl-2-(2,4-dimethoxyphenyl)-4-phenyl-5oxazolidinecarboxylic acid methyl ester (SAa 30 N-Benzoyl--phenyl isoserine methyl ester (3A, 0.5 g, 1.67 mM) is dissolved in dry :'THF (10 mL) and benzene (10 mL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal 0.420 g, 1.98 mM) and pyridinium p-toluenesulfonate (12 mg) and the solution warmed to reflux. After 30 minutes the reaction is cooled to RT and allowed to stand overnight. It is then again warmed to slowly distill off 1/2 of the solvent over 1 hr. TLC shows the reaction to be finished at this point. The reaction is concentrated in vacuo and the residue chromatographed over 50 g silica gel packed in (5-95) methanol-toluene. The column is eluted with methanol-toluene Fractions of 12 niL are collected. The product elutes as a mixture. Thus, fractions containing both 5Aa 5Ab are recombined and evaporated. The residue (0.90 g) is rechrornatographed over silica gel (100 g) The column is eluted with ethyl acetate-toluene (500 mL of 15-85 and 500 mL of 20-80). Fractions of 20 mL are collected and analyzed by TLC The fractions containing each 5Aa 5Ab are combined and -evaporated under vacuum.

less polar isomer mixture of less polar and more polar isomers SAa and SAb more polar SAb Isomer SAb is crystallized firom EtOAc to give white crystals (142 mg. mp 138-141 0

C).

Data for TLC: silica gel; 20% EtOAc-80% toluene; Rtf: 0.50 'H NMR (CDCI 3 TM) 3.77 3H); 3.86 3H); 4.93 1H). 5.6 (brs, IH); 6.28-6.37 (in. 211); 6.90 lH); 7.03 IH); 7.15-7.55 (in. Data for SAb: TLC: silica gel;, 20% EtOAc-80% toluene; Rf: 0.41.

1 H NMR (CDC1 3 TMS): 8 3.62 (bs, 3H); 3.75 (brs, 6H); 4.65 1H); 5.68 (bs. 1H); 6.2-6.5 2H); 6.8-7.55 (mn, I I1H).

UV: EtOH;. 229 (16,000), 277 (3,240), 281sh (3,170).

Elemental analysis: Calculated: C 69.79; H 5.63; N 3.13.

Found: C 69.61; H15.61; N 2.93.

Preparation 3: Preparation of (4S,5R)-N-benzyl-2-(2,4 carboxylic acid potassium salt. 6Ab (4S,5R)-N-benzyl-2-(2,4 dimnethoxyphenyl)-4 -phenyl-5-oxazolidine carboxylic acid methyl ester (Preparation 2, 5Ab, 3S5rng,0.79rM is dissolved in 9ml methanol. To the solution is added water (350ji1) and* potassium carbonate (I155mg, 1. 12mM). After stirring hours no solids remain and TLC indicates very little methyl ester remaining. The solvent is concentrated in vacuo and water (l0mI) added to the oil. 7he solution is freeze dried leaving 500mg fluffy white powder whi'ehixmtains 374mg of the potassium salt.

TLC: silica gel 60;, 1:2 EtOAc:Hcxane; R:origin.

Prparaion Preparation of 7-TES-baccatin II-13,-{4S.5R)-N-Benzoyl-2-(2,4-diinethoxyphenyl)-4-phenyl-5-oxazoldinecarboxylic acid ester (9AbA) A solution of (4S,5R)-N-benzoyl-2-(2.4 carboxylic acid potassium salt (6Ab, Preparation 3, 91.4 mng. approximately 0.15 mM) in ethylL acetate is washed with 5% aqueous NaHSO 4 The ethyl acetate solution is dried and evaporated leaving the corresponding acid MA. The residue is dissolved in methylene chloride (0.8 ml) and toluene (1.75 ml), and combined with 7-triethylsilyl-baccatin III (68 mg). The mixture is treated with 4-dimethylaminopyridine (6.3 mg) and 1.3-dicyclohexylcarbodiimide (34 mg). The reaction is heated to 80 C for 90 minutes, cooled, filtered, and chromatographed on silica gel in ethyl acetate-hexane mixtures. An 86% yield of the coupled product 9AbA was obtained.

NMR (CDC1 3 TMS): 5 0.58 6H); 0.90 1.73 3H); 1.87 2.03 2.17 (bs,3H); 2.20 2.23 2.50 1H); 3.78 (bs. 3H); 3.80 3H); 3.85 1H); 4.13 1H); 4.27 1H); 4.50 1H); 4.90 2H); 5.63 (bs, 1H); 5.68 1H); 6.25-6.48 3H); 6.50 1H); 6.86 1H); 7.09 1H); 7.15-7.65 13H); 8.05 2H).

Preparation 5: Preparation of Taxol (Compound 7-TES-baccatin m-13-(4S,5R)-N-Benzoyl-2-(2.4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (9AbA) is deprotected by stirring in 0.1 M HCI in methanol for minutes. After diluting with ethyl acetate, the solution is washed with 5% NaHCO 3 dried and evaporated. The product is purified by column chromatography on silica gel in acetone-hexane mixtures. The proton and carbon NMR data are identical with natural taxol.

Preparation 6: Preparation of (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (SBa,& N-Boc-p-phenyl isoserine methyl ester (3B) (0.5 g, 1.69 mM) is dissolved in dry THF mL) and toluene (10 mL) and concentrated to dryness to remove any water of crystallization. The residue is then dissolved in dry THF (10 mL) and the solution treated with 2.4dimethoxy benzaldehyde dimethyl acetal (0.425 g. 2.0 mM) and pyridinium p-toluenesulfonate (12 mg) and the solution warmed to reflux. After 30 minutes the reaction is cooled to RT and allowed to stand overnight. It is then again warmed to reflux for 3 hours. The reaction is checked by TLC and is found to be incomplete. The reaction is then heated to 85°C to distill off about 2/3 of the THF. Then fresh THF (10 mL) and acetal (200 mg) is added and the reaction refluxed another 2 hours. TLC shows the reaction to be finished at this point. The reaction is concentrated in vacuo and the residue chromatographed over 100 g silica gel packed Sin (15-85) acetone-hexane. The column is eluted with acetone-hexane (500 mL of 15-85 and 500 e mL of 20-80). Fractions of 20 mL are collected. The desired product isomers elute as a mixture. The fractions containing e mixture of 5Ba,& 5Bb and are combined and concen- 30 trated in vacuo leaving a white foam. The foam is rechromatographed over 100 g silica gel packed and eluted with (10-90) EtOAc-toluene. Fractions of 20 mL are collected and analyzed by TLC. There is thus isolated 34 mg of the less polar isomer 5Ba, 187 mg of a mixture of less polar and more polar isomers 5Ba and 5Bb, and 500 mg of the more polar isomer Isomer 5Bb is crystallized from EtOAc-hexane to give white crystals (378 mg).

The mixture of isomers is also crystallized from EtOAc-hexane to give crystalline (113 mg) of similar purity by TLC as the mother liquors from the isomer 5Bb crystallization.

-21- These crystals and the mother liquors are therefore combined and recrystallized from EtOAc-bexane to give more pure SBb (160 mg).

Data for SBa- TLC. silica gel 60. 10% EtOAc-90% toluene: Rf: 0.44.

'H NMR (CDCI 3 l M) 3.80 3H); 3.84 3H); 3.85 3H1); 4.86 1H); 5.24 1H); 6.40 (dd, 1H); 6.47 (di, IH); 6.72 1H); 7.12 7.30-7.43 (in. 3H); 7.53 2H1).

Data for SBb: TLC silica gel 60 10% EtOAc-90% toluene; Rf:- 0.38.

1 H NMR (CDC1 3 TMS): 8 1.10 9H); 3.52 (bd, 3H); 3.81 3.87 3H)-.

a4.54 (di, 111); 5.43 (bs, IH); 6.48 2H1);' 6.81 fbt IH); 7.13 Cbs, 1H); 7.30-7.48 (mn. UV: EtOH; 233 (10,600), 260sh (10 10), 277 (2840), 28 1sh (2680).

Elemental analysis: Calculated: C 65.O00, H 6.59; N 3.16.

Found:- C 64.86; H 6.42; N 3.24.

Prearation 7: Preparation of 4 S,5R)-N-Boc-2-(2.4-durnethoxyphenyl)4-phenyl-5-oxazli.

dinecarboxylic acid potassium salt (6Ba) and its free acid Ma.

A 100 mng (0.23 mM) quantity (4S,5R)-N -Boc-2-(2.4-dimethoxyphenyl)-4-phenyl5.

oxazolidinecarboxylic acid methyl ester (Prparation 6, 5Ba) is stirred at room temperature under nitrogen in 3 rnL MeOX. Added 0.1 ml, water and 43 mng (0.31 mM) potassium carbonate. After 1 hour, TLC shows no starting mnaterial left. Stored in freezer overnight. The next morning the solvent is evaporated to give (4S,SR)-N-Boc-2-(2,4-dimethoxyphenyly-4acid potassium salt (OBa). The residue is partitioned between methylene chloride and water containing 0.9 mL IN HO. The layers are separated and the.

aqueous layer reextracted with methylene chloride. The organic layers are combined. dried over sodium sulfa te and evaporated. This leaves 4 SSR)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl5 oxazolidinecarboxylic acid (7Ba) as a white solid.

TLC (silca gel 60): 20% EtOAc-80% hexane.2% HOAc: RI: 0.07 'H NM~R (CDCl 3 TMS): 8 1.26 9H1); 3.76 6H); 4.77 111); 5.34 1H); 6.33-6.45 (di, 2H); 6.60 IH); 7.07-7.16 (ci. 1W); 7.24-7.40 (mn, 3H); 7.42-7.54 211).

Preparation 8: Preparation of 7-TES-baccatin M-l3-(4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4acid ester (9BaA) A 0.23 mM quantity (4,R--o--24dmtoyhnl--hnl5oaoiie carboxylic acid (Preparation 7, 7Ba) is dissolved in 1.5 ruL methylene chloride-3 znL toluene.

To this is added 106 mg (0.15 mM) 7-TES-baccatin MI 11Img (0.09 mM) DMAP and 49 mg (0.24 mM) DCC. The reaction is stirred under nitrogen and heated to 75 0 C for 90 minutes then cooled to RT. The resultant urea side product is removed by filtration and the filtrate is evaporated under vacuum. The residue'.is chrormatographed over 20 g silica gel. eluting with EtOAc-hexane.. Fractions of 5 mL are collected, analyzing them by TLC. Fractions 17-34 contain the desired product and are combined and evaporated. 7-TES -baccatin III- I 3-(4S.SR)-N- Boc-2-(2.4-dimthoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid ester (9BaA) is obtained as a white solid.

TLC: silica gel 60;.30% EtOAc-70% hexane; RE: 0.56 Mass Spec (FAB.! mlz) 1112, 1012, 874, 328. 284, 115, 105, 87.

H1 NMR (CDCI 3 TMS): 8 0.52-0.66 614); 0.85-1.00 (in, 9H1); 1.80-1.93 (in H1); 2.15 3H1); 2.20 3H). 2.21-2.30 (mn. 1H); 2.40-2-54 (in, 1H); 3.82 3H); 3.87 311); 3.81 (dA IH); 4.10 11H); 4.26 I1H); 4.49 (ffn, 4.83-4.93 (in, 2H1); 5.31 I 5.67 111); 6.29 1H); 6.38-6.53 (in. 3H); 6.69 1H); 7.13 111); 7.29-7.65 (in. 8H); 8.05 (d.

2H1).

Prevaration 9: Preparation of 13-(N-Boc-f -phenyl isoserinyl)- baccatin Ell (lOBA) A 0.1 M HG1 solution is prepared from 0.07 1 mnL acetyl chloride and 9.929 mL of MeOH, leaving it sit for 30 minutes before using.

To 57 mug (0.051 m.M) 7-TES -baccatin ElI3-(4S,SR)-N-Boc-2-(2,4-dixnethoxyphenyl)acid ester (Preparation 8, 9BaA) is added 0.5 mIL of the above methanolic HGl solution with stirring under nitrogen. The reaction is complete after 75 minutes as shown by TLC. T1he reaction mixture is partitioned between ethyl acetate-5% sodium bicarbonate. The layers are separated and the aqueous layer reextracted with ethyl acetate. The organic layers are combined, dried over sodiun sulfate and evaporated under vacuum.

The crude product is chromatographed over 10 g silica gel. eluting with 50-50 ethyl acetate-toluene. Fractions of 2rnL are collected, analyzing them by TLC. Pure product is found in fractions 19-42, w hich are combined and evaporated. 13-(N-Boc-f -phenyl isoserinyl)baccain(1BA) isobtined as awhitesolid,.

TL(Q silica gel 60; 50-50 EtOAc-toluene; RE: 0.38.

Mass Spec (FAR): measured at 850.3680; theory for C 45 11 56 N 1 0 15 is 850.3650; mltz 794, 569, 509, 105, 57 1 H NMIR (CDCI 3 TS:811(s31)1.7s 3);1.33 1.67 1.84 3H); 2.24 3H); 2.38 3H); 3.44 111); 3.81 IH); 4.17 1H); 4.30 1ii); 4.41 ~(Mn 1M1; 4.63 (bs, 111); 4.95 111); 5.26 (lxi. 1H); 5.43 (bd, IH); 5.67 6.23 IH); 6.28 114); 7.27-7.45 5H1); 7.50 211); 7.62 111); 8.11 2H).

*:Preparation 10: Preparation of (4S,5R) -N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid Potassium Salt (6Bb) A solution of (4S,5R)-N-Boc-2-(2,4-imethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (Preparation 6; SBb, 374 mig. 0.84 mM) in MeOH (I I mL) is stirred at RT under nitrogen and treated with water (0.37 rub) and potassium carbonate (161 mg. 1. 17 mM).

After 2 hours, TLC indicates the reaction to be about 70% done. After stirring overnight. thereaction is found to be complete. The solvent is evaporated and the residue dissolved in 10 ruL water and freeze dried. This left 507 mug fluffy white solid, which contains (4S.5R)-N--Boc-2- (2,4-duxethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid Potassium Salt (6Bb, 393 mug).

TLC- silica gel; 20% EtQAc-80% hexane; Rf: origin.

Preparation-11- Preparation of 7-TES -baccatin rnI-i3-(4S.SR)-N-Boc-2-(2.4-dirnethoxy-phenyl)acid ester (MBA) A 0.12 mM quantity of crude (4S.5R}-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl.5oxazolidinecarboxylic acid potassium salt (Preparation 10. 6Bb) is partitioned between ethyl sodium bisulfate. The layers are separated and the aqueous layer reextracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum.

The resulting acid 7Bb is dissolved- in 0.8 rub methylene chloride-I 1.5 mL toluene along with 53 mug (0.076 mM) of 7-TES-baccatin M (8A: See Denis, Greene. A. Gudnard, Gu~itte-Vogelein, Mangatal, Potier, P. J1. Am. Chem. Soc. 1988. 1)0. 5917.), 6 mg (0.049 ruM) 4-dinethylaminopyridine (DMAP) and 25 rmg 12 mM) dicyclohexylcarbodiimide (DCC). The reaction is stirred under nitrogen and, heated to 75*C for 90 minutes. Cooled to RT and filtered off the urea side product. The filtrate is evaporated under vacuum.

The residue is chromatographed over 15 g silica gel, eluting with 30-70 EtOAc-hexane.

Collected 7 ruL fractions, analyzing them by ILC. Fractions 16-38 contain the product andt are combined and evaporated. 7-TM -baccatin ]fl13..(4S.5R)-N-Boc-2-(2,4-dirnethoxyphenyl).4acid ester (MBA) is obtained as a white solid.

TLC: silica, gel 60; 30% EtOAc-70% hexane; RE: 0.33 Mass Spec (FAB, miz) 1112., 1012,384, 328, 284, 115, 105, 87. 57.

1 H NMR (CDCl 3 TMS): 8 0.50-0.61 (mn. 6H); 0.84-0.97 9H); 1.08 9H); 2.21 (s, t3H); 3.67 111); 3.84) 3H); 3.90.(s. 3H); 4.07 (ci, 11); 4.23(d, IH); 4.40 In 4.53 (bd, IH); 4.87 (ci, IH); 5.44 bdl);5.60 111); 6.34 lH); 6.44 (bs, 1H); 6.48 1H), 7.20 1Hf); 7.30-7.50 (in, 7H1); 7.60 1H); 8.01 (cL 2H)'.

Preparation 12: Preparatio n of l3-(N-Boc-f -phenyl isoserinyl)- baccatin III (lOBA) A 0.1 M HOI solution is prepared from 0.071 mL acetyl chloride and 9.929 mL. of MeOH. leaving it sit for 30 minutes before using.

To 45 rug (0.040 m.M) 7-TES-baccatin Mf-13-(4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4acid ester (Preparation 11, 9BbA) is added 0.395 ML of the above Muethanolic HOI solution with stirring under nitrogen. The reaction is complete after minutes as shown by TLC.

After 30 minutes the reaction mixture is partitioned between ethyl acetate-5% sodium bicarbonate. The layers are separated and aqueous layer reextracted with ethyl acetate. The organic layers are combined. dried over sodium sulfate and evaporated under vacuum.

The crude product is chromatographed over 5 g silica gel, eluting with 50-50 ethyl acetate-toluene. Fractions of 5 ruL are collected and analyzed by TLC. Pure product is found in fractions 5-12 which are combined and evaporated. 1 3-(N-Boc-f~-phenyl isoserinyl). baccatin III (lOBA) is obtained as a white solid.

TLC: silica gel 60,.50-50 EtOAc-toluene; RI: 0.42 1 H NMIR (CDCI 3 TMS): 8 1.15 1.27 3H); 1.33 9H); 1.68 3H-) 1.85 3H); 2.25 3H); 2.38 3H); 3.44 I 3.80 IlH); 4.17 lH); 4.30 I 4.41 (in. I 4.62 (bs, I 4.95 11H); 5.26 (bd, I 5.43 (bd, I 5.67 I 6.23 I H); 6.29 lH); 7.13-7.45 (mn. 511); 7.49 2H); 7.62 1H); 8.1 1 2H).

Preparation 13: Preparation of 7 2 2 .2-trichloroethoxycarbonyl)-baccatin I- I 3-(4S.5R)-N-Boc..

2-(2,4-dixnthoxyphenyl)-4pbenyl-5-oxazolidinecarboxylic acid ester (9BaB. 9BbB) A 0.39 mM quantity of 4 S.SR)-N-Boc-2-(2.4-dimethoxyphenyl)-4-phenyl-5-oxazolidne.

carboxylic acid potassium salt (6134, 613b) is partitioned between ethyl acetate-5% sodium bisulfate. The layers are separated and the aqueous layer reextrated with ethyl acetate. The organic layers are combined. dried over sodium sulfate and evaporated under vacuum.

The residual acid 7Ba,7Bb is dissolved with stirring under nitrogen in 2 mL methylene chloride-6 mnL toluene. To this is added 187 mg (0.245 iM 7 -(2,2.2-trichloroethoxycarbonyl).

baccatin Ifl (8B. See for example Mangatal. Adeline, Guenard, Gueritte- Vogel em.

Potier, P. Tetrahedron 1989, 45, 4177.), folowed by 22 mg (0.18 mM) DMAP and 80 mg (0.39 mM) DCC. Soon after everything goes into solution, the urea side product starts to precipitate. Heat to 80 0 *C for 70 minutes, following the reaction by TLC. After cooling to room temperature, the solid is filtred off and the filtrate evaporated under vacuum. The crude product is chromatographed over 50 g silica gel, eluting with 400 niL 30-70. 200 mL 40-60, 100 mL 70-30 ethyl acetate-bexane. Fractions of 15 rnL are colected, analyzing them by TLC. The following fractions are combined ancdevaporated under vacuum to give white solids.

Fr 14-20, less polar isomer 9B~aB Fr 21-26, mixed isomers 9BaB, 9BbB Fr 27-32, more polar isomer 9BbB Fr 37-44, recovery of starting alcohol 8B Data for isomer MRaB TLC: silica gel 60; 40-60 ethyl acetate-hexane, Ri: 0.67.

35lH1 NMR (CDC1 3 TMS) 8 1.26 1.82 3H); 2.12 3H); 2.19 3H): 2.58 (m, IH); 3.81 3H); 3.91 3H1); 3.97 I 4.13 4.28 I 4.66 I 4.92 (in.

2H); 5.03 5.36 (di. 5.63 (in, 11); 5.67 11); 6.32 tm. 111); 6.40 6.51 (di.

IH); 6.69 111); 7.16 (ci, 1H1); 7.37-7.62 (i 8H); 8.02 2H).

Data, for isomer 9BbB: TLC: silica gel 60; 40-60 ethyl acetate-hexane; Rf: 0.55.

111 NMR (CDC1 3 TMS) 8 2.17 (lbs); 3.47 3.79-3.94 4.08 4.27 4.54 4.65 4.89 5.01 5.40 5.50 5.62 6.24 6.49 7.37-7.65 8.03 Preparation 14: Preparation of 7Z(.2-trichloroethoxycrbonyl)-13{N.-Bocp-phenyI isosernyl)-baccatin III lOBE A 0.1M HCI solution in MeOH is prepared from 0.071 niL acetyl chloride and 9.929 niL MeOH and left standing for 30 minutes before using.

A 252 mig (0.216 mM) quantity of 7-(2,2,2-trichloroethoxycarbonyl)-baccatin, 11-13- (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazoidinec arboxylic acid ester (Preparation 13; 9BaB,9BbB) is stirred at RT under nitrogen with, 2.2 rnL of the above 0. 1 M HCI solution in MeOHr. The reaction is followed by TLC and since it is incomplete after minutes, another 0.5 mL HCI solution is added and the reaction continued for 15 minutes.

The reaction mixture is then diluted with ethyl acetate and washed with 5% sodium bicarbonate. The layers are separated and the aqueous layer reextracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum. The crude product is chromatographed over 30 g silica gel. eluting with 200 niL 35-65 and 300 mL 40-60 ethyl acetate-hexane. Fractions of 5 niL are collected, analyzing them by mLc. Fractions 25-54 contain the pure product and are combined and evaporated under vacuum to give 7-(2,2.2trichloroethoxycarbonyl)-13-(N-Boc-11-phenyl isoserinyl)-baccatin Ill 1OBB. as a white.solid.

TLC: silica gel 60, 40-60 ethyl acetate-hexane; Rf: 0.36 Mass Spec -(FAB, mlz) at 1024. 1026, 1028; measured at 1024.2656; theory for C48H 57 Cl 3

N

1

O

17 is 1024.2692; 1024, 968, 924. 743, 683, 105, 57.

1 H NMR (CDC13. TMS) 8 1.17 3R1; 1.724 3H); 1.34 911); 1.83 1.91 3H1); 2.17 2.39 3H); 2.62 (mn, 1I1); 3.60 (di, 11H); 3.94 (di, 111); 4.16 (di, I 4.30 11-1); 4.63 and 5.04 (2d, 2H1); 4.62 11H); 4.95 111); 5.26 (bd, lH); 5.45-5.60 (in, 2H).

5.66 (di, 11H); 6.20 (t4 11H); 6.36 11H); 7.24-7-44 (mn, 511); 7.49 2H1); 7.61 I 8.08 2H1).

Preparation 15: Preparation of 13-(N-Boc-f -phenyl isoserinyl)-baccatin II (1BRA) and 7-(2,2- (..dichloroethoxycarbonyl)-l 3-(N-Boc-f-pheny1 isoserinyl)-baccatin III IOBG.

A 150 mig (0.146 mM) quantity of 7-(2.2.2-trichloroethoxycarbonyl)-1I3-(N-Boc-f-phenyI isoserinyl)-baccatin Ill (Preparation 14, IOBB) is stirred at RT under nitrogen in 13.5 mL MeOH and 1.5 mL HOAc. To this is added 150 mng activated zinc and the reaction heated to 50*C for minutes. The reaction is followed by TLC and adding 4 more 150 mg portions of zinc.

heating for 45 minutes after each addition. The reaction mixture is filtered and the filtrate evaporated under vacuum. The residue is partitioned between mnethylene chloride-water. The layers are separated and the aqueous layer backextracted with rmethylene chloride. The organic layers are combined, dried over sodiumn sulfate and evaporated.

~The crude product is chromatographed over 20 g silica gel, eluting with 200 nil604 and 200mL. of 70-30 ethyl acetate-hexane. Fractions of 5 mL. are collected. analyzing them by TLC. The following fr-actions are combined and evaporated to give white solids.

Fr 9-13. 7 -(2,2-dichloroethoxycarbonyl).l3-(N-Boc-f-phenyI isoserinyl)-baccatin III 1OBG.

Fr 14-44. 13-(N-Boc--pheny1 isoserinyl)-baccatin fl (lOBA) Data for 7-(2.2-dichloroethoxycarbonyl)-13-(N-Boc-f -phenyl isoserinyl)-baccatin Il IOBG TLC: silica gel 60; 50-50 ethyl acetate-hexane: RfE 0.81 (ths product and starting material run together in this TLC system).

'H1 NN%. (CDCI 3 TMS) 8 1.17 3H1); 1.24 3H); 1.35 9H); 1.61 1.81 3H); 2.19 311); 2-39 3H); 2.52-2.68 (mn. 3.37 (di. IH). 3.92 IH); 4.16 (di, lH); 4.32 (di, I1H); 4.53 (in. 211); 4.63 (bs, I1H); 4.95 (di. 1HI)FI 5.26 (bd. IlH); 5.40 (bd. I 4.48 (in.

IH); 5.67 (di, 111); 5.96 (in, IH); 6.20 111); 6.45 1H); 7.28..7.44 (in. 5H); 7.50 (tL 21H); 7.62 (t4 111); 8. 10 (ci. 211).

Data for TLC: silica gel 60-,50-50 ethyl acetate-hexane; RIE 0.32 1 H NMIR: (CDCI 3 TMS) 8 1.14 311); 1.24 3H); 1.32 9H): 1.67 3H); 1.84 311); 2.23 3H1); 2.37 311); 2.44-2-59 (mn, 11); 2.64 (bd, 1H). 3.70 (bs. 1H); 3.78.(d, 1H); 4.15 (di, 1H); 4.28 (di, 11); 4.40 (nm, 111); 4.61 1H); 4.94 lH); 5.25 (bd. lHM; 5.57 (bd, 111); 5.65 IH); 6.22 111); 6.29.(s, IH); 7.24-7.44 7.48 211); 7.60 IlH); 8.08 211).

's Prprto 6 Preparation of 7.10-bis-Troc-baccatin Ifl13.(4S.5R)-N-BOC-2-(2,4-dimethoxy- '.pnenyl)-4-penyl-5-oxazolidinecax~boxylic acid ester (9BbC) Crude (4S.5R)-N-Boc-2-(2,4-dimethoxyphenl)-4-phenyl5-oxazoliiinecarboxylic acid 30 potassium salt (Preparation 10; 6Bb) (0.089 is partitioned between, EtOAc- 5% NaI-S0 4 The layers are separated and the aqueous layer reextracted with EtOAc. The organic layers are combined, dried over sodium sulfate and evaporated' under vacuum leaving (4S.5R)-N-Boc-2- *(2,4-dirnethoxyphenyl)-4-pie.nyl-5-oxazolidinecarboxylic acid -This residue is stirred at room temperature under nitrogen in methylene. chloride (0.8 inL) and toluene (1.5 mL). To this is added 7.10-bis-Troc-1O-deacetyl baccatin Ill (8C. see for example Senilh. Guerittes* Vogelein, Guenard, Colin, Potier, P. C. R. Acad. Sci. Paris 1984. 299. 4177.). mng. 0.056 mM. The resultant solution is treated with 4-dirnethylarninopyridine (5 mg. 0.0)4 m.M) and I .3-dicyclohexyl carbodiirnide (18 mg, 0.087 mM) and then heated to 75 0 C (25 mmd).

TLC analysis after 15 mninutes heating shows the reaction to be complete.

The precipitated. dicyclohexyl urea is filtered off. The filtrate is coated on silica gel (I g) and chromatographed over silica gel (10 which is eluted with EtOAc-hexane (30-70) Fractions of 4 mL. are collected. analyzing them by TLC. Fractions 16&42 contain the product and are combined and evaporated under vacuumn. This produces 7,10-bis-Troc-bawccatin II- I 3 4 S.SR)-N-Boc- 2 -(,A-diithoxypenyl)-4-phenyl.5.oxazolidinecarboxyI ic acid ester (9BbC) as a -white solid.

10 TLC (silica gel 60): 40% EtOAc-60% hexane; RF 0.56 Mass Spec (FAB, mlz) 13041. 1306. 1308 1204, 875. 683, 384. 328 284. 105 (base). 57.

1 H NMR (CDCl 3 TMS): 8 1.07 3H); 1.14 3H);'1.22 1.79 3H). 2.56 (iIH); 3.79 IH); 3.81 311); 3.89 3H); 4.08 IH); 4.25 lH); 4.54 lH); 4.59 and 4.88 (2d4 2H1); 4.78 2H); 4.89 (bt, I1H); 5.43(rm, I1H), 5.50 (in. I1H); 5.62 I1H). 6.05 (bs. 1H); 6.12 1H); 6.47 114); 6.49 114); 6.75 (bs, 1H); 7.21. (in. 1H); 7.35-7.53 (mn.

7H); 7.62 1H); 8.01 21H).

Preparation 17: Preparation of 7.1O-bis-Troc-13-(N-Boc.-phenyI isoseninyl)-baccatin In (1013Q.

Acetyl chloride (0.071 mil, 80 mg. 1.0 mMI) is added to methanol (10 mL) and the solution allowed to stand for 30 minutes, giving a 0.1 N HC] solution. 7.10-Bis-Troc-baccatin 11-1 3 4 S.SR)-N-Boc- 2 2 4 dimnethoxyphenyl)4phenyl5.oxazolidinecarboxylic acid ester (Preparation 16; 9BbC) (73 mg, 0.056 mnM) is dissolved in the above methanolic HG1 solution (0.553 mL.) and allowed to stand (25 min). The reaction is then diluted with EtOAc and washed with 5% sodiumn bicarbonaie. The layers are s'?plrated and the aqueous layer reextracted with EtOAc. The organic phases are combined, dried over sodium sulfate and evaporated under vacuann. The cnde product is coated on silica gel (I g) and chromatographed over silica gel The column is eluted .with 20% EtOAc-80% toluene. Fractions of 4 mlJ are collected, analyzing them by TLC. Pure product is 'found in fractions 10-20 which are combined and *30 evaporated. Impure product in fractions 7-9, is rechromatographed as above. Fractions 11-26 contained the pure product and are combined with pure product from the first column.

This gives 7,10-bis-Troc-13-(N-Boc--phenyl isoserinyl)-baccatin III (IOBC) as a white solid.

TLC (silica gel 60): 30% EtOAc-70% toluene; Rf: 0.59; the side product 2.4-dimethoxy benzaldehyde runs just ahead of product and right where starting material comes.

Mass Spec (FAB, mlz) 1156, 1158, 1160 1100, 1056. 701. 685. 105 (base), 57.

1 H NMR (CDCl 3 TMS): 8 1.20 3H); 1.27 3H); 1.35 9H); 1.85(s. 3H); 1.95 3H); 2.35 3.41 Il-H), 3.90 I1H); 4.17 (do; 4.33 I 4.60 and 4.92 (2d.

2H); 4.62 (bs, I1H); 4.78 4.95 I 5.26 (bd, IlH); 5.42 (bd, I1H); 5.54 (dci, I 5.69 I1H). 6.21 I1H); 6.24 I 7.12-7.42 (in, 6H); 7.49 (to 2H); 7.62' (to I 8.09 (do 2H).

Preparation 18: Preparation of 7 -(2,2-dichloroethoxycarbonyl)l 3-(N-Boc-f -phenyl isoserinyl).

baccatin III (OBD), 1O-( 2 ,2-dichloroethoxycarbonyl)-13(N..Boc-p..phenyl isoserinyl)..baccatin

III

(lOBE), and l3-(N-Boc-11-pheny1 isoserinyl)-baccatin 11I (IOBF, Taxotere) 7,1l0-Bis-Troc-13-(N-Boc-..phenyI isoserinyl)-baccatin Ill (Preparation 17; IOBC) (48 ing, 0.041fmM) is stirred at room temperature under nitrogen in 90% MeOH- 10% HOAc (3 nil) and the solution treated with activated zinc (85 nmg). After 30 minutes reaction a cloudiness occurs. One niL more of the MeOH-HOAc solution is added, and the. reaction becomes clear. TLC after 30 and 60 minutes look very similar, namely no starting material and two minor and one major more polar products. After 70 minutes reaction, the solid zinc is filtered off. The filtrate is evaporated under vacuum. The residue is partiticned between methylene chloride and water. The layers are separated and the aqueous layer re-extracted with methylene chloride. The organic layers are again washed with water, dried Over sodium !.Ulfate, combined and evaporated under vacuum. The crude product mixture is coated on silica gel (I g) and chroinatographed over silica gel (5 The column is eluted with EtOAc-hexane (100 niL each of 40-60, 50-50. 60-40, and 70-30). Fractions of 4 mL are collected, analyzing them by TLC. The following fractions are combined and evaporated.

Fr. 12-24, 1OBD Fr. 29-42, lOBE Fr. 48-84, lOEF Data for lOED: TLC (silica gel 60): 60% EtOAc-40% hexane; Rf: 0.92 Mass Spec (FAB, m/z) 948, 950, 952 892, 848, 830, 667. 649, 105 -(base), 57.

'H NMiR (CDCI 3 TMS): 8 1.09 3H); 1.23 3H); 1.34 9H); l.86(s, 3H); 1.89 3H); 2.04 (mn, 111); 2.29 (di, 2H); 2.39 3H); 3.4 (bs, 1H); 3.99 11-1); 4.05 11H); 4.20 I 4.33 111); 4.48. (in, 21H);.4.62 and 4.93 (2d, 2H); 5.30 (in, 5.37 5.46 (do, IH); 5.68 (di, I1H); 5.83 I 6.21 IlH); 7.3-7.45 (mn, 6H); 7.50 2H); 7.62 I H); 30 8.10 (do 2H).

Data TLC (silica gel 60): 60% EtOAc-40% hexane; 0.65.

Mass Spec (FAB. nilz) 948, 950, 952 892, 848, 667, 5 27, 509, 105 (base), 57.

'H NMR (CDCI 3 TMS): 8 1.16 3H); 1.27 3H); 1.33 9H); 1.70 3H); 1.89 fe* 35 3H); 2.39 2.57 (in, 111); 3.40 1H1); 3.75 11-1); 4.17 (di, lH); 4.33 1H); 4.35 (in, IlH);. 4.56 (dd, 2H); 4.64 I 4.95 I1-H); 5.28 (in. I 5.37 I 5.68 I H); fe*:p 5.92 IlH); 6.15 I1-H); 6.25 I1H); 7.20-7.45 6H); 7.50 2H); 7.64 I 8. 2H).

Data for 1OBF: TLC (silica gel 60): 60% EtOAc-40% hexane; Rf: 0.23.

Mass Spec (FAB, mlz) 808 790, 752, 708, 527, 509, 345, 327. 105 (base), 57.

18 NMR (CDCI 3 TMS): 8 1.12 3H); 1.23 3H); 1.33 9H); 1.74 3H); 1.84 3H1); 2.37 3H); 2.56 (mn, 18); 3.60 (bs, 18); 3.89 1H); 4.18 lH); 4.21 1H); 4.30 18H); 4.32 18H): 4.62 (bs. I 4.94 18H); 5.23 IlH); 5.28 Cbs. 18H); 5.54 I 5.66 1H); 6.20 Ct, 18); 7.25-7.45 (in, 6H); 7.50 2H); 7.61 18); 8.09 2H).

Preparation 19: Preparation cf (2R.3S}-N-carbobenzyloxy-f.phenyl isoserine methyl ester (3C) A solution of (2RZ,3S)- -phenyl isolserine methyl ester (Preparation 1. 2 mM) in pyridine containing a small amount of DMAP is cooled in an ice bath and treated with benzyl chloroformate (0.8 ml). After stirring at room temperature overnight, the reaction is diluted with ethyl acetate, washed with 5% aqueous sodium bisulfate, dried and evaporated. The product is otaied ureby siiaglchromatography in ethyl acetate-hexane mixtures. Mp 120-121 *C.

NMR(CDC1 3 TMS): 8 3.26 (r lH). 3.79 38); 4.47 (in, IH); 5.06 (in. 2H); 5.27 I H); 5.75 118); 7.20-7.50 (in, 10 H).

Preparation 20: Preparation of (4S,5R)-N-Carbobenzyloxy-2-(2.4..dimethoxyphenyl).4-plenyl-5oxazolidinecarboxylic acid methyl ester N-.Cabobenzyloxy-f -phenyl isoserie methyl ester (Preparation 19. 3C. 0.375 g. 1.14 ffiM) is dissolved in dry THIF (10 rnL) and the solution treated with 2,4-dimethoxy benzaldehyde dimethyl acetal 0.30 0 g. 1.42 mM) and pyridinium p-toluenesulfonatc (10 mng) and the solution heated to distill off the TH-F and methanol. After 1/2 the THF is distilled off, TI-F mL) is added and the reaction distilled to 1/2 volume again. The process is repeated three times.* The reaction is then concentrated in vacuo and the residue chromatog raphed over 75 g silica gel packed and eluted in acetone-hexane (300 m.L of 20-80 and 300 mL of 25-75).

0 Fractions of 20 m'L are ce..ected and analyzed by TLC. The following fractions are conmined S 5 and evaporated under vacuum.* -Fr. 26-44, 543 mg, isomer 5Cb (other runs have shown this to be the more polar 30 isomer).

Data for silica gel; 20% acetone-80% hexane; Rf: 0.19.

18 NMR (CDOl 3 TMS): 8 3.51 (bs, 3H); 3 .81 (bs, 6H); 4.56 I 4.8 (bd, I H); 4.3Y4 18); 5.54 18); 6.4 Cbs. 2H); 6.78 3H); 7.05.7.50 9H).

~*35 Preparation 21: Preparation of (4S,5R)-N-CBZ-2-(2,4 S.....carboxylic acid potassium salt. 6Cb (4S,5R}-N-CBZ-2-(2,4 dimethoxyphenyl)-4-phenyl-5-oxazolidine carboxylic acid methyl ester (Preparation 20. SCb, 444mg.0.93mM) is dissolved in l0mi methanol. To the solution is added water (400p]l) and potassium carbonate (200mg, 1.45mM). After stirring overnight no solids remain and TLC indicates very little methyl ester remaining. The solvent is concentrated in vacuo and water (20m1) added to the oil. The solution is freeze dried leaving 638mg fluffy white powder which contains 466mg of the potassium salt 6Cb.

TLC: silica gel 60; 1:4 EtOAc:Toluene; Rf: origin.

Preparation 22: Preparation of 7-Triethylsilyl-Baccatin III-1I3-{4S.SR)-N-CBZ-2-(2,4 dimethoxyacid ester. 9CbA Crude (4S.SR)-N-CBZ-2-(2,4 dirnethoxyphenyl)-4-phenyl-5-oxazolidine carboxylic acid potassium salt (6Cb. Preparation 21; 75mg,0.1 1mM) is partitioned between CH 2

CI

2 and NaHSQ 4 solution. The layers are separated and the aqueous layer extracted with EtOAc. The combined organic layers are filtered through anhydrous sodium sfaeand concentrated in vacuo leaving 5Mg of (4S,5R)-N-CBZ-2-(2.4 carboxylic acid (7Cb).

7-Triethylsilyl-baccatin Mn (8A, 50mg, 0.07 mM) is dissolved in 70DpL toluene. All of the (4S,SR)-N-CBZ-2-(2,4 dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid is added in a solution of CH 2 C1 2 To the solution. is added DCC (25mg. 0.11 mM) and DMAP (4mg.

0.04mM) and the solution heated to 80*C driving off the CH 2

CI

2 The reaction is checked by TLC and after 1.5 hours very little 7-triethylsilyl-baccatin MI is seen. The reaction is allowed to cool and the slurry fitered. The filtrate is concentrated in vacuo and chromatographed over 7gmn of silica gel packed in 1:3 EtOAc:Hexane. The column is eluted with 4OmL 1:3 EtOAc:Hexane and 75m1 1:2 EtOAc:Hexane collecting 3m1 fractions. The desired product is found in fractions 17-32.

Mass Spec (FAB-High Res.) Theoy. 1146.4882 Found: 1146.4915 to 1 H NUR (CDCI 3 TMS): 8 0.51-0.59 0.88-0.94 1. 13 1. 18 (OftH) o 1.79-1.89 2.17 2.40-2.50 (mlH); 3.67 3.80 (br s,6H); 4.07 4.22 4.39 4.54 4.77 4.86 4.94 (dIH); 5.54 5.61 KdIM) 5.90 (mIlH); 6.33 6.43 6.78 7.12-7.21 (ni,4H): 7.38-7.50 (rn,7H); 7.59 8.01 (d.2H Preparation 23: Preparation of I 3-(N-CBZ-f3-phenyl-isoserinyl)-baccatin Ifl IOCA anti 0too 0 deacety1-13-(N-CBZ-fl-phenyl-isoseriny1)-baccatin III 1OCB 7-Triethylsilyl-Baccatin Ill-I 3-(4S,5R)-N-CBZ-2-(2.4 oxazolidinecarboxylic acid ester (9CbA, Preparation 22; 630mg. 0.55mM) is di isolved in I OrniL .:too 35 0.IN HO1 in methanol. The 0.lN HC1 solution is made by diluting 71PL acetyl chloride to lOmL with methanol and allowing to react for a minimum of 0.5 hours. The reaction is checked by TLC and after 0.5 hours no starting materials is seen. The reaction solution is partitioned between brine, 5%NaHCO 3 solution. and EtOAc. The layers are separated and the organic layer is extracted with 5%NAIICO 3 solution. The combined aqueous layers are extracted with EtOAc and the combined organic layers are filtered through anhydrous sodium sulfate. The solvent is concentrated in vacua aind the residue chromatographed over 60 gin siiica gel packed in 1: 1 EtOAc:Hexane. The column is eluted with 500 mL 1: 1 EtOAc:Hexane.

250 rnL 3:2 EtOAc:Hexane, 240mL 2:1 EtOAc:Hexane collecting, 25 rnL fractions.

Fractions 16-36. 1 3-(N-CBZ-0-pheny-isoserinyl)-baccatin ITH. Fractions 44-52. 10-deacetyl-13-(N-CBZ-f-phenyl-isoserinyl)-baccatin III 1OCB Data for Mass Spec (FAB-High Res.) Theory: 884.3493 Found: 884.3490 1H1 NMR (CDCI 3 TMS): 8 1.13 (s,3H1);l.80(s,3H); 1.86 2.24 (s,314); 2.37 (sOH); 2.54 (rn2H); 3.43 (minl); 3.76(d,1H); 4.19 4.28 4.39 4.66 (br s,1H); 4.90-4.97 4.94 5.05 5.34 5.64 (dIlH); 5.75 (d,lH); 1 5 6.23 6.25 (s,l11); 7.17 (br 7.25 (hr s,3H); 7.29-7.41 7.50 7.61 (rn,IH); 8.12 (d,2M1 Data for Mass Spec (PAB-High Res.) Theory: 842.3388 Found: 842.3364 1 H NMR (CDCl 3 TMS): 8 2.37. 2.57 (m,1lD; 3.40 (d.111); 3.87 4.18- 4.32 4.65 (hr s.IH); 4.92 4.95 5.06 5.18 (slH); 5.35 5.65 (dil11); 5.78 KI.) 6.20 (m.111); 7.18 (mIlH); 7.22-7.46 7.50 (m.21-D; 7.6 1 (mn,lI)K 8.11 (d,2H) Preparation 24: Preparation of 13-@f phenyl isoserinyl)-baccatin III (11A) from I 3-(N-Cbz-f phenyl isoseninyl)-baccatin MI (1OCA) .A 405 mug (0.46 mM) quantity 13-(N-Cbz-f-pbenyl isoscrinyl)-baccatin- Ell (Preparation 23; IOCA) is stinerd at room temperature and hydrogenated at atmospheric pressure with 40 mL *:.:absolute ethanol and 100 mug 10% Pd'C. The reaction is followed by TLC. being complete after hours.

reaction is filtered through Celite, washing with ethyl acetate. Te combined filtrate and %,aih are evaporated under vacuum. The residue is treated with a small amount of ethyl acetate and a larger amount of hexane and reevaporated twice more. 13-($-phenyl isoserinyl)baccatin Ml (11A) is obtained ms a white solid.

-TLC: silica gel 60; 70-30 EtOAc-hexane; RI': streak between origin and 1/3 up the plate.

1 H NMR (CDC1 3 TMS): 8 1.13 3H); 1.24 1.66 3H); 1.88 3H); 2.23 S 35 3H); 2.24 3H); 2.45-2.61 (in, 111); 3.75 lH); 4.14 1H1); 4.23-4.33 (in. 3 4.40 in1H); 4.93 lH); 5.63'(d, 1H1); 6.13 IH); 6.27 111); 7.26 (Cm. 1H); 7.39 4H); 7.52 2H); 7.65 IH); 8.06 2H).

Preparation 25: Preparation of (2R.3S)-N-(2,2.2-trichloroethoxycarbonyl)- .phenyI isoserne methyl ester (3D) Following the general procedure of Preparation 19 2 R.3S)-N-Carbobenzyloxy-f pheny isoserine methyl ester but starting with 2.2.2-trichloroethoxycarbonyl chloride to acylate the arnine f -phenyl isoserine methyl ester the product N-(2.2,trichloro-ethoxycazbonyl)p..

phenyl isoserine methyl ester (3D) is prepared.

Preparation 26: Preparation of 4

S

9 5R)-N-(2.2.2-trichloroethoxycarbonyl)-2-(2.4.dimethoxy.

acid mfethyl ester SDa Following the general procedure of Procedure 20 [Preparation of benzyloxy-2-(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (SCb)I, but starting with (2,2.2-trichloroethoxycarbonyl)-f -phenyl isoserine methyl ester (3D) the product (4,.)N(,,-rclrehxcroy)--24dmtoyhnl--hnl5oa zolidinecarboxylic acid methyl ester (SDa. 5Db) is prepared.

-Preparation 27: Preparation of (4S.5R)-N-(2,2.2-trichloroethoxycairbonyl)-2(2.4-dinethoxy.

acid potassium salt (6Da, 6Db) Following the general procedure of Preparation 21 [(4S 5R)-N-Carbobenzyloxy-2-(2,4acid potassium salt (6Mb]. but starting with 4 S,5R)-N-(2,2,2-trichloroethoxycarbonyl)-2-(2,4-diethoxyphenyl)4phenyls.oxazoliinecarboxylic acid methyl ester (SN. 5Db) the product (4S.5R)-N-(2.2,2-trichloroethoxycarbonyl)- 2 -(2,4-dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid potassium salt (6Da, 6Db) is prepared.

Preparation 28: Preparation of 7-Triethylsilyl-Baccatin M-i3-(4S.SR)-N-(2.2.2trichloroethoxycarbonyl)-2-(24-dimethoxyphenyl)4 phenyl-5oxazoidinecarboxylic acid ester (9DaA, 9DbA) Following the general procedure of Preparation 22 [preparation of 7-Triethylsilyi- Baccatin Ml-i 3-(4S,5R)-N-CBZ-2-(2.4-dirnethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid *ester, 9CbAI, but. starting with 4 S.SR)-N-(2.

2 ,2-chloroethoxycarbonyl)-2-(2.4-dimethoxyphenyl).

****4-ph--nyl-5-oxazolidine carboxylic acid (6Da, 6Db) is prepared the desired 7-Triethylsilyl- Baccatin 11-1 3-(4S.5R)-N-(2, 2 .2-trichloroethoxycarbonyl)-2-(2,4-dimethoxyphcnyl)-4-pheny.5 oxazolidinecarboxylic acid ester (9DaA, 9DbA).

Preparation 29: Preparation of l 3 2 ,2-trichloro-ethoxycarbonyl)f-phenylisoserinyl).

baccatin III (1ODA) 0000 Following the general procedure of Preparation 23 [preparation of 1 3-(N-CBZ-f -phenylisoseninyl)-baccatin MI (lOCA)). but starting instead with 7 -triethylsilyl-baccatin III- I3-(4sSR)- N-(2,2.2-tfichloroethoxycarbonyl)-2-(2,4 -33acid ester (91)a, 9Db)] the product 3-(N-(2.2,2-trichloroethoxycabonyl)-ARphenyl-isoserinyl).

baccatin III (lODA) is prepared.

Preparation 30- Preparation of 13-(f-pheny-isoserinyl)-baccatin Ill (11A) from 13-(N-(2.2.2trichlorochloro-ethoxycarbonyl)-p-phenyl-isoseriyl).baccatin III (lODA), 1 3 2 ,2,2-Trichlorochloro-ethoxycarbonyl)- .pheny-isoserinyl).baccatin III (Preparation 29; lODA, IS) is dissolved in methanol (50 mL) and the solution treated with zinc powder (2 g) and ammionium chloride (2g) with stirring at room temperature. After stirring 3 hr. the reaction is filtered and the filtrate evaporated under vacuum.(less than 20 torr). The residue is partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The organic layer is separated, dried (sodium sulfate) and concentrated under vacuum leaving the product 13- f phenyl-isoserinyly-baccatin Ill (hA).

Preparation 31: Preparation of 13-(N-Boc-f -phenyl isoserinyl)- baccatin Ill (IOBA) A 68 mg (0.09 mM) quantity of 13-(f-phenyl-isoserinyl)-baccatin III (Preparation 24; 11A) is stirred atroom temperature undernitrogen inO.5mL dryTHE. To this is added .(0.092 mM) di-t-butyl-dicarbonatein 0.2 mnt dry THE and 0.0 13 mL (0.093 mM) triethylamine.

The reaction is allowed to react for 24 hours, TLC after 5 hours shows the reaction to be mostly done.

The reaction mixture is partitioned between ethyl acetate-brine. The layers are separated and the aqueous layer reextracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum.

The crude product is chromatographed over 10 g silica gel. eluting with 60-40 ethyl acetate-hexane. Fractions of 2 mL are collected. analyzing them by TLC. Fractions 12-30 contained the product, and are combined and evaporated under vacuum. This produces the title compound, IOBA, as a white solid.

TLC: silica gel 60;, 60-40 EtOAc'hexane; RE: 0.46.

1 H NMR (CDC1 3 TMS) 8 1.15 3H4); 1.33 911); 1.85 311); 2.25 3H); 2.30 2.38 3H); 2.54 3.46 (Ki IN); 3.80 (Ki 1H) 4.17 (d lH); 4.31 (Ai lH); 4.41 (in, IH); 4.63 (bs, 111); 4.95 1H); 5.28 (bd IH); 5.42 (bd. 111); 5.67 11); 6.24 IH); 6.29 111); 7.18 IH); 7.38'Trrr5H); 7.50 2H); 7.62 lH); 8.10 211).

Preparation 32: Preparation of 13-(N-(l-adaiiatoyl)-f -phenyl isoserinyl)-baccatin Ill (1OEA) A 44 mg (0.06 mM) quantity of 13-(f.phenyl-isoserinyl)-baccatin HII (Preparation 24; is' stirred at 0 0 C under nitrogen in I mL dry pyridine. Syringed in 0.2 mld methylene chloride containing 13 mg (0.06 mM) I -adamantane-carbonyl chloride. After 30 minutes reaction, ThC shows the reaction to be complete.

The reaction is partitioned between IN HCIl-ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and evaporated under vacuum.

The residue is chromatographed over 5 g silica gel. eluting with 65-35 EtOAc-hexane.

Fractions of 2 mnL are collected, analyzing them by TLC. The product is found in fractions 8-23.

which upon combining and evaporating left 33 mg (60% yield) white solid. Spectral data still showed the pre-sence of 1 -adaxnantane carboxylic acid.

The impure product is dissolved in 1 mb freshly distilled THF. Excess ethereal diazomethae is added and the reaction left to react for 30 minutes. The reaction is then evaporated under vacuum and chrornatographed as before. Pure product is found in fractions 6-25, leaving 13-(N-(l-adamnantoyl)-j -phenyl isoserinyl)-baccatin M 1OEA, as a solid.

TLC: silica gel 60. 50-50 EtOAc-hexane; RE: 0.48.

Mass Spec (FAB.- mz): measured: at 912.4168;'- theory for CS IH 62 N 1 0 14 is 912.4170; 912, 852, 834, 569, 551, 509. 344. 326, 298, 268, 180. 135, 105.

'H1 NMR (CDC1 3 TMS) 8 1. 16 1.27 1.60-2. 10 2.24 311); 2.30 2.36 311); 2.52 3.54 11H); 3.77 I 4.18 (di, I 4.29 IH); 4.40 (m.I1H); 4.68 (mn, 111); 4.94 1H); 5.56 (cid, lH); 5.68 1H); 6.15 lH); 6.28 lH); 6.47 1H); 7.37 (mn, 5H); 7.50 211); 7.61 1H); 8.10 (di, 2H).

Preparation 33: Preparation of 1 3-(N-(3-tezrahydrofuranyloxycarbonyl)-P -pheny isoserinyl)baccatin M1 (lOFA) 13-(f -phenyl-isoserinyl)-baccatin 111 (Preparation 24; 11A) 16.8 mg, 0.022 m.M) is treated with racemic 3-tetrahydrofuranol succinimidyl carbonate (5.0 mg. 0.023 pyridine (5 and mnethylene chloride (180 p 1 The reaction is stirred at room temperature 2 dayi.

It is diluted with ethyl acetate and washed with 5% aqueous sodium bisulfate and 5% aqueous sodium bicarbonate. The organic solution was dried and evaporated to give a mixture of diastereoiners, 1 3-N-(3-tetrahydrofuranyloxycarbonyl)--phenyl isoserinyl)-baccatin III (lOFA).

TLC: silica gel 60; 40-60 acetone acetate-hexane; Rf: 0.16.

25 1 H NMR (CDCl 3 1 TNIS) 8 1.16 1.27 1.68 1.83 1.90 2.25 2.37 2.55 3.7-4.0 4.18 (di, IH); 4.30 lH); 4.43 (in,lH); 4.64 (in, 111); 4.95 (cid, 1H); 5.09 111); 5.30 (in. 111); 5.67 (mn. 211); 6.28 2H); 7.39 (in. 5H); 7.50 (mn, 2H); 7.62 111); 8.12 (ciL 2H).

Prearation 34: Preparation of 13-(N-(4-tetrahydropyranyloxycarbonyl)Pf-phenyl isoserinyl)baccatin M1 (1OGA) *.13-$f-phenyl-isoserinyl)-baccatin III (Preparation 24; 11A, 10 mg. 0.013 mnM) is treated with 4-tetrahydropyranol succinimidyl carbonate (3.3 mg. 0.014 mM), pyridline (5 11b) and mnethylene chloride (100 The mixture is stirred overnight at room temperature. The reaction is diluted with ethyl acetate and washed with 5% aqueous sodium bisulfate and aqueous sodium bicarbonate. The ethyl acetate solution is dried and evaporated, giving 10.3 mg crude product. Purification by column chromatography on silica gel in (40-60) acetone-hexane yields pure 13-(N-(4-etahydropyranyl-oxycarbony)-f-phenyI isoserinyl)-baccatin III (IO)GA).

TLC: silica gel 60; 40-60 acetone acetate-hexane; Rf: 0.17.

1 H NMR (CDCI 3 TNIS) 8 1.15 1.27 1.5-1.8 1.68 1.84 1.89 (mn): 2.1-2.4 2.2 5 3H); 2.41 3H); 2.49 IH); 2.55 3.08 (mn. IH); 3.27 (in. 1H); 3.33 1H); 3.70 (mn, 1H); 3.80 2H); 4.16 4.29 IH); 4.42 (rnIH); 4.66 (mn, 2H); 4.94 111); 5.33 (in, IH); 5.57 (i lH); 5.65 (d 6.28 2H); 7.37 (mn. 7.51 (mn, 2H); 7.61 (im, 1H); 8.14 211).

Preparation 35: Preparation of 13-(N-(tert-butylaceyl)-f-phenyI isoserinyl)-baccatin III (IOHA) and 2'-t-butylacctyl- 13-(N-(tert-butylacetyl)-f -pbenyI isoserinyl)-baccatin III (I2CA) A 51 mng (0.068 rM) quantity of 13-(f -phenyl-isoserinyl)-baccatin III (Preparation 24.

1hA) is stirred under nitrogen at 0 0 T in I mL. dry pyridine. Take 0.01 m-L (9.1 mng.

0.068 mM) tert-butylacetyl chloride and dissolved it in 0.1 niL muethylene chloride. Add this dropwise to the starting amnine. Leave to react at 0 0 C for 3 hours and in the freezer overnight.

The reaction is diluted with ethyl acetate and washed with IN HCI and 5% sodium bicarbonate. The aqueous layers are backextracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum.

The crude product is chroniatographed over 7 g silica gel. dluring with 50-50 and 70-30 EtOAc-hexane. Fractions of 2 mL. are collected, analyzing them by T"nC. The following fractions are combined and evaporated under vacuum.

Fr. 11-21. impure 2'-t-butylacetyl-13-(N-(tert-butylacetyl)-f -phenyl isoserinyl)-baccatin III1 (12CA) Fr. 22-45. 13-(N-(tert-butylacetyl)-f -phenyI isoserinyl)-baccatin III (lOHA). white solid.

12CA is still impure and is rechromatographed over 3 g silica gel, eluting wiih 10-90 acetone-methylene chloride. Fractions of I aL. are collected, analyzing them by TLC. Fractions :25 11-28 contained the product and are co mbined and evaporated under vacuum to give pure 2'-tbutybacetyl13-(N-(tert-butylacetyl)--phenyl- isoserinyl)-baccatin Ml (12CA) as a whiL- solid.

Data for 12CA: TLC: silica gel 60; (I4)ethyl acetate hexane; RE: 0.70.

Mass Spec (FAB, m/z) measured at 946.4618; theory for C 52

H

68

N

1 0 15 is 946.4589; 946, 509, 378, 360, 280, 262, 234, 105, 99, 57, 43.

H NMR (CDC1 3 TMS) 850.98 1.28 3H); 2.23 2.42 3H); 2.53 (mn); 3.81 Kd lH); 4.19 111) 4.31 IH); 4.45 1H); 4.97 (di. 5.34 11-' 5.69 11-); 5.75 (mn, 1H); 6.08 Kci 6.24 (mn, 1H); 6.31 IH); 7.28-7.45 (in. 5H); 7.51 7.61 (t, Data for TLC: silica gel 60;, 6040 ethyl acetate hexane; RE: 0.27 -36- Mass Spec (FAB. mlz) measured at 848.3863:, theory for C46H 5 8

N

1

O

1 4 is 848.3857, 848. 830, 788, 770, 569. 551. 509. 280, 262. 234, 182. 136. 115. 105. 99, 57. 43.

1H NMR (CDCI3, TMS) 5 0.97 1.26 3H); 2.24 311); 2.33 3H); 2.52 (in.

2H); 3.60 (di, lH); 3.78 111); 4.18 III); 4.29 111); 4.39 (in. 111); 4.65 (in. 1H); 4.93 111); 5.55 (cid, 1H); 5.67 (di, IH); 6.19 111); 6.28 7.39 (mn. 511); 7.50 2H1); 7.62 (t.

111); 8.10 (Ki 2H).

Preparation 36: Preparation of 13-(N-(pivaloyl).-3phenyl isoserinyl)-baccatin III (101A) A 44 mg (0.06 mM) quantity of I 3.$f-phenyl-isoserinyl)-baccatin III (Preparation 24; 11A) is stirred'at 0 0 C under nitrogen in 1 mnL dry pyridine. To this is added over 5 mmi a solution of 8 mg (0.06 mM) tinmethylacetyl chlor ide in 0.2 mL methylenechioride. After minutes reaction, TLC shows most of the, amine to have reacted.

The reaction is partitioned between IN HI-Iethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and evaporated under vacuium.

The crude product is chromatographed over 5 g silica gel, eluting with (65-35) EtOAc-hexane. Fractions of 2 mL are collected, analyzing them by TLC. The product is found in fractions 10-38, which upon combining and evaporating under vacuum yields the title compound.

Spectral data indicates the presence of a small amount of pivalic acid. Therefore, the product is dissolved in ethyl acetate, washed with 5% sodium bicarbonate, dried over sodium sulfate and evaporated under vacuum. This yields IOIA, as a white solid.

TLC: silica gel 60-. 50-50 EtOAc-hexane; Rf: 0.29.

Mass Spec (FAB. mlz) measured at 834.3712; theory for C 45

H

56

N

1 0 1 4 is 834.3700; 834, 816, 774, 569, 551. 509, 387, 327, 266, 248. 220, 190. 105, 57.

1H1 NMR-(CDC1 3 TMS) 5 1.16 1.23 2.23 3H); 2. 29 1H); 2.35 311); 2.51 (in, 111); 3.77 (Ki 1H); 4.17 (di, IH); 4.28 (ci. 11); 4.38 (mn, lH); 4.68 (di, 1H); 4.93 (di, 1H); 5.56 (cid, 111);5.66 Ki 111); 6.17 (mn IH); 6.28 111); 6.54 (Ki lH); 7.35 511); 7.49 (mn, 211); 7.60 (in, 111); 8.10 (di, 211).

.9....Preparation 37: Preparation of -phenyl-isoserinyl)-7-cdeoxy-A 6 7 _baccatin Mf (17) from 13- (N-(benzyloxy-carbonyl)-f -phenyl-isoserinyl)-7-deoxy-A 6 7 _baccatin III (16B) Following the general procedure of Preparation 24 [preparation of I 3-(f -phenyl isoserinyl)-baccatin LU 11A], but starting with I 3-(N-(benzyloxycarbonyl)-p-phenyl-isoserinyl)- 7-deoxy-A 6 7 -baccatin In (16B from Examnple 4) 13-(R -phenyl-isoserinyl)-7-deoxyA 6 7 -baccatin HIi is prepared (17).

Preparation 38: Preparation of 13-($-phenyl-isoseriny)-7-deoxy-A _'baccatin 111 (17) from 13- (N-(2.2,2-trichlorocbloroethoxycarbonyl)-f-pheny-isoserinyl)-7-deoxy-A 6 7 -baccatmn III (16C) :9 1 3-(N-(2,2.2-trichlorochlorocthoxycarbonyl)-p-phenyl-isoserinyl)-7-deoxy-6 6 7 _baccatin .37- II (Preparation 12A; 16C. I g) is dissolved in methaol (50 mL) and the solution treated with zinc powder (2 g) and ammonium chloride (2g) with stirring at room temperature.. After stirring 3 hr. the reaction is filtered andl the filtrate evaporated under vacuum (less than 20 torr). The residue is partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The organic layer is separated, dried (sodium sulfate) and concentrated under vacuum leaving the product 13- ($-pheny-isoserinyl)-7-deoxy-A 6 7 -baccatin 111 (17).

Preparaion 39: Preparation of 7-Fluoro-l3-(N-Cbz--phnyl-isoserinyl)-baccatin 111 (18) from 7-Fluoro- 13-(N-Cbz- -phenyl-isoserinyl)-2'-troc-bac'catin M1 (13BA) A solution of 7-fluoro-1 3-(N-Cbz-f -phenyl-isoserinyl)-2'-tro-baccatin 1Hl (13BA, Example 3) (0.079 g) in 9:1 methanol/acetic acid (20 rnL) and ethyl acetate (8mL) is stirred with activated zinc (0.15i g) at room temperature for two hours. Following workup, the crude product is chromatographed over silica gel using 40% EtOAc-hexane for elution to give 7-fluoro-l 3-(N-Cbz-f -phenyl-isoserinyl)-baccatin Ell mass' spectrum. 886. 571, 511. 371.

.347. 329. 316, 298, 105, 91 rfl/L Preparation 40: Preparation of 7-Fluoro-13-( .phcnyl isoserinyl)-baccatin HI1(19) A 23.5 mg (0.027 mM)- quantity 7-Fluoro,-13-(N-Cbz--phcnyl isoscrinyl)-baccatin III (Preparation 39, 18,) is dissolved in 3 rnL absolute ethaol and the solution treated with 7 mg Pd/C and hydrogenated at atmospheric pressure and room temperature for 4.5 hours. The disappearance of starting material is followed by TLC. The reaction is filtered through Celite, washing the Celite with ethyl acetate. Thec combined filtrate and wash are evaporated under vacuum. The residue is treated twice with ethyl acetate-hexane and evaporated under vacuum.

This yields 7-Fluoro-13-(J .phenyl isoserinyl)-baccatin Ell (19) as a white solid.

TLC: silica gel 60;, 50-50 ethyl acetate -hexane; RE: 0.11.

'H NMR (CDC1 3 TMS): 8 2.20 3H); 2.26 3H); 2.54 (in, 1H). 3.99 (dI, 1H). 4.24 (di, lIi); 4.27-4.42 (mn, 3H); 4.55 (ddi. J-48 Hz, J-5 Hz, lH); 4.99 Kd 1W); 5.72 1W); 6.11 1W); 6.55 1W); 7.27 1W); 7.39 (mn, 4H); 7.51 (in, 2H); 7.64 (in, 1H); 8.08 2H).

Preparation 41: Preparation of 7-Fluoro-13{N-Boc--phenyl isoserinyl)-baccatin MI (20) and 7- Fluoro-2'-Boc-13--Boc-f-phenyI isosednyl)-baccatin M (13CA) A 0.027 ruM quantity 7-Fluoro-13-(P-phenyl isoserin yl)-baccatin Ml (Preparation 40; 19) is dissolved with stirring in 0.2 ruL freshly distilled THF at room temperature and under nitrogen. Add 6 rug (0.027 mM) di-tert-butyl dicarbonate and 0.004 ruL (0.029 mM) triethylainine. Left to react for 20 hours.

The reaction is partitioned between ethyl acetate-brine. The layers are separated and the A: aqueous layer reextracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated under vacuum.

:The product mixture is chromatographed over 3 g silica gel. eluting with 30-70 ethyl acetate-hexane until the first product comes off and then switching to 50-50 ethyl acetat, hexane. Fractions of 1 mL. are collected, analyzing them by TLC. The following fractions are combined and evaporated to leave white solids.

Fr. 16-30, 13CA Fr. 32-46, Data for I3CA.

TLC: silica gel 60; 50-50 ethyl acetate-hexane; RI: 0.83 Mass Spec (FAB, mlz) 952 878, 822, 778, 571, 511. 389. 329, 106. 162, 105.

57.

1H1 NMR (CDCI 3 TMS): 8 1.17 1.24 311); 1.25 911); 1.90 2.08 3H); 2-22 3H); 2.0-2.7 (mn, 4H); 4.02 4.24 111); 4.36 111); 4.59 (dd, 1-48 Hz, J-5 Hz, I1H); 4.77 (bs, 111); 5.02 I 5.22 (bs, I 5.68 (in, I 5.77 IlH); 6.27 (in, Ili); 6.57 111); 7.27-7.70 (in, 911); 8.09 2H1).

Data for TLC: silica gel 60; 50-50 ethyl acetate-hexane; RI:- 0.54 Mass Spec (FAB. mlz): measured at 852.3638; theory for C 45

H

55

F

1

N

1 0 1 4 is 852.3606; 852, 796, 752, 692, 674, 571, 511, 389, 347, 329, 105, 57, 43.

1 H NMR (CDC1 3 TMS): 8 1.17 3H); 1.23 3H); 1.34 9H1); 2.22 311); 2.39 311); 2.0-2.7 (mn, 411); 3.36 (mn, IH); 4.04 lH); 4.28 111); 4.37 111); 4.48-4.68 (in, 211); 5.01 111); 5.30 (mn, 111); 5.45 (in, 111); 5.76 1H); 6.21 (mn, 111); 6.56 111);- 7.30- 7.70 (mn, 911); 8.13 211).

Preparation 42: Preparation of 13 NBnyoyabnlfpeyiioeiy)7doy7,f, methanobaccatin MI (21) from 13-(N-Benzyloxycarbonyl- .phenyl-isoserinyl)-2'troc-7-deoxy- 70,80-methanobaccatin Ml (14BA) A solution of I 3-(N-benzyloxycarbonyl-f-pheniyl-isoserinyl)-2' -troc-7-deoxy-703,8f inmethanobaccatin MI (14BA, Example 3) (0.040 g) in 9:1 methanol/acetic acid (10 mL.) is stirred at room temperature with activated zi nc: (0.144 g) for 3 hours. Following workup, the crude ~reaction product is chromato rphed over silica gel using 40% EtOAc-hexane for elution to gv I 3.(N-benzyloxycarbonyl--phenyl-isoseriny)-7-eOxy-703,8D-inethaobaccatin MI (21): mass spectrum, found. 866.3423, C48H 5 INO 14 H requires 866.3388, 848, 806, 788, *551, 533, 491, 105, 91 m/z.

Preparation 43: Preparation of 13-$f-phenyl isoserinyl)-7-deoxy-70,8f -iethanobaccatin 111 (22) -A 14 mg (0.016 miM) quantity of 13-(N-benzylozycarbony1.f -phenyI isoserinyl)-7deoxy-70,8f -methantobaccatin II (Preparation 42, 21) is dissolved in 2 ml, absolute ethanol.

Add 5 mg 10% Pd/C and hydrogenate at room temperature and atmospheric pressure for 6 a:...:hours. Th"e reaction is followed by TLC and upon Completion is filtered through Celite. washing -39with ethyl acetate. The filtrate and wash is combined and evaporated under vacuum. Add ethyl acetate-hexane twice, reevaporating. to give 22 as a white solid. Stored in freezer overnight to be used as is in Preparation 44.

TLC: silica gel 60; 50-50 EtOAc-hexane; RE: streak from origin partly up the plate.

1 Hl NMR (CDCI 3 TMS 8 5.62 I1-I); 6.11 I1H); 6.31 l 7.39 7.53 (in.

211); 7.66 (mn, IH); 8.08 211).

Preparation 44: Preparation of 13-(N-Boc-O -phenyl isoserinyIY.7-deoxy- 7 p,80 -methanobaccatin M1 (23) and 13-(N-Boc-2'-Boc-j -phenyI isoserinyl)-7-deoxy-70,8fmcthaobaccatin III (I4CA) A 0.016 mM quantity of 22 (Preparation 43) is dissolved with stirring under nitrogen in 0.12 ruL dry THE. To this is added 3.5 mg (0.016 mM) di-t-butyl dicarbonate in 0.05 niL dry THF and 0.0025 niL (0.018 mM) triethyl an-ine in 0.015 mL dry THE. Left to react for 27 hours.,when TLC shows the reaction to be fairly complete.

The reaction mixture is partitioned between ethyl acetate-brine. The layers are separated and the aqueous layer reextracted with ethyl acetate. The combined organic layers are dried over sodium sulfate and evaporated under vacuum.

The crude product mixture is chromatographed over 3 g silica gel. Eluted with a gradient of 30-70 to 50-50 EtOAc-hexane. Fractions of I mL are collected, analyzing them by TLC. The following fractions are com bined and evaporated, giving white solids.

Fr. 16-30. 14CA Fr. 33-53, 23 23 is not quite pure and is rechromatographed'over 1 g silica gel. eluting with a gradient of 40-60 to 50-50 EzOAc-hexane. Fractions of 0.5 n-L were collected and analyzed by TLC. Pure product is found in fractions 11-20, which upon combining and evaporating under vacUUrn.leaVeC the desired product as a white solid 4 mg.

Data for 14CA.

TLC: silica gel 60; 50-50 EtOAc-hexane; RI: 0.87 Mass Spec (FAB, mtlz) 858, 803, 798,' 551, 491, 369, 327. 206, 105, 57.

NMR. (CDCI TMS) 8 1.25 2.01 2.21 3H); 2.43 4.01 11H); 4.07 I1H); 4.28 I1H); 4.70 (in, 2H1); 5. 18 (bs. I1H); 5.64 (mn. 2H); 6.25 (mn, I 6.3 3 (s.

1H1); 7.39 (mn, 511); 7.51 7.64 (in, 1H); 8.09 Kd 2H-).

Data for 23 TLC: silica gel 60, 50-50 EtOAc-hexane; RI: 0.77 Mass Spec (FAB, ,lz) (M+11) ieasurc 832.3588; theory for C 45

H

54

N

1 0 3 4 is 832.3544; 832, 814, 776, 732, 714, 696. 672, 551, 491. lO5, 57.

1 H NMfR: (CDCI 3 TMS) 8 1.28 1.37 1.68 1.85 2. 10 2.21 (s.

3H); 2.26 2.39 3H); 2.47 3.30 (mn, 4.06 (in, 2H); 4.31 1H); 4.63 (in. I H); 4.74 (di. 1H); 5.30 (mn. 5.36 IH); 5.66 6.28 (in. 6.33 1H); 7.37 (n 7.51 (in, 7.61 (mn. 1H); 8.15 (di. 2H).

Preparation 45: Preparation of I 3-(N-phenyl urea-f -phenyl-isoscrinyl)-baccatin 111; I 3-(f phenyl-isoserinyl)-baccatin II N-phenyl urea (lOJA) A 48 mg (0.064 mM) quantity of 13-($-phenyl-isoserinyl)-baccatin III (Preparation 24; 11A) is, dissolved in 700pi THF and 6.5pI (0.060mM) phenyl isocyanate added. TLC shows no amine remained. Th~e solution is diluted with EtOAc and extracted with sat. CuSO 4 The organic layer is filtered through Na 2

SO

4 and concentrated in vacuo and chroinatographed Over of silica gel packed in 1: 1 EtOAc:H-exane. The column is eluted with 20m1 1: 1 EtOAc:Hexane, 20ml 3:2 EtOAc:Hexane, and 20m1 2:11 EtOAc:Hexane collecting -3n1 frasctions.- The desired product is found in fractions 17-3 1.

Mass Spec (FAB-High Res.) Theory: 869.3496 Found: 869.3512 'H NMR (CC 3 TMS): 8 1.13 (sOH); 1.19 1L81 (sOfHt 2.19 2.27 2.37 4s,311); 2-51 (inlH); 2.66 (rn.1H); 3.76 4.18 4.28 4.37 (mlH); 4.67 (mInH); 4.93 (dIlH); 5.49 (ddIH); 5.67 (dIlH); 6.21 6.27 6.93 (m,2H); 7.07 (in,2H); -1.19 7.26-7.40 7.48 (in.1H); 7.60 8,.10 0d.2H), Preparation 46: Preparation of 13-(N-t-butyl urea- -phenyl-isoserinyl)-baccain II; I 3-f-phenylisoserinyl)-baccatin III N-t-butyl urea (1OKA) A 51 mng (0.07 mM) quantity of 13-($-phenyl-isoserinyl)-baccatin III (Preparation 24; 11A) is dissolved in 700pl THF and 7p1 (0.061mM) t-butyl isocyanate added. TLC shows some amine remained so another 3pl aidded. This was repeated twice more until TLC showed little amine left (3pIl and 4jil). The solution is diluted with EtOAc and extracted with sat.

CuSO 4 The organic layer is filtered through Na 2

SO

4 and concentrated in vacuo and chromatographed over 5gm of silica gel packed in 1:1 EtOAc:Hexane. The column is eluted 25 with S0mI 1:1 EtOAc:Hexane, 25in- 3:2 EtOAc:Hexane, and 25m1 2:1 EtOAc:Hexane collecting 3m1 fractions. The desired product is found in fractions 21-40.

Mass Spec (FAB-High Res.) Theory: 849.3809 Found: 849.3809 1 H NIM1R (CDCI 3 TMS):j_.1~4 1.22 1.24 1.83 (sOH). 2.23 (s,3H); 2.44 (s3H); 2.50 (mn,lIH); 3.77 (d.lIH); 4.17 (d.lIH). 4.29 IH); 4.38 4.61 (mn.I 4.94 30 KIMH) 5.29 5.67 (dIlH); 6.18 (minH); 6.29 7.33 7.49 7.61 I 8.09 (d.2H Preparation 47: Preparation of 1 1-methyl-i -cyclohexamide- -phenyl-isoserinyl)-baccatin MI; 1 -methyl-i -cyclohexanoyl)- -phenyl-isoserinyl)-baccatin III (1OMA) A 30 mg (0.04 mM) quantity of 13-(f -phenyl-isoserinyl)-baccatin III (Preparation 24: 11A) is dissolved in 400 pI pyridine and cooled to 0 0 C. Once cooled 2Opl of 3 00mg per I ml of l-methyl-i-cyclohexyl carbonyl chloride in CH 2

CI

2 (0.037mM) is added. TLC showed some amine remained so another lOpIl added. TLC shows little amnine left. The solution is diluted with EtOAc and extracted with sat. CUSO 4 The organic layer is filtered through Na 2

SO

4 and concentrated in vacuo and chromatographed ovcr 3gm of silica gel packed in 1: 1 EtOAc:Hexane. The column is eluted with 50ml 1:1 EtOAc:Hexane and 20m] 3:2 EtOAc:Hexane collecting 2ml fractions. The desired product is found in fractions 11-28:' Mass Spec (FAR-Hfigh Res.) Theory: 874.4013 Found: 874.4011 1 H NMR (CDC1 3 TMS): 8 1.12 (OH31); 1.15 1.26 1.81 1.87 2.24 2.36 2.54 (m.I 3.78 (d.I 4.18 IH); 4.29 IH); 4.40 4.70 (d1H); 4.94 (d.111); 5.61 (dd.IH); 5.67 6.19 (m.111); 6.28 6.51 7.38 7.50 (rn 1 7.61 8.11 (d.2H) Preparation 48': Preparation of 13-(N-1-phenyl-l-cyclopentamide--phenyl-isoscninyl)-baccatin III; 1 -phenyl-l -cyclopcntanoyl)-R-phenyl-isoserinyl)-baccatin IfI (Il-ONA) A 26 mg (0.035 mM) quantity of 13-(f-pheny-isoserinyl)-baccatin II (Preparation 24; 11A) is dissolved in 40011 pyridine and cooled to 0 0 C. Once cooled 2OjIl of 350mg per I ml of I-phenyl-1-cyclopentyl carbonyl chloride in C11 2 0 2 (0.033mM) was added. TLC showed some amine remained so another 2Ojil added. ThC showed no amine. The solution is diluted with EtOAc and extraced with Sat. CUSO 4 The organic layer is filtered through Na 2

SO

4 and concentrated in vacuo and chromatographed over 3gm of silica gel packed in 1: 1 EtOAc:Hexane. The column is eluted with S5rnI 1: 1 EtOAc:Hexane and 25m1d 3:2 EtOAc:Hexane collecting 2nd fractions. The desired product is found in fractions 12-29.

Mass Spec (FAR-High Res.) Theory- 922.4013 Found: 922.4022 1 H NMR (CDC1 3 TMS): 8 1.16 (sOH); 1.27 1.77 1.60-2.10 *2.25 2.35 2.25-2.65 3.75 4.19 (dlH); 4.28 4.38 4.59 4.92 5.49 (dd,1H); 5.66 6.10 6.26 7.08 7.29 7.53 (nM2); 7.63 8.12 (d.2H) Preparation 49: Preparation of 13-(N-phthalimide- -phenyl-isoserinyl)-baccatin IIL l3-(phenyl-isoserinyl)-baccatin Il N-phthalimnide (lOPA) 29 mg (0.34 mM) qu~i of 13-($-phenyl-isoserinyl)-baccatin III (Preparation 24; 11A) is dissolved in 40011 pyrjdi-. and 15mg (0.07mM) carbethoxyphthalirnide. The reaction to. 30 is checked by TLC and after 72 hours no amine is seen. The solution is diluted with EtOAc and extracted with sat. CuSO 4 The organic layer is filtered through Na 2

SO

4 and concentrated in vacuo and chromatographed over 4gmn of silica gel packed in 1:1 EtOAc:Hexane. The column is eluted with 20M 1:1 EtOAc:Hexane. 20m1 3:2 EtOAc:Hexanc. 20ml 2:1 EtOAc:Hexanc. and- 'a 2Ornl 4:1 EtOAc:Hexane collecting 2ml fractions. The desired product is found in fractions 16- 35 2 1 H N M R(CDC 3 TM 8 1.09 1.16 1.81 1 H 24 NM(Dl .1(14.24 -42- 2.52 3.76 I1); 4.15 IH); 4.28 KdI1H); 4.41 4.96 5.31 5.61 5.76 KdH); 6.0A 6.24 7.23 (inIH); 7.36 7.52 7.66 7.80 (m.411); 8.10 (d.211) Preparation 50: Preparation of 1 phenyl-isosenyl)-baccatin Il N-t-butylthiourea (lOLA) A 24 mg (0.032 mM) quantity of I 3-$-phenyl-isoserinyl)-baccatin Ml (Preparation 24; 11A) is stirred at room temperature under nitrogen in 0.2 muL dry THE. 4 ul (0.032 mM) tbutyl-isothiocyanaze is added. TLC after 5 hours shows the reaction to be incomplete. Add 4 ul more t-butyl-isothiocyanate and leave the reaction go overnight. The crude product is coated on 0 .5 g silica gel and chr6matographed over 3 g silica gel, eluting with 60-40 ethyl acetatehexane. Fractions of I mL are collected, ana!gthmbyTC Fractions 7-20 contain the.

product and are combined and evaporated under vacuum to yield the desired product.

TLC: silica gel 60; 60-40 EtOAc-hexane; RE: 0.40.

1 H NMR (CDCI 3 TMS) 8 1.14 3H); 1.40 9H); 1'80 3H1); 2.25 3H1); 2.40 (s.

3H); 3.50 1H); 3.80 111); 4.23 (in. 2H). 4.40 (bs, 111); 4.86 IH); 4.93 IH): 5.66 (d.

1H1); 6.18 1H); 6.27 IH); 6.28-6.40 (mn. 2H); 6.59 1H); 7.30-7.54 (in, 7H1). 7.58 (t, I 8.09 (d 2H).

Mass Spec (FAB. mlz) measured at 865.3577; theory for C 45

H

57

N

2 0 13 S is 865.3581; 865, 569, 509, 297, 279, 2.51, 133, 105, 77, 57.

Preparation 51: Preparation of Taxotere (1OBF) from lO-Acetyl Taxotere (IOBA) A 25 mng (0.029 mM) quantity of lO-acetyl Taxotere (Preparation 1. IOBA) is stirred at room temperature under nitrogen in 1.0 mnL 95% ethanol. Add 2 drops anhydrous hydrazine and leave to react for 1.5 hours, when TLC showed the reaction to be mostly complete. The reaction is partitioned between water-mathylene chloride. The aqueous layer is backextracted with methylene chloride. The organic layers are combined. dried over sodium sulfate and.

evaporated underA vacuum.

The crude product is chromatographed over 3 g silica gel, eluting with 70-30 ethyl acetate-hexane. Fractions, of 1 mL are collected, analyzing them by TLC. Fractions 14-28 contain the product and are combined and evaporated under vacuum.

TLC: silica gel 60; 70-30 EzOAc-htexane; RE: 0.33.

ec...30 11 NMR (CDCI 3 TMS) 8 1. 12. 3H1); 1.23'(s, 3H); 1.34 9H); 1.74 3H1); 1.85 (s, Kd 111); 4.32 IH); 4.62 (bs. 1H); 4.94 111); 5.23 IH); 5.28 (bs, 5.52 5.66 Ce~e I 6.20 1 7.25-7.45 (mn, 6H); 7.5 2H1); 7.6 1 11H); 8.11 2H1).

Prprto 52:. P reparatin of 13i phn"yl-isosernyl)-baccatin II IN-t-amyluredwae (IORA) Part A: Preparation of t-aniyl 4-nitrophcnyl carbonate amC 0 0,0 A souino-anmyl alcohol (0.54 ml. 5.0 mM) in pyridine (I mld) was treated at 0 0

C

with 4-nit 'rophenyl chloroformate (1.00 g. 4.97 mM). After adding 1.5 mld of methylene chloride, the reaction was stirred at room temperature overnight. The reaction was diluted with toluene and filtered. Impurities crystallized out from methylene chioride-hexane.

NMR 8 0.981 3H1); 1.54 6H); 1.88 211); 7.36 2H); 8.28 211).

Part B: A 29 mg (0.039 mM) quantity of 1 3-($-phenyl-isoserinyl)-baccatin III (Preparation 24; 11A) and t-ainyl 4-nitrophenyl carbonate (13 mg. 0.051 mM) in pyridine (0.10 mld) are stirred at room temperature 3 diys. The reaction is diluted with ethyl acetate and washed with aqueous sodium bisulfate. The ethyl acetate solution is dried over anhydrous sodium sulfate, evaporated. and chromatographed on a column of silica gel g. 230-400 mesh). The column is eluted with ethyl acetate-hexane mixtures. The desired product is not completely pure, and is therefore rechromatographed in an acetone-hexane system.

NMR (CDCL 3 TMS): 8 0.86 Nt 1.15 3H); 1.27 (sO3ft 1.29 1.30 1.68 311); 1.85 4H1); 2.25 4H); 2.38 3H); 2.53 (in, 2H). 3.37 (ci. 11H); 3.80 (di, 1H1); 4.17 111); 4.30 (di, 111); 4.41 (in. 111); A.63 (mn, IH); 4.95 (di, 11H); 5.30 (mn.

1H); 5.40 (in, 1H1); 5.67 114); 6.24 (in, 1H1); 6.29 11-1); 7.3 1-7.68 (in, 8H); 8.11 2H).

13 C-NMR (CDC1 3 TMS): 8.16, 9.53, 14.85. 20.85, 21.86, 22.61, 25.25. 25.71, 25.9 1, 26.73, 33.22, 35.42, 35.56, 43.18, 45.59, 56.05, 58.53, 72.14, 72.36, 73.57. 74.94, 75.55, 76.44, 79.03, 79.28, 81.05, 82.68, 84.37, 126.67, 128.05, 128.68, 128.84, 128.91, 130.16. 132.95, 133.69, 138.28, 142.28, 155.25, 167.03, 170.16, 171.27, 172.92, 203.66.

MS (FAR): 864. Major ions m/z 794,569, 527,509,345,327.

Preparation 5: Preparation of I 3-(0-phenyl-isoserinyl)-baccatin II N-neopentylurethane (1OUA) Part A. Preparation of Neopentyl 4.-Nitropheny1 Carbonate A solution of neopentyl alcohol (0-54 ml, 5.01 mM), pyridine (1 ml), 4-nitrophenyl chloroformate (1.00 g. 5.0 mM), and distilled rF (2 ml) in a flame-dried flask is stirred at room temperature 40) h. lbe reaction is diluted with hexane, filt' -ed and evaporated. The product is chromatographed on silica gel in ethyl acetate-hexane mixtures. The product which eluted from the column is further purified by recrystallization from methylene chioride-hexane.

30 NMR (CDC1 3 TMS): 8 1.02 9H); 3.99 211); 7.39 (di, 2H); 8.29 2H).

Part B: A 20 mg (0.027 mM) quantity of I 3-(fr-phenyl-isoserinyl)-baccatin II (Preparation 24; 11A) and neopentyl 4-nitrophenyl carbonate (7.4 mg, 0.031 mM) in pyridine (80 p1) is stirred at ~room temperature overnight. The reaction is diluted with ethyl acetate and washed 5% aqueous sodium bisulfate. The organic solution is dried over anhydrous sodium sulfate and concentrated.

The crude product is chromatographed twice on silica gel, first in acetone-hexane, then in ethyl -44acetate-hexane mixtures to yield the desired product.

NMR (CDCL3, TMS): 8 0.82 9H1); 1.15 3H); 1.26 3H). 1.68 1.84 (s+in, 4H); 2.25 4H); 2.38 3H1); 2.52'(mn. 3.40 (di, 1H); 3.61 (d 111): 3.72 (in.

111); 3.79 Wei 4.18 (K 111); 4.29 (d 1H); 4.41 (in, 111); 4.66 (in, 4.94 5.33 (in, 1H); 5.59 1H); 5.66 (di, 111); 6.28 (s+rn, 2H); 7.30-7.70 811): 8.12 (di. 2H).

3 c-ghn~(CD1 3 1 TMS): 9.45, 14.74, 20.73, 21.79, 22.47, 26.09. 26.72. 31.32, 35.46, 43.05, 45.50, 56.38, 58.45, 72.03, 73.47, 74.57, 75.42, 76.36, 79.02. 81.00, 84.28, 126.6 1, 128.09, 128.58, 128.79, 128.96, 130.11, 132.97, 133.61, 138.10. 141.97. 156.30. 166.91. 170.2-3, 171.14, 172.47, 203.50.

MS (FAB): (rn+H) 864. Major ions mi/z.569, 55.1,509. 327. 296. 250.

Preparation 54: Preparation of 13-($-phenyl-isoserinyl)-baccatin Ill N-(2-chloro- 1.1 .dimethylethyl)urethane (lOSA) Part A: A solution of 1-chloro-2-methyl-2-propanol (0.51 ml. 5.0 mM). 4-nitrophenyl chiorofomt 099g .0m) yiie(0 l .0mMadTF( l nadyfaki tre at room temperature 40 h. The reaction is diluted with hexane and filtered. The filtrate is evaporated and recrystallized from methylene chloride-hex ane to yield the desired product.

NMR (CDC1 3 TMS): 8 1.64 6H); 3.87 2H1); 7.38 211); 8.28 2H).

Part B: A 28 mg (0.037 mM) quantity of 13- Ophenyl-isoserinyl)-baccatin mH (Preparation 24; 11A) and chloro-t-butyl 4-itrophenyl carbonate (12.0 mg, 0.044 mM) in pyridine 10 ftl) is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with 5% aqueous sodium bisulfate. The organic layer is dried over anhydrous sodium sulfate so o.and evaporated. The crude product is purified by column chromatography on silica gel in acetone-hexane mixtures.

NMR (CDCI 1 TMS): 8 0.82 911); 1.15 3H); 1.26 3H); 1.68 311); 1.84 (9+mn 4H1); 2.25 (s+in, 411); 2.38 3H); 2.52 (in, 2H); 3.40 I1H); 3.61 I 3.72 (in, 111); 3.79 Ki 111); 4.18 (cd, 111) 4.2-91d. 111); 4.41 (mn, 111); 4.66 (in. 1H); 4.94 5.33 111); 5.59 (mn 111); 5.66 (di, 111); 6.28 (s+in, 211); 7.30-7.70 (in. 811); 8.12 211).

30 13 C-NMR (CDC1 3 TMS): 9.45, 14.74, 20.73, 21.79, 22.47, 26.09, 26.72, 31.32, 35.46, '06:0. 43.05, 45-50, 56.38, 58.45, 72.03, 73.47, 74.57, 75.42, 76.36, 79.02, 81.00, 84.28, 126.6 1.

128.09, 128.58, 128.79, 128.96, 130.11, 132.97, 133.61, 138.10, 141.97, 156.30, 166.91, 170.23, 17114 17.4, 03.0.MS(FAB): (mH) 864. Mjrions m/z 569, 551. 509. 327,296, &too.:250.

Preparation 55: Preparation of 13-(f -phenyl-isoserinyl)-baccatin III N-(3-Methyl-3pentyl)urethane (IOTA) Part A: Preparation of 3-Methyl-3-pentyl 4-Nitrophenyl Carbonate A mixture of 3-methyl-3-pentanol (0.62 ml. 5.0mM). 4-nitrophenyl chloroformate (1.01 g. 5.0 mM), Tf{F (2 ml). and pyridine (1 ml) is stirred at room temperature 40 h. Acetonlitnile (2 ml) is added and stirring continued overnight. The re-action,-is diluted with methylene chloride and hexane. filtered and evaporated. The product is chromnatographed on silica gel in ethyl acetate-hexane mixtures.

NMR (CDC1 3 TMS): 8 0.95(t, 6H);1.50 3H);1.90 (in. 4H); 7.35(d. 8.27 (d.

211).

Part B: A 32 mg (0.043 mM) quantity of 13..$-pheny-isoserinyl).baccatin M (Preparation 24; 11A) and 3-methyl-3-pentyl 4-nitrophenyl carbonate (12.5 mg, 0.047 mM) in pyridine (0.15 ml) is stirred at room temperature 60 h. The reaction is diluted with ethyl acetate and washed with aqueous sodium bisulfate, dried over anhydrous sodium sulfate and evaporated. The product is purified by column chromatography on silica gel in acetone-hexane mixtures.

NMR (CDCL 3 TMS): 8 0.76 6H1); 1.15 311); 1.24 1.27 1.50-1.98 (3 s +rn, 12H1); 2.25 5H1); 2.38 (so 3H1); 2.53 (in, 211); 3.37 (bs, lH); 3.80 111); 4.17 (d.

I 4.30 (di, 11H); 4.41 (in, 111); 4.64 (mn, I1H); 4.95 I1H); 5.29 (in, 11H); 5.42 (in, I 5.66 (do, 11); 6.24 (rn, 1H); 6.29 (s 111); 7.30-7.70 (in, 8H1); 8.11 (di. 2H).

13_M (CDCI 3 TMS): 7.61, 9.27. 14.58, 20.58, 21.63, 22.35, 22.58. 26.46, 30.18, 30.26. 35.15, 35.29, 42.91, 45.31, 55.68, 58.26, 71.88, 72.13, 73.27. 74.71, 75.29, 76.31. 78.78, 80.79. 84.10, 84.95, 126.38, 127.77, 128.41, 128.58, 128.81, 129.90, 132.71, 133.41. 138.06.

1142.03, 154.86, 166.70, 169.88, 171.00, 172.68, 203.40. MS (FAB): 878. Major ions m/z 794, 569, 527, 509, 345, 327.

Preparation 56: Preparation of N-(t-butylazninocarbonyl)-f -phenyI isosenine methyl ester (3K) 25 (2R,3S)-f -phenyl-isoserine methyl ester (4.35g, 22 mM) is dissolved in I 0mL dry THF and the flask cooled to 0 0 C. To the solution is added t-butyl isocyanate (2.8 mL, 25mM). TLC e.:e *after 15 minutes shows some starting material left so another 0.5 ml. of the isocyanate is added.

TLC after 1 hour shows no starting material so the solvent is concentrated in vacuo leaving N- (t-butylanminocarbonyl)-f -phenyl isoserine methyl ester (3K).

Proton NMR (CDC1 3 TMS): 8 1.27 3.43 3.81 4.34 (br s,1H); 4.48 (mWH); 5.27 (mn1H); 5.32 7.29 7.34 (m,3H) Mass spec (FAB-High Res.) Theory for C 15 H22N 2

O

4 295.1658 Found: 295.1663 Preparation 57: Preparation of (4S.SR)-N-(t-butylaminocarbonyl)2-(2,4-dimethoxyphenyl).4 acid methyl ester (5Ka N-(t-butylaminocarbonyl)-]3-phenyl-isoserine methyl ester (68 mg. 0.23 mM; 3K.

Preparation 56) is dissolved in 5 ml, dry Ti-F and the solution treated with 2.4-dimethoxy benzaldehyde dimethyl acetal (70 mg. 0.33 mM) and pyridinium p-toluenesulfonate (6 mng. 0.02 mM) and the solution warmed to reflux. Approximately 2 rnL solvent is boiled away 3 times in a 45 minute period replenishing with 2 n-L of fresh THE at which time flC shows no starting material. The solvent is concentrated in vacuio and chroniatographed over 7 gm of silica gel packed in 1:3 EtOAc:Hexane. 'The column is eluted with 80 rnL 1:3 EtOAc:Hexane, 45 mL 1:2 EtOAc:Hexane,. 30 mL 2:3 EtQAc:Hexane, and 30 mL 1:1 EtOAc:Hexane collecting 3 mL fractions.

A less polar isomer, (4S,5R)-N-(t-butylaminocarbonyl)2(2.4-dimethoxyphenyl).4.

.oxylic acid methyl ester (5Ka) is found in fractions 21-31.

Proton NMR (CDCI 3 TMS): 8 1.19 3.82 3.85 3.89 4.68 (br s,1H); 4.88 KIMH) 5.52 KIMH) 6.46 6.70 7.25-7.50 (in Mass spec (FAB-High Res.): Theory for C 24

H

31

N

2 0 6 443.2182 Found: 443.2172 A more polar isomer, (4S,SR)-N-(t-butylaminocarbonyl)2-(2.4-diniethoxyphenyl).4acid methyl ester (5Kb) is found in fractions 33-42.

Proton NMR (CDC1 3 TMS): 8 0.99 (in.9H); 3.53 3.81 (in.3H); 3.88 (in,3H);.

4.05 (m,lH);v 4.55 (rn,lH); 5.45 (mn,1H); 6.48 6.79 7.2.5-7.50 (in) Mass spec(FAB-High Res.): Theory for C 24

H

31

N

2 0 6 443.2182 Found: 443.2180 Preparation 58: Preparation of 4 S.SR)-N-(t-butylaminocarbonyl)-2-(2.4-dimethoxyphenyl..4 acid potassium salt (61(a) and its free acid (71(a) A 100 mg (0.23 mM) quantity the less polar isomer of (4SSR)-N-(t-butylaminocarbonyl)- 2 2 ,4-dixnethoxyphenyl)-4-phenyl-5-oxazoidinecarboxylic acid methyl ester (Preparation 57, 51(a) is stirred at room temperature under nitrogen in 3 mL MeOH. To this is added 0. 1 mL. water and 43 mug (0.31 mM) potassium carbonate. After 1 hour. TLC shows no starting material left. Store in frezer overnight. The next morning the solvent is evaporated to 25 give 4 S,SR)-N-(t-butylaminocarbony1)-2-(2.4-dimethoxyphenyl)-4-phenyl5oxazoliline.

caxboxylic acid potassium salt (6Ka).

Proton N!{R (d 6 -DMSO): 8 1.20 9H): 3.51 IH); 3.76 3H); 3.96 3H); U. 4.32 2H); 4.80 1H); 5.29 6.60-6.68 (in, 2H); 6.71 (di. lH); 7.26 (di, 1H); 7.35 111); 7.45 211); 7.53 (ci, 2H).

30 Preparation 59: Preparation of (4S.5R)-N-(t-buty lamiino-carbonyl).2.(2,4-dimethoxyphenyl)-4acid (7Ka) 4 S.SR)-N-(t-butylainocarbonyl)-2-(2,4dimethoxyphenyl)4phenyl-5-oxaolidnecarboxylic acid potassium salt (61(a, Preparation 58) is partitioned between methylene chloride anid water containing 0.9 mL IN HO. 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 (4S.5R)-N-(t-butylaminocarbonyl)2-(2.4-dimethoxyphenyl)-4- .47acid (7ka) as a white solid.

Preparation 60: Preparation of 7-TES-baccatin Ill-13-(4S.5R)-N-(t-butylamirlocarbonyl)-2..(2.4 acid ester (9KaA) (4S,5R)-N-(t-butylaminocarbonyI)-2-(2,4-dixncthoxyphenyl)-4-phenyl5.oxazolidin..

carboxylic acid (1.07 mM, Preparation 59, 7Ka) is dissolved in 1.5 mnL mnethylene chloride-3 mnL toluene. To this is added 7-TES-baccatin M11(500 mg, 0.71 mM, 8A). DMAP (45 mg, 0.36 mM) and DCC (240 mg. 1.15 rnM). The reaction is stirred under nitrogen for one hour at RT.

The resultant urea side product is removed by filtation and the filtrate is evaporated under vacuum. The residue is chrornatographed over silica gel (80 elutinig with 25-75 EtOAchexane (200 mnL) and 33-67 EtOkc-hexane (14L) Fractions of 20 mL are collected, analyzing them by TLC. Fractions 28-47 contain the desired product and are combined and evaporated. 7- TES -baccatin 11-1I 3-(4S.5R)-N-(t-butylam-inocarbonyl)-2-(2.4..dimethoxyphenyl)-4 oxazolidinecarboxylic acid ester (9KaA) is obtained as a white solid.

Mass Spec (FAB, M+Jf): Calc'd for C6wH 79

N

2

O

16 Si 1111.5198: Found 1111.5189.

Preparation 61: Preparation of 13-(N-(t-butylanminocarbonyl)- -phenyl isoserinyl)- baccatin 111; N-debenzoyl-N-(:-butyl)aminocarbonyl-taxol; I 3-f-phenyl-isoserinyl)-baccatin MI N-t-butyl urea (lOKA) A 0.1 M HOI solution is prepared from 0.071 mL acetyl chloride and 9.929 mL of MeOH, leaving it sit for 30 minutes before using.

7-TES -baccatin III-1I 3-(4S,5R)-N-(t-butylaminocarbonyl)-2-(2,4-dimthoxyphenyl)-4 acid ester (100 mg, Preparation 60. 9KaA) is treated with the above methanolic HOl solution (0.5 rnL) with stirring under nitrogen. The reaction is complete after 45 minutes as shown by TLC. T7he reaction mixture is partitioned between ethyl acetate- Ve~ 5% sodium bicarbonate. The layers are separated and the aqueous layer reextracted with ethyl acetate. The organic layers are combined, dfied over sodium sulfate and evaporated under vacuum.

The crude product is chromnatographed over silica ge](8 eluting with 33-67 acetonehexane (70 niL) and 40-60 acetoi~e.?l.axne (35 mL). Fractions of 2 mL are collected, analyzing them by, TLC. Pure product is found in fractions 18-29, which which are combined and 30 evaporated. 13-(N-(t-butylaniinocarbonyl)-f-phenyI isoserinyl)- baccatin Ill (I OKA) is obtained *as a white solid. The physical data correspond to t hose obtained previously in Preparation 46.

PREPARATION 1IA 2'-[{(2,22-Trichloroethyl)oxy }carbonyl]-taxol, 7-Methylxanthate Methyl iodide (1.3 equivalents) is added to a stirred solution of 2 chloroethyl)-oxy)carbonylltaxol (I equivalent) in carbon disulfide. Sodium hydride (2.1 equivalents) is added and the resulting mixture is stirred and checked by tlc for formation of the *0 methyl xanthate. When reaction is complete, the excess carbon disulfide and methyl iodide are removed by evaporation. The residue is partitioned between water and ether, the layers are separated, the organic layer is dried, filtered, and concentrated to give the title compound.

PREPARATION 2A: 2'-[{(2.2,2-Trichloroethyl)oxy)carbonyl]taxol. 7-Methanesulfonate Methanesulfonyl chloride (1.2 equivalents) is added dropwise to a solution of 2 2 ,2, 2 -trichloroethyl)oxy)carbonyl]taxol (1 equivalent) and pyridine (5 equivalents) in CHCl2 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

C

2 and these extracts are washed successively with dilute aqueous acid, dilute aqueous NaHC0 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 3A: 2'-[((2,2,2-Trichloroethyl)oxy)carbonyl]taxol, 7-Trifluoromethylsulfonate Trifluoromethanesulfonic anhydride (1.3 equivalents) is added dropwise to a solution of 2 2 ,2,2-trichloroethyl)oxy)carbonyl]taxol (1 equivalent) in pyridine which is stirred and cooled to -30*C. The reaction mixture is allowed to warm and stirring is continued until tic evidence indicates the reaction is complete. The reaction solution is quenched with ice water and is extracted with CH 2

CI

2 The CH2I 2 extracts are washed successively with cold, 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 4A: 2'-[{(2,22-Trichloroethyl)oxy )carbonyl]-7-deoxy-7-azidotaxol A solution of 2 '-[((2,2.2-trichloroethyl)oxy}carbonyl]-taxol,. 7-trifluoromethylsulfonate (1 equivalent) in NN-dimethylformamide is stirred with potassium azide (10 equivalents). The mixture is stirred and warmed until tic evidence indicates the reaction is complete. The reaction S 25 mixture is quenched with cold water and the resulting solution is extracted with ether. The ether extract is washed thoroughly with water, dried, filtered, and concentrated to give the crude reaction product Chromatography of the crude product over silica gel gives pure title compound.

PREPARATION 5A: 2 '-[{(2,2.2-Trichloroethyl)oxy)carbonyl]-7-deoxy-7-aminotaxol A solution of 2 2 2 ,2-trichloroethyl)oxy)carbonyl]-7-deoxy-7-azidotaxol in ethanol is stirred with 10% palladium-on-carbon catalyst in a hydrogen atmosphere. Following reaction, the catalyst is removed by filtration and the filtrate is concentrated to give the crude reaction product. Chromatography of the crude product over silica gel gives pure title compound.

PREPARATION 6A: Preparation of N-Desbenzoyl-N-benzyloxycarbonyl-2'-{[(22,2trichloroethyl)oxy]carbonyl )-taxol, (({2aR-[2aa,4 ,4ap,60.9a,(caR*,S*), la,12a,12aau,12ba] }--(Benzyloxycarbonylamino)-a-{[( 2 2 2 -trichloroethoxy)-carbonyl]oxy~benzenepropionic Acid. 6,12b-Bis(acetyloxy)-1 2-(benzoyloxy)-2a.3.4.4a.5.6,9.- 10,11.12, 12a,12b-dodecahydro-4.l 1 -dihydroxy-4a,8.l 3.1 3-tetraznethyl-5-oxo-7.1 1 -methano- 1Hcyclodeca[3,4]benz[1 ,2-b]-oxet-9-yl Ester)) (12BA); and N-Desbenzoyl-N-benzyloxycarbonyl-2' ,7-bis((2.2,2-tri chloroethyl)oxy]carbonyl )-taxol.

(({2aR-[2aa,4,4ap,6fI,9a,(aR*4,S),1 I a, 1 2aa, 1 2baJ )-f-(B3enzyloxycarbonylamino)-a- [((2,22-richloroethoxy)-carbonvl)oxylbenzenepropanoic acid, 6,12b-Bis(acetyloxy).l 2- (benzoyloxy)-4- {[(trichloroethoxy)carbonyl~oxy )-2a,3 ,4,4a,5,6,9, 10.11,12,1 2a.l2b-dodecahydro- 11 -hydroxy-4a,1 3,1 3-tetrmethyl-5-oxo-7, 1-methao- IH-cyclodeca[3.4Jbenz[1I.2-bJ-oxet-9-yI Ester)).

The procedure described for the preparation of 2*-troc-taxol (Magri et al.. J. Org. Chem..

1986, 51, 797) is followed, using N-desbenzoyl-N-benzyloxycarbonyltaxo (0.290 g, 0.3 28 mrmol) and 2,2.2-trichloroethyl chloroformate (59 iiL. 0.091 g, 0.43 mmnol) in CH 2

CI

2 (1t mrL) containing pyridine (1.6 ruL). Following workup, the crude product (0.340 g) is chrornatographed over silica gel (40-63 pm. Merck size B column) using a CH 2 Cl 2 solution for application of the material to the column and 40% EtOAc-hexane (90 fractions), 60% EtOAc-hexane fractions), and EtOAc to elute the column (8 mL fractions are collected). N-Desbenzoyl-Nbenzyloxycarbonyl-2',7-bistro-taxol (0.053 g. 13%) is eluted in fractions 14-23. Starting material (0.014 g. is recovered in fractions 139-143. The desired N-desbenzoyl-Nbenzyloxycarbonyl-2'-troc-taxol 12BA (0.248 g, 0.234 mnol, 71 is eluted in fractions 49-80 and is characterized by the following spectral data: 1 H NM (CDCI 3 TMS) 8 8.15 2H. aromatic), 7.62 I H. aromatic), 7.52 2H, aromatic), 7.30-7-50 (mn. 5H, aromatic), 7.17 (in, 2H, aromatic), 6.26 (in, IH. H 13 6.25( I H,

H

10 5.71 (in, 1H, 5.67 1H, H 2 5.58 (in, IH. HO.) 5.41 1H, H 2 5.08 IH.

**PhCH.HO-), 4.96 1H, PhCHHbO-), 4.9 (m Il H, H 4.9(d aOHCC 3 4.68 (d.

~25 1 H, J 11.8 Hz, OCHHbCCI 3

H

7 4.31 I1H. H2D), 4.18 I H, Hob.37 III. H 3 2.55 (mn, 1H, H62), 2.47 (mn, 1H, Hla), 2.45 3H. -CH 3 2.31 (in. 114, H 1 4b), 2.24 3H.,-CH 3 1.92 (mn, 1H, 1.86 3H. -CH 3 1.68 3H, -CH 3 1.23 3H.

*.CH

3 1.14 3H., -CH 3 mass spectrum 1058, 569, 551, 509, 105, 91 m/z.

.*30 PREPARATION 7A: A solution of taxol (0.026 g. 0.030 mmol) and 98% hydrazine (0.035 g, 1.1 inmol) in ethanol (1.0 mL) is stirred at room temperature for 2 hr. The solution is poured into water and ether, the mixture is shaken well, and the layers separated. The aqueous layer is extracted with additional ether. The combined ether extracts are dried over Na 2

SO

4 filtered and 35 concenttrated, giving 0.021 g of the title compound: 1H NMR spectrum in CDCI 3 is identical to :the spectrum reported for- 1O-deacetyltaxol (Ringel, Horwitz, S. B. J. Pharmacol. Exp. Ther., 1987, 242, 692) and is identical to the spectrum of an authentic sample.

PREPARATION 8A: lO-Deacetylbaccatin IM A solution of baccatin 111(0.024 g, 0.041 mxnol) in 95% ethanol (1.0 miL) is prepared by warming the mixture. The solution is cooled to room temperature. 98* hydrazine (0.035 g.

1.1 mmol) is added and the solution is stirred at room temperature for 24 hr. The solution is poured into water/ether, shaken well, and the layers are separated. The ether layer is washed with water, dried (Na 2

SO

4 filtered, and concentrated. giving 0.010 g of the title compound: 1

H

NMR spectrum in CDC1 3 (sparingly soluble) is identical to that of an authentic sample of deacetylbaccatin MI.

PREPARATION 9A: 7-Deoxy-A 6 7 -baccatin Ea1 The procedure described in Example I for the reaction of 2'-troc-taxol with methylDAST is followed using baccatin M1. Following woricup of the reaction, the crude product mixture is separated by medium pressure chromatography over silica gel, giving the title compound.

PREPARATION lOA: N-Debenzoyl-N-{[(2.2,2-tfichloroethyl)oxy]-carbonyl-2T-triethylsilyltaxol N-Debenzyl-N-((2,2,2-trichloroethyl)oxylcarbonyl }taxol 3-[N-(2.2.2-trichloroethoxycarbonyl)-f -phenyl-isoserinyl]-baccatin 111; 1ODA, Preparation 28)) is selectively silylated by reaction with triethylsilyl, chloride in pyridine containing a catalytic amount of 4-dimethylaminopyridine. The reaction is quenched by pouring into ice water and extracting with CH 2

CI

2 The extract is dried, filtered, concentrated and the crude product is purified by silica gel chromatography, giving the pure title compound.

PREPARATION 11 A: N-Debenzoyl-N- {[(2,22-trichloroethyl)-oxy~carbonyl '-triethylsilyl-7deoxyA 6 7 _taxol 25 Following the procedure described in Example 1, N-debenzoyl-N-{[(2.2,2-trichloroethyl)-oxylcarbonyl)-2'-triethylsiyltaxol (Preparation IOA) is allowed to react with methyl- DAST in C22. Following workup, the crude reaction mixture is separated and purified chromatographically, giving N-debenzoyl-N-((2,2.2-trichloroethyl)oxylcarbonyl '-triethylsilyl- 7-deoxy-7-fluorotaxol, N-cIbenzoyl-N-{[(2,2,2-trichloroethyl)oxy]carbonyl '-triethylsilyl -7deoxy-70,8 -methanotaxol, and the title compound.

PREPARATION 12A N-Debenzoyl-N-{[(2,2,2-trichloroethyl)-oxyjcarbonyl}-7-deoxy-A 6 ,7_taxo (16C) A solution of N-debenzoyl-N- {[(2,2,2-trichloroethyl)oxy]carbonyl }-2'-triethylsily-7.

deoxy-A 6 7 -taxol in acetic acid-H 2 0-tetrahydrofuran is stirred at room temperature until removal of the silyl group is complete. Following worlcup. the crude reaction product is subjected to silica gel chromatography. giving the pure title compound.

-51- PREPARATION 1 3A N-Debenzoyl-N-Q-butyl)oxycarbonyl-2 -{[(2.2.2-trichloroethyl)oxy]carbonyl )-taxol A (Compound 12DA); (({2aR[2a L,4P,4aP.6R,9C,(aR I Ix 1. 2at, 1 2ar.1 2baJ }-f-[(t-Butyl)oxycarbonylaminoJ-a-{[(22-trichloroethoxy)carbonyl]oxy benzenepropionic Acid, 6,12b-Bis(acetyloxy)-I 2-(benzoyloxy)-2a.3,4,4a.5.6,9.- 10.11,*12,1 2a. 121,dodecahydro-41 I -dihydroxy-4a,8,1 3,1 3-tetrxnthyl-5-oxo-7. I1 -methano- I H- cyclodeca[3,4]benz [1,2-b]-oxet-9-yl Ester))-. and N-Debcnzoyl-N-Qt-butyl)oxycaxbonyl-2'.7-bis{((2,2,2-trichloro-ethyl)oxy]carbonyI }-taxol (({2aR-[2aa,$,4aN,6p,9cz,(a.R*.DS),I I1 cx,!212aacL 2bcrJ }-P41[-Butyl)oxycarbonylamino-{x.

[{(2,2,-trichlorothoxyXcarbonyl )oxylbenzcnepropanoic acid, 6,1 2b-Bis(acetyloxy).1 2-(benzoyl.

oxy)74-{[(trichloroethoxy)carbonyl]oxy)-2a,3,4,4a,5.69,10, ll,12,12a.12b-dodecahydro-l 1hydroxy-4a,8,13,l 3-teramthyl-S-oxo -7.1 1 -methano-1 H-cyclodeca[3,4]benz[ 1 2-b]-oxet-9-yl Ester)).

Following the procedure for the preparation of 2'-troc-axol (Magri et al., J. Org. Chem.

1986, 5, 797), but starting with N-debenzoyl-N-Q-butyl)oxycarbonyitaxo (Compound IOBA; 1.98 g, 2.33 mmol) and 2,2-trichloroethyl chloroformate (405 jiL, 0.622 g. 2.94 mmol) in

CH~

2 0 2 (80 niL) the product 12DA is prepared. Following workup, the crude product is chromatographed over silica gel (40-63 pm. 37 x 350 mm, 190 g) using a CH 2

CI

2 solution for application of the material to the column and 40% EtOAc-hexane (63 fractions) followed by EtOAc-hexane to elute the columnn (45 niL fractions are collected). N-Debenzoyl-N-(tbutyl)oxycarbonyl-2',7-bistro-taxoI (0.140 g) is eluted in fraction 6. Starting material (0.192 g) is recovered in fractions 70-78. The desired N-debenzoyl-N-Qt-butyl)oxycarbonyl.2'-troc-taxol (Compound 12DA) is eluted in fractions 18-38 and characterized by the following spectral data: 'H NMR (CDCI 3 TMS) 8 8.12 2H1, J 8.1 Hz), 7.62 (t4 1H, J 7.2 Hz), 7.51 (t, 2M1 J 7.7 Hz), 7.30-7.44 (in, 5H1), 6.30 1H. H 10 6.30 lH. H 13 5.68 KI lH. J 7.1l 25 Hz, H 2 5.48 Kci 1H -NH- or 113), 5.44 (di, iH, H 3 or 5.36 1H. J 2.2 Hz, H 2 4.98 I HJ. 93 Hz,H5). 4.79(d. 2H, J -l1.9 Hz. 2'troc-H.), 4.70 (d.2H. J 11.8 Hz, 2 '-troc-Hb), 4.44 (in, 1H., H 7 4.32 (di, 111. J 8.4 Hz, H2N). 4.18 1H. J1 8.4 Hz. H,) 3.82 111,3J- 6.8 Hz. H 3 PREPARAIION 14A 2'-Triethylsilyl-taxol. 7-methylxanthate A 500mg (0.52 mM) quantity of 2'-Triethylsilyl-taxol is dissolved in 5 mL of distilled THfF. To the solution is. added 50 p1. (0.80mM) methyl iodide and 155 p1. (2.58mM) carbon disulfide. A slurry of 40mg (60% sodium hyedr'do in oil) in distilled THF is made and approximately half added and the resulting mixture stirred and chocked by tic for formation of the methyl xanthate. After 0.5 hours the residue is partitioned between saturated NH4Cl solution and EtOAc, the layers are separated, the organic layer is filtered through Na 2

SO

4 and concentrated to give the title compound. The product is purified by column chromatography using 60 gin of silica gel in 1:4 EtOAc:hexane. The product is added using mnethylene chloride .and the column eluted with 400m1 1:4 400m1L 1:3 EtOAc:hexane. and 30Dml 1:2 EtOAc:hexane.

The fractions containing product are found by TLC and are combined and evaporated giving the 2'-triethylsilyl-taxol, 7-inethylxanthate as a white solid.

TLC: silica gel 60 33% EtQAc-67% hexane; Rf: 0.40.

NMR (CDC1 3 TMS): 8 0.44 (in, 6H); '0.81 1.19 3H); 1.22 2.16 (s, 3H); 2.48 3H1); 2.58 314); 2.94 (mn, 1H1); 4.03 Kd 4.25 Kd lH); 4.37 4.70 (s, IH); 5.00 Kd 1H); 5.73 (m,2H; 6.28 (mn, 1H); 6.32 6.40 (mn. 1H); 7.11 lH); 7.30.

7.65 7.75 8.15 214).

PREPARATION 15A 2'-TES-Taxol 7-Triflate A solution of 2'-triethylsilyltaxol [0.10 g; Chaudhary et al., J. Org. Chem. 1993. 58, ,37981 and dry pyridine (0.29 ruL) in CH 2 C1 2 (4 tnL) is cooled to -20 0 C and triflic anhiydride (0.17 nl, is -added. The solution is stirred and allowed to warmh to about -10*C. After 3 hours.

.saturated NH 4 CI is added to the reaction and the mixture is extracted with EtOAc. The organic extract solution is washed with dilute aqueous NaHSO 4 with saturated NaHCO 3 is dried over Na 2

SO

4 filtered and concentrate at room temperature. T he crude reaction product is chroinatograhed over silica gel (flash) using 30% EtOAc: in hexane to elute the column and collecting fractions of 5 mL volume. The fractions (4-10) containing the desired product are combined and give the title compound (0.094 g).

The following Examples further illustrate the subject invention.

Example I Preparation of~ 2'-{((2.2,2-Tricbloroethyl)-oxylcarbonyl )-7-deoxy-7-f'uorotaxol (Compound 13AA;Ia), (({2aR[2act,4af,6f,9aL.(aLR 1c1 I2ac.-1 2aa, 1 2ba] -Benzoylamino)-a- ((22.-trichloroetoxy~carbonylj-oxy )bnzeneprpanoic acid, 6,1 2b.Bis(acetyloxy)- 12- (benzoyloxy)-2a,3,4,4a,5,6,9,10.l1,-12,12a,12b-dodecahydroA-rluoro-l l-hydroxy-4a,8,13,13tetramtyl-5-oxo-7,1 1-inethano-IH-cyclodcca[3,4]benzll ,2-b]-oxet-9.yI Ester)); 2'-{[(2,2,2-Trichloroethyl)oxy]carbonyl )-7-deoxy-70,8f -iethanotaxoI *::*(Compound 14AA). ((2R[am ia. .ccR.j3). 11cL. 12cr.,- 12aa.12ba] -(Benzoylamino)..a.. [(222-trichloroethoxy)-carbonyljoxy )benzenepropanoic acid. 6,1 2b-Bis(acetyloxy)- 30 12-(benzoyloxy)-2a,3.4.4a,5,6,9-,lO0l l,12,12a, I2b-dodecahydro- I I-hydroxy-8.13.13-trimethyl-5oxo-4,4a;7,1 I-bismeduano-IH-cyclodeca(3,4]benz[1,2-b-oxet-9-y Ester)); and 2'-{[(2.2,2-Trichloroethyl)oxy]carbonyl )-7-deoxy-A 6 7 -taxoI (Compound 4ap,6*19czaR 0 S 0)J 11a,1 2a, 12ac.,1 2ba] -(Benzoylamino)-z- ([(2,2,2-trichloroethoxy)carbonyl~oxy)benzenepropanoic acid, 6,1 2b-Bis(acetyloxy)- 12-(benzoyloxy)-2a,4a,5 10.1 1 12,12a,12b-decahydro.- 1-hydroxy-4a,8, 13,1 3 -tetramethyl-5-oxo-7.1 I-methano- 1H-cyclodeca[3,4]benz[ 1,2-b]-oxet-9-yl Ester)) Dimethylaminosulfur trifluoride (methylDAST) (250 pL, 0.340 g, 2.56 mmole) is added at once by syringe to a stirred and cooled (acetone-Dry Ice bath) solution of trichloro-ethyl)oxy]carbonyl)taxol 12AA [Magri, N. Kingston, D. G. I. J. Org. Chem., 1986.

51, 797] (1.60 g, 1.55 mmole) in CH 2

CI

2 (180 mL). The cooling bath is removed and the reaction container is allowed to come to room temperature. The reaction is stirred and starting material is found to be completely consumed within 70 minutes judging from tic evidence. The reaction is quenched by the addition of water and transferred to a separatory funnel with the aid of additional CH 2

C

2 The layers are separated and the organic layer is washed once with water, dried (Na 2

SO

4 filtered, and concentrated to give a white solid (1.65 The residue is chromatographed over silica gel (40-63 pm, 195 g in a 3.7 x 35 cm column; 40 mL fractions) using a CH 2

C

2 solution for application on the column and 25% acetone in hexane for elution of the column.

Fractions 32-39 contain a mixture of at least two compounds.

Fractions 40-42 contain a mixture which may include some of compound 14AA.

Fractions 43-49 (0.391 g) contain primarily compo.ad 14AA (Rf 0.22 in acetone-hexane) together with two minor components.

Fractions 50-54 contain 0.162 g of a mixture of 14AA and 13AA. This mixture is rechromatographed over silica gel (Merck Lobar® size B column, 8 mL fractions) using CH 2

CI

2 for application to the column and 25% acetone-hexane for elution of the column. Fractions 58- 70 contain 0.056 g of 14AA, which is combined (pool A) with the aforementioned 0.391 g from fractions 43-49 (total, 0.447 and fractions 76-92 contain 0.053 g of 13AA.

One of the two minor components of pool A is separated and is obtained as a pure compound by rechromatography of the mixture over silica gel (two Merck Lobar® size B columns, 9 mL fractions). The mixture is applied to the column in CH 2 Cl 2 and the column is 25 eluted with 25% EtOAc-hexane through fraction 72, 30% EtOAc-hexane through fraction 180.

and with 40% EtOAc-bexane thereafter. Fractions 164-180 contain the pure minor component, characterized as 15AA on the basis of the following analytical data: IH NMR (CDCI 3 TMS) 8118 (dd, 2H, J 1.5, 7.0 Hz), 7.76 (dd, 2H, J 1.5, Hz), 7.63 1H). 7.48-7.55 3H), 735-7.45 7H), 6.92 1H, J 9.4 Hz, -CONH-).

30 6.37 1H, H13), 6.23 1H, H 10 6.02-6.10 2H, H 6 5.86 (pair of d. 2H. J 9.6 z, H H17), 5.53 1H. J 2.7 Hz, H 2 5.12 IH, J 5.6 Hz. H 5 4.77 (dd, 2H, J 15.4, 11.8 Hz, troc,-CH2-), 4.46 1H, J 8.3 Hz, H20a), 4.32 1H, J 8.2 Hz. H20b), 4.02 1H, J 6.5 Hz, H3), 2.48 3H. -CHj), 2.45 1H. H 1 4a), 2.24 1H. H 1 4b), 2.22 (s, S" 3H, -CH 3 1.87 3H, -CH 3 1.84 3H, J 1.7 Hz. -CH 3 1.24 3H. -CH 3 1.15 3H, -CH3); FAB mass spectrum, 1010.2357, C 5 0

H

5 0

C

3

NOI

5

H

1 requires 1010.2324. 551. 460, 442, 210, 105 m/e.

Fractions 195-215 (0.373 g) contain 14AA and the second minor component which is not separated until after removal of the troc protecting groups. Despite the presence of the minor component, compound 14AA forms beautiful crystals upon slow evaporation of the solvent and the following spectral data are recorded: FAB mass spectrum gives peaks at 1012, 1010, 551. 5 33 511, 49 1, 460, and 442 mass units; IH NMR (CDC1 3 TMS) 8 8.19 2H, J 7.1 Hz). 7.71 2H. J 7.2 Hz). 7.59 (t.

1H), 7.48 7.36 6.98 1H. 6.57 1H. H 10 6.28 1H., J 8.7 Hz. H 13 6.08 (dd, IH, J 9.5, 2.7 Hz, H 3 5.67 1H. J 7.6 Hz. H2). 5.54 1H, J 2.8 Hz, H 2 4.77 (dd, 2H. 2'-troc 4.74 (1H, H 5 4.32 1H. J 8.6 Hz, H20a), 4.09 1H. J 8.6 Hz, H20b), 4.07 (1H, H 3 2.47 3H, -CH 3 2.23 (dd. 1H, JH-7 9.9 Hz, JH-19a 5.3 Hz, H19), 2.19 3H, -CH 3 1.90 3H, J 1.3 Hz, -CH3). 1.67 (dd, 1H. JH-7 7.2.

J

H-19a 53 Hz, H 1 9 1.38 1H, H 7 26 3H, -CH 3 and 1.21 3H, -CH 3 13 C NMR (CDC1 3 TMS) 201.88, 169.64, 169.59, 167.45, 167.03, 166.96. 153.24. 140.41. 136.43, 133.89.

133.61, 133.36, 132.05. 130.31. 129.25, 129.15, 129.07, 128.95, 128.75, 128.68. 128.39. 127.17, 126.49. 93.82, 84.83. 80.11. 79.56, 79.47. 77.78, 77.23, 75.66, 75.41, 72.17. 52.58. 42.85, 38.57, 35.93. 35.04. 32.26, 26.05, 22.30, 21.60, 20.83. 15.82, 14.56 ppm.

Fractions 55-65 (0.480 g) contain pure compound 13AA and when taken with the 13AA obtained from the above rechromatography of mixed fractions, give 13AA as a colorless crystalline solid: Rf 0.19 in 30% acetone-hexane; FAB mass spectrum gives peaks at 1034, 1032, 1030, 571. 511., 460, 442. 210, and 105 mass units; 25 1 H NMR (CDCI3. TMS) 5 8.18 (dd. 2H, J 7.0. 1.5 Hz). 7.76 (dd, 2H. J 7.0,1.5 Hz), 7.62 1H), 7.50 7.43 6.95 1H, 6.57 1H, Hio). 6.27 1H. Hi3).

6.08 (dd, 1H. J 9.5, 2.6 Hz, 5.78 1H. J 7.3 Hz, H2). 5.55 1H, J 2.7 Hz, H 2 5.05 1H. J 7.5 Hz, H 5 4.78 1H, J 11.8 Hz, H20a), 4.74 IH. J 11.8 Hz, 4.48 (dd, 1H, JF 48 Hz, H7), 4.40 1H. J 8.4 Hz, H20a). 4.31 IH, J 8.2 Hz, 4.04 1H, 7.2 Hz, H3), 2.63-2.45 2.49 3H), 2.27-2.10 2.20 3H). 1.91 3H), 1.74 3H), 1.20 3H), and 1.17 3H); 13 C NMR (CDC 3 TMS) 206.0, 169.9, 168.8, 167.2, 167.17, 153.2, 140.9, 136.4, 133.7, 133.5, 132.1, 130.3. 129.3, 129.2. 128.8. 128.7.

128.6, 127.2, 126.5, 96.2, 93.9, 81.9, 80.8, 78.8, 77.9, 77.8, 77.4. 77.2, 75.0, 72.1, 56.8 J 18 Hz), 52.7, 42.7, 40.1, 35.7, 33.9. 33.6, 25.8, 22.6, 21.3, 20.8, 14.6, 14.4 ppm.

Example 2 Preparation of 7-Deoxy-A 6 7 -taxol (Compound 16A), {2aR-[2aa,4ap,6p,9a.aR*,pS), 11a,12a,12aa,12ba] }-f-(Benzoylamino)-a-hydroxybenzenepropanoic acid, 6,12ba, Bis(acetyloxy)-1I2-(bc~nzoyloxy)-2a,4a,5.6.,1 0,11,12.1 2a 12b-decahydro- 1-hydroxy-4a.8. 13.13tetramethyl-5-oxo-7,l I -methane- I H-cyclodeca[3,4lbenz[ I .2-b]-oxet-9-yl Ester)) A solution of 2'-{((2.2,2-trichioroethyl)oxy]carbonyl }-7-deoxy-A 6 7 -taxol (ISAA. 0.010 g, 0.0099 nrnol) in MeOH-HOAc 2.0 rnL) is deprotected with activated zinc (24 mg plus 50 mng additional during the course of the reaction). Following woricup and chromatography of the crude product over silica gel (40% EtOAc in hexane). there is obtained less than 1 mg of less polar materials and the more polar desired product 16A (6.0 mg. 0.0072 mmnole) as a white solid.

1 H NMR (CDCI 3 TMS) 8 8.17 2H). 7.75 2H). 7.64 1H). 7.36-7.55 (in. IO1-1 aromatic protons), 7.02 (di, IH. 6.21 IH, H 13 6.20 lH, H 1 )6.6(dIHH 6 o 5.87 (di, IH, H 3 5.83 (mn, 2H, H 2 and H 6 r7.51 d H 5 .47 1 .4.44 1H, 4.32 (ci, IH. H 2 4.00 (di, Ili, H- 3 2.39 3H. -CH- 3 2-23 3H. -C H 3 1.87 3H, -CH 3 1.70 3H, CH 3 1.24 3H. -CH- 3 1.16 3H. -CH- 3 Example 3 Preparation of: N-Desbenzoyl-N-benzyloxycarboniyl-2'- {f(2.22-trichloroethyl)oxyjcarbonyl deoxy-7-fluorotaxol (13BA), (({2aR-[2aa,4ap,60,9a,-(aIC43S), 11a,1 2t, 12az, 1 (Benzloxycarbonylamino)-a-{(22,2-trichloroethoxy)-carbnyloxy )enzenepropanoic acid.

6,1 2b-Bis(acetyloxy)-l 2-(benzyloxy)-2a,3,4.4a,5.6,9,- 10,11.12,1 2.12b-dodecahydro-4-fluoro- 11 -hydroxy-4a,B,1 3,1 3-tetaxethyl-5-oxo-7i,il1-inethano- IH-cyclodeca[3.4]benz[ 1.2-b] -oxet-9-yl Ester)); N-Desbenzoyl-N-benzyloxycarbonyl-2*- [(2,2-trichloroethyl )oxylcarbonyl deoxy-70,8f-methanotaxo1 (14BA). (({2aR-[2a,40,4ao,60.9a.(aR.OS 11 a.1 2t, 12aa,1I2&t] 0-{Benzyloxy-carbnyiamino)-a-((22.-trichloroethoxy)carbonylloxy }benzenepropanoic acid.

6,12b-Bis(acetyloxy)-1I 2-(benzoyloxy)-2a,3.4,4a,5,6,9, 10,11,- 12,1 2a, I2b-dodecahydro-lIl S2 25 hydroxy-8,13,13-riethyl-5-oxo-4,4a;7,1 Il-bismethano-1IH-cyclodeca[3,4]benz[ 1 ,2mb]-oxet-9-yl Ester)); and 6,7 N-Desbenzoyl-N-benzyloxycarbonyl-2'- {((2,2,2-trichloroethyl)oxy]carbonyl deoxy-A6,-taxol (Compound I5BA), (({2aR[2aa,4ao,6,9a,-R.?),1 .L.12a.12.aa.l2ba]}- (Benzyloxy-carbonylamino)-a-{[(2,Z2-trichloroethoxy)-carbonylloxy }benzenepropanoic acid.

30 6,1 2b-Bis(acetyloxy)- 1 2-(benzoyloxy)-2a,4a,5,6.9, 10,11,12,1 2a, I12b-decahydro-lI I -hydroxy- 4a,8,1 3,1 3-tetrarnthyl-5-oxo-7, 11-methan-i H-cyclodeca[3,4]benz[1I,2-b]-oxet-9-yI Ester)) The procedure described for the treatment of 2'-troc-taxol with methylDAST is followed (Example using N-desbenzoyl-N-benzyloxycarbo6nyl-2'-troc-taxoI (12BA. Preparation 6A; 0.223 g. 0.21 inmol) and dimethylaminosulfur trifluoride (methylDAST, 49 il-, 0.066 g, 0.50 inmol total, added 'in two portions) in CH 2

C*

2 (20 mL) under N 2 at -78 0 C. Following workup.

the crude reaction product mixture (0.211 g. white solid) is chromatographed over silica gel -56- 63 pm, two Merck size B columns) using a CH 2

CI

2 solution for application of the material to the column and 25% acetone-hexane for elution of the column. Fractions of 8 mL volume are collected. Fractions 107-118 contain a mixture of two components (0.065 g) w hich are separated in a second chromatography as described below. Fractions 128-140 contain compound 13BA (0.08 1 g, 0.076 mmol, 36%) which is characterized by the following spectral data: 1 H NMR (CDCI 3 TMS) 868.16 (di, 2H, J-7.2 Hz, aromatic) 7.63 I H, J3-7.5 Hz, aromatic), 7.53 2H, J 7.6 Hz, aromatic). 7.30-7.45 (in, 5H, aromatic), 7.24 (in, aromatic), 7.12-7.15 (in, 211, aromatic), 6.56 1H. H1 10 6.24 11H1 14 13 0, .74 III. J 7.4 Hz, H 2 5.74 (1 H, 5.62 (di, IH. H 3 5.44 (di, IH, H 2 5.0 I1H, J1 12.5 Hz, PhCH AHO-), 5.03 (dI 1H. H 5 I H, PhCHHbO-), 4.77 (di, I H. J 1.1.9 Hz, -OCHaHCC1 3 4.68 (di, IH. J 11.9 Hz, -OCHHbCCI 3 4.56 (dci, I1H, JF 50 Hz, H- 7 4.37 I1H. H.tja), 4.30 (ci, I H. H 2 4.00 (di, IH, J 7.3 Hz, H 3 2.57 (in, I1H, H 6 2.46 3H, -CH 3 2.40 (m lH.

1114,), 2-21 3H, -CH 3 2.15 1H. H14b)- 1.89 3H. -CH- 3 1.85 (in. 1H, H6b,), 1.74 (s.

3H. CH 3 1.19 3H. -Cl! 3 1.16 3H, -CM- 3 mass spectrum (FAB) 1060.2466, C 5 lH 53 C1 3 FN'0 16 H requires 1060.2492, 571, 553.

511, 472, 389, 347, 329, 105, 91 m/z.

Pooled fractons 107-118 (0.065 g) from the preceding column are rechromatographed over silica gel (40-63pmn one Merck size B column) using CH 2

CI

2 for application to the column and 10% MeCN-CH 2

CI

2 for elution of the column. Fractions of 8 mL volume are collected.

Fractions 55-70 contain 0.011 g of compound 1 H NMR (CDCI 3 TMS) 8 8.17 (cd. 2H, J 7.2, 1.3 Hz, aromatic), 7.63 J 7.3 Hz, aromatic), 2H. aromatic), 7.32-7.46 5H, aromatic). 7.28 (mn. aromatic), 7.15. 7.22 (mn, 211, aromatic), 6.25 111, HIP), 6.21 IH, H 10 6.05 lH, J1 9.9, 5.7 Hz. H 6 5.85 (di.

I1H, J1 9.7 Hz, 117). 5.83 (dI, 1-1H 2 5.75 (di, I H, I 9.7 Hz, 5.57 (di, I H, J 9.8 Hz, H 5.40(d, 1I H.J 2.7 Hz, 5.110 (di, I1H, J3-5.7 Hz, H 5 .9(.IHJ-1. z ArCII 5 4.97 (ci, 1H,J 12.5 Hz, ArCHHbQ-), 4.77 1II.,J 11.8 Hz, -OCH,HC 3 4.67 (di, 1H., J 11.8 Hz, -OCHHbCCI3), 4.43 IH, J 8.3 Hz, H20a), 4.31 (d.Ici J, 8.3 Hz. H20b), 3.99 J, 6.6 HzH 3 2.46 311, -CH 3 2.36 (in. 1H, 1 4a). 2.23 3H, Cl! 3 1.93 11 H HI 1.87 311, -Cl! 3 1.81 3H-, -CH 3 1.24 3H. -CH 3 1.14 (s, 30 3H. -Cl! 3 rnM (FA) 140.~6,C 51 5 2

CQ

3

N

16 11 requires 1040.2430, 551. 491, 369, 327, 105 nv'z.

Fractions 96-120 contain 0.043 g (0.041 mniol, 20%) of compound 14BA: 'H1 NMR (CDC1 3 TMS) 8 8.17 (di, 2H.1 J 7.1 Hz, aromatic), 7.59 IlH, aron~dtitc), 7.52 2H, aromatic). 7.31-7.46 (in, 5H, aromatic). 7.24 (in, aromatic), 7.09 (in. 2H aroma'Jc), 9 6.32 1H1, Hio), 6.28 111. I 8.6 H7, H 13 5.75 IH. J 10.0 Hz, 5.64 il-I. 3 -7.8 Hz, H 2 5.59 1H, H 3 5.41 I H. J3 2.6 Hz, 112.), 5.00 I1H. J 12.5 Hz, AICHaHO-), 4.91 (Ki 1H, J 12.6 Hz, ArCHHbO-. 4.76 IIH, J 9.8 Hz, -OCaCC 3 4.73 I1H. H 5 4.68 (di,1 I 9.9 Hz, -OCHHbCCI 3 4.30 I H. I 8.6 Hz, H 20 4.07 (di, MH, H 3 4.05 (di, 1H. H 2 0b), 2.50 (in, 1H., H 1 4a), 2.43 3H1, -CH3). 2.36 (in, 1H1, H 2.24 (mn, lH, H 1 19ad, 2.20 3H, -CH3), 2. 10 I1H, J 16.1 Hz, 11I4b,), 1.88 311, -CH 3 1.66 (mn, 1H. 11i9b, 1.38 1H, H 7 1.26 3H, -Cf- 3 1.21 3H. -CH3),; mass spectrum (FAB) 1040.2416, C 5 I 52 C1 3 N0 16 H requires 1040.2430, 980, 962, 551, 491, 369, 105, 91 m/z.

Example 4 Preparation of N-Desbenzoyl-N-benzyloxycarbonyl-7-deoxy-A 6 .7_taxoI (Compound 16B) Following the procedure described in Example 2, N-desbenzoyl-N-benzyloxycarbonyl- 2'-{[(2,2,-trichloroethyl).oxy]carbonyl )-7-deoxy-A 6 7 taxol (Compound 1SBA. Example 3) is deprotected. Following deprotection with activated zinc in MeOHIHOAc the isolated crude product is purified by chromatography over silica gel to give the pure title compound.

Exle 5i Preparation of Compound ISAA from 2'-{[(2,2,2-trichloroethyl)oxy]carbonyl~t.-xol, 7-(Methyl)xanthate (Preparation IA) 2'-{[(2,2,2-Trichloroethyl)oxy~carbonyl }taxol, 7-(methyl)xanthate (Preparation IA) is placed in round-bottomed flask which is heated under an atmnosphere of N 2 in an oil bath to a temperature of 150-225 0 C. The crude product from this pyrolysis is purified by column chromatography, giving pure title compound.

Example 6 Preparation of 2'-[{(2,2,2-trichloroethyl)-oxy)carbonyl]-7-cleoxy-el 6 7 -taxo (Compound 15AA) from ((2,2,2-Trichloroethiyly-oxy )carbonyl]-7-deoxy-7-aminotaxoI (Preparation An ice-cold solution of sodium nitrite (1.5 equivalents) is added in portions to a :x 25 vigorously stirred, icc-cold two phase mixture of a solution of 2'-[{(2,2,2-Trichloroethyl)oxy )carbonyl]-7-deoxy-7-aminotaxol (1 equivalent) in ether and a solution of sulfuric acid in water. The Mixture is stirred at ice-bath temperature for several hours following the addition.

Then, excess nitrous acid is quenched by the addition of an aqueous solution of urea. The aqueous phase of the mixtre is brought to near neutral pH by the careful addition of sodium carbonate, the layers are separated, and the aqueous phase is further extracted with additional ether. The combintd ether extracts are dried, filtered, and concentrated to give the crude reaction product. Chromatography of the crude product over silica gel gives pure compound Example 7 Preparation of 2'-[{(2,2,2-trichloroethyl)-oxy~carbonyl]-7-deoxy.&A.' -taxol (Compound 1SAA) from 2'-f {(2,2,2-Trichloroethyl)-ox y carbonyl]taxol 7-Trifluoromethylsulfoniate (Preparation 3A) .A solution of 2'-[[(22,2-Trichloroethyl)oxylcarbonylltaxoI 7-Trifluorornethylsulfonate in 80% ethanol-water is warmed and the reaction is followed by tic techniques. When complete.

the reaction solution is neutralized with sodium bicarbonate, excess ethanol is removed under reduced pressure, and the aqueous phase is extracted with methylene chloride. The extracts are dried, filtered, and concentrated to give the crude reaction product. The crude product is chrornatographed over silca gel to give pure compound 1SAA.

Example 8 Preparation of 134(N-Boc-f-phenyl-isoserinyl)-7-deoxyA 6 7 -baccatin MU (16D)) from I 3-$f-phenyl-isoserinyl)-7-deoxy_A 6 7 _baccatin (17).

Following the general procedure of Preparation No.31 [preparation of I 3-(N-Boc.phenyl isoserinyl)..baccatin II (1OBA) from 13.(N-f-phenyl isoserinyl)-baccatin III (11A)] but starting with l3-$fphenyl-isoserinyl)-7-deoxy-A 6 7 .baccatin 111(17) is prepared l3-(N-Boc-f phenyl-isoserinyl)-7-deoxy-A 6 7 -baccatin III (161)).

Example 9 Preparation of 10-Deacetyl-l3-(N-Boc--phenyl-isoerinyl).7deoxy-A 6 7 _baccatin III (16E) A solution of 1 3-(N-Boc-P-pheny-isoserinyl)-7-deoxy-A 6 7 -baccatin Ml (161), Example 8)'(0.010 g) and 98% hydrazine (0.050 g) in 95% ethanol is stirred at room temperature until tdc evidence reveals the reaction to be complete. Following workup, the crude reaction product is chrornatographed over silica gel giving pure compound 16E.

Derivatives of the 7-deoxy-A 6 7 _taxols in which the 2'-hydroxyl group is esterified are prepared directly from the desired 7-deoxy-A 6 7 -taxol by methods which are given in: Mathew.

A. er.aI., J. Mort Chem., 1992. 35. 145; U. S. Patent 4,960,790; U.S. Patent 4,942,184; U.S.

Patent 5,059,699.

Following the general procedures of Mathew et al. (see, U.S. Patent 4,960,790, ~4,924,184 and 5,059,699) but substituting the appropriate 7-deoxyA 6 7 _taxol analog, the following compounds are prepared.

2'-succinyl-7-deoxy- 6 -txl -alanyl)-7-deoxyA 6 7 taxoformate; 2V-glutaiyl-7-deoxy-A 0 -taxol; 2 2 3

C(O)NH(CH

2 3

N(CH

3 )2-7-deoxy-A 6 7 _taxol; 2'-(13-sulfopropionyl)-7-deoxyA 6 7 -taxol; 2'-(2-sulfoethylamido)succinyl-7-deoxy-A 7 _taxol; 2'-(3-sulfopropylaznido)succinyl-7-deoxy-A 6 7 taxol; 2'-(triethylsilyl}.7-deoxy-A 7 taxol; 2'-(t-butyldimethylsilyl)-7-deoxyA 6 7 -taxol; 2'-(N,N-diethylaminopropionyl)-7-deoxy-A 6 7 _taxo[; 2'-(N,N-diinethylglycyl)-7-deoxy-A 6 7 taxol; 2'-(glycyl)-7-deoxyA 6 '7_taXol:.

2'(L-alanyl)-7-deoxyA 6 '7-taxol; 2'-(L-leucyl)-7-deoxy.A 6 7 taxol; 2'-(L-isoleucyl)-7-deoxy-A 6 7 _axol; 2'-(L-valyl)-7-deoxyA 6 7 taxol; 2'-(L-phenylalanyl)-7-deoxy-A 6 7 -taxol; 2'-(L-proly)-7-deoxyA 6 7 _taxol; 2'-(L-lysyl)-7-deoxy-A 6 7 -taxol; 2'-(L-glutamyl)-7-deoxy-A6 -taxol; 2'-{L-arginyl)-7-deoxy-A 6 7 -taxol; 7-deoxy-A 6 7 -taxote; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group.

Example 10 Preparation of [2aR-{2act,4a60.9ca(aR O1 c,12cr,12aa,12ba)]-}-W(Ber'zoylamino)-a-({(2 1 2,2-trichloroetboxy)carbonyl )oxy]benzenepropanoic acid, 6,1 2b-Bis(acetyloxy)- 12-(benzoyloxy)-2a,3,4,4aS,6,9,10,11,12.12a, 1 2b-dodecahydro-4-fluoro- 1 -hydroxy-4a,8,13,13terarethyl-5-oxo-7,1 1 -metbano- 1 H-cyclodeca[3,4]benz[ ,2-b]-oxet-9-y Ester, Trichloroethyl)oxy)carbonylJ-7-deoxy-7-fluorotaxo (Compound 13AA, Ila) A solution of 2'-[{(2,2,2-trichloroethyl)oxy carbonylltaxol [Magri, N. Kingston, D.

G. 1. 1. Org. Chem, 1986, 51, 797] (0.021 g, 0.020 rnrole) in CH 2

CI

2 (1.5 niL) was added by syringe over a period of 5 min to a stirred and cooled (acetone-Dry Ice bath) solution of dimethylaminosulfur trifluoride (DAST) (2 p, 0.014 mnole) in CH 2

CI

2 (0.5 rnL) contained in a 3 mL Reacti-vialO. The cooling bath was removed after 15 min and the reaction container was allowed to come to room temperature. The reaction was stirred and the solution- was again cooled in an acetone-Dry Ice bath and more DAST (4 pl, 0.028 mmole) in CH 2

CI

2 was added to the reaction. The cooling bath was removed after 15 min. and after 90 min. the reaction solution was diluted with additional CHC12 and then was washed with water. The layers were separated and the organic laycr was dried (Na 2 SQ4), filtered, and concentrated to give a residue (0.017 The residue was chromatographed over silica gel (40-63 pm, 60 g) using a CH 2

CI

2 30 solution for application on the column and 30% acetone in hexane for elution of the column to give the desired title product having a Rf 0.19 (30% acetone-hexane): FAB mass spectrum gives peaks at 1034, 1032, 1030, 571, 511, 460, 442, 210, and 105 mass units; 1 H NMR (CDC1 3 TMS) 5 8.18 (dd. 2H), 7.76 (dl, 2H). 7.62 1H). 7.50 7.43 6.95 IH), 6.57 I 6.27 I1H), 6.08 (dd, 1 5.78 I 5.55 IlH), 5.05 (d.

1H) 4.78 and 4.76 2H), 4.66 0.5H) 4.50 0.5H), 4.40 1H), 4.3.1 IH), 4.04 (d, 1H), 2.63-2.45 2.49 311), 2.27-2.10 2.20 3H). 1.91 31-1), 1.74 1.20 (s.

3H), and 1. 17 3H); 13 C NMR (CDC1 3 TMS) 206.0. 169.9, 168.8, 167.2, 167.17, 153.2.

140.9, 136.4, 133.7, 133.5, 132.1, 130.3. 129.3, 129.2. 128.8, 128.7, 128.6, 127.2, 126.5, 96.2.

93.9, 81.9, 80.8, 78.8, 77.9, 77.8. 77.4. 77.2, 75.0, 72.1, 56.8 d. J1 18H-z), 52.7. 42.7. 40. 1.

35.7, 33.9, 33.6, 25. 22.6, 21.3, 20.8, 14.6, 14.4 ppm.

Example I11 Preparation of [2aR- {2ac,4aP,60,9ctaR,W), 1~1d2a, 1 2acr, I2ba (Benzoylamino)-a-hydroxybenzenepropanoic Acid, 6,1 2b-Bis(acetyloxy)-1I2.{benzoyloxy)-2a.3,4,4a.5,6.- 9,1 0, 11,12,1 2a, 1 2b-dodecahydro-4-fluoro- I11 -hydroxy-4,8, 13,1 3-tetramethyl-5-oxo-7,1 I1methano-1H-cyclodeca[3,4]benzll,2-b]-oxet-9-yI Ester 7-Deoxy-7-fluorotaxol (Compound Ifib) A solution of 2'-[{(2,2,2-trichloroethiyl)oxy )carbonyll-7-deoxy-7-fluorotaxol (Compound 13AA, m0a; 0.010g, 0.0097 mmole) in 9:1 methanol/acetic acid (1.0 rnL) was stirred with activated zinc mietal (0.012 g) at room temperature. After 90 mai, the reaction was worked up by removal of the zinc by filtration and concentration of the filtrate under reduced pressure.

.The residue was dissolved in CHi 2

CI

2 and this solution was washed with 0. IN aq. HCI, with aq. NaHCO 3 and with water. The aqueous layer was back extracted with C2C2 and the combined organic extracts were dried (Na 2

SQ

4 filtered, and concentrated to give a residue (0.009 The residue was chromatograpbed over silica gel (40-63 pim, 8mm x 250mm column) and was applied to the column in a CH 2

CI

2 solution. The column was eluted with 60 mL of EtOAc in hexane and then was eluted with 4D% EtOAc in hexane. The desired product (Compound E1Th) is obtained as a solid.

FAB mass spectrum 856, 571. 511, 286, 268, 240, 210, 105 mass units; 'H1 NM~R (CDCI 3 TMS) 8 8.15 (dd, 211). 7.75 (dd. 2H). 7.63 1H1). 7.50 7.38 7.06 1H1), 6.53 li). 6.18 I1H). 5.83 (dci. IH), 5.76 (di, IlH). 5.02 I 4.80O (t, 1I1H), 4.65 (di, 0.511), 4.50 (di, 4.38 (di, 11H), 4.29 I 4.04 IlH). 3.55 I 2.70.

4 25 2.40 2.40 311), 2.37-2.25 2.21 311), 1.75 (3H1), 1.62 3H), 1.20 1. 18 311); 1 C NMR'(CDCI 3 TMS) 205.7. 172.4, 169.5. 169.4, 167.1, 166.9, 140.4, 138.0, 133.8, 133.7, 132.4. 131.9. 130.2, 129.2, 129.0, 128.75. 128.71, 128.3, 127.02, 126.98, 81.9, 78.6, 77.2, 74.8, 73.2, 72. 1 W57-.0 01 17 Hz), 54.7, 42.6, 39.9, 35.8, 16.0, 22.5, 21.0. 20.8.

14.7, 14.2 ppm.

Following the procedure described by Magri and Kingston for the preparation of 2'.

[{(2,2,2-trichloroethyl)oxy)carbonylltaxol, the 2'-[{(2,2,2-trichloroethyl)oxy~carbonyl] derivative of 7-epitaxol (met.: Ringel, Horwitz, S. B. J. Pharmacol. Exp. Ther., 1987, 242, 692;, preferably Chaudhary et al., J. Org. Chemn., 1993, 58 3798) is prepared.

Example 12 2'-f ((2,2,2-Trichloroethyl)oxy }cabonyl]-7-deoxy-7-epifluorotaxol Following the procedure of Example 10, but substituting 2'-[((2,2,2-trichlorocthyl)oxy }carbonyll-7-epitaxol for 2' {(2,2.2-trichloroethyl)oxy )carbonyl].7.taxol. the title compound -61is prepared. The term 7-deoxy-7-epifluorotaxol as used in the name of the title compound means only that the configuration of the fluorine substituent is epimeric to that of Tricbloroethyl)oxy)carbonyl]-7-deoxy-7-fluorotaxo (Compound 13AA. M1a; Example 1) and does not imply a configuration analogous to that of 7-epitaxol.

Example 13 7-Deoxy-7-epifluorotaxol Following the procedure of Example 11, but substituting 2'-[{(2,2.2-trichloroethyl)oxy)carbonyll-7-deoxy-7-epifluorotaxol for 2'-[{(2,2.2-trichloroethyl)oxy )carbonyl]-7deoxy-7-fluorotaxol. the title compound is prepared. The term 7 -deoxy-7-epifluorotaxol as used in the name of the title compound means only that the configuration of the fluorine substituent is epimeric-.to that of 7-deoxy-7-fluorotaxol (Compound Mlb. Example 11) and does not imply a configuration analogous to that of 7-epitaxol.

Example 14 2'-((2,2,2-Trichloroethyl)oxy )carbonyl]taxol, 7-Methanesulfonate Methanesulfonyl chloride (1.2 equivalents) is added dropwise to a solution of trichloroethyl)oxy)carbonyl]taxol (1 equiv.) and pyridine (5 equiv.) in C202 which is stirred at* ice bath temperature. The reaction mixture is allowed to warm and stirring is continued until tlc evidence indicates that reaction is complete. 71e reaction mixture is quenched with ice water and is extracted with CH 2

CI

2 and thes.e 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.

Example 15 2'-[{(2,2,2-Trichloroethyl)oxy)6arbonyl]-7-deoxy-7a-chlorotaxoI A solution of 2'-[{(2,2,2-trichloroethyl)oxy)carbonyl~taxol. 7-methanesulfonate (I equiv.) in N.N-dimethylformaxnide (DMF) is stirred with potassium chloride (10 equiv.). A phase tr Ansfer catalyst is added and the reaction mixture is warmed to increase the rate of reaction. The course of the reaction is folowed by tic. The reaction mixture is worked up by the addition of water and extraction with CH 2

C]

2 The orgawic extracts are dried, filtered, and concentrated and the crude reaction product residue is chromatographed over silica gel, yielding the pure title compouind.

Example 16 7-Deoxy-7cc-chlorotaxol Following the procedure of Example 11, but substituting 2'-[{((2,2,2-trichloroethyl)oxy )carbonyl]-7-deoxy-7a-chlorotaxoI for rchlorothyl)oxy )carbonyl]-7deoxy-7-fluorotaxol, the title compound is prepared.

Example 17 7-Deoxy-7 -chlorotaxol Following the procedures of Examples 14 and 15. but starting with 2'-[{(2,2,2-tichloroethyl)oxy~carbonyl]-7-epitaxol. the title compound is prepared.

Following the general procedures of Examples 15 and I11 but using appropriate metal -62salts. such as sodium or potassium bromide and sodium or potassium iodide, in the procedure of Example 15, the following compounds ame prepared: 7-Deoxy-7ct-bromotaxol; 7-Deoxy-7f -bromotaxol; 7-Deoxy-7a-iodotaxol; 7-Deoxy-7f-iodotaxol., Compounds of Formula Il wherein X chlorine, bromine or iodine can also prepared by reaction of an appropriately Protected precursor I wherein RI -C 6 1- 5

R

2

-NHC(O)C

6

H

5

R

3 H. R 4 -OTOC; R 5 H; RIO -COCH 3 and X OH) with

(C

6

H

5 3 P1X 2

(C

6

H

5 3

P/CX

4 Or (C 6

H

5 0) 3

P/X

2 following, for example, the numerous examples and experimental conditions described in Castro, Organic Reactions, 1983, 29.

pp 1- 162.

Derivatives of the 7-deoxy-7-halotaxols in which the 2'-hydroxyl group is esterified are prepared directly from the desired 7 -deoxy-7-halotaxol by methods which are given in: Mfithew.

A. et.al,. J. Mcd Chem., 1992, 35, 145; U.S. Patent 4,960,790;, U.S. Patent 4.942,184; U.S.

Patent 5,059,699.

Following the general procedures of Mathew et al. (see, U.S. Patent 4,960,790, 4,924,184 and 5,059,699) but substituting the appropriate 7 -deoxy-7-halotaxoi analog, the folowing compounds are prqepaed 2 '-succinyl-7-deoxy-7-fluootaxol; 2 '-(fi-alanyl).7-deoxy-7-fluootaxolfornate; 2 '-glutaryl-7-deoxy-7-fluorotaxol; 2'-[C(O)(C1 2 3

C(O)NH(CH

2 3

N(CH

3 2 ]-7-dexy.7.fluorotaol; 2'-$fsulfopropionyl)-7-deoxy-7-fluortaxol; '9 9'(-ufehbad~ucnl7doy7furtxl 2A 2'-(-sulfoprohylamido)succinyl7-deoxy7fluorotaxol; 2'-4sulfoproylanopdopcionyl-7-deoxy-7.nuorotaxol; ~2'-(trNimethiyl)-7-deox-7-deo7fluorotaxol; 30 tyglycyl)-7-deoxy.fluorotaxol; '2 -(Lglcyl)-7-eoxy-7fuorotaxol; 2'-(L-lanyl)-7-deoxy-7-fluorotaxol; 2* 9..ecl)7doy--lortxl 2'-(L-vleuyl)-7-deoxy-7-fluorotaxol; 2'-(L-isolcyl)-7-deoxy-7-fluorotaxol; -63- 2*-(L-prolyl)-7-deoxy-7-fluorotaxol; 2'-(L-Iysyl)-7-deoxy-7-fluorotaxol; 2'-(L-glutamyl)-7-deoxy-7-fluorotaxol;.

2'-(L-arginyl)-7-deoxy-7-fluorotaxol; 7-deo"XY-7-fluorotaxot=r; 2'-succimyl-7-deoxy-7-chlorotaxol.

2'n-(-aa)7-doxy-7-choroaxofornatw; 2*-glutazyl-7-deoxy-7-cblorotaxol: 2'-[-C(OXCH 2 3

C(O)NH(CH

2 3

N(CH

3 2 1.7-deoxy-7-chlootaxo; 2'-$f-sufopmrpionyl)-7-deoxy-7-chlorotaxol; 2'-(2-su~foethylaniido)succiny-7-deoxy-7-choroaxol; 2'-(3-sulfopropylaznido)succinyl-7-dcoxy-7-chlorotaxol; 2'-Qnrethylsilyl)-7-deoxy-7-chlorotaxol; 2'-(t-butyldixnethylslyl)-7-deoxy-7-chlorotaxol; .2'-(N.N-diethylaniinopropionyl)-7-deoxy-7-chorotaxol; 2'-N.N-direthylglycyl)-7-deoxy-7-chlomtaxol; 2'-Wgycyl)-7-deoxy-7-chlorotaxol; 2'-(L-alaziyl)-7-deoxy-7-chlorotaxol;.

2'-(L-Ieucyl)-7-deoxy-7-cblorozaxol; 2'-(L-isoleucyl)-7-deoxy-7-chlorotaxol; 2'-(L-valyl)-7-deoxy-7-chlorotaxol; 2'-(L-pbenylaanyl)-7-deoxy-7-chlorotaxol; 2'-{L-prolyl)-7-dcoxy-7-chlorotaxol; 2'-(L-lysyl)-7-dcoxy-7-chlorotaxol; 4*25 2'-(L-glutamyI)-7-deoxy-7-chlorotaxol; *be.2'-(L-arginyl)-7-dcoxy-7-chlorotaxol; 7-deoxy-7-chlomotaxotere; **2'-succinyl-7-deoxy-7-*t6notaxol; 2'-$f-alny)-7-dexy-7-bronoaxolfornate: 2'-gluaryl-7-deoxy-7-brornotaxol; 2 -[-C(OX(CH 2 3

C(O)NH(CH

2 3

N(CH

3 2 ]-7-deoxy-7-bromotaxol; 2'-(-sulfopropionyl)-7-deoxy-7-brornotaxoI; 2'-(2-ufohyanido)succinyl-7-deoxy-7-bromotaol; 2'-(3-sulfopropylamido)succinyl-7-deoxy-7.bromotaxol; 2'-(tiethylsilyl)-7-deoxy-7-bromotaxol; 909.: .2'-(t-butyldimethylsilyl)-7-deoxy-7-bromotaxol;.

-64- 2 '-(N.N-dicthylaminopropionyl)-7-deoxy-7.bromota(ol; 2 '-(N.N-dinmethylglycyl)-7-deoxy-7-bomoaoI; 2 '-(glycyI)-7-deoxy-7-bronmotaxoI; 2 '-(L-alanyl)-7-deoxy-7-bromotaxol; 2'-(L-leucyl)-7-deoxy-7-bromotaxol; 2'-(L-isoleucyl)-7-deoxy-7-bromotaxol; 2'-(L-valyl)-7-deoxy-7-bromotaxol; 2'-(L-phenylalanyl)-7-dcoxy-7-bromotaxol; 2'-(L-prolyl)-7-deoxy-7-bromotaxol;, 2'-L-ysyl)-7-deoxy-7-bromotaxol;, 2'-(L-glutany>-7-deo xy-7brornotaxol; 2 '-(L-arginyl)-7-deoxy-7-brornotaxol; 7-deoxy-7-bromotaxotere; 2 '-succinyl-7-deoxy-7-iodotaxol; 2 '-(f-alanyl)-7-deoxy-7-iodotaxolforiate; 2 '-glutaryl-7-deoxy-7-iodotaxol;.

2'-[C(OXC 2 3

C(O)NH(C

2 3

N(CH

3 2 -7-deoxy.7.iodotaxol; 2'-$-sulfopropionyl)-7dexy-7-iodotaxol; 2 '-(2-sulfoethylamido)succinyl-7-deoxy-7-iodotaxol; 2 '-(3-sulfopropylamido)succinyl-7-deoxy-7-iodoaol; 2'-(triethylsilyl)-7-deoxy-7-iodotaxol; 2'-(t-butyldimethylsilyl)-7-deoxy-7-iodotaxol; 2'-(NN-diethylaminopropionyl)-7-deoxy-7iodotaxol; us 2'-(NN-dinicthylglycyl)-7-deoxy-7-iodotaxol; S2'-(lcyl)-7-deoxy-7-iodoaxol; 2'-(L-alyl)-7-deoxy-7-iodotaxol; 2'-(L-peucyl)-7-deOXY-7-iodotaxol; 2'-(L-is~yl)7eox?7odoaxo; .2'-(L-glayl)-7-deoxy-7-iodotaxol; 2'-(L-phenllnyl)-7-deoxy-7-iodotaxol; 35(Lply)7-deoxy-7-iodotaxotee; n :phannaceuuically acceptable salts thereof when the compound contains either an acidic or basic functional group.

Example 18 Preparation of {2aR-[2aa,40.4a,6.9a,(caR*S), 11a, 1 2a. 12aa.l2ba]}-f- (Benzoylamino)-a- {([(2,2,2-trichloroethoxy)carbonyl]oxy }benzenepropic'-'c acid, 6.12b- Bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a.5.6,9, 10.11,12,12a,12b-dodecahydro-I 1 -hydroxy- 8,13,1 3-trimethyl-5-oxo-4,4a;7, I -bismethano-l H-cyclodcca[3,4]benz[ 1,2-b)-oxet-9-yl Ester, 2'- {[(2,22-Trichloroethyl) oxylcarbonyl )-7-deoxy-7,8-methanotaxol (Compound 14AA; ia) A solution of 2'-{[(2,2,2-trichloroethyl)oxy]carbonyl }taxol [Magri, N. Kingston, D.

G. I. J. Org. Chem., 1986, 51, 7971 (0.021 g, 0.020 mmole) in CH 2

CI

2 (1.5 mL) was added by syringe over a period of 5 min to a stirred and cooled (acetone-Dry Ice bath) solution of dimethylaminosulfur trifluoride (DAST) (2 0.014 mole in CH 2

CI

2 (0.5 mL) contained in a 3 mL Reacti-vial®. The cooling bath was removed after 15 min and the reaction container was allowed to come to room temperature. The reaction was stirred and the solution was again cooled in an acetone-Dry Ice bath and more DAST (4 pL, 0.028 mmole) in CH 2 Cl2 was added to the reaction. The cooling bath was removed aftc 15 min and after 90 min the reaction solution was diluted with additional CH 2 Cl 2 and then was washed with water. The layers were separated and the organic layer was dried (Na 2

SO

4 filtered, and concentrated to give a residue (0.017 The residue was chromatographed over silica gel (40-63 pm, 60 g) using a CH 2 Cl2 solution for application to the column and 30% acetone in hexane for elution of the column.

The desired title compound has Rf 0.22 (30% acetone-hexane) and crystallizes from acetonehexane as colorless needles: FAB mass spectrum gives peaks at 1012, 1010, 551, 533, 511. 491, 460, and 442 mass units; 1 H NMIR (CDCI 3 TMS) 8 8.19 2H), 7.71 2H), 7.59 IH), 7.48 7.36 6.98 1I), 6.57 1I), 6.28 1H) 6.08 (dd, 1I), 5.67 1H), 5.54 1H), 4.77 (dd, 2H).

A

474, 4.32 4.09 IH), 4.07, 2.47 3H), 2.19 3H), 1.90 3H), 1.67 (dd, 1H).

1.38 IH), 1.26 3H), and 1.21 3H); 13 C NMR (CDCl 3 TMS) 201.88, 169.64, 169.59.

167.45, 167.03, 166.96, 153.24, 140.41, 136.43, 133.89, 133.61, 133.36, 132.05, 130.31, 129.25, 129.15, 129.07, 128.95, 128.75, 128.68, 12859, 127.17, 126.49, 93.82, 84.83, 80.11, 79.56.

79.47, 77.78, 77.23, 75.66, 75.41, 72.17, 5258, 42.85, 38.57, 35.93, 35.04. 32.26, 26.05. 22.30.

30 21.60, 20.83, 15.82, 14.56 ppm.

Example 19 Preparation of (2aR-[2aca4,,4.,63,9a,(acR,IS*).1 la,12a,12aa.12ba] (Benzoylamino)-a-hydroxybenzenepropanoic Acid, 6,12b-Bis(acetyloxy)-1 2-(benzoyloxy)- 2a,3,4,4a,5,69,10,11 ,12,12al2b-dodecahydro-1 1-hydroxy-8.13.13-trimethyl-5-oxo-4,4a;7. 1 bismethano-l H-cyclodeca[3,4lbenz 1.2-bJ-oxet-9-yl Ester. 7-Deoxy-70,80-methanotaxol (Compound IIb) A solution of {[(2,2.2-trichloroethyl)oxy]carbonyl )-7-deoxy-7[,8-methanotaxol (Compound 14AA, Ha; 0.008 g, 0.0079 mmole) in 9:1 methanol/acetic acid (1.0 mL) was stirred with activated zinc metal (0.010 g) at room temperature. After 60 min, additional zinc (0.010 g) was added and stirring was continued for 30 min. Solids were removed from the reaction mixture by filtration and the filtrate was concentrated under reduced pressure. The residue so obtained was dissolved in CH 2

C

2 and the solution was washed successively with aqueous 0.1 N HCI, with aqueous 5% NaHCO 3 and with water. The organic layer was dried (Na 2

SO

4 filtered, and concentrated and the residue was chromatographed over silica gel (40-63 pm. 8 x 250 mm column, applied in CH 2

CI

2 solution and eluted with 40% ethyl acetate in hexane). The title compound is a colorless solid: FAB mass spectrum gives peaks at 836, 776, 758, 551, 533. 491. 286, 240, and 105 mass units; 1 H NMR (CDC1 3 TMS) 8 8.19 2H), 7.69 2H). 7.60 1H). 7.60-7.35 6.95 1H), 6.31 1H), 6.25 1H), 5.82 1H). 5.66 IH). 4.78 (dd. 1H), 4.72 1H). 4.31 1H), 4.07 1H), 4.06 1H), 2.40 3H), 2.20 3H), 1.60 3H). 1.38 IH). 1.26 3H). and 1.22 3H); 13 C NMR (CDCI 3 TMS) 204.45. 201.81, 172.74, 169.87. 169.56, 167.41, 166.96, 140.12, 138.04, 134.07, 133.53, 131.93. 130.33, 129.28, 129.04, 128.74, 128.55, 128.32, 127.04, 126.86, 84.86, 80.03, 79.57, 79.40, 77.21, 75.66, 75.46, 73.22, 72.28, 54.79.

42.86, 38.54, 36.07, 35.09, 32.15, 26.11, 22.27, 21.49, 20.88, 15.77. and 14.59 ppm.

Example 20 Preparation of 2'-[{(2,2,2-trichloroethyl)oxy)carbonyl]-7-deoxy-7.,8p-methanotaxol (14AA; HI) from 2'-[{(2.2,2-Trichloroethyl)-oxy)carbonyl]-7-deoxy-7-aminotaxol An ice-cold solution of sodium nitrite (1.5 equivalents) is added in portions to a vigorously stirred, ice-cold two phase mixture of a solution of 2'-[{(2.2,2-Trichloroethyl)oxy)carbonyl]-7-deoxy-7-aminotaxol (1 equivalent) in ether and a solution of sulfuric acid in water. The mixture is stirred at ice-bath temperature for several hours following the addition.

.25 Then. excess nitrous acid is quenchec by the addition of an aqueous solution of urea. The aqueous phase of the mixture is brought to near neutral pH by the careful addition of sodium carbonate, the layers are separated, and the aqueous phase is further extracted with additional ether. The combined ether extracts are dried, filtered, and concentrated to give the crude reaction product. Chromatography of the crude product over silica gel gives pure compound 30 14AA.

Example 21 Preparation of 2'-[((2,2,2-trichloroethyl)oxy)carbonyl]-7-deoxy-7B.8B-methanotaxol (14AA, Ha) from 2'-[{(2,2,2-Trichloroethyl)-oxy)carbonyl]taxol 7-Trifluoromethylsulfonate A solution of 2'-[[(2.2,2-Trichloroethyl)-oxy]carbonyl]taxol 7-Trifluoromethylsulfonate in 80% ethanol-water is warmed and the reaction is followed by tic techniques. When complete.

the reaction solution is neutralized with sodium bicarbonate, excess ethanol is removed under reduced pressure, and the aqueous phase is extracted with methylene chloride. The extracts are dried, filtered, and concentrated to give the crude reaction product. The crude product is chromatographed over silica gel to give pure compound I4AA.

Example 22 N-Debenzoyl-N-benzyloxycarbonyl-7-deoxy-7-fluorotaxoI (Compound 18); (({2aR- [2aa,4ao,60,9at,-(ciRje), Icz,1 2a1 2ac1 2ba] )-{Benzyloxycarbonylamino).a-hyroxybenzenepropanoic acid, 6.1 2b-Bis(acetyloxy)-1 2-(benzoyloxy)-2a,3,4,4a,5,6,9, 10.11.12.12a. 12bdodecahydro-4-fluoro- 11-hydroxy-4a.813,1 3-tetramethyl-5-oxo-7. 11-methano-] H-cyclodeca[3,4]benzl ,2-b]-oxet-9-yl Ester)) Following the general procedure of Example No. 11 [reaction of 2'-troc-7-deoxy-7fluorotaxol with activated zinc], but using N-dbenzoyl-N-benzyloxycarbonyl-2'-([(2,22trichloroethyl)oxy]carbonyl)-7-deoxy-7-fluorotaxo (Example 3. Compound 13BA; 0.079 g.

0.074 minol) and activated zinc metal (0.153 g) in CH 3 OH-HOAc 16 mL) and EtOAc (8 mL) the desired product 18 is prepared. Following workup (tw6 hrs reaction time) and chromatography (silica gel, 40% EtOAc-hexane, 8 mrL fractions) of the crude product is obtained and the desired product 18 is eluted in fractions 59-76 as a solid and characterized on the basis of the following analytical dat: 'H NMR (CDC1 3 TMS) 8 8.14 2H, J 7.4 Hz), 7.62 11, J 7.4 Hz). 7.52 (t.

2H, J 7.75. 7.30 Hz), 7-30-7.42 (in 5H), 7.17 (in, 214), 6.53 iH. H 10 6.18 IH, H 13 5.75 1H1, 5.73 (ci I1H. J 7.2 Hz. 142), 5.38 (di, IH. 5.09 1H, J 12.5 Hz. OCialPh), 4.99 IH, H 5 4.96 (d 1H, J 12.3 Hz, -OCHHbPh), 4.66 IH.-H 2 4.57 (dc, I1H, JF 54 HZ, H- 7 4.36 I H. J 8.4 Hz, H20a), 4.29 I H. H20b), 3.4! I H, J 7.3 Hz. 13), 2.63-2.46 (7 lines. 1H). 2.38 31. -CH 3 2.43-2.30 1H) 2.28-2.10 1H).

2.22 31, -CH 3 2.01 111), 1.77 311, -CH 3 1.73 3H, -CH 3 1.19 3H. -CH 3 1.16 31, -CH 3 13 C NMR (CDCI 3 TMS), 206, 172, 169.5, 169.3, 166.9. 156. 140.5, 138. 137, 133.7, 132, 130.2, 129-3, 128.8, 128.7. 128.4, 128.0 127.6. 126.7, 96, 93, 81.9. 80.9, 78.6. 78, 74.8.

73.6. 71.8, 66.8, 57, 56, 42.5, 39.9, 35.9. 34, 34, 25.9, 22.4, 21.0, 20.8. 14.5. 14 ppm; mass spectrum 886, 571, 511. 371, 347, 329, 316, 298, 105, 91 m/z.

Example 23 N-Debenzoyl-N-b-ni1oxycarbony1-7-deoxy-70,8-methanotaxo (Compound 21); ((12aR-[2ac140.4a,,6099r,(CL I(I, 12a1a,12ba] -(Benzyloxycarbonylamino)-ahydroxybenzenepropanoic acid, 6,1 2b-Bis(acetyloxy)-1 2-(benzoyloxy)-2a.3,4.4a,5.6.9, iO1,1,12,1 2a,12b-dodecahydro-1 1-hychoxy-8,13,13-tunethyl-5-oxo4,4a;7. 1-bismethano.1Hcyclodeca[3,4]benz[1,2-b]-oxet-9-yI Ester)) Following the general procedure of Example 11 [reaction of 2'-troc-7-deoxy-7fluorotaxol with activated zinc], but using N-debenzoy-N-benzyloxycarbonyl-2'([(2,2.2trichloroethy)oxylcarbonyl }-7-dxxy-70,8-eethandtaxol (14BA; 0.040 g. 0.038 imol) and -68activated zinc metal (0.072 8 followed by an additional 0.072 g) in *CH 3 OH-HOAc 10 ml) the desired product 21 is prepared. Following workup after 3 hrs reaction time and chromatography (silica gel, 40% EtOAc-hexane, 8 rnL fractions) of the crude product, starting material (0.007 g) is recovered in fractions 30-37 and the desired product (21, 0.020 g. 0.023 mrol.

61%) is eluted in fractions 75-100 and obtained as a solid and characterized on the basis of the following analytical data: 1 H NMR (CDCI 3 TMS) S 8.17 2H, J 7.3 Hz). 7.58 1H). 7.50 2H). 7.42- 7.30 511). 7.24 7.08 2H). 6.31 1H. H 1 6.26 IH. 8.6 Hz. H 1 3 5.70 (d.

IH, J 9.6 H, 5.64 1H, J 7.7 Hz, H 2 5.38 IH. J 8.1 Hz. H 3 4.98 lH, J 12.5 Hz, -OC4aHPh), 4.88 I H, J 12.5 Hz, -OCHHbPh). 4.71 IH. I 3.7 Hz. H 5 4.65 IH, H 2 4.28 1H, J 8.6 Hi. 4.07 IH. H 3 4.05 (di IH. H 2 fb). 2.49- 2.34 1H), 2.38 3H. -CH 3 2.23 2.21 3H. -CH 3 2.08 1.94 1.82 3H.

-CH

3 1.37 1H, H 7 1.25 3H, -CH 3 1.21 3H, -CH 3 1 3 C NMR (CDCI 3 TMS) 202, 172.5, 169.2, 169.1. 167. 155.5. 149.5. 138. 136. 133.5.

133, 130.0. 128.6, 128.4, 128.1. 127.7. 127.2. 126.3, 84-5, 79.9. 79.2, 79.0, 75.3. 75.2, 73, 71.7, 66.5, 56. 42.5, 38.2. 36. 34.7, 32, 25.7, 21.5, 21. 20.5, 15.5, 14.2 ppm; mass spectm: 866.3423. C48H 5 1

NO

1 4 H requires 866.3388. 848, 806, 788, 551, 533, 491, 105, 91 m/z.

Example 24 N-Debcnzoyl-N-(t-butyl)oxycarbonyl-2'- [(2.2.2-trichloroethyl )oxycarbonyl}-7deoxy-7-fluorotaxol (Compound 13DA); (({2aR-[2aa,4aO,6R,9a(aR 11 Ia. 1 2a. I 2ac.- 12baI )-JV(t-Butyl)oxycarbnylaminoj-a- 2-tichloroethoxy)carbonyl]oxy )benzenepropanoic acid, 6,1 2b-Bis(acetyloxy)- 2-(benzoyloxy)-2a,3.44a.5 .6.9,10,11.12,12a.121> dodecahydro-4-fluoro- 11-hydroxy-4a,8.13.13-tetramethyl-5-oxo-7, 11-methano-IHcyclodeca[3,4)benz[ 12-b]-oxet-9-yI Ester)); and N-Debenzoyl-N-Qt-butyl)oxycarbonyl-2'- 2 2 2 -trichloroethyl)oxy]carbonyl)-7-deoxy- 7.8,8-methanotaxcl (Compound 14DA), (({2aR-[2ac4L,.4ao,6R9a,(aR*,O). 1 Ia.12a,- 12aa,1 2ba] }-P-(r-Butyl)oxycarbonylanino]-a-([(2.2.2-trichioroethoxy) carbonyloxy }benzcnepropanoic acid, 6,1 2b-Bis(acetyloxy- I2-(benzoyloxy)-2a,3,4,4a5,6 9.10,11,12.12a.12bdodecahydro- 11 -hydroxy-8,13.1 3-trimethyl-5-oxo-4,4a;7,1 I -bisiethano- 1 H-cyc lodeca- [3.4]benz[1.2-b]-oxet-9-yl Ester)); and N-Debenzoyl-N-Qr-butyl)oxycarbonyl-2 2 2 2 -tichloroethyl)oxy]carbonyl }-7-deoxy-

A

6 7 _taxol (Compound 1SCA). 4a.6P.9a,aR43S),1 l,12I.2aa. 12ba])- Butyl) oxycarbonylanino-a- {[(2.2.2-trichloroethoxy)carbonyloxy )benzenepropanoic acid, see*6,1 21>Bis(acetyloxy)- 2-(benzoyloxy)-2a.4a.5,6,9, 10,11,12,12a, 1 2 -decahydro- I1 -hydroxy- .4a,8,13,1 3-tetramethyl-5-oxo-7. 11-methano-I H-cyclodeca[34]benz[I .2-b]-oxet-9-yI Ester)) Following the geneial procedure of Example 10 [reaction of 2'-troc-taxol with methylDAST], but using N-debenzoyl-N-(t-butyl)oxycarbonyl-2'-troc-taxoI (Compound 12DA; 1.800 g, 1.75 inmoles) and diniethylaminosulfur trifluoride (methylDAST. 286 pL., 0.390 g, 2.93 mmnoles) in CH2CC (120 rnL under N 2 at -78*C. Following workup. the crude product mixture (1.77 g) is chromatographed over silica gel (40-63 pmn, 191 g in a 37 x 350 mm column. 45 mL fractions) using a CH1 2 C1 2 solution for application of the material to the column and acetone-hexane (1.5 L) followed by 25 acetone-hexane to elute the column. A mixture of' and 14DA (0.511 g) is eluted in fractions 41-46. Fractions 47-48 (0.085 g) contain a mixture of all three reaction products. Fractions 49-61 (0.8 14 g) contained pure 13DA.

Rechromatography of the mixed fractions 47-4 provides additional amounts of the mixture of 14DA and 15CA and of pure 13DA.

Pure 13DA is obtained as a solid and characterized on the basis of the following analytical data: 'H NMR (CDC1 3 TMS) 8 8.15 Kci 2H, J 7.2 Hz), 7.62 I H, J 7.2 Hz). 7.51 (t, 211, 1 7.7 Hz), 7.25-7.44 (in, 511), 6.58 I H. H 10 6.28 IlH. J 8.7 Hz, H 13 5.77 (d.

1 H, J 7.2 Hz, H 2 5.51 (di, IH, 5.48 I H, .1 10.0 Hz, H 3 5.40 (ci. I H, J 2. 0 Hz, H 2 5.05 (ci, IH. J 8.1 Hz, H, 5 4.77 IlH, .J 11.8 Hz, troc-Ha). 4.68 I H. 3 11.8 Hz, troc-11b), 4.58 (dci, I1H. J 4.6, 46.9 Hz, H 7 4.39 (di. I1H, J 8.4 Hz, H20.), 4.27 I H, Jl -8.4 Hz, 112o), 4.04 Kci I H. I 7.1 Hz, H1 3 2.57 (in, IH, 1- 6 2.48 3H, -CIA 3 2.21 (s, 311, -CIA 3 1.91 3H,

-CH

3 1.73 3H. -CIA 3 1.34 9H. Ne.

3 1.23 311I, -CH 3 1.17 3H. -CH 3 mass spectrum, found: 1026.2660, C48H 55 Ql 3 FNO 16 H requires 1026.2648. 970, 571.

511, 407, 389,' 347. 329, 105, 57 ink.

All fractions containing a mnixture of 14DA and 15CA are combined and rechroinatographed over silica gel (two size B Merck Lobar columns, 9 mL fractions) by applying the material to the column in a CH C 2 luto n ltn h ounwt 0 C C-C 2

CI

2 (68 fractions) followed by 15% CH 3

CN-CH

2

CI

2 The pure olefin 15CA is eluted in fractions 76-94 and obtained as a solid and characterized on the basis of the following analytical data: 'H1 NMR (CDCl1 3 TMS) 5 8.16 (di. 2H, J 7.1 Hz), 7.63 I1H, J 7.4 Hz). 7.52 (t, 211, J 7.5 Hz), 7.30-7.45 (mn, 511), 6.27 I1H, 3 9.2 Hz, H 13 6.24 11H, 10). 6.07 (dci.

1H, J 5.7, 9.9 Hz, 116). 5.86 (c I 10.0 Hz, H 7 5.85 I1H, 1-12), 5.52 (di, I H, 5.45 (ci. I11 5.36 (di, 11I1H J 2.4 Hz, H 2 5.12 1 H. J 5.6 Hz, H 5 4.77 (di. I1H. 3 11.8Hz,7 tI*oc-Ha), 4.68 (ci, I1H.,J- 11.8 Hz, aro-Hb). 4.45 (di. I H, J 8.0 Hz, H 2 4.30 (ci, H,3- 8.1 Hz, H20,), 4.03 (di. I H. J 6.6 Hz, H) .1(n H 1 ~~35 2.23 I1H, -Cl- 3 1.87 311, -CIA 3 1.84 3H, J 2.8 Hz. -CH 3 3 s H eC) 1.27 3H. -CH 3 1.16 3H. -CIA 3 mass spectrum, found: 1006.2580, C 48

H

54 C1 3 N0 16 H requires 1006.2586. 950. 55 1.

491, 369, 105, 57 mlz.

The pure compound 14DA is eluted in fractions 100- 131 as a solid and characterized on the basis of the following analytical data:~ 1 H NMIR (CDCI 3 TMS) 8 8.15 2H., J 7.1 Hz). 7.61 I1H, J 7.3 Hz). 7.51 (t.

2H1, 3 7.5 Hz), 7.30-7.44 (mn. 5H), 6.34 I1H, H 10 6.30 I1H, I1 8.6 Hz. 13). 5.67 (d.

1H, J 7.6 Hz, 112). 5.54 (di, 11H, 5.45 (di, I H. J 10O.1 Hz, H 3 5.38 111, J 2.3 Hz, HT2. 4.76 (di, 1H. J 11.8 Hz, t1roc(>a), 4.76 (1H, 115). 4.69 (di, 1H, J 11.8 Hz, troc-Hb).

4.33 11H.,J 8.6 Hz, H20), 4.09 (di, IH. J1 7.5 Hz, H 3 4.04 11H, J 8.7 Hz, Hw0b).- 2.48 (mn, I1H, H14a), 2.44 311. -CH 3 2.37 (in, I1H, 2.24 (in, I1-1 H 19a). 2.20 3H, C11 3 2.11 (di, 1H.,J 16.0 Hz, H 1 4b). 1.90 3H, -CH 3 1.66 (in. 1H, H- 19 1.37 1H.,

H

7 1.28 9H, Me 3 1.27 311, mass spectrum, found. 1006.2560, C 48 H5 4 C1 3 NO 16 H requires 1006.2486. 950, 55 1.

533, 491, 369, 327, 105, 57 m/e.

Exampvle 25 N-Debenzoyl-N-Qt-butyl)oxycarbonyl-7-deoxy-7-fluorotaxo (Compound (({2aR-[2a,4ap.60.9a(cR.S). 1a,1 2o.12ac.1 2ba] }-f-[Qt-Butyl)oxycarbonylamino-zhydroxybenzene-propanoic acid, 6,1 2b-Bis(acetyloxy)- 12-(benzoyloxy)-2a.3.4,4a,5.6,9,- 10.1 1,12,12a,12b-dodecahydro-4-fluor 1-hydroxy-4a,8.1 3,1 3-tetrarnethyl-5-oxo-7.1 I-methano- 1 H-cyclodeca[3,4]benz 1 ,2-bJ-oxet-9-yl Ester)), Following the general procedvre of Example I11 [reaction of 2'-Uroc-7-deoxy-7fluorotaxol with activated zinc], but using N-debenzoyl-N-(t-butyl)oxycarbonyl-2'-{f(2,2.2.

trichloroethyl)oxy]carbonyl}-7-deoxy-7-fluorotaxo (13DA. 0.100 g, 0.097 mrnol) and activated zinc metal 183 g followed by an additional 0.050 g) in CH 3 OH-HOAc 1, 10 mL). 'After I hr of reaction time, the reaction mixture is stored overnight at -33'C. then worked up and the crude product chrornatographed (silica gel, 40% EtOAc-hexane, 8 mL fractions) to give the desired product 20 in fractions 53-76 as a solid and characterized on the basis of the following analytical data.

111 NMIR (CDCI 3 TMSW&8.13 (di, 211. J 7.2 Hz), 7.62 11H. J 7.4 Hz). 7.51 (t, ~~211, J 7.5 Hiz), 7.30-7.42 511), 6.56 111 H0 6.21 111, 11H .57 Hz, 112), 5.42 111, J 9.7 Hz. 5.29 (di, 111. 113.). 5.01 111, J 7.5 Hz, H 5 4.63 (mIn 11, 112.), 4.57 (cid, I1H. J 4.3, 46.8 Hz, 1-17), 4.37 (di, 111, J 8.4 Hz, 11203). 4.27 I H, .1 -8.4 Hz, F1). 4.04'(d, 111 H,1 7.1 Hz, 13). 2.56 (seven lines,, 11-1. H-6a). 2.39 311,.

CH-

3 2.31 (mn, 111), 2.25 (in, 11-1), 2.22 311, -Cl! 3 2.14 (dd, 11-1). 81 3H. -CH 3 1.73 3H, -CH 3 1.34 911, Me 3 1.23 311, -Cl1 3 1.18 3H1, -CH 3 Example 26 N-Debenzoyl-N-(t-butyl)oxycarbonyl-7-deoxy-7,8 rnehanotaxo (Compound 23).

(({2aR-[2aa,4W,4ao,69a(aRPS*).I 1a,1 2a 1 2aa, 121ba] }-I-[(t-Butyl)oxycarbonylamino]-a- -71hydro, .jbenzencpropanoic acid. 6,1 2b-Bis(acetyloxy)- 12-(benzoyloxy)-2a.3 ,4.4a,5.6,9, 10,11.1 2,- 1 2b-dodecahydro-1 1 -hydroxy-8. 13.1 3-trnethyl-5-oxo-4,4a;7, 1-bismethano- 11cyclodieca[3,4lbenz 1 ,2-b]-oxer-9-yI Ester)) Following the general procedure of Example I11 [reaction of 2'-troc-7-deoxy-7fluorotaxol with activated zinc], but using N-debenzoyl-N-(:-butyl)oxycarbonyl-2'-{[(2,22trichloroethy1)toxy]carbonyl)-7-deoxy-70,8f -methaotaxol (14DA, 0.100 g. 0.099 rnmol) and activated zinc nxetal (0.200 g followed by an additional 0.050 g) in CH 3 QH-HOAc 1, niL). Following workup after 3 his reaction time and chromatography (silica gel, 40% EtOAchexane, 8 niL fraction3) of the crude product is obtained, the desired product 23 is eluted in fractions 58-86 and was a solid and characterized-on the basis ofithe following analytical data: HNMR (CDC1 3 TMS) 8 8.15 211, J 7.2 Hz), 7.61 11H, J 7.3 Hz). 7.51 (t.

2H. J 7.7 Hz), 7.28-7.45 5H), 6.33 lH, H 10 6.27 lH, H 13 5.67 J. 7.6 Hz, H 2 5.36 III, J 9.5 Hz, 5.30 1H, 4.73 I1H, J 3.7 Hz, 4.62 (in, IH, 1-15), 4.31 IlH, J1 8.6 Hz, H20a). 4.09 IH. J 7.5 Hz. H1 3 4.04 (di, 11H. J 8.7 Hz, H 2 0b), 2.46 (ci of t, IH, J 4.3, 16.1 Hz, H6.a), 2.38 311, -Cl- 3 2.24 (mn 1H1), 2.21 (s, 3H, -Cl! 3 2.10 (di, I1H,3J 16.0 Hz), 1.85 3H, -Cl! 3 1.67 (ddi, I H, J 7.1, 5.2 Hz), 1.36 (mn, I H. H 7 1.28 12 H, Me 3 Cl! 3 1.25 3H., -Cl- 3 Example 27 N-Debenzoyl-N-(t-butyl)oxycar ,onyl-7-deoxy-A6.-taxol (Compound 16D), (({2aR- [2aat, 4afp,69aacR.S), 11a, 1 2ct,1I2aa, I2ba])- -fQ-Butyl)oxycarbonylarninol-a-hydroxybenzenepropanoic acid, 6,1 2b -Bis(acetyloxy)- 12-(benzoyloxy)-2a,4a,5,6,9, 10.11 .12.1 2a, I2bdecahydro- 1-hydroxy-4a,8, 13,1 3-tetraniethyl-5-oxo-7, 1-methano- 1H-cyclodeca[3 ,4]benz[ 1.2-b] oxct-9-yl. Ester)) Following the general procedure of Example 11 reaction of 2*-troc-7-deoxy-7fluorotaxol with activa*t2 zinc], but using N-debenzoyl-N-(t-butyl)oxycarbonyl-2'-{[(2,2.2trichloroethyl)oxy]carbonyl}-7-deoxy-A 6 7 -taxol (15CA. 0.086 g. 0.085 nimol) and activated zinc metal 180 g followed by an additional 0.030 g) in CH-1 3 01-HQAc 1, 10 mL). Aft r I hr of reaction time, the reaction is worked up, and the crude product chromatographed (silica gel, 40% EtOAc-hexane, 9 niL fractions) to give the desired product 16D in fractions 42-65 as a solid and characterized on the basis of the following analytical data: 111 NNM (CDCl 3 TMS) 5 8.15 (di, 211, I 7.2 Hz), 7.61 111), 7.51 2H. J Hz), 7.30-7.43 5H1), 6.22 I1H, 1 0)o. 6.21 11H, 1113), 6.06 (cid, IlH, J 5.6, 9.9 Hz, H 6 5.87 (di, 111, J 9.6 Hz, 11 7 5.84 (di, IlH. H 2 5.39 111, 1 9.6 Hz, -NH- or H 3 5.26 I1H. 113 or 5. 10 (di, I11, J 5.6 Hz, 4.61 (in, IlH, 112.). 4.43 I1H, J 8.1 Hz,

H

208 4.30 lH. J 8.2 Hz, 1120b,). 4.01 111, J 6.5 Hz, H- 3 2.39 3H. -CH 3 2.33 11-1), 2.24 3H, 1.86 311, -CH 3 1.76 3H1, -Cl- 3 1.34 9H, Me 3 1.27 311, -CH 3 1.16 311. -CH 3 -72- Example 28 Preparation of 7-Deoxy-A 6 7 -taxol (16A) from 2'-TES-taxol 7-Triflate A solution of 2'-TES-taxol 7-triflate (Preparation 15A; 0.044 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 34 pi) in THF (0.4 mL) is stirred overnight at room temperature. Water and ethyl acetate are mixed with the reaction solution, the layers are separated, and the organic layer is washed with aqueous NaHC03 and NaCI solutions. The organic layer is dried (Na 2

SO

4 filtered, and concentrated. The crude product is chromatographed over silica gel (flash column) using 42.5% EtOAc in hexane to elute the column and collecting fractions of 5 mL volume. Fractions containing the desired product (identified by tic) are combined to give 16A (0.009 1 H NMR (CDC 3 is identical to that of the 16A obtained in Example 2.

Example 29 2'-TES-7-deoxy-7a-chlorotaxol A solution of 2'-TES-taxol 7-triflate (Preparation 15A; 1 equiv.) in NN-dimethylformamide (DMF) is stirred with potassium chloride (10 equiv.). A phase transfer catalyst is added and the reaction 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 2

CI

2 The organic extracts are dried, filtered, and concentrated and the crude reaction product residue is chromatographed over silica gel, yielding the pure title compound.

Example 30 7-Deoxy-7a-chlorotaxol Following the procedures of Preparation 12A, but starting with 2'-TES-7-deoxy-7achlorotaxol, the title compound is prepared.

Followl v the general procedures of Example 29 and 30 but using appropriate metal salts, such as sodium or potassium bromide and sodium or potassium iodide, in the procedure of Example 29, the following compounds are prepared: 7-Deoxy-7a-bromotaxol; 25 7-Deoxy-7p-bromotaxol; 7-Deoxy-7a-iodotaxol; 7-Deoxy-73-iodotaxol.

Example 31 Preparation of N-debenzoyl-N-(t-butyl)aminocarbonyl-7-deoxy-7-fluoro-taxol; Compound 29 N-Debenzoyl-N-Cbz-7-deoxy-7-fluoro-taxol 18 (60 mg, 0.07 mM; Preparation 39) is dissolved in 3 mL absolute ethanol and 20 mg 10% Pd on carbon is added. This is hydrogenated at atmospheric pressure for 6 hrs. TLC shows no starting material left so reaction is filtered through Celite and concentrated in vacuo. The residue, which is 13-($-phenylisoserinyl)-7-fluoro-baccatin m, (19, 52 mg, 0.07 mM; Preparation 40) is dissolved in 700 pL THF and cooled to 0°C and 7 L (0.061mM) t-butyl isocyanate added. TLC shows some amine remaining so another 7 pL is added. After 20 hrs the solution is concentrated in vacuo and -73.

chromatographed over. 6 gm of silica gel packed in 1:2 EtOAc:hexane. The column is eluted with 30 rnL 1:2 EtOAc:Hexane, 60 mLt 2:3 EtOAc:hexane. 50 mLt 1: 1 EtOAc:hexane. and tnt 2:1 EtOAc:hexane collecting 3 mLt fractions. The desired N-debenzoyl-N-Q-butyl)aminocarbonyl-7-deoxy-7-fluoro-taxol is found in fractions 35-52.

Mass Spec (FAB-Hfigh Res.) Theory: 851.3766 Found: 851.3792 'H NMR (CDC1 3 TMS): 8 1.16 1.20 1.72 1.80 2.15-2.60 2.19 2.2 4.02 Wd,1IH);- 4.28 KI 4.35 (d,1IH); 4.55 (dd, IH); 4.59 (d.lIH); 4.88 (br s,1H); 4.99 5.34 5.76 6.13 6.55 7.32 7.49 7.61 8.11 (d.2H Example 32 Preparation of N-debenzoyl-N-(:-butyl)aminocarbonyl-7-deoxy-.78methanotaxol; Compound N-Debenzoy-N-Cbz-7-doxy-70,80-methano-taxo 21 (60 mng, 0.07 mM; Preparation 42) is dissolved in 3 mLt absolute ethanol and 20 mng 10% Pd on caibon is added. This is hydrogenated at atmospheric pressure for 5.5 hrs. TLC shows no starting material left so reaction is filtered through Celite and concentrated in vacuo.

The residue, which is 13-$f-pbenyl-isoserinyl)-7-deoxy-7.8f-mehao-baccatin M1. (22.

52 mng, 0.07 mM; Preparation 43) is dissolved in 1 tnt THE and-8 mL (0.07mM) t-butyl isocyanate added. TLC shows some amine remains so the reaction is cooled to 0 0 C and 7 mL t.

butyl isocyanate added. Amine still remains so another 7 mLt and 3x 5mL is added checking the reaction by TLC between each addition. To the reaction is added water to quench and the solution is partitioned between acidic brine and EtOAc. The layers are separated and the organic layer is filtered through Na 2

SO

4 and concentrated in vacuo and chromatographed over 6 gm of silica gel packed in 1:2 EtOAc:hexane. The column is eluted with 30 mL 1:2 2.3 EtOAc:hexane, and 80 mt. 1:1 EtOAc:hexane collecting 3 mL fractions. The desired N-debenzoyl-N-(f-butyl)aminocarbonyl.7-deoxy-70,8f-methano-taxoI is .9..found in frac.tions 29-48.

Mass Spec (FAB-High Res.) Theory: 831.3704 Found: 831.3717 1 H NMR (CDCl 3 TS:,L18 1.23 1.26 1.66 1.82 (s.3H); 1.98-2.48 2.20 2.38 (s,314); 4.05 4.30 4.50 4.60 (d.lH); 4.73 (m,114); 5.33 5.66 6.19 6.31 7.32 7.51 7.61 (iu,1H) 8.13 (d,21-) Example 33 Preparation of Baccatin-I-7-O-triflate (Compound 8D) A solution of baccatin-Ifl (Example 33; 5.25 g, 8.93 mrnoles) in CH 2

CI

2 (21 tnt) and pyridine (18.1 mlt.) is cooled in a -30'C bath. Trifluoroinethanesulfonic anhydride (3.76 tnt, 6.31 g. 22.3 inmoles) is added and the resulting mixture stirred and allowed to warm to room temperature over a period of an hour. The reaction is complete after 4 hrs; saturated-aq NH 4

CI

-74niL) is added and the mixture is extracted with CH CI 2 h rai xrc swse successively with 1. M aq NaHSO 4 (50 mL), saturated aq NaHCO 3 (2 x 50 inL), saturated aqj NaCI, and was dried (Na 2

SO

4 filtered, and concentrated under reduced pressure. Care is taken not to warm the solution to higher than 40*C during removal of the solvent. A solid is obtained and was flash chrornatographed over silica gel silica gel in a 75 min column. 125 mL fractions). The material is applied to the column in a CH 2

CI

2 solution and the column eluted with 5% CH 3 CN-C1 2 C1 2 Fractions 19-35 contained the desired 7-O-triflate 8D (4.837 g. 6.71 rnxoles, 75%) which is a solid.

'H NMR (CDC1 3 TMS) 8 8.10 (di, 2H. J 7.2 Hz), 7.63 lH, J1 7.4 Hz), 7.49 (t, 211, J 7.6 Hz), 6.63 1H, Hj 0 5.68 (di, 11, I1 7.0 Hz, H 2 5.52 (dd. 1H, J 7.5. 10.1 Hz.

H

7 4.94 111, J1 8.4 Hz, H4 5 4.86 (in. 11, H 13 4.35 (ci 1H. J 8.4 Hz, H20a). 4.15 (d.

111, J1 8.4 Hz, H20). 4.01 (ci, 111, J 7.0 Hz, H 3 2.87 (5 lines, H 1 2.30 3H, -Cl- 3 2.20 3H, -CH- 3 2.10-2.30 He,, H, H 1 4b). 1.87.(s. 3H; -Cl- 3 1.59 3H. -C11 3 1.19 3H. -CH- 3 1,05 311, -CH 3 Example 34 .Preparation of 'A 6 7 -Bactin-Ml A solution of baccatin-II1-7-O-triflate (Compound 8D; 0.97 g, 1.35 mmoles) and 1,8diazabicyclo[5.4.0]undec-7-ene (1.01 mL, 1.03 g, 6.76 mrnoles) in THF (6 rnL) 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 was complete. EtOAc was added and the solution was washed with saturated aq NaHCO 3 and with saturated aq NaCi. The organic layer was dried (Na 2

SO

4 filLered, and evaporated under reduced pressure. The residue (0.876 g) was flash chromatographed over silica gel silica gel ini a 45 mm column) using a solution in CH 2

CI

2 (1 mL) for application to the column. The column was eluted with 10% CH 3

CN-CH

2

CI

2 (1 15% CH 3 Cn-C1 2 C1 2 and with 20% CH 3

CN-CH

2

CI

2 (0.5 Fractions containing the desired material were de~ected by TLC and were combined to give the title compound (0.556 g. 0.978 mmol, 72%).

111 NMR (CDC1 3 TMS) 8 8.1 (i 211, J 7.2 Hz), 7.63 111, J1 7.3 Hz), 7.50 (t, 211, J1 7.6 Hz), 6.24 (s M1, H10), 6.07 (dci, IH, J 5.7, 9.9 Hz, 5.87 Ki 111, J1 9.9 Hz, 117), 5.80 (di, 11H. J 6.6 Hz;11H2), 5.12 (ci, 1I1 H.J 5.5 Hz, 115), 4.87 (in, IH. H 13). 4.43 (dI. H1.

J 8.1 Hz, H20,), 4.29 (di, 1I1 H.J 8.1 Hz, H 2 0b), 4. 10 (ci. 111.,1 6.6 'Hz, 113). 2.31 311, 30 CH 3 2.20-2,31 (mn, 211, H414a), 2.24 3H1, -CH- 3 1.97 311, -CH 3 1.85 3H1, -CH 3 1.12 611, 2 -CH- 3 13 c NMR (CDC1.

3 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, 55.5, 42.7. 41.7, 39.0, 30.9, 26.3, 2.2.7, 21.0, 20.9, 20.2. 15.0.

Example 35 Preparation of 13-(N-Benzyloxycarbonyl- -phenyl-isoserinyl)-2'-triethylsilylbaccatin mH (Compound I2DA) 13-(N-Benzyloxycvbonyl-f-phenyl-isosrnyl).-baccain III (Preparation 23; 450 mng.

0.51 mM) is dissolved in 5 ml dry pyridine and cooled to 0' C. To the solution is added chlorotriethylsilane (100 p1, 0.61 mM). The solution is allowed to warn to room temperature and after stirring for 1 hour TLC shows no reaction. After 3 additions of 100 pl, 200 p1. and 100 111 of chlorotriethylsilane VWC shows no starting material remaining. The reaction is partitioned between saturated CUS0 4 and EtOAc. The layers are separated and the organic reextracted using sat. CuSO 4 The organic layer is filtered through Na 2

SO

4 and concentrated in vacuo. The residue is chroinatographed over 40 gm of silica gel packed in 1:3 EtOAc:hexane.

The product is added using CH 2 C1 2 and the column eluted with 300 mlJ 1:3 EtOAc:hexane, 450 ml 1:2 EtOAc:bexane, and 150 mW 1:1 EtOAc:hexane collecting 20 ml fractions. Compound 12DA is found in fractions 17-32, 502 ing. 98%.

1 H NMR (CDCI 3 TMS): 8 0.38 (in, 6H1); 0.77 (mn. 9H); 1.14 3H). 1.26 3H); 1.69 311); 1.84 3H); 1.91 (mn, 2H1); 2.24 3H); 2.35 (mn, 1H); 2.55 (in. 4H); 3.79 (di. 1H-); 4.21 IH); 4.30 (d 4.43 (in, IH); 4.58 lH); 4.94 2H); 5.04 (di. IH); 5.33 IH); 5.66 1H); 5.76 (di, 6.26 IH); 6.29 (mn. 1H); 7.27 7.38 (Mn 2H); 7.50 (mn. 2H); 7.59 (in, 11); 8.12 (di, 2H). Mass spectrum, theory: 998.4358; found: 998.4344.

Example 36 Preparation of 1 3-(N-Benzyloxycarbonyl-f-phenyl-isoserinyl)-2 '-triethylsilylbaccatin Il 7-0-triflate (Compound 24) 1 3-(N-Benzyloxycarbony1-f-pheny1-isoserinyl)-2>-triethylsilyl-baccatin II (Compound 12DA; 200 mng, 0.20 mM) is dissolved in 2.5 m) C}1 2 C1 2 and dry pyridine (500 p1. 6 mM) and cooled to -40 0 C. To the solution is added triflic anhydride (100 p1. 0.60 mM). After minutes the solution is allowed to warm to room temperature and after stirring for 2.5 hours TLC shows no starting material remained. The reaction is partitioned between saturated CuSO 4 and EtOAc. The layers are separated and the organic reextracted using sat. CUSO 4 Theorganic layer is filtered through Na2SO 4 and concentrated in vacuo. The residue. is chroina- 25 tographed over 20 gm of silica gel packed in 1:4 EtOAc:hexane. The product is added using CH Cl 2 and the column eluted with 150 ml 1:4 EtOAc:hexane and 200 ml 1:3 EtOAc:hexane collecting 10 ml fractions. Compound 24 is found in fractions 9-28, 212 mg, 94%.

1 H NR (CCI 3 TMS.~_0.38 (in, 6H); 0.77 (in, 9H); 1.88 I .89(,3 2.04 3H); 2.20 3H); 2.30 2H); 2.54 3H); 2.87 (in, IH); 3.93 1H); 4.22 (di, IH);, 4.33 (di, 4.58 (di, 1H); 4.93 2H); 5.04 (ci, 1H); 5.35 (di, lH); 5.49 (in, lH); 5.73 (mn, 2H); 6.26 (mn, 11); 6.61 lH); 7.14-7.41 7.52 (in, 2H); 7.62 (in, IH); 8.12 2H). Mass spectrum. theory: 1130.3851; found. 1130.3845.

Example-37 Preparation of 13.{N-t-Butylurea-f -phenyl-isoserinyl)-baccatin II (Compound 27) 1 3-(N-Benzyloxycarbonyl-fP-phenyl-isoserinyl)- 2 -triethylsilyl-baccatin IJI (Compound 24; 191 mng. 0.18 m.M) is dissolved in 3 ml methanol 2 Hl dry THFE To the -76solution is added ammonium formate (100 mg) and 10% Pd/C (50 mng). After stirring for hour TLC shows no starting material remained. The reaction is filtered through Celite and the filtrate partitioned between 5% NaHCO 3 and EtOAc and the organic layer is filtered through Na 2

SQ

4 and concentrated in vacuo leaving 160 mg. The residue is dissolved in 5 ml dry THF and t-butyl isocyanate (200 p1. 1.6 mM) added. After stirring for 1 hour TLC shows starting material remainininig so an additonal 200 p1 t-butyl isocyanate is added. To get comp lete reaction and additional 2 times 200 p1 t-butyl isocyanate is needed. The reaction is concentrated in vacuo and 9 nil of 0.IN HO -in methanol added. After stirring for 0.25 hour TLC shows no starting material rem-ained. The reaction is partitioned between 5% NaHCO 3 and EtOAc and the organic layer is filtered through Na 2

SQ

4 and concentrated in vacuo. The residue is chromnatogaphed over 20 gmn of silica gel packed in .1:2 EtQAc:hexane. The product is added using CH0 and the column is eluted with 100 mlJ 1:2 EtQAc:hexaneand 150 mal 2:3 EtOAc:hexane collecting 10 ml -fractions. Compound 27 is found in fractions 19-40. 159 mg, 1 H NMR (CDCl 3 TMS): 8 1.22 1.87 3H1); 2.01 3H1); 2.18 3H); 2.28 (in.

3H); 2.42 311); 2.85 (in, 114); 3.92 (di, 1H); 4.17 (di, 1H), 4.33 lH); 4.55 (in. 1H); 4.63 (d, 111); 4.91 (di, lH); 5.20 (mn 114); 5.32 (mn. 1H); 5.45 (mn. 1H1); 5.73 111); 6.15 (in. 111); 6.60 111). 7.32 514); 7.50 (mn, 2H); 7.62 (mn. 1H1); 8.08 2H1).

Mass spectrumn, theory: 981.3302; found: 981.3302.

Example 38 Preparation of Baccatin MI 7-O.Triflate, 13.((4S.5R)-N-Benzyloxycarbonyl-2-(2.4acid ester. (Compound 26) Crude (4S,5R)-N-beazyloxycarbonyl-2-(2,4-dinethoxyphenyl)-4-phenyl5-oxazolidine carboxylic acid potassium salt (Preparation 21; 700 ing. 1.05 mM) is partitioned between C2C2 and 5% NaHSO 4 solution. The, ayers are separated and the aqueous layer extracted with EtOAc. The combined organic layers are filtered through anhydrous sodium sulfate and concentrated in vacuo leaving 465 mg of (4S.5R)-N-benzyloxy-2-(2,4-dimethoxyphenyl)-4acid. All of the 4 S,5R)-N-bcnzyloxycarboriyl-2-(2,4-dimethoxy- :.phemyl)-4-phnyl-5-oxazoli carboxylic acid was added in a solution of 3 mld toluene and 3 ml ~CH2CO2 to baccatin Ml 7-0-triflate (Compound 81); 500 mg. 0.70 mM). To the slurry is added DCC (230 ing, 1.12 mM) and DMAP (40 mg. 0.35 mM). After stirring 4 hours the reaction is filtered through Celite. The filtrate is concentrated in vacuo and the residue is chromatographed t. *over 70 g of silica gel packed in 1:3 EtOAc:hexane. The product is added using CH 2 Cl 2 and the column is eluted with 900 ml 1:2 EtOAc:hexane. 500 ml 2:3 EtOAc:hexane, and 200 n-d1: EtOAc:hexane collecting 25 ml fractions.

rdctwsfun nfrcins1.8 A le polar product was found in fractions 17-8.

-77- The less polar product was collected in fractions 17-22, 1 H NMR (CDCI 3 TMS): 1.23 6H); 1.86 2.08 3H); 2.22 6H); 2.38 (in, I1H); 2.82 (mn. I 3.82 6H); 3.98 18H); 4.15 IlH); 4.31 I 4.89 I H); 4.96 (in. 18H); 5.02 5-52 28); 5.72 I 6.26 (mn. 18H); 6.40 (mn. I 6.48 18H); 6.65 IH); 6.74 1H). 7.40 1H); 7.22 7.37-7.67 8.03 2H).

The mnore polar product was collected in fractions 39 and 40. 56mg.

1 H NMR (CDC1 3 TMS): 1.13 3H); 1.17 3H); 1.81 3H8); 2.03 3H); 2.10 (mn, 18); 2.18 (mn. 1H); 2.19 3H); 2.80 18); 3.81 (in. 6H); 4.09 1H): 4.28 1H); 4.54 Kd I 4.80 (in, 211);, 4.94 (d 18H); 5.41 I 5.57 I 5.65 Kd I 5.89 (in.

1H); 6.48 6.78 7.15 7.43 7.62 (mn. 1H); 8.00 2H) midxed fractions (fractions 23-38) contained 650 mng, total 706 ing. 87%.

Examp~le 39 Preparation of 13-(N-Benzyloxycarbony1-f -phenyl-isoseninyl)-baccatin 111 Triflate. (Compound The mixed fractions 23-38 (Example 38; 650 ing, 0.56 inM) are dissolved in 1 nml CH0 and 30 nil of 0.1N HC1 in methanol. After stirring for 1 hour TLC shows no staring mnaterial. The reaction is partitioned between 5% NaHCO 3 brine, and EtOAc. The layers are separated and the aqueous reextracted using EtOAc. The combined organic layers are filtered through Na 2

SO

4 and concentrated in vacuo. The residue is chromatographed over 60 gmn of silica gel packed in 1:3 EtOAc:hexane. The residue is added using CH 2

CI

2 and the column is eluted with 900 -l1 1:2 EtOAc:hexane, 200 mal 1:1 EtOAc:hexane, and 210 -lI 2:1 EtOAc:hexane collecting 25 ml fractions.

Compound 25 is found in fractions 25-43, 525 mng. 93%.

18 NMR (CDC1 3 TMS): 8 1.22 3H); 1.26 3H); 1.92 3H); 2.02 3H); 2.24 3H); 2.29 2.43 3H); 2.88 (mn. I18); 3.40 18H); 3.94 18H); 4.23 I 4.36 (d, 18); 4.71 (mn IH); 4.93 1H); 5.00 18); 5.12 5.39 IH); 5.48 (in. 5.74 (d, 28); 6.24 18); 6.63 18); 7.23 7.30 7.40 7.56 (in. 28); 7.67 (in. 18); 8.15 2H1). Mass spectrum, theory: 1016.2986:. found: 1016.3008.

Example 40 Preparation of 1 3-(N-t-Butylurea-f -phenyl-isoserinyl).baccatin Mf .~.*(Compounrd 27) The 13-(N-benzyloxycarbonyl--phenyl-isoseriny1)-baccatin M1 7-0-triflate (Compound 200 mrg. 0.20 mM) is dissolved in 2 ml dry THE and 3 mrl methanol. To the solution is ***added 100 mg NH 4 CO H and 50 mng 10% Pd/C. After stirring for 0.5 hours TLC shows no starting material. The reaction is filtered through celite and the filtrate partitioned between 3 brine, and EtOAc. The layers are separated and the organic layer is filtered through Na 2

SQ

4 and concentrated in vacuo leaving 160 ing (0.18 m.M. 90% yield). The residue is dissolved in 5 ml dry THE and cooled to 0' C. To the solution was added t-butyl isocyanate p1, 0.23 mM). TLC after 1 hour shows starting material so another 15 p] t-butyl isocyanate is added. After a total time of 2 hours TLC showed no starting material so the reaction was concentrated in vacuo. The residue is chromatographed over 18 g of silica gel packed in 1:2 EtQAc:hexane. The residue is added using CI- 2 C1 2 and the column is eluted with 100 ml 1:2 EtQAc:hexane, 100 ml 2:3 EtQAc:hexane, and 200 ml 1:1 EtQAc:hexa-ne collecting 10 ml fractions. The Compound 27 is found in fractions 17-31, 160 mg, 83%.

1 H NMR (CDCI 3 TMS): 8 1.22 1.87 3H). 2.01 3H); 2.18 3H); 2.28 (in, 3A1; 2.42 3H); 2.85 (in, I 3.92 I1H); 4.17 (d I1H); 4.33 (Ki 1H); 4.55 (in, 4.63 (d, 1H); 4.91 1H); 5.20 (in, 1W); 5.32 (mn, 11-1), 5.45 (in. 1H). 5.73 (di, 1H); 6.15 (in. IH); 6.60 1H); 7.32 5H); 7.50 (in, 2H); 7.62 (in, 1H); 8.08 (di, 2H). Mass spectrum. theory: 981.3302; found: 981.3302.

Example 41 Preparation of 13-(N-t-Butylure-a-f -phenyl-isoserinyl)-A 6 7 _baccatin III (Comnpound 16F) The 13-(N-t-butylurea-f -phenyl-isoserirnyl)-baccatin III 7-0-triflate (20 mg. 0.02 m.M) is dissolved in 0.2 mld dry TWF and DBU (15 pi1,.0.1,0 mM) is added. The solution is heated to 600 C and after s tiring for 1 hour TLC shows still starting material. An additional 10 Id DBU and 2 ml THF are added. After 2.5 hours the reaction is partitioned between 5% NaHCO 3 1 brine. and EtOAc. The layers are separated and the organic layer is filtered through Na 2 S0 4 and concentrated in vacuo. The re-sidue is chromatographed over 2 g of silica gel packed in 1:2 EtOAc:hexane. The product is added using CH 2

CI

2 and the column is eluted with 10 ml 1:2 EtOAc:hexane, 30 ml 2:3 EtOAc:hexane, and 15 ml 1: 1 EtOAc:hexane collecting I n- fractions.

Compound 16F is found in fractions 32-51. 13 mg, 1 H NMR (CDC1 3 TMS): 8 1.23 1.75 3H); 1.86 3W); 2.23 3W); 2.32 (in, 2H); 2.42 3H); 3.99 1WH); 4.30 1WH); 4.42 (di, 1WH); 4.60 (in, 2W); 5. 10 (di. 1WH); 5.15 (mn, 25 1W); 5.33 5.85 (in, 2H); 6.04 (mi, 1H), 6.17 (mn, 11W); 6.22 7.33 (mn. 5H). 7.51 'j(in, 211); 7.63 (in, 11); 8.14 (di, 2H1). Mass spectrum, theory: 831.3704; found: 831.3742.

Example 42 Preparation of 1 3 -(N,;pC-f-phenyl-isoserinyl)-7-tiflate-Baccatin M (Compound -28) The 13.{N-CBZ-0-pheny1-isoscrinyl)-7-triflate-Baccatin Ill (Compound 25; 200mg, 0.20 m.M) is dissolved in 2m1d dry THE and 31nl methanol. To the solution is added 100mg

NH

4

CO

2 W and 50mg 10% Pd/C. After stirring for 0.5 hours TLC shows no starting material.

The reaction is filtered through celite and the filtrate partitioned between 5% NaHCO 3 brine.

and EtOAc. The layers are separated and the organic layer is filtered through NaSO and id! 35 concentrated in vacua leaving 160mg (0.18 mnM, 90% yield). The residue is dissolved in dry THY and to the solution is added di-t-butyl-dicarbonate 4 3mg. 0.20 mM) and triethylamine Iii, 0.22 mM). TLC after stirring for 18 hours shows no starting material. The reaction is concentrated in vacuo and the residue was chromatographed over 18gm of silica gel packed in 1:2 EtQAc:hexane. The product is added using CH- 2 C1 2 and the column was eluted with 2 00m1 1:2 EtQAc:hexane and 2 00 m] 2:3 EtOAc:hexane collecting l0rmi fractions.

Compound 28 is found in fractions 13:-33. Yield 165mg. 86% 1 H NMR (CDCI 3 TMS): 8 1.22 3H); 1.24 3H); 1.35 9H); 1.88 3H); 2.02 3H); 2120 3H); 2.28 (in, 3H); 2.40 3H); 2.86 lH); 3.93 1H); 4.17 1H); 4.34 (Ki IH); 4.63 (mn, I 4.91 Ad I1-H); 5.26 (in, I 5.37 (ci. IH); 5.46 (mn, IH); 5.73 I H); 6.20 111); 6.61 1H); 7.38 (in, 5H). 7.51 (in, 211); 7.63 (mn. 11H); 8.10 2H) Mass Spec. Theory 982.3142 Found 982.3120 Example 43 Preparation of I 3-(N-BOC-f-phenyl-isoserinyl)-A 6 7 _Baccatin III (Compound 16D) The 13-(N-BOC--phenyl-isoserinyl)-7-triflate-Baccatin mU (Compound 28; 165mg. 0.17 mM) is dissolved in 3mI1 dry THF and DBU (250 pl, 1.7 mM) added. The solution is heated to and after stirring for 2.5 hours TLC shows some startirg material. An additional 50 jil DBU is added. After 5 hours the TLC shows no starting material. The reaction is partitioned between 5% NaHCO 3 brine, and EtOAc. The layers are separated and the organic layer is filtered through Na 2

SO

4 and concentrated in vacuo. The residue is chrornatographed over 16gm of silica gel packed in 1:2 EtOAc:hexane. The product is added using CH 2

CI

2 and the column was eluted with 200m1 1:2 EtOAc:hexane and 250m1 2:3 EtOAc:hexane collecting 8m1 fractions.

Compound 16D is found in fractions 17-32. Yield 115mg. 82%.

Derivatives of the 7 -deoxy-70,8f -methano-taxols in which the 2'-hydroxyl group is esterified are prepared directly from the desired 7-deoxy-70,7-methano-taxol by methods which are given in: Mathew. A. E, et.al., J. Med. Chernt. 1992, 35, 145; U.S. Patent 4,960,790; U.S.

Patent 4,942,184; U.S. Patent 5,059,699.

Following the general procedures of Mathew et al. (see. U.S. Patent 4,960,790, 4.924,184 and 5.059.699) but substituting the appropriate 7-doxy-7,8 -methano-taxol analog.

the following compounds are prepared.

2 '-succinyl-7-deoxy-7~,ptfnethao-taxol; 2 '-$-aanyl)-7-deoxy-7,8 -mehanotaxolfomnate; 2 '-glutaryl-7-deoxy-70,8-mehao-taxol; 2 2 3 C(O)iqH(CH 2 3

N(CH

3 2 -7deoxy70,fr8methano-taxoI; 2 '-sufopropionyl)-7-deoxy-7,8-inethano.raxol; 2 '-(2-sulfoethylarnido)succinyl-7-deoxy-70,85-inetano-taxol; ~2 3 -sulfopropylamido)succinyl-7-deoxy-7,85-methano.taxol; 2 '-(tfiethylsilyl)-7-deoxy-70,8f -meano-taxol; 2'-(t-butyldimethylsilyl 7 -deoxy-7fr8f-methano-taxol; 2'-(N,N-diethylam inopropionyl)-7-deoxy-70.8-methano-taxol; 2'-(N,N-dimethylglycyl)-7-deoxy-7 .8f-methano-taxol; 2'-(glycyl)-7-deoxy-7 ,8-methano-taxol; 2'-(L-alanyl)-7-deoxy-70.8 -methano-taxol; 2'-(L-leucyl)-7-deoxy-7,8-methano-taxol; 2'-(L-isoleucyl)-7-deoxy-7,8-methano-taxol; 2'-(L-vayl)-7-deoxy-7,8g-methano-taxol; 2'-(L-phenylalanyl)-7-deoxy-70,8&-methano-taxol; 2'-(L-prolyl)-7-deoxy-7,8f-methano-taxol; 2'-(L-lysyl)-7-deoxy-7.8f-methano-taxol; 2'-(L-glutmyl)-7-deoxy-7,8-methano-taxol; 2'-(L-arginyl)-7-deoxy-7.8f-methano-taxol; 7-deoxy-7,8-methano-taxotere; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group.

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 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 S 25 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 S. 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 ether, an alkyl ester, or mixtures -81thereof, 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. 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. 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 metho 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 standard V-blender and usually under anhydrous conditions. Next, the just prepared mixture can be slugged through conventional tablet machines and the slugs fabncated into tablets. The freshly prepared tablets can be coated.

25 or they can be left uncoated. r presentative of suitable coatings are the nontoxic coatings including shellac, methylcellulose, carnauba wax, styrene-maleic acid copolymers, and the like.

S ,For oral administration, compressed tablets containing 0.01 milligram. 5 milligrams, milligrams, 50 milligrams, 500 milligrams, etc., up to 2500 milligrams are manufactured in the light of the above disclosure and by art known fabrication techniques well known to the art and set forth in Remington's Pharmaceutical Science, Chapt 39, Mack Publishing Co., 1965.

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 comstarch 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 tablets, 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.

FORMULATION I 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 nontoxic 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 mg. 125 mg, and the like, of the novel compound.

singularly or mixtures of two or more of the novel compounds are prepared, for example, as follows: FORMULATION II Ingredients Per Capsule, mg.

30 Active compound 50.0 Calcium carbonate 100.0 Lactose, U.S.P. 200.0 Starch 130.0 Magnesium stearate The above ingredients are blended together in a standard blender and then discharged r..

'S

9 f* 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.

1I Typically the compounds of the invention can be administered by intravenous injection at doses of 1-500 mg per patient per course of treatment, preferable with doses of 2-100 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 dextrose in water p-ior to infusion or injection.

The compounds of Formula I (including I, III and IV) 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 25 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, Ant-Cancer Drugs, Vol. 2, pp 519-530, 1991.

The biological activity of the 7-deoxy-7p,8p-methanotaxol compounds (Formula II) of 30 the invention has been confirmed using well known procedures. For example, comparison of the cytotoxicity of 7-deoxy-7p,8-methano-taxol (Compound lIb: product of example 19) with taxol itself in L1210 mouse leukemia carcinoma cells in culture indicated that the IC9 growth inhibitory concentration) for 7-deoxy-7 ,8 -methanotaxol was 0.025 micrograms/ml and for taxol was 0.06 micrograms/ml. In an in vitro tubulin polymerization assay, conducted after the manner of F. Gaskin, et al., J. Mol. Biol. 89:737, 1974, 7-deoxy-7,.8-methano-taxol was able to induce tubulin polymerization in vitro at 20°C in a manner very similar to taxol.

-84- The biological activity of the 7-deoxy-7-halotaxol compounds (Fonnula Ill) of the invention has been confirmed using well known procedures. For example, comparison of the cytotoxicity of 7-deoxy-7-fluorotaxol (Compound mb; product of example 11) with taxol itself in A2780 (human ovarian carcinoma) cells in culture indicated that the IC0 (90% growth inhibitory concentration) for 7-deoxy-7-fluorotaxol was 0.016 micrograms/ml and for taxol was 0.007 micrograms/ml. In an in vitro tubulin polymerization assay, conducted after the manner of F. Gaskin, et Mol. M Biol. 89:737, 1974, 7-deoxy-7-fluorotaxol was able to induce tubulin polymerization in vitro at 20 0 C in a manner very similar to taxol. In this assay. 7deoxy-7-fluoro taxol was approximately half as potent as taxol.

The biological activity of the compounds of this invention has been further confirmed using well known procedures against L1210 leukemia and the results set forth in Table I. The results were obtained using standard well known procedure (Li, Kuentzel, Murch, Pschigoga, and W.C. Krueger, "Comparative biological and biochemical effects of nogalamycin and its analogs on L1210 leukemia," Cancer Res. 39:4816-4822 (1979)). The results are expressed as an IC 50 which is the drug concentration required to inhibit cell proliferation to 50% of that of untreated control cells. Lower numbers indicated greater activity.

TABLE I Compound No. L1210 (IC 5 z _gml 13AA 0.054 14AA 0.1 0.012 mb 0.010 ib 0.012 25 16A 0.0042 13DA 0.015 14DA 0.012 15DA 0.006 30 20 0.0038 23 0.0046 16D 0.0016 16F 0.0032 Taxol 0.015 Taxotere 0.004 CHART A-1

OR

10 0 CR 3 R

H

0 H 3C jcR\kT 3 2CN 0 .13

CH

3

R

4 H 00R

COC

6

H

RORI

0 0 CR 3 A2 0 R 3 C CR 3 7 0o- 13 CR 3

CCH

0C3 H3C

A-

3 7 R ORN 3 2 0 *HO 5 2 @030 HO 0 OH *0 CHART A-11

OH

3 H 3 C C 3 7 H R s 2 0I 13 CH 3 3

A-'

R

4 HO

COCH

3 C00 6

H

~OR 10 0

R

3 0 HC7 0 2 R0 RCOCAH- 0CUC 6

H

I.

OR

0

R

C-1 13 GCl 3 R 0A'-3 2* 0 HOH 0 6HO 0

COC

6

H

5

GOH

-87- CHART A-UI

OR,

0 0 H 3 C CH, 0 13 R4

HO

O,

R R 3 0 3c.I 0 C,, 2o 205- 30R5-10-- 13 6O HO *Goo a of -88- CHART A'

N

3

~R

3 0 H 2

H

2 N.R3 0 R 0 1Pd/C

OHH

OH

Rt R 3 0

OHH

3

R

11 CH(0R 12 2 4 or

RI

1

CHO

4A 0H RI, H H R, 0

R

12 %l-H

R

11 H7 -0 0 0

,R

14 9'.

(9 9 I.

r~.

'*9 .9 9-9 9* 9 9* 9.

.9999.

HO 1 omz -89- CHART B

R

12 -N 0 00..R 1 Fl R 0 lH HO g"cOO AzO 0c 01 IOMY

R

2

R

3 o Rl 1 0 0

I

HO

BZO Acd 101VZ N deprotection

H

2 N R 3 0 RI10 0 I acylatlon oHO BzO AcO liz N deprotection HNA 1 N acy'latlon NH0 (9 BzO AcO 15 0 0 H 0' iomz A I

R,

6 BzO Aco *999..

CHART B-1l

OR

1

O

0 CH 3

\JJH

H3C (CH 7 HO

OOH

Z 13 COCH

CCH

B-I

OR 10

H

3 C

CM

3 HO-- 13 OH 3 2 b: H 0 HO 6

COCH

3 c 006

H

B-2 0 C H

~OH

B3-3 25 1 0

C

6

H

5 3 C

CH

3 30 0

CH

3 BOC-HX 0 H 0 0 1 0C 3 B-4 -91- CHART B-Ill

OR

10 0 CH 3 H3C y 4 C 7,1,13 ZI 1CH 3

H

00

HOO

CCOC

6

B

BC

6

H

*OR

O

0

~H

3 C H Ho- 13 C 3 3 2 0 HO 0 1I

COC

6

H

0 3 .CHART C 13 1 2MZ 14 9 9

S*

S

955

S

S.

R

H

2 N R 3 0 R 1 5 0 0 HO 0

HO

BzO Aco 17 -93- CHART D AC 0 HU R 5 0 HO 0 AcO C00 6

HS

ACO 0

R

2

R

3 0 S lEt 3 H c 00H ACO 0 ACO 0

R

2

R

3 0

R

1 300 ACO 0 FORMULA

CHART

Ph 0 6H moo OM.

OM.

4 Ph 0

H

2

N~

1

O.

OH

2

CHO

OMe 4A 0 Ph 0 H CH 3A 0 Ph 0 cr- H moo Omi.

6Aa, 6Ab 7As, 7Ab R. He Ac-o.

a a

S

a a 9AaA 5 9AbA Ac 0 Ph 0

OH

30

IOAA

taxol TES SI(Et) 3 Ph =phenyl Ac =C(o)CH 3 Bz C(O)Ph FORMULA

CHART

cont.

Ph 0

OH

Ph 0 BOc~cNj-:' 2 ko-R, MOO 6 5Db Rl me 6Ba, 6Bb R:,2K 78a, 7Bb Ft.= H i

OBA

9BaA, QBbA

HO.

a

C

~CHC 12 Ph 0 Boc-Nil:k I H OH Ph 0 Boc-NJA H 6H

IOBG

Troc =C(O)OCH 2

CCI

2 Boc =C(O)O-t.Bu FORMULA

CHART

Cont- 9BaC, 9BbC Boo-N'

H

1 oBc Ph 0 Cbz-N4" H6H 3C BD Rb= H* R, C(O)OCH 2

CHC

2 BE Rb C{0)OCH 2 CHC1 2 R, H BF Rb aH, R=H Taxotere Ac-o.

9C t..

-9 9 .9 5Ca, SCb R, zMe 6Ca, 6Cb R, zK 7C8, 7Cb R, uH 9CaA, 9CbA Ph 0 Cbz -N--tA

H

6H Cbz =C{0)OCH 2 CeHs -97- FORMULA CHART cont.

Ph 0 0..

OH

Ph 0 Hro 0-Me 3D Ph 0 Troc-Nj-k.:kO-R moo

H

moo 5Da, 5Db Ra Me 6D8, 6Db Ra aK 7Da, 7Db Ra a I Ph 0 Ac-o 0

O-

Troc-N-r)Qk.. IN HHF BzoAO moo gDaA, 9DbA Ph 0 Ac-o. 0 WIH Troc-Wl%'o...

H6H H z Acd 0 I ODA .0 Ac-o 10FPA 1 OGA FORMULA CHART cont.

Ac=o 12CA

AC.

0 Ac-o 0 lOHA HNIH 00~l SzO Aco 101A 0- Ph 0 Ac.

0 0 1 0~~ O>=O H~O'A.O C1 3 C~o azO AcO 12AA o Ph 0 Ac- 0 0

HH

=Oo HO 0j~C Ci 3 -O BzO AcO 14AA Ac i F 0* 'C (9.

-C (9 13AA FORMULA

CHART

cont.

C1 3

C

0 1 2BA Ac~ 0 14BA

H

0 N, Ph 0

H

2 N0

OH

17 138A i

S

(S C..

'S (S

S

It 4..q

*S~S

1 2DA -100- FORMULA

CHART

cont.

16C 1 6D Boc

H

6H *4

I..

I* .C (C

C

C C 9 (C ~CC

(C

19

H

<0 13CA -101- FORMULA CHART cont.

Ac-O Ac- 0 21 22

C

H I

OH

23 Ph 0 AF

H

C13HO BzO AcO 13DA 0 Ph 0 Ac.

0 0 H 6 C1HC BzO AcO 14DA 4 (e Ac0.

0 Bzo Aco CHO z AcO 1 4CA i I r

I

~c b -102- FORMULA

CHART

cont.

0 Ph 0 3K 0 Ph 0

H

moo 51(a,5Kb R. uMe 61a, 6Keb R. aK 7K2, 7Kb Ra aH Ph .0 Ac .o 0 0 j~

H

moo HOBzO AcO M o gKaAgKbA 4*

S

4 I. .S S S is (S.

4 'S ~I5 4* (e

S

S

S@

4 Si -103- FORMULA

CHART

conL Compound Ila Compound lb 0* *a i I. a a a.

a (a.

(a a (aa a a a. 'a -104- FORMULA

CHART

cont.

Compound Lila Compound 11Th 4 4 4 r.* I. *1*

V

V

a. C -105- FORMULA

CHART

cont.

Compound flIaci Compound Ma3 9* 9 9 .9 9* 9 *9*9 9* 9. i 9 9.

9 9 9999 9. 9 9 9 999999 .4 9 *i -106& FORMULA

CHART

cunt.

Compound Illba Compound H1114 *9 S. 6 0 *9 .0

S

4

S

See.

C'S.

950e

SO

S

p.

S S 0* 00 S C 9.

**0S 0S

C

S

S

6.55..

C

C

5* 0

S.

-107- FORMULA

CHART

cont.

101LA 0 0 0 0 0: 0 0 10PA

IOLA

-108- FORMULA

CHART

cont.

0 3-a 303 I

IOUA

-11)9- FORMULA CHART cont.

PhO0 Cbz-NJ o

S~

3 HO 6AcO I 2DA co 6

H

5 PhO0 6H HO AcO 16F

CSHS

SiEt 3 24

COCAH

S

S..

I

*5 AcO 0 0T1 coc 6

HS

8D HM 0 H 6 HO 6AcOI

/\OCH

3 CC

CH

3 O 2 Ph 0 AcO 0 f FH OH AcO 0 Ph 0 c 0 f BOOCN HO n0 AcO 28 6 0C H 11b 6

H

TBU (CH 3 3

CNHCO-

Claims (9)

1. 4-(SO3H)phenyl, -OH, -NHC(0)- 1 -adamantyl, -NHC(O)O-3 -tetrahydrofuranyl, -N HIC(O)O-4-tetraliydropyranyl, -NHC(O)0C 1 -C 1 oalkyl, -NHC(O)NHC I -C 1 IOalkyl, '5 -NI-IC(O)NHPh, -NHC(O)-NHPh substituted with one, 2 or 3 C 1 -C 4 alkyl, C 1 -C 3 alkoxy, halo, CI-C 3 alkylthio, trifluoroemethyl, C 2 -C 6 dial kylarnino, or nitro, -NHC(O)C 3 C'.,cyc loal kyl, -NHC(O)C(CH 3 2 CH 2 CI, plithalimido, -N I-phIenyl- I-cyclopentyl, -N l-IC(O)- Iimethyl- I -cyclohexyl and -NHC(S)NHC(CH3) 3 R 3 is -NHC(O)phenyl or -NHC(O)OC(CH 3 3 with the proviso that one of R 2 and R-,K i -1-I but and are not both -H; R 4 is selected from -OH, -QAc (-OC(O)CHA) -OC(O)OCH 2 C(CI) 3 -OCOCH1CHNH +HCOO-, -NHC(O)phenyl, -NHC(O)OC(CH3) 3 -OCO-CH 2 CH 2 COOH, 0:-OCO(C- 2 3 C001-, [where Z is ethylene (-CH 2 CH 2 propylene (-ClCI-CHCH-),) -CH=CH-, 1 ,2-cyclohexane or I ,2-phenylene and R' is -OH, -OH base, NR'2R' 3 -OR' 3 -SR' 3 -OCH 2 C(O)NR' 4 R' 5 where R' 2 is -1-I or -CH 3 R' 3 is -(CH 2 6 R' 7 or (CI-) 1 N'R' 6 R' 7 R'gX- where n is 1-3, R' 4 is -H or -CI-C 4 alkyl, R' 5 is -Ci-C 4 alkyl, benzyl, hydroxyethyl, -CH 2 CO 2 H or dimethylaminoethyl, R' 6 and R' 7 are -CH 3 CH 2 CH 3 or benzyl or R' 6 and R' 7 together with the nitrogen of NR' 6 form a pyrrolidino, piperidino, morpholino or N-methylpiperizino group, and R'p, is -CH 3 -CH 2 CH 3 j or benzyl, X- is halide, 'Ind base is NH 3 (HOC 2 H 4 3 N, N(CH 3 3 CH 3 N(CH 4 2 NH 2 NI-1 2 (CH 2 6 NH 2 4 a III N-rnethylglucamine, NaOH or KOH], -OC(O)(CH 2 ),,NR 2 R 3 [where n is 1 R 2 is -H or -Cl-C 3 alkyl and R 3 is -H or -Ci-C 3 alkyl], -OC(O)CI-(R')NH 2 [where R" is selected from -IA' -CH 3 -CH 2 CH(CH 3 2 -CH(CH 3 )CH 2 CH 3 -CH(CH 3 2 -CH(CH 3 2 -CI- 2 phenyl, -(C-1 2 4 N1- 2 -CH 2 CH 2 COOH, -(CH 2 3 NHC(=NH)NH 2 the residue of' the amino acid Sproline, -CO(O)CH=CH 2 -C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 SO 3 -O)C(O)CH 2 CH 2 C(O)NHCH 2 CH 2 SO3;y+ wherein Y+ is Na+ or Na+(Bu) 4 and -OC(O)CH-?CH 2 C(O)OCH 2 CH 2 OH; R 5 is or -OH, with the provisos that when R, is -OH, R 4 is and that when R 5 is R 4 is other than -H; Rj 1 is -H or -C(O)CH 3 l(17 is -H4 or -C(O)phenyl optionally Substituted with one, 2 or 3 azido, cyano, methoxy, or halo substituents; and pharmaceutically acceptable salts thereof when the compound contains either an acidic or basic functional group; Is with the overall proviso that the following combination is excluded: 1 is -CIA 3 -C 6 H 5 or phenyl substituted with one to 3) alkyl, alkoxy, halo or CF 3 groups; R) is m-NHC(O)H, -NHC(O)Ct- 6 alkyI, -NHC(O)phenyl, -NHC(O)phenyl substituted with one to 3) alkyl, alkoxy, halo or CF 3 groups, -NHC(O)C(CH 3 )=CHCH 3 -NHC(O)0C 1 :2o (,alkyl or -NHC(O)C 3 6 cycloalkyl; k 3 is H-; R 4 is OH; Ri is and R 1 7 is -C(O)phenyl. 152 A compound according to claimn 1, whcrein R 17 is -C(O)phenyl substituted with one azido, cyano, methoxy or halo substituent. A compound according to claim 1, wherein R 1 7 is -C(O)phenyl substituted with one azido, cyano, mnethoxy or halo substituent in the meta position. 4. A compound according to claim 1, wherein RP- is -CO(O)phenyl. A compound according to claim 4, wherein R2 is -NI-C(O)C 6 H 5 R 4 is hydroxy, R 3 and R 5 are H, and R, is phenyl or substituted phenyl.
2. 6. A compound according to claim 4, wherein R 2 is -NHC(O)OC(CH 3 3 R 1 is phenyl or substituted phenyl, R 4 is hydroxy, and R 3 and R 5 are -H.
3. 7. A compound according to claim 4, wherein R 2 is -NI-C(O)NHC(CH 3 3 R, is phenyl or substituted phenyl, R 4 is hydroxy, and R 3 and R 5 are -H4. A1ABNXj0221;0.d- KWW 112
4. 8. A compound according to any preceding claim, wherein R-2 is -NHCONHalkyI or optionally-substituted -NHCONPh.
5. 9. A compound according to claim 4, which is N-debenzoyl-N-t buLtylaiiinocarboniyl-7-deoxy-A 6 7 -taxol. 1 0. A compound according to claim 1, selected from (2,2,2-trichloroethyl)oxy)carbonyl)J7-deoxy-A 6 7 taxol; 2 '-sLICCinyl-7-deoxy-A 6 7 -taxol; 2 [3-a anylI)-7-deoXY-A 6 7 -taxol formnate; 2 '-(13-lfpropioneyl-67deoyAl -txl 2 fotyaiosciy--ex- 7 -taoxol;.7-axl 2 -sut fopropioylmidoxcciny7 -deoyAl -tx; 2'-(triethylsilyl--doxy-A 6 'y 7 x 67_ax is2'-(t-buthyldis yslyl)-7-deoxy-A -taxol; *oo. 1* 2'-(N,-buyd ithylmiopropidoy-67e ol;tao 2 ,N-d iethy Igmycyl)-7-deoxy-A 7 xo A6t; 1 2'-(NN-lycyl gycl-7-deoxy-A -t-taxol 2'-(Llcyl-7-deoxy-A 6 7 -taxol; 2'-(L-isleuyl)-7-deoxy-A '-taxol; 2'-(L-vluyl)-7-deoxy-A 6 7 taxol; 2'-(L-proleyl)-7-deoxy-A 7 taxol; 25 2'-(L,-Iysyl)-7-deoxy-A 7 taxol; 5* l- e x 6,7x l 2 utarnyl)-7-deoxy-A -,7taxol; and 2'-(L-arginyl)-7-deoxy-A 6 7 -taxol.
6. 11. A compound according to claim 1, selected from N- Debeinzoyl -N -t-butylam-inocarbonyl-7-deoxy-A 6 7 -taxol; M N -Debenzoy 1 -methyl- I -cyclohexanoy)-7-deoxy-A 6, 7 -taxol; N-Debenzoyl-N I -phenyl- 1 -cyclopentanoyl )-7-deoxy- 6 ,7-taxol; N-Debenizoyl-N-phthalirnido-7-deoxy-A 6 7 -taxol; N-Debenzoyl-N-t-butylaminothiocarbonyl-7-deoxy-A 6 7 -taxol; N-Debenizoyl-N-t-amyloxycarbonyI-7-deoxy-A 6 ,7 taxol; N -Debenzoyl-N -neopentyloxycarbonyl -7-deoxy-A 6 1 7 -taxol; and I I \LIBXXjO228O.doc.KWNV 0 f (,0 113 N-Debenzoyl-N-(2-chloro- 1, 1 -dirnethylethyl)oxycarbonyl-7-deoxy-A 6 7 _taxol;
7. 12. A compound according to claim 1, selected from 2- Debenizoyl-2-(m-azidobenzoyl)-7-deoxyA 6 7 -taxotere; 2-Debenzoyl-2-(m-azidobenzoyl)- I 0-acetyl- 7-deoxy-A 6 7 -taxotere; N_92- B ]oebno 2-maioezyI--tbt rioabn 7- ox- -taxol; 2- DebenzoyI-2-(m--chlorobenzoyl)-7-deoxy-A~ -,taxotere; 2-Debenzoyl-2-(m-chlorobenzoyl)- 1 O-acetyl-7-deoxy-A 6 7 -taxoterc; N_9- Biodebenzoyl- 2 -(mi-clorobenzoyI-Nt-butylaim-inocarbonyl-7deoxy- 6 7 _taxol; 2- Dcbenzoyl -2-(m-miethoxybenzoyl)-7-deoxy-A 6 t 7 taxotere; 1 2- Debenzoyl -2-(mi-methoxybenzoyl)- I 0-acetyl 7-deoxy-A 6 7 -taxotere; N, 9-B3 odebenizoyl-2-(m-mthoxybenzoyl)-Ntbutyl aminocarbonyl -7-deoxy-A 6 7 taxo I; 2- Debcnzoyl-2-(mi-cyaniobenzoyl )-7-deoxy-A 6 7 taxotere; 2- Debenzoyl-2-(mi-cyanobenzoyl)> I O-acetyl-7-dcoxy-A 6 7 -taxotere; and I N,9- Biodebenizoyl-2-(mi-cyanobenzoyl)-N-t-butylaminocarbonly-7-deoxy-A 6 7 -laxol. 1 3. A pharmaceutical composition comprising a Compound according to any one of -ccecding claims and a non-toxic carrier. '14. Use of' a compound according to any onie of claims 1 to 12, for the manufacture of a medicament for use in the treatment of cancer. to 2( 15. A process of making a compound according to claim I which process is Substantially as herein described with reference to the Examples.
8. 16. A compound of claim 1 when made by the process of claim
9. 17. A method of' treating cancer in a patient requiring such treatment comprising **t0 *1 administering to said patient a therapeutically effective anmount of a compound of claim 1. 400 1 18. A compound of claim 1 when used for the treatment of 'cancer. too* Vo Dated 26 April, 2000 Pharmacia Upjohn Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON