fHl BP
`PCX
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 94/18164
`(51) International Patent Classification 5 :
`(11) International Publication Number:
`C07D 205/08, 305/14
`
`(43) International Publication Date:
`
`18 August 1994 (18.08.94)
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`A1
`
`(21) International Application Number:
`
`PCT/US94/00669
`
`(22) International Filing Date:
`
`28 January 1994 (28.01.94)
`
`(81) Designated States: AU, CA, CZ, FT, JP, KR, NO, NZ, PL,
`RU, SK, European patent (AT, BE, CH, DE, DK, ES, FR,
`GB, GR, IE, IT, LU, MC, NL, PT, SE).
`
`(30) Priority Data:
`08/011,922
`
`1 February 1993 (01.02.93)
`
`US
`
`Published
`With international search report.
`
`(71) Applicant: THE RESEARCH FOUNDATION OF STATE
`UNIVERSITY OF NEW YORK [US/US]; State University
`of New York, Stony Brook, NY 11794-0001 (US).
`
`(72) Inventor: OJEVLA, Iwao; 6
`11790 (US).
`
`Ivy League Lane, Stony Brook, NY
`
`(74) Agent: CALVETO, Frederick, F.; Morgan & Finnegan, 555
`13th Street, N.W., Suite 480 West, Washington, DC 20004
`(US).
`
`(54) Title: PROCESS FOR PREPARATION OF TAXANE DERIVATIVES AND /3-LACTAM INTERMEDIATES THEREFOR
`
`(57) Abstract
`
`Taxol (I) is a complex diterpene which is currently considered the most exciting lead in cancer chemotherapy. Taxol possesses high
`cytotoxicity and strong antitumor activity against different cancers which have not been effectively treated by existing antitumor drugs.
`However, taxol has a problem with solubility in aqueous media, which may impose some serious limitation in its use. TAXOTERE (III)
`seems to have antitumor activity superior to taxol with better bioavailability. Taxot&re has a modified taxol structure with a modified C-13
`side chain. This fact strongly indicates that modification on the C-13 side chain would provide a new series of taxol and TAXOTERE
`analogues which may have higher potency, better bioavailability and less unwanted toxicity. The present invention provides efficient and
`practical methods for the syntheses of TAXOTERE and its analogues through /3-lactam intermediates and their coupling with baccatin m.
`
`Sanofi Exh. 2005
`Neptune v. Aventis
`IPR2019-00136
`
`

`

`r
`
`*
`
`t
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Ccxies used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`ES
`FI
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cflte d'lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`Mauritania
`MR
`MW Malawi
`NE
`Niger
`NL
`Netherlands
`Norway
`NO
`New Zealand
`NZ
`PL
`Poland
`PT
`Portugal
`RO
`Romania
`RU
`Russian Federation
`SD
`Sudan
`SE
`Sweden
`Slovenia
`SI
`Slovakia
`SK
`Senegal
`SN
`Chad
`TD
`TG
`Togo
`TJ
`Tajikistan
`TT
`Trinidad and Tobago
`UA
`Ukraine
`US
`United States of America
`UZ
`Uzbekistan
`VN
`Viet Nam
`
`

`

`WO 94/18164
`
`PCX /US94/00669
`
`1
`PROCESS FOR PREPARATION OF TAXANE
`DERIVATIVES AND B-LACTAM INTERMEDIATES THEREFOR
`FIELD OF THE INVENTION
`The present invention relates to a process for
`the preparation of taxoid(s)
`including TAXOTERE and its
`analogs and the B-lactam intermediates useful in this
`process.
`
`BACKGROUND OF THE INVENTION
`Taxol (I) is a complex diterpene which is
`currently considered the most exciting lead in cancer
`chemotherapy.
`Taxol possesses high cytotoxicity and
`strong antitumor activity against different cancers which
`have not been effectively treated by existing antitumor
`drugs.
`For example, taxol is currently in phase III
`clinical trials for advanced ovarian cancer, phase II for
`breast cancer, and phase I for lung cancers, colon cancer
`and acute leukemia.
`
`11
`
`• 6
`
`1
`
`2
`
`8
`3
`
`.Y>H r?i9 OH
`0 V V
`
`0
`
`NH
`
`O
`
`• 2 '
`
`OH
`
`12
`
`7>
`5
`4
`0
`I7*i
`O*4"13
`14 HO C - o 20
`O
`O
`
`(I)
`
`Although taxol is an extremely important "lead"
`in cancer chemotherapy, taxol has a problem with
`solubility in aqueous media, which may impose some serious
`limitation in its use.
`It is common for improved drugs to
`be derived from naturally occurring lead compounds,
`In
`fact, French researchers, Potier, Gueritte-Voegelein,
`SUBSTITUTE SHEET (RULE 26)
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`WO 94/18164
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`PCT/US94/00669
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`2
`Guenard et al. have discovered that a modification of the
`C-13 side chain of taxol brought about a new anticancer
`agent which seems to have antitumor activity superior to
`taxol with better bioavailability. This synthetic
`compound was named "TAXOTfiRE (11)", which has t-
`butoxycarbonyl instead of benzoyl on the amino group of
`(2R,3S)-phenylisoserine moiety at the C-13 position and a
`hydroxyl group instead of an acetoxy group at C-10.
`[Colin, M. et al. Eur. Pat. Appl. EP253,738 (1988)].
`Taxotere is currently in phase II clinical trial in both
`United States and Europe. TAXOTERE has been synthesized
`by a semisynthetic process, including a coupling of N-
`tert-butoxycarbonyl-(2R,3S)-3-phenylisoserine with 10-
`deacetylbaccatin III with proper protecting groups.
`(Denis, J.-N. recently reported (Commercon, A. et al.,
`Tetrahedron Letters, 1992, H 5185)).
`
`o
`
`NH
`
`OX
`
`OS
`
`fUl
`
`It is known that the C-13 side chain of taxol,
`i.e., N-benzoyl-(2R, 3S)-3-phenylisoserine (III) moiety,
`is crucial for the strong antitumor activity of taxol.
`(Senilh et al., C.R. Seancas Acad. Sci. Ser. 2 1984, 299,
`1039; Gueritte-Voegelein et al., Tetrahedron, 1986, 42,
`4451, and Mangatal et al., Tetrahedron, 1989, 45, 4177;
`Gueritte-Voegelein et al. J. Med. Chem. 1991, 34, 992; and
`Swindell et al., J. Med. Chem. 1992, 35, 145; Mathew, A.E.
`et al., J. Med. Chem. 1992, 35, 145).
`Moreover, some
`modification of the C-13 side chain can provide a new
`series of taxol analogs which may have higher potency,
`better bioavailability and less unwanted toxicity, as
`
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`WO 94/18164
`
`PCT/US94/00669
`
`3
`exemplified by the discovery of TAXOTfiRE (II) .
`
`0
`
`0
`
`HH 9
`
`HO
`
`10
`
`OK
`f
`
`O1''^
`
`3 * ^2 *
`OK
`
`'O
`
`HO
`0
`o=^ IT o
`^ //
`
`(in)
`
`5
`
`10
`
`15
`
`Accordingly, the development of an efficient
`ffl*»thod which can be applied to various analogs of taxol
`and TAXOT^RE and analogs thereof, i.e., a method having
`flexibility and wide applicability, is extremely important
`and of current demand.
`It has been shown that such a new
`and efficient method with flexibility can be developed by
`using enantiomerically pure fi-lactams as key-intermediates
`[Ojima, I. et al., J. Org. Chem., 1991, 56, 1681; Ojima et
`al., Tetrahedron, 1992, 48
`6985; Holton, R.A., Eur.
`Patent Appl. EP 400,971 (1990)].
`Lithium chiral ester enolate-imine
`cyclocondensation strategy has been applied to the
`asymmetric synthesis of the side chain of taxol via a
`(3J?,4S) —3-hydroxy-4-phenylazotidin—2-one (IV) as the key-
`(Ojima, I. et al., J. Org. Chem., 1991, 56,
`intermediate .
`1681; Ojima et al., Tetrahedron, 1992, 48, 6985)
`11
`
`HQ
`
`a
`
`•HH
`
`(17)
`
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`

`WO 94/18164
`
`PCT/US94/00669
`
`5
`
`10
`
`4
`Based on this protocol, the side chain can be
`obtained in 3 steps in high yield wrch virtually 100% e.e.
`(Ojima, I. et al. J. Org. Chem. 1991 56, 1681). Recently,
`it was found that l-benzoyl-(3J?,4S)-3-(l-ethoxyethoxy)-4-
`phenylazetidin-2-one (V), readily derived from the
`hydroxy-B-lactam (IV) , served as the key-intermediate for
`the synthesis of taxol [Holton, R.A. Eur. Pat. Appl. EP
`400,971 (1990)]. Therefore, this B-lactam intermediate
`serves as the key-intermediate for both coupling methods.
`
`r 0 \
`I O-O
`
`on
`
`AcO
`
`o osist 2
`h
`10
`7
`
`HO'lJ
`
`0
`
`3
`
`t V
`HQ 0=
`^ //
`7-TES-baccacin III (VI)
`In the published European application to Holton
`(hereinafter Holton) , the fl-lactam intermediate (V) was
`
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`WO 94/18164
`
`PCT/US94/00669
`
`5
`
`10
`
`5
`obtained through tedious optical resolution of the racemic
`According to Holton's procedure,
`cis-3-hydroxy-S-lactam.
`the coupling of the B-lactam (V) with 7-
`(7-TES-baccatin III)
`triethylsilylbaccatin III (VI)
`proceeds at 250C in the presence of dimethylaminopyridine
`(DMAP) and pyridine for 12 hours to give protected taxol
`in 92% yield, which was deprotected with 0.5% hydrochloric
`acid in ethanol at 0oC to afford taxol in ca. 90% yield.
`However, the Holton procedure did not work at
`all when l-tert-butoxycarbonyl-fS-R^SJ-S-^l-
`ethoxylethoxy)-4-phenylazetidin-2-one (VII) was used for
`the attempted synthesis of TAXOTERE (II) by the present
`inventors.
`
`,o
`£ro)(i M 08ue
`"Y Q
`
`(vn)
`
`15
`
`20
`
`It is believed that this may be due to the lack
`of reactivity of the i-tert-butoxycarbonyl-B-lactam (VII)
`toward the C-13 hydroxyl group of a protected baccatin III
`(VI or VIII) under the conditions used by Holton.
`The
`lack of reactivity may be ascribed to the substantially
`weaker electron-withdrawing ability of tert-butoxycarbonyl
`group than that of benzoyl group.
`
`

`

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`
`6
`
`Cl3CCH20C(0)0 0 0C(0)0CH2CCl3
`7
`10
`
`V
`13
`HO^
`
`o
`
`^ O
`
`HO V
`o Of o
`
`7. l 6-di-Troc-lO-deacetylbaccatin III (VIII)
`
`5
`
`10
`
`Therefore, it was an objective of the present
`invention to develop a new method which can achieve the
`coupling of the l-tert-butoxycarbonyl-B-lactam (VII) with
`the protected baccatin III (VIII) for the synthesis of
`TAXOTERE (II).
`All of the references cited above and any
`reference which nay be mentioned herein below are
`expressly incorporated into the present disclosure.
`It is an object of the present invention to
`provide new B-Iactams useful in the syntheses of TAXOTfiRE
`(II) and analogs thereof.
`It is further object of the present invention to
`provide a new coupling method for the syntheses of
`TAXOTfiRE (II) and analogs thereof.
`
`SUBSTITUTE SHEET (RULE 26)
`
`

`

`WO 94/18164
`
`PCT/US94/00669
`
`7
`SUMMARY OF THE INVENTION
`A B-lactam of the forxriuia (XX)
`
`\
`
`G.O A
`0^ Y-(K) Y
`
`5
`
`10
`
`15
`
`20
`
`in which
`
`Pj. represents an RO-, RS- or RR'N- in which R
`represents an unsubstituted or substituted straight chain
`or branched alkyl, alkenyl or alkynyl, cycloalkyl,
`heterocycloalkyl, cycloalkenyl, heterocycloalkeny1,
`carbocyclic aryl or heteroaryl, wherein substituents
`bearing one or more active hydrogens such as hydroxy1,
`amino, marcapto and carboxyl groups are protected; R' is a
`hydrogen or R as defined above; R and R' can be connected
`to form a cyclic structure; Examples of R2« include
`methoxy, ethoxy, isopropoxy, tert-butoxy, neopentyloxy,
`cyclohexyloxy, allyloxy, propargyloxy, adamantyloxy,
`phenyoxy, 4-methoxyphenoxy, 2-fluorophenoxy, 4-
`methoxycarbonylphenoxy, methylthio, ethylthio,
`isopropylthio, tert-butylthio, neopentylthio,
`cyclohexylthio, phenylthio, 3,4-dimethoxyphenylthio,
`methylamino, ethylamino, isopropylamino, tert-butylamino,
`neopentylamino, cyclohexylamino, dimethylamino,
`pyrrolidinef piperidino and morpholino group.
`R3» represents an unsubstituted or substituted
`straight chain or branched alkyl, alkenyl or alkynyl
`
`

`

`WO 94/18164
`
`PCT/US94/00669
`
`8
`radical, an unsubstituted or substituted cycloalkyl, or
`cycloalkenyl radical, an unsubstituted or substituted aryl
`radical wherein substituents bearing one or more active
`hydrogens such as hydroxy, amino, mercapto and carboxyl
`groups are protected; Examples of R3. include phenyl, 4-
`methoxypheny1, 3,4-dimethoxyIpheny1, 4-fluoropheny1, 4-
`trifluoromethylphenyl, 4-chlorophenyl, 4-bromophenyl,
`naphthyl, cyclohexyl, cyclohexylmethyl, 2-phenylethenyl,
`2-phenylethyl, benzyl, neopentyl, tert-butyl, isobutyl,
`isopropyl, allyl and proparagyl;
`Gj represents a hydrogen or hydroxyl protecting
`group such as methoxyxnethyl (MOM) , methoxylethyl (MEM) , 1-
`ethoxyethyl (EE) benzyloxymethyl, (B-
`trimethylsilylethoxyl)methyl, tetrahydropyranyl, 2,2,2-
`trichloroethoxycarbonyl (Tror) tert-butoxycarbonyl (t-
`BOC), 9-fluorenylmethoxycarbonyl (Fmoc), 2,2,2-
`tricholoroethoxymethyl, trimethylsilyl, triethylsilyl,
`dimethylethylsilyl, dimethyl(t-butyl)silyl,
`diethylmethylsilyl, dimethylphenylsilyl and
`diphenylmethylsilyl;
`Y is oxygen or sulfur.
`The present inventor investigated the 6-lactam
`coupling reaction with protected Baccatin III in detail
`and found that the coupling could be achieved by
`increasing the nucleophilicity of the 13-hydroxyl group of
`a protected baccatin III (VI or VIII) through
`transformation of the hydroxyl group to the corresponding
`Such a C-13 metal alkoxide of a baccatin
`metal alkoxide.
`Ill was readily generated by reacting the baccatin III (VI
`or VIII) with an alkali or alkaline earth metal base.
`This finding is the basis of the present invention,
`The
`method of the present invention not only enables the
`coupling of the fi-lactam (VII) and its derivatives and
`analogs with a protected baccatin III, but also requires
`only a stoichiometric amount of the 6-lactams.
`The latter
`makes a sharp contrast with the Holton procedure for taxol
`
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`WO 94/18164
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`PCT/US94/00669
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`9
`synthesis which needs 5-6 equivalents of the more reactive
`Moreover, the coupling reactions of the
`B-lactam (V).
`present invention proceeds very smoothly and complete
`0oC.
`typically within 30 minutes at -300C
`The present invention also relates to a process
`for the preparation of taxane derivatives of the formula
`(X)
`
`Y -A
`
`NH 0
`B= e
`0RS
`
`.9 OR*
`/
`
`R,q
`
`10
`
`HO 0 0.
`
`0 V
`
`W
`
`in which
`
`Rj represents a hydrogen atom or an acyl or an
`alkyl or an alkehyl or an alkynyl or carbocyclic aryl or a
`heteroaryl radical or a hydroxy1 protecting group (Gj
`defined above);
`1*2 represents an RO-, RS- or RR'N- in which R
`represents an unsubstituted or substituted straight chain
`or branched alkyl, alkenyl or alkynyl, cycloalkyl,
`heterocycloalkyl, cycloalkenyl, heterocycloalkenyl,
`carbocyclic aryl or heteroaryl; R' is a hydrogen or R as
`defined above; R and R' can be connected to form a cyclic
`structure;
`Y is oxygen or sulfur;
`R3 represents an unsubstituted or substituted
`straight chain or branched alkyl, alkenyl radical, an
`
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`
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`PCT/US94/00669
`
`10
`unsubstituted or substituted cycloalky1, cycloalkenyl
`radical or an unsubstituted or substituted carbooyclic
`aryl radical;
`R4 represents a hydrogen or an acyl radical or
`an unsubstituted or substituted straight chain or branched
`alkyl, alkenyl or alkynyl radical, an unsubstituted or
`substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or
`heterocycloalkenyl radical, an unsubstituted or
`substituted carbocyclic aryl or heteroaryl radical, or a
`hydroxy1 group protecting group (Gj defined above);
`R5 represents a hydrogen or an acyl radical or
`an unsubstituted or substituted straight chain or branched
`alkyl, alkenyl or alkynyl radical, an unsubstituted or
`substituted cycloalkyl, heterocycloalkyl, cycloalkenyl or
`heterocycloalkenyl radical, an unsubstituted or
`substituted carbocyclic aryl or heteroaryl radical, or a
`hydroxyl protecting group (G1 defined above);
`which comprises condensing a B-lactam of the formula
`
`Rr
`
`GA, P 1 Y
`
`in which
`
`Y and Gj are defined above;
`R2» represents a radical Rj as defined above or a
`protected Rj whenever Rj includes one or more active
`hydrogens such as hydroxyl, amino, mercapto and carboxyl
`groups;
`
`R3. represents a radical as R3 defined above or a
`protected R3 whenever R3 includes one or more active
`
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`WO 94/18164
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`PCT/US94/00669
`
`11
`hydrogens such as hydroxy1, amino, mercapto and carboxyl
`groups; with a baccatin III derivative of the formula:
`
`7
`
`% OGj
`10
`V
`MO**
`
`It3
`
`0
`HO y
`
`c:
`a a
`ii
`a=r
`
`5
`
`10
`
`• 15
`
`in which
`
`M is an alkali metal or alkaline earth metal
`atom (ion);
`G2 represents a hydroxy1 protecting group (Gj
`defined above) or an acyl radical or an unsubstituted or
`substituted straight chain or branched alkyl, alkenyl or
`alkynyl radical, an unsubstituted or substituted
`cycloalkyl, heteroycloalkyl, cycloalkenyl or
`heterocycloalkenyl radical, an unsubstituted or
`substituted carbocyclic aryl or heteroaryl radical;
`G3 represents a hydroxyl group protecting group
`(G3 defined above) or an acyl radical or an unsubstituted
`or substituted straight chain or branched alkyl, alkenyl
`or alkynyl radical, an unsubstituted or substituted
`cycloalkyl, heterocycloalkyl, cycloalkenyl or
`heterocycloalkenyl radical, an unsubstituted or
`
`

`

`WO 94/18164
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`PCT/US94/00669
`
`12
`substituted carbocyclic aryl or heteroaryl radical.
`
`DETAILED DESCRIPTION OF THE INVENTION
`The new B-lactams of the formula (IX) herein
`above are synthesized by modifying the B-lactams of the
`formula (XI)
`
`5
`
`GO \ A J-HH
`
`Q'
`
`wherein G is a hydroxyl protecting group such as
`triisopropylsilyl (TIPS) and dimethyl(tert-butyl) silyl
`(TBDHS), and R3' has been defined hereinabove.
`The fi-lactams (XI) are readily prepared by using
`the chiral enolate - imine cyclocondensation method which
`has been developed in the present inventor's laboratory as
`shown in Scheme 1 (Ojima, I. et al., Tetrahedron, 1992,
`48, 6985; Ojima, I. et al., J. Org. Chem. 1991, 56, 1681).
`In this preparation the B-lactams (XI) with extremely high
`enantiomeric purities are obtained in high yields.
`In
`Scheme 1, R* is a chiral auxiliary moiety which is (-)-
`trans-2-phenyl-l-cyclohexyl, TMS is a trimethylsilyl
`radical, and base is lithium diisopropylamide or lithium
`hexamethyldisilazide; G and R3' have been defined
`hereinabove.
`
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`WO 94/18164
`
`Scheme 1
`
`G-O-CH2-COOR*
`
`13
`
`1. base
`2. R3'-CH=N-TMS
`3. H2O
`
`G-O-CHz-COOR*
`
`1. base
`
`2.R3'CH=N
`3. H2O
`
`PCT/US94/00669
`
`G-0
`
`R3'
`
`0
`
`(XI)
`
`CAN
`
`G-0
`
`R3*
`
`O M e
`
`o
`
`II
`
`O M e
`
`5
`
`10
`
`15
`
`20
`
`25
`
`The B-lactams {V'T) are converted to the 3-
`hydroxy-6-lactains (XII) , followed by protection with
`ethoxyethyl group (EE) to give the B-lactams (XIII) .
`The
`B-lactams (XIII) are reacted with chloroformates or formic
`anhydrides or thiocholorformates or thioforraic anhydrides
`in the presence of a base to yield the B-lactams (XIV) (or
`thioanalogs thereof) which are used for the coupling with
`protected 10-deacetylbaccatin III to produce TAXOTERE and
`its analogs.
`The 6-lactams (XIV) are deprotected under
`weakly acidic conditions to afford the 6-lactams (XV)
`which can serve as very useful intermediates to the 6-
`iactams (XVI) bearing a variety of protecting groups (Gj)
`at the C-3 position of 3-lactam skeleton.
`The B-lactams
`(XVI) can also be used for the coupling with a protected
`10-deacetylbaccatin III to produce Taxotere and its
`analogs after deprotection.
`In a similar manner, the B-lactams (XVII) are
`prepared by reacting the B-lactams (XIII) with isocyanates
`or isothiocyanates in the presence of a base which can be
`used for the protection of other potent anticancer agents
`The 3-lactams
`-f formula (X) in which R-, represents RRN-.
`XVII) are deprotected under weakly acidic conditions to
`rive the B-iactams (XVIII) which can serve as very useful
`intermediates to a variety of protected 3-hydroxy1-3-
`SUBSTITUTE SHEET (RULE 26)
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`14
`The ^-lactams (XVII and XIX) can also be
`lactams (XIX).
`used for the coupling with a protected 10-deacetylbaccatin
`III to yield a compound of formula (X) in which Rj
`represents RR'N- after deprotection.
`In a manner similar to that described above, the
`B-lactams (XX) are prepared by reacting the B-lactaas
`(XIII) with N^-disubstituted carbamoyl halides in the
`presence of a base.
`The B-lactams (XX) are deprotected
`under weakly acidic conditions to give the 3-hydroxy-B-
`lactams (XXI), which can serve as very useful
`intermediates to various protected 3-hydroxy-B-lactains
`The B-lactams (XX and XXII) can readily be used
`(XXII).
`for the coupling with a protected baccatin III to afford a
`compound of formula (X) after deprotection.
`The transformations described above are
`illustrated in Scheme 2. In Scheme 2, X represents a
`leaving group such as fluoride, chloride, bromide, iodide,
`tosylate, mesylate and trifluoromesylate. Gl represents a
`group protecting the hydroxyl function selected from
`methoxylmethyl (MOM), methoxyethyl (MEM), 1-ethoxyethyl
`(EE), benzyloxymethyl, (B-trimethylsilylethoxyl) methyl,
`tetrahydropyranyl, 2,2,2-trichloroethoxylcarbonyl (TROC),
`benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (t-BOC), 9-
`fluorenyl methoxycarbonyl (FMOC) 2,2,2-
`trichloroethoxymethyl, trimethyl silyl, dimethyl(t-
`butyl)silyl, diethylmethylsilyl, dimethyl phenylsilyl and
`diphenylmethylsilyl, acetyl, chloroacetyl, dichloroacetyl,
`trichloroacetyl and trifluoroacetyl. R2', R3', R, and R'
`are defined hereinabove.
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`Scheme 2
`
`0,0
`
`R3'
`
`A-
`
`0
`Y
`(XIX)
`
`G-0
`
`R3'
`
`J-"*
`0
`(XI)
`
`PCT/US94/00669
`
`15
`
`GiX
`
`base
`
`NH-R
`
`HO
`
`R3'
`
`A
`
`NH-R
`
`T
`0
`(XVIII) Y
`
`EEO
`
`R3'
`
`P.
`
`NH-R
`
`0
`(XVII) Y
`
`HO
`F- or HF *
`O
`
`P-
`
`R3-
`
`(XII)
`
`R-N=C=Y
`base
`
`<^0^
`H+
`
`EEO
`
`R3'
`
`O
`
`(XIII)
`
`G-,0
`
`R3'
`
`0
`COOR
`(XVI)
`
`A
`.-s A-
`
`GiX
`
`base
`
`HO
`
`R3'
`
`A
`
`0
`COOR
`(XV)
`
`HaO*
`
`<*-
`
`XCOOR
`base
`
`EEO
`
`R3"
`
`A
`
`COOR
`
`O
`(XIV)
`
`EEO
`
`R3'
`
`o
`
`(XIII)
`
`RR'NCOX
`base
`
`*•
`
`R3'
`
`EEO
`Y
`J-N.
`0
`(XX) Y
`
`NRR'
`
`HO
`
`R3'
`
`'A
`
`NRR'
`
`0
`(XXI)
`
`Y
`
`GiX
`base
`6,0
`
`R3'
`
`NRR1 T
`o
`(XXII) Y
`The fi-lactams (XIV) and (XVI) are readily used
`for the coupling with protected baccatin Ills in the
`presence of base, followed by deprotection to give
`7AX0T£RE and its analogs in high yields (Scheme 2).
`similar -anner, the :3-iactams (XVII and XIX; with
`SUBSTITUTE SHEET (RULE 26)
`
`In a
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`
`16
`protection of -NH- moiety) and the R-lactams (XX and XXII)
`can be used for the coupling with protected baccatin Ills,
`followed by deprotection to give a compound of formula (X)
`in which RT represents RRrN- (Scheme 3).
`Scheme 3
`G2-0 0 o-Gs
`10
`
`Gj-O 0 O-G3
`10
`
`base
`
`0
`
`MO
`
`HO
`
`[13v'
`\\*'
`HO 0
`O =3s
`
`tT
`^\0
`
`0
`13 N'
`i
`-
`HO 0 0\^-
`^ I
`0=^
`11
`SS=\0
`
`-y'
`
`1. XIV or XVI
`2. deprotection
`
`*•
`
`o A
`
`RO
`R3
`
`NH 0
`Jl
`T
`±2' OH
`
`RiO
`
`0 0R4
`
`10
`
`O
`
`l« \ XV
`HO 0 0
`0
`5=\0
`
`1. xvii or XIX (NH protectedi:
`XX or XXII
`2. deorotectlon
`
`RR'N
`
`NH 0 >v
`
`10
`
`Y A
`R1O O OR4
`7 A b3
`
`R3
`
`£2-OH
`
`0
`HO 0 0Nk^—
`0 =3^
`''
`j-rvO
`
`G-» and G3 represents an hydroxyl protecting
`group or an acyl radical or an unsubstituted or
`substituted straight chain or branched alkyl, alkenyl
`radical, an unsubstituted or substituted cycloalkyl,
`heterocycloalkyl, cycioalkenyl or heterocycloalkenyl
`radical, an unsubstitured cr substituted carbocyclic aryl
`or heteroaryl radical.
`When G-i and C-T are hydroxyl protecting groups ;G,
`defined above and i-ethoxyethoxyi (EE)], these protecting
`
`SU8SmUIEStCET(RULE2l8
`
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`

`17
`groups can be attached to the hydroxy 1 groups of 10-
`deacetylbaccatin III and its analogs by methods which are
`generally known to those skilled in the art.
`The coupling reaction of the protected baccatin
`III and the B-lactam is carried out via an alkali metal or
`alkaline earth metal alkoxide of the protected baccatin
`III at the C-13 hydroxyl group,
`The alkoxide can readily
`be generated by reacting the protected baccatin III with
`an alkali metal or alkaline earth metal base such as
`sodium hexamethyldisilazide, potassium
`hexamethyldisilazide, lithium hexamethyldisilazide, sodium
`diisopropylamide, potassium diisopropylamide, lithium
`diisopropylamide, sodium hydride, potassium hydride,
`lithium hydride, calcium hydride, magnesium hydride, in a
`dry nonprotic organic solvent such as tetrahydrofuran
`(THE), dioxane, ether, dimethoxyethane (DME), diglyme,
`dimethylformamide (DMF), mixtures of these solvents with
`hexane, toluene, an xylene, in a preferred temperature
`range from about -1000C to about 500C, more preferably at
`about -780C to about 250C. This reaction is preferably
`carried out under inert atmosphere such as nitrogen and
`argon.
`The amount of the base used for the reaction is
`preferably approximately equivalent to the amount of the
`protected baccatin III when soluble bases such as sodium
`hexamethyldisilazide, potassium hexamethyldisilazide,
`lithium hexamethyldisilazide, sodium diisopropylamide,
`potassium diisopropylamide, lithium diisopropylamide are
`used.
`The use of a slight excess of the base does not
`adversely affect the reaction.
`When heterogeneous bases
`such as sodium hydride and potassium hydride are used, 5-
`10 equivalents of the base (to the amount of the protected
`baccatin III) is preferably employed.
`The coupling reaction of the metal alkoxide of
`the protected baccatin III thus generated with the B-
`lactam is typically carried out by adding the solution of
`the G-lactam in a dry organic solvent exemplified above in
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`a preferred temperature range from about -1000C to 50oCf
`mors preferably at about -350C to 250C. The mixture of
`reactants is stirred for 15 minutes to 24 hours and the
`progress and the completion of the reaction is monitored
`by thin layer chromatography (TLC), for example. When the
`limiting reactant is completely consumed, the reaction is
`quenched by addition of a brine. The crude reaction
`mixture is worked up using the standard isolation
`procedures which are generally known to those skilled in
`the art to give the corresponding protected taxoid. The
`proportion of the B-lactam and the protected baccatin III
`is in a range from 2:1 to 1:2, more preferably
`approximately 1:1 for purposes of economy and efficiency,
`but the ratio is not critical for the reaction.
`The protecting groups, EE, Gj, G2 and G3, can
`then be removed by using the standard procedures which are
`generally known to those skilled in the art to give the
`desired taxane derivatives. For example, EE and
`triethylsilyl groups can be removed with 0.5 N HC1 at room
`temperature for 3 6 h, and Troc group can be removed with
`zinc and acetic acid in methanol at 600C for 1 hour
`without disturbing the other functional groups and the
`skeleton of the taxoid.
`The following non-limiting examples are
`illustrative of the present invention,
`It should be noted
`that various changes would be made in the above examples
`and processes therein without departing from the scope of
`the present invention.
`For this reason, it is intended
`that the illustrative embodiments of the present
`application should be interpreted as being illustrative
`and not limiting in any sense.
`
`Examples 1-2
`(3R, 4S)-3-Triisopropylsilyloxy-4-phenyl-2-
`azetidinone (la):
`To a solution of 645 mL (4.6 mmol) of
`diisopropylamine in 10 mL of THF, was added 1.85 mL (4.6
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`nmiol, 2.5M) of n-BuLi at 0oC. The solution ^as stirred 1
`h at 0"C followed by the addition of 1.5 g (3.3 nmol) of
`(-) TIPS ester in 15 mL of THF over a l h period (using a
`cannula) at -780C. The reaction was stirred 2 h at this
`temperature followed by the addition of 817 mg (4.6 nmol)
`of N-TMS benzaldimine in 15 mL of THF over a 2 h period at
`-950C. The reaction was stirred overnight at this
`temperature and allowed to slowly warm up at room
`temperature. The reaction was quenched by addition of
`sat. NH4C1. The aqueous layer was extracted with ether.
`The organic layer was washed with 3% HC1 and brine, dried
`over MgS04 and concentrated. The crude oil was purified
`by chromatography on silica gel using 1:5 EtAcO/hexanes to
`give 1.03 g (84%) of B-lactam as a white solid: Mp 76-
`770C; [a]D20 +52.7° (C 1.00, CHCI3) ; NMR (300 MHz,
`CDCI3) <? 0.86-0.93 (m, 21H) , 4.81 (d, J - 4.7 Hz, 1H) ,
`5.17 (dd, J = 4.7, 2.6 Hz, 1H), 6.18 (bs, 1H), 7.17-7.35
`(m, 5H) ; 13C NMR (75 MHz, CDCI3 6 11.8, 17.4, 17.5, 59.6,
`79.9, 127.9, 128.0, 128.1, 136.4, 170.0; IR (KBr) 3234,
`2946-2866, 1760, 1458 cm"1. Anal. Calcd for C^^pl^Si: C
`67.66%, H 9.15%, N 4.38%. Found: C 67.64%, H 9.25%, N
`4.44%.
`
`In the same manner.
`6-lactam lb was obtained in
`good yield.
`(3R, AS) -3 -TriisopropyIsilylojcy-4- (2 -
`phenylethenyl)-2-azetidinone (lb): 72%; colorless liquid;
`jH NMR (300 MHz, CDCI3) <5 0.98-1.02 (m, 21H) , 4.36 (dd, J
`= 4.6, 8.3 HZ, 1H), 5.09 (dd, J = 2.3, 4.6 Hz, 1H), 6.29
`(dd, J = 8.3, 16.0 HZ, 1H), 6.59 (d, J = 16.0 Hz, 1H) ,
`6.83, (bs, 1H) , 7.23-7.39 (m, 5H) ; NMR (75 MHz^DClj) S
`11.79, 17.61, 17.66, 58.34, 79.86, 126.05, 126.45, 127.90,
`128.56, 134.41, 136.30, 169.69; IR (neat) 3262, 3032,
`2944, 2865, 1748, 1672, 1623 cm'1. Anal. Calcd for
`c20®3lNO2si: c' 69'52? H' 9-04; N, 4.05. Found: C,
`69.75; H, 9.02; N, 3.89.
`
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`Bxamples 3-4
`To a solution of 2.51 mmol of diisopropylamine
`in 15 mL of THF was added 2.51 mL of n-butyllithium (2.5M
`in THF) at -100C. After 30 min, the lithium
`diisopropylamide (LDA) was generated and the solution was
`cooled to -950C. A solution of 2.17 mmol of chiral ester
`in 5 mL of THF was added. After 1 hr, a solution of 2.5
`mmol of the appropriate imine in 3mL of THF was added.
`The mixture was stirred at -950C overnight, and the
`progress of the reaction was monitored by TLC or ^ NMR.
`The reaction was quenched with sat. NH4C1 and THF was
`removed using a rotary evaporator. Ether (10 mL) was
`added and the aqueous layer was extracted with ether (10
`mL x3) . Drying and removal of the solvent gave the crude
`product which was purified by silica gel column
`chromatography (hexane/ethyl acetate=10:1) to afford the
`corresponding pure 6-lactam. The enantimeric excess was
`determined by HPLC using a CHIRALCEL OD column using n-
`hexane/i-PrOH (90/10) as the eluent.
`(3J?, AS) -4- (2-Methylpropyl) -1- (4-methoxYphenyl) -
`3-trii3opropylsilyloxy-2-azetidinone (2a): 87%; pale
`yellow solid; mp 59-60oC; [cr]D20 +60.46° (c 1.26, CHCI3) ;
`1
`H NMR (300 MHz, CDCI3) 8 0.96 (d, J = 6.4 Hz, 3H) , 1.03
`(d, J = 6.4 HZ, 3H), 1.10-1.30 (m, 21H), 1.60-1.68 (m,
`1H), 1.70-1.92 (m, 2H), 3.75 (s, 3H), 4.16-4.22 (m, 1H) ,
`5.06 (d, J = 5.1 Hz, 1H), 6.86 (d, J = 9.0 Hz, 2H), 7.32
`(d, J = 9.0 HZ, 2H) ; 13C NMR (75 MHz, CDCI3) S 12.34,
`17.82, 17.91, 22.18, 23.37, 25.34, 35.89, 55.50, 57.33,
`76.34, 114.52, 118.73, 131.00, 156.29, 165.58; IR (KBr)
`2946, 1742, 1513, 1458, 1249 cm"1. Anal. Calcd for
`C^^pNOjSi: C, 68.10; H, 9.70; N, 3.45. Found: C,
`68.26; H, 9.85; N, 3.35.
`(3J?, 45) -4-(Cyclohexylmethyl) -1- (4-
`methoxyphenyl)-3-triisophropylsilyloxy-2-azetidinone (2b):
`83%; low melting point solid; [ajD20 +4 3 . 7° (c 0.92,
`
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`21
`CHC1-;) ; 1H' NMR (300 MHz, CDCI3) S 0.85-1.95 (m, 34H) , 3.78
`(S, 3ii) , 4.19-4.25 (m, 1H) , 5.05 (d, J = 5.1 H2, 1H) , 6.86
`(d, J = 9.0 HZ, 2H) , 7.32 (d, J = 9.0 Hz, 2H) ; 13C NMR (75
`MHz, CDC^) S 12.15, 17.76, 17.83, 26.12, 26.22, 26.47,
`32.84, 34.22, 34.51, 55.36, 56.41, 76.13, 114.30, 118.45,
`130.81, 155.99, 165.55; IR (neat) 2925-2865, 1749, 1513,
`1464, 1448, 1389, 1246, 1174, 1145, 1128, 939, 882, 828#
`684 cm*1. Anal. Calcd for C^H^NC^Si: C, 70.06; H, 9.72;
`N, 3.14. Found: C, 69.91; H, 9.71; N, 3.02.
`
`Examples 5-6
`To a solution of 0.24 mmol of l-(4-
`methoxyphenyl)-6-lactam in CH3CN (20 mL) was added 0.65
`mmol of CAN in 10 mL CH-,CN and 20 mL of water in 20 min at
`-150C. After stirring for 1 hr, it was diluted with water
`(20 mL) , and the mixture was then extracted with ethyl
`acetate (15 mL x2). The combined organic layer was washed
`with NaHSOj water (7 mL) , 5% (10 mL x 2) , 5% Na2C03 (10 mL)
`and brine (5 mL) in sequence. Drying, removal of the
`solvent in vacuo followed by decolorization with activated
`charcoal afforded the crude product. It was further
`purified by silica gel column chromatography
`(hexanes/ethyl acetate, 3/1) to furnish N-deprotected
`fi-lactam.
`
`(3 J?, 4S) -4- (2-Methylpropyl) -3-
`83%; yellow oil;
`triisopropylsilyloxy-2-azetidinone (ic):
`[cr] D20+35. 45° (c 1.33, CHCI3) ;
`H NMR (300 MHz, CDCI3) S
`1
`0.96 (d, J = 6.6 Hz, 3H), 1.05-
`0.93 (d, J = 6.6 Hz, 3H),
`1.25 (m, 22H) , 1.52 (M, 1H) , 1.67 (m, 1H) , 3.78
`(m, 1H),
`13
`4.96 (dd, J = 4.8, 2.4 Hz, 1H) , 6.02 (bs, 1H);
`C NMR
`(75MHZ, CDCI3) S 12.12, 17.72, 17.80, 22.29, 23.08, 25.35,
`39.08, 54.45, 78.04, 170.00; IR (neat) 3238, 1759, 1465,
`C