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`PCT/US94/00669
`
`38
`1.62-1.82 (m, 3H), 4.12 (m, 1H), 4,30 (bsf IK), 4.93 (d,
`= 5.9 Hz, 1H); 13 C NMR (75 MHz, CDCI3) S 22.45, 22.78,
`25.12, 27.96, 36.28, 57.59, 75.39, 83.46, 148.13, 168.00;
`IR (KBr) 3363, 2960, 2926, 1733,
`1763, 1458, 1370, 1350,
`Anal. Calcd. for
`1303, 1153 cm-1.
`C, 59.24; H,
`8.70; N, 5.76.
`Found:
`C, 59.47; H, 8.91; N, 5.51.
`
`J
`
`(3J?, AS) -l-tert-Butoxycarbonyl-4-cyclohexyl
`methyl-3-hydroxy-2-azetidinone
`(6j): 100%; white solid; mp
`105—106oC; [a]D20 +61.89° (c 0.74, CHCI3) ; lli NMR (300 MHz,
`COCI3) S 0.82-1.84 (m, 13H) , 1.50 (S, 9H) , 3.82 (bs, 1H) ,
`13 C NMR (75 MHZ,
`4.14 (m, 1H), 4.93 (d,
`J
`=
`5.8
`Hz,
`CDCI3) S 26.12, 26.17, 26.42, 33.20, 33.47, 33.59, 34.71,
`28.00, 57.13, 75.49, 83.47r 148.08, 167.57; IR
`(KBr)
`2921, 2850, 1797, 1682, 1447, 1354, 1342, 1159 cm-1.
`C, 63.58; H, 8.89; N, 4.94.
`Anal. Calcd. for C15H25N04:
`4.68.
`Found: C, 63.76; H,
`8.72;
`N,
`
`(3J?, 4S) -3-hydroxy-4-phenyl-1-phenylcarbamoyl-
`2-azetidinone (8a): 88%; white solid; mp l97-200oC;
`(a]D20 +206.4° (c 1.26, CHCI3) ; lH NMR (250 MHz, CD3COCD3) 6
`5.39-5.47 (m, 2H), 7.07-7.60
`(m,
`10H),
`8.80
`NMR (63 MHZ, CD3COCD3) S 61.98, 78.06, 119.85, 124.31,
`128.11, 128.31, 128.60,
`
`129.48, 135.31, 138.43, 148.17,
`169.76; IR (CHCI3) 3343, 3018, 2975, 1772, 1712, 1603,
`1548, 1447, 1362, 1219, 1045 cm*1; MS (FAB) m/Z(%)
`283(2),
`263 (33) 207(22), 143(100).
`
`(3J?, 4S) -l-te.rt-Butylcarbainoyl-3-hydroxY-4-
`89%; white solid;
`mp
`phenyl-2-azetidinone
`(8b):
`20
`1 H NMR (250 MHz,
`+160.9° (c 1.28,
`
`CHCI3) ;
`148—1510C; [a]D
`CDCI3) 5 1.35 (S, 9H), 3.16
`
`(bs, 1H), 4.97 (d, J = 5.5 Hz,
`
`1H), 5.11 (d, J = 5.5 HZ, 1H), 6.60 (bs, 1H), 7.19-7.38
`13
`51.53, 60.74,
`C NMR (63 MHz, CDCI3) <S 28.84
`(m, 5H);
`76.61, 127.00, 128.61, 128.70, 133.13, 148.78, 168.30;
`
`IR
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`
`MYLAN - EXHIBIT 1004 (Part 6 of 13)
`
`

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`WO 94/18164
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`PCT/US94/00669
`
`Hz,
`
`39
`(CHCI3) 3362, 3018, 2975, 1767, 1710, 1533, 1422, 1318,
`1216, 1045 cm
`Anal. Calcd for C14H18N203: c, 64.11; H,
`6.92; N, 10.68. Found: C, 64.10; H, 7.08; N, 10.49.
`
`(3R, AS) -l-Benzylcarbamoyl-3-hydroxy-4-phenyl-
`2-azetidinone (8c): 63%; white solid;
`mp 165-1680C;
`[a]D20 +139° (c 0.64, CHCI3) ; ^ NMR (300 MHz, CDCI3) 6
`
`J 3.10 (bs, 1H), 4.43 (dd, = 15.2, 5.8 Hz, 1H), 4.50 (dd,
`
`
`J = 15.2, 5.8 Hz, 1H), 5.03 (d, J
`=
`
`
`Hz, 5.6 1H), 5.20 (d,
`J = 5.6 Hz, 1H), 7.06
`(t,
`J
`=
`
`5.8 (m,
`10H) ; 13C NMR (63 MHz, CDCI3) S 43.79, 61.01, 76.94,
`127.13, 127.73, 128.80, 128.86, 132.94, 137.59, 150.15,
`168.34; IR (CHCI3) 3364, 3028, 2925, 1771, 1704, 1537,
`1455, 1361, 1219, 1190, 987 cm"1. Anal. Calcd for
`C7H16N203: CJ 68.91; H, 5.44; N. 9.45. Found: C1 68.89;
`H. 5.66; N, 9.34.
`
`(3R, 4S) -l-Etliylcarbamoyl-3-Iiydroxy-4-ptaenyl-
`2-azetidinone (8d) :
`55%; white solid;
`mp 141- 420C;
`
`20
`1
`+211.4° (c 0.44, CHCI3) ;
`H NMR (250 MHz, CDCI3) S
`[ a ] D
`(t, J = 7.2 Hz, 3H),
`
`3.34 (qd, J = 7.2, 1.6 Hz, 2H),
`1. 19
`5.09 (d, J = 5.6 Hz, 1H) , 5.27 (d, J = 5.6 Hz, 1H), 6.63
`(bt, J = 1.6 Hz, 1H) , 7.23-7.44 (m,
`
`5H) ;
`C NMR (63 MHz,
`13
`CDCI3) d 15.04, 34.94, 60.77, 76.98, 127.00, 128.92,
`3381, 3018,
`129.06, 132.83, 149.96, 167.98; IR (CHCI3)
`2990, 1770, 1732, 1651, 1589, 1422, 1298, 1210, 1045
`cm"1.
`
`(31?, AS) -3- (1-Hydroxy) -l-phenyltliiocarbamoyl-4-
`pbenyl-2-azetidinone
`(8e): 78%; yellow solid;
`mp 85­
`88 0C; [ a ] D20 + 156 . 7° (c 0.67, CHCI3) ; ^ NMR (300 MHz,
`CDCI3) 6 5.16 (d, J = 5.8 Hz, 1H), 5.53 (d, J = 5.8 Hz,
`
`1H) , 7.31-7.44 (m, 8H) , 7.66 (d, J = 7.8 Hz, 2H) , 10.33
`(bs, 1H) ; 13C NMR (63 MHZ, CDCI3) S 63.97, 15.12, 123.29,
`126.49, 127.27, 128.77, 132.49, 137.26, 174.87; IR (CHCI3)
`
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`40
`3553, 3295, 3048, 2949, 1760, 1601, 1384, 1313 cm"1; MS
`299(M+l,
`46),
`179(100).
`(FAB) m/z (%)
`
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`
`(3JR, 4S) - 1 - (Morpholinecarljonyl) -3-hydroxys-
`plieiiyl-2-azetidinone (8f) : 83%; white solid;
`mp
`H NMR (250 MHz,
`
`CDC13) 3.05 (bs, 1H), 5
`
`3.56-3.78
`8H) , 5.00 (d, J = 5.9 HZ, 1H) , 5.38 (d, J
`
`= Hz, 1H) , 5.9
`
`7.24-7.40 (m,
`5H).
`
`1
`
`55-570C;
`(m,
`
`{3R, AS) -l- (M/N-Dinethylcarbamoyl) -3-hydroxy-4-
`ph.enyl-2-azetidinone (8g) : 88%; white
`crystal;
`1250C; jH NMR (250 MHz, CDCI3) 53.06 (bs, 6H, 4.98 (d,
`J=5.9 Hz, 1H), 5.35 (d, J=5.9 Hz, 1H), 7.29-7.39 (m, 5H).
`
`mp
`
`123-
`
`dichloromethane,
`
`overnight
`
`(3R, 4S) -l-tert—Butoxycarbonyl-4-phenyl-3-
`(1,1, l-trichloroethoxycarbonyl)-2-azetidinone
`(9a): To a
`
`solution of 99
`mg
`
`(0.38 ramol) of l-te.rt-butylcarbonyl-3-
`hydroxy-4-phenyl-
`
`2-azetidinone, mg of DMAP and 263 mL 5
`
`(2 mmol) of triethylamine
`in
`5
`mL
`of
`added at 0oc 105 mL (0.8 mmol) of
`l, l, l-trichloroethyl-
`chloroformate. The reaction mixture
`was
`stirred
`at room temperature. The organic layer
`was
`
`washed several
`times with brine,
`
`dried MgS04 and concentrated. The over
`
`crude solid was
`purified
`by
`chromatography
`to yield 65 mg (40%) of O-protected
`
`/3-lactam: White
`solid; mp 122-1240C; [a]D20 +28° (c 0.5, CHCI3) ; ^ NMR
`(250 MHZ, CDCI3) & 1.39 (S, 9H) , 4.43 (d, J = 11.7 Hz,
`
`1H) , 4.55 (d, J = 11.7 HZ, 1H) , 5.28 (d, J = 5.5 Hz, 1H),
`5.76 (d, J = 5.5 Hz, 1H) , 7.30 (m, 5H) ; 13C NMR (63 MHz,
`CDCI3) & 27.81, 60.80, 77.03, IB.16, 84.40, 127.73,
`IR (CHCI3)
`128.58, 129.09, 131.55, 147.71, 152.17, 160.34;
`3016, 2976, 1819, 1771, 1732, 1683, 1244 cm"1. Anal.
`Calcd for C17H18C13N06: c, 4 6.54; H, 4.14; N, 3.19. Found:
`C, 46.33 ,* H, 4.34; N, 3.33.
`
`on
`
`00945
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`5
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`
`41
`(3R, 4S) -3-Acetoxy-l-tert-b\iw03Eycarbonyl-4-phenyl
`-2-azetidinone (9b): To a solution of 82 mg (0.3 mmol) of
`l-tert-butylcarbonyl-3-hydroxy-4-phenyl-2-azetidinonef 5
`mg of DMAP and 210 mL (1.5
`mmol)
`of
`
`triethylamine mL
`of dichloromethane, was added at 0oC
`58
`mL
`(0.7
`acetic anhydride. The reaction mixture was stirred
`overnight at room
`temperature. The organic layer
`washed several times
`with
`brine,
`
`dried and
`concentrated. The crude solid was
`
`purified by
`chromatography on
`silica
`gel
`
`to mg (75%) of yield
`
`0-acetyl 0-lactam: White solid; mp 63-640C; [a]D20 +32.1°
`(c 0.81, CHCI3) ; ^ NMR (250 MHz, CDCI3) S 1.37 (s, 9H) ,
`1.65 (s, 3H) , 5.22 (d, J = 5.5 Hz, 1H) , 5.83 (d, J =
`Hz, 1H) , 7.23-7.33 (m, 5H) ; 13C NMR (63 MHz, CDCI3) S
`19.71, 27.81, 60.84, 75.94, 84.07, 127.43, 128.31, 128.67,
`132.44, 147.25, 162.39, 168.83; IR (CHCI3) 3026, 2984,
`1815, 1752, 1731, 1497, 1371, 1286, 1224, 1152, 1024 cm*1.
`Anal. Calcd for C16H19N05: c, 62.94; H, 6.27; N, 4.59.
`Found: C, 63.17; H, 6.14; N, 4.52.
`
`was
`over
`
`71
`
`5.5
`
`Example 54
`To a suspension of NaH (35 mg in 1.0 mL of DME) ,
`was added at -10"C, a solution of 133 mg (0.15 mmol) of
`7,10—ditroc—10—deacetylbaccatin
`III
`
`and mg (0.30 mmol) 100
`
`of 5d in 1.5 mL of DME. The reaction was
`
`monitored by TLC
`and quenched at -80C by addition of brine. The aqueous
`layer was extracted with dichloromethane. The combined
`organic layers were
`
`
`with washed brine, dried over Na2C03
`and concentrated. The crude oil was
`
`purified by
`(1/2)
`chromatography on
`silica
`gel using AcOEt/hexanes
`
`the eluant to
`give
`
`mg 148 of the coupling
`
`product
`2'—EE-7,10-ditroc—Taxotere
`as a white solid (81% yield;
`90% conversion yield)
`
`
`12 and mg of
`7,10—ditroc—10—deacetylbaccatin
`III (10% recovery).
`The EE protecting
`group
`was
`
`removed by stirring
`
`as
`
`00946
`
`

`
`WO 94/18164
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`PCT/US94/00669
`
`42
`
`
`90 2/-EE-7,10-ditroc-TaxotSre mg of
`at room temperature
`
`3 mL of THE
`
`and 2 mL of 0.5N HC1 for 1
`
`hr. The reaction
`mixture was
`diluted
`with dichloromethane. The organic
`
`phase was washed with
`sat.
`
`NaHCC^ brine dried over sol.,
`
`MgS04 and concentrated. The crude
`oil
`was
`purified
`chromatography
`on
`silica
`gel
`using
`the eluant
`to
`give 60 mg (71%) of
`
`white Mp
`
`a
`2'—OH—7,10-ditroc—Taxotere
`as
`154-1550C; [a]D20 -38° (c 0.74, CHC13) ; ^ NMR (250
`MHz,
`CDCI3) & 1.19 (S,
`
`3H) , 1.26 (S,
`
`3H) , 1.35 (s,
`9H),
`1.85
`(S, 3H), 1.95 (S, 3H), 2.04 (m, 1H), 2.34 (m,
`2H), 2.39
`(s, 3H), 2.62 (m, 1H), 3.90 (d, J = 6.4 Hz, 1H), 4.17
`J = 8.4 Hz,
`1H),
`4.32
`
`(d, 1H) , 4.60 (d, J = J
`
`11.9 Hz, 1H), 4.64 (m, 1H),
`4.78
`(s, 4.91 (d, J= 2H).
`
`
`
`
`, 11.9 Hz, 1H) 4.95 (m,
`
`
`1H) , 5.26 (bd, J 8.7 Hz, 1H) , =
`
`5.46 (bd, J
`=
`9.2
`
`HZ, 5.54 (dd, J = 10.4, 7.1 Hz, 1H),
`
`1H), 5.69 (d,
`=
`6.8
`Hz,
`1H), Hz, 1H),
`
`J
`6.24 (s, 1H),
`7.32-7.35
`
`
`
`7.5
`(m, 7.50 (t, J 5H), =
`7.62 (t, J
`=
`
`7.3 1H), 8.10 (d, Hz,
`
`=
`J
`
`7.5 13C
`NMR (63 MHz, CDCI3) S 10.69, 14.63, 20.91, 22.47, 26.25,
`28.14, 33.20, 35.21, 43.07, 46.91, 56.14, 72.17, 73.50,
`74.10, 76.48,
`77.33, 77.51, 78.55, 79.08, 80.23, 80.67,
`83.61, 94.11,
`126.70, 128.06, 128.70, 128.88, 130.12,
`131.91, 133.79, 138.20, 142.48, 153.12, 153.17, 155.36,
`166.82, 170.33, 172.78, 200.70;
`IR
`
`(CHCI3) 3444, 3572,
`
`3034, 2979, 1759, 1737, 1724, 1490, 1450, 1376, 1106 cm-1.
`
`(d,
`
`Bgamplfi 5 5
`To a solution
`of 9 0 mg (0.1 mmol) of 7,10-
`mg (0.14 mmol) of 5d
`ditroc-10-deacetylbaccatin
`III
`and
`47
`in 5 mli of THF, was added at -30oC
`110 mL
`(0.11
`mmol,
`of sodium hexamethyldisilazide.
`The reaction
`was
`in THF)
`The
`monitored by TLC and quenched by addition of brine.
`The
`aqueous layer was
`
`extracted with dichloromethane.
`combined organic layers were washed with brine, dried over
`
`5
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`
`
`
`3H),
`),
`
`43
`Na2C03 and concentrated. The crude oil was purified by
`chromatography on silica
`gel
`using
`AcOEt/hexanes
`the eluant to give 117 mg of the
`coupling
`product
`7,10—ditroc—TAXOTERE
`as a white solid (94%). All physical
`and spectral data are
`
`with identical those of 2,-EE-7,10-
`
`ditroc-TAXOTERE
`described
`in Example 54.
`
`removed
`was
`The Troc protecting
`group
`stirring at 60oc 50 mg of 7,10-ditroc-TAXOTi£RE in 1 mL of
`MeOH and 1
`
`mL of AcOH in presence
`
`
`mg of 150 of zinc for 1
`with
`hr. The reaction mixture was filtrated and diluted
`with
`dichloromethane. The organic phase
`was
`washed
`NaHC03 sol., brine dried over MgS04 and concentrated. The
`crude oil was purified
`by
`
`chromatography on silica gel
`using AcOEt/hexanes
`
`(1/1) the eluant to give 28 mg as
`
`{80%) of TAXOTERE as
`a
`white
`solid: [cr]D20 -34° (c 0.7,
`
`EtOH) ; NMR (250 MHz, CDCI3) S 1.13 (S,
`
`3H) , 1.26 (s,
`3H) ,
`1.35 (s, 9H), 1.80
`(s, 3H) , 1.85 (m, ), 1.90
`
`(S,
`(m, 2H), 2.39 (s, 3H), 2.55 (m, )# 2.62 (m, ), 3.53 (S,
`
`3.92 (d, J = 7.0 ), 4.18 (d, J = 8.4 Hz, ), 4.22 Hz,
`
`(m,
`), 4.32 (d, J = 8.4 HZ, ), 4.66 (d, J = 6.9 Hz, ), 6.19
`(bt, J = 8.1
`
`Hz, ), 7.32-7.35 (m, 5H), 7.50 (t, J = 7.5
`Hz, 2H) , 7.62 (t, J = 7.3 Hz, ), 8.10 (d, J = 7.5 Hz, 2H) .
`
`These data are consistent with those reported
`for
`TAXOTfiRE
`by Mangatal, L. et al. (Ref.
`Mangatal,
`L.; Adeline, M.T.;
`
`Guenard, D.; Gueritte-Voegelein,
`F.;
`Potier,
`P.
`Tetrahedron 1989, 45, 4177.)
`in
`described
`been
`has
`Although the invention
`conjunction with specific
`
`embodiments, is evident that it
`
`many alternatives
`and variations will
`be apparent
`to
`skilled in the art in light of the
`foregoing
`description.
`Accordingly, the
`invention
`is
`intended
`to
`the alternatives
`and variations
`that
`fall
`claims. The above
`spirit and scope
`of the
`appended
`references are hereby
`incorporated
`by
`
`within
`
`reference.
`
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`00948
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`

`
`WO 94/18164
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`PCT/US94/00669
`
`We Claim:
`1.
`
`in which
`
`formulri;
`
`44
`
`A 6-lactam of the
`G.O
`
`^R3-P o'
`R2/ r
`
`RRN-
`or
`RS-
`R2» represents an RO-,
`represents an unsubstituted or substituted straight chain
`or branched alkyl, alkenyl or alkynyl, cycloalkyl,
`heterocycloalkyl,
`cycloalkenyl,
`heterocycloalkenyl,
`a hydrogen or R as
`carbocyclic aryl
`or
`heteroaryl;
`is
`defined above;
`
`R and R' can be connected
`to
`form
`structure;
`R3. represents an unsubstituted
`or
`straight or
`branched
`
`alkyl, alkenyl or alkynyl
`unsubstituted or
`substituted
`cycloalkyl,
`radical, an
`unsubstituted
`or
`substituted
`
`Gj represents a hydrogen or a hydroxy 1
`protecting group;
`Y is oxygen or sulfur.
`
`a cyclic
`
`substituted
`radical,
`cycloalkenyl
`carbocyclic
`
`to claim 1 in which
`A B-lactam according
`2 .
`
`RO-, RS- or RR'N- in
`R2' represents a radical
`or
`
`branched alkyl
`which R represents a straight chain
`radical containing
`
`
`to 1 10 carbon atoms, a straight chain
`or branched alkenyl
`radical
`containing
`2
`atoms, or a straight chain or branched alkynyl
`radical
`containing 2 to
`
`10 carbon atoms, a cycloalkyl radical
`containing 3 to 10 carbon atoms, a heterocycloalkyl
`radical containing
`3 to 10 carbon atoms,
`a cycloalkenyl
`radical containing
`3 to 10 carbon atoms,
`a
`heterocycloalkenyl
`radical
`
`containing to 10 carbon 3
`
`
`
`to
`
`5
`
`10
`
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`00949
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`WO 94/18164
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`PCT/US94/00669
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`a
`
`radicals,
`
`2-10
`
`45
`atoms, a polycyclo^.lkyl radical
`to
`6
`containing
`carbons,
`atoms, an aryl radical containing 6 to
`20
`atoms; these
`heteroaryl radical
`
`containing to 15 carbon 3
`
`or
`radicals being optionally substituted
`with one
`amino,
`halogen, hydroxy1,
`alkoxy, aryloxy, heteroaryloxy,
`alkylamino, dialkylamino,
`mercapto, alkylthio, arylthio,
`heteroarylthio, cyano,
`carboxyl,
`alkoxycarbonyl
`the alkyl portion of which contain 1 to 15 carbon atoms,
`aryloxycarbonyl the aryl portion of
`which
`
`containing 6 to
`20 carbon atoms,
`or
`
`heteroaryloxycarbonyl the heteroaryl
`portion of which
`containing
`3 to
`15
`carbon is a
`
`hydrogen or R
`as
`defined
`
`R above; can be connected and
`
`
`to form a cyclic
`structure
`which
`contains
`atoms;
`
`alkynyl
`
`branched
`or
`chain
`R3, represents a straight
`straight
`a
`alkyl radical
`
`containing to 10 carbon atoms, l
`
`chain or branched
`alkenyl
`radical
`
`containing 10
`carbon atoms, or a straight chain or
`branched
`radical containing
`2 to
`10
`carbon
`atoms,
`a
`3 to 10 carbon atoms,
`cycloalkenyl
`radical containing
`a
`radical containing
`3 to 10 carbon atoms,
`polycycloalkyl
`radical containing
`6
`to
`
`20 atoms, or an aryl carbon
`
`radical containing
`
`2 6 to 0 carbons; these radicals being
`
`optionally substituted
`
`
`one with or more halogen,
`hydroxyl,
`alkoxy, aryloxy, heteroaryloxy, amino, alkylamino,
`dialkylamino, mercapto,
`
`alkylthio, arylthio,
`heteroarylthio, cyano,
`radicals,
`
`carboxyl, alkoxycarbonyl
`the alkyl portion
`of which contain 1 to 15 carbon atoms,
`aryloxycarbonyl the
`aryl
`
`portion of which contain 6 to 20
`carbon atoms, or heteroaryloxycarbonyl
`the
`heteroaryl
`portion of which containing 3 to 15 carbon
`atoms.
`
`A jS-lactam according
`claim l in which
`
`to
`3 .
`R2 represents an R0-, RS-, or RR'N- in which R
`is an unsubstituted or substituted alkyl radical
`selected
`from methyl, ethyl, propyl, isopropyl, butyl, isobutyl.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`00950
`
`

`
`WO 94/18164
`
`PCT/US94/00669
`
`46
`tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,
`heptyl, isoheptyl, octyl, isooctyl, cyclopropyl,
`cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
`or
`cyclooctyl, 9-fluorenylmethyl, benzyl and adamantyl,
`alkenyl radical selected
`from
`
`vinyl and allyl, or an aryl
`radical selected from
`
`phenyl naphthyl, or a heteroaryl and
`
`radical selected from
`furyl,
`
`and pyrrolyl, pyridyl, or a
`
`cycloalkenyl radical selected from cyclopentenyl,
`cyclohexenyl and cycloheptenyl,
`
`a or heterocycloalkyl
`
`radical selected from
`an
`oxiranyl,
`tetrahydrofuryl,
`pyrrolidinyl, piperdinyl, tetrahydropyranyl, or a
`dihydrofuryl,
`heterocycloalkenyl
`radical
`selected
`from
`R' is a
`dihydropyrrolyl, dihydropyranyl, dihydropyridyl;
`hydrogen or R as defined above;
`cyclic
`RR'N-
`includes aziridino, azetidino, pyrrolidine, piperidino
`morpholino group;
`R3f is an unsubstituted or substituted
`radical selected from
`
`methyl, ethyl, propyl, isopropyl,
`butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl,
`hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl,
`cyclohexylmethyl,
`cyclohexylethyl, benzyl, phenylethyl,
`cyclopropyl, cyclobutyl,
`
`cyclopentyl, cyclohexyl,
`cycloheptyl, cyclooctyl,
`
`9-fluorenylmethyl, benzyl and
`adamantyl, or an
`alkenyl
`radical
`selected
`alkynyl radical
`selected
`allyl, 2-phenylethenyl,
`or
`an
`from ethynyl and
`propargyl
`or
`an
`aryl
`from phenyl and naphthyl, or a cycloalkenyl
`radical
`selected from cyclopentenyl, cyclohexenyl and
`cycloheptenyl;
`Gj represents a hydrogen or a group protecting
`the hydroxyl function
`
`
`from selected methoxylmethyl
`(MOM),
`methoxyethyl (MEM),
`1-ethoxyethyl (EE), benzyloxymethyl,
`(£-trimethylsilylethoxyl) , methyl, tetrahydropyranyl,
`2,2,2—trichloroethoxylcarbonyl (Troc),
`benzyloxycarbonyl
`(CBZ), tertbutoxycarbonyl (t-BOC), 9-
`fluorenyImethoxycarbony1
`(Fmoc),
`
`radical
`or
`
`alkyl
`
`from
`
`radical
`
`2,2,2-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`00951
`
`

`
`WO 94/18164
`
`PCT/US94/00669
`
`which
`R
`
`47
`trichloroethoxymethyl,
`trimethylsilyl f triethylsilyl,
`tripropylsilyl, dimethylethylsilyl, dimethyl(t-
`butyl)silylf diethylmethylsilyl,
`dimethylphenylsilyl,
`diphenylmethylsilyl,
`acetyl, chloroacetyl, dichloroacetyl,
`trichloroacetyl and trifluoroacetyl.
`
`A /3-lactam according to
`in
`claim 1
`4.
`which
`Y is oxygen and R2< represents R0-
`in
`a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-
`butyl, neopentyl, cyclohexyl, phenyl, benzyl, or 9-
`fluorenylmethyl; R3. is a phenyl, tolyl, 4-methoxyphenyl,
`3,4—dimethoxyphenyl,
`4-fluorophenyl,
`4-
`trifluoromethylphenyl,
`1-naphthyl,
`2-phenylethenyl;
`G1 is a hydrogen, 1-ethoxyethyl (EE),
`2,2,2-
`trichloroethoxylcarbonyl
`(Troc),
`trimethylsilyl,
`triethylsilyl or acetyl.
`
`A 0-lactam according to claim 1 in which
`5.
`Y is oxygen and R2» is a methylamino,
`ethylamino, propylamine, isopropylamino, butylamino,
`isobutylamino, tert-butylamino,
`neopentylamino,
`benzylamino,
`cyclohexylamino, phenylamino
`or
`dimethylamino, diethylamino,
`
`dipropylamino, dibutylamino,
`dipentylamino, dihexylamino,
`dicyclohexylamino,
`methyl(tert-butyl)amino,
`cyclohexyl(methyl)amino,
`methyl(phenyl)amino,
`pyrrolidine, piperidino or morpholino
`group;
`
`Gj is a hydrogen, 1-ethoxyethyl (EE),
`2,2,2-
`trichloroethoxycarbonyl
`(Troc),
`trimethylsilyl,
`triethylsilyl or acetyl.
`
`•
`
`6
`
`A /3-lactam according to claim l in which
`Y is sulfur and R2< represents R0- in which R is
`a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-
`butyl, neopentyl, cyclohexyl, phenyl, benzyl or 9-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`00952
`
`

`
`WO 94/18164
`
`PCT/US94/00669
`
`48
`fluorenylmethyl;
`a phenyl, tolyl, 4-inethGxyphenyl,
`R3. ir
`
`3,4 —dimethoxypheny 1, 4-t'luorophenyl, 4-
`trifluoromethylphenyl,
`l-naphthyl, 2-naphthyl;
`2,2,2-
`Gj is a hydrogen, 1-ethoxyethy1 (EE),
`trichloroethoxylcarbonyl
`(Troc),
`trimethylsilyl,
`triethylsilyl
`or acetyl.
`
`which
`
`in
`1
`claim
`A /3-lactam according to
`7.
`Y is sulfur and R2 is a methylamino, ethylamino,
`propylamine, isopropylamino, butylaxnino, isobutylamino,
`tert-butylamino,
`neopentylamino,
`cyclohexylamino,
`phenylamino, or benzylamino, dimethylamino,
`diethylamino,
`dipropylamino, dibutylamino,
`
`dipentylamino, dihexylamino,
`dicyclohexylamino, methyl(tert-butyl)amino,
`cyclohexyl(methyl) amino, methyl(phenyl)amino,
`piperidino, or
`morpholino
`group;
`(EE),
`is a hydrogen, 1-ethoxyethyl
`trichloroethoxylcarbonyl
`(Troc),
`trimethylsilyl,
`triethylsilyl
`or acetyl.
`
`pyrrolidine,
`
`2,2,2-
`
`A /3-lactam according to
`1
`claim
`8 .
`in which
`Y is oxygen, 1*2- represents RO-
`methyl, ethyl, butyl, tert-butyl, phenyl or benzyl and R2
`is a phenyl, 2-phenylethenyl, cyclohexylmethyl or
`isobutyl;
`
`in
`R
`
`which
`
`Y is oxygen, R2» is an ethylamino,
`tert-
`butylamino, phenylamino, benzylamino, dimethylamino
`
`morpholino group, and R3- is a phenyl;
`Y is sulfur, R2' is
`a
`
`or morpholino group, R3r is a phenyl;
`2,2,2-
`Gj is a hydrogen or 1-ethoxyethyl (EE),
`trichloroethoxylcarbonyl
`(Troc)
`or
`acetyl.
`
`or
`
`phenylamino, dimethylamino
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`A. process for the
`9.
`derivative of the
`formula
`
`
`
`of preparation a taxane
`
`
`
`00953
`
`

`
`WO 94/18164
`
`-49-
`
`PCT/US94/00669
`
`Y A
`
`R 2
`
`NH O
`
`MB
`
`O O R 4
`
`10
`
`7
`
`>•
`13
`
`o
`
`HO
`
`O
`
`o
`o
`"tr
`o
`
`R3
`
`i S '
`0R5
`
`5
`
`10
`
`15
`
`2 0
`
`. 25
`
`in which
`
`Rj represents a hydrogen or an acyl or an alkyl
`
`or an alkenyl or an alkynyl or an aryl or a heteroaryl
`radical or a hydroxy1 protecting group;
`R2 represents an RO-, RS- or RR'N- in which R
`represents an unsubstituted or substituted straight chain
`or branched alkyl, alkenyl or aklynyl, cycloalkyl,
`heterocycloalkyl, cycloalkenyl, heterocycloalkenyl,
`aryl
`or heteroaryl; R'
`
`is a hydrogen or R defined above; R and
`R7 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 or alkynyl
`radical, an unsubstituted or substituted cycloalkyl,
`cycloalkenyl or an unsubstituted or substituted
`carbocyclic aryl;
`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
`heterocycloalkenyl
`radical, an unsubstituted or
`substituted aryl or heteroaryl radical, or a hydroxyl
`group protecting group;
`R5 represents a hydrogen or a 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 aryl or heteroaryl radical, or a hydroxyl
`
`or
`
`
`
`
`
`SUBSTITUTE SHEET (RULE 26)
`
`00954
`
`

`
`WO 94/18164
`
`PCT/US94/00669
`
`protect ing group;
`which comprises
`
`reaching a |3-lactaxn of the formula
`
`50
`
`G-iQ
`
`R
`3"
`
`\ P R2.. Y
`
`O
`
`Y
`
`5
`
`10
`
`15
`
`in which
`
`Y is defined above; Gl represents an hydroxy!
`protecting group;
`R2» represents a radical R2 defined above or a
`protected R2 whenever R2 includes one or more active
`hydrogens,
`R3- represents a radical R3 defined above or a
`protected R-j whenever R3 includes one or more active
`hydrogens;
`of the formula:
`with a baccatin III derivarive
`
`O OG3
`
`G2O
`
`'13
`MO**
`
`10
`
`o
`
`o 0
`
`HO 0< V Q"
`
`in which M is an alkali metal or alkaline earth metal atom
`(ion);
`
`G-. represenrs a hydroxyl protecting group 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
`SUBSTITUTE SHEET (RULE 26)
`
`00955
`
`

`
`group
`
`9,
`
`atoms,
`10
`
`WO 94/18164
`
`PCT/US94/00669
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`51
`unsubstituted or substituted aryl or heteroaryl -radical;
`G3 represents ^ hydroxyl group protecting
`
`
`an or an acyl radical or unsubstituted or substituted
`straight chain or branched radical
`alkyl, alkenyl or
`
`alkynyl radical, an unsubstituted or substituted
`cycloalkyl, heterocycloalkyl,
`cycloalkenyl,
`or
`heterocycloalkenyl radical,
`an unsubstituted
`substituted aryl or
`heteroaryl.
`claim in which
`
`to
`The process according
`1 0 .
`
`
`RS-, R0-, or RR'N- in
`R2 represents a
`radical
`which R represents a straight chain or branched alkyl
`radical containing 1
`to
`10
`carbon
`or branched alkenyl radical
`containing
`2
`
`to carbon
`atoms, or a straight chain or branched alkynyl radical
`containing 2 to 10
`
`carbon atoms, a cycloalkyl radical
`
`containing 3 to 10 carbon atoms, heterocycloalkyl a
`
`radical containing 3 to
`10
`carbon
`atoms,
`radical containing 3 to 10 carbon atoms,
`a
`heterocycloalkenyl
`radical
`
`3 containing to 10 carbon
`
`atoms, a polycycloalkyl radical
`
`containing to 20 carbon 6
`
`atoms, an aryl radical
`containing
`6
`to
`heteroaryl radical containing 3 to 15 carbon atoms; these
`radicals being optionally substituted with one or more
`halogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, amino,
`alkylamino, dialkylamino, mercapto, alkylthio, arylthio,
`heteroarylthio, cyano,
`
`carboxyl, alkoxycarbonyl the
`portion of which contains 1
`
`to 15 carbon atoms,
`aryloxycarbonyl the
`aryl
`portion
`of containing 6 to which
`
`
`20 carbon atoms, or
`heteroaryloxycarbonyl
`the
`portion of which containing
`3 to 15 carbon atoms;
`R'
`hydrogen or R defined above; R and R' can form a cyclic
`2-10
`carbon
`atoms;
`structure which contains
`R3 represents a straight chain or branched alkyl
`radical containing
`1
`to
`10
`atoms, carbon straight chain
`
`
`or branched alkenyl radical
`
`
`containing to 10 carbon 2
`
`a
`
`20
`
`alkyl
`
`is
`
`00956
`
`

`
`WO 94/18164
`
`PCT/US94/00669
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`52
`
`atoms/ or a straight chain
`or branched alkynyl radical
`containing 2 to
`10
`carbon
`atoms, cycloalkyl radical a
`
`
`
`
`containing 3 to 10 carbon atoms, cycloalkenyl radical a
`
`containing 3 to 10 carbon atoms, polycycloalkyl radical a
`
`containing 6 to
`20
`carbon
`atoms,
`an
`aryl
`these radicals being
`containing 6 to
`20
`carbons;
`optionally
`substituted with one or more halogen, hydroxy 1,
`alkoxy, aryloxy, heteroaryloxy, amino, alky1amino,
`dialkylamino, mercapto,
`alkylthio, arylthio,
`alkoxycarbonyl, alkyl
`heteroarylthio, cyano,
`carboxyl,
`
`portion of which containing
`1
`to
`15
`to
`aryloxycarbonyl, the
`aryl
`portion
`of
`which
`20 carbon atoms, or
`heteroaryloxycarbonyl
`the
`portion of which containing 3 to 15 carbon atoms;
`Rj- represents a radical
`Rj defined above or a
`protected
`whenever Rj includes one
`or
`more
`active
`hydrogens;
`R3* represents a radical defined above
`
`R3
`protected R3 whenever R3 includes one
`or
`more
`hydrogens.
`
`a
`or
`active
`
`R
`radical
`
`11.
`to claim 9, wherein
`
`The process according
`Rj represents an
`RO-,
`
`RS-, or RR'N- in which
`is an unsubstituted
`or
`substituted
`alkyl
`from methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
`tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,
`hep-cyl, isoheptyl, octyl, isooctyl, cyclopropyl,
`cyclobutyl, cyclopentyl,
`
`cyclohexyl, cycloheptyl,
`cyclooctyl, and adamantyl, or an alkenyl radical
`selected
`from vinyl and allyl, or an aryl radical
`selected
`from
`phenyl and naphthyl, or a heteroaryl radical
`selected
`from
`furyl, pyrrolyl, and pyridyl, or a cycloalkenyl radical
`selected from cyclopentenyl, cyclyhexenyl and
`radical
`cycloheptenyl, or a heterocycloalkyl
`an oxiranyl, tetrahydrofuryl,
`pyrrolidinyl, piperidinyl.
`
`selected
`
`00957
`
`

`
`WO 94/18164
`
`PCT/US94/00669
`
`radical
`
`hydrogen
`
`an
`an
`
`and
`
`R2 defined above or
`one
`or
`
`a
`more
`
`53
`tetrahydropyranyl,
`cr a hGterocycloalkenyl
`selected from dihydrofuryl, dihydropyrrolyl,
`R
`a
`is
`dihydropyranyl, dihydropyridyl;
`R'
`aziridino,
`defined above;
`cyclic RR'N- radical includes
`azetidino, pyrrolidine, piperidino or
`morpholino
`group;
`R3 is an unsubstituted or substituted alkyl
`radical selected
`from
`
`methyl, ethyl, propyl, isopropyl,
`butyl, isobutyl,
`tert-butyl,
`
`pentyl, isopentyl, neopentyl,
`hexyl, isohexyl,
`heptyl,
`isoheptyl,
`
`octyl, isooctyl,
`cyclohexylmethyl,
`cyclohexylethyl,
`
`benzyl, phenylethyl,
`cyclopropyl, cyclobutyl,
`cyclopentyl,
`cyclohexyl,
`cycloheptyl, cyclooctyl,
`and adamantyl, or an
`alkenyl
`radical selected
`from
`vinyl,
`allyl
`or
`aryl radical
`selected from
`ethynyl
`and
`propargyl
`or
`selected from phenyl and naphthyl,
`
`or cycloalkenyl a
`
`radical selected from cyclopentenyl, cyclohexenyl
`cycloheptenyl.
`R2" represents a radical
`protected Rj wherever
`R2 includes
`hydrogens;
`a
`defined above or
`R3» represents a radical
`R3
`protected R3 wherever R3 includes one or
`more
`active
`hydrogens;
`the
`protecting
`Gj represents a group
`
`function selected
`from
`methoxylmethyl
`(MOM), methoxyethyl
`(MEM), 1-ethoxyethyl
`(EE),
`benzyloxymethyl,
`(£-
`trimethylsilyl-ethoxyl)-methyl,
`tetrahydropyranyl,
`trichloroethoxylcarbonyl
`(Troc),
`benzyloxycarbonyl
`tert-butoxycarbonyl
`(t-BOC),
`9-fluorenylmethoxycarbonyl
`(Fmoc), 2,2,2—trichloroethoxymethyl,
`trimethylsilyl,
`triethylsilyl,
`tripropylsilyl,
`dimethylethylsilyl,
`dimethyl(t-butyl)silyl,
`diethylmethylsilyl,
`acetyl,
`dimethylphenylsilyl
`and diphenylmethylsilyl,
`chloroacetyl, dichloroacetyl,
`trichloroacetyl
`trifluoroacetyl;
`
`hydroxyl
`
`2,2,2-
`
`and
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`00958
`
`

`
`WO 94/18164
`
`PCT7US94/00669
`
`5
`
`10
`
`15
`
`20
`
`25
`
`54
`G2 represents an acetyl or a 2,2,2-
`trichloroethoxycarbonyl
`(Tzoc)
`group;
`G3 represents a 2,2, 2-trichloroethoxycarboriyl
`(Troc) or silyl
`group
`
`from selected trimethylsilyl,
`
`triethylsilyl, tripropylsilyl,
`dimethylethylsilyl,
`dimethylphenylsilyl,
`dimethyl(t-butyl)silyl,
`diethylmethylsilyl
`and diphenylmethylsilyl.
`
`12.
`The process according
`is an alkali metal.
`
`
`
`to claim 9, wherein
`
`M
`
`13 .
`The process according
`M is an alkali
`metal
`selected
`potassium.
`
`claim
`to
`
`from sodium and lithium,
`
`
`10,
`
`14.
`The process according
`M is sodium or potassium.
`
`
`
`to claim 11, wherein
`
`15.
`11
`claim
`to
`The process according
`Rj is a hydrogen, an acetyl or an
`trichloroethoxycarbonyl
`
`or
`(Troc) ; R4 is a hydrogen, a triethylsilyl a
`trichloroethoxycarbonyl
`
`(Troc); is a hydrogen, a R5
`
`triethylsilyl or
`ethoxyethyl.
`16.
`claim 11 wherein
`
`to
`The process according
`
`
`methyl, a is ethyl, propyl,
`
`R2 represents RO-
`in
`which
`R
`neopentyl,
`isopropyl, butyl, isobutyl, tert-butyl,
`cyclohexyl, phenyl, benzyl or 9-fluoroenylmethyl;
`R3 is a
`
`phenyl, tolyl,
`4-methoxyphenyl, 3,4-dimethoxyphenyl,
`4-
`fluorophenyl, 4-trifluoromethylphenyl,
`
`1-naphthyl, 2-
`naphthyl and 2-phenylethenyl;
`
`R5 is a hydrogen.
`
`17.
`The process according to claim 11 wherein
`R2 is a methylamino, ethylamino, propylamine,
`isopropylamino, butylamino, isobutylamino, tert-
`
`00959
`
`

`
`"WO 94/18164
`
`PCT/US94/00669
`
`55
`butylamino, neopentylamino, cyclohexylamino, phcnylaiaino
`or bemzylamino, dimethylaxnino or morpholino group;
`Rj is
`hydrogen.
`
`a
`
`5
`
`The process according
`^
`claim
`to
`1 8 .
`is a hydrogen or a acetyl; R2 (= R2") is tert-butoxy
`or
`tert-butylamino;
`R3 (= R3") is a phenyl; Y is oxygen? R4 is
`a hydrogen; R5 is a hydrogen; Gi is an ethoxyethyl,
`triethylsilyl or trichloroethoxycarbonyl
`(Troc); M is
`sodium or potassium.
`
`9
`
`00960
`
`

`
`INTERNATIONAL SEARCH REPORT
`
`jnai Application No
`Inte
`PCT/US 94/00669
`
`A. CLASSIFICATION OF
`IPC 5 C07D205/08
`
`MATTER
`SUBJECT
`C07D305/14
`
`According to International Patent
`B. FIELDS SEARCHED
`Minimum documentation
`IPC 5
`C07D
`
`Classification
`
`
`
`(IPC) both national clasafication and IPC or to
`
`
`
`
`
`searched (classification system followed by classification symbols)
`
`Documentation searched other
`
`than
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`minimum
`
`
`
`documentation to the extent that
`
`such documents
`
`are
`
`included
`
`in
`
`the
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`fields
`
`searched
`
`Electronic data
`
`
`
`
`
`the base consulted during international search (name
`
`of
`
`data
`
`
`
`
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`where and, base practical, search terms used)
`
`
`
`
`
`TO RELEVANT BE
`
`
`C. DOCUMENTS CONSIDERED
`Category" Citation of document, with indication, where appropriate, of the
`
`relevant passages
`
`Relevant to
`
`claim No.
`
`X
`
`TETRAHEDRON, (INCL. TETRAHEDRON REPORTS)
`vol. 48, no. 34 , 1992 , OXFORD GB
`7012
`pages 6985
`I. OJIMA ET AL.
`I New and efficient
`approaches to the semisynthesis of taxol
`and its C-13 side chain analogs by means
`of beta-lactam synthon method'
`cited in the application
`see the whole document
`
`1-18
`
`m
`
`* Special categories of
`
`cited documents
`
`:
`
`Further documents are
`
`listed
`
`in
`
`
`
`continuation the box C.
`
`
`
`of
`| ^ | Patent family members are
`
`
`
`listed in annex.
`
`the international
`after
`later document published
`T'
`conflict with
`in
`or priority date and not
`is
`not
`which
`theory
`bted to understand
`the
`principle or
`invention
`international
`claimed
`the
`relevance;
`*X' document of particular
`cannot
`cannot be considered novel or
`
`be to
`involve an
`inventive step when the
`document
`'Y* document of particular
`relevance;
`the
`claimed
`cannot be considered to
`involve an
`inventive
`use, exhibition
`or
`document is combined with one or
`more
`ments, such combination being
`obvious
`to
`a
`in the art.
`but
`patent
`document memuer of the same
`Date of mailing of the
`
`international search report
`2 8.
`S1!
`
`the general
`document defining
`considered to be of particular
`earlier document but
`published
`filing date
`priority on claim(s) or
`
`
`doubts
`throw
`document which may
`
`publication another
`date
`the
`establish
`which is dted
`to
`specified)
`citation or other
`special
`reason
`(as
`document referring
`to
`an
`oral
`disclosure,
`other means
`to
`document published prior
`later than the priority date
`Date of the actual completion of
`the
`
`of
`state
`relevance
`on
`or
`
`the