CA2264527A1 - Process to prepare pharmaceutical compounds - Google Patents

Process to prepare pharmaceutical compounds Download PDF

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Publication number
CA2264527A1
CA2264527A1 CA002264527A CA2264527A CA2264527A1 CA 2264527 A1 CA2264527 A1 CA 2264527A1 CA 002264527 A CA002264527 A CA 002264527A CA 2264527 A CA2264527 A CA 2264527A CA 2264527 A1 CA2264527 A1 CA 2264527A1
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alkyl
hydrogen
phenyl
substituted
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French (fr)
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Eric David Moher
Michael John Martinelli
Andrew Hendley Fray
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University of Hawaii
Wayne State University
Eli Lilly and Co
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

This invention provides novel cryptophycin compounds and a process for preparing cryptophycin compounds.

Description

101520253035W0 98/09601CA 02264527 1999-03-02PCT/US97/1 5668_1..PROCESS TO PREPARE PHARMACEUTICAL COMPOUNDSThis invention relates to the fields ofpharmaceutical and organic chemistry and provides a processfor preparing cryptophycin compounds useful as anti-microtubule agents.Cryptophycin compounds can be useful for thetreatment of cancer and neoplasms, and are thus usefulpharmaceutical agents.The literature discloses a protocol for cyclizingcertain cryptophycin compounds. Barrow, R. Al; Hemscheidt,T.; Liang, J.; Paik, S.; Moore, R. E.; Tius, M. A. J.Am. Chem. Soc. 1995, 117, 2479. This three—step sequence(hereinafter "Barrow synthetic sequence") commenced with theconversion of trichloroethyl ester to the correspondingcarboxylic acid using zinc and acetic acid. Conversion ofcrude to the amino carboxylate was accomplished withtrifluoroacetic acid followed by an aqueous basic work—up.In the final step, ring closure was achieved in the presence(FDPP) in N, N-dimethylformamide to provide the desired product 3 (3 isillustrated infra.of pentafluorophenyldiphenylphosphinatein Scheme 1 to provide furtherclarification) (61% after chromatography).In contrast, the presently claimed processprovides a shorter (two—steps) process which is moreadaptable for large scale or commercial preparation of themacrocyclic core of cryptophycin derivatives. The claimedprocess can reduce reagent expense, as well as minimize thepotential waste-stream issues associated with the use ofcertain reagents in the Barrow synthetic sequence. Further,purification via the claimed process may be accomplishedwithout chromatography, which is expensive and difficult toimplement on a large scale.The presently claimed invention provides a processfor preparing a compound of Formula II101520CA 02264527 1999-03-02W0 98/09601 PCT/US97/15668_2_R? $5R4Ar |AVO18 | 16 14O X. HIJ Rb3 R50 R11 R3 0R9 </)\\DJR1 0 R7 R8 H 0whereinAr is selected from the group consisting of phenyl, anysimple unsubstituted aromatic, simple substituted aromatic,substituted heteroaromatic group, unsubstitutedC]‘C12 3.]. , C2‘C12alkenyl, C2—C12 alkynyl, NR51R52, COR52, OR53, and Formula Ar’I ’\heteroaromatic group, heterocyclic, R56R5 5R54 Ar ' ;R“ is selected fromC3 alkyl;the group consisting of hydrogen and C1-R” is selected from theC3 alkyl;group consisting of hydrogen and C1-thethe consisting of hydrogen,alkyl, C1—C6alkyl(R57'R57"R57'”), simple unsubstitutedaromatic,R“ is selected from group consisting of C1—Cu alkyl;R“ is selected from group C1-C6simple substituted aromatic, heterocyclic, phenyl,halogen, 4-(tert—butyldimethylsiloxy)—benzyltriphenylphosophonium, COORW, PO3H, SO3H, SOfi9B,N(R59)R6°, NHOR61, NHCHRG1’, CN, NO2, halogen, OR“, cH2(o)R62’, —RmIC3KcH2oc (0) R95, CHZN (R96) R96’ , coR1°°, (C1-Cgalkyl) oR1°°, ,SR63;1015202530W0 98/09601CA 02264527 1999-03-02PCT/U S97/ 15668-3-R% is selected from the group consisting of -R%NH3;R” and R%' are each independently selected from the groupconsisting of hydrogen and C1-C6 alkyl, -RWNH3, and —R” NR”'99!! .IW is selected from the group consisting of Cy%x alkyl;99 is C1-C6 alkyl;RR” is selected from the group consisting of Crfix alkyl;RR“" and R9?’are each independently selected from the groupconsisting of hydrogen and Cyflk alkyl;Rwo is selected from the group consisting of hydrogen, andSi (R‘°1R“’2R1°3) ,-R10‘ is c1—c6 alkyl;RN” is C1-C5 alkyl;RN3 is C1-C5 alkyl;Rm‘ is selected from the group consisting of C(O)C1-C6alkylN(R1°6) (R59)R6°, c(o)c1—c6 alkylN*,NHR105N (R106) (R59) R60;fused bicyclic, andR”” is selected from the group consisting of C(O)C1—C6 alkyl,C1'C5 alkyl;R106 isselected from the group consisting of hydrogen, C1-C6alkyl, c(o)oR“’7;Rw7 is selected from the group consisting of hydrogen, C1-C6alkyl, cR1°8 R109 R1”Rmg is selected from the group consisting of hydrogen andC1-C6 alkyl;R“” is selected from the group consisting of hydrogen andC1‘Cg alkyl;R”° is selected from the group consisting of hydrogen andCywx alkyl;R“ is selected from the group consisting of hydrogen, C1-C5alkyl, c(R57’R“"R57"'),substituted aromatic, phenyl, COOR“, Pofib SOJL SOJVWNR59R“°, NHOR6‘, NHCHR6", CN, N02, halogen, OR62, and SR63;simple unsubstituted aromatic, simple1015202530WO 98/09601CA 02264527 1999-03-02PCT/U S97/ 15668-4-R“ is selected from the group consisting of hydrogen, C1-C6alkyl, C(R5"R5W'R“”'), simple unsubstituted aromatic, simplesubstituted aromatic, phenyl, COOR”, POJL SCgH, sogfie,NR59R6°, NHOR6‘, NHCHR61’, (C1-C6)alkylNR59R6O, CN, NO2, halogen,OR1°4, CR1“, OR62, and SR“;R“ is selected from the group consisting of hydrogen and C1-Cn alkyl;Rm’ is selected from the group consisting of hydrogen,halogen, and C1—Cn alkyl;Raw‘ is selected from the group consisting of hydrogen,halogen, and C1-Cm alkyl;R"”' is selected from the group consisting of hydrogen,halogen, and C1-Cm alkyl;R” is selected from the group consisting of hydrogen and C1-Cm alkyl;R” is selected from the group consisting of hydrogen,C6) alkyl,and fluorenylmethoxycarbonyl(C1‘tert-butoxycarbonyl, carbo—tert—butoxy (t—BOC)(FMOC);R“ is selected from the group consisting of hydrogen and(C1-C6) alkyl;R“ is selected from the group consisting of hydrogen, OR“,CEQNHR“, NHRFE and fluorenylmethoxycarbonyl (FMOC);Rm’ is selected from the group consisting of hydrogen, OR“,CEQNHR“, NHR“' and fluorenylmethoxycarbonyl (FMOC);R“ is selected from hydrogen, and C1-C6 alkyl;R”' is selected from hydrogen, OH, OR“, and C1-C6 alkyl;R“ is selected from hydrogen and C1-C6 alkyl;R“ is selected from the group consisting of hydrogen,C6) alkyl, CH2NR66R67;(C1-R“ is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, (FMOC);R“' is selected from the group consisting of hydrogen andC1-C6 alkyl, NH2, (EMOC);and fluorenylmethoxycarbonyland fluorenylmethoxycarbonyl 10152025W0 98/09601CA 02264527 1999-03-02PCT/US97ll5668_5._R“ is selected from the group consisting of hydrogen and C1-(FMOC);R“ is selected from the group consisting of hydrogen and Cr‘C5 alkyl;C5 alkyl and fluorenylmethoxycarbonylR3 is a lower alkyl group;R4 is H or OH;R5 is H or OH;R4 and R5 may be taken together to form a second bondbetween C” and C”;R6 is a substituent selected from the group consisting ofbenzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl,dihalohydroxybenzyl, haloalkoxybenzyl, ordihaloalkyoxybenzyl group, B-ring heteroaromatic,substituted heteroaromatic,(C;-C6)alkyl,substitutedB-ring(C3-Cg)cycloalkyl,(C1"C5) alkyl,substituted C3-C8 cycloalkyl,a group of the formula III’ III‘and a group of the formula III":R16\ _,/&R15R17-—zIII"R7 is selected from the group consisting of NRMRQ, RENRBRW,51OR”, H and a lower alkyl group; R and R” are independentlyselected from the group consisting of Cyflg alkyl; R“ is C1-C3 alkyl;R8 is H or a lower alkyl group; or1015202530W0 98/0960 1CA 02264527 1999-03-02PCTIUS97/15668-6-R7 and R8 can form a cyclopropyl ring;R9 is selected from the group consisting of H, a lower alkylgroup,cycloalkyl,unsaturated lower alkyl, lower alkyl-C3-C5and benzyl;R” is H or a lower alkyl group;R“ is selected from the group consisting of hydrogen, OH,lower alkyl group, substitutedsubstituted phenyl, benzyl,benzyl and phenyl;R”, R”, and R” are each independently selected from thegroup consisting of hydrogen, OR”, halo, NR”'R”', NOWOPO3H2, OR19phenyl, SCH2phenyl, CONH2, co,H, P03!-I2, SO2R23, andZZ;R” is selected from the group consisting of hydrogen, aryl,Cyfg alkyl, C(O)R% and fluorenylmethoxycarbonyl (FMOC);Rm’ is selected from the group consisting of hydrogen, (C1-ce) alkyl and c(o)R9°';R” is Cyflk alkyl, C(O)R%” and fluorenylmethoxycarbonyl(EMOC);R”' is selected from the group consisting of hydrogen, (C1-Cg)alkyl, and c(o)R9°”',-Rw, Ray, R%”, and Rmyu are each independently selected fromthe group consisting of hydrogen, (Cy%k)alkyl, OR”' andaryl;Rm’ is selected from the group consisting of (Cy%g)alkyl,aryl, and hydrogen;R“ is selected from the group consisting of hydrogen and(C1-C3) alkyl;R” is hydrogen or C1-C6 alkyl; orR” may be taken together with the N at C-11 to form a threeto seven membered cyclic ring;0AR50 is hydrogen or ;n is O, l, or 2;m is O, l, or 2;101520WO 98/09601CA 02264527 1999-03-02PCT/U S97/ 15668p is O, l,or 2;X is selected from the group consisting of O, C, S, NH andalkylamino;Y is selected from the group consisting of C, O, NH, S, SO,S02 and alkylamino;Z is selected fromt he group consisting of —(CHfln—,O‘(CH2)m" and (C3‘C5)‘(CH2);>‘cycloalkyl;ZZ is selected from the group consisting of a simpleunsubstituted aromatic group and a simple substitutedaromatic group;comprising contacting a compound of Formula IIIR3 1:|{54\ 1&3 O}§r~ 19 1718 16 14 YO X HN R69 Rll OR’ lOR 8 NH2 0 CCl3R7 R IIIwith a solvent and a catalyst of the formula IVM\XcatYcatA\Rcat2‘LoanIVwherein M is selected from the group consisting ofhydrogen, Na, Li, K, and Cs;Xcat is selected from the group consisting of O,N, and S;Ycat is selected from the group consisting of O,N, and S;Rcatl is selected from the group consisting of C1-C5 alkyl and aryl;CA 02264527 1999-03-02W0 98/09601 PCT/US97/15668_ 8 ._Rcatz is selected from the group consisting of C1-C6 alkyl and aryl.Additionally, the present invention provides a newcryptophycin compound of Formula III3 R;R4 IAr 19 17 |%3\fO18 16 143 R50 R309 Rm. 0R 10 OR 8 NH2 CCl35 R7 R IIIwhereinAr is selected from the group consisting of phenyl, anysimple unsubstituted aromatic, simple substituted aromatic,substituted heteroaromatic group, unsubstituted10 heteroaromatic group, heterocyclic, C1-Cm alkyl, C2—Cmalkenyl, C2-Cm alkynyl, NR“R“, COR", OR”, and Formula Ar’ 54R Ar..IR“ is selected from the group consisting of hydrogen and C1-15 C3 alkyl;R” is selected from the group consisting of hydrogen and C1—C3 alkyl;R” is selected from the group consisting of C1-Cm alkyl;R“ is selected from the group consisting of hydrogen, C1-C620 alkyl, C1—C6alkyl(R5"R5"'R“”'), simple unsubstitutedaromatic, simple substituted aromatic, heterocyclic, phenyl,halogen, 4-(tert-butyldimethylsiloxy)—benzyltriphenylphosophonium, cooR57, PO3H, SO3H, SO2R58,1015202530W0 98/09601CA 02264527 1999-03-02PCT/U S97/ 15668-9-N(R59)R6°, NHOR61, NHCHRG1’, CN, N02, halogen, OR“, cH2(o)R6-2',RmIE")LCH2OC(O)R95, cH2N(R96)R%’,coR‘°°, (C1-C6alkyl)OR‘°°, ,SR63'andR% is selected from the group consisting of -R%NH3;R% and R%' are each independently selected from the groupconsisting of hydrogen and CV43 alkyl, —R”NH3, and -R%’NR”'99:: .R ,R” is selected from the group consisting of Cyig alkyl;R” is selected from the group consisting of Cyfk alkyl;R99 is C1'Cg alkyl;R”' and R9?’ are each independently selected from the groupconsisting of hydrogen and C1-C1 alkyl;Rmo is selected from the group consisting of hydrogen, andSi (R1o1R102R1o3) I,R101 is C1-C6 alkyl;Rmz is C1-C6 alkyl;Rw3 is C1-C6 alkyl;Rm“ is selected from the group consisting of C(O)C1-C6alkylN(R‘°6) (R59)R“°, c(o>c1—c,«, alkylN*, fused bicyclic, andNHR1°5N (R106) (R59) R60;RN5 is selected from the group consisting of C(O)C1-C6 alkyl,C1-C6 alkyl;R106 selected from the group consisting of hydrogen, C1-C5alkyl, c(o)oR“’7;RW7 is selected from the group consisting of hydrogen, C1-C6alkyl, CR108 R109 R“Rme is selected from the group consisting of hydrogen andC1-C6 alkyl;Rmg is selected from the group consisting of hydrogen andC1-C6 alkyl;R“° is selected from the group consisting of hydrogen andC1-C6 alkyl;l0l5202530W0 98/09601CA 02264527 1999-03-02PCT/US97/15668_:]_O._R“1 is selected from the group consisting of hydrogen, C1-C6alkyl, and C(O)ORm7R“ is selected from the group consisting of hydrogen, C1-C6alkyl, C(R5WR5W'R“”'), simple unsubstituted aromatic, simplesubstituted aromatic, phenyl, COOR57, PO3H, SO3H, SO2R58,NR59R6°, NHOR61, NHCHR6“, CN, NO2, halogen, OR62, and SR63;R“ is selected from the group consisting of hydrogen, C1-C6alkyl, C(R5"R5W'R“'”), simple unsubstituted aromatic, simplesubstituted aromatic, phenyl, COOR57, PO3H, SO3H, so2R59,NR59R6°, NHOR61, NHCHRG", (C1-C5)alkylNR59R6°, CN, NO2, halogen,ORW4, CR1“, OR“, and SR63;R“ is selected from the group consisting of hydrogen and C1—Cm alkyl;Rm’ is selected from the group consisting of hydrogen,halogen, and C1-Cm alkyl;Rm” is selected from the group consisting of hydrogen,halogen, and C1-C9 alkyl;Rm'” is selected from the group consisting of hydrogen,halogen, and C1—Cm alkyl;R“ is selected from the group consisting of hydrogen and C1-Cu alkyl;(Cf(t-BOC)R” is selected from the group consisting of hydrogen,C6) alkyl, tert-butoxycarbonyl, carbo—tert-butoxy(FMOC);R” is selected from the group consisting of hydrogen and(C1-C6) alkyl;and fluorenylmethoxycarbonylR“ is selected from the group consisting of hydrogen, OR“,CH3NHR%, NHR“' and fluorenylmethoxycarbonyl (FMOC);R“' is selected from the group consisting of hydrogen, OR“,CHQNHR“, NHR“' and fluorenylmethoxycarbonyl (FMOC);R” is selected from hydrogen, and C1-C5 alkyl;R“' is selected from hydrogen, OH, OR”, and C1-C6 alkyl;R“ is selected from hydrogen and cymg alkyl;CA 02264527 1999-03-02W0 93/09501 PCT/US97/15668-11-R“ is selected from the group consisting of hydrogen, (C1-C6) alkyl, CH2NR66R67;R“ is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC);R6” is selected from the group consisting of hydrogen andC1-C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC);R“ is selected from the group consisting of hydrogen and C1-C6 alkyl and fluorenylmethoxycarbonyl (FMOC);R“ is selected from the group consisting of hydrogen and C1-C5 alkyl;R3 is a lower alkyl group;R4 is H or OH;R5 is H or OH;R4 and R5 may be taken together to form a second bondbetween C” and C”;R6 is a substituent selected from the group consisting ofbenzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl,dihalohydroxybenzyl, haloalkoxybenzyl, ordihaloalkyoxybenzyl group, B-ring heteroaromatic,substituted heteroaromatic, B-ring(C1—C6)alkyl, (C3-C8)cycloalkyl, substituted C3‘C3 cycloalkyl,substituted (C1—C6)alkyl, a group of the formula III’R16\ lR” III‘and a group of the formula III":—z10152025CA 02264527 1999-03-02wo 93/09501 PCT/US97/15668_ 1 2 _R16--2 /\ R15R" I I I ' 'R7 is selected from the group consisting of NRMR”, RBNRMR”,OR”, H and a lower alkyl group; R“ and R” are independentlyselected from the group consisting of Cyflh alkyl; R“ is C1-C3 alkyl;R8 is H or a lower alkyl group; orR7 and R8 can form a cyclopropyl ring;R9 is selected from the group consisting of H, a lower alkylgroup,unsaturated lower alkyl, lower alkyl—Cy%gcycloalkyl, and benzyl;R” is H or a lower alkyl group;R“ is selected from the group consisting of hydrogen, OH,lower alkyl group, substituted phenyl, benzyl, substitutedbenzyl and phenyl;R”, R”, and R” are each independently selected from thegroup consisting of hydrogen, OR”, halo, NR”"R”', NO“OPO3H2, oR”pheny1, SCH2phenyl, CONH2, co2H, PO31-I2, so2R23, andZZ;R” is selected from the group consisting of hydrogen, aryl,Cyfk alkyl, C(O)R% and fluorenylmethoxycarbonyl (FMOC);Rm’ is selected from the group consisting of hydrogen, (C1-C6)alkyl and c(o)R9°’;R” is C1-C6 alkyl, C(O)R”y' and fluorenylmethoxycarbonyl(FMOC);R”' is selected from the group consisting of hydrogen, (C1-C6)alkyl, and C(O)R%”';R”, Rm”, R%”, and R””' are each independently selected from(C1-C6) alkyl, OR91’the group consisting of hydrogen, andaryl;1015202530WO 98/09601CA 02264527 1999-03-02PCT/U S97/ 15668-13-Rm’ is selected from the group consisting of (C1—C6)alkyl,aryl, and hydrogen;R“ is selected from the group consisting of hydrogen and(C1-C3) alkyl;R” is hydrogen or Cyflx alkyl; orR“ may be taken together with the N at C-11 to form a threeto seven membered cyclic ring;0AR50 is hydrogen or ;n is O, l, or 2;m is O, 1, or 2;p is O, l,or 2;X is selected from the group consisting of O, C, 8, NH andalkylamino;Y is selected from the group consisting of C, O, NH, S, SO,S02 and alkylamino;Z is selected fromt he group consisting of -(CHyn—,O"’(CH2)m’ and (C3"C5)_(CH2)P_cycloalkyl;ZZ is selected from the group consisting of a simpleunsubstituted aromatic group and a simple substitutedaromatic group; ora pharmaceutically acceptable salt or solvate thereof.As used herein, the term "simple alkyl" shallrefer to C1-C7 alkyl wherein the alkyl may be saturated,unsaturated, branched,or straight chain. Examples include,but are in no way limited to, methyl, ethyl,PI0PYl,isobutyl,n—propyl, iso-n-butyl, propenyl, sec—butyl,tert—butyl,tert pentyl,and the like.ethenyl, n—pentyl,sec-butyl, methylated butyl groups,pentyl, sec—pentyl, methylated pentyl groupsThe term "alkenyl" refers to an alkyl group,as defined above, having from one to three double bonds.The term "alkynyl" refers to an alkyl group, as definedabove, having at least one triple bond. It is especiallypreferred that alkynyl has only one triple bond. The term1015202530WO 98109601CA 02264527 1999-03-02PCT/US97/15668-14..C1-Cnv alkyl; wherein n' is an integer from 1 to 12 means analkyl group having from one to the indicated number ofcarbon atoms. The C1-Cn- alkyl can be straight or branchedchain.As used herein, the term "B-ring C1-C6 alkyl”refers to saturated, unsaturated, branched and straightchain alkyl wherein the B-ring C1-C6 alkyl group may includeup to three (3) non-carbon substituents. Such non—carbonsubstituents are most preferredly selected from the groupconsisting of OH, SCH2phenyl, NH2, CO, CONH2, CO2H, PO3H2,SO2R21 wherein R21 is selected from hydrogen and C1-C3 alkyl;As used herein, the term "(C1—C6)alkyl linker"refers to C1-C6 alkyl group having from zero to threesubstituents selected from the group consisting of C1-C6alkyl, NH2 and amino acid.As used herein the term "amino acid" means anorganic acid containing an amino group. The term includesboth naturally occuring and synthetic amino acids,therefore,be,refer to, but is in no way limited tothe amino group can be, but is not required toThe term shall(CH2)2NH2COOH,attached to the carbon next to the acid.(CH2) 3NH2COOC (CH3) 3 CH2NH2COOC (CH3) 3,CH2CH(NH2)CH2COOC(CH3)3, and the like.CH2CH (NH2) CH2COOH ,IAs used herein, the term "carbohydrate" refers toa class of substituents made up of carbon, hydrogen, andoxygen wherein hydrogen and oxygen are in the sameproportions as in water or nearly the proportions as water.The term "carbohydrate" further refers to an aldehyde orketone alcohol or a compound which on hydrolysis producesand aldehyde or ketone. The term "carbohydrate" is ascommonly understood by the skilled artisan.the term refers to,and C6H1oO5 _For example,but is in no way limited to, C12H22O1110152025CA 02264527 1999-03-02W0 93/09501 PCTIUS97/15668-15-Ascarbohydrateused herein, the term "amino sugar" refers to agroup containing from one to three aminosubstituents at any available position on the carbohydratemolecule.Ascarbohydratethesubunits to formused herein, term "saccharide" refers todisaccharides orpolysaccharides.limited to,the like.As used herein,The term means for example, but in no waylactose, maltose, sucrose, fructose, starch, andthe term "substituted phenyl"shall refer to a phenyl group with from one to three non-hydrocarbon substituents which may be independently selectedCl, Br, F, and I.the term "substituted benzyl"from the group consisting of simple alkyl,As used herein,shall refer to a benzyl group with from one to three non-hydrocarbon substitutents which may be independentlyselected from the group consisting of simple alkyl, Cl, Br,F, and I wherein such substituents may be attached at anyavailable carbon atom.As used herein "B-ring heterocyclic group" refersto aromatic or unsaturated rings which contain one or morenon-carbon substituent selected from the group consisting ofoxygen, and sulfur.nitrogen, Especially preferred B—ringheterocyclic groups are selected from, but not limited to,the group consisting ofCA 02264527 1999-03-02wo 93/09501 PCT/US97/15668_16._2Q ENE &j>R20 is selected from hydrogen and C1-C6 alkyl.wherein R20 is selected from hydrogen and C1-C6 alkyl.It is especially preferred that "B—ring5 heteroaromatic group" refers to a substituent selected fromthe group consisting of:\ . ._ OR2°-NIN/>y\§QlZ]Ql\ oR2°200 S ,and'5NAs used herein "cycloalkyl" refers to a saturatedC—C cycloalkyl group wherein such group may include from10 zero to three substituents selected from the group101520253035WO 98/09601CA 02264527 1999-03-02PCT/US97/15668-17..halo, and OR22 wherein R22 isselected from hydrogen and C1-C3 alkyl.consisting of C1-C3 alkyl,Such substituentsIt isespecially preferred that cycloalkyl refers to substitutedor unsubstituted cyclohexyl.may be attached at any available carbon atom.As used herein "Lower alkoxyl group" means anyalkyl group of one to five carbon atoms bonded to an oxygenatom. As used herein "lower alkyl group" means an alkylgroup of one to five carbons and includes linear and non-including for example, but notpropyl, butyl,sec-butyl, methylated butyl groups,linear hydrocarbon chains,limited to, methyl, ethyl,tert-butyl,tert pentyl,isopropyl,isobutyl,pentyl,sec—pentyl, and methylated pentylgroups. As used herein "allylically substituted alkene"means any alkene having from one to seven carbon atoms whichcontains an alkyl substitution on it. As used herein theterm "unsaturated lower alkyl" means a lower alkyl group asdefined supra. wherein from one to two double bonds arepresent in the unsaturated lower alkyl substituent. Apreferred unsaturated lower alkyl is —CH2-CH=CH2. The term"lower alkyl—C3-C5 cycloalkyl" refers to C—C alkylsubstituted with a C3—C5cycloalkyl group. A preferred loweralkyl-C3-C5 cycloalkyl group is -CH2—cyclopropyl; whereinthe group is attached to the cryptophycin core structure atR9 via the CH2_As used herein "epoxide ring" means a three-membered ring whose backbone consists of two carbons and anoxygen atom. As used herein, "aziridine ring" means athree-membered ring whose backbone consists of two carbonatoms and a nitrogen atom. As used herein "sulfide ring"means a three—membered ring whose backbone consists of twocarbon atoms and a sulfur atom. As used herein "episulfidering" means a three—membered ring whose backbone consists oftwo carbon atoms and a sulfur atom. As used herein "sulfategroup" means a five membered ring consisting of a carbon-carbon-oxygen-sulfur-oxygen backbone with two additional101520253O35WO 98/09601CA 02264527 1999-03-02PC1YUS97fl5668_18_oxygen atoms connected to the sulfur atom. As used herein"cyclopropyl ring" means a three member ring whose backboneconsists of three carbon atoms. As used herein,"monoalkylphosphate ring" means a five membered ringconsisting of a carbon-carbon-oxygen—phosphorous—oxygenbackbone with two additional oxygen atoms, one of whichbears a lower alkyl group, connected to the phosphorousatom.As used herein, "simple unsubstituted group"refers to common aromatic rings having 4n+2 n electrons in abut not limitedpyridyl and the like,monocyclic conjugated system, for example,to: furyl, pyrrolyl, thienyl, or abicyclic conjugated system, for example but not limited toindolyl or naphthyl.As used herein "simple substituted aromatic group"refers to a phenyl group substituted with a single groupselected from the group consisting of halogen and loweralkyl group.As used herein, the term “fused bicyclic” refersto two joined ring systems which are optionallySuchgroups include but are in no way limited to naphthyl,independently saturated, or aromatic.unsaturated,groupswhich fuse an unsaturated ring with an aromatic ring, groupshaving a heterocyclic group fused with a heteroaromaticgroup,group.and a heterocyclic group fused with an aromaticThe fused bicyclic is optionally substituted withone or more substituents selected from the group consistingof C1-C6 alkyl and halogen.As used herein, "heteroaromatic group" refers toaromatic rings which contain one or more non-carbon atomsindependently selected from the group consisting of oxygen,nitrogen, and sulfur. It is most preferred that theheteroaromatic group will have from three to eight membersin the ring. It is especially preferred that the number ofnon-carbon members will be from one to three.As used herein, the term “heterocyclic” refers tosaturated or unsaturated rings containing one or more non101520253035WO 98/09601CA 02264527 1999-03-02PCT/US97/15668-19..carbon atoms independently selected from the groupconsisting of oxygen, nitrogen, and sulfur. It is mostpreferred that the heterocyclic group will have from threeto eight members in the ring. It is especially preferredthat the number of non—carbon members will be from one tothree.As used herein, "halogen" or "halo" refers tothose members of the group on the periodic tablehistorically known as halogens. Methods of halogenationinclude,halides,photohalogenation,but are not limited to, the addition of hydrogensubstitution at high temperature,etc., and such methods are known to theskilled artisan. Especially preferred halogens are chloro,bromo, fluoro, and iodo. For some purposes within the scopeof this invention, chloro, bromo and fluoro are especiallypreferred halogens.Compounds of Formula III are particularly usefulfor the preparation of cryophycin compounds.The starting material corresponding to a compoundof Formula 1 as illustrated in Scheme 1 can be preparedusing the disclosures available to the skilled artisan.Barrow, id.SeeThe processes for preparing compound 2 asillustrated in Scheme 1' used TFA; however, the artisan willrecognize that alternative agents can be used in thisprocess.Likewise, the basic workup uses sodium hydroxide;however, the artisan will appreciate that other basic agentscan be effective as well.The processes to prepare the compounds of thisinvention most preferably are completed in the presence of asolvent. The skilled artisan can select appropriatesolvents using known methodologies. While in no waylimiting the scope of the present invention, some preferredsolvents are provided for the guidance of the artisan,but not limited to,group consisting of toluene, N,N—dimethylformamide,including, a solvent selected from theethylacetate,tetrahydrofuan, and acetonitrile.CA 02264527 1999- 03 - 02wo 98/09601 PCT/US97/15668-20-The reaction time is related to the startingmaterials and operating temperature. The optimum reactiontime for a given process is, as always, a compromise whichis determined by considering the competing goals of5 throughput, which is favored by short reaction times, andmaximum yield, which is favored by long reaction times.The process of this invention can be furtherillustrated by the following Scheme 1’:R3 5 R3 54 4\ O \ 0Ar 6 Ar0 x NH R . , x NH R6Q’“\ /~\R1oY NBoc CC'3 Y NH2 0 C03R7 88 R10R7R3 54\\ 0Ar0 X NH R5:......._..n> 50 11 ‘R300R10 Y NHR7 810 And more particularly, Scheme 1:/\O0 Cl Ar/§J\/\/YO CIHN .—OMe ' H ,OMe/Ki ° NHB c / H 0 .51O.\| :0° ' \ basic or>ku )3 0cl 0" ccna W p'-.- -N 2o 0" CCI32O HN flflcatalyst Jfi O l"’ 0)‘):/‘ u oToluene, rtAs illustrated above, the catalyst is mostpreferrably selected from the group consisting of alky andaryl substituted metal carboxylates, carboxylic acids, and15 other bifunctional compounds according to the Formula IV.1015WO 98/09601CA 02264527 1999-03-02PCT/U S97/ 15668._2]__Especially preferred catalysts are selected from the groupconsisting of 2-hydroxypyridine, tetrabutylammonium cyanideand sodium benzoate/n-tetrabutylNHSO4.The following is provided to further illustratethe advantages of the claimed process:As shown in Table 1,2-hydroxypyridine (entries 2-4)and tetrabutylammonium benzoate (entry 5) have been shown tosignificantly accelerate the macrolactamization process. Incontrast, ring closure was very slow when the reaction wasallowed to stir at room temperature without catalyst1). Although not listed in Table 1,(NaBu4NCN 4- NaCN) also promoted macrolactamizationof 2. As the 2 and 3 refer to thestructures of Scheme 1 wherein Ar is phenyl.(entrytetrabutylammoniumcyanideshown in Table 1,TABLE 1Entry Catalyst Stoichiometry % Conversion(Equivalents) of 2 to 3after 6h ofreaction(HPLC)None ——— 4.72 2- 0.5 41.9Hydroxypyridine3 2— 1 44.8Hydroxypyridine4 2- 5 40.2Hydroxypyridine5 Sodium 1 / 0.1 41.0benzoate /nBu4NHSO4101520253035W0 98/091501CA 02264527 1999-03-02PCT/US97/15668_ 2 2 _Example 1Cryptophycin—51 (3)Compound 111.2 mmol)trifluoroacetic acid(as illustrated by Scheme 1 supra.)(10.2 g,was cooled to 0 °C and dissolved in(TFA) (50 mL).°C for 30 min and was then concentratedThe resulting solutionwas stirred at 0under reduced pressure.(250 mL)(50 mL)were back-extracted with fresh tolueneorganic phases were combined and driedThe resultant syrup was diluted withand washed with 1N NaOH (2x100 mL)to break up emulsions. The aqueous extracts(lx5O mL) and the(MgSO4). TLC analysisindicated no trace of starting 1. The filtered solution ofamino ester 2 was diluted to 500 mL and 2-hydroxypyridine(5.34,yellow solution was allowed to stir at room temperature fortoluene usingbrine56.2 mmoles) was added. The resulting clear, pale14 h. The reaction mixture became turbid so the suspensionwas diluted with CH2Cl2 (250 mL)product. The mixture was washed with saturated,NaHCO3 (3 x 100 mL) (1 x 100 mL). The aqueousextracts were back—extracted with CH2Cl2 (1 x 100 mL)(M9504 ),concentrated to a thick syrup. A solution of hexanes andEtOAc (100 mL, 1:1 v/v)cooled to 0 °C. Spontaneous crystallization occurred after30 min.to assure solubility ofaqueousand brineandthe organic extracts were combined, dried andwas added and the solution wasThe mixture was filtered, and the filtrate wasconcentrated and induced to crystallize two additionaltimes. The collected crops were combined to give 5.04 g(69%) of compound 3 (LSN 354504) as a white powder. HPLC(85:15 CH3CN / H20, 0.05% TEA in both organic and aqueousphases; flow 1 mL / min; wavelength: 225 nm; column: ZorbaxSB—C18) Rt = 6.09 min 95% pure. 1H NMR (300 MHz, CDC13) d7.32-7.17 (m, 8H); 7.04 (dd, 1H, J‘: 2.2, 8.4); 6.82 (d, 1H,J = 8.5); 6.76 (m, 1H); 6.39 (d, 1H, J'= 15.9); 5.99 (dd,1H, J'= 8.8, 15.8); 5.73 (dd, 1H, J = 2.3, 16.4); 5.50 (d,1H, J'= 7.8); 5.03 (m, 1H); 4.83 (dd, 1H, J'= 3.3, 9.9);4.73 (ABq, 1H, J = 6.4); 3.86 (s, 3H); 3.39 (dd, 1H, J'=8.6, 13.5); 3.10 (m, 2H); 2.53 (m, 2H); 2.36 (m, 1H); 1.62CA 02264527 1999-03-02WO 98/09601 PCT/U S97/ 15668-23..(m, 3H); 1.21 (s, 3H); 1.14 (s, 3H); 1.11 (d, 3H, J = 6.9);0.71 (app. t, 6H, J: 6.0).

Claims (13)

We claim:
1. A compound of Formula III

wherein Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, C1,-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, NR51R52, COR52, OR53, and Formula Ar' R51 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R52 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R53 is selected from the group consisting of C1,-C12 alkyl;
R54 is selected from the group consisting of hydrogen, C -C
alkyl, C1-C6 alkyl(R57' R57'' R5'''), simple unsubstituted aromatlc, simple substituted aromatic, heterocyclic, phenyl, halogen, 4-(tert-butyldimethylsiloxy)-benzyltriphenylphosophonium, COOR57, PO3H, SO3H, SO2R58, N(R59)R60, NHOR61, NHCHR61, CN, NO, halogen, OR6, CH2(O)R62', - CH2OC(O) R 95, CH2N (R 96) R 96', COR I00, (C1,-C6alkyl ) OR 100, , and SR 63;
R 95 is selected from the group consisting of -R 98 NH3;
R 96 and R 96' are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, -R 97 NH , and -R NR
R 99';
R 97 is selected from the group consisting of C1,-C6 alkyl;
R 98 is selected from the group consisting of C1,-C6 alkyl;
R 99 is C1-C6 alkyl;
R 99' and R 99'' are each independently selected from the group consisting of hydrogen and C1-C6 alkyl;
R 100 is selected from the group consisting of hydrogen, and Si (R 100 R 102 R 103);
R 101 is Cl-C6 alkyl;
R 102 is C1-C6 alkyl;
R 103 is Cl-C6 alkyl;
R l04 is selected from the group consisting of C(O)C1-C6 alkylN(R 106)(R 59)R 60, C(O)C1-C6 alkylN +, fused bicyclic, and NHR 105 N ( R 106 ) ( R 59)R 60;
R 105 is selected from the group consisting of C(O)C1-C6 alkyl, C1-C6 alkyl;
R 106 is selected from the group consisting of hydrogen, C1-C6 alkyl, C(O)OR 107;
R 107 is selected from the group consisting of hydrogen, C1-C6 alkyl, CR108 R 109 R 110 R 108 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 109 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 110 is selected from the group consisting of hydrogen and C1-C6 alkyl;

R 111 is selected from the group consisting of hydrogen, C1-C6 alkyl, and C(O)OR 107 R55 is selected from the group consisting of hydrogen, C1-C6 alkyl, C(R 57' R 57'' R 57'''), simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR 57, PO3H, SO3H, SO2R 58, NR 59 R 60, NHOR 6l, NHCHR 61', CN, NO2, halogen, OR62, and SR63;
R 56 is selected from the group consisting of hydrogen, C1-C6 alkyl, C(R 57' R 57'' R 57''' ), simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR 57, PO3H, SO3H, SO R 58, NR 59 R 60, NHOR 61, NHCHR 61', (C1-C6)alkylNR 59R , CN, NO2, halogen,OR 104 CR 104 OR 62, and SR63;
R 57 is selected from the group consisting of hydrogen and C1-C12 alkyl;
R57' is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl;
R 57'' is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl;
R 57''' is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl;
R 58 is selected from the group consisting of hydrogen and C1-C12 alkyl;
R59 is selected from the group consisting cf hydrogen, (C1-C6) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC);
R60 is selected from the group consisting of hydrogen and (C1-C6) alkyl;
R 61' is selected from the group consisting of hydrogen, OR 64, CH2NHR 65, NHR 65', and fluorenylmethoxycarbonyl (FMOC);
R 61' is selected from the group consisting of hydrogen, OR 64, CH2NHR 65, NHR 65' and fluorenylmethoxycarbonyl (FMOC);
R 62 is selected from hydrogen, and C1-C6 alkyl;
R 62' is selected from hydrogen, OH, OR 62, and C1-C6 alkyl;
R 63 is selected from hydrogen and C1-C6 alkyl;

R 64 is selected from the group consisting of hydrogen, (C1-C6) alkyl, CH2NR 66 R 67;
R 65 is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC);
R 65' is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC);
R 66 is selected from the group consisting of hydrogen and C1-C6 alkyl and fluorenylmethoxycarbonyl (FMOC);
R 67 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 3 is a lower alkyl group;
R 4 is H or OH;
R 5 is H or OH;
R 4 and R 5 may be taken together to form a second bond between C 13 and C 14;
R 6 is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (C1-C6)alkyl, (C3-C8)cycloalkyl, substituted C3-C8 cycloalkyl, substituted (C1-C6)alkyl, a group of the formula III' and a group of the formula III'':

R 7 is selected from the group consisting of NR 51 R 52, R 53 NR 51 R 53, OR 53, H and a lower alkyl group; R 51 and R 52 are independently selected from the group consisting of C1-C3 alkyl; R 53 is C1-C3 alkyl;
R 8 is H or a lower alkyl group; or R 7 and R 8 can form a cyclopropyl ring;
R 9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-C3-C5 cycloalkyl, and benzyl;
R 10 is H or a lower alkyl group;
R 11 is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl;
R 15, R 16, and R 17 are each independently selected from the group consisting of hydrogen, OR 18, halo, NR 18' R 19', NO2, OPO3H2, OR 19 phenyl, SCH2phenyl, CONH2, C02H, PO3H, SO2R 23, and ZZ;
R 18 is selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, C(O)R 90 and fluorenylmethoxycarbonyl (FMOC);
R 18 is selected from the group consisting of hydrogen, C1-C6)alkyl and C(O)R 90;
R 19 is C1-C6 alkyl, C(O)R 90'' and fluorenylmethoxycarbonyl (FMOC );
R 19' is selected from the group consisting of hydrogen, C1-C6)alkyl, and C(O)R 90''';
R 90, R 90', R 90'' , and R 90''' are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, OR 9l and aryl;
R 91 is selected from the group consisting of (C1-C6)alkyl, aryl, and hydrogen;
R 23 is selected from the group consisting of hydrogen and (C1-C3 ) alkyl;
R 30 is hydrogen or C1-C6 alkyl; or R 30 may be taken together with the N at C-ll to form a three to seven membered cyclic ring;

R 50 is hydrogen or n is 0, 1, or 2;
m is 0, 1, or 2;
p is 0, 1,or 2;
X is selected from the group consisting of O, C, S, NH and alkylamino;
Y is selected from the group consisting of C, O, NH, S, SO, SO2 and alkylamino;
Z is selected from the group consisting of -(CH2)n-, - (CH2)p-O-(CH2)m- and (C3-C5) cycloalkyl;
ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a slmple substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof.
2. A compound of Claim 1 wherein the compound of Formula III is defined as follows:

wherein Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group, C1-C12 alkyl, C1-C12 alkene, C1-C12 alkyne, NR 5l R 52, OR 53, Formula Ar' R 51 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R 52 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R 53 is selected from the group consisting of C1-C12 alkyl;
R 54 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COOR 57, PO3H, SO3H, SO2R 58 NR 59 R 60, NHOR 61, NHCHR 61' , CN, NO2, halogen, OR62, and SR 63;
R 55 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COOR 57, PO3H, SO3H, SO2R 58' NR 59 R 60, NHOR 61, NHCHR 61' , CN, NO2, halogen, OR 62, and SR 63;
R 56 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COCR 57, PO3H, SO3H, SO2R 58, NR 59 R 60, NHOR 61, NHCHR 61' , CN, NO2, halogen, OR 62, and SR 63;
R 57 is selected from the group consisting of hydrogen and C1-C12 alkyl;
R 58 is selected from the group consisting of hydrogen and C1-C12 alkyl;
R 59 is selected from the group consisting of hydrogen, C1-C6) alkyl and fluorenylmethoxycaronyl (FMOC);
R 60 is selected from the group consisting of hydrogen and (C1-C6) alkyl;
R 61 is selected from the group consisting of hydrogen, OR 64, CH2NHR 65, NHR 65 and fluorenylmethoxycaronyl (FMOC);
R 61' is selected from the group consisting of hydrogen, OR 64, CH2NHR 65, NHR 65 and fluorenylmethoxycaronyl (FMOC);
R 62 is selected from hydrogen and C1-C6 alkyl;
R 63 is selected form hydrogen and C1-C6 alkyl;
R 64 is selected from the group consisting of hydrogen, C1-C6) alkyl, CH2NR 66 R 67 R 65 is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, and fluorenylmethoxycaronyl (FMOC);
R 66 is selected from the group consisting of hydrogen and C1-C6 alkyl and fluorenylmethoxycaronyl (FMOC);
R 67 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 3 is a lower alkyl group;
R 4 is H or OH;
R 5 is H or OH;
R 4 and R 5 may be taken together to form a second bond between C13 and C14;
R 6 is selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (C1-C6)alkyl, (C3-C8)cycloalkyl, substituted C3-C8 cycloalkyl, substituted (C1-C6)alkyl, a group of the formula III':

and a group of the formula III'':

R 7 is H or a lower alkyl group;
R 8 is H or a lower alkyl group;
R 9 is H or a lower alkyl group;
R 10 is H or a lower alkyl group;
R 11 is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substltuted benzyl;

R 15, R 16, and R 17 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, OR 18, halo, NR 18' R 19' , NO2, OPO4H2, OR 19 phenyl, SCH2phenyl, CONH2, CO2H, PO3H2, So2R23, and ZZ;
R 18 is selected from the group consisting of hydrogen, aryl, and C1-C6 alkyl;
R 18 is selected from the group consisting of hydrogen and (C1-C6)alkyl;
R 19 is C1-C6 alkyl;
R 19' is selected from the group consisting of hydrogen and (C1-C6)alkyl;
R 23 is selected from the group consisting of hydrogen and (C1-C3)alkyl;
R 30 is hydrogen or C1-C6 alkyl;
R 50 is hydrogen or n is 0, 1, or 2;
p is 0, 1, or 2;
m is 0, 1, or 2;
q is 2, 3, or 4;
X is O, NH or alkylamino;
Y is C, O, NH, S, SO, SO2 or alkylamino;
Z is selected from the group consisting of -(CH2) n-, - ( CH2 ) p-O- ( CH2 ) m- and (C3-C5)cycloalkyl;
ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group; or a pharmaceutically acceptable salt thereof.
3. A compound of Claim 1 wherein Ar is selected from the group consisting of phenyl, aromatic, or simple substituted aromatic.
4. A compound of Claim 2 wherein Ar is a parafluoro substituted phenyl ring.
5. A compound of Claim 1 wherein R 30 is hydrogen, R 7 and R 8 are each methyl, X is O, Y is O, and R 50 is a group of the formula .
6. A compound of Claim l wherein R 30 is hydrogen, one of R 7 and R 8 is methyl, X is O, Y is O, and R 50 is a group of the formula
7. A process for preparing a compound of Formula II

wherein Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, NR 51 R 52, COR 52, OR 53, and Formula Ar' R 51 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R 52 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R 53 is selected from the group consisting of C1-C12 alkyl;
R 54 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6alkyl(R 57' R 57'' R 57'''), simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4-(tert-butyldimethylsiloxy)-benzyltriphenylphosophonium, X COOR 57, PO3H, SO3H, SO2R 58, N (R 59) R 60, NHOR 61, NHCHR 61', CN, NO2, halogen, OR 62, CH2 (O) R 62', CH2OC (O) R 95, CH2N (R 96) R 96', COR 100, (C1,-C6alkyl) OR 100, , and SR 63;
R 95 iS selected from the group consisting of -R 96 NH3;
R 96 and R 96' are each independently selected from the group consisting of hydrogen and C1-C6 alkyl, -R 97 NH3, and -R 99 NR99' R 99'';
R 97 is selected from the group consisting of C1-C6 alkyl;
R 98 is selected from the group consisting of C1-C6 alkyl;
R 99 is C1-C6 alkyl;
R 99' and R 99'' are each independently selected from the group consisting of hydrogen and C1-C6 alkyl;
R 100 is selected from the group consisting of hydrogen, and Si (R 101 R 102 R 103);
R 101 is C1-C6 alkyl;
R 102 i s C1-C6 alkyl;
R 103 is C1-C6 alkyl;
R 104 is selected from the group consisting of C (O) C1-C6 alkylN (R 106) (R 59) R 60, C (O) C1-C6 alkylN +, fused bicyclic, and NHR 105N (R 106) (R 59) R 60;
R 105 is selected from the group consisting of C (O) C1-C6 alkyl, C1-C6 alkyl;
R 106 is selected from the group consisting of hydrogen, C1-C6 alkyl, C (O) OR 107;
R 107 is selected from the group consisting of hydrogen, C1-C6 alkyl, CR 108 R 109 R 110 R 108 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 109 iS selected from the group consisting of hydrogen and C1-C6 alkyl;

R 110 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 55 is selected from the group consisting of hydrogen, C1-C6 alkyl, C(R 57' R 57'' R 57'''), simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR 57, PO3H, SO3H, SO2R 58, NR 59 R 60, NHOR 61, NHCHR 61', CN, NO2, halogen, OR 62, and SR 63;
R 56 is selected from the group consisting of hydrogen, C1-C6 alkyl, C(R 57' R 57'' R 57'''), simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR 57, PO3H, SO3H, SO R 58, NR 59 R 60, NHOR 61, NHCHR 61, (C1-C6) alkylNR 59 R 60, CN, NO2, halogen, OR 104 CR 104 OR 62, and SR 63;
R 57 is selected from the group consisting of hydrogen and C2-C12 alkyl;
R 57' is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl;
R 57'' is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl;
R57''' is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl;
R 58 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 59 is selected from the group consisting of hydrogen, (C1-C6) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC);
R 60 is selected from the group consisting of hydrogen and (C1-C6) alkyl;
R 6l is selected from the group consisting of hydrogen, OR 64, CH2NHR 65, NHR 65' and fluorenylmethoxycarbonyl (FMOC);
R 6l' is selected from the group consisting of hydrogen, OR 64, CH2NHR 65, NHR 65' and fluorenylmethoxycarbonyl (FMOC);
R 62 is selected from hydrogen, and C1-C6 alkyl;
R 62' is selected from hydrogen, OH, OR 62, and C1-C6 alkyl;
R 63 is selected from hydrogen and C1-C6 alkyl;

R 64 is selected from the group consisting of hydrogen, (C1-C6) alkyl, CH2NR 66 R 67;
R 65 is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC);
R 65' is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC);
R 66 is selected from the group consisting of hydrogen and C1-C6 alkyl and fluorenylmethoxycarbonyl (FMOC);
R 67 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 3 is a lower alkyl group;
R 4 is H or OH;
R 5 is H or OH;
R 4 and R 5 may be taken together to form a second bond between C 13 and C l4;
R 6 is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (C1-C6)alkyl, (C3-C8)cycloalkyl, substituted C3-C8 cycloalkyl, substituted (C1-C6)alkyl, a group of the formula III' and a group of the formula III'':
R 7 is selected from the group consisting of NR 51 R52,, R 53 NR51 R52,OR 53, H and a lower alkyl group; R 51 and R 52 are independently selected from the group consisting of C1-C3 alkyl; R 53 is C1-C3 alkyl;
R 8 is H or a lower alkyl group; or R 7 and R 8 can form a cyclopropyl ring;
R 9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-C3-C5 cycloalkyl, and benzyl;
R 10 is H or a lower alkyl group;
R 11 is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl;
R 15, R l6, and R 17 are each independently selected from the group consisting of hydrogen, OR 18, halo, NR 18 R19, NO2, OPO3H2, OR 13 phenyl, SCH2phenyl, CONH2 , CO2H, PO3H2, SO2R 23, and ZZ;
R 18 is selected from the group consisting of hydrogen, aryl, C1-C6 alkyl, C(O)R 90 and fluorenylmethoxycarbonyl (FMOC);
R 18 is selected from the group consisting of hydrogen, (C1-C6)alkyl and C(O)R 90';
R 19 is C1-C6 alkyl, C(O)R 90'' and fluorenylmethoxycarbonyl ( FMOC );
R 19 is selected from the group consisting of hydrogen, (C1-C6)alkyl, and C(O)R 90''';
R 90, R 90', R 90'' , and R 90''' are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, OR 91' and aryl;
R 91 is selected from the group consisting of (C1-C6)alkyl, aryl, and hydrogen;
R 23 is selected from the group consisting of hydrogen and ( C1 -C3 ) alkyl;
R 30 is hydrogen or C1-C6 alkyl; or R 30 may be taken together with the N at C-11 to form a three to seven membered cyclic ring;

R 50 is hydrogen or n is 0, 1, or 2;
m is 0, 1, or 2;
p is 0, l,or 2;
X is selected from the group consisting of O, C, S, NH and alkylamino;
Y is selected from the group consisting of C, O, NH, S, SO, SO2 and alkylamino;
Z is selected fromt he group consisting of -(CH2)n-, -(CH)p-O-(CH2)m- and (C3-C5) cycloalkyl;
ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group;
comprising contacting a compound of Formula III

with a solvent and a catalyst of the formula IV

wherein M is selected from the group consisting of hydrogen, Na, Li, K, and Cs;
x cat is selected from the group consisting of O, N, and S;
y cat is selected from the group consisting of O, N, and S;
R cat1 is selected from the group consisting of C1-C6 alkyl and aryl;
R cat2 is selected from the group consisting of C1-C6 alkyl and aryl.
8. A process of Claim 7 wherein the solvent is selected from the group consisting of toluene, N,N-dimethylformamide, ethyl acetate, tertrahydrofuran and acetonitrile.
9. A process of Claim 7 wherein the Formula II
compound is defined as follows:

wherein Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group, C1-C12 alkyl, C1-C12 alkene, C1-C12 alkyne, NR 51 R 52, OR 53, Formula Ar' Ar';
R 51 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R 52 is selected from the group consisting of hydrogen and C1-C3 alkyl;
R 53 is selected from the group consisting of C1-C12 alkyl;
R 54 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COOR 57, PO3H, SO3H, SO2R 58 NR 59 R 60, NHOR 61, NHCHR 61' , CN, NO2, halogen, OR 62, and SR 63;
R 55 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COOR 57, PO3H, SO3H, SO2R 58, NR 59 R 60, NHOR 61, NHCHR 61' , CN, NO2, halogen, OR 62, and SR 63;
R 56 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COOR57, PO3H, SO3H, SO2R 58, NR 59 R 60, NHOR 61, NHCHR 61', CN, NO2, halogen, OR 62, and SR 63;
R 57 is selected from the group consisting of hydrogen and C1-C12 alkyl;
R 58 is selected from the group consisting of hydrogen and C1-C12 alkyl;
R 59 is selected from the group consisting of hydrogen, (C1-C6) alkyl and fluorenylmethoxycaronyl (FMOC);
R 60 is selected from the group consisting of hydrogen and (C1-C6) alkyl;
R 61 is selected from the group consisting of hydrogen, OR 64, CH2NHR 65, NHR 65 and fluorenylmethoxycaronyl (FMOC);
R 61' is selected from the group consisting of hydrogen, OR 64, CH2NHR 65, NHR 65 and fluorenylmethoxycaronyl (FMOC);
R 62 is selected from hydrogen and C1-C6 alkyl;
R 63 is selected form hydrogen and C1-C6 alkyl;
R 64 is selected from the group consisting of hydrogen, (C1-C6) alkyl, CH2NR 66 R 67 R 65 is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, and fluorenylmethoxycaronyl (FMOC);
R 66 is selected from the group consisting of hydrogen and C1-C6 alkyl and fluorenylmethoxycaronyl (FMOC);
R 67 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R 3 is a lower alkyl group;
R 4 is H or OH;
R 5 is H or OH;
R 4 and R 5 may be taken together to form a second bond between C 13 and C 14;
R 6 is selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (C1-C6)alkyl, (C3-C8)cycloalkyl, substituted C3-C8 cycloalkyl, substituted (C1-C6)alkyl, a group of the formula III':

and a group of the formula III'':

R 7 is H or a lower alkyl group;
R 8 is H or a lower alkyl group;
R 9 is H or a lower alkyl group;
R 10 is H or a lower alkyl group;
R 11 is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl;

R 15, R 16, and R 17 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, OR 18, halo, NR 18 R 19 , NO2, OPO4H2, OR 19 phenyl, SCH2phenyl, CONH2, CO2H, PO3H2, SO2R23, and ZZ;
R 18 is selected from the group consisting of hydrogen, aryl, and C1-C6 alkyl;
R 18 is selected from the group consisting of hydrogen and (C1-C6)alkyl;
R 19 is C1-C6 alkyl;
R 19 is selected from the group consisting of hydrogen and (C1-C6)alkyl;
R 23 is selected from the group consisting of hydrogen and (C1-C3)alkyl;
R 30 is hydrogen or C1-C6 alkyl;

R 50 is hydrogen or ;
n is 0, 1, or 2;
p is 0, 1, or 2;
m is 0, 1, or 2;
q is 2, 3, or 4;
X is O, NH or alkylamino;
Y is C, O, NH, S, SO, SO2 or alkylamino;
Z is selected from the group consisting of -(CH2) n-, -(CH2)p-O-(CH2)m- and (C3-C5)cycloalkyl;
ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group.
10. A process of Claim 7 wherein the solvent is toluene.
11. A process of Claim 7 wherein Ar is aromatic or substituted aromatic.
12. A process of Claim 7 wherein R 30 is hydrogen, R 7 and R 8 are each methyl, X is O, Y is O, and R 50 is a group of the formula
13. A process of Claim 7 wherein R 30 is hydrogen, one of R 7 and R 8 is methyl, X ls o, Y is O, and R 50 is a group of the formula
CA002264527A 1996-09-06 1997-09-05 Process to prepare pharmaceutical compounds Abandoned CA2264527A1 (en)

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