Classifications

• • 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
  • 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
  • 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

Definitions

• This invention relates to the fields of pharmaceutical and organic chemistry and provides a process for preparing cryptophycin compounds useful as anti- microtubule agents.
• Cryptophycin compounds can be useful for the treatment of cancer and neoplasms, and are thus useful pharmaceutical agents.
• the literature discloses a protocol for cyclizing certain cryptophycin compounds.
• This three-step sequence (hereinafter "Barrow synthetic sequence") commenced with the conversion of trichloroethyl ester to the corresponding carboxylic acid using zinc and acetic acid. Conversion of crude to the amino carboxylate was accomplished with trifluoroacetic acid followed by an aqueous basic work-up.
• the presently claimed process provides a shorter (two-steps) process which is more adaptable for large scale or commercial preparation of the macrocyclic core of cryptophycin derivatives.
• the claimed process can reduce reagent expense, as well as minimize the potential waste-stream issues associated with the use of certain reagents in the Barrow synthetic sequence. Further, purification via the claimed process may be accomplished without chromatography, which is expensive and difficult to implement on a large scale.
• the presently claimed invention provides a process for preparing a compound of Formula II
• Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, d-Ci? alkyl, C?-C ⁇ 2 alkenyl, C 6 -C 1? alkynyl, NR 51 R 52 , COR 5 , OR 5 ', and Formula Ar'
• R >5 3 1 1 is selected from the group consisting of hydrogen and C- C 3 alkyl
• R 5 is selected from the group consisting of hydrogen and d ⁇ C 3 alkyl
• R 53 is selected from the group consisting of C ⁇ C ⁇ 2 alkyl
• R 54 is selected from the group consisting of hydrogen, d ⁇ C 6 alkyl, Ci-dalkyl (R 5 ' R 57" R 57'” ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) - benzyltriphenylphosophonium, COOR 57 , P0 3 H, S0 3 H, S0 2 R 5 ⁇ , N(R 59 )R 60 , NHCHR 61 ', CN, NO?, halogen, OR 62 , CH 2 (0)R 6 ", -
• R 95 is selected from the group consisting of -R 98 NH 3 ;
• R 9b and R 96' are each independently selected from the group consisting of hydrogen and d-C 6 alkyl, -R 97 NH 3 , and -R 99 NR 99' R 99" ;
• R 97 is selected from the group consisting of C ⁇ -C fe alkyl;
• R 98 is selected from the group consisting of d-Ce alkyl;
• R 99 is d-C 6 alkyl;
• R 99' and R 9C " ' are each independently selected from the group consisting of hydrogen and C ⁇ -C 6 alkyl;
• R 100 is selected from the group consisting of hydrogen, and s i ( R 1 0 , R 1 02 R 10 3 ) .
• R 101 is C ⁇ -C 6 alkyl
• R o? i s d-Ce, alkyl ;
• R 103 is C -C 6 al kyl
• R 104 is selected from the group consisting of C ( 0) d -C 6 alkylN (R 10fa ) (R 59 ) R 60 , C ( 0) d-C 6 alkylN + , fused bicyclic, and
• R 105 is selected from the group consisting of C(0,d-C 6 alkyl,
• R 106 is selected from the group consisting of hydrogen, -d alkyl, C(0)OR 107 ;
• R 107 is selected from the group consisting of hydrogen, d _ d alkyl, CR 108 R 109 R no
• R 108 is selected from the group consisting of hydrogen and C ⁇ -C 6 alkyl
• R 109 is selected from the group consisting of hydrogen and
• R 110 is selected from the group consisting of hydrogen and d-C 6 alkyl
• R 55 is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl, C (R 57' R 57" R 57'” ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR 57 , P0 3 H, S0 3 H, S0 2 R 58 ,
• R 5b i s selected from the group consisting of hydrogen, C ⁇ -C b al kyl , C ( R 7 ' R 57 " R 57" ' ) , simple unsubstituted aromat ic, simple substituted aromatic , phenyl , COOR f57 , P0 3 H, S0 3 H, S0 2 R 58 ,
• R ⁇ is selected from the group cons i sting o f hydrogen and d -
• 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 C ⁇ C ⁇ 2 alkyl
• R 57'" is selected from the group consisting of hydrogen, halogen, and d-C 12 alkyl
• R 58 is selected from the group consisting of hydrogen and Cj- C 1? alkyl
• R 59 is selected from the group consisting of hydrogen, (C ⁇
• C fc alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC) ;
• R 60 is selected from the group consisting of hydrogen and (Ci-d) alkyl
• R 61 is selected from the group consisting of hydrogen, OR 1 ' 4 ,
• R 61' is selected from the group consisting of hydrogen, OR 64 ,
• R 6? is selected from hydrogen, and d-C b alkyl
• R 62' is selected from hydrogen, OH, OR 62 , and d ⁇ C b alkyl
• R bi is selected from hydrogen and Cj-d, alkyl
• R 64 is selected from the group consisting of hydrogen, (Ci-
• R G5 is selected from the group consisting of hydrogen and Ci-
• R 65' is selected from the group consisting of hydrogen and
• R 66 is selected from the group consisting of hydrogen and Ci- d alkyl and fluorenylmethoxycarbonyl (FMOC) ;
• R 6 ' is selected from the group consisting of hydrogen and Ci-
• 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 3 and d
• 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 (d-C 6 ) alkyl, (d-C 8 ) cycloalkyl, substituted C 3 -C 8 cycloalkyl, substituted (C,-C b ) alkyl, a group of the formula III'
• R 7 is selected from the group consisting of NR R ',? , R 53 NR R 5? , OR 53 , H and a lower alkyl group;
• R 51 and R " ' 2 are independently selected from the group consisting of d _ d alkyl;
• R 53 is d ⁇ C 3 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-C 3 -d cycloalkyl, and benzyl;
• R 10 is H or a lower alkyl group;
• R n is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl;
• R ⁇ r ', R l , and R 1 ' are each independently selected from the group consisting of hydrogen, OR 18 , halo, NR 18' R 19' , N0 2 ,
• R 18 is selected from the group consisting of hydrogen, aryl,
• R 18' is selected from the group consisting of hydrogen, (d-
• R 19 is Ci- alkyl, C(0)R 9n" and fluorenylmethoxycarbonyl
• R 19' is selected from the group consisting of hydrogen, (d ⁇ C alkyl, and C (0) R 90'" ;
• R 90 , R 90' , R 90" , and R 90" ' are each independently selected from the group consisting of hydrogen, (Ci-d) alkyl, OR 91' and aryl;
• R 91' is selected from the group consisting of (Ci-d) alkyl, aryl, and hydrogen;
• R 23 is selected from the group consisting of hydrogen and
• R 30 is hydrogen or Ci- alkyl
• R 3 ⁇ may be taken together with the N at C-11 to form a three to seven me bered cyclic ring
• R 50 is hydrogen or n is 0, 1, or 2; m is 0, 1, or 2; -1-
• p 0, l,or 2;
• X is selected from the group consisting of 0, C, S, NH and alkylamino
• Y is selected from the group consisting of C, O, NH, S, SO,
• Z is selected fromt he group consisting of -(CH 2 ) n -, -(CH ? ) P -
• 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
• M is selected from the group consisting of hydrogen, Na, Li, K, and Cs;
• X cat is selected from the group consisting of 0, N, and S;
• y cat _ s selected from the group consisting of 0, N, and S;
• Rca tl i s selected from the group consisting of C ⁇ C 6 alkyl and aryl
• R cat2 is selected from the group consisting of C ⁇
• Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, C] -C ⁇ 2 al kyl , C 2 -C J 2 alkenyl, C 2 -C 12 alkynyl, NRbl l rR-,52 COR s OR 53 and Formula Ar'
• R 51 is selected from the group consisting of hydrogen and Ci- C 3 alkyl
• R 52 is selected from the group consisting of hydrogen and d ⁇
• R 53 is selected from the group consisting of C ⁇ -C ⁇ 2 alkyl
• R is selected from the group consisting of hydrogen, Ci- alkyl, d ⁇ dalkyl (R 5 ' R b7" R 57'" ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) - benzyltriphenylphosophonium, COOR 57 , PO ⁇ H, S0 3 H, S0 7 R 5 ⁇ , N(R 59 )R 60 , NHOR 61 , NHCHR 61' , CN, N0 2 , halogen, OR 62 , CH 2 (0)R ⁇ ?'
• R is selected from the group consisting of -R NH 3 ;
• R 96 and R 96' are each independently selected from the group consisting of hydrogen and Ci- alkyl, -R 9 NH 3 , and -R 9 NR 99'
• R 97 is selected from the group consisting of C ⁇ -C h alkyl
• R 98 is selected from the group consisting of C]-C f , alkyl; R 99 is Ci-Ce alkyl;
• R 99' and R 99" are each independently selected from the group consisting of hydrogen and d _ alkyl;
• R 100 is selected from the group consisting of hydrogen
• R 101 is d-Ce alkyl
• R 102 is d-d alkyl
• R 103 is d-d alkyl
• R 104 is selected from the group consisting of C(0)C ⁇ -C b alkylN(R 106 ) (R 59 )R B0 , C (0) C,-C 6 alkylN + , fused bicyclic, and NHR 105 N(R 106 ) (R f,9 )R 60 ;
• R 105 is selected from the group consisting of C(0)d-C 6 alkyl
• R 106 is selected from the group consisting of hydrogen, C ⁇ C 6 alkyl, C(0)OR 107 ; R 107 is selected from the group consisting of hydrogen, C ⁇ C alkyl, CR 108 R 109 R 110
• R 108 is selected from the group consisting of hydrogen and
• R 109 is selected from the group consisting of hydrogen and d-d alkyl
• R o is selected from the group consisting of hydrogen and
• Ci-d alkyl is selected from the group consisting of hydrogen, d-C b alkyl, and C(0)0R 107
• R 55 is selected from the group consisting of hydrogen, d ⁇ d alkyl, C (R 57' R 57" R 5 ' "' ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR 57 , P0 3 H, S0 3 H, S0 2 R 58 ,
• R 56 is selected from the group consisting of hydrogen, C ⁇ d alkyl, C (R 7' R ' " R h7'" ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR 57 , P0H, S0 3 H, S0 ? R 58 , NR b9 R 60 , NHOR 61 , NHCHR 61' , (C,-C 6 ) alkylNR b9 R G0 , CN, NO , halogen,
• R 57 is selected from the group consisting of hydrogen and d- d? alkyl
• R 57' is selected from the group consisting of hydrogen, halogen, and d-C 12 alkyl
• R 57" is selected from the group consisting of hydrogen, halogen, and C ⁇ -C 12 alkyl
• R 57'" is selected from the group consisting of hydrogen, halogen, and C ⁇ -C ⁇ 2 alkyl;
• R 58 is selected from the group consisting of hydrogen and d-
• R 59 is selected from the group consisting of hydrogen, (Ci-
• R 60 is selected from the group consisting of hydrogen and (d-d) alkyl;
• R 61 is selected from the group consisting of hydrogen, OR ,
• R 61' is selected from the group consisting of hydrogen, OR 64 , CH 2 NHR 65 , NHR 65' and fluorenylmethoxycarbonyl (FMOC) ;
• R 62 is selected from hydrogen, and C _ alkyl
• R 62' is selected from hydrogen, OH, OR 62 , and Ci-d alkyl
• R 63 is selected from hydrogen and Ci- alkyl
• R b4 is selected from the group consisting of hydrogen, (Ci-
• R 65 is selected from the group consisting of hydrogen and d-
• R 65' is selected from the group consisting of hydrogen and
• R 66 is selected from the group consisting of hydrogen and d-
• R 67 is selected from the group consisting of hydrogen and d- C b alkyl
• R J is a lower alkyl group
• R 4 is H or OH
• R ' is H or OH
• R 4 and R 5 may be taken together to form a second bond between C 13 and d 4 ;
• 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
• R 7 is selected from the group consisting of NR 51 R 5? , R 53 NR 51 R 51 ,
• R 51 and R 52 are independently selected from the group consisting of C 1 -C3 alkyl;
• R 53 is Ci- C 3 alkyl;
• R 8 is H or a lower alkyl group
• R 7 and R e can form a cyclopropyl ring
• R 9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-C 3 -C b 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 lb , R 16 , and R 17 are each independently selected from the group consisting of hydrogen, OR 18 , halo, NR 18' R 19' , N0 2 ,
• R 18 is selected from the group consisting of hydrogen, aryl, d-C 6 alkyl, C(0)R 90 and fluorenylmethoxycarbonyl (FMOC);
• R 18' is selected from the group consisting of hydrogen, (Ci-
• R 19 is d-Ce alkyl, C(0)R 90" and fluorenylmethoxycarbonyl ( MOC) ;
• R :9' is selected from the group consisting of hydrogen, (Ci-
• R 90 , R 90' , R 90" , and R 90'" are each independently selected from the group consisting of hydrogen, (Ci-Ce) alkyl, OR 91' and aryl; R 91 ' is selected from the group consisting of (C ⁇ -d) alkyl, aryl, and hydrogen;
• R 2J is selected from the group consisting of hydrogen and
• R 30 is hydrogen or C ⁇ C 6 alkyl
• R 30 may be taken together with the N at C-11 to form a three to seven membered cyclic ring; o
• 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 0, C, S, NH and alkylamino
• Y is selected from the group consisting of C, 0, NH, S, SO, S0 2 and alkylamino;
• Z is selected fromt he group consisting of -(CH 2 ) n -, - (CH?) P - 0-(CH 2 ) m - and (C 3 -C 5 ) cycloalkyl;
• ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof.
• the term "simple alkyl” shall refer to C 2. -C 7 alkyl wherein the alkyl may be saturated, unsaturated, branched, or straight chain. Examples include, but are in no way limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, propenyl, ethenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, methylated pentyl groups and the like.
• alkenyl refers to an alkyl group, as defined above, having from one to three double bonds.
• alkynyl refers to an alkyl group, as defined above, having at least one triple bond. It is especially preferred that alkynyl has only one triple bond.
• the Ci-Cn 1 alkyl can be straight or branched chain.
• B-ring Ci-C ⁇ alkyl refers to saturated, unsaturated, branched and straight chain alkyl wherein the B-ring Ci-C ⁇ alkyl group may include up to three (3) non-carbon substituents.
• non-carbon substituents are most preferredly selected from the group) consisting of OH, SCH phenyl, NH 2 , CO, CONH 2 , C0 2 H, P0 3 H 2 ,
• R 21 is selected from hydrogen and C 3. -C 3 alkyl
• (Ci-C ⁇ ) alkyl linker refers to Ci-C ⁇ alkyl group having from zero to three substituents selected from the group consisting of C ⁇ -C6 alkyl, NH 2 and amino acid.
• amino acid means an organic acid containing an amino group.
• the term includes both naturally occuring and synthetic amino acids, therefore, the amino group can be, but is not required to be, attached to the carbon next to the acid.
• the term shall refer to, but is in no way limited to (CH ) 2 NH 2 COOH, (CH 2 ) 3 NH 2 COOC(CH 3 ) 3 , CH 2 NH 2 COOC (CH 3 ) 3 , CH 2 CH (NH 2 ) CH 2 COOH, CH 2 CH(NH 2 )CH 2 COOC(CH 3 )3, and the like.
• the term “carbohydrate” refers to a class of substituents made up of carbon, hydrogen, and oxygen wherein hydrogen and oxygen are in the same proportions as in water or nearly the proportions as water.
• the term “carbohydrate” further refers to an aldehyde or ketone alcohol or a compound which on hydrolysis produces and aldehyde or ketone.
• the term “carbohydrate” is as commonly understood by the skilled artisan. For example, the term refers to, but is in no way limited to, C ⁇ 2 H 2 0n and C 6 H 10 O 5 .
• amino sugar refers to a carbohydrate group containing from one to three amino substituents at any available position on the carbohydrate molecule .
• saccharide refers to carbohydrate subunits to form disaccharides or polysaccharides .
• the term means for example, but in no way limited to, lactose, maltose, sucrose, fructose, starch, and the like.
• substituted phenyl shall refer to a phenyl group with from one to three non- hydrocarbon substituents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I.
• substituted benzyl shall refer to a benzyl group with from one to three non- hydrocarbon substitutents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I wherein such substituents may be attached at any available carbon atom.
• B-ring heterocyclic group refers to aromatic or unsaturated rings which contain one or more non-carbon substituent selected from the group consisting of oxygen, nitrogen, and sulfur. Especially preferred B-ring heterocyclic groups are selected from, but not limited to, the group consisting of
• R 20 is selec ed from hydroge alkyl. wherein R 20 is selected from hydrogen and Ci-C ⁇ alkyl.
• B-ring heteroaromatic group refers to a substituent selected from the group consisting of:
• cycloalkyl refers to a saturated C-C cycloalkyl group wherein such group may include from zero to three substituents selected from the group consisting of C 1 -C 3 alkyl, halo, and OR 22 wherein R 22 is selected from hydrogen and C 1 -C 3 alkyl. Such substituents may be attached at any available carbon atom. It is especially preferred that cycloalkyl refers to substituted or unsubstituted cyclohexyl.
• Lower alkoxyl group means any alkyl group of one to five carbon atoms bonded to an oxygen atom.
• lower alkyl group means an alkyl group of one to five carbons and includes linear and non- linear hydrocarbon chains, including for example, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, and methylated pentyl groups.
• allylically substituted alkene means any alkene having from one to seven carbon atoms which contains an alkyl substitution on it.
• unsaturated lower alkyl means a lower alkyl group as defined supra , wherein from one to two double bonds are present in the unsaturated lower alkyl substituent.
• lower alkyl-C 3 ⁇ C 5 cycloalkyl refers to C-C alkyl substituted with a C 3 -C 5 cycloalkyl group.
• a preferred lower alkyl-C 3 ⁇ C 5 cycloalkyl group is -CH 2 -cyclopropyl; wherein the group is attached to the cryptophycin core structure at R 9 via the CH 2 .
• epoxide ring means a three- membered ring whose backbone consists of two carbons and an oxygen atom.
• aziridine ring means a three-me bered ring whose backbone consists of two carbon atoms and a nitrogen atom.
• sulfide ring means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom.
• episulfide ring means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom.
• sulfate group means a five membered ring consisting of a carbon- carbon-oxygen-sulfur-oxygen backbone with two additional oxygen atoms connected to the sulfur atom.
• cyclopropyl ring means a three member ring whose backbone consists of three carbon atoms.
• monoalkylphosphate ring means a five membered ring consisting of a carbon-carbon-oxygen-phosphorous-oxygen backbone with two additional oxygen atoms, one of which bears a lower alkyl group, connected to the phosphorous atom.
• “simple unsubstituted group” refers to common aromatic rings having 4n+2 ⁇ electrons in a monocyclic conjugated system, for example, but not limited to: furyl, pyrrolyl, thienyl, pyridyl and the like, or a bicyclic conjugated system, for example but not limited to mdolyl or naphthyl.
• “simple substituted aromatic group” refers to a phenyl group substituted with a single group selected from the group consisting of halogen and lower alkyl group.
• fused bicyclic refers to two joined ring systems which are optionally independently saturated, unsaturated, or aromatic. Such groups include but are in no way limited to naphthyl, groups which fuse an unsaturated ring with an aromatic ring, groups having a heterocyclic group fused with a heteroaromatic group, and a heterocyclic group fused with an aromatic group.
• the fused bicyclic is optionally substituted with one or more substituents selected from the group consisting of Ci- alkyl and halogen.
• heteroaromatic group refers to aromatic rings which contain one or more non-carbon atoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. It is most preferred that the heteroaromatic group will have from three to eight members in the ring. It is especially preferred that the number of non-carbon members will be from one to three.
• heterocyclic refers to saturated or unsaturated rings containing one or more non carbon atoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. It is most preferred that the heterocyclic group will have from three to eight members m the ring. It is especially preferred that the number of non-carbon members will be from one to three.
• halogen or “halo” refers to those members of the group on the periodic table historically known as halogens. Methods of halogenation include, but are not limited to, the addition of hydrogen halides, substitution at high temperature, photohalogenation, etc., and such methods are known to the skilled artisan. Especially preferred halogens are chloro, bromo, fluoro, and lodo . For some purposes within the scope of this invention, chloro, bromo and fluoro are especially preferred halogens.
• Compounds of Formula III are particularly useful for the preparation of cryophycin compounds.
• the starting material corresponding to a compound of Formula 1 as illustrated in Scheme 1 can be prepared using the disclosures available to the skilled artisan. See Barrow, id.
• the processes for preparing compound 2 as illustrated in Scheme 1' used TFA; however, the artisan will recognize that alternative agents can be used in this process.
• the basic workup uses sodium hydroxide; however, the artisan will appreciate that other basic agents can be effective as well.
• the processes to prepare the compounds of this invention most preferably are completed m the presence of a solvent.
• a solvent selected from the group consisting of toluene, N,N-d ⁇ methylformamide, ethyl acetate, tetrahydrofuan, and acetonitrile.
• the reaction time is related to the starting materials and operating temperature. The optimum reaction time for a given process is, as always, a compromise which is determined by considering the competing goals of throughput, which is favored by short reaction times, and maximum yield, which is favored by long reaction times.
• the catalyst is most preferrably selected from the group consisting of alky and aryl substituted metal carboxylates, carboxylic acids, and other bifunctional compounds according to the Formula IV.
• Especially preferred catalysts are selected from the group consisting of 2-hydroxy ⁇ yridine, tetrabutylammonium cyanide and sodium benzoate/n-tetrabutylNHS0 4 .
• the filtered solution of amino ester 2 was diluted to 500 mL and 2-hydroxypyridine (5.34, 56.2 mmoles) was added. The resulting clear, pale yellow solution was allowed to stir at room temperature for 14 h. The reaction mixture became turbid so the suspension was diluted with CH2CI2 (250 mL) to assure solubility of product. The mixture was washed with saturated, aqueous NaHC0 3 (3 x 100 mL) and brine (1 x 100 L) . The aqueous extracts were back-extracted with CH 2 CI 2 (1 x 100 mL) and the organic extracts were combined, dried (MgS0 4 ) , and concentrated to a thick syrup.

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