Claims
- 1. A process for the synthesis of a compound of Formula A: ##STR16## wherein R.sup.1 represents H, alkyl, substituted alkyl, --OH, --OC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, --C.sub.1-4 alkyl aryl, optionally substituted aryl, or an optionally substituted allyl;
- R.sup.2 and R.sup.3 independently at each occurance represent H, or a group selected from --C.sub.1 -C.sub.6 alkyl, --C.sub.3 -C.sub.6 cycloalkyl aryl, --C.sub.2-8 alkenyl, --C.sub.1-6 alkoxy, --C.sub.1-4 alkyl aryl, and aryl, said group optionally substituted with halogen, --C.sub.1-4 alkyl, --C.sub.1-4 alkoxy, allyl, heteroaryl, --SC.sub.1-4 alkyl, --OC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, or benzyl;
- R.sup.4 represents H or R.sup.5 ;
- R.sup.5 represents C.sub.4-10 branched alkyl or cyclo alkyl, --C.sub.1-4 alkyl-N(R.sup.6).sub.2, --C.sub.2-6 alkynyl, halo substituted C.sub.1-10 alkyl, --C.sub.2-4 alkenyl, aryl, --C.sub.1-8 alkyl, heteroaryl, --C.sub.1-4 alkyl aryl, said --C.sub.1-8 alkyl, --C.sub.2-14 alkenyl, --C.sub.1-4 alkyl aryl, and aryl optionally substituted with one to tour substituents independently selected from a group consisting of halogen, --C.sub.1 -C.sub.6 alkyl, --C.sub.1-6 alkoxy, --CF.sub.3, --SC.sub.1-6 alkyl, P(O)(OCH.sub.3).sub.2, --S--(CH.sub.2).sub.0-4 aryl, --O--(CH.sub.2).sub.0-4 aryl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
- R.sup.6 represents --C.sub.1-4 alkyl, phenyl, H, --C.sub.1-4 alkyl aryl, and heterocyclyl;
- X represents --OH, or --NH.sub.2 ;
- the process comprising:
- (a) reacting a compound of Formula 2
- SS--X Formula 2
- with a compound of Formula 3 ##STR17## in the presence of a coupling agent, wherein PG represents an amino protecting group;
- X, and R.sup.1 are as defined earlier,
- to yield a compound of Formula 4 ##STR18## wherein Y represents --NH--, or --O--; SS represents a solid support; and
- R.sup.1, and PG are as defined above;
- (b) treating a compound of Formula 4 with a deprotecting agent to yield a compound of Formula 5 ##STR19## wherein SS, Y, and R.sup.1 are as defined above; (c) reacting the compound of Formula 5 with a compound of Formula 6a ##STR20## or a compound of Formula 6b ##STR21## in the presence of a coupling agent, to yield a compound of Formula 7 ##STR22## or a compound of Formula 9 respectively ##STR23## wherein SS, Y, R.sup.1, R.sup.2, and R.sup.3 are as defined above; (d) reacting a compound of Formula 7 with a compound of Formula 8 ##STR24## to yield a compound of Formula 9 ##STR25## where SS, Y, R.sup.1, R.sup.2, and R.sup.3 are as defined above; (e) reacting the compound of Formula 9 with a compound of Formula 10 ##STR26## to yield a compound of Formula 11 ##STR27## where SS, Y, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined above; (f) optionally alkylating a compound of Formula 11, wherein R.sup.4 is H, with a compound of Formula 12
- R.sup.5 --OH Formula 12
- to yield a compound of Formula 11, wherein R.sup.4 is R.sup.5 ; and
- (g) treating a compound of Formula 11 with a cleaving agent to yield compound of Formula A.
- 2. A process of claim 1 wherein:
- R.sup.1 represents H, --C.sub.1-4 alkyl, substituted alkyl, optionally substituted aryl, or --C.sub.1-4 alkyl aryl; and
- R.sup.2 and R.sup.3 independently at each occurance represent H, --C.sub.1 -C.sub.4 alkyl, --C.sub.1-4 alkyl aryl, or aryl, said alkyl, alkyl aryl, and aryl groups optionally substituted with halogen, --C.sub.1-4 alkyl, --SC.sub.1-4 alkyl, --OC.sub.1-4 alkyl, --N(C.sub.1-4 alkyl).sub.2, or benzyl.
- 3. A process of claim 2 wherein the coupling agents in steps (a) and (c) are selected from a group consisting of PyBop, HBTU, TBTU, TNTU, TSTU, HOBT, DIC, DCC, HATU, and HOAT.
- 4. A process of claim 3 wherein steps (a) and (c) are independently carried out in the presence of a tertiary amine.
- 5. A process of claim 4 wherein the coupling agent is PyBop, HOBT, DIC, or DCC; and the tertiary amine is N-methyl morpholine, or diisopropyl amine.
- 6. A process of claim 3 wherein step (d) comprises a deprotecting agent selected from a group consisting of piperidine, morpholine, dicyclohexyl amine, p-dimethyl aminopyridine, diisopropyl ethyl amine, triethyl amine, and tetrabutyl ammonium fluoride.
- 7. A process of claim 6 wherein the deprotecting agent is a 10 to 50% solution of piperidine in DMF, THF, DMA, or DCM.
- 8. A process of claim 3 wherein step (d) comprises a basic reagent selected from a group consisting of DBU, DBN, DABCO, triethyl amine, diisopropyl ethyl amine; and
- a solvent selected from a group selected from THF, acetonitrile, dioxane, and DCM.
- 9. A process of claim 8 wherein the basic reagent is DBU, and the solvent is THF.
- 10. A process of claim 3 wherein step (e) is carried out in the presence of iodobenzene diacetate [Phl(OAc).sub.2 ].
- 11. A process of claim 10 wherein when R.sup.4 =H, step (e) is carried out in the presence of at least one of dioxane and THF.
- 12. A process of claim 3 wherein step (f) is performed in the presence of DEAD or DIAD; and
- at least one of triphenylphosphine and tributyl phosphine.
- 13. A process of claim 3 wherein the cleaving agent in step (g) is selected from HCl, and TFA.
Parent Case Info
This application claims the benefit under 35 U.S.C Sec. 119 (e)(1) of prior filed U.S. Provisional Application 60/097,443 filed Aug. 21, 1998.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
4307094 |
Hassall et al. |
Dec 1981 |
|
Non-Patent Literature Citations (1)
Entry |
Boldi et al, Chemical Abstracts, vol. 130, abstract 223211, 1999. |