Claims
- 1. A process of preparing a compound of the formula: ##STR70## wherein: V is --O-- N--CH.sub.3 ;
- W is --O--, --S--, --SO--, --SO.sub.2 --, --CO--, C.sub.2 -C.sub.6 alkylene, optionally protected substituted alkylene, C.sub.2 -C.sub.6 alkenylene, -aryl-, -aryl(CH.sub.2).sub.m O--, -heterocycle-, -heterocycle-(CH.sub.2).sub.m O-, -fused bicyclic-, -fused bicyclic-(CH.sub.2).sub.m O-, --NR.sub.3 --, --NOR.sub.3 --, --CONH--, or --NHCO--;
- X and Y are independently C.sub.1 -C.sub.4 alkylene, optionally protected substituted alkylene, or together X, Y, and W combine to form --(CH.sub.2).sub.n --AA--;
- R.sub.1 is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sub.4 R.sub.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sub.3 is hydrogen, (CH.sub.2).sub.m aryl, C.sub.1 -C.sub.4 alkyl, --COO(C.sub.1 -C.sub.4 alkyl), --CONR.sub.4 R.sub.5, --(C.dbd.NH)NH.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sub.4 R.sub.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 to 6 member ring;
- AA is an amino acid residue;
- m is independently 0, 1, 2, or 3; and
- n is independently 2, 3, 4, or 5; which comprises:
- Combining a mixture of a compound at a concentration of about 1.5 molar to about 0.001 molar of the formula: ##STR71## and an alkylating agent at a concentration of about 1.5 molar to about 0.001 molar of the formula: ##STR72## wherein: L is a leaving group;
- with about 0.5 to about 10 equivalents of Cs.sub.2 CO.sub.3 at a rate from about 0.1 mL/hour to about 2.0 mL/hour in a polar aprotic solvent.
- 2. The process of claim 1, which further comprises:
- Reacting a compound of the formula: ##STR73## wherein: V is N--CH.sub.3 ;
- with a base, selected from sodium hydroxide, potassium hydroxide, or a mixture thereof, in a solvent selected from an alcohol, DMSO and water, dioxane and water, or acetonitrile and water, at a temperature ranging from about 25.degree. C. to about reflux to form a compound of the formula: ##STR74## wherein: V is O; and
- Reacting a compound of the Formula IIb with an excess of a mixture of a reagent and a C.sub.1 -C.sub.4 alcohol in a polar aprotic solvent, said reagent being selected from hexamethyldisilazane or an ammonium salt.
- 3. The process of claim 1, which further comprises reacting a compound of the Formula: ##STR75## wherein: V is O;
- with an excess of a mixture of a reagent and a C.sub.1 -C.sub.4 alcohol in a polar aprotic solvent, said reagent being selected from hexamethyldisilazane or an ammonium salt.
- 4. A process of preparing a compound of the formula which comprises,
- Combining a compound at a concentration of about 3 molar to about 0.001 molar of the formula: ##STR76## wherein: L.sup.2 is independently a leaving group;
- V.sub.1 is --O--, NH, or N--CH.sub.3 ;
- W is --O--, --S--, --SO--, --SO.sub.2 --, --CO--, C.sub.2 -C.sub.6 alkylene, optionally protected substituted alkylene, C.sub.2 -C.sub.6 alkenylene, -aryl-, -aryl(CH.sub.2).sub.m O-, -heterocycle-, -heterocycle-(CH.sub.2).sub.m O-, -fused bicyclic-, -fused bicyclic-(CH.sub.2).sub.m O-, --NR.sub.3 --, --NOR.sub.3 --, --CONH--, or --NHCO--;
- X and Y are independently C.sub.1 -C.sub.4 alkylene or optionally protected substituted alkylene;
- R.sub.1 is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sub.4 R.sub.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sub.3 is hydrogen, (CH.sub.2).sub.m aryl, C.sub.1 -C.sub.4 alkyl, --COO(C.sub.1 -C.sub.4 alkyl), --CONR.sub.4 R.sub.5, --(C.dbd.NH)NH.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sub.4 R.sub.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring;
- m is independently 0, 1, 2, or 3;
- which comprises:
- Combining a compound at a concentration of about 3 molar to about 0.001 molar of the formula: ##STR77## wherein: L.sup.2 is a leaving group;
- with about 0.5 to about 10 equivalents of Cs.sub.2 CO.sub.3 at a rate from about 0.1 mL/hour to about 2.0 mL/hour in a polar aprotic solvent.
- 5. The process of claim 4, which further comprises:
- Reacting a compound of the Formula: ##STR78## wherein: V is N--CH.sub.3 ;
- with a base, selected from sodium hydroxide, potassium hydroxide, or a mixture thereof, in a solvent selected from an alcohol, DMSO and water, dioxane and water, or acetonitrile and water, at a temperature ranging from about 25.degree. C. to about reflux to form a compound of the formula: ##STR79## wherein: V is O; and
- reacting a compound of the Formula IIb with an excess of a mixture of a reagent and a C.sub.1 -C.sub.4 alcohol in a polar aprotic solvent, said reagent being selected from hexamethyldisilazane or an ammonium salt.
- 6. The process of claim 4, which further comprises:
- Reacting a compound of the Formula: ##STR80## wherein: V is O;
- with an excess of a mixture of a reagent and a C.sub.1 -C.sub.4 alcohol in an polar aprotic solvent, said reagent being selected from hexamethyldisilazane or an ammonium salt.
- 7. A process of claim 1, wherein the alkylating agent is of the formula ##STR81## wherein: R.sub.6 ' is --NR.sub.4 R.sub.5, protected amine, or protected hydroxy;
- Z is --(CH.sub.2)--.sub.p ;
- q is independently 2 or 3; and
- p is 0, 1, or 2.
- 8. The process of claim 7, wherein R.sub.6 ' is --O--triphenylmethyl.
- 9. A process of claim 4, wherein the compound is ##STR82## wherein: m is independently 2 or 3;
- Z is --(CH.sub.2).sub.p --;
- R.sub.6 ' is NR.sub.4 R.sub.5, protected amino, or protected hydroxy; and
- p is0, 1, or 2.
- 10. The process of claim 9, wherein R.sub.6 ' is --O--triphenylmethyl.
- 11. A process of preparing a compound of the formula: ##STR83## wherein V is --O-- or N--CH.sub.3 ;
- W is --O--, --S--, --SO--, --SO.sub.2 --, --CO--, C.sub.2 -C.sub.6 alkylene, optionally protected substituted alkylene, C.sub.2 -C.sub.6 alkenylene, -aryl-, -aryl(CH.sub.2).sub.m O-, -heterocycle-, -heterocycle-(CH.sub.2).sub.m O-, -fused bicyclic-, -fused bicyclic-(CH.sub.2).sub.m O-, --NR.sub.3 --, --NOR.sub.3 --, --CONH--, or --NHCO--;
- X and Y are independently C.sub.1 -C.sub.4 alkylene, optionally protected substituted alkylene, or together X, Y, and W combine to form --(CH.sub.2).sub.n --AA--;
- R.sub.1 is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sub.4 R.sub.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sub.3 is hydrogen, (CH.sub.2).sub.m aryl, C.sub.1 -C.sub.4 alkyl, --COO(C.sub.1 -C.sub.4 alkyl), --CONR.sub.4 R.sub.5, --(C.dbd.NH)NH.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sub.4 R.sub.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring;
- AA is an amino acid residue;
- m is independently 0, 1, 2, or 3; and
- n is independently 2, 3, 4, or 5; which comprises:
- Alkylating a compound of the formula: ##STR84## with an alkylating agent of the formula: ##STR85## wherein: L is a leaving group.
- 12. A process of preparing a compound of the formula: ##STR86## wherein: V.sub.1 is --O--, NH, or N--CH.sub.3 ;
- W is --O--, --S--, --SO--, --SO.sub.2 --, --CO--, C.sub.2 -C.sub.6 alkylene, optionally protected substituted alkylene, C.sub.2 -C.sub.6 alkenylene, -aryl-, -aryl(CH.sub.2).sub.m O-, -heterocycle-, -heterocycle-(CH.sub.2).sub.m O-, -fused bicyclic-, -fused bicyclic-(CH.sub.2).sub.m O-, --NR.sub.3 --, --NOR.sub.3 --, --CONH--, or --NHCO--;
- X and Y are independently C.sub.1 -C.sub.4 alkylene or optionally protected substituted alkylene;
- R.sub.1 is independently hydrogen, halo, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, haloalkyl, nitro, NR.sub.4 R.sub.5, or --NHCO(C.sub.1 -C.sub.4 alkyl);
- R.sub.3 is hydrogen, (CH.sub.2).sub.m aryl, C.sub.1 -C.sub.4 alkyl, --COO(C.sub.1 -C.sub.4 alkyl), --CONR.sub.4 R.sub.5, --(C.dbd.NH)NH.sub.2, --SO(C.sub.1 -C.sub.4 alkyl), --SO.sub.2 (NR.sub.4 R.sub.5), or --SO.sub.2 (C.sub.1 -C.sub.4 alkyl);
- R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring;
- m is independently 0, 1, 2, or 3;
- which comprises:
- Intramolecular alkylation of a compound of the formula: ##STR87## wherein: L.sup.2 is a leaving group.
Parent Case Info
This application is a division of application Ser. No. 08/413,735 filed Mar. 30, 1995 now pending which is a continuation-in-part of Heath et al., U.S. Ser. No. 08/316,973, filed Oct. 3, 1994 now abandoned, which is a continuation-in-part of Heath et al., U.S. Ser. No. 08/163,060, filed Dec. 7, 1993 now abandoned.
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Divisions (1)
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Continuation in Parts (2)
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316973 |
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