US5466834A — Preparation of substituted isoserine esters using…

Claim 1

Independent Claim 277 words

A process for the preparation of an isoserine ester having the formula ##STR50## comprising reacting a β-lactam with the metal alkoxide of a secondary or tertiary alcohol, the β-lactam having the formula ##STR51## and the alkoxide having the formula ##STR52## wherein R 1 is --OR 6 , --SR 7 , or --NR 8 R 9 ; R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R 3 and R 4 are not both acyl; R 5 is --COR 10 , --COOR 10 , --COSR 10 , --CONR 8 R 10 , --SO 2 R 11 , or --POR 12 R 13 , R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group, R 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 9 is an amino protecting group; R 10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, R 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 , R 12 and R 13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 , and R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; M is a Group IA, IIA, IIIA, IVA, VA, VIA or transition metal, zinc, or cadmium; E 1 and E 2 and the carbon to which they are attached comprise a carbocyclic or heterocyclic skeleton containing about 6 to 20 ring atoms, the hetero atoms being oxygen; and E 3 is hydrogen or a hydrocarbon.

Claim 2

Dependent Claim 277 words

A process for the preparation of an isoserine ester having the formula ##STR50## comprising reacting a β-lactam with the metal alkoxide of a secondary or tertiary alcohol, the β-lactam having the formula ##STR51## and the alkoxide having the formula ##STR52## wherein R 1 is --OR 6 , --SR 7 , or --NR 8 R 9 ; R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R 3 and R 4 are not both acyl; R 5 is --COR 10 , --COOR 10 , --COSR 10 , --CONR 8 R 10 , --SO 2 R 11 , or --POR 12 R 13 , R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group, R 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 9 is an amino protecting group; R 10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, R 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 , R 12 and R 13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 , and R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; M is a Group IA, IIA, IIIA, IVA, VA, VIA or transition metal, zinc, or cadmium; E 1 and E 2 and the carbon to which they are attached comprise a carbocyclic or heterocyclic skeleton containing about 6 to 20 ring atoms, the hetero atoms being oxygen; and E 3 is hydrogen or a hydrocarbon.

Claim 3

Dependent Claim 62 words

The process of claim 1 wherein R 1 is --OR 6 ; R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 5 is --COR 10 or --COOR 10 ; R 6 is a hydroxy protecting group; and R 10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl.

Claim 4

Dependent Claim 14 words

The process of claim 1 wherein the metal alkoxide comprises the tricyclic taxane nucleus.

Claim 5

Dependent Claim 129 words

The process of claim 1 wherein the metal alkoxide comprises the tricyclic taxane nucleus; R 1 is --OR 6 or --SR 7 ; R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 5 is --COR 10 , --COOR 10 , --COSR 10 , --CONR 8 R 10 , or --SO 2 R 11; R 6 is a hydroxy protecting group; R 7 is a sulfhydryl protecting group, R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, R 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 ; and R 14 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl.

Claim 6

Dependent Claim 14 words

The process of claim 1 wherein the metal alkoxide comprises the tetracyclic taxane nucleus.

Claim 7

Dependent Claim 130 words

The process of claim 1 wherein the metal alkoxide comprises the tetracyclic taxane nucleus; R 1 is --OR 6 or --SR 7 ; R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 5 is --COR 10 , --COOR 10 , --COSR 10 , --CONR 8 R 10 , or --SO 2 R 11 ; R 6 is a hydroxy protecting group; R 7 is a sulfhydryl protecting group, R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, R 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 ; and R 14 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl.

Claim 8

Dependent Claim 58 words

The process of claim 1 wherein M is sodium, potassium, lithium, magnesium, titanium, zirconium, zinc or cadmium; R 1 is --OR 6 ; R 5 is --COR 10 , --COOR 10 , or --CONR 8 R 10 ; R 6 and R 8 are as defined in claim 1; and R 10 is alkyl, phenyl, furyl or thienyl.

Claim 9

Dependent Claim 35 words

The process of claim 1 wherein R 5 is --COR 10 , and R 10 is phenyl, methoxy, ethoxy, tert-butoxy or ##STR53## wherein X is Cl, Br, F, CH 3 O-- or NO 2 --.

Claim 10

Dependent Claim 30 words

The process of claim 1 wherein R 3 is ##STR54## wherein Ph is phenyl, Me is methyl, and X is Cl, Br, F, CH 3 O-- or NO 2 --.

Claim 11

Dependent Claim 39 words

A process as set forth in claim 1 wherein the metal alkoxide has the formula ##STR55## wherein Ph is phenyl, Ac is acetyl, Z is --OCOCHB or --OT 2 and T 1 and T 2 are hydroxy protecting groups.

Claim 12

Dependent Claim 94 words

A process as set forth in claim 1 wherein the metal alkoxide has the formula ##STR56## Z is --OCOCH 3 or --OT 2 ; T 1 and T 2 are hydroxy protecting groups; M is as defined in claim 46; Ph is phenyl; Ac is acetyl; R 1 is --OR 6 ; R 2 is hydrogen; R 3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 4 is hydrogen; R 5 is --COR 10 or --COOR 10 ; R 6 is a hydroxy protecting group; and R 10 is alkyl, alkenyl, aryl or heteroaryl.

Claim 13

Dependent Claim 278 words

A process for the preparation of a taxane comprising: reacting an alkoxide having the formula MOCE 1 E 2 E 3 with a β-lactam to form an intermediate and converting the intermediate to the taxane, wherein the β-lactam has the formula: ##STR57## M is a Group IA, IIA, ILIA, IVA, VA, VIA or transition metal, zinc or cadmium; one of E 1 , E 2 and E 3 is hydrogen or a hydrocarbon and the other two of E 1 , E 2 and E 3 together with the carbon to which they are attached comprise a taxane nucleus, R 1 is --OR 6 , --SR 7 , or --NR 8 R 9 ; R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R 3 and R 4 are not both acyl; R 5 is --COR 10 , --COOR 10 , --CONR 8 R 10 , --COSR 10 , --SO 2 R 11 , or --POR 12 R 13 ; R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group; R 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 9 is an amino protecting group; R 10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 ; R 12 and R 13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 ; and R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl.

Claim 14

Dependent Claim 278 words

A process for the preparation of a taxane comprising: reacting an alkoxide having the formula MOCE 1 E 2 E 3 with a β-lactam to form an intermediate and converting the intermediate to the taxane, wherein the β-lactam has the formula: ##STR57## M is a Group IA, IIA, ILIA, IVA, VA, VIA or transition metal, zinc or cadmium; one of E 1 , E 2 and E 3 is hydrogen or a hydrocarbon and the other two of E 1 , E 2 and E 3 together with the carbon to which they are attached comprise a taxane nucleus, R 1 is --OR 6 , --SR 7 , or --NR 8 R 9 ; R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R 3 and R 4 are not both acyl; R 5 is --COR 10 , --COOR 10 , --CONR 8 R 10 , --COSR 10 , --SO 2 R 11 , or --POR 12 R 13 ; R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group; R 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 9 is an amino protecting group; R 10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 ; R 12 and R 13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 ; and R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl.

Claim 15

Dependent Claim 14 words

The process of claim 2 wherein the metal alkoxide comprises the tricyclic taxane nucleus.

Claim 16

Dependent Claim 14 words

The process of claim 5 wherein the metal alkoxide comprises the tetracyclic taxane nucleus.

Claim 17

Dependent Claim 110 words

A process for the preparation of taxol comprising reacting a metal alkoxide with a β-lactam wherein, the metal alkoxide has the formula ##STR58## the β-lactam has the formula: ##STR59## Z is --OCOCH 3 or --OT 2 , T 1 is a hydroxy protecting group, T 2 is a hydroxy protecting group, Ph is phenyl, Ac is acetyl, M is a Group IA, IIA, IIIA, IVA, VA or VIA or transition metal, zinc, or cadmium, R 1 is --OR 6 , R 2 is hydrogen, R 3 is phenyl, R 4 is hydrogen, R 5 is --COR 10 , R 6 is a hydroxy protecting group, and R 10 is phenyl.

Claim 18

Dependent Claim 110 words

A process for the preparation of taxol comprising reacting a metal alkoxide with a β-lactam wherein, the metal alkoxide has the formula ##STR58## the β-lactam has the formula: ##STR59## Z is --OCOCH 3 or --OT 2 , T 1 is a hydroxy protecting group, T 2 is a hydroxy protecting group, Ph is phenyl, Ac is acetyl, M is a Group IA, IIA, IIIA, IVA, VA or VIA or transition metal, zinc, or cadmium, R 1 is --OR 6 , R 2 is hydrogen, R 3 is phenyl, R 4 is hydrogen, R 5 is --COR 10 , R 6 is a hydroxy protecting group, and R 10 is phenyl.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1998-11-13	1999-05-15	1999-11-14	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2002-11-13	2003-05-15	2003-11-14	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2006-11-13	2007-05-15	2007-11-14	$7700.00	Window Closed / Lapsed

Preparation of substituted isoserine esters using metal alkoxides and .beta.

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