US5430160A — Preparation of substituted isoserine esters using…

Claim 1

Independent Claim 263 words

A process for the preparation of a substituted isoserine ester having the formula ##STR38## comprising reacting a β-lactam with an alkoxide, the β-lactam having the formula ##STR39## and the alkoxide having the formula ##STR40## 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 ; R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; M is an ammonium containing substituent; E 1 and E 2 and the carbon to which they are attached comprise a carbocyclic or a heterocyclic skeleton having about 6-20 ring atoms, the hereto atoms of the heterocyclic skeleton being oxygen; and E 3 is hydrogen or a hydrocarbon.

Claim 2

Dependent Claim 263 words

A process for the preparation of a substituted isoserine ester having the formula ##STR38## comprising reacting a β-lactam with an alkoxide, the β-lactam having the formula ##STR39## and the alkoxide having the formula ##STR40## 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 ; R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; M is an ammonium containing substituent; E 1 and E 2 and the carbon to which they are attached comprise a carbocyclic or a heterocyclic skeleton having about 6-20 ring atoms, the hereto atoms of the heterocyclic skeleton being oxygen; and E 3 is hydrogen or a hydrocarbon.

Claim 3

Dependent Claim 50 words

The process of claim 1 wherein M is tetraalkylammonium, R 1 is --OR 6 ; R 5 is --COR 10 , --COOR 10 , or --CONR 8 R 10 ; R 10 is alkyl, phenyl, furyl or thienyl; and R 6 and R 8 are as defined in claim 1.

Claim 4

Dependent Claim 35 words

The process of claim 2 wherein R 5 is --COR 10 , and R 10 is phenyl, methoxy, ethoxy, tert-butoxy or ##STR41## and X is Cl, Br, F, CH 3 O-- or NO 2 --.

Claim 5

Dependent Claim 35 words

The process of claim 1 wherein M is an ammonium containing substituent, R 3 is ##STR42## wherein Ph-is phenyl, Me is methyl, and X is Cl, Br, F, CH 3 O-- or NO 2 --.

Claim 6

Dependent Claim 205 words

A process as set forth in claim 1 wherein the alkoxide has the formula: ##STR43## wherein M is an ammonium containing substituent; R 15 is hydrogen or together with R 16 forms an oxo, R 16 is hydrogen, --OCOR 29 , hydroxy, or protected hydroxy, or together with R 15 forms an oxo; R 17 is hydrogen or together with R 18 forms an oxo, R 18 is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R 17 forms an oxo; R 19 is hydrogen; R 20 is halogen, protected hydroxy, or --OR 28 ; R 21 is hydrogen; R 22 is acyloxy or together with R 23 and the carbon atoms to which they are attached form an oxetane ring; R 23 together with R 24 forms an oxo, or together with R 22 and the carbon atoms to which they are attached form an oxetane ring; R 24 is hydroxy or --OCOR 30 ; R 25 is hydroxy, or --OCOR 31 ; R 26 is hydrogen; R 27 is hydroxy or protected hydroxy; R 28 is hydrogen, acyl, or hydroxy protecting group; and R 29 , R 30 , and R 31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl.

Claim 7

Dependent Claim 266 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 forman intermediate and converting the intermediate to the taxane, wherein the β-lactam has the formula: ##STR44## M is an ammonium containing substituent; 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, 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 , --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 8

Dependent Claim 266 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 forman intermediate and converting the intermediate to the taxane, wherein the β-lactam has the formula: ##STR44## M is an ammonium containing substituent; 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, 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 , --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 9

Dependent Claim 9 words

The process of claim 6 wherein M is tetraalkylammonium.

Claim 10

Dependent Claim 53 words

The process of claim 6 wherein M is tetraalkylammonium, R 1 is --OR 6 , the alkoxide has the formula ##STR45## Z is --OCOCH 3 or --OT 2 , T 1 and T 2 are hydroxy protecting groups, Ph is phenyl, Ac is acetyl and R 6 is as defined in claim 6.

Claim 11

Dependent Claim 35 words

The process of claim 6 wherein R 5 is --COR 10 , and R 10 is phenyl, methoxy, ethoxy, tert-butoxy or ##STR46## and X is Cl, Br, F, CH 3 O-- or NO 2 --.

Claim 12

Dependent Claim 30 words

The process of claim 6 wherein R 3 is ##STR47## wherein Ph is phenyl, Me is methyl, and X is Cl, Br, F, CH 3 O-- or NO 2 --.

Claim 13

Dependent Claim 97 words

A process for the preparation of taxol comprising reacting an alkoxide with a β-lactam wherein, the alkoxide has the formula ##STR48## the β-lactam has the formula: ##STR49## 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 an ammonium containing substituent, 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 14

Dependent Claim 97 words

A process for the preparation of taxol comprising reacting an alkoxide with a β-lactam wherein, the alkoxide has the formula ##STR48## the β-lactam has the formula: ##STR49## 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 an ammonium containing substituent, 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 15

Dependent Claim 13 words

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

Claim 16

Dependent Claim 13 words

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

Claim 17

Dependent Claim 51 words

The process of claim 1 wherein R 1 is --OR 6 ; 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 hydroxy protecting group; and R 10 is alkyl, alkenyl, alkynyl, aryl or heteroaryl.

Claim 18

Dependent Claim 37 words

The process of claim 1 wherein the alkoxide has the formula ##STR50## wherein Ph is phenyl; Ac is acetyl; Z is --OCOCH 3 or --OT 2 ; and T 1 and T 2 are hydroxy protecting groups.

Claim 19

Dependent Claim 83 words

The process of claim 1 wherein the alkoxide has the formula ##STR51## wherein Ph is phenyl; Ac is acetyl; Z is --OCOCH 3 or --OT 2 ; T 1 and T 2 are hydroxy protecting groups; R1 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 20

Dependent Claim 75 words

The process of claim 12 wherein R 1 is --OR 6 or --SR 7 ; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R 5 is --COR 10 or --COOR 10 , --COSR 10 , --CONR 8 R 10 , or --SO 2 R 11 ; R 6 is hydroxy protecting group; R 7 is a sulfhydryl protecting group; and R 14 is alkyl, alkenyl, alkynyl, aryl or heteroaryl.

Claim 21

Dependent Claim 75 words

The process of claim 13 wherein R 1 is --OR 6 or --SR 7 ; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R 5 is --COR 10 or --COOR 10 , --COSR 10 , --CONR 8 R 10 , or --SO 2 R 11 ; R 6 is hydroxy protecting group; R 7 is a sulfhydryl protecting group; and R 14 is alkyl, alkenyl, alkynyl, aryl or heteroaryl.

Claim 22

Dependent Claim 13 words

The process of claim 6 wherein the alkoxide comprises the tricyclic taxane nucleus.

Claim 23

Dependent Claim 13 words

The process of claim 6 wherein the alkoxide comprises the tetracyclic taxane nucleus.

Claim 24

Dependent Claim 50 words

The process of claim 6 wherein R, is --OR 6 ; 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 hydroxy protecting group; and R 10 is alkyl, alkenyl, alkynyl, aryl or heteroaryl.

Claim 25

Dependent Claim 37 words

The process of claim 6 wherein the alkoxide has the formula ##STR52## wherein Ph is phenyl; Ac is acetyl; Z is --OCOCH 3 or --OT 2 ; and T 1 and T 2 are hydroxy protecting groups.

Claim 26

Dependent Claim 83 words

The process of claim 6 wherein the alkoxide has the formula ##STR53## wherein Ph is phenyl; Ac is acetyl; Z is --OCOCH 3 or --OT 2 ; T 1 and T 2 are hydroxy protecting groups; R1 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 27

Dependent Claim 75 words

The process of claim 19 wherein R 1 is --OR 6 or --SR 7 ; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R 5 is --COR 10 or --COOR 10 , --COSR 10 , --CONR 8 R 10 , or --SO 2 R 11 ; R 6 is hydroxy protecting group; R 7 is a sulfhydryl protecting group; and R 14 is alkyl, alkenyl, alkynyl, aryl or heteroaryl.

Claim 28

Dependent Claim 75 words

The process of claim 20 wherein R 1 is --OR 6 or --SR 7 ; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R 5 is --COR 10 or --COOR 10 , --COSR 10 , --CONR 8 R 10 , or --SO 2 R 11 ; R 6 is hydroxy protecting group; R 7 is a sulfhydryl protecting group; and R 14 is alkyl, alkenyl, alkynyl, aryl or heteroaryl.

Claim 29

Dependent Claim 34 words

The process of claim 6 wherein R 2 and R 4 are hydrogen or lower alkyl, R 3 is aryl, R 1 is --OR 6 , and R 6 is a hydroxy protecting group.

Claim 30

Dependent Claim 24 words

The process of claim 11 wherein R 3 is phenyl and R 1 is --OR 6 wherein R 6 is triethylsilyl, ethoxyethyl, or 2,2,2-trichloroethoxymethyl.

Claim 31

Dependent Claim 15 words

The process of claim 11 wherein the alkoxide is an alkoxide of 7-protected baccatin III.

Claim 32

Dependent Claim 9 words

The process of claim 6 wherein M is tetraalkylammonium.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1998-07-03	1999-01-02	1999-07-04	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2002-07-03	2003-01-02	2003-07-04	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2006-07-03	2007-01-02	2007-07-04	$7700.00	Window Closed / Lapsed

Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides

Abstract

Inventors

Bibliographic Details

Claims Analysis

References Cited (Backward Citations)

USPTO Annuity & Maintenance Windows

Assigned Categories & Tags

Assign Category Tag