Phosphorous (V)-based reagents, processes for the preparation thereof, and their use in making stereo-defined organophoshorous (V) compounds

Patent metadata

Field	Value
Publication number	US-11613554-B2
Application number	US-201916382692-A
Country	US
Kind code	B2
Filing date	Apr 12, 2019
Priority date	Apr 13, 2018
Publication date	Mar 28, 2023
Grant date	Mar 28, 2023

Abstract

The present invention relates to novel phosphorous (V) (P(V)) reagents, methods for preparing thereof, and methods for preparing organophosphorous (V) compounds by using the novel reagents.

First claim

What is claimed is:

1. A compound of any one of formulae (II)-(IIc):

wherein
(a) R 1 , R 3 , R 5 and R 6 are independently hydrogen, CD 3 or CF 3 , linear or branched C 1 -C 20 alkyl, optionally substituted with one or more, the same or different, R a groups; linear or branched C 2 -C 12 alkenyl, optionally substituted with one or more, the same or different, R a groups; linear or branched C 2 -C 12 alkynyl, optionally substituted with one or more, the same or different, R a groups; aryl, optionally substituted with one or more, the same or different, R a groups; heteroaryl, optionally substituted with one or more, the same or different, R a groups; heterocyclyl, optionally substituted with one or more, the same or different, R a groups; or C 3 -C 8 cycloalkyl, optionally substituted with one or more, the same or different, R a groups;
or
(b) any two of R 1 , R 3 , R 5 , and R 6 together with the carbons to which they are attached form a C 4 -C 8 cycloalkyl group, optionally substituted with one or more, the same or different, R a groups, while the remaining R 1 , R 3 , R 5 , and R 6 are as defined in (a);
R a is hydrogen, deuterium, CD 3 , C 1 -C 6 alkyl, OH, halogen, CN, CF 3 , O-C 1 -C 6 alkyl, O-aryl, O-heteroaryl, O-C 3 -C 8 cycloalkyl, O-heterocyclyl, —NR b R b , —COOR b or —CONR b R b ;
R b is independently at each occurrence, the same or different, hydrogen, linear or branched C 1 -C 12 alkyl, aryl, heteroaryl, heterocyclyl or C 3 -C 8 cycloalkyl;
Y is O, S or NR c , where R c is hydrogen or C 1 -C 4 alkyl;
m is 0, 1 or 2, and
LG is a leaving group selected from the group consisting of

provided that either the carbon bearing the R 1 group, the carbon bearing the R 3 group, or both, is chiral;
wherein the compound of any one of formulae (II)-(IIc) is at least 90% stereochemically pure.

2. The compound according to claim 1 , selected from the group consisting of

3. The compound according to claim 1 , having any one of formulae (IId)-(IIg)

wherein
(a) R 1 and R 3 are independently hydrogen, CD 3 or CF 3 , linear or branched C 1 -Cao alkyl, optionally substituted with one or more, the same or different, R a groups; linear or branched C 2 -C 12 alkenyl, optionally substituted with one or more, the same or different, R a groups; linear or branched C 2 -C 12 alkynyl, optionally substituted with one or more, the same or different, R a groups; aryl, optionally substituted with one or more, the same or different, R a groups; heteroaryl, optionally substituted with one or more, the same or different, R a groups; heterocyclyl, optionally substituted with one or more, the same or different, R a groups; or C 3 -C 8 cycloalkyl, optionally substituted with one or more, the same or different, R a groups;
or
(b) R 1 , and R 3 together with the carbons to which they are attached form a C 4 -C 8 cycloalkyl group, optionally substituted with one or more, the same or different, R a groups;
R a is hydrogen, deuterium, CD 3 , C 1 -C 6 alkyl, OH, halogen, CN, CF 3, 0 -C 1 -C 6 alkyl, O-aryl, O-heteroaryl, O-C 3 -C 8 cycloalkyl, O-heterocyclyl, —NR b R b , —COOR b or —CONR b R b ;
R b is independently at each occurrence, the same or different, hydrogen, linear or branched C 1 -C 12 alkyl, aryl, heteroaryl, heterocyclyl or C 3 -C 8 cycloalkyl;
provided that either the carbon bearing the R 1 group, the carbon bearing the R 3 group, or both, is chiral;
wherein the compound of any one of formulae (IId)-(IIg) is at least 90% stereochemically pure; and
LG is a leaving group selected from the group consisting of

4. The compound according to claim 3 , wherein
R 1 and R 3 are independently hydrogen, CD 3 or CF 3 , linear or branched C 1 -C 6 alkyl, optionally substituted with one or more, the same or different, R a groups; or aryl, optionally substituted with one or more, the same or different, R a groups;
R a is hydrogen, deuterium, CD 3 , C 1 -C 6 alkyl, OH, halogen, CN, CF 3, 0 -C 1 -C 6 alkyl, O-aryl, O-heteroaryl, O-C 3 -C 8 cycloalkyl, O-heterocyclyl, —NR b R b , —COOR b or —CONR b R b ;
R b is independently at each occurrence, the same or different, hydrogen, linear or branched C 1 -C 12 alkyl, aryl, heteroaryl, heterocyclyl or C 3 -C 8 cycloalkyl;
provided that either the carbon bearing the R 1 group, the carbon bearing the R 3 group, or both, is chiral; and
LG is a leaving group selected from the group consisting of

5. The compound according to claim 1 , wherein the leaving group has a pKa of less than about 10.

6. A method of making the compound of claim 1 , comprising reacting a compound of formula (VII):

wherein X and Y are independently O or S, and
Ph is phenyl, optionally substituted with on one or more groups chosen from linear or branched C 1 -C 6 alkyl, aryl, heteroaryl, halogen, CN, or NO 2 ,
with an epoxide or an episulfide to form the compound of claim 2 .

7. The method of claim 6 , wherein the epoxide has the following formula (VIII):

wherein
(a)R 1 , R 2 , R 3 and R 4 are independently hydrogen, CD 3 , CF 3 , linear or branched C 1 -C 20 alkyl, optionally substituted with one or more, the same or different, R a groups; linear or branched C 2 -C 12 alkenyl, optionally substituted with one or more, the same or different, R a groups; linear or branched C 2 -C 12 alkynyl, optionally substituted with one or more, the same or different, R a groups; aryl, optionally substituted with one or more, the same or different, R a groups; heteroaryl, optionally substituted with one or more, the same or different, R a groups; heterocyclyl, optionally substituted with one or more, the same or different, R a groups; or C 3 -C 8 cycloalkyl, optionally substituted with one or more, the same or different, R a groups; or
(b) any two of R 1 , R 2 , R 3 , and R 4 together with the carbons to which they are attached form C 4 -C 8 cycloalkyl, optionally substituted with one or more, the same or different, R a groups, while the remaining R 1 , R 2 , R 3 , and R 4 are as defined in (a);
R a is hydrogen, deuterium, tritium; halogen; linear or branched C 1 -C 6 alkyl; OH, CN, CF 3 , O-C 1 -C 6 alkyl, O-aryl, O-heteroaryl, O-C 3 -C 8 cycloalkyl, O-heterocyclyl, —NR b R b , —COOR b , —CONR b R b ; linear or branched C 2 -C 6 alkenyl, optionally substituted with linear or branched C 1 -C 6 alkyl; or linear or branched C 2 -C 6 alkynyl, optionally substituted with linear or branched C 1 -C 6 alkyl; and
R b is independently at each occurrence, the same or different, hydrogen, linear or br

Assignees

• Bristol Myers Squibb Co
• Scripps Research Inst

Inventors

• Schmidt Michael Anthony
• Zheng Bin
• Knouse Kyle
• Degruyter Justine
• Eastgate Martin D
• Baran Phil
• Ewing William R
• Olson Richard E
• Mcdonald Ivar M

Classifications

• C07F9/65785 Primary

  the ring phosphorus atom and, at least, one ring sulfur atom being part of a thiophosphonic acid derivative · CPC title

• C07F9/65742

  non-condensed with carbocyclic rings or heterocyclic rings or ring systems · CPC title

• C07H21/00 Primary

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• C07H19/213

  containing cyclic phosphate · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title