Phospholipidation of imidazoquinolines and oxoadenines

Patent metadata

Field	Value
Publication number	US-10774099-B2
Application number	US-201616060142-A
Country	US
Kind code	B2
Filing date	Dec 12, 2016
Priority date	Dec 14, 2015
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

The present invention relates to a process for phospholipidation of imidazoquinolines and oxoadenines. More particularly, the present invention relates to a high-yielding and scalable procedure for the phospholipidation of imidazoquinolines and oxoadenines which obviates the need to isolate unstable phosphoramidite intermediates. This process may be used for the phospholipidation of toll-like receptor 7 (TLR7)—active and toll-like receptor (TLR8)—active imidazoquinolines and oxoadenines.

First claim

The invention claimed is:

1. A process for preparing a compound of formula (I) comprising the steps of:
a) reacting a compound of formula (IV)

wherein
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
with a compound of formula (V)

wherein
PG is a protecting group suitable for hydroxyl protection, including but not limited to cyanoethyl, methyl, ethyl, benzyl and allyl group;
to prepare a compound of formula (VI)″;

PG is a protecting group suitable for hydroxyl protection, including but not limited to cyanoethyl, methyl, ethyl, benzyl and allyl group; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

b) reacting a compound of formula (VI)″ with a compound of formula (VII)

wherein
R 1 is selected from H, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkylamino, C 3-6 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkylamino and C 1-6 alkoxyC 1-6 alkoxy; wherein the C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkylC 1-6 alkylamino, C 3-6 cycloalkylC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkylamino or C 1-6 alkoxyC 1-6 alkoxy is branched or unbranched and optionally terminally substituted with a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group;
Z is selected from C 2 -C 6 alkyl and C 2 -C 6 alkenyl, wherein the C 2 -C 6 alkyl or C 2 -C 6 alkenyl is unsubstituted or terminally substituted by —(O—C 2 -C 6 alkyl) 1-6 —;
to prepare a compound of formula (IX)″; and

wherein

c) oxidizing a compound of formula (IX)″ and removing the hydroxyl protecting group to obtain a compound of formula (I)

2. The process of claim 1 wherein 1H-tetrazole is added to a compound of formula (IV).

3. The process of claim 1 wherein 1H-tetrazole is added in several portions over 20 to 40 minutes.

4. The process of claim 1 wherein imidazolium triflate is added with a compound of formula (VII).

5. The process of claim 1 wherein the coupling agent used with a compound of formula (IV) and a compound of formula (V) is at 2.1 equivalents, the compound of formula (IV) is at 2.0 equivalents, the compound of formula (V) is at 2.1 equivalents, the compound of formula (VII) is at 1.0 equivalent and the oxidizing agent for the compound of formula (IX)″ is at 1.5 equivalent.

6. The process of claim 4 wherein imidazolium triflate is added with the compound of formula (VII) to the same reaction mixture produced by the reaction of compound of formula (V) with the compound of formula (IV).

7. The process of claim 1 wherein the reaction mixture containing the compound of formula (VI)″ is cooled to 0° C. before the addition of a compound of formula (VII).

8. The process of claim 1 wherein the hydroxyl protecting group is cyanoethyl and deprotection is with triethylamine (TEA).

9. A process for preparing a compound of formula (II) comprising the steps of:
a) reacting a compound of formula (III)

wherein
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
R 2 is H or a straight or branched, optionally unsaturated, C 4 -C 24 alkyl, or a straight or branched, optionally unsaturated, C 4 -C 24 acyl;
R 3 is a straight or branched, optionally unsaturated, C 4 -C 24 alkyl or a straight or branched, optionally unsaturated, C 4 -C 24 acyl;
with a compound of formula (V)

wherein
PG is a protecting group suitable for hydroxyl protection, including but not limited to cyanoethyl, methyl, ethyl, benzyl and allyl group;
to prepare a compound of formula (VI); and

wherein
R is

b) reacting a compound of formula (VI) with a compound of formula (VIII)

wherein
d is 0, 1, 2, 3, 4, 5 or 6;
Het is a four-, five-, or six membered saturated nitrogen heterocycle wherein X,Y=CH or N, and at least one of X and Y is a nitrogen atom;
m is 0, 1, 2, 3, 4, 5 or 6;
to prepare a compound of formula (IX)*; and

wherein
R is

R* is

c) oxidizing a compound of formula (IX)* and removing the hydroxyl protecting group to obtain a compound of formula (II)

10. A process for preparing a compound of formula (II) comprising the steps of:
a) reacting a compound of formula (IV)

wherein
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;
with a compound of formula (V)

wherein
PG is a protecting group suitable for hydroxyl protection, including but not limited to cyanoethyl, methyl, ethyl, benzyl and allyl group;
to prepare a compound of formula (VI)″;

wherein
R″ is

b) reacting a compound of formula (VI)″ with a compound of formula (VIII)

wherein
d is 0, 1, 2, 3, 4, 5 or 6;
Het is a four-, five-, or six membered saturated nitrogen heterocycle wherein X,Y=CH or N, and at lea

Assignees

• Glaxosmithkline Biologicals Sa

Inventors

• Bazin-Lee Helene G
• Bess Laura S
• Johnson David A

Classifications

• C07F9/65616

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61P37/04 Primary

  Immunostimulants · CPC title

• C07F9/10

  Phosphatides, e.g. lecithin · CPC title

• C07F9/65583 Primary

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title