Compounds for preparing immunological adjuvant
The present invention provides methods for preparing TLR-4 receptor agonist E6020: and stereoisomers thereof, which compounds are useful as an immunological adjuvants when co-administered with antigens such as vaccines for bacterial and viral diseases. Also provided are synthetic intermediates.
1. A compound of formula (16):
wherein:
n is 0 or 1;
R 1a is a C 1 -C 6 alkyl group, a C 3 -C 6 alkenyl group, a C 3 -C 6 alkynyl group, a phosphite oxygen protecting group, or a phosphate oxygen protecting group trimethylsilyl ether, triethylsilylether, triisopropylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenyl silyl ether, 2-trimethylsilylprop-2-enyl, 2-(trimethylsilyl)ethyl, or trimethylsilyl;
in each occurrence of R 2a and R 2c , one of R 2a and R 2c is H and the other is selected from the group consisting of tert-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl(Fmoc), 2,2,2-trichloroethoxycarbonyl (TROC), trimethylsilylethyloxycarbonyl (TMS-ethyloxycarbonyl), cyanoethyloxycarbonyl, allyloxycarbonyl, tetrachlorophthalimide, —C(O)OR x and —C(O)CH 2 C(O)R 6 ; or R 2a and R 2c taken together are a divalent nitrogen protecting group;
R 4 is a C 5 -C 12 alkyl group or a C 5 -C 12 alkenyl group;
R 5 and R 6 are independently a C 5 -C 15 alkyl group or a C 5 -C 15 alkenyl group; and
Rx is a substituted or unsubstituted lower alkyl;
or a salt thereof.
2. A compound of claim 1 , wherein n is 1; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
3. A compound of claim 1 , wherein n is 1; R 1a is allyl; R 2a is hydrogen; R 2c is Boc; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
4. A compound of claim 3 , having the formula ER-819409:
5. A compound of claim 1 , wherein n is 1; R 2c is hydrogen; R 2c is —C(O)CH 2 C(O)R 6 ; R 4 is a C 7 alkyl; R 5 is a C 11 alkyl; and R 6 is a C 11 alkyl.
6. A compound of claim 1 , wherein n is 0; R 1a is allyl; R 2a is hydrogen; R 2c is —C(O)OR x , wherein R x is a C 1 -C 6 alkyl; R 4 is a C 7 alkyl; and R 5 is a C 11 alkyl.
7. A compound of claim 6 , having the formula ER-821843:
8. A compound of claim 1 , wherein n is 1; R 1a is allyl; R 2a is hydrogen; R 2c is —C(O)CH 2 C(O)R 6 ; R 4 is a C 7 alkyl; R 5 is a C 11 alkyl; and R 6 is a C 11 alkyl.
9. A compound of claim 8 , having the formula ER-807285:
10. The compound of claim 1 , wherein one of R 2a and R 2c is H and the other is independently selected from the group consisting of Boc, Fmoc, TROC, TMS-ethyloxycarbonyl, cyanoethyloxycarbonyl, allyloxycarbonyl, tetrachlorophthalimide, and —C(O)OR x ; or R 2a and R 2c taken together are a divalent nitrogen protecting group.
11. The compound of claim 1 , wherein one of R 2a and R 2c is H and the other is —C(O)CH 2 C(O)R 6 .