Process for making hydroxylated cyclopentylpyrimidine compounds
The invention provides processes for preparing a compound of formula I and salts thereof, wherein R 1 is defined herein, and compounds and intermediates of said formula.
1. A process comprising cyclizing a compound of formula II:
or a salt thereof, to form a compound of formula I
or a salt thereof, wherein:
R 1 is hydrogen or an amino protecting group;
R 2 is —CN, —COOR a or —CONR a R b ;
R a and R b are independently hydrogen, —OR c , substituted or unsubstituted C 1-12 alkyl, substituted or unsubstituted C 2-12 alkenyl, substituted or unsubstituted C 2-12 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 3 to 12 membered heterocyclyl; or
R a and R b are taken together with the atom to which they are attached to form a 3-7 membered heterocyclyl;
R c is independently hydrogen or optionally substituted C 1-12 alkyl; and
M is Li or Mg.
2. The process of claim 1 , further comprising, contacting a compound of formula III, or a salt thereof, with a magnesium or lithium metalating agent:
wherein R 3 is bromo or iodo; to form the compound of formula I or a salt thereof.
3. The process of claim 2 , further comprising contacting a compound of formula IV:
or a salt thereof, with a compound
or a salt thereof, wherein Lv is a leaving group, and each R 3 is independently iodo or bromo, to form the compound of formula III or a salt thereof.
4. The process of claim 3 , further comprising brominating or iodinating a compound of formula V:
or a salt thereof, wherein R 4 is —Cl or —OH, to form the compound of formula IV or a salt thereof.
5. The process of claim 1 , wherein M is Mg.
6. The process of claim 2 , wherein the metalating agent is an alkylmagnesium halide.
7. The process of claim 2 , wherein the metalating agent is iPrMgCl.
8. The process of claim 1 , wherein R 1 is —C(O)OR d , wherein R d is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted heterocyclyl.
9. The process of claim 1 , wherein R 1 is a Boc group.
10. The process of claim 1 , wherein R 2 is —COOR a or —CONR a R b .
11. The process of claim 1 , wherein R 2 is —C(O)N(R a )OR c .
12. The process of claim 1 , wherein R 2 is —C(O)N(CH 3 )OCH 3 .
13. The process of claim 2 , wherein R 3 is iodo.
14. The process of claim 3 , wherein Lv is hydrogen and R 1 is an amino protecting group.
15. The process of claim 1 , wherein R 1 is selected from acetyl, trifluoroacetyl, phthalimidyl, benzyl, triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and carbobenzyloxy.