Process and intermediates for preparing macrolactams
The present invention relates to macrolactam compounds, intermediates useful in the preparation of macrolactams, methods for preparing the intermediates, and methods for preparing and modifying macrolactams. One use of the compounds and methods described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity. An example of an HCV inhibitory compound that can be synthesized using the procedures described herein is Compound A and derivative thereof.
1. A compound selected from the group consisting of:
or a salt thereof; and
or a salt thereof;
wherein R 1 is either a C 1-6 alkyl, C 3 -C 8 cycloalkyl, or Aryl;
R 2 and R 3 are each either H, C 1-6 alkyl, C 3 -C 8 cycloalkyl, or Aryl;
R 1a , R 2a , and R 3a are each either C 1-6 alkyl or C 3 -C 8 cycloalkyl;
n is 0-5;
Aryl is either phenyl, substituted phenyl, naphthyl, or substituted naphthyl, provided that substituted phenyl and substituted naphthyl each have 1 to 5 substituents independently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 1-6 alkyl substituted with OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , SO 2 R A , SO 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )SO 2 R B , N(R A )SO 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(3) O—C 1-6 alkyl,
(4) C 1-6 haloalkyl,
(5) O—C 1-6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) NO 2 ,
(10) N(R A )R B ,
(11) C(O)N(R A )R B ,
(12) C(O)R A ,
(13) C(O)—C 1-6 haloalkyl,
(14) C(O)OR A ,
(15) OC(O)N(R A )R B ,
(16) SR A ,
(17) S(O)R A ,
(18) SO 2 R A ,
(19) SO 2 N(R A )R B ,
(20) N(R A )SO 2 R B ,
(21) N(R A )SO 2 N(R A )R B ,
(22) N(R A )C(O)R B ,
(23) N(R A )C(O)N(R A )R B ,
(24) N(R A )C(O)C(O)N(R A )R B , or
(25) N(R A )CO 2 R B ; and
R A and R B are each independently H or C 1-6 alkyl.
2. The compound of claim 1 , wherein said compound has the structure:
or a salt thereof.
3. The compound of claim 2 , wherein said compound has the structure:
or a salt thereof and R 2 is a H or C 1-6 alkyl.
4. The compound of claim 3 , wherein said compound is a salt of:
5. The compound of claim 4 , wherein said compound is:
6. A method of making the Formula IIa compound of claim 2 , comprising the step of coupling
or salt thereof to form
or a salt thereof; wherein
R 1 is either a C 1-6 alkyl, C 3 -C 8 cycloalkyl, or Aryl;
R 2 is either H, C 1-6 alkyl, C 3 -C 8 cycloalkyl, or Aryl;
Aryl is either phenyl, substituted phenyl, naphthyl, or substituted naphthyl, provided that substituted phenyl and substituted naphthyl each have 1 to 5 substituents independently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 1-6 alkyl substituted with OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , SO 2 R A , SO 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )SO 2 R B , N(R A )SO 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(3) O—C 1-6 alkyl,
(4) C 1-6 haloalkyl,
(5) O—C 1-6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) NO 2 ,
(10) N(R A )R B ,
(11) C(O)N(R A )R B ,
(12) C(O)R A ,
(13) C(O)—C 1-6 haloalkyl,
(14) C(O)OR A ,
(15) OC(O)N(R A )R B ,
(16) SR A ,
(17) S(O)R A ,
(18) SO 2 R A ,
(19) SO 2 N(R A )R B ,
(20) N(R A )SO 2 R B ,
(21) N(R A )SO 2 N(R A )R B ,
(22) N(R A )C(O)R B ,
(23) N(R A )C(O)N(R A )R B ,
(24) N(R A )C(O)C(O)N(R A )R B , or
(25) N(R A )CO 2 R B ; and
R A and R B are each independently H or C 1-6 alkyl.
7. The method of claim 6 , wherein R 1 is C 1-6 alkyl and R 2 is a H or C 1-6 alkyl.
8. A method of making the Formula IV compound or salt thereof, comprising the steps of:
a) ring closure and hydrogenation of
or salt thereof to form a compound of
or salt thereof;
wherein R 2 and R 4 are either H, C 1-6 alkyl, C 3 -C 8 cycloalkyl, or Aryl, provided that said Aryl is either phenyl, substituted phenyl, naphthyl, or substituted naphthyl, provided that substituted phenyl and substituted naphthyl each have 1 to 5 substituents independently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 1-6 alkyl substituted with OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , SO 2 R A , SO 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )SO 2 R B , N(R A )SO 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(3) O—C 1-6 alkyl,
(4) C 1-6 haloalkyl,
(5) O—C 1-6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) NO 2 ,
(10) N(R A )R B ,
(11) C(O)N(R A )R B ,
(12) C(O)R A ,
(13) C(O)—C 1-6 haloalkyl,
(14) C(O)OR A ,
(15) OC(O)N(R A )R B ,
(16) SR A ,
(17) S(O)R A ,
(18) SO 2 R A ,
(19) SO 2 N(R A )R B ,
(20) N(R A )SO 2 R B ,
(21) N(R A )SO 2 N(R A )R B ,
(22) N(R A )C(O)R B ,
(23) N(R A )C(O)N(R A )R B ,
(24) N(R A )C(O)C(O)N(R A )R B , or
(25) N(R A )CO 2 R B ; and
R A and R B are each independently H or C 1-6 alkyl.
9. A method of making
or a pharmaceutically acceptable salt thereof, comprising the steps of:
a) ring closure and hydrogenation of
or salt thereof to form a compound of
or salt thereof;
b) hydrolyzing the compound of Formula IV or salt thereof to form
or salt thereof;
c) coupling Compound 11 or salt thereof to
or salt thereof, to form Compound A or salt thereof, and
d) optionally converting Compound A or salt thereof into a pharmaceutically acceptable salt;
wherein R 2 and R 4 are either H, C 1-6 alkyl, C 3 -C 8 cycloalkyl, or Aryl, provided that said Aryl is either phenyl, substituted phenyl, naphthyl, or substituted naphthyl, provided that substituted phenyl and substituted naphthyl each have 1 to 5 substituents independently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 1-6 alkyl substituted with OH, O—C 1-6 alkyl, O—C 1-6 haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , SO 2 R A , SO 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )SO 2 R B , N(R A )SO 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B ,
(3) O—C 1-6 alkyl,
(4) C 1-6 haloalkyl,
(5) O—C 1-6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) NO 2 ,
(10) N(R A )R B ,
(11) C(O)N(R A )R B ,
(12) C(O)R A ,
(13) C(O)—C 1-6 haloalkyl,
(14) C(O)OR A ,
(15) OC(O)N(R a )R B ,
(16) SR A ,
(17) S(O)R A ,
(18) SO 2 R A ,
(19) SO 2 N(R A )R B ,
(20) N(R A )SO 2 R B ,
(21) N(R A )SO 2 N(R A )R B ,
(22) N(R A )C(O)R B ,
(23) N(R A )C(O)N(R A )R B ,
(24) N(R A )C(O)C(O)N(R A )R B , or
(25) N(R A )CO 2 R B ; and
R A and R B are each independently H or C 1-6 alkyl.
10. The method of claim 9 , wherein said Step C coupling is performed using EDC and pyridine or a pyridine derivative, wherein the pyridine derivative is
wherein R 5 is either hydrogen, Aryl, halogen, C 1-6 alkyl, O—C 1-6 alkyl or C 3 -C 8 cycloalkyl.
11. The method of claim 8 , wherein the compound of Formula IIa is a salt of:
12. The method of claim 8 , wherein the compound of Formula IIa is:
13. The method of claim 8 , wherein R 4 is either H or C 1-6 alkyl.
14. The method of claim 8 , further comprising the step of producing the compound of Formula IIa or salt thereof comprising the step of coupling
or a salt thereof, wherein R 1 is either a C 1-6 alkyl, C 3 -C 8 cycloalkyl, or Aryl.
15. The method of claim 14 , further comprising the
step of making the compound of Formula Ia by coupling
or salt thereof and
or salt thereof.
16. The method of claim 15 , wherein
or salt thereof is
17. The method of claim 16 , wherein R 1 is either H or C 1-6 alkyl.
18. The method of claim 17 , wherein
is made by a process comprising the following steps:
19. The method of claim 8 , wherein said ring closure is performed by slow addition of catalyst and the compound of Formula IIa to a solvent at approximately the same time, wherein:
said solvent is provided at about 5-25 liters per Kg of substrate;
said catalyst is provided at a concentration of about 250 ml to 3 L per Kg of catalyst;
said compound is provided at a concentration of about 500 ml to 6 L per Kg of substrate; and
said compound-solution, said catalyst-solution and said solvent are combined together over a period of 0.5-2.5 hrs.
20. The method of claim 9 , where Compound A-11 or a salt thereof is produced by a process comprising the following steps: