Processes for the preparation of benzodiazepine derivatives

1. A process for preparing a compound of formula (I),

wherein

{circle around (A)} is an optionally substituted aryl or optionally substituted heteroaryl; each n is independently selected from 1 and 2;

m is 0, 1, 2, 3, or 4; and

R 1 is selected from the group consisting of:

1) optionally substituted —C 1 -C 8 alkyl;

2) optionally substituted —C 3 -C 8 cycloalkyl;

3) optionally substituted 3- to 12- membered heterocyclic;

alternatively, two adjacent R 1 groups are taken together with the carbon atoms to which they are attached to form a fused ring; two geminal R 1 groups are taken together with the carbon atom to which they are attached to form a spiro ring; or two R 1 groups on nonadjacent carbon atoms are taken together to form a bridging group;

said process comprising the steps of:

(a) reacting a compound of formula (VII),

wherein R 7 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, 3- to 8- membered heterocyclic, aryl, and heteroaryl; and X is a leaving group;

with a compound of formula (VII-X),

wherein PG is hydrogen or an amine protecting group;

to produce a compound of formula (VIII):

(b) reacting the compound of formula (VIII) with a compound of formula (IX):

to produce a compound of formula (X):

(c) reacting the compound of formula (X) with a compound of formula (III)

wherein R 5 is selected from the group consisting of —O(CO)O—R 6 , optionally substituted aryl, and optionally substituted heteroaryl; and R 6 is selected from the group consisting of optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 8 cycloalkenyl, optionally substituted 3- to 8 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

to produce a compound of formula (V),

 and

(d) reacting the compound of formula (V) with a cyclizing reagent to form the compound of formula (I).

2. The process of claim 1 , wherein

3. The process of claim 1 , wherein step (a) is conducted in a protic solvent at a temperature of about 10° C. to about 70° C.

4. The process of claim 1 , wherein R 7 is hydrogen, and step (a) is conducted in the presence of an amide coupling agent.

5. The process of claim 4 , wherein the amide coupling agent is HATU or EDU.

6. The process of claim 4 , wherein step (a) is conducted in a solvent selected from the group consisting of isopropyl acetate, ethyl acetate, dichloromethane, acetone, THF, NMP, 2-methyltetrahydrofuran, and acetonitrile.

7. The process of claim 1 , wherein R 7 is C 1 -C 8 alkyl, and step (a) is conducted in the presence of protic solvent.

8. The process of claim 7 , wherein the protic solvent is methanol, ethanol, or isopropyl alcohol.

9. The process of claim 8 , wherein step (a) is conducted at a temperature of about 10° C. to about 70° C. for about 3 to 12 hours.

10. The process of claim 1 , wherein step (b) is conducted (i) neat or (ii) in an aprotic solvent; at a temperature about 10° C. to about 100° C.

11. The process of claim 1 further comprising the step of reacting compound (IV),

with a compound of the formula Y—C(O)R 5 , wherein Y is a leaving group, to produce the compound of formula (III).

12. The process of claim 11 , wherein the compound of the formula Y—C(O)R 5 is 1,1′-carbonyldiimidazole or nitrophenyl chloroformate.

13. The process of claim 12 , wherein the compound of formula IV is reacted with the amine activating agent is a solvent selected from the group consisting of acetonitrile, THF, DMSO, and dichloromethane.

14. The process of claim 1 , wherein in step (c) is conducted in acetonitrile, THF, DMSO, DMF, sulfolane or 1-methyl-2-pyrrolidone.

15. The process of claim 14 , wherein step (c) is conducted for 6 to 48 hours at a temperature of about 10 to 50° C.

16. The process of claim 1 , wherein the cyclizing agent of step (d) is para-toluenesulfonyl chloride.

17. The process of claim 16 , wherein step (d) is conducted (i) in the presence of triethylamine or diisopropylethylamine; (ii) in a solvent selected from the group consisting of acetonitrile, THF, DMF, DMSO, NMP, acetone, dichloromethane, ethyl acetate and isopropyl acetate; (iii) at a temperature from about 0° C. to about 30° C., (iv) for about 3 to 15 hours; (v) with a concentration of the compound of formula (III) of about 1 M to 3 M, and (vi) at a ratio of the concentration of the compound of formula (III) and the concentration of the compound of formula (V) of about 1:1.

18. The process of claim 1 , wherein the compound of formula I is compound I-a: