Process for preparation of roflumilast
The present invention provides novel processes for the preparation of N-substituted benzamides having the formula (VIc). In some embodiments, the invention provides a process for preparation of roflumilast and other pharmaceutically active species. Novel compounds, including intermediates for the synthesis of roflumilast, are also provided.
1. A process for the preparation of a compound of formula VIc
the process comprising:
a) reacting a compound of formula IIc
with an aldehyde protecting reagent to provide a compound of formula IIIc
b) reacting the compound of formula IIIc with a compound of formula IVa
to provide a compound of formula Vc
in a one-pot reaction; and
c) oxidizing the compound of formula Vc to provide the compound of formula VIc;
wherein
R 1 and R 2 are independently selected from the group consisting of H; C 1-6 alkyl; C 3-7 cycloalkyl; C 3-7 cycloalkylmethyl; and C 1-4 alkyl which is partially or completely substituted with fluorine;
R 4 and R 5 are independently selected from the group consisting of C 1-6 alkyl and acyl; or
R 4 and R 5 are taken together to form an optionally substituted 5-7 member cyclic ring.
2. The process of claim 1 , wherein:
step a) is conducted in a non-polar organic solvent in the presence of an acid.
3. The process of claim 2 , wherein the non-polar organic solvent is selected from the group consisting of toluene and xylene.
4. The process of claim 2 , wherein the acid is selected from the group consisting of p-toluenesulfonic acid, camphorsulfonic acid, polymeric resin based sulfonic acid and acetic acid.
5. The process of claim 1 , wherein the aldehyde protecting reagent is selected from the group consisting of trimethyl orthoformate, triethyl orthoformate, triethyl orthoacetate, trimethyl orthoacetate, acetic anhydride and ethylene glycol.
6. The process of claim 1 , wherein step c) comprises an oxidant selected from the group consisting of a chlorite, a transition metal catalyst, nickel peroxide, m-CPBA, TBHP, potassium peroxomonosulfate and mixtures thereof.
7. The process of claim 6 , wherein the chlorite is selected from the group consisting of chlorous acid, magnesium chlorite, sodium chlorite and potassium chlorite.
8. The process of claim 6 , wherein the chlorite is buffered with an electrolyte selected from the group consisting of HCl/sodium citrate, citric acid/sodium citrate, acetic acid/sodium citrate, potassium dihydrogen phosphate, dipotassium phosphate/sodium dihydrogen phosphate, acetic acid and disodium phosphate.
9. The process of claim 1 , wherein the compound of formula VIc is:
10. A process for the preparation of a compound of formula VIc
the process comprising:
a) reacting a compound of formula IIc
with a compound of formula IVa
in the presence of a Lewis acid catalyst and/or a silylation reagent to form the compound of formula Vc;
and
b) oxidizing the compound of formula Vc to provide the compound of formula VIc;
wherein R 1 and R 2 are independently selected from the group consisting of H; C 1-6 alkyl; C 3-7 cycloalkyl; C 3-7 cycloalkylmethyl; and C 1-4 alkyl which is partially or completely substituted with fluorine.
11. The process of claim 10 , wherein the Lewis acid is selected from the group consisting of TMSOTf, TMSCl, PTSA, TfOH, MSA, TFA and mixtures thereof.
12. The process of claim 10 , wherein the silylation reagent is selected from the group consisting of BSA, BSTFA and mixtures thereof.