Process for the preparation of an orexin receptor antagonist
View Patent ↗The present invention is directed to processes for preparing a diazepane compound which is an antagonist of orexin receptors, and which is useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is further directed to crystalline forms of this diazepane compound and pharmaceutical compositions thereof.
1. A process for preparing a compound of the formula I:
or a pharmaceutically acceptable salt thereof,
which comprises:
contacting a compound of the formula II:
with an activating agent to form an acid chloride,
followed by contacting the acid chloride with a compound of the formula III:
or a salt thereof,
in the presence of a weak base to give the compound of the formula I, or a pharmaceutically acceptable salt thereof.
2. The process of claim 1 wherein the activating agent is selected from oxalyl chloride, thionyl chloride, POC 1 3 , pivaloyl chloride, benzyl chloroformate, CDI, EDC, DCC, HOBt, HOAt, T3P, and HAUT.
3. The process of claim 1 wherein the weak base is selected from triethylamine, diisopropylethylamine, tributylamine, dicyclohexylmethylamine, N,N-dimethylaniline, diazabicyclononane, 1,2,2,6,6-pentamethylpiperidine, diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine, pyridine, 2,6-lutidine, N-methylmorpholine, and N,N,N′,N′-tetramethylethylene diamine, KHCO 3 , NaHCO 3 , Cs 2 CO 3 , K(CO 3 ) 2 , Na(CO 3 ) 2 , NaOH, KOH, and a phosphate base.
4. The process of claim 1 wherein the step of contacting the compound of the formula II with an activating agent to form an acid chloride is conducted in an organic solvent selected from: dichloromethane, isopropyl acetate, acetonitrile, ethyl acetate, tetrahydrofuran, methyl-tetrahydrofuran, toluene, methyl acetate, and methyl tert-butyl ether.
5. The process of claim 1 wherein the step of contacting the compound of the formula II with an activating agent to form an acid chloride is conducted in an amide solvent selected from the group consisting of: formamide, N-methylformamide, N,N-dimethylformamide, acetamide, N-methylacetamide, N,N-dimethylacetamide, N,N,N′,N′-tetramethylurea, 2-pyrrolidone, and N-methylpyrrolidone.
6. A process for preparing a compound of the formula III:
or a salt thereof,
which comprises:
contacting a compound of the formula IV:
with an asymmetric reducing agent in the presence of a weak base, and a terminal reductant to give the compound of the formula III, or a salt thereof.
7. The process of claim 6 wherein the asymmetric reducing agent is selected from Ir or Ru with a diamine ligand of the formula Ar-sulfonyl-1,2-diphenylethylenediamine or Ar-sulfonyl-1,2-trans-diaminocyclohexane where Ar is an aryl group, and with an ancillary ligand selected from p-cymene, benzene, mesitylene, pentamethylcyclopentadienyl, and hexamethylbenzene.
8. The process of claim 6 wherein the weak base is selected from triethylamine, diisopropylethylamine, tributylamine, dicyclohexylmethylamine, N,N-dimethylaniline, diazabicyclononane, 1,2,2,6,6-pentamethylpiperidine, diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine, pyridine, 2,6-lutidine, N-methylmorpholine, and N,N,N′,N′-tetramethylethylene diamine.
9. The process of claim 6 wherein the weak base is triethylamine.
10. The process of claim 6 wherein the terminal reductant is selected from formic acid, an alcohol, hydrogen, and a metal hydride.
11. The process of claim 6 wherein the reaction is conducted in an organic solvent selected from dichloromethane, acetonitrile, toluene, anisole, 1,2-dichloroethane, trifluorotoluene, chlorobenzene, 4-chlorotoluene, isopropyl acetate, ethyl acetate, 2-methyl-2-butanol , ethanol, isopropanol, benzyl alcohol, 1-octanol, tetrahydrofuran, 2-methyltetrahydro-furan, isopropylmethyl ketone, tetramethylurea, N,N-dimethylacetamide, N-ethylpyrrolidinone, triethylamine, dimethyl sulfoxide, cyclopentylmethyl ether, or mixtures thereof.