1. A process for the preparation of Suvorexant (1),
which comprises,
a) reacting compound of formulae (14)
5
with benzaldehyde (13)
in the presence of reducing agent to provide tert-butyl 2-(benzylamino)
ethyl carbamate (12),
10
b) reacting the compound of formula (12) with methyl vinyl ketone (11)
to provide tert-butyl 2-(benzyl(3-oxobutyl) amino) ethyl carbamate (10),
26
c) cyclizing the compound of formula (10) with an acid to provide 1-benzyl5-methyl-2,3,6,7-tetrahydro-1H-1,4-diazepine (9),
d) reducing the compound of formula (9) in presence of reducing agent to
5 provide 1-benzyl-5-methyl-1,4-diazepane (8),
e) resolution of the compound of formula (8) in presence of resolution agent
to provide (R)-1-benzyl-5-methyl-1,4-diazepane tartrate (7), optionally,
purifying (R)-1-benzyl-5-methyl-1,4-diazepane tartrate(7),
10
f) converting compound of formula (7) to (R)-1-benzyl-5-methyl-1,4-
diazepane (6) in the presence of a base
g) reacting the compound of formula (6) with 5-methyl-2-(2H-1,2,3-triazol-2-
15 yl)benzoyl chloride (5)
in the presence of a base to provide (R)-(4-benzyl-7-methyl-1,4-diazepan1-yl) (5-methyl-2-(2H-1,2,3-triazol-2-yl) phenyl) methanone (4),
27
h) hydrogenating the compound of formula (4) with suitable hydrogenating
agent to provide (R)-(7-methyl-1,4-diazepan-1-yl) (5-methyl-2-(2H-1,2,3-
triazol -2-yl) phenyl) methanone (3),
5
or its salt
i) reacting the compound of formula (3) or its salt with 2,5-
dichlorobenzo[d]oxazole (2)
10 in the presence of a base to provide Suvorexant (1), and
j) purifying crude Suvorexant (1) to obtain pure Suvorexant (1)
2. A process for preparation of (R)-1-benzyl-5-methyl-1,4-diazepane tartrate (7)
which comprises,
a) reducing the compound of formula (9)
in presence of reducing agent selected to provide 1-benzyl-5-methyl-1,4-
15 diazepane (8),
28
b) resolution of the compound of formula (8) in presence of resolution agent
to provide compound of formula (7), optionally, purifying compound of
formula (7),
3. The process as claimed in claim 1, wherein the acid is selected from hydrochloric
acid, ethyl acetate hydrochloric acid, MTBE hydrochloric acid, 1,4-dioxane
hydrochloric acid, methanolic hydrochloric acid, trifluoroacetic acid (TFA), pToluenesulfonic acid (PTSA or pTsOH), methane sulfonic acid and the like.
4. The process as claimed in claim 1 and 2, wherein the reducing agent is selected
from sodium triacetoxyborohydride (NaBH(OAc)3), sodium
cyanoborohydride(NaBH3CN), sodium borohydride, RuCl [(S, S)-Ts DPEN]
(mesitylene) and/or mixtures thereof.
5. The process as claimed in claim 1 and 2, wherein the resolution agent is selected
from camphor sulfonic acid, methane sulphonic acid, 1-phenylethylamine, Dtartaric acid, L-tartaric acid, malic acid, mandelic acid and/or mixtures thereof.
6. The process as claimed in claim 1, wherein the base is selected from is
triethylamine triethylamine, methylamine, ethylamine, diisopropylamine
(DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP) and or
mixture there of.
7. A process for the purification of (R)-1-benzyl-5-methyl-1,4-diazepane tartrate
(7), with purity greater than 99%, comprising the steps of:
a) dissolving crude compound of formula (7) in one or more solvents,
b) heating the reaction mass to below 80°C,
c) cooling to a suitable temperature,
d) adding the obtained solution of step c) to water, and
e) isolating pure compound of formula (7).
8. A process for the purification of Suvorexant (1) with purity greater than 99%,
5 comprising the steps of:
a) dissolving crude Suvorexant (1) in one or more solvents,
b) heating the reaction mass to below 80°C,
29
c) cooling to a suitable temperature,
d) adding the obtained solution of step c) to water, and
e) isolating pure Suvorexant (1).
9. A process for the preparation of amorphous form of Suvorexant (1), comprising
5 the following steps:
a) heating Suvorexant to 145-150°C,
b) applying high vacuum to the reaction mass obtained in step a),
c) cooling the reaction mass to 100°C,
d) adding water at below 100°C, and
10 e) stirring and isolating the amorphous form of Suvorexant (1).
10. A process for the preparation of amorphous form of Suvorexant (1), comprising
the following steps:
a) dissolving Suvorexant (1) in one or more solvent (s),
b) stirring the reaction mass for 5-10 minutes,
c) spray drying the solution obtained in step b), and
d) isolating the amorphous form of Suvorexant (1)