Process for the preparation of suvorexant

Abstract

The present invention relates to a process for the preparation of Suvorexant (1) having a purity greater than 99.5% by High-performance liquid chromatography (HPLC). The present invention also relates to novel process for the preparation of 5 (R)-1-benzyl-5-methyl-1,4-diazepane tartrate (7). The present invention further relates to a process for pure solid forms of Suvorexant (1).

Description

[0001] “PROCESS FOR THE PREPARATION OF SUVOREXANT”

[0002] FIEED OF THE INVENTION

[0003] The present invention relates to a process for the preparation of Suvorexant (1) having a purity greater than 99.5% by High-performance liquid chromatography (HPLC). The present invention also relates to novel process for the preparation of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7). The present invention further relates to a process for pure solid forms of Suvorexant (1).

[0004] BACKGROUND OF THE INVENTION

[0005] Suvorexant is marketed under the trade name BELSOMRA. The Chemical name is

[0006] [(7R)-4-(5-chloro-2-benzoxazolyl) hexahydro-7 -methyl- 1 H- 1 ,4-diazepin- 1 -yl] [5- methyl-2-(2H-l,2,3-triazol2-yl) phenyl] methanone. Its empirical formula is

[0007] C23H23CIN6O2. Suvorexant is a white to off-white powder that is insoluble in water.

[0008] The structure is given below:

[0009] The prior art process discloses process for the preparation of Suvorexant (1), which are illustrated below:

[0010] Merck’s patent US7951797 discloses process for the preparation of Suvorexant (1) using Benzyl chloroformate (Cbz-Cl) protecting group and dibenzoyl-tartaric acid as resolving agent. The solid obtained was purified by using mixture of hexane and ethyl acetate to obtain pure Suvorexant (1).

[0011] Merck’ s patent US 9108959 discloses process for the preparation of Suvorexant (1), which involves coupling of 5-methyl-2-[l,2,3] triazol-2-yl-benzoic acid and (R)-5- Chloro-2-(5-methyl-[l,4] diazepan-l-yl)-benzoxazole. The preparation of diazepine intermediate is carried out by racemic direct reductive amination of 4-[(2-Amino- ethyl)-(5-chlorobenzoxazol-2-yl)amino]butan-2-one-bis-methane sulfonic acid salt with a reducing agent in the presence of a weak base, followed by chiral resolution. Organic Letters, 2012, Vol. 14, No. 13, discloses an asymmetric transamination of 4- [(2- Amino-ethyl) (5-chlorobenzoxazol-2-yl) amino] butan-2-one-bis-methane sulfonic acid salt by biocatalytic transamination technology.

[0012] Dr Reddy’s patent application no. US20160168138 discloses process for the preparation of suvorexant (1) using amino protecting group intermediates. It involves coupling reaction of (R)-(7-methyl-l,4-diazepan-l-yl) (5-methyl-2-(2H- l,2,3-triazol-2-yl) phenyl) methanone and 5 -Chloro- 1,3 -benzoxazole in presence of catalyst to obtain Suvorexant (1).

[0013] Though there are several processes for the preparation of Suvorexant (1), there remains a need to provide an improved process for the preparation of Suvorexant (1), The present invention relates to compounds and its intermediates, which are simple, economical, and commercially viable.

[0014] OBJECTIVE OF THE INVENTION

[0015] Accordingly, in one objective, the present invention provides a process for the preparation of Suvorexant (1) having purity greater than 99.5% by High- performance liquid chromatography (HPLC).

[0016] In another objective, the present invention provides a novel process for the preparation of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) using reducing agent.

[0017] In another objective, the present invention provides a process for the purification of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) with purity greater than 99.0%.

[0018] In another objective, the present invention provides a novel process for the preparation of Suvorexant using (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7).

[0019] In another objective, the present invention provides a process for the preparation of pure solid forms of Suvorexant (1). In yet another objective, the present invention provides a process for the purification of Suvorexant (1) controlling total impurities less than 0.1%, more preferably less than 0.5%.

[0020] SUMMARY OF THE INVENTION

[0021] Accordingly, the present invention relates to a process for the preparation of Suvorexant (1) with purity greater than 99.5% by High-performance liquid chromatography (HPLC).

[0022] In one aspect, the present invention provides a process for the preparation of Suvorexant (1), as shown in scheme 1 which comprises:

[0023] A) reacting N-Boc ethylenediamine (14) with benzaldehyde (13) in the presence of sodium borohydride to provide tert-butyl 2-(benzylamino) ethyl carbamate (12),

[0024] B) reacting the compound of formula (12) with methyl vinyl ketone (11) in presence of catalyst to provide tert-butyl 2-(benzyl(3-oxobutyl) amino) ethyl carbamate (10),

[0025] C) cyclizing the compound of formula (10) with an acid to provide l-benzyl-5- methyl-2,3,6,7-tetrahydro-lH-l,4-diazepine (9),

[0026] D) reducing the compound of formula (9) in presence of reducing agent to provide l-benzyl-5-methyl-l,4-diazepane (8),

[0027] E) resolution of compound of formula (8) in the presence of resolution agent to provide (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7), purifying (R)-l- benzyl-5-methyl-l,4-diazepane tartrate (7),

[0028] F) converting compound of formula (7) to (R)-l-benzyl-5-methyl-l,4-diazepane (6) by treating with base,

[0029] G) reacting the compound of formula (6) with 5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl chloride (5) in presence of a base to provide (R)-(4-benzyl-7- methyl-l,4-diazepan-l-yl) (5-methyl-2-(2H-l,2,3-triazol-2-yl) phenyl) methanone (4), H) hydrogenating the compound of formula (4) with suitable hydrogenating agent to provide (R)-(7-methyl-l,4-diazepan-l-yl) (5-methyl-2-(2H-l,2,3-triazol -2- yl) phenyl) methanone (3) or its salt,

[0030] I) reacting the compound of formula (3) or its salt with 2, 5 -dichlorobenzo [d]oxazole (2) in the presence of a base to provide crude Suvorexant (1), and

[0031] J) purifying crude Suvorexant (1) to obtain pure Suvorexant (1).

[0032] In another aspect, Suvorexant (1) process as shown in scheme- 1 can be proceeded by without isolating compounds of formulae 12, formulae 10 & formulae 9.

[0033] In another aspect, the present invention provides a process for the purification of Suvorexant (1) with purity greater than 99%, comprising the steps of: a) dissolving Suvorexant (1) 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 one or more anti-solvents, and e) isolating pure Suvorexant (1).

[0034] In another aspect, the present invention provides a process for the preparation of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) as shown in scheme 2, comprising the steps of:

[0035] I) reducing of l-benzyl-5-methyl-2,3,6,7-tetrahydro-lH-l,4-diazepine (9) in presence of reducing agent to obtain l-benzyl-5-methyl-l,4-diazepane (8),

[0036] II) resolution l-benzyl-5-methyl-l,4-diazepane (8) using resolution agent to obtain crude (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7), and

[0037] III) purifying crude (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) in a solvent and isolating to obtain pure (R)- 1 -benzyl-5 -methyl- 1,4-diazepane tartrate (7).

[0038] In another aspect, the present invention provides a process for the purification of (R)-l-benzyl-5-methyl-l,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).

[0039] In another aspect of the invention is to provide a process for the preparation of amorphous form of Suvorexant (1), comprising the following steps:

[0040] Stage a) heating Suvorexant to 145-150°C,

[0041] Stage b) applying high vacuum to the reaction mass obtained in step a),

[0042] Stage c) cooling the reaction mass to 100°C,

[0043] Stage d) adding water at below 100°C, and

[0044] Stage e) stirring and isolating the amorphous form of Suvorexant (1).

[0045] In another aspect of the invention is to provide another process for the preparation of amorphous form of Suvorexant (1), comprising the following steps:

[0046] Stage I) dissolving Suvorexant (1) in one or more solvent (s),

[0047] Stage II) stirring the reaction mass for 5-10 minutes,

[0048] Stage III) spray drying solution obtained in step b), and

[0049] Stage IV) isolating the amorphous form of Suvorexant (1).

[0050] In another aspect, the present invention relates to a process for the preparation of pure crystalline form of Suvorexant (1), which comprising of:

[0051] 1) dissolving Suvorexant (1) in one or more suitable solvents; and

[0052] 2) isolating crystalline form of Suvorexant (1).

[0053] In yet another aspect, the present invention provides a compound of formula (7).

[0054] In further aspect, the solid forms of Suvorexant obtained in the present invention are having purity greater than 99.5% by HPLC. DETAILED DESCRIPTION OF THE INVENTION

[0055] Accordingly, the present invention relates to the process for the preparation of

[0056] Suvorexant, having purity greater than 99.5% by High-performance liquid chromatography (HPLC) as illustrated in scheme 1.

[0057] Scheme 1

[0058] In step A) of the forgoing process, the reaction of N-Boc ethylenediamine (14) with benzaldehyde (13) is carried out in the presence of sodium borohydride and a solvent under appropriate reaction conditions to provide tert-butyl 2-(benzylamino) ethyl carbamate (12). The suitable solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; preferably methanol. The step A) reaction is carried out at a suitable temperature of about 25°C to about 35°C for a sufficient period till completion of the reaction. In step B) of the foregoing process, the reaction of tert-butyl 2-(benzylamino) ethyl carbamate (12) with methyl vinyl ketone (11) is carried out in a solvent under appropriate reaction conditions to provide tert-butyl 2-(benzyl(3 -oxobutyl) amino) ethyl carbamate (10). The suitable solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; preferably methanol The step B) coupling reaction is carried out at a suitable temperature of about 25°C to about 40°C for a sufficient period till completion of the reaction.

[0059] In step C) of the foregoing process, the cyclization of tert-butyl 2-(benzyl(3- oxobutyl) amino) ethyl carbamate (10) is carried out with an acid reagent under appropriate reaction conditions to provide l-benzyl-5-methyl-2,3,6,7-tetrahydro- lH-l,4-diazepine (9). The suitable acid reagent is selected from hydrochloric acid, ethyl acetate hydrochloric acid, MTBE hydrochloric acid, 1,4-dioxane hydrochloric acid, methanolic hydrochloric acid, trifluoroacetic acid (TFA), p-Toluenesulfonic acid (PTS A or pTsOH), methane sulfonic acid and the like; preferably aqueous hydrochloric acid. The step C) coupling reaction is carried out at a suitable temperature of about 25°C to about 30°C for a sufficient period till completion of the reaction.

[0060] In step D) of the foregoing process, the reduction of l-benzyl-5-methyl-2,3,6,7- tetrahydro-lH-l,4-diazepine (9) is carried out with a suitable reducing agent and in a solvent (or) in the presence of a base, chiral reducing agent, and formic acid in a solvent under appropriate reaction conditions to providel-benzyl-5-methyl-l,4- diazepane (8). The suitable reducing agent is selected from sodium triacetoxyborohydride (NaBH(OAc)3), sodium cyanoborohydride(NaBH3CN), sodium borohydride and the like; preferably sodium triacetoxyborohydride (NaBH(OAc)3) or sodium cyanoborohydride (NaBH CN) and more preferably RuCl [(S, S)-Ts DPEN] (mesitylene). The suitable solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “chloro solvents” such as methylene chloride, di chloroethane, chloroform, carbon tetrachloride, chlorobenzene and the like; preferably methanol and methylene chloride. The step D) reductive reaction is carried out at a suitable temperature of about 25°C to about 30°C for a sufficient period till completion of the reaction. None of the prior art methods teaches the preparation of l-benzyl-5- methyl-l,4-diazepane (7) using sodium cyanoborohydride (NaBHsCN) or sodium triacetoxyborohydride (NaBH(0Ac)3). None of the prior art methods teaches RuCl [(S, S)-Ts DPEN] (mesitylene). The step E) coupling reaction is carried out at a suitable temperature of about 25 °C to about 30°C for a sufficient period till completion of the reaction.

[0061] In step E) of the foregoing process, the resolution of racemic l-benzyl-5-methyl- 1,4-diazepane (8) is carried out with a suitable resolving agent in a solvent under appropriate reaction conditions to provide (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7). The suitable resolving agent is selected from camphor sulfonic acid, methane sulphonic acid, 1 -phenylethylamine, D-tartaric acid, L-tartaric acid, malic acid, mandelic acid; preferably D-Tartaric acid. The suitable solvent is selected from ether solvents and alcohol solvent; preferably methanol and tetrahydrofuran. The step F) resolution reaction is carried out at a suitable temperature of about 25 °C to about 30°C for a sufficient period till completion of the reaction. Optionally, purification of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) is carried out in a solvent to provide pure (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7). The suitable solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; water; preferably methanol and water. The step E) is carried out at a suitable temperature of about 60°C to about 80°C for a sufficient period till completion of the reaction. The disadvantages of using dibenzoyl-tartaric acid as resolving agent is that it is very expensive, compound can only be re-used in the racemate separation with considerable difficulties.

[0062] In step F) of the foregoing process, conversion of (R)-l-benzyl-5-methyl-l,4- diazepane tartrate (7) to (R)-l-benzyl-5-methyl-l,4-diazepane (6) and is carried out in the presence of a base in a solvent under appropriate conditions. The suitable solvent is selected from “chloro solvents” such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and the like; polar aprotic solvent such as water; preferably methylene chloride and water. The suitable base is selected from "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; preferably sodium hydroxide. The step F) reaction is carried out at a suitable temperature of about 25°C to about 30°C for a sufficient period till completion of the reaction.

[0063] In step G) of the foregoing process, the reaction of (R)-l-benzyl-5-methyl-l,4- diazepane (6) with 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl chloride (5) is carried out in the presence of suitable base in a solvent under appropriate reaction conditions to provide (R)-(4-benzyl-7-methyl-l,4-diazepan-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone (4). The suitable base is selected from triethylamine, methylamine, ethylamine, and the like; preferably triethylamine. The suitable solvent is selected from chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; preferably dichloromethane. The step G) coupling reaction is carried out at a suitable temperature of about 0°C to about 10°C for a sufficient period till completion of the reaction. The rection was worked up and isolated compound 4 as solid material in one or more suitable solvent(s).

[0064] In step H) of the foregoing process, the hydrogenation reaction of (R)-(4-benzyl-7- methyl-l,4-diazepan-l-yl) (5-methyl-2-(2H-l,2,3-triazol-2-yl) phenyl) methanone (4) is carried out with a suitable hydrogenation catalyst in a suitable solvent under appropriate conditions to provide (R)-(7-methyl-l,4-diazepan-l-yl)(5-methyl-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone (3) or its salt. The suitable hydrogenation catalyst is selected from Pt, Pt / C, PtO2 , Pd, Pd / C, Rh, Ru, Ni; preferably palladium carbon and acetic acid or Raney Nickel. The suitable solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; preferably methanol. The step H) hydrogenation reaction is carried out at a suitable temperature of about 25 °C to about 30°C for a sufficient period till completion of the reaction. The suitable acid is acetic acid. In step I) of the foregoing process, reaction of (R)-(7-methyl-l,4-diazepan-l-yl) (5- methyl-2-(2H-l,2,3-triazol-2-yl) phenyl) methanone (3) or its salt with 2,5-dichloro benzo[d]oxazole (2) is carried out in the presence of a base in a solvent under appropriate reaction conditions to provide Suvorexant (1). The suitable base is selected from triethylamine, methylamine, ethylamine, and the like; preferably triethylamine. The suitable solvent is selected from chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; preferably dichloromethane. The step I) reaction is carried out at a suitable temperature of about 0°C to about 10°C for a sufficient period till completion of the reaction.

[0065] In another embodiment, the above process can be prepared by one pot process without isolating compounds of formulae 12, 10 & 9.

[0066] In another embodiment, the present invention provides a process for the purification of Suvorexant (1) with purity greater than 99%, comprising the steps of: a) dissolving crude Suvorexant (1) in one or more solvents, b) heating the reaction mass at 70 to 80°C, c) cooling to a suitable temperature, d) adding the obtained solution of step c) to one or more anti-solvents, and e) isolating pure Suvorexant (1).

[0067] In step a) of the forgoing process, the solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; and the anti-solvent in step d) is water.

[0068] In another embodiment, the present invention provides a novel process for the preparation of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) as illustrated in scheme 2.

[0069] Scheme 2

[0070] In step I) of the foregoing process, the reduction of l-benzyl-5-methyl-2,3,6,7- tetrahydro-lH-l,4-diazepine (9) is carried out with a suitable reducing agent and in a solvent (or) in the presence of a base, chiral reducing agent, and formic acid in a solvent under appropriate reaction conditions to providel-benzyl-5-methyl-l,4- diazepane (8). The suitable reducing agent is selected from sodium triacetoxyborohydride (NaBH(0Ac)3), sodium cyanoborohydride(NaBH3CN), sodium borohydride and the like; preferably sodium triacetoxyborohydride (NaBH(0Ac)3) or sodium cyanoborohydride (NaBH CN). The chiral reducing agent is RuCl [(S, S)-Ts DPEN] (mesitylene). The suitable solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “chloro solvents” such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and the like; preferably methanol and methylene chloride. The step I) reductive reaction is carried out at a suitable temperature of about 25°C to about 30°C for a sufficient period till completion of the reaction. None of the prior art methods teaches the preparation of l-benzyl-5- methyl-l,4-diazepane (7) using sodium cyanoborohydride (NaBH CN) or sodium triacetoxyborohydride (NaBH(0Ac)3). None of the prior art methods teaches RuCl [(S, S)-Ts DPEN] (mesitylene). The step I) coupling reaction is carried out at a suitable temperature of about 25 °C to about 30°C for a sufficient period till completion of the reaction.

[0071] In step II) of the foregoing process, the resolution of racemic l-benzyl-5-methyl- 1,4-diazepane (8) is carried out with a suitable resolving agent in a solvent under appropriate reaction conditions to provide (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7). The suitable resolving agent is selected from camphor sulfonic acid, methane sulphonic acid, 1 -phenylethylamine, D-tartaric acid, L-tartaric acid, malic acid, mandelic acid; preferably D-Tartaric acid. The suitable solvent is selected from ether solvents and alcohol solvent, preferably methanol and tetrahydrofuran. The step II) resolution reaction is carried out at a suitable temperature of about 25 °C to about 30°C for a sufficient period till completion of the reaction. Optionally, purification of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) is carried out in a solvent to provide pure (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7). The suitable solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; water; preferably methanol and water in the ration of 1:5. The step II) is carried out at a suitable temperature of about 60°C to about 80°C for a sufficient period till completion of the reaction. The disadvantages of using dibenzoyl-tartaric acid as resolving agent is that it is very expensive, compound can only be re-used in the racemate separation with considerable difficulties.

[0072] In another embodiment, the present invention provides a process for the purification of (R)-l-benzyl-5-methyl-l,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).

[0073] In an embodiment, wherein in step a) the suitable solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like.

[0074] In another embodiment, the present invention relates to chlorination of 5-methyl-2- (2H-l,2,3-triazol-2-yl) benzoic acid (17) is carried out with the suitable chlorinating agent in a solvent under appropriate reaction conditions to provide 5-methyl-2-(2H- l,2,3-triazol-2-yl)benzoyl chloride (5). The suitable chlorinating agents are selected from hosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride and the like; preferably thionyl chloride. The suitable solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; preferably toluene. The reaction is carried out at a suitable temperature of about 70°C to about 80°C for a sufficient period till completion of the reaction.

[0075] Scheme 3

[0076] In another embodiment, the present invention relates to chlorination of 5-chloro-2- mercaptobenzoxazole (18) is carried out with the suitable chlorinating agent and a base in a solvent under appropriate reaction conditions to provide 2,5- dichlorobenzo[d]oxazole (2). The suitable chlorinating agents are selected from phosphorus oxychloride, oxalyl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride and the like; preferably oxalyl chloride. The base is selected from triethylamine, trimethyl amine, diisopropylethylamine, diethyl amine, isopropyl amine, N-butyl lithium, imidazole, morpholine, N-methyl morpholine, pyridine, ammonia and the like. The suitable solvent is selected from hydrocarbon solvents such as toluene, xylene, cyclohexane, hexane, heptane, n- pentane, petroleum ether and the like; preferably toluene. The reaction is carried out at a suitable temperature of about 70°C to about 80°C for a sufficient period till completion of the reaction.

[0077] Scheme 4

[0078] In another embodiment of the present invention is to provide a process for the preparation of amorphous form of Suvorexant (1) by melt crystallization method, comprising the following steps,

[0079] Stage a) heating Suvorexant (1) to 145-150°C,

[0080] Stage b) applying high vacuum to the reaction mass obtained in step a),

[0081] Stage c) cooling the reaction mass to 100°C. Stage d) adding water at below 100°C, and

[0082] Stage e) stirring and isolating the amorphous form of Suvorexant (1).

[0083] In another embodiment of the present invention is to provide another process for the preparation of amorphous form of Suvorexant (1) by spray drying method, comprising the following steps,

[0084] Stage I) dissolving Suvorexant (1) in one or more solvents;

[0085] Stage II) stirring the reaction mass for 5-10 minutes

[0086] Stage III) spray drying the solution obtained in step b); and Stage IV) isolating the amorphous form of Suvorexant (1).

[0087] In step I) of the forgoing process, providing a solution of suvorexant (1) can be carried out by dissolving suvorexant (1) in a alcohol solvent at a suitable temperature from about 25°C to reflux temperature of the solvent used; wherein the alcohol solvent is selected from methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; preferably methanol and finally isolation of pure amorphous form of suvorexant (1) can be carried out by any conventional techniques known in the art, for example filtration or decantation of solution followed by drying, preferably isolation of pure amorphous form of suvorexant (1) by filtration.

[0088] In another embodiment, amorphous form is isolated by removal of solvent at step II) above, which may be carried out by methods known in the art or any procedure disclosed in the present invention wherein said method is selected from, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or under suitable temperatures. Moreover, drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or Micronisation may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

[0089] In another embodiment, the present invention provides a process for the preparation of pure crystalline form of Suvorexant (1) having a purity of greater than 99% by HPLC, which comprises: a) providing a solution of Suvorexant (1) in alcohol at a suitable temperature; and b) isolating the pure crystalline form of Suvorexant (1).

[0090] In step a) of the aforementioned process, providing a solution of suvorexant (1) can be carried out by dissolving suvorexant (1) in a alcohol solvent at a suitable temperature from about 50°C to about 55 °C; wherein the alcohol solvent is selected from methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; preferably ethanol and finally isolation of pure crystalline form of suvorexant (1)

[0091] Further embodiment of the present invention is to provide process for the preparation of amorphous solid dispersion comprising Suvorexant and at least one excipient.

[0092] Another embodiment of the invention is to provide Suvorexant (1) with heavy metals less than 10 ppm. In another embodiment the palladium is less than 10 ppm, preferably less than 5 ppm, more preferably less than 2 ppm and Ruthenium is less than 10 ppm, preferably less than 5 ppm, more preferably less than 2 ppm. In another embodiment the Suvorexant (1) obtained by the above process may be having purity greater than 99.0% HPLC and preferably greater than 99.5% with total impurities less than 1.0%, more preferably less than 0.5%.

[0093] In another embodiment the Suvorexant (1) obtained by the above process is having total impurities represented as impurity A, impurity B, impurity C, impurity D, impurity E and impurity E are less than 1.0% (w / w), preferably less than 0.5%

[0094] (w / w). Each individual impurity is controlled less than 0.1% (w / w).

[0095] In another embodiment, the Suvorexant (1) obtained according to the present invention has water content not more than 2.0% (w / w).

[0096] In another embodiment, the solid forms of Suvorexant (1), are characterized by particle size distribution of less than about 300pm, preferably less than about 200pm and most preferably about 100pm.

[0097] In another embodiment, the solid forms of Suvorexant (1), are characterized by particle size distribution wherein, d90 is between 0.1pm to 200 pm, specifically d90 is between 2.0 pm to 150pm, more specifically d90 is between 1.0 pm to 100pm.

[0098] Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application. Examples:

[0099] Example-1: Preparation of Preparation of tert-butyl 2-(benzylamino)ethyl carbamate (12)

[0100] A mixture of 1000 ml of dichloromethane and 137 g of ethylene diamine (15) was cooled to -10 to 0°C. A solution of 100 g of Boc anhydride (16) in 400 ml of dichloromethane was added to the reaction mass and stirred for 3 hours. After completion of the reaction, washed with aqueous sodium chloride solution and distilled dichloromethane under reduced pressure to afford (14). To the obtained N-Boc ethylenediamine (14), 100ml of methanol and molecular sieves were added under nitrogen atmosphere at 25-30 °C. The reaction mass was cooled to 0-5 °C and 20g of benzaldehyde (13) was added. The reaction mass was heated to a temperature of 25-30 °C, cooled to 10-20 °C. To the reaction mass add 20g of sodium borohydride and stirred at a temperature of 25-35 °C, filtered 15 and washed with methanol. The solvent was distilled out under vacuum at below 60 °C. Mixture of water and ethyl acetate was added to the reaction mass and the layers separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and distilled out under vacuum at below 60 °C to obtain tert-butyl 2- (benzylamino) ethyl carbamate (12).

[0101] Example-2: Preparation of tert-butyl 2-(benzyl(3-oxobutyl) amino) ethyl carbamate (10)

[0102] 50g of tert-butyl 2-(benzylamino) ethyl carbamate (12) was dissolved in 300ml of methylene dichloride and heated to 25-30 °C. The reaction mass was cooled to 0- 10 °C. To the reaction mass 10ml of 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU) and 10ml of methyl vinyl ketone (11) was added and heated to 25-40 °C. 100ml water was added to the reaction mass and the layers separated. The aqueous layer was extracted with methylene dichloride. The organic layers washed with sodium hydroxide solution. The solvent was distilled under vacuum at below 50 °C to obtain tert-butyl 2-(benzyl(3-oxobutyl) amino) ethyl carbamate (10).

[0103] Example-3: Preparation of l-benzyl-5-methyl-2,3,6,7-tetrahydro-lH-l,4- diazepine (9)

[0104] 30g of tert-butyl 2-(benzyl(3-oxobutyl) amino) ethyl carbamate (10) was dissolved in 100ml of methanol under nitrogen atmosphere at 25-30 °C and cooled to 0-5 °C. 1500ml of methanolic hydrochloride was added to the reaction mass and heated to 25-30 °C. The solvent was distilled out at temperature below 50 °C. To the reaction mass 1000ml of mixture of methylene dichloride and water was added and stirred at 25-30 °C. The layers were separated, the aqueous layer was extracted with methylene dichloride and pH was adjusted using sodium bicarbonate solution. The layers were separated, organic layers were distilled under vacuum at below 50 °C to obtain l-benzyl-5-methyl-2,3,6,7-tetrahydro-lH-l,4-diazepine (9).

[0105] Example-4: Preparation of l-benzyl-5-methyl-l,4-diazepane (8)

[0106] 20g of l-benzyl-5-methyl-2,3,6,7-tetrahydro-lH-l,4-diazepine (9) was dissolved in 100ml of methanol under nitrogen atmosphere at 25-30 °C and cooled to 0-5 °C. 5ml of acetic acid and 8g of sodium cyanoborohydride was added slowly to the reaction mass and heated to a temperature of 25-30 °C. After completion of the reaction, the reaction mass was quenched with water and stirred. Methanol was dissolved under reduced pressure. The concentrated mass was dissolved in dichloromethane and water and adjusted the pH with 2-3 using concentrated hydrochloric acid. Layers were separated. The organic layer was washed with water and finally the concentrated mass was reduced under pressure to yield the title compound. Yield: 70%; Purity: 85%.

[0107] Example-5: Preparation of l-benzyl-5-methyl-l,4-diazepane (8)

[0108] 20g of l-benzyl-5-methyl-2,3,6,7-tetrahydro-lH-l,4-diazepine (9) was dissolved in 100ml of methanol under nitrogen atmosphere at 25-30 °C and cooled to 0-5 °C. 5ml of acetic acid and 8g of sodium triacetoxy borohydride was added slowly to the reaction mass and heated to a temperature of 25-30 °C. After completion of the reaction, the reaction mass was quenched with water and stirred. Methanol was dissolved under reduced pressure. The concentrated mass was dissolved in dichloromethane and water and adjusted the pH with 2-3 using concentrated hydrochloric acid. Layers were separated. The organic layer was washed with water and finally the concentrated mass was reduced under pressure to yield the title compound. Yield: 70%; Purity: 85%.

[0109] Example-6: Preparation of l-benzyl-5-methyl-l,4-diazepane (8)

[0110] A mixture of 1000 ml of dichloromethane and 137 g of ethylene diamine (15) was cooled to -10 to 0°C. A solution of 100 g of Boc anhydride (16) in 400 ml of dichloromethane was added to the reaction mass and stirred for 3 hours. After completion of the reaction, washed with aqueous sodium chloride solution and distilled dichloromethane under reduced pressure to afford (14). Further, compound of formula (14) was dissolved in 400 mF of methanol at 25-35°C under nitrogen atmosphere and cooled to 0-10°C, then Benzaldehyde methanolic solution was added and maintained the reaction mass for 3 hours. The reaction mass was cooled to 0-10°C, then added sodium borohydride in lot wise and stirred for 3 hours. Worked up the concentrated mass and extracted the product with methylene dichloride followed by distillation resulting compound of formula (12). 400 ml of methanol was added to the reaction mass at 25-35°C and subjected to 35 g of Methyl vinyl ketone was added at 25-35 °C. After completion of the reaction, distilled the mass under reduced pressure at <40°C. Extracted the product with methylene dichloride and washed with water followed by distillation to afford compound of formula (10). 400 ml of pre-cooled aqueous hydrochloric acid solution was added to the reaction mass at 25-35°C. After completion of the reaction, the mass was washed with 400 ml of Dichloromethane, and cooled to 5-15°C, then 500 ml of aqueous sodium carbonate solution was added. The product was extracted with dichloromethane and the organic layer was treated with 34 g of formic acid and 75 g of triethyl amine at 0-10°C under nitrogen. The reaction mass was warmed to 25- 35°C and 0.22g of RuCl[(S, S)-TsDPEN](mesitylene) was added. The product was extracted from aqueous layer with dichloromethane. Filtered the solid and dried to get the title compound. Yield: 45%; Purity: 90%

[0111] Example-7: Preparation of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7)

[0112] 100 g of l-benzyl-5-methyl-l,4-diazepane (8) was dissolved in 250 ml of tetrahydrofuran and 250 ml of methanol at 20-30°C and stirred. A solution of (D)- Tartaric acid in a mixture of 150 ml of methanol and 150 ml of tetrahydrofuran was added at the same temperature for not less than 120 min and stirred for about 3hours. Filtered the product and washed with 50 ml of methyl tertiary butyl ether, followed by mixture of 25 ml of methanol and 25 ml of tetrahydrofuran and dried to get the title compound.

[0113] Example-8: Purification of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) 100 g of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) was dissolved in 400 ml of Methanol at 20-30°C and heated to 60-65°C, then 200 ml of water was added and stirred for 15 minutes. Thereafter, 600 ml of methanol was added and stirred. The reaction mass was cooled to 20-25°C and stir for about 3hours. Filtered the solid, washed with 50 ml methanol and dried.

[0114] Yield: 80%; Purity: 99%

[0115] Example-9: Preparation of (R)-(4-benzyl-7-methyl-l,4-diazepan-l-yl) (5- methyl-2-(2H-l,2,3-triazol-2-yl) phenyl) methanone (4)

[0116] 100 g of (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7) was dissolved in 30 ml of water at room temperature and stirred for 25 minutes. The reaction mass was cooled to 10-20°C, then 100ml of aqueous sodium hydroxide solution was added and warmed to 20-30°C. 400 ml of dichloromethane was added and distilled the organic layer to afford compound of formula (6). 65 g of triethylamine was added to the above solution and cooled to 0-10°C. compound of formula 5 in dichloromethane solution was added and stirred for 3 hours at 0-10°C. After completion of the reaction, 100 ml of water was added and warmed to 20-30°C. Distilled the organic layer under reduced pressure and Co-distilled with Ethyl acetate to afford compound of formula (4).

[0117] Example-10: Purification of (R)-(4-benzyl-7-methyl-l,4-diazepan-l-yl) (5- methyl-2-(2H-l,2,3-triazol-2-yl) phenyl) methanone (4)

[0118] 130 ml of Ethyl acetate was added to the concentrated mass. The mass was heated to 70-80°C for 30 minutes. The reaction mass was cooled to 20-30°C, then 400 ml of heptane was added and cooled to 10-20°C and stirred for 90 minutes. Filtered the product and washed with precooled mixture of 25 ml of ethyl acetate and 75 ml of heptane. The material was dried under reduced pressure to get the title compound. Yield: 85%; Purity: 99.5%

[0119] Example-11: Preparation of (R)-(7-methyl-l,4-diazepan-l-yl)(5-methyl-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone acetic acid (3)

[0120] 100g of (R)-(4-benzyl-7-methyl-l,4-diazepan-l-yl) (5-methyl-2-(2H-l,2,3-triazol- 2-yl) phenyl) methanone (4) was dissolved in 1500 methanol followed by , 1.0 g of palladium on carbon was added at 20-30 °C & stiired for 15 minutes. Filtered the reaction mass and washed with 100 ml of methanol. 17 g of acetic acid was added to the filtrate to get clear solution, then 10 g of 10% palladium on carbon was added and applied hydrogen gas at a pressure of 4-10 Kg / Cm2 and stirred for 13 hours at 20-30°C. The mass was washed with 100 ml of methanol.

[0121] Example-12: Purification of (R)-(7-methyl-l,4-diazepan-l-yl)(5-methyl-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone acetic acid (3)

[0122] 300 ml of Ethyl acetate was added to the concentrated mass. The mass was heated to 70-80°C for 30 minutes. The reaction mass was cooled to 20-30°C, then 300 ml of heptane was added and stirred for 90 minutes. Filtered the product and washed with precooled mixture of 50 ml of ethyl acetate and 50 ml of heptane.The material was dried under reduced pressure at 50-60°C for about 13h±lh.

[0123] Yield: 90%; Purity: 99.5%

[0124] Example-13: Preparation of Suvorexant (1)

[0125] 100 g of (R)-(7-methyl-l,4-diazepan-l-yl)(5-methyl-2-(2H-l,2,3-triazol-2- yl)phenyl)methanone acetic acid (3) was dissolved in 300 ml of dichloromethane at 20-30°C and stirred for 10-20 minutes. The reaction mass was cooled to 0-10°C, then 56 g of triethylamine was added and stirred, thereafter 2,5- dichlorobenzo[d]oxazole (2) in dichloromethane was added and stirred for 3 hours. After completion of the reaction, 200 ml of water was added at 0-10°C and heated to 20-30°C and stirred for 15 minutes. Layers were separated and washed the organic layer with 100 ml of water. 2.0 g of activated carbon was added to the organic layer and distilled under reduced pressure to afford Suvorexant (1)

[0126] Example-14: Purification of suvorexant (1)

[0127] 110 g of suvorexant was dissolved in 440 ml of methanol at 20-30°C. The reaction mass was heated to 60-65°C and stirred for 15 minutes. The reaction mass was gradually cooled to 15-25°C, then 440 ml of water was added and stirred. Filtered the product under nitrogen pressure and washed the wet material with particle free mixture of 27 ml of Methanol and 27 ml of water. The material was dried under reduced pressure at 60-65°C for about 15-18 h.

[0128] Yield: 90%; Purity: 99.8%

[0129] Example-15: Preparation of 2,5-dichlorobenzo[d]oxazole (2)

[0130] 73 g of compound of formula (15) was dissolved in Dichloromethane at 20-30°C, then 116 g of thionyl chloride was added. The reaction mass was cooled to 10-20°C, then 9.0 ml of dimethyl formamide was added. The reaction mass temperature was raised to 20-30°C and stirred for lOhours. After completion of the reaction, the reaction mass was cooled to 10-15°C, then aqueous sodium carbonate solution was added. The reaction mass was warmed to 20-25°C and stirred for 30-40 min. Filtered the reaction mass and washed the bed with 50 mL of dichloromethane. Distilled the organic layer under reduced pressure. 300 mL of n-heptane was added to the concentrated mass and stirred the mass for 15-25 min at 20-30°C. Filtered the mass through Hyflo (10 g) under vacuum and finally passed the solution through micron filter and washed the bed with 50 ml of n-heptane. Distilled the filtered solution under reduced pressure, then 200 ml of dichloromethane was added to the concentrated mass, this solution was used in the further reactions.

[0131] Example-16: Preparation of 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoyl chloride (5)

[0132] 50 g of compound of formula (14) was dissolved in 250 ml of toluene at 20-30°C, then 50 g of thionyl chloride and 0.5 ml of dimethylformamide was added. Thereafter, the reaction mass was heated to 50-60°C and stirred for 2hours. After completion of the reaction, the reaction mass was cooled to less than 35°C and 3.0 g of thionyl chloride was added. The reaction mass was heated to 50-60°C and stirred for 2hours. Distilled the reaction mass under reduced pressure at below 60°C and Cooled the mass to 20-30°C, then 100 ml of dichloromethane was added, this solution was used in the further reactions.

[0133] Example- 17: Process for the preparation of crystalline form of Suvorexant (1) 300 ml of ethanol was added to crude compound of formula (III) and heated to 50- 55 °C. The reaction mass was stirred for 1-2 hours and cooled to 0-10 °C. The obtained solid was filtered and washed with cold ethanol. The obtained solid was taken in 7.5 vol of isopropyl acetate and heated to 80-85° C. The solution was cooled to 65° C. over 2 hrs, the solution was charged with 0.3 wt % seed in n- Heptane. The solution was cooled to 45° C for 2.5 hrs. The material was filtered and washed with n-Heptane: isopropyl acetate and dried to give as a crystalline white powder.

[0134] Example- 18: Preparation of amorphous form of Suvorexant (1) 100 g of suvorexant was heated to 145-150°C. After complete melting apply high vacuum to the reaction mass at the same temperature and maintained for 30-60 minutes. After 30-60 minutes, the high vacuum was removed and cooled to 100°C. 1000 ml of chilled water was added at below 100°C and stirred for 1-2 hours at room temperature. Filtered the reaction mass, washed with chilled water, and dried to get amorphous form of Suvorexant (1). Yield: 90-95 g; PXRD: Fig. 1

[0135] Example-19: Preparation of amorphous form of Suvorexant (1)

[0136] 100 g of Suvorexant was dissolved in 1000 ml of (1:1) methanol and acetone at room temperature. The reaction mass was stirred for 5 to 10 minutes at the same temperature to get clear solution. The total reaction mixture was then transferred to a beaker and spray dried with the below parameters:

[0137] Inlet Temperature : 50°C

[0138] Aspirator : 1600

[0139] Feeding : 10 mL

[0140] N2 Pressure : 2.0 kg / cm2

[0141] The solid so obtained was unloaded and dried at below 50°C for 12-15 hours to get amorphous form of Suvorexant (1). Yield: 55-60 g; PXRD: Fig. 2

Claims

We claim:

1. A process for the preparation of Suvorexant (1),which comprises, a) reacting compound of formulae (14)with benzaldehyde (13)in the presence of reducing agent to provide tert-butyl 2-(benzylamino) ethyl carbamate (12),b) reacting the compound of formula (12) with methyl vinyl ketone (11)to provide tert-butyl 2-(benzyl(3-oxobutyl) amino) ethyl carbamate (10),c) cyclizing the compound of formula (10) with an acid to provide 1-benzyl-5-methyl-2,3,6,7-tetrahydro-lH-l,4-diazepine (9),d) reducing the compound of formula (9) in presence of reducing agent to provide l-benzyl-5-methyl-l,4-diazepane (8),e) resolution of the compound of formula (8) in presence of resolution agent to provide (R)-l-benzyl-5-methyl-l,4-diazepane tartrate (7), optionally, purifying (R)-l-benzyl-5-methyl-l,4-diazepane tartrate(7),f) converting compound of formula (7) to (R)-l-benzyl-5-methyl-l,4- diazepane (6) in the presence of a base(6) R-Isomer g) reacting the compound of formula (6) with 5-methyl-2-(2H-l,2,3-triazol-2- yl)benzoyl chloride (5)in the presence of a base to provide (R)-(4-benzyl-7-methyl-l,4-diazepan- 1-yl) (5-methyl-2-(2H-l,2,3-triazol-2-yl) phenyl) methanone (4),h) hydrogenating the compound of formula (4) with suitable hydrogenating agent to provide (R)-(7-methyl-l,4-diazepan-l-yl) (5-methyl-2-(2H- 1,2,3- triazol -2-yl) phenyl) methanone (3),or its salt i) reacting the compound of formula (3) or its salt with 2,5- dichlorobenzo[d]oxazole (2)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)-l-benzyl-5-methyl-l,4-diazepane tartrate (7)which comprises, a) reducing the compound of formula (9)in presence of reducing agent selected to provide l-benzyl-5-methyl-l,4- diazepane (8),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), p- Toluenesulfonic acid (PTS A 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(0Ac)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, D- tartaric acid, L-tartaric acid, malic acid, mandelic acid and / or mixtures thereof.

6. The process as claimed in claim 1 and 2, wherein solvents are selected from “chloro solvents” such as methylene chloride, di chloroethane, chloroform, carbon tetrachloride, chlorobenzene and the like; “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; ether solvents such as tetrahydrofuran.

7. 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.

8. A process for the purification of (R)-l-benzyl-5-methyl-l,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, ande) isolating pure compound of formula (7).

9. A process for the purification of Suvorexant (1) with purity greater than 99%, comprising the steps of: a) dissolving crude Suvorexant (1) 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 Suvorexant (1).

10. The process as claimed in claim 8 and 9, wherein the solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like.

11. A process for the preparation of amorphous form of Suvorexant (1), comprising 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 e) stirring and isolating the amorphous form of Suvorexant (1).

12. 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)13. A compound of formula (7)

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