DESC:NOVEL PROCESS FOR THE PREPARATION OF SUVOREXANT

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Suvorexant.
BACKGROUND OF THE INVENTION
Suvorexant, [(R)-4-(5-Chlorobenzoxazol-2-yl)-7-methyl- [1,4]diazepan-1 -yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl) formula I orexin receptor antagonist.

Suvorexant contains chiral centres in its structure. Hence, chirality must be generated using different techniques during the preparation of Suvorexant. In most of the prior art, chiral resolution is an essential step in the synthesis of Suvorexant.
WO 2008069997 A1 discloses a process for the preparation of Suvorexant as shown in Scheme 1. 1,4-addition of Boc-ethylenediamine to methyl vinylketone is followed by Cbz-protection of the free amine to give a Boc- protected intermediate. The Boc- protected intermediate is cleaved with HCl to obtain amine intermediate which undergoes reductive amination to give a racemic compound. The free amine of the racemic compound is protected with Boc-protective group followed by resolution using preparative chiral HPLC. The resulting enantiomerically pure amine is coupled with a triazole benzoic acid derivative under known peptide coupling conditions followed by hydrogenation to cleave Cbz-protecting group. The resulting amine is then coupled with a benzoxazole derivative to give Suvorexant. This scheme involves use of methyl vinyl ketone as starting material which is toxic, irritating and difficult to handle. Further, this process involves multiple steps and chiral HPLC for isomer separation, resulting in lower yield. The process is not appropriate for industrial scale production.
Scheme 1
WO 2012148553 A1 discloses ruthenium-catalyzed intramolecular asymmetric reductive amination for the preparation of Suvorexant using 5- Chloro-2-(5-methyl-[1,4] diazepan-1 -yl)-benzoxazole (diazepine intermediate). The racemic 4-[(2-Amino-ethyl)-(5- chlorobenzoxazol-2-yl)amino]butan-2-one-bis-methane sulfonic acid salt undergoes reductive amination in the presence of a weak base to obtain diazepine intermediate, followed by chiral resolution to obtain a chiral intermediate. This process involves use of chiral resolution and expensive ruthenium metal to catalyze asymmetric reductive amination and chiral resolution, and is not suitable for the industrial scale production.
Scheme 2
Stereo selective Suvorexant synthesis is also described in prior art.
CN 105330657 A & CN 105367506 A disclose a process for the preparation of Suvorexant with 1,2-diamine as starting material. The chirality is retained up to the end of the reaction. WO 2016020406A & CN 103923068A disclose a process for the preparation of Suvorexant with amino acids as starting material. The chirality is retained up to the end of the reaction. These processes involve expensive starting materials and pyrophoric reagents such as LiAlH4.
IN 3470/MUM/2015 describes the use of amino alcohol for the synthesis of Suvorexant is shown in Scheme 3.

Scheme 3
This process results in generation of tautomerized impurities including formation of undesired isomers, resulting in yield of 65 %.
There exists a need for an economically viable process for large scale production of Suvorexant, with improved yield.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an economically viable process for preparation of Suvorexant.
Another object of the present invention to provide a cost effective, stereoselective high yielding process for preparation of Suvorexant.
Another object of the present invention is to provide a process for preparation of Suvorexant wherein the desired optically active intermediate(s) with high optical purity is produced to ensure minimization of the undesired isomers.

SUMMARY OF THE INVENTION
The present invention provides cost effective, stereoselective, commercially scalable process for preparation of Suvorexant via novel intermediates represented by formula IX, X or salts thereof.
;
wherein PG1 is methanesulfonyl, trifluoromethanesulfonyl, p-tolylesulfonyl, Nitrobenzenesulfonyl, dinitrobenzenesulfonyl; PG2 is benzyl, 4-methoxy benzyl, 2-chloro benzyl, 4-methyl benzyl.
The present invention provides a process of Suvorexant as shown in Scheme 4.

wherein PG1 is methanesulfonyl, trifluoromethanesulfonyl, p-tolylesulfonyl, Nitrobenzenesulfonyl, dinitrobenzenesulfonyl; PG2 is benzyl, 4-methoxy benzyl, 2-chloro benzyl, 4-methyl benzyl.
Scheme 4

The present invention provides a process for the preparation of Suvorexant has several advantages over the processes described in the prior art, namely:
a. Suvorexant is produced in high yield;
b. Reduces the number of steps as compared to those taught in the prior art; and
c. Avoid the use of hazardous materials such as LiAlH4, n-Butyllithium and Lithium diisopropylamide.

DETAILED DESCRIPTION OF INVENTION
The present invention provides a process for the preparation of Suvorexant, comprising steps:
a) reacting compound of formula XII, with compound of formula XI in the presence of base and solvent to obtain a compound of formula X;

wherein PG1 is methanesulfonyl, trifluoromethanesulfonyl, p-tolylesulfonyl, Nitrobenzenesulfonyl, dinitrobenzenesulfonyl; PG2 is benzyl, 4-methoxy benzyl, 2-chloro benzyl, 4-methyl benzyl.
b) cyclising the compound of formula X in presence of phosphine reagent, azo reagent and solvent to obtain a compound of formula IX;

c) treating the compound of formula IX with base and solvent to produce a compound of formula VIII;

d) reacting the compound of formula VIII with a carbamate source in the presence of base and solvent to obtain a compound of formula VII.

e) converting the compound of formula VII to Suvorexant by any method known in the art.
The compounds of formula IX and X are novel intermediates.
The base in step (a) is selected from an inorganic base or organic base. The inorganic bases such as alkaline metal carbonates, bicarbonates and hydroxides. The carbonates are selected from potassium carbonate and sodium carbonate. The bicarbonates are selected from sodium bicarbonate and potassium bicarbonate. The hydroxides are selected from sodium hydroxide, potassium hydroxide and Lithium hydroxide. The organic base is selected from N, N-dimethylamine, N-ethyl-N-methyl amine, triethylamine (TEA), N-N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methylmorpholine, dimetylaminopyridine and pyridine. The preferred base is potassium carbonate.
The organic solvent in the step (a) is selected from halogenated hydrocarbons, nitriles, amides, ethers and mixture thereof. The halogenated hydrocarbons are selected from methylene chloride (MDC), ethylene chloride, chloroform and mixture thereof. The nitriles are selected from acetonitrile, propionitrile, benzonitrile and mixtures thereof. The amides are selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and mixture thereof. The ethers are selected from tetrahydrofuran (THF), dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixture thereof. The preferred solvent is acetonitrile.
The base used in condensation reaction ranges from 1 to 4 mole per mole of compound of formula (XI) or formula (XII). In a preferred embodiment, the condensation reaction is carried out in presence of 2 mole of base per mole of compound of formula (XI) or formula (XII).
The reaction in step (a) is carried out at 20°C – 100°C, preferably at 20°C – 80°C for 1 to 10 hours, preferably for 1 to 8 hours.
The phosphine reagent in step (b) process is selected from tri-substituted phosphine such as Triphenylphosphine (PPh3), Triethyl phosphite, Trioctylphosphine, Trioctylphosphine, Tricyclohexylphosphine, Tri-tert-butylphosphonium tetrafluoroborate, Tri(o-tolyl) phosphine, t-Bu-BrettPhos, XPhos, Xantphos, preferably Triphenylphosphine.
The azo reagent in step (b) process is selected from Dibenzyl azodicarboxylate (DEAD), Diisopropyl azodicarboxylate, Di-(4-chlorobenzyl)azodicarboxylate, Bis(2,2,2-trichloroethyl)azodicarboxylate, Di-2-methoxyethyl azodicarboxylate, Di-tert-butyl azodicarboxylate, Azodicarboxylic dimorpholide, Diphenyl azodicarboxylate, Diethyl azodicarboxylate, polymer-bound, 1,1'-(Azodicarbonyl)dipiperidine, Diamide, 4-Phenyl-1,2,4-triazoline-3,5-dione, preferably Diethyl azodicarboxylate.
The organic solvent in the step (b) is selected from halogenated hydrocarbon, nitrile, amide, ether and hydrocarbon. The halogenated hydrocarbon is selected from methylene chloride, ethylene chloride, chloroform and mixture thereof. The nitrile is selected from acetonitrile, propionitrile, benzonitrile and mixture thereof. The amides are selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof. The ether is selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The hydrocarbon is selected from toluene, xylenes, toluene and petroleum ether. The preferred solvent is tetrahydrofuran.
The phosphine reagent, azo reagents used in cyclisation reaction ranges from 1 to 3 mole per mole of compound of formula (X). In a preferred embodiment, cyclisation reaction is carried out in presence of 1.5 mole phosphine reagent, azo reagents per mole of compound of formula (X).
The reaction in step (b) is carried out at out at 0 °C – 8 0°C, preferably at 0 °C – 30 °C for 10 to 48 hours, preferably for 15 to 24 hours.
The step (c) of aforesaid process i.e. de-protection of PG1 is carried out in presence of hydroxy base and organic solvent.
The base of step (c) is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide.
The organic solvent in the step (c) is selected from alcohol, halogenated hydrocarbon, nitrile, amide, ether and mixture thereof. The alcohol is selected from C1-C9 alcohol and mixture thereof. The halogenated hydrocarbon is selected from methylene chloride, ethylene chloride, chloroform, and mixture thereof. The nitrile is selected from acetonitrile, propionitrile, benzonitrile and mixture thereof. The amide is selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and mixture thereof. The ethers are selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The preferred solvent is methanol.
The base used in sulphamide deprotection reaction ranges from 5 to 20 mole per mole of compound of formula (IX). In a preferred embodiment, the sulphamide deprotection is carried out in presence of 10 mole of base per mole of compound of formula (IX).
The de-protection reaction of step (c) is carried out at 20 °C – 80 °C, preferably at 30 °C- 64 °C over a period of about 0.5 to 6 hours, preferably for 0.5 to 4 hours.
The carbamate in step (d) is selected from Di-tert-butyl pyrocarbonate (Boc2O), tert-Butyl chlorocarbonate preferably Di-tert-butyl pyrocarbonate.
The base of step (d) is selected from inorganic base or organic base. In particular, the inorganic bases such as alkaline metal carbonates, bicarbonates and hydroxides. The carbonates are selected from potassium carbonate and sodium carbonate; The bicarbonates are selected from sodium bicarbonate and potassium bicarbonate; and the hydroxides are selected from sodium hydroxide (NaOH), potassium hydroxide (KOH) and Lithium hydroxide (LiOH). The organic base is selected from N,N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, N-N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methylmorpholine, dimetylaminopyridine, pyridine and the mixture thereof. The preferred base is triethylamine.
The solvent in step (d) is selected from halogenated hydrocarbon, nitrile, amide and ether. The halogenated hydrocarbon is selected from methylene chloride, ethylene chloride, chloroform and mixture thereof. The nitrile is selected from acetonitrile, propionitrile, benzonitrile and mixture thereof. The amide is selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and mixture thereof. The ether is selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixture thereof. The preferred solvent is methylene chloride.
The carbamate protection of the step (d) carried out at 0°C – 30°C for 0.5 to 6 hours, preferably for 0.5 to 3 hours.
In an embodiment, the present invention provides a process for the preparation of Suvorexant, comprising steps:
a) reacting compound of formula XIIa, with compound of formula XIa in the presence of K2CO3 and acetonitrile to obtain a compound of formula X;

b) cyclising the compound of formula Xa in presence of DEAD, PPh3 and THF to obtain a compound of formula IXa;

c) treating the compound of formula IXa with NaOH and methanol to produce a compound of formula VIIIa;

d) reacting the compound of formula VIIIa with a Di-tert-butyl pyrocarbonate in the presence of TEA and MDC to obtain a compound of formula VIIa.

e) converting the compound of formula VIIa to Suvorexant by any method known in the art.

In an embodiment, the intermediate compound of formula Xa is

In an embodiment, the intermediate compound of formula IXa is

The invention is illustrated with non-limiting examples.
Example(s):
Example-1: Preparation of (R)-N-(2-(benzyl(4-hydroxybutan-2-yl)amino)ethyl)-4-nitrobenzenesulfonamide (X)
(R)-3-(benzylamino)butan-1-ol (13.4 g), N-(2-bromoethyl)-4-nitrobenzene sulfonamide (23 g) were dissolved in acetonitrile (200 mL) and potassium carbonate (20.63 g) was added to reaction mixture. The reaction mixture was heated to 82°C and stirred for 8 h. After completion of the reaction, the reaction mixture was filtered over a celite and the celite bed was washed with ethyl acetate. The organic layer was distilled under reduced pressure to obtain residue. The resultant residue is diluted with ethyl acetate and washed with water. Separated the layers and the organic layer was dried over sodium sulfate and distilled under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain 22.71 g desired product with 74.5% yield. [a]D25: -27.0 (c 1.0, CHCl3); Appearance: colourless oil.
1H NMR (400 MHz, CDCl3) d 8.33 – 8.24 (m, 2H), 7.98 – 7.91 (m, 2H), 7.32 – 7.16 (m, 5H), 5.02 (s, broad 1H), 3.86 (m, 1H), 3.73 – 3.63 (m, 2H), 3.25 (m, 1H), 3.05 – 2.83 (m, 3H), 2.73 (m, 1H), 2.52 (m, 1H), 1.88 – 1.74 (m, 1H), 1.51 – 1.42 (m, 1H), 1.00 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 149.83, 145.89, 138.94, 128.82, 128.63, 128.30, 127.42, 124.26, 61.95, 54.47, 54.30, 48.72, 41.64, 35.14, 13.13. Mass m/z calculated for C19H25N3O5S: 408.48; found 408.3.
Example-2: Preparation of (R)-N-(2-(benzyl(4-hydroxybutan-2-yl)amino)ethyl)-4-nitrobenzenesulfonamide (X)
(R)-3-(benzylamino)butan-1-ol (13.4 g), N-(2-bromoethyl)-4-nitrobenzene sulfonamide (23 g) were dissolved in N,N-dimethylformamide (200 mL) and potassium carbonate (20.63 g) was added to reaction mixture. The reaction mixture was heated to 82°C and stirred for 8 h. After completion of the reaction, the reaction mixture was filtered over a celite and the celite bed was washed with ethyl acetate. The organic layer was distilled under reduced pressure to obtain residue. The resultant residue is diluted with ethyl acetate and washed with water. Separated the layers and the organic layer was dried over sodium sulfate and distilled under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain 20.71 g desired product with 67.9% yield.
Example-3: Preparation of (R)-N-(2-(benzyl(4-hydroxybutan-2-yl)amino)ethyl)-4-nitrobenzenesulfonamide (X)
(R)-3-(benzylamino)butan-1-ol (13.4 g), N-(2-bromoethyl)-4-nitrobenzene sulfonamide (23 g) were dissolved in acetonitrile (200 mL) and TEA (15.7 g) was added to reaction mixture. The reaction mixture was heated to 82°C and stirred for 8 h. After completion of the reaction, the reaction mixture was filtered over a celite and the celite bed was washed with ethyl acetate. The organic layer was distilled under reduced pressure to obtain residue. The resultant residue is diluted with ethyl acetate and washed with water. Separated the layers and the organic layer was dried over sodium sulfate and distilled under reduced pressure to obtain crude product. The crude product was purified by column chromatography to obtain 20.35 g desired product with 66.7% yield.
Example-4: Preparation of (R)-4-benzyl-5-methyl-1-((4-nitrophenyl)sulfonyl)-1,4-diazepane (IX)
(R)-N-(2-(benzyl (4-hydroxybutan-2-yl)amino)ethyl)-4-nitrobenzenesulfonamide (24 g) was dissolved in dry THF (240 mL) and cooled to 0°C followed by addition of diethyl azodicarboxylate (DEAD) (15.40 g). After 15 mins, triphenylphosphine (23.20 g) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 24 h. After completion of reaction, THF was distilled completely to obtain a residue. The resultant residue was diluted with MeOH and cooled to 0°C and stirred for 30 mins. The resultant precipitated Yellow solid was filtered over whatman filter paper to obtain 20 g desired product with 87.29% yield. [a]D25: +16.4 (c 1.0, CHCl3); M.P.: 105-110 °C.
1H NMR (400 MHz, CDCl3) d 8.34 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 8.9 Hz, 2H), 7.25 (t, J = 4.5 Hz, 5H), 3.67 (q, J = 13.8 Hz, 2H), 3.50 (dd, J = 8.9, 3.2 Hz, 1H), 3.46 – 3.36 (m, 1H), 3.25 (dd, J = 7.4, 3.2 Hz, 1H), 3.06 (dd, J = 6.7, 3.2 Hz, 2H), 2.94 – 2.85 (m, 1H), 2.68 (dd, J = 7.2, 2.9 Hz, 1H), 2.03 (m, 1H), 1.72 (dd, J = 7.9, 3.0 Hz, 1H), 1.10 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 149.92, 144.78, 139.65, 128.53, 128.34, 128.18, 127.07, 124.40, 56.01, 55.46, 48.79, 48.46, 45.11, 35.50, 16.64. Mass m/z calculated for C19H23N3O4S: 389.47; found 390.3.
Example-5: Preparation of (R)-4-benzyl-5-methyl-1-((4-nitrophenyl)sulfonyl)-1,4-diazepane (IX)
(R)-N-(2-(benzyl (4-hydroxybutan-2-yl)amino)ethyl)-4-nitrobenzenesulfonamide (24 g) was dissolved in toluene (240 mL) and cooled to 0°C followed by addition of diethyl azodicarboxylate (DEAD) (15.40 g). After 15 mins, triphenylphosphine (23.20 g) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 24 h. After completion of reaction, THF was distilled completely to obtain a residue. The resultant residue was diluted with MeOH and cooled to 0°C and stirred for 30 mins. The resultant precipitated Yellow solid was filtered over whatman filter paper to obtain 18.5 g desired product with 80.74% yield.
Example-6: Preparation of (R)-4-benzyl-5-methyl-1-((4-nitrophenyl)sulfonyl)-1,4-diazepane (IX)
(R)-N-(2-(benzyl (4-hydroxybutan-2-yl)amino)ethyl)-4-nitrobenzenesulfonamide (24 g) was dissolved in dry THF (240 mL) and cooled to 0°C followed by addition of diisopropyl azodicarboxylate (DIAD) (17.87 g). After 15 mins, triphenylphosphine (23.20 g) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 24 h. After completion of reaction, THF was distilled completely to obtain a residue. The resultant residue was diluted with MeOH and cooled to 0°C and stirred for 30 mins. The resultant precipitated Yellow solid was filtered over whatman filter paper to obtain 17.8 g desired product with 76.44% yield.
Example-7: Preparation of (R)-4-benzyl-5-methyl-1-((4-nitrophenyl)sulfonyl)-1,4-diazepane (IX)
(R)-3-(benzylamino)butan-1-ol (13.4 g), N-(2-bromoethyl)-4-nitrobenzene sulfonamide (23 g) were dissolved in acetonitrile (200 mL) and potassium carbonate (17.51 g) was added to the reaction mixture and heated to 82°C and stirred for 8 h. After completion of the reaction, the reaction mixture was filtered over a celite and the celite bed was washed with ethyl acetate. The organic layer was distilled under reduced pressure to obtain residue. The resultant residue is diluted with ethyl acetate and washed with water. Separated the layers and the organic layer was dried over sodium sulfate and distilled under reduced pressure to obtain residue (35 g yellow oil). The obtained residue was dissolved in dry THF (300 mL) and cooled to 0°C followed by addition of diethyl azodicarboxylate (DEAD) (22.44 g). After 15 mins, triphenylphosphine (33.80 g) was added to the reaction mixture. The reaction was warmed to room temperature and stirred for 24 h. After completion of reaction, THF was distilled to obtain residue. The resultant residue was diluted with MeOH (100 mL) and cooled to 0°C and stirred for 30 mins. The resultant precipitated Yellow solid was filtered over whatman filter paper to obtain 28 g desired product with 83.70 % yield. [a]D25 : +16.4 (c 1.0, CHCl3); M.P.: 105-110 °C.
Example-8: Preparation of (R)-tert-butyl 4-benzyl-5-methyl-1,4-diazepane-1-carboxylate (VII)
(R)-4-benzyl-5-methyl-1-((4-nitrophenyl)sulfonyl)-1,4-diazepane (9 g) was added to the solution of sodium hydroxide (9.012 g of NaOH was dissolved in methanol (90 mL)). The reaction mixture was heated to 64°C and stirred for 4 h. The reaction was monitored by TLC. After completion of the reaction, methanol was distilled under reduced pressure to obtain residue. The resultant residue was diluted with dichloromethane (DCM) and washed with water. Separated the layers and the organic layer was dried over sodium sulphate and distilled under reduced pressure to obtain de-protected compound of formula VIII (6 gm colour less gel). The crude product was dissolved in dry DCM (50 mL) and cooled to 0°C followed by addition of triethylamine (5.96 g) and Di-tert-butyl dicarbonate (7.69 g). The reaction was warmed to room temperature and stirred for 3 h. After completion of the reaction, reaction mass was diluted with DCM, washed with water, dried over the sodium sulphate and evaporated under reduced pressure followed by purification using column chromatography to obtain 6.32 g desired product with 70.87% yield.
Example-9: Preparation of (R)-tert-butyl 5-methyl-1,4-diazepane-1-carboxylate (VI)
(R)-tert-butyl 4-benzyl-5-methyl-1,4-diazepane-1-carboxylate (5 g) was dissolved in MeOH (50 mL) and added 10% Pd/C (175 mg) under nitrogen purging. The reaction was stirred under the H2 pressure for 24 h. The reaction was monitored by TLC. After completion of reaction, the reaction mass was filtered through celite. The resultant solvent was evaporated under reduced pressure to obtain 3.26 g desired product with 92.87 % yield.
Example-10: Preparation of (R)-tert-butyl5-methyl-4-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepane-1-carboxylate (IV)
(R)-tert-butyl 5-methyl-1,4-diazepane-1-carboxylate (3 g) was dissolved in DMF (30 mL) and added 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (3.12 g), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (3.22 g), HOAt (1-Hydroxy-7-azabenzotriazole) (2.26 g), N-methylmorpholine (2.83 g) to the reaction mixture. The reaction mixture was stirred for 16 h at room temperature. After completion of reaction, the reaction mixture was diluted with EtOAc and sat. NaHCO3 aqueous solution. Separated the layers and the aqueous layer was washed with EtOAc. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to obtain crude residue which was purified using column chromatography to obtain 4.86 g desired product with 86.94 % yield.
Example-11: Preparation of (R)-(4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2, 3-triazol-2-yl)phenyl)methanone (I)
(R)-tert-butyl 5-methyl-4- (5-methyl-2-(2H-1,2,3-triazol-2-yl) benzoyl)- 1,4-diazepane-1-carboxylate (3.3 g) was dissolved in DCM (30 mL) and trifluoro acetic acid (TFA) (30 mL) was added at room temperature. The reaction mixture was stirred for 12 h. After completion of reaction, the solvent and TFA were removed under reduced pressure, and then the product was used for the next reaction without purification. The crude was diluted with acetonitrile (30 mL) and potassium carbonate (5.7 g), 2,5-dichlorobenzo[d]oxazole (1.86 g) was added at room temperature. the reaction mixture was stirred for 3 h at 65°C. After completion of reaction, the reaction mixture was diluted with DCM and filtered through a Celite. The resultant filtrate was evaporated under reduced pressure to obtain residue which was purified using column chromatography to obtain 2.7 g desired product with 73 % yield.
,CLAIMS:We Claim:
1. A process for the preparation of Suvorexant, comprising steps:
a) reacting compound of formula XII, with compound of formula XI in the presence of base and solvent to obtain a compound of formula X;

wherein PG1 is methanesulfonyl, trifluoromethanesulfonyl, p-tolylesulfonyl, Nitrobenzenesulfonyl, dinitrobenzenesulfonyl; PG2 is benzyl, 4-methoxy benzyl, 2-chloro benzyl, 4-methyl benzyl.
b) cyclising the compound of formula X in presence of phosphine reagent, azo reagent and solvent to obtain a compound of formula IX;

c) treating the compound of formula IX with base and solvent to produce a compound of formula VIII;

d) reacting the compound of formula VIII with a carbamate source in the presence of base and solvent to obtain a compound of formula VII.

e) converting the compound of formula VII into Suvorexant by any method known in the art.
2. The process as claimed in claim 1, wherein the base used in steps (a) & (d) is selected from inorganic base or organic base.
3. The process as claimed in claims 1 - 2, wherein the inorganic base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and Lithium hydroxide.
4. The process as claimed in claims 1 - 2, wherein the organic base is selected from N, N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, N-N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methylmorpholine, dimetylaminopyridine, pyridine, and mixture thereof.
5. The process as claimed in claim 1, wherein the phosphine reagent in step (b) is selected from tri-substituted phosphine such as Triphenylphosphine, Triethyl phosphite, Trioctylphosphine, Trioctylphosphine, Tricyclohexylphosphine, Tri-tert-butylphosphonium tetrafluoroborate, Tri(o-tolyl) phosphine, t-Bu-Brett-Phos, XPhos, Xantphos.
6. The process as claimed in claim 1, wherein the azo reagent in step (b) is selected from Dibenzyl azodicarboxylate, Diisopropyl azodicarboxylate, Di-(4-chlorobenzyl)azodicarboxylate, Bis(2,2,2-trichloroethyl)azodicarboxylate, Di-2-methoxyethyl azodicarboxylate, Di-tert-butyl azodicarboxylate, Azodicarboxylic dimorpholide, Diphenyl azodicarboxylate, Diethyl azodicarboxylate, polymer-bound, 1,1'-(Azodicarbonyl)dipiperidine, Diamide, 4-Phenyl-1,2,4-triazoline-3,5-dione.
7. The process as claimed in claim 1, wherein the base used in steps (c) is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide preferably sodium hydroxide.
8. The process as claimed in claim 1, wherein the carbamate source used in steps (d) is selected from Di-tert-butyl pyrocarbonate and tert-Butyl chlorocarbonate.
9. A compound of formula X:

wherein PG1 is methanesulfonyl, trifluoromethanesulfonyl, p-tolylesulfonyl, Nitrobenzenesulfonyl, dinitrobenzenesulfonyl; PG2 is benzyl, 4-methoxy benzyl, 2-chloro benzyl, 4-methyl benzyl.
10. A compound of formula Xa:

11. A compound of formula IX:

wherein PG1 is methanesulfonyl, trifluoromethanesulfonyl, p-tolylesulfonyl, Nitrobenzenesulfonyl, dinitrobenzenesulfonyl; PG2 is benzyl, 4-methoxy benzyl, 2-chloro benzyl, 4-methyl benzyl.

12. A compound of formula IXa: