Sign In to Follow Application
View All Documents & Correspondence

Novel Process For The Preparation Of Suvorexant And Intermediates Thereof

Abstract: The present invention relates to a novel process for preparation of Suvorexant. The present invention also provides novel intermediates that may be used for the preparation of Suvorexant.

Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
10 September 2015
Publication Number
18/2017
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

MEGAFINE PHARMA PVT LTD
4TH FLOOR,SETHANA,55,MAHARSHI KARVE ROAD,MARINE LINES,MUMBAI-400002, MAHARASHTRA,INDIA

Inventors

1. MATHAD VIJAYAVITTHAL THIPPANNACHAR
FLAT NO 5,NIRMAN CLASSIC,BEHIND HDFC BANK, THATTE NAGAR,NASHIK-422005, MAHARASHTRA,INDIA
2. DESHMUKH DATTATRAY GULABRAO
AP DAHIGAON BOLKA,TAL-KOPARGAON,DIST-AHMEDNAGAR, -423603,MAHARASHTRA,INDIA
3. MALI ANIL CHATURLAL
6-B,PUJA DARSHAN SOCIETY,NAVRANG COLONY, JAIL ROAD,NASHIK ROAD,NASHIK,422101, MAHARASHTRA,INDIA
4. PATEKAR MUKUNDA RAJENDRA
N-53,AF-1,19/02,SAIBABA NAGAR,CIDCO,NASHIK- 422009,MAHARASHTRA,INDIA
5. GADEKAR BHASKAR SURESH
FLAT NO 14,KSHITIJ APARTMENT,SAI CITY,YEOLA ROAD, KOPARGAON-423601,MAHARASHTRA,INDIA

Specification

FIELD OF THE INVENTION: The present invention relates to a novel process for the preparation of Suvorexant (1) and intermediate's thereof. The present invention also relates to a process for the preparation of novel intermediates and their use in the preparation of Suvorexant (1). BACKGROUND OF THE INVENTION: Suvorexant is chemically known as 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzoyl]-l,4-diazepan-lyl}-l,3-benzoxazole or [(R)-4-(5-chloro-benzooxazol-2-yl)-7-methyl-[l,4]diazepan-l-yl]-(5-methyl-2-[l,2,3]triazol-2-yl-phenyl)-methanone or [(7R)-4-(5-chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4-diazepan-l-yl]-[5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl]methanone and it is structurally represented by formula (1). o VN Suvorexant (1) Suvorexant is marketed by Merck & Co. for the treatment of insomnia under the brand name BELSOMRA® in the form of oral tablets with strengths 5, 10, 15 and 20 mg. Suvorexant was approved by the U.S. Food and Drug Administration (FDA) on August 13, 2014. Suvorexant is a potent dual orexin receptor antagonist that blocks both OX1R and OX2R. It promotes sleep through the binding inhibition of orexin A and B, neuropeptides that promote wakefulness. Suvorexant and its pharmaceutically acceptable salts were first disclosed in U.S. Patent No. 7,951,797. The patent describes the process for the preparation of Suvorexant. The process is schematically represented by scheme 1: Scheme-1 0 is 11 NHI 2 3 Et20/ benzylchloro formate/ / \ ' HCI/ EtOAc/ TEA y-V ^ Na(OAc)3BH/AcOH/DCM~ °C /^X NHBoc / 4J 4 « 6 0 *-—' Boc20/TEA/ DCM NHX o ^V HCI/ethyl acetate if^° *l N^0 ™ralpakAD f^ 0 II s % O EDC/HOBt/ NMP/DMF O if ft YA N-N o / 9 wherein Y = -OH Cl V^fV- r^Vnpd(oH)^, Air wherei2x=.c. M. /V EA/MeOH N_^ /J *■ Suvorexant (1) O 10 >> R' 1, Y wherein R[ - -H International (PCT) publication WO2015/008218 discloses the preparation of Suvorexant and its intermediates which is schematically represented by scheme 2: Scheme-2 p >H <\/ 0^ H H P' Pf ^^^NH Pf > Pi pf 13 14 15 ^NH2 16 17 ( P 1 18 ^ 0 N 11 1 wherein P, = -CH2Ph "to XX? , 0n 20 M J ,N 1 r—K 1 - wherein Y = -OH Suvorexant (1) * \ J1 V^^x R1 11 >^ OX) Pi 19 f wherein Rt= -H I Another International (PCT) publication WO2013/169610 (thi 3 '610 publication) describes and cl aims the process for preparation of intermediate of Si uvorexant and discloses its conversion into final product viz. Suvorexant. The process disclosed in '610 publication is schematically represented by scheme 3: Scheme-3 YT P-TSOH/HC(OMe), H2N^0H C^N K^M '- *■ I T >-NH ^^ OH THF K^-o LiHMDS/THF/Hexane K^o \—^ 21 . 20 NBS/MeCN 23 OH 22 N HO \=^ MVK/NaOH/DMF/ MsCl/IPAc 26 x 0 KJCOJ/CUI/DMF ' ur. SEQ ID NO: 1 Cl ^^--N r~^ N V "* ^^0 N . \ 1, Triethanolamine/ QMs 1-$^ " DMF/IPAc/HCl 94 jy^?^ ^^ 9 \ ^^ wherein Pj = -H wherein Y =-0H 1 (C0C1)2/DMF/ KJCOJ/ACN • Suvore Kant (1) The above discussed prior arts have the following drawbacks: a. Butanone (2) is unstable and is difficult to store, hence not feasible for industrial use * b. US' 797 involves the use of chiral column chromatography, hence making separation of isomers not feasible at industrial scale; and c. WO'610 discusses use of hazardous, flammable, and corrosive base i.e. LiHMDS, hence, not user friendly. To overcome, the said drawbacks, present invention provides novel, efficient, economic and impurity free process for the preparation of Suvorexant which offers assurance about the ease of scalability at industrial level. The present invention also provides a novel and highly economic process for the preparation of intermediates used for the synthesis of Suvorexant. The present invention further provides the novel intermediates for the preparation of Suvorexant. The primary object of the present invention is to provide novel, efficient, economic and industrially viable process for the preparation of Suvorexant (1). Another object of the present invention is to provide a novel intermediates for the preparation of Suvorexant (1). Another object of the present invention is to provide a process for preparing Suvorexant (1) using novel intermediates. DETAILED DESCRIPTION OF THE INVENTION: The term "suitable solvent" used herein the present invention refers to solvents selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene; halogenated hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride, chlorobenzene; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofuran, 1,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran; alcohols such as but not limited to methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, diethylene glycol; esters; ketones such as but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N-dimethyl acetamide; nitriles such as but not limited to acetonitrile, and propionitrile; ionic liquids, hexamethylphosphorous triamide , hexamethylphosphoramide and water or mixtures thereof. The term "suitable base" or "base" used herein the present invention refers to the base selected from inorganic bases such as but not limited to alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate; alkali metal bicarbonates such as but not limited to sodium bicarbonate, potassium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide , lithium hydroxide; metal hydrides, metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, potassium tert butoxide; metal amides or liquor ammonia; and organic bases such as but not limited primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol; secondary amines such as but not limited to N,N-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine,; tertiary amines like triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, N,N-dimethylethyl amine and their mixtures thereof. The "coupling agent" used herein the present invention is selected from but not limited to N,N'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDCI) or its salts, l,1'carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), 3- (diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one (DEPBT), 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), (0-(7-azabenzotriazole-1 -y1)-N,N',N'- tetramethyluronium tetrafluoroborate) (TATU), 2-(lH-benzotriazole-l-yl)-l,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(lH-benzotriazole-l-yl)-1,1,3,3-tetra methyluronium tetrafluoroborate (TBTU), boric acid or its derivatives such as phenyl boronic acid, trimethyl borate and the like. The "catalyst" used herein the present invention is selected from DMF, 4-DMAP, HOBt, KI, Nal, dimethyl aniline, Lutidine, DIPEA, CuCl, CuBr and the like. The "carbonyl inserting agent" or "carbon mono-sulfide inserting agent" used herein the present invention is selected from phosgene or thio-phosgene, phosgene equivalents like N,N-carbonyldiimidazole(CDI) or anhydrides or bis (aryl) carbonate, urea, thio-urea, potassium carbonate, and the like. The "suitable halogenating agent" used herein the present invention is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorus oxychloride, phosphorous pentachloride, phosphorous tribromide, phosphorous penta bromide, N-bromo succinamide, N-chloro succinamide, chlorine, bromine, sulfuryl chloride, copper (II) chloride, copper (II) bromide, ferric chloride, ferric bromide and the like., The term "amino-protecting group'' used herein the present invention refers to a protecting group suitable for preventing undesired reactions at an amino group, and which can be removed by conventional chemical or enzymatic steps to reestablish the amino group. Representative amino-protecting group is selected from, but not limited to aryloxycarbonyl such as benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc); alkoxycarbonyl such as methyloxycarbonyl, acetoxycarbonyl, propoxycarbonyl, tert-butyloxycarbonyl (Boc); acyl such as acetyl, propanoyl, iso-butyryl, tert-butyryl, tert-butylacetyl, pivaloyl; aroyl groups such as benzoyl; silyl such as trimethylsilyl, terbutyldimethylsilyl; sulphonyl such as methanesulphonyl, p-tolylsulphonyl; sulphenyl such as 2-nitorphenylsulfenyl; urea; urethane; nitroso; nitro and the like. The term "amino-protecting reagent" used herein the present invention refers to a reagent used to protect an amino group. Representative amino-protecting reagent is selected from, but not limited to di-tert-butyl dicarbonate (DIBOC), benzyl chloro formate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, alkyl or aryl sulfonyl halides or anhydrides such as mesyl halides, mesyl anhydride, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride and the like. The term "suitable reagent" having formula (LX) for the activation of hydroxyl group used herein the present invention is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p-halobenzene sulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, halomethyl methyl ether (MOM), t-butyl chloride, t-butyl bromide, benzyl bromide, benzyl acetate, benzyl ethers, benzyl benzoate, benzyl chloride, p-methoxybenzyl chloride, halotrimethylsilanes, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triisopropylsilyl chloride, triphenylmethyl chloride, acyl chloride, acetic anhydride, t-butylacetyl chloride, t-butylacetic anhydride, alkyl halides and the like. The "deprotecting agent55 as used herein in the present invention is selected based on the protecting group employed. The suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methane sulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; thiols such dodecane thiol, thiophenol; catalyst such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni in the presence of hydrogen source or hydrogen gas including but not limited to sodium borohydride, and ammonium formate. The term "acid addition salt" as used in the present invention means a salt of an acid selected from the group containing hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthaIenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, flimaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. The first aspect of the present invention provides a novel process for the preparation of Suvorexant compound of formula (1), comprising of; reacting 2-amino-4-chlorophenol compound of formula (21) with carbonyl or carbon mono-sulfide inserting agent to provide 5-chloro-l,3-benzoxazol-2(3H)-one compound of formula (27); halogenating the compound of formula (27) with a suitable halogenating agent to provide compound of formula (12); reacting compound of formula (12) with compound of formula (28) to provide the compound of formula (25); and reacting the compound of formula (25) with compound of formula (9) to provide Suvorexant (1). Wherein, reaction of 2-amino-4-chlorophenol compound of formula (21) with carbonyl inserting agent or carbon mono-sulfide inserting agent in step (a) is carried out, optionally in a suitable solvent, optionally in the presence of base and catalyst; halogenation of compound of formula (27) in step (b) is carried out using a suitable halogenating agent, optionally in a suitable solvent, optionally in the presence of base and catalyst; reaction of the compound of formula (12) with compound of formula (28) in step (c) is carried out, optionally in a suitable solvent and optionally in the presence of base; reaction of the compound of formula (25) with compound of formula (9) is carried out, optionally in a suitable solvent, optionally in the presence of base and catalyst. Further, the first aspect of the present invention is represented schematically as shown below: Wherein: X is Halogen; Y is Halogen, -OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole and the like; Z is -O or -S; Pi is "amino-protecting group"; In the above aspect, compound of formula (25) and (1) may be further purified either by acid-base treatment, or suitable solvent crystallization, or converting into its acid addition salts. In the above aspect, the process of step (a), (b) and (c) can be carried out without isolating the intermediates compound of formula (27), (12) and (25). The products formed in the steps (a), (b) and (c) can be used in the next stage with or without isolation. The second aspect of the present invention provides a novel process for the preparation of intermediate of Suvorexant of formula (25), comprising of; condensing compound of formula (29) with compound of formula (12) to provide compound of formula (30); activating the hydroxy 1 group of compound of formula (30) to give compound of formula (31); selectively deprotecting the amino group of compound of formula (31) to provide compound of formula (32); and d) cyclising the compound of formula (32) to give compound of formula (25). Wherein, condensation of compound of formula (29) with compound of formula (12) in step (a) is carried out, optionally in a suitable solvent and optionally in the presence of base; activation of the hydroxyl group of compound of formula (30) in step (b) is carried out using a suitable reagent having formula (LX), optionally in a suitable solvent, optionally in the presence of base and catalyst; selective deprotection of the amino group of compound of formula (31) in step (c) is carried out using a suitable deprotecting agent, optionally in a suitable solvent; cyclisation of the compound of formula (32) in step (d) is carried out, optionally in a suitable solvent, optionally in the presence of base and catalyst; Further, the second aspect of the present invention is represented schematically as shown below: NH carbonylor Z ,,n 1 2 carbon mono- sulfide >-NH N<^| inserting agent °yL Halogenating XV„N agent _ ^ •ci 12^ H2N 6 32 P2 PrNH ^\ P1 29 , f^Y°. > 21 2? Cyclisation 25 30 < OH hydroxyl activating agent D P1NH Deprotection _. * /"'" of amine aXjT^ > N 3 0 P2 Wherein: X is Halogen; Z is -CO or -CS; Pi is "amino-protecting group"; 0-P2 = -Halogen, -OSO2CH3, -OS02CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, -OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,-OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. In the above aspect, the compound of formula (30), (31), (32) and (25) may be further purified either by acid-base treatment, or suitable solvent crystallization. In the above aspect, compound of formula (30), (31) and (32) may be further converted into its acid addition salts. In the above aspect, the process of steps (b) and (c) can be carried out without isolating the intermediates compound of formula (30), (31) and (32). The products formed in the steps (a) to (c) can be used in the next stage with or without isolation. The third aspect of the present invention provides a novel process for preparation of compound of formula (18), a Suvorexant intermediate, the process comprising: a. activating hydroxyl group of compound of formula (33) using a suitable reagent having formula (LX), in a suitable solvent and optionally in the presence of base to provide a compound of formula (34); b. reacting the compound of formula (34) with 2-aminoethanol (35) in a suitable solvent and in the presence of base to provide compound of formula (29); c. activating the hydroxyl group of the compound of formula (29) using a suitable reagent having formula (LX), in a suitable solvent and optionally in the presence of base to provide a compound of formula (36); d. selectively deprotecting the secondary amine of compound of formula (36) using a suitable deprotecting agent, in a suitable solvent to provide a compound of formula (37); and e. cyclising the compound of formula (37) in a suitable solvent, in the presence of base and optionally in a catalyst to provide a compound of formula (18). H2N^-^N—^°-P2 cychzatlon. PI-N^\NH 37 18 Wherein, Pi is "amino-protecting group"; and 0-P2 = -Halogen, -OS02CH3, -OS02CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, -OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,-OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. Further, Pi and P2 may be either same or different. In the above aspect, compounds of formula (34), (29), (36), (37), and (18) may be further purified either by acid-base treatment, or suitable solvent crystallization, or converting into its acid addition salts. The acid addition salts of compounds of formula (34), (29), (36), (37), and (18) can be prepared by treating the same with suitable acid. Further, the compounds of formulae (37) and (18) can be used as a key intermediate for preparation of Suvorexant (1). The fourth aspect of the present invention provides a process for preparation of Suvorexant of formula (1), the process comprising: a. reacting a compound of formula (18) with a compound of formula (9) in a suitable solvent, in the presence of base to provide compound of formula (11); P1-N/_~~XJH Y >=0 „/Tl9 , -v\ X..IJ 18 11 b. deprotecting the compound of formula (11) using suitable deprotecting agent in suitable solvent to provide a compound of formula (1 la); b. deprotecting the compound of formula (11) using suitable deprotecting agent in suitable solvent to provide a compound of formula (1 la); /T~ft /Ho VN r-^\N JJ^^L deprotection of amine /^^M^S^W. c. reacting the compound of formula (11a) with a compound of formula (12) in a suitable solvent and base, optionally in the presence of catalyst to provide Suvorexant(l). PI-VA XJ : - HV>... y 11 T na T c. reacting the compound of formula (11a) with a compound of formula (12) in a suitable solvent and base, optionally in the presence of catalyst to provide Suvorexant(l). oV kArx j Y Wherein: X is Halogens; Y is Halogens,-OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole and the like; Pi is "amino-protecting group"; 0-P2 = -Halogen, -OSO2CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph5 -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. Further, Pi and P2 may be either same or different. In the above aspect, based on the 'Y' group of compound of formula (9), step (a) can be carried out using a coupling agent and a catalyst In the above aspect, compounds of formula (11), (11a) and (1) may be further purified either by acid-base treatment, or suitable solvent crystallization, or converting into its acid addition salts. lla ' Suvorexant(l) Wherein: X is Halogens; Y is Halogens,-OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole and the like; Pi is "amino-protecting group"; 0-P2 = -Halogen, -OSO2CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph5 -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. Further, P1 and P2 may be either same or different. In the above aspect, based on the 'Y' group of compound of formula (9), step (a) can be carried out using a coupling agent and a catalyst In the above aspect, compounds of formula (11), (lla) and (1) may be further purified either by acid-base treatment, or suitable solvent crystallization, or converting into its acid addition salts. The acid addition salts of compounds of formula (11), (11a) and (1) can be prepared by treating the same with suitable acid. The products formed in step (a) and (b) can be used in the next stage with or without isolation of the product. The fifth aspect of the present invention provides a novel process for the preparation of intermediate of Suvorexant of compound of formula (11), comprising of: reacting the compound of formula (33) with compound of (9) to provide compound of (38); activating the hydroxyl group of compound of formula (38) to provide compound of formula (39); reacting the compound of formula (39) with 2-aminoethanol (35) to provide compound of formula (40); activating the hydroxyl group of compound of formula (40) to provide the compound of formula (41); cyclizing the compounds of formula (41) to provide compound of formula en). Wherein, reaction of the compound of formula (33) with compound of formula (9) in step- (a) is carried out, optionally in a suitable solvent, optionally in the presence of base, coupling agent and catalyst; activation of the hydroxyl group of compound of formula (38) in step (b) is carried out using a suitable reagent having formula (LX), optionally in a suitable solvent and optionally in the presence of base; reaction of the compound of formula (39) with 2-aminoethanol (35) in step (c) is Scheme-7 ■ Y ■ OH P1 /={ N-^ / / HO^ NH —i ^-K J \ ""V hydroxyl activating /=\ . ,--OP2 N-N 38 (| N 0 TV-alkylation H0 35 « N "N if1 y ^NH II ] r\ 'T hydroxylactivatmg / > ''''t^ RI-N'I (M «cyclization *vVNH agem y\ N/H Wherein: Y is Halogen, -OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole; Pi is "amino-protecting group"; O-P2 = -Halogen, -OS02CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. Wherein: Y is Halogen, -OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole; Pi is "amino-protecting group'1; 0-P2 = -Halogen, -OSO2CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. In the above aspect, Pi and P2 may be same or different as defined above. In the above aspect, compound of formula (38), (39), (40), (41) and (11) may be further purified either by acid-base treatment, or suitable solvent crystallization. In the above aspect, compound of formula (40) (41), and (11) may be further purified by converting into its acid addition salts. The sixth aspect of the present invention provides a novel process for the preparation of Suvorexant of formula (1), comprising of; reacting the compound of formula (40) with compound of formula (12) to provide compound of formula (42); activating the hydroxyl group of compound of formula (42) to provide compound of formula (43); cyclizing the compound of formula (43) to provide Suvorexant of formula (1). Wherein, reaction of the compound of formula (40) with compound of formula (12) in step (a) is carried out, optionally in a suitable solvent and optionally in the presence of base; activation of the hydroxyl group of compound of formula (42) in step (b) is carried out using a suitable reagent having formula (LX), optionally in a suitable solvent and optionally in the presence of base; cyclization of the compound of formula (43) in step (c) is carried out, optionally in a suitable solvent, optionally in the presence of base and catalyst; Further, the sixth aspect of the present invention is represented schematically as shown below: Wherein: X is Halogen; 0-P2 = -Halogen, -OSO2CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, -OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPSrOCPh3rOCORrOCOC(CH3)3rOR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. In the above aspect, compound of formula (42), (43) and (1) may be further purified either by acid-base treatment, or suitable solvent crystallization. In the above aspect, compound of formula (42) and (43) may be further purified by converting into its acid addition salts. The seventh aspect of the present invention provides a novel process for the preparation of intermediate of Suvorexant of formula (37), comprising of: reacting the compound of formula (44) with compound of formula (45) to provide compound of formula (46); activating the hydroxyl group of compound of formula (46) to provide compound of formula (37). reaction of the compound of formula (44) with compound of formula (45) in step (a) is carried out, optionally in a suitable solvent and optionally in the presence of base; activation of the hydroxyl group of compound of formula (46) in step (b) is carried out using a suitable reagent having formula (LX), optionally in a suitable solvent and optionally in the presence of base; Further, the seventh aspect of the present invention is represented schematically as shown below: Scheme-9 44 =46 *^N i „ ?2 Pi 37 Wherein, Ri is "amino-protecting group" or -H Y is Halogen, -OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole; 0-P2 = -Halogen, -OSO2CH3, -OS02CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. In the above aspect, compound of formula (46) and (37) may be further purified either by acid-base treatment, or suitable solvent crystallization. In the above aspect, compound of formula (46) and (37) may be further purified by converting into its acid addition salts. The eight aspect of the present invention provides a purification process for Suvorexant (1), comprising of; a) treating Suvorexant of compound of formula (1) in a suitable solvent or mixture of suitable solvents; OR treating the solution of Suvorexant which may be obtained directly from a reaction in which Suvorexant is formed with solvent or mixture of solvents. optionally heating the mixture of step (a); crystallizing the Suvorexant from step (a) or (b); isolating the suvorexant the compound of formula (1) from step (a) or (b) or (c) to provide Suvorexant the compound of formula (1), wherein the content of impurity is not more than 0.15% measured by high performance liquid chromatography (HPLC). Suvorexant prepared according to any of the processes of the present invention has less than 0.15% of compound of formulae (47), (48), (49), (50), (51), (52), (53) and (54). OX*^> XrK^ XcK3# 50 ' X^ 51 [ 52 T 0>" °CCKW> 53 54 ' BEST MODE OF THE INVENTION The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention. 2-amino-4-chloro phenol (50g, 0.349 moles), carbonyl diimidazole (84.8g, 0.523 moles), potassium carbonate (48 g, 0.349 moles) and DCM (500 ml) were charged in round bottom flask at room temperature (RT). Reaction mass was stirred for 2-3 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, concentrated the reaction mass, charged the water (250 ml) and stirred the reaction mass for 1 h at room temperature, filtered the solid and washed with water (50 ml) to give 5-chloro-l,3-benzoxazol-2(3H)-one (27) as off white to beige color solid. [Yield = 53g (90%)] 5-chloro-l,3-benzoxazol-2(3H)-one (27) (50g, 0.294 moles) and phosphorus pentachloride (76.7g, 0.368 moles) and toluene (250 ml) were charged into round bottom flask at room temperature and heated the reaction mass to 80-85 °C for 4-6 h. The progress of the reaction was monitored by TLC, after completion of the reaction, the reaction mass was cooled to 5-10 °C, quenched with water (250 ml) and stirred the reaction mass followed by extraction of product in toluene. The obtained toluene layer dried over sodium sulfate followed by distillation of toluene to give pale yellow colored solid of 2,5-dichloro-l,3-benzoxazole (12). [Yield = 47.2g (85.00%)] Tert-butyl [(lR)-3-hydroxy-l-methylpropyl]carbamate (33) (20 g, 0.105 moles), 4-methylbenzenesulfonyl chloride (22.09g, 0.116 moles), triethylamine (21.21 g, 0.21 moles) and toluene (200 ml) were charged in round bottom flask at RT and stirred for 3 h at RT. After completion of the reaction, 2-aminoethanol (35, 6.41 gm, 0.105 moles) and triethylamine (5.3 g, 0.0525 moles) was added at RT, heated the reaction mass to 75-80 °C for 5-6 h. The progress of the reaction was monitored by TLC, after completion of the reaction, concentrated the reaction mass and water was added to precipitated the off white solid, filtered and washed the solid with water to give tert-butyl {(lR)-3-[(2-hydroxyethyl)amino]-l-methylpropyl}carbamate (29) as off white color liquid.Yield = 17.2 g (70.00%) diazepane (18) H O ^ i^ T PTSCI/ TEA/toluene —o y- O ^•J-Q- 0 ^-.. 18 Toluene/ TEA Dilute HCl 9 37 Tert-butyl {(lR)-3-[(2-hydroxyethyl)amino]-l-methylpropyl}carbamate (29) (20g, 0.086 moles), 4-methylbenzenesulfonyl chloride (18.05 g, 0.0947 moles), triethylamine (13.02 g, 0.129 moles) and toluene (200 ml) were charged in round bottom flask at RT and stirred for 3 h at RT. After completion of the reaction, dilute HC1 (50 mL) was added to the reaction mass and stirred for 1 h at 25-30 °C. separated the layers, dried the toluene layer over sodium sulfate and triethylamine was added to the toluene layer. Heated the toluene layer to 80-85 °C for 5-6 h, progress of cyclization reaction was monitored by TLC, after completion of reaction, concentrated the reaction mass to get residue. The obtained residue was purified by column chromatography (DCM: MeOH/ 9:1) to give (5R)-5-methyl-l-[(4-methylphenyl)sulfonyl]-l,4-diazepane (18) as dark brown color syrup.[Yield=15g (65%)] Tert-butyl {(lR)-3-[(2-hydroxyethyl)amino]-l-methylpropyl}carbamate (29) (20g, 0.086 moles), 2,5-dichloro-l,3-benzoxazole (12) (16.8 g, 0.086 moles), triethylamine (10.4 g, 0.103 moles) and toluene (150 ml) were charged were charged in round bottom flask. Reaction mass was heated to 100-110 °C for 8-10 h, progress of reaction monitored by TLC, after completion of reaction, reaction mass was cooled to 25-30 °C. 4-methylbenzenesulfonyl chloride (17.9g, 0.0946 moles) was added at 25-30 °C, stirred the reaction mass for 4-5 h at 25-30 °C, cone. HC1 (10 ml) and water (50 ml) were added to the reaction mass and stirred for 2-3 h at 25-30 °C. Toluene layer was separated and triethylamine (17.3 g, 0.172 moles) was added to toluene layer. Heated the toluene layer to 85-90 °C for 9-10 h. progress of cyclization reaction was monitored by TLC, after completion of reaction, cooled the reaction mass to RT and quenched with water (100 ml), product was extracted in toluene followed by distillation of toluene to give compound (25) as a brown color solid. Yield = 14.8 g (65.00%) Compound (25) (12g, 0.0591 moles), thionyl chloride (14g, 0.11 moles), DMF (1.0 g) and Toluene (50 ml) were charged in round bottom flask, heated the reaction mixture to 80-85 °C for 3 h. Distill out the mixture of thionyl chloride and toluene under reduced pressure to get brown color syrup, cooled the syrup to RT. DCM (100 ml) and TEA (15g, 0.073 moles) was charged to syrup at RT, followed by 29a (14 g, 0.053 moles) was added and stirred for 3-5 h at room temperature. After completion of reaction, charged the water and extracted the product in DCM layer. The obtained DCM layer dried over sodium sulfate and concentrated to obtained light brown color solid of crude Suvorexant (1). The obtained Suvorexant recrystallized from IPA to give white to off white crystalline solid of Suvorexant (1). N' 0 SN' III 1 0 AX,H Oxalyl chloride ^ A^, UJ Toluene/DMF/10-15 °C U g^ T T MTB (9) 0 u -^^ Na2C03/ toluene ' O 0 N^l) SRT-I(ll) V^ jf J 1 /NH ethyl acetate/DIPE MDA(18) / 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid (9, 38.8 g, 0.20 mol), DMF (3.8 mL) and toluene (250 mL) were charged in round bottom flask at 25-30 °C. The reaction mixture was cooled to 0-5 °C and to this cold solution oxalyl chloride (30.3 g, 0.238 mol) was added under inert atmosphere. The temperature of reaction mass was raised to 15-20 °C and stirred for 2 h. In another RBF benzyl (5R)-5-methyi-l,4-diazepane-1-carboxylate (50.0 g, 0.21 mol), sodium carbonate (60.0 g, 0.573 mol) and toluene (100 mL) were charged at 5-10 °C followed by slow addition of above solution containing triazole and oxalyl chloride was slowly added. Temperature of reaction mass was raised to 25-30 °C and maintained for 2 h. After completion of reaction, the reaction mixture was diluted with water (400 mL) and extracted with toluene (2x150 mL). The combined organic layer concentrated under reduced pressure to give thick syrup. Ethyl acetate (50 mL) and DIPE (500 mL) were added to the syrup at 25-30 °C and stirred for 8-10 h. Filtered the precipitated solid and washed with DIPE to give white solid of benzyl (5R)-5-methyl-4-[2-(2H-l,2,3-triazol-2-yl)benzoyl]-l,4-diazepane-l-carboxylate (11). [Yield - 75.0 g (87.0%), HPLC purity: 99.60 %] Benzyl (5R)-5-methyl-4-[2-(2H-l5253-triazoI-2-yl)benzoyl]-l,4-diazepane-l- carboxylate (11, 80 g, 0.183 mol), 10% Pd/C (16 g) and IPA (400 mL) were charged in a autoclave at 25-30 °C. The reaction mixture was hydrogenated using hydrogen gas at 25-30 6C for 10 h. After completion of reaction the mixture was filtered through celite and washed with IPA (160 mL). Filtrate was concentrated under reduced pressure to give (7R)-7-methyl-l-[2-(2H-l52?3-triazol-2-yl)benzoyl]-l,4-diazepane (1 la) as pale brown syrup. [Yield = 46.0g (83.0 %)] Example-9: Preparation of Suvorexant (1) jV > R' 1, Y wherein R[ - -H International (PCT) publication WO2015/008218 discloses the preparation of Suvorexant and its intermediates which is schematically represented by scheme 2: Scheme-2 p >H <\/ 0^ H H P' Pf ^^^NH Pf > Pi pf 13 14 15 ^NH2 16 17 ( P 1 18 ^ 0 N 11 1 wherein P, = -CH2Ph "to XX? , 0n 20 M J ,N 1 r—K 1 - wherein Y = -OH Suvorexant (1) * \ J1 V^^x R1 11 >^ OX) Pi 19 f wherein Rt= -H I Another International (PCT) publication WO2013/169610 (thi 3 '610 publication) describes and cl aims the process for preparation of intermediate of Si uvorexant and discloses its conversion into final product viz. Suvorexant. The process disclosed in '610 publication is schematically represented by scheme 3: Scheme-3 YT P-TSOH/HC(OMe), H2N^0H C^N K^M '- *■ I T >-NH ^^ OH THF K^-o LiHMDS/THF/Hexane K^o \—^ 21 . 20 NBS/MeCN 23 OH 22 N HO \=^ MVK/NaOH/DMF/ MsCl/IPAc 26 x 0 KJCOJ/CUI/DMF ' ur. SEQ ID NO: 1 Cl ^^--N r~^ N V "* ^^0 N . \ 1, Triethanolamine/ QMs 1-$^ " DMF/IPAc/HCl 94 jy^?^ ^^ 9 \ ^^ wherein Pj = -H wherein Y =-0H 1 (C0C1)2/DMF/ KJCOJ/ACN • Suvore Kant (1) The above discussed prior arts have the following drawbacks: a. Butanone (2) is unstable and is difficult to store, hence not feasible for industrial use * b. US' 797 involves the use of chiral column chromatography, hence making separation of isomers not feasible at industrial scale; and c. WO'610 discusses use of hazardous, flammable, and corrosive base i.e. LiHMDS, hence, not user friendly. To overcome, the said drawbacks, present invention provides novel, efficient, economic and impurity free process for the preparation of Suvorexant which offers assurance about the ease of scalability at industrial level. The present invention also provides a novel and highly economic process for the preparation of intermediates used for the synthesis of Suvorexant. The present invention further provides the novel intermediates for the preparation of Suvorexant. The primary object of the present invention is to provide novel, efficient, economic and industrially viable process for the preparation of Suvorexant (1). Another object of the present invention is to provide a novel intermediates for the preparation of Suvorexant (1). Another object of the present invention is to provide a process for preparing Suvorexant (1) using novel intermediates. DETAILED DESCRIPTION OF THE INVENTION: The term "suitable solvent" used herein the present invention refers to solvents selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene; halogenated hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride, chlorobenzene; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofuran, 1,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran; alcohols such as but not limited to methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, diethylene glycol; esters; ketones such as but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N-dimethyl acetamide; nitriles such as but not limited to acetonitrile, and propionitrile; ionic liquids, hexamethylphosphorous triamide , hexamethylphosphoramide and water or mixtures thereof. The term "suitable base" or "base" used herein the present invention refers to the base selected from inorganic bases such as but not limited to alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate; alkali metal bicarbonates such as but not limited to sodium bicarbonate, potassium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide , lithium hydroxide; metal hydrides, metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, potassium tert butoxide; metal amides or liquor ammonia; and organic bases such as but not limited primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol; secondary amines such as but not limited to N,N-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine,; tertiary amines like triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, N,N-dimethylethyl amine and their mixtures thereof. The "coupling agent" used herein the present invention is selected from but not limited to N,N'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDCI) or its salts, l,1'carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), 3- (diethoxyphosphoryloxy)-l,2,3-benzotriazin-4(3H)-one (DEPBT), 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), (0-(7-azabenzotriazole-1 -y1)-N,N',N'- tetramethyluronium tetrafluoroborate) (TATU), 2-(lH-benzotriazole-l-yl)-l,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(lH-benzotriazole-l-yl)-1,1,3,3-tetra methyluronium tetrafluoroborate (TBTU), boric acid or its derivatives such as phenyl boronic acid, trimethyl borate and the like. The "catalyst" used herein the present invention is selected from DMF, 4-DMAP, HOBt, KI, Nal, dimethyl aniline, Lutidine, DIPEA, CuCl, CuBr and the like. The "carbonyl inserting agent" or "carbon mono-sulfide inserting agent" used herein the present invention is selected from phosgene or thio-phosgene, phosgene equivalents like N,N-carbonyldiimidazole(CDI) or anhydrides or bis (aryl) carbonate, urea, thio-urea, potassium carbonate, and the like. The "suitable halogenating agent" used herein the present invention is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorus oxychloride, phosphorous pentachloride, phosphorous tribromide, phosphorous penta bromide, N-bromo succinamide, N-chloro succinamide, chlorine, bromine, sulfuryl chloride, copper (II) chloride, copper (II) bromide, ferric chloride, ferric bromide and the like., The term "amino-protecting group'' used herein the present invention refers to a protecting group suitable for preventing undesired reactions at an amino group, and which can be removed by conventional chemical or enzymatic steps to reestablish the amino group. Representative amino-protecting group is selected from, but not limited to aryloxycarbonyl such as benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc); alkoxycarbonyl such as methyloxycarbonyl, acetoxycarbonyl, propoxycarbonyl, tert-butyloxycarbonyl (Boc); acyl such as acetyl, propanoyl, iso-butyryl, tert-butyryl, tert-butylacetyl, pivaloyl; aroyl groups such as benzoyl; silyl such as trimethylsilyl, terbutyldimethylsilyl; sulphonyl such as methanesulphonyl, p-tolylsulphonyl; sulphenyl such as 2-nitorphenylsulfenyl; urea; urethane; nitroso; nitro and the like. The term "amino-protecting reagent" used herein the present invention refers to a reagent used to protect an amino group. Representative amino-protecting reagent is selected from, but not limited to di-tert-butyl dicarbonate (DIBOC), benzyl chloro formate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, alkyl or aryl sulfonyl halides or anhydrides such as mesyl halides, mesyl anhydride, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride and the like. The term "suitable reagent" having formula (LX) for the activation of hydroxyl group used herein the present invention is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p-halobenzene sulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, halomethyl methyl ether (MOM), t-butyl chloride, t-butyl bromide, benzyl bromide, benzyl acetate, benzyl ethers, benzyl benzoate, benzyl chloride, p-methoxybenzyl chloride, halotrimethylsilanes, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triisopropylsilyl chloride, triphenylmethyl chloride, acyl chloride, acetic anhydride, t-butylacetyl chloride, t-butylacetic anhydride, alkyl halides and the like. The "deprotecting agent55 as used herein in the present invention is selected based on the protecting group employed. The suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methane sulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; thiols such dodecane thiol, thiophenol; catalyst such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni in the presence of hydrogen source or hydrogen gas including but not limited to sodium borohydride, and ammonium formate. The term "acid addition salt" as used in the present invention means a salt of an acid selected from the group containing hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthaIenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, flimaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. The first aspect of the present invention provides a novel process for the preparation of Suvorexant compound of formula (1), comprising of; reacting 2-amino-4-chlorophenol compound of formula (21) with carbonyl or carbon mono-sulfide inserting agent to provide 5-chloro-l,3-benzoxazol-2(3H)-one compound of formula (27); halogenating the compound of formula (27) with a suitable halogenating agent to provide compound of formula (12); reacting compound of formula (12) with compound of formula (28) to provide the compound of formula (25); and reacting the compound of formula (25) with compound of formula (9) to provide Suvorexant (1). Wherein, reaction of 2-amino-4-chlorophenol compound of formula (21) with carbonyl inserting agent or carbon mono-sulfide inserting agent in step (a) is carried out, optionally in a suitable solvent, optionally in the presence of base and catalyst; halogenation of compound of formula (27) in step (b) is carried out using a suitable halogenating agent, optionally in a suitable solvent, optionally in the presence of base and catalyst; reaction of the compound of formula (12) with compound of formula (28) in step (c) is carried out, optionally in a suitable solvent and optionally in the presence of base; reaction of the compound of formula (25) with compound of formula (9) is carried out, optionally in a suitable solvent, optionally in the presence of base and catalyst. Further, the first aspect of the present invention is represented schematically as shown below: Wherein: X is Halogen; Y is Halogen, -OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole and the like; Z is -O or -S; Pi is "amino-protecting group"; In the above aspect, compound of formula (25) and (1) may be further purified either by acid-base treatment, or suitable solvent crystallization, or converting into its acid addition salts. In the above aspect, the process of step (a), (b) and (c) can be carried out without isolating the intermediates compound of formula (27), (12) and (25). The products formed in the steps (a), (b) and (c) can be used in the next stage with or without isolation. The second aspect of the present invention provides a novel process for the preparation of intermediate of Suvorexant of formula (25), comprising of; condensing compound of formula (29) with compound of formula (12) to provide compound of formula (30); activating the hydroxy 1 group of compound of formula (30) to give compound of formula (31); selectively deprotecting the amino group of compound of formula (31) to provide compound of formula (32); and d) cyclising the compound of formula (32) to give compound of formula (25). Wherein, condensation of compound of formula (29) with compound of formula (12) in step (a) is carried out, optionally in a suitable solvent and optionally in the presence of base; activation of the hydroxyl group of compound of formula (30) in step (b) is carried out using a suitable reagent having formula (LX), optionally in a suitable solvent, optionally in the presence of base and catalyst; selective deprotection of the amino group of compound of formula (31) in step (c) is carried out using a suitable deprotecting agent, optionally in a suitable solvent; cyclisation of the compound of formula (32) in step (d) is carried out, optionally in a suitable solvent, optionally in the presence of base and catalyst; Further, the second aspect of the present invention is represented schematically as shown below: NH carbonylor Z ,,n 1 2 carbon mono- sulfide >-NH N<^| inserting agent °yL Halogenating XV„N agent _ ^ •ci 12^ H2N 6 32 P2 PrNH ^\ P1 29 , f^Y°. > 21 2? Cyclisation 25 30 < OH hydroxyl activating agent D P1NH Deprotection _. * /"'" of amine aXjT^ > N 3 0 P2 Wherein: X is Halogen; Z is -CO or -CS; Pi is "amino-protecting group"; 0-P2 = -Halogen, -OSO2CH3, -OS02CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, -OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,-OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. In the above aspect, the compound of formula (30), (31), (32) and (25) may be further purified either by acid-base treatment, or suitable solvent crystallization. In the above aspect, compound of formula (30), (31) and (32) may be further converted into its acid addition salts. In the above aspect, the process of steps (b) and (c) can be carried out without isolating the intermediates compound of formula (30), (31) and (32). The products formed in the steps (a) to (c) can be used in the next stage with or without isolation. The third aspect of the present invention provides a novel process for preparation of compound of formula (18), a Suvorexant intermediate, the process comprising: a. activating hydroxyl group of compound of formula (33) using a suitable reagent having formula (LX), in a suitable solvent and optionally in the presence of base to provide a compound of formula (34); b. reacting the compound of formula (34) with 2-aminoethanol (35) in a suitable solvent and in the presence of base to provide compound of formula (29); c. activating the hydroxyl group of the compound of formula (29) using a suitable reagent having formula (LX), in a suitable solvent and optionally in the presence of base to provide a compound of formula (36); d. selectively deprotecting the secondary amine of compound of formula (36) using a suitable deprotecting agent, in a suitable solvent to provide a compound of formula (37); and e. cyclising the compound of formula (37) in a suitable solvent, in the presence of base and optionally in a catalyst to provide a compound of formula (18). H2N^-^N—^°-P2 cychzatlon. PI-N^\NH 37 18 Wherein, Pi is "amino-protecting group"; and 0-P2 = -Halogen, -OS02CH3, -OS02CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, -OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,-OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. Further, Pi and P2 may be either same or different. In the above aspect, compounds of formula (34), (29), (36), (37), and (18) may be further purified either by acid-base treatment, or suitable solvent crystallization, or converting into its acid addition salts. The acid addition salts of compounds of formula (34), (29), (36), (37), and (18) can be prepared by treating the same with suitable acid. Further, the compounds of formulae (37) and (18) can be used as a key intermediate for preparation of Suvorexant (1). The fourth aspect of the present invention provides a process for preparation of Suvorexant of formula (1), the process comprising: a. reacting a compound of formula (18) with a compound of formula (9) in a suitable solvent, in the presence of base to provide compound of formula (11); P1-N/_~~XJH Y >=0 „/Tl9 , -v\ X..IJ 18 11 b. deprotecting the compound of formula (11) using suitable deprotecting agent in suitable solvent to provide a compound of formula (1 la); b. deprotecting the compound of formula (11) using suitable deprotecting agent in suitable solvent to provide a compound of formula (1 la); /T~ft /Ho VN r-^\N JJ^^L deprotection of amine /^^M^S^W. c. reacting the compound of formula (11a) with a compound of formula (12) in a suitable solvent and base, optionally in the presence of catalyst to provide Suvorexant(l). PI-VA XJ : - HV>... y 11 T na T c. reacting the compound of formula (11a) with a compound of formula (12) in a suitable solvent and base, optionally in the presence of catalyst to provide Suvorexant(l). oV kArx j Y Wherein: X is Halogens; Y is Halogens,-OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole and the like; Pi is "amino-protecting group"; 0-P2 = -Halogen, -OSO2CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph5 -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. Further, Pi and P2 may be either same or different. In the above aspect, based on the 'Y' group of compound of formula (9), step (a) can be carried out using a coupling agent and a catalyst In the above aspect, compounds of formula (11), (11a) and (1) may be further purified either by acid-base treatment, or suitable solvent crystallization, or converting into its acid addition salts. lla ' Suvorexant(l) Wherein: X is Halogens; Y is Halogens,-OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole and the like; Pi is "amino-protecting group"; 0-P2 = -Halogen, -OSO2CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph5 -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. Further, P1 and P2 may be either same or different. In the above aspect, based on the 'Y' group of compound of formula (9), step (a) can be carried out using a coupling agent and a catalyst In the above aspect, compounds of formula (11), (lla) and (1) may be further purified either by acid-base treatment, or suitable solvent crystallization, or converting into its acid addition salts. The acid addition salts of compounds of formula (11), (11a) and (1) can be prepared by treating the same with suitable acid. The products formed in step (a) and (b) can be used in the next stage with or without isolation of the product. The fifth aspect of the present invention provides a novel process for the preparation of intermediate of Suvorexant of compound of formula (11), comprising of: reacting the compound of formula (33) with compound of (9) to provide compound of (38); activating the hydroxyl group of compound of formula (38) to provide compound of formula (39); reacting the compound of formula (39) with 2-aminoethanol (35) to provide compound of formula (40); activating the hydroxyl group of compound of formula (40) to provide the compound of formula (41); cyclizing the compounds of formula (41) to provide compound of formula en). Wherein, reaction of the compound of formula (33) with compound of formula (9) in step- (a) is carried out, optionally in a suitable solvent, optionally in the presence of base, coupling agent and catalyst; activation of the hydroxyl group of compound of formula (38) in step (b) is carried out using a suitable reagent having formula (LX), optionally in a suitable solvent and optionally in the presence of base; reaction of the compound of formula (39) with 2-aminoethanol (35) in step (c) is Scheme-7 ■ Y ■ OH P1 /={ N-^ / / HO^ NH —i ^-K J \ ""V hydroxyl activating /=\ . ,--OP2 N-N 38 (| N 0 TV-alkylation H0 35 « N "N if1 y ^NH II ] r\ 'T hydroxylactivatmg / > ''''t^ RI-N'I (M «cyclization *vVNH agem y\ N/H Wherein: Y is Halogen, -OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole; Pi is "amino-protecting group"; O-P2 = -Halogen, -OS02CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. Wherein: Y is Halogen, -OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole; Pi is "amino-protecting group'1; 0-P2 = -Halogen, -OSO2CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. In the above aspect, Pi and P2 may be same or different as defined above. In the above aspect, compound of formula (38), (39), (40), (41) and (11) may be further purified either by acid-base treatment, or suitable solvent crystallization. In the above aspect, compound of formula (40) (41), and (11) may be further purified by converting into its acid addition salts. The sixth aspect of the present invention provides a novel process for the preparation of Suvorexant of formula (1), comprising of; reacting the compound of formula (40) with compound of formula (12) to provide compound of formula (42); activating the hydroxyl group of compound of formula (42) to provide compound of formula (43); cyclizing the compound of formula (43) to provide Suvorexant of formula (1). Wherein, reaction of the compound of formula (40) with compound of formula (12) in step (a) is carried out, optionally in a suitable solvent and optionally in the presence of base; activation of the hydroxyl group of compound of formula (42) in step (b) is carried out using a suitable reagent having formula (LX), optionally in a suitable solvent and optionally in the presence of base; cyclization of the compound of formula (43) in step (c) is carried out, optionally in a suitable solvent, optionally in the presence of base and catalyst; Further, the sixth aspect of the present invention is represented schematically as shown below: Wherein: X is Halogen; 0-P2 = -Halogen, -OSO2CH3, -OSO2CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, -OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPSrOCPh3rOCORrOCOC(CH3)3rOR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. In the above aspect, compound of formula (42), (43) and (1) may be further purified either by acid-base treatment, or suitable solvent crystallization. In the above aspect, compound of formula (42) and (43) may be further purified by converting into its acid addition salts. The seventh aspect of the present invention provides a novel process for the preparation of intermediate of Suvorexant of formula (37), comprising of: reacting the compound of formula (44) with compound of formula (45) to provide compound of formula (46); activating the hydroxyl group of compound of formula (46) to provide compound of formula (37). reaction of the compound of formula (44) with compound of formula (45) in step (a) is carried out, optionally in a suitable solvent and optionally in the presence of base; activation of the hydroxyl group of compound of formula (46) in step (b) is carried out using a suitable reagent having formula (LX), optionally in a suitable solvent and optionally in the presence of base; Further, the seventh aspect of the present invention is represented schematically as shown below: Scheme-9 44 =46 *^N i „ ?2 Pi 37 Wherein, Ri is "amino-protecting group" or -H Y is Halogen, -OH and OR, where R is selected from the group consisting of alkyl, aryl, substituted aryl, imidazole; 0-P2 = -Halogen, -OSO2CH3, -OS02CF3, -OTs, -OBs, -OCH2OCH3, -OC(CH3)3, - OCH2Ph, -O-p-methoxybenzyl, -OTMS, -OTES, -OTBDMS, -OTBDPS, -OTIPS,- OCPh3,-OCOR,-OCOC(CH3)3,-OR; -R is selected from the group consisting of alkyl, acetyl, aryl, substituted aryl and the like. In the above aspect, compound of formula (46) and (37) may be further purified either by acid-base treatment, or suitable solvent crystallization. In the above aspect, compound of formula (46) and (37) may be further purified by converting into its acid addition salts. The eight aspect of the present invention provides a purification process for Suvorexant (1), comprising of; a) treating Suvorexant of compound of formula (1) in a suitable solvent or mixture of suitable solvents; OR treating the solution of Suvorexant which may be obtained directly from a reaction in which Suvorexant is formed with solvent or mixture of solvents. optionally heating the mixture of step (a); crystallizing the Suvorexant from step (a) or (b); isolating the suvorexant the compound of formula (1) from step (a) or (b) or (c) to provide Suvorexant the compound of formula (1), wherein the content of impurity is not more than 0.15% measured by high performance liquid chromatography (HPLC). Suvorexant prepared according to any of the processes of the present invention has less than 0.15% of compound of formulae (47), (48), (49), (50), (51), (52), (53) and (54). OX*^> XrK^ XcK3# 50 ' X^ 51 [ 52 T 0>" °CCKW> 53 54 ' BEST MODE OF THE INVENTION The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention. 2-amino-4-chloro phenol (50g, 0.349 moles), carbonyl diimidazole (84.8g, 0.523 moles), potassium carbonate (48 g, 0.349 moles) and DCM (500 ml) were charged in round bottom flask at room temperature (RT). Reaction mass was stirred for 2-3 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, concentrated the reaction mass, charged the water (250 ml) and stirred the reaction mass for 1 h at room temperature, filtered the solid and washed with water (50 ml) to give 5-chloro-l,3-benzoxazol-2(3H)-one (27) as off white to beige color solid. [Yield = 53g (90%)] 5-chloro-l,3-benzoxazol-2(3H)-one (27) (50g, 0.294 moles) and phosphorus pentachloride (76.7g, 0.368 moles) and toluene (250 ml) were charged into round bottom flask at room temperature and heated the reaction mass to 80-85 °C for 4-6 h. The progress of the reaction was monitored by TLC, after completion of the reaction, the reaction mass was cooled to 5-10 °C, quenched with water (250 ml) and stirred the reaction mass followed by extraction of product in toluene. The obtained toluene layer dried over sodium sulfate followed by distillation of toluene to give pale yellow colored solid of 2,5-dichloro-l,3-benzoxazole (12). [Yield = 47.2g (85.00%)] Tert-butyl [(lR)-3-hydroxy-l-methylpropyl]carbamate (33) (20 g, 0.105 moles), 4-methylbenzenesulfonyl chloride (22.09g, 0.116 moles), triethylamine (21.21 g, 0.21 moles) and toluene (200 ml) were charged in round bottom flask at RT and stirred for 3 h at RT. After completion of the reaction, 2-aminoethanol (35, 6.41 gm, 0.105 moles) and triethylamine (5.3 g, 0.0525 moles) was added at RT, heated the reaction mass to 75-80 °C for 5-6 h. The progress of the reaction was monitored by TLC, after completion of the reaction, concentrated the reaction mass and water was added to precipitated the off white solid, filtered and washed the solid with water to give tert-butyl {(lR)-3-[(2-hydroxyethyl)amino]-l-methylpropyl}carbamate (29) as off white color liquid.Yield = 17.2 g (70.00%) diazepane (18) H O ^ i^ T PTSCI/ TEA/toluene —o y- O ^•J-Q- 0 ^-.. 18 Toluene/ TEA Dilute HCl 9 37 Tert-butyl {(lR)-3-[(2-hydroxyethyl)amino]-l-methylpropyl}carbamate (29) (20g, 0.086 moles), 4-methylbenzenesulfonyl chloride (18.05 g, 0.0947 moles), triethylamine (13.02 g, 0.129 moles) and toluene (200 ml) were charged in round bottom flask at RT and stirred for 3 h at RT. After completion of the reaction, dilute HC1 (50 mL) was added to the reaction mass and stirred for 1 h at 25-30 °C. separated the layers, dried the toluene layer over sodium sulfate and triethylamine was added to the toluene layer. Heated the toluene layer to 80-85 °C for 5-6 h, progress of cyclization reaction was monitored by TLC, after completion of reaction, concentrated the reaction mass to get residue. The obtained residue was purified by column chromatography (DCM: MeOH/ 9:1) to give (5R)-5-methyl-l-[(4-methylphenyl)sulfonyl]-l,4-diazepane (18) as dark brown color syrup.[Yield=15g (65%)] Tert-butyl {(lR)-3-[(2-hydroxyethyl)amino]-l-methylpropyl}carbamate (29) (20g, 0.086 moles), 2,5-dichloro-l,3-benzoxazole (12) (16.8 g, 0.086 moles), triethylamine (10.4 g, 0.103 moles) and toluene (150 ml) were charged were charged in round bottom flask. Reaction mass was heated to 100-110 °C for 8-10 h, progress of reaction monitored by TLC, after completion of reaction, reaction mass was cooled to 25-30 °C. 4-methylbenzenesulfonyl chloride (17.9g, 0.0946 moles) was added at 25-30 °C, stirred the reaction mass for 4-5 h at 25-30 °C, cone. HC1 (10 ml) and water (50 ml) were added to the reaction mass and stirred for 2-3 h at 25-30 °C. Toluene layer was separated and triethylamine (17.3 g, 0.172 moles) was added to toluene layer. Heated the toluene layer to 85-90 °C for 9-10 h. progress of cyclization reaction was monitored by TLC, after completion of reaction, cooled the reaction mass to RT and quenched with water (100 ml), product was extracted in toluene followed by distillation of toluene to give compound (25) as a brown color solid. Yield = 14.8 g (65.00%) Compound (25) (12g, 0.0591 moles), thionyl chloride (14g, 0.11 moles), DMF (1.0 g) and Toluene (50 ml) were charged in round bottom flask, heated the reaction mixture to 80-85 °C for 3 h. Distill out the mixture of thionyl chloride and toluene under reduced pressure to get brown color syrup, cooled the syrup to RT. DCM (100 ml) and TEA (15g, 0.073 moles) was charged to syrup at RT, followed by 29a (14 g, 0.053 moles) was added and stirred for 3-5 h at room temperature. After completion of reaction, charged the water and extracted the product in DCM layer. The obtained DCM layer dried over sodium sulfate and concentrated to obtained light brown color solid of crude Suvorexant (1). The obtained Suvorexant recrystallized from IPA to give white to off white crystalline solid of Suvorexant (1). N' 0 SN' III 1 0 AX,H Oxalyl chloride ^ A^, UJ Toluene/DMF/10-15 °C U g^ T T MTB (9) 0 u -^^ Na2C03/ toluene ' O 0 N^l) SRT-I(ll) V^ jf J 1 /NH ethyl acetate/DIPE MDA(18) / 5-methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid (9, 38.8 g, 0.20 mol), DMF (3.8 mL) and toluene (250 mL) were charged in round bottom flask at 25-30 °C. The reaction mixture was cooled to 0-5 °C and to this cold solution oxalyl chloride (30.3 g, 0.238 mol) was added under inert atmosphere. The temperature of reaction mass was raised to 15-20 °C and stirred for 2 h. In another RBF benzyl (5R)-5-methyi-l,4-diazepane-1-carboxylate (50.0 g, 0.21 mol), sodium carbonate (60.0 g, 0.573 mol) and toluene (100 mL) were charged at 5-10 °C followed by slow addition of above solution containing triazole and oxalyl chloride was slowly added. Temperature of reaction mass was raised to 25-30 °C and maintained for 2 h. After completion of reaction, the reaction mixture was diluted with water (400 mL) and extracted with toluene (2x150 mL). The combined organic layer concentrated under reduced pressure to give thick syrup. Ethyl acetate (50 mL) and DIPE (500 mL) were added to the syrup at 25-30 °C and stirred for 8-10 h. Filtered the precipitated solid and washed with DIPE to give white solid of benzyl (5R)-5-methyl-4-[2-(2H-l,2,3-triazol-2-yl)benzoyl]-l,4-diazepane-l-carboxylate (11). [Yield - 75.0 g (87.0%), HPLC purity: 99.60 %] Benzyl (5R)-5-methyl-4-[2-(2H-l5253-triazoI-2-yl)benzoyl]-l,4-diazepane-l- carboxylate (11, 80 g, 0.183 mol), 10% Pd/C (16 g) and IPA (400 mL) were charged in a autoclave at 25-30 °C. The reaction mixture was hydrogenated using hydrogen gas at 25-30 6C for 10 h. After completion of reaction the mixture was filtered through celite and washed with IPA (160 mL). Filtrate was concentrated under reduced pressure to give (7R)-7-methyl-l-[2-(2H-l52?3-triazol-2-yl)benzoyl]-l,4-diazepane (1 la) as pale brown syrup. [Yield = 46.0g (83.0 %)] Example-9: Preparation of Suvorexant (1) jV

Documents

Application Documents

# Name Date
1 3470-MUM-2015-Abstract-070916.pdf 2018-08-11
1 3470-MUM-2015-Form 5-070916.pdf 2018-08-11
2 3470-MUM-2015-Claims-070916.pdf 2018-08-11
2 3470-MUM-2015-Form 3-070916.pdf 2018-08-11
3 3470-MUM-2015-DISCRIPTION(COMPLETE)-070916.pdf 2018-08-11
3 3470-MUM-2015-Form 26-070916.pdf 2018-08-11
4 3470-MUM-2015-Form 2(Title Page)--070916.pdf 2018-08-11
4 3470-MUM-2015-FORM 2-070916.pdf 2018-08-11
5 3470-MUM-2015-Form 2(Title Page)-070916.pdf 2018-08-11
6 3470-MUM-2015-Form 2(Title Page)--070916.pdf 2018-08-11
6 3470-MUM-2015-FORM 2-070916.pdf 2018-08-11
7 3470-MUM-2015-DISCRIPTION(COMPLETE)-070916.pdf 2018-08-11
7 3470-MUM-2015-Form 26-070916.pdf 2018-08-11
8 3470-MUM-2015-Claims-070916.pdf 2018-08-11
8 3470-MUM-2015-Form 3-070916.pdf 2018-08-11
9 3470-MUM-2015-Abstract-070916.pdf 2018-08-11
9 3470-MUM-2015-Form 5-070916.pdf 2018-08-11