(19) TZZ Z_T (11) EP 2 680 697 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A01N 43/62 (2006.01) A61K 31/55 (2006.01) 10.01.2018 Bulletin 2018/02 C07D 413/04 (2006.01) C07D 413/14 (2006.01) C07D 249/06 (2006.01) (21) Application number: 12776679.8 (86) International application number: (22) Date of filing: 27.02.2012 PCT/US2012/026691 (87) International publication number: WO 2012/148553 (01.11.2012 Gazette 2012/44) (54) PROCESS FOR THE PREPARATION OF AN OREXIN RECEPTOR ANTAGONIST VERFAHREN ZUR HERSTELLUNG EINES OREXIN-REZEPTOR-ANTAGONISTEN PROCÉDÉ DE PRÉPARATION D’UN ANTAGONISTE DES RÉCEPTEURS DES OREXINES (84) Designated Contracting States: • STROTMAN, Neil AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Rahway, NJ 07065-0907 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • WALLACE, Debra, J. PL PT RO RS SE SI SK SM TR Rahway, NJ 07065-0907 (US) •WRIGHT,Timothy (30) Priority: 03.03.2011 US 201161448814 P Rahway, NJ 07065-0907 (US) (43) Date of publication of application: (74) Representative: Jaap, David Robert et al 08.01.2014 Bulletin 2014/02 Merck Sharp & Dohme Corp. European Patent Department (73) Proprietors: Hertford Road • Merck Sharp & Dohme Corp. Hoddesdon, Hertfordshire EN11 9BU (GB) Rahway, NJ 07065-0907 (US) • Merck Sharp & Dohme Limited (56) References cited: Hoddesdon, Hertfordshire EN11 9BU (GB) US-A- 3 222 359 US-A1- 2008 132 490 US-A1- 2009 124 603 US-A1- 2009 187 028 (72) Inventors: • BAXTER, Carl, A. • NEIL A. STROTMAN ET AL: "Reaction Hoddesdon, Hertfordshire EN11 9BU (GB) Development and Mechanistic Study of a • CLEARTOR, Edward Ruthenium Catalyzed Intramolecular Hoddesdon, Hertfordshire EN11 9BU (GB) Asymmetric Reductive Amination en Route to the • KRSKA, Shane, W. Dual Orexin Inhibitor Suvorexant (MK-4305)", Rahway, NJ 07065-0907 (US) JOURNAL OF THE AMERICAN CHEMICAL • SHEEN, Faye SOCIETY, vol. 133, no. 21, June 2011 (2011-06), Hoddesdon, Hertfordshire EN11 9BU (GB) pages8362-8371, XP055127239, ISSN: 0002-7863, • STEWART, Gavin DOI: 10.1021/ja202358f Hoddesdon, Hertfordshire EN11 9BU (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 680 697 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 680 697 B1 Description BACKGROUND OF THE INVENTION 5 [0001] The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic or insomniac 10 patients (Chemelli R.M. et al., Cell, 1999, 98, 437-451). Orexins have also been indicated as playing a role in arousal, reward, learning and memory (Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): the orexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. The physiological actions in which orexins are presumed to participate 15 are thought to be expressed via one or both of OX 1 receptor and OX 2 receptor as the two subtypes of orexin receptors. [0002] Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as 20 Huntington’s disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinson’s disease; Cushing’s syndrome/disease; basophile adenoma; prolactino- ma; hyperprolactinemia; hypophysis tumour/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcers; Froehlich’s syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis 25 hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman’s syndrome (anosmia, hypos- mia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic- adrenal dys- function; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth defi- ciency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, 30 acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myo- cardinal infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related 35 to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; conditions associated with visceral pain such as irritable bowel syndrome, and angina; migraine; urinary bladder incon- tinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; nar- colepsy; insomnia; parasomnia; jet lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure dis- 40 orders and other diseases related to general orexin system dysfunction. [0003] The compound of the formula I: 45 50 55 is disclosed as an antagonist of orexin receptors in US Patent Application Publication US 2008/0132490, PCT Patent Publication WO 2008/069997 and Cox et al., J. Med. Chem. 2010, 53, 5320-5332. This compound may be named as "5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole," "[(R)- 2 EP 2 680 697 B1 4-(5-chloro-benzooxazol-2-yl)-7-methyl-[1,4]diazepan-1-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone" or "[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]meth- anone." 5 SUMMARY OF THE INVENTION [0004] The present invention is directed to processes for preparing a diazepane compound which is an antagonist of orexin receptors, and which is useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. Also disclosed are crystalline forms of this diazepane compound and pharma- 10 ceutical compositions thereof BRIEF DESCRIPTION OF THE DRAWINGS [0005] 15 FIG. 1 shows an X-ray diffraction pattern of anhydrous Form I of the compound [(7R)-4-(5-chloro-1,3-benzoxazol- 2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone. FIG. 2 shows a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of anhydrous Form I of the compound [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl] 20 [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone. FIG. 3 shows a DSC curve of anhydrous Form I of the compound [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl- 1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone. FIG. 4 shows an X-ray diffraction pattern of anhydrous Form II of the compound [(7R)-4-(5-chloro-1,3-benzoxazol- 2-yl)-7-methyl-1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone. 25 FIG. 5 shows a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of anhydrous Form II of the compound [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1- yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone. FIG. 6 shows a DSC curve of anhydrous Form II of the compound [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl- 1,4-diazepan-1-yl] [5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone. 30 DETAILED DESCRIPTION OF THE INVENTION [0006] The present invention is directed to a process for preparing a compound of the formula I: 35 40 45 or a pharmaceutically acceptable salt thereof, which comprises: 50 contacting a compound of the formula II: 55 3 EP 2 680 697 B1 5 10 with an activating agent selected from oxalyl chloride, thionyl chloride, POCl 3, pivaloyl chloride, benzyl chloroformate, to form the acid chloride, 15 followed by contacting the acid chloride with a compound of the formula III: 20 25 or a salt thereof, in the presence of a weak base to give the compound of the formula I, or a pharmaceutically acceptable salt thereof; wherein the compound of the formula III or salt thereof, is prepared by: 30 contacting a compound of the formula IV: 35 40 with an asymmetric reducing agent in the presence of a weak base, and a terminal reductant to give the compound of the formula III, or a salt thereof.