The U.S. Food and Drug Administration today approved Belsomra (suvorexant) tablets for use as needed to treat difficulty in falling and staying asleep (insomnia).

Belsomra is an orexin receptor antagonist and is the first approved drug of this type. Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake. Belsomra alters the signaling (action) of orexin in the brain.

Insomnia is a common condition in which a person has trouble falling or staying asleep. It can range from mild to severe, depending on how often it occurs and for how long. Insomnia can cause daytime sleepiness and lack of energy. It also can make a person feel anxious, depressed, or irritable. People with insomnia may have trouble with attentiveness, learning, and memory.

“To assist health care professionals and patients in finding the best dose to treat each individual patient’s sleeplessness, the FDA has approved Belsomra in four different strengths – 5, 10, 15, and 20 milligrams,” said Ellis Unger, M.D., director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research. “Using the lowest effective dose can reduce the risk of side effects, such as next-morning drowsiness.”

Belsomra should be taken no more than once per night, within 30 minutes of going to bed, with at least seven hours remaining before the planned time of waking. The total dose should not exceed 20 mg once daily.

The most commonly reported adverse reaction reported by clinical trial participants taking Belsomra was drowsiness. Medications that treat insomnia can cause next-day drowsiness and impair driving and other activities that require alertness. People can be impaired even when they feel fully awake.

The FDA asked the drug manufacturer, Merck, Sharpe & Dohme Corp., to study next-day driving performance in people who had taken Belsomra. The testing showed impaired driving performance in both male and female participants when the 20 mg strength was taken.  Patients using the 20 mg strength should be cautioned against next-day driving or activities requiring full mental alertness. Patients taking lower doses should also be made aware of the potential for next-day driving impairment, because there is individual variation in sensitivity to the drug.

The effectiveness of Belsomra was studied in three clinical trials involving more than 500 participants. In the studies, patients taking the drug fell asleep faster and spent less time awake during the remainder of the night compared to people taking an inactive pill (placebo). Belsomra was not compared to other drugs approved to treat insomnia, so it is not known if there are differences in safety or effectiveness between Belsomra and other insomnia medications.

Like other sleep medicines, there is a risk from Belsomra of sleep-driving and other complex behaviors while not being fully awake, such as preparing and eating food, making phone calls, or having sex. Chances of such activity increase if a person has consumed alcohol or taken other medicines that make them sleepy. Patients or their families should call the prescribing health care professional if this type of activity occurs.

Belsomra will be dispensed with an FDA-approved patient Medication Guide that provides instructions for its use and important safety information. Belsomra is a controlled substance (Schedule-IV) because it can be abused or lead to dependence.

Belsomra is made by Merck, Sharpe & Dohme Corp. of Whitehouse Station, N.J.

Old article CUT PASTE

[(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

Suvorexant

may23,2013

A panel of experts at the US Food and Drug Administration has recommended Merck & Co’s insomnia drug suvorexant when given in lower dosages but rejected the higher dose that the company was seeking.———read more at

http://www.pharmatimes.com/Article/13-05-23/FDA_panel_backs_Merck_Co_sleep_drug_but_at_low_doses.aspx

MAIN PART

Suvorexant (MK-4305) is a dual orexin receptor antagonist in development by Merck & Co.^[1][2][3] Suvorexant works by turning off wakefulness rather than by inducing sleep.^[4] It is not currently approved for commercial use, but it has completed three Phase III trials.^[5]The recent FDA review showed that the drug is associated with increased somnolence the next day and users of higher doses had an increased rate of suicidal ideation. ^[6] It is one of two such compounds currently in development, the other being GlaxoSmithKline‘s SB-649,868.

OREXINS A AND B ARE EXCITATORY NEUROPEPTIDES THAT STIMULATE WAKEFULNESS. SUVOREXANT IS A DUAL OREXIN RECEPTOR ANTAGONIST THAT IS IN PHASE III CLINICAL TRIALS FOR THE TREATMENT OF INSOMNIA. THE KEY STEP IN THE ASYMMETRIC SYNTHESIS ­DEPICTED IS A TANDEM ENZYMATIC TRANSAMINATION–ANNULATION SEQUENCE (F → G → H).

A previous synthesis of suvorexant (N. A. Strotman et al. J. Am. Chem. Soc. 2011, 133, 8362) involved an asymmetric Ru-catalyzed reductive amination in the construction of the diazepane ring. The present route benefits from the circumvention of transition-metal catalysis and dichloromethane as solvent.

PATENT

http://www.google.co.in/patents/US7951797

benzyl (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane-1-carboxylate (G-1)

To a solution of 22.3 g (78 mmol) of the hydrochloride salt of F-1, 15.9 g (78 mmol) A-2, 12.8 g (94 mmol) 1-hydroxy-7-azabenzotriazole, and 43.1 mL (392 mmol) N-methylmorpholine in 300 mL of DMF was added 22.5 g (118 mmol) EDC and the reaction was stirred overnight at room temperature. The reaction was partitioned between EtOAc and saturated aqueous NaHCO₃, washed with water, brine, dried over MgSO₄, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc/hexanes) to provide G-1 as a colorless gum. Data for G-1: LC/MS: rt=2.22 min; m/z (M+H)=434.2 found; 434.2 required.

(7R)-7-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane (G-2)

A round bottom flask containing a solution of 29.6 g (68.3 mmol) G-1 in 300 mL EtOAc and 200 ml MeOH was evacuated under reduced pressure and purged three times with an atmosphere of N₂. To the flask was then added 2.4 g of 20% Pd(OH)₂on carbon. The flask was again evacuated under reduced pressure and purged three times with an atmosphere of N₂, and then three times with H₂. The reaction was stirred under an atmosphere of H₂ for three days, then filtered through a pad of celite, rinsing with EtOAc followed by MeOH. The filtrate was concentrated to provide G-2 as a white foam. Data for G-2: LC/MS: rt=0.96 & 1.13 min (see two conformers under these conditions); m/z (M+H)=300.0 found; 300.2 required.

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 (G-3)

To 21.0 g (70.1 mmol) G-2 in 250 mL DMF was added 29.3 mL (210 mmol) triethylamine and 13.2 g (70.1 mmol) D-1 and the mixture was heated in an oil bath at 75° C. for 2 h. After cooling to room temperature, the reaction was diluted with EtOAc, washed with saturated aqueous NaHCO₃, water, brine and dried over MgSO₄. Following concentration by rotary evaporation, the residue was purified by flash column chromatography (hexanes/EtOAc) to provide a gum. The gum was stirred in a mixture of 150 ml EtOAc and 300 ml hexanes overnight. Filtration provided G-3 as a white solid. Data for G-3: LC/MS: rt=2.29 min; m/z (M+H)=451.1 found; 451.2 required; HRMS (APCI) m/z (M+H) 451.1631 found; 451.1644 required.

PATENT

http://www.google.com/patents/CN103923068A?cl=en

Scheme (1) US2008 / 132490 reported as follows:

 (2) Org.Process Res.Dev.2011,15,367 – 375 reported a synthetic route is as follows:

 the two lines above has the following disadvantages: starting materials using highly toxic compound methyl vinyl ketone, methyl vinyl ketone to the eyes, skin, mucous membranes and upper respiratory tract irritation strong, easy to operate when used; and finally to preparation suvorexant, the need to chiral separation, is not conducive to industrial production, but low yield.

 (3) W02012148553 and J.Am.Chem.Soc.2011,133,8362 – Scheme 8371 report as follows:

 The route disadvantages: starting materials using highly toxic compound methyl vinyl ketone, methyl vinyl ketone to the eyes, skin, mucous membranes and upper respiratory tract irritation strong, easy to operate when used; also use a heavy metal catalyst, high cost, and environmentally unfriendly.

 (4) Org.Lett, synthetic route Vol.14, N0.13,2012,3458-3461 reported as follows:

 The disadvantage of this route: starting materials using highly toxic compound methyl vinyl ketone, methyl vinyl ketone pairs of eyes, skin, mucous membranes and upper respiratory tract irritation strong. ; Additional use of biocatalysis, high cost.

 (5) Angew.Chem.1nt.Ed.2011,50,11511 – 11515 reported synthetic route is as follows:

Example 1:

Synthesis – (((tert-butoxycarbonyl) amino) butanamide N- benzyl-3-yl) acetate – [0064] (R) methyl-2-

 The methyl-2- (benzylamino) ethyl ester (20mmol), (R) _3_ ((tert-butoxycarbonyl) amino) butyric acid (21mmol), 1- hydroxybenzotriazole (25mmol), dried triethylamine (30mmol) added to the flask, anhydrous DMF25ml, stirring was added EDC (24mmOl), 10 ° C the reaction 5h. Was added 10% citric acid solution, extracted with ethyl acetate, 5% Na2CO3 solution The organic layer was washed with saturated brine, MgSO4 dried, filtered and evaporated to dryness, the product obtained from ethyl acetate and petroleum ether (1: 2, volume ratio ) recrystallized to obtain (yield 98%, mp: 107 ° C, [a] 26D = 21.97 (103.76mg / 20ml, MeOH)). IHNMR (600MHz, DMS0_d6) δ ppm7.38-7.23 (m, 5H), 6.73-6

• 72 (d, I Η), 4.75-4.4 (m, 2H), 4.31-3.95 (m, 2H), 3.89-3.87 (t, I Η), 3.64-3.62 (d, 3Η), 2.64-2.50 ( m, 1Η), 2.37-2.23 (m, 1Η), 1.38-1.37 (d, 9Η), 1.08-1.06 (m, 3Η); (FIG. 1) MS (ESI) m / ζ365.20 ([Μ + Η ] +).

Example 2:

Synthesis – (((tert-butoxycarbonyl) amino) butanamide N- benzyl-3-yl) acetate – [0068] (R) methyl-2-

 The methyl-2- (benzylamino) ethyl ester (20mmol), (R) _3_ ((tert-butoxycarbonyl) amino) butyric acid (21mmol), 1_ hydroxybenzotriazole (25mmol), potassium carbonate (60mmol) added to the flask, anhydrous dichloromethane 50ml, was added under stirring ⑶I (22mmOl), 20 ° C reaction 6h. Was added 10% citric acid solution, extracted with ethyl acetate, 5% Na2CO3 solution The organic layer was washed with saturated brine, MgSO4 dried, filtered and evaporated to dryness, the product obtained from ethyl acetate and petroleum ether (1: 2, volume ratio ) recrystallization, that was (yield 97.5%, mp: 107 ° C, [a] 26D = 21.97 (103.76mg / 20ml, MeOH)).

 Example 3:

Synthesis – (((tert-butoxycarbonyl) amino) butanamide N- benzyl-3-yl) acetate – [0071] (R) methyl-2-

 The methyl-2- (benzylamino) ethyl ester (20mmol), (R) _3_ ((tert-butoxycarbonyl) amino) butyric acid (21mmol), 1- hydroxybenzotriazole (25mmol), Sodium hydride (24mmol) added to the flask, anhydrous acetone 50ml, was added with stirring 1 (Shu ^ (25 dirty 01), 301:! 411. The reaction was added 10% citric acid solution, extracted with ethyl acetate, 5% Na2CO3 The organic layer was washed with a solution, and saturated brine, MgSO4 dried, filtered and evaporated to dryness, the product obtained from ethyl acetate and petroleum ether (1: 2, volume ratio) was recrystallized to obtain (yield 97%, mp: 107 ° C, [a] 26D =

21.97 (103.76mg / 20ml, MeOH)).

Example 4: [0074] (R) -4- benzyl-7-methyl-1,4-diaza Synthesis heptane-2,5-dione

 The 3g (8.2mmol) (R) – methyl _2_ (N- benzyl _3_ ((tert-butoxycarbonyl) amino) butanamide yl) acetate were added to the flask, and dissolved in ethyl acetate was added IOml added 30ml45% of acetate hydrochloride gas, 25 ° C reaction 4h.Evaporated to dryness, and saturated NaHC03 solution, methylene chloride and ethanol (2: 1, volume ratio) was extracted, MgSO4 organic layer was dried and evaporated to dryness to give a pale yellow oil. It was dissolved in 30ml MeOH and dried added 0.487g (9.02mmol) NaOMe, under nitrogen, 10 ° C reaction 4h. Quenched with saturated NH4Cl solution was added 5 ^ Na2CO3 solution, methylene chloride and ethanol (2: 1, volume ratio) was extracted organic layers were combined, MgSO4 dried, rotary evaporated to give a white solid (yield 98.93%, mp: 122_123 ° C , [a] 26D = 33.49 (112.87mg / 20ml, MeOH)). IH NMR (600MHz, DMS0_d6) δ ppm7.77-7.76 (bd, 1H), 7.33-7.25 (m, 5H), 4.59-4.53 (m, 2H), 4.10-4.02 (m, 2H), 3.65-3.62 ( m, 1H), 2.93-2.90 (m, 1H),

2.76-2.72 (m, 1H), 1.14-1.13 (d, 3H); (FIG. 2) MS (ESI) m / z233.10 ([M + H] +) ..

 Example 5:

(R) -4- benzyl-7-methyl-1,4-diaza Synthesis heptane-2,5-dione

The 3g (8.2mmol) (R) – methyl _2_ (N_ _ _3 benzyl ((tert-butoxycarbonyl) amino) butanamide yl) acetate were added to the flask, dissolved in dichloromethane was added IOml adding 30ml methylene chloride solution containing 10% of CF3COOH of, 25 ° C reaction 4h. Evaporated to dryness and saturated NaHCO3 solution, methylene chloride and ethanol (2: 1, volume ratio) was extracted, MgSO4 organic layer was dried and evaporated to dryness to give a yellow oil. This was dissolved in 50ml of dry toluene, was added 0.156g (6.5mmol) of sodium hydride, 110 ° C reaction 4h. After cooling to room temperature, quenched with saturated NH4Cl solution, 5% Na2CO3 solution is added, methylene chloride and ethanol (2: 1, volume ratio) was extracted organic layers were combined, MgSO4 dried, rotary evaporated to give a white solid 1.83g (yield 90.34 %, mp: 122-123 ° C, [a J26D = 33.49 (112.87mg / 20ml, MeOH)).

Example 6:

 (R) -4- benzyl-7-methyl-1,4-diaza Synthesis heptane-2,5-dione

The 3g (8.2mmol) (R) – methyl _2_ (N_ _ _3 benzyl ((tert-butoxycarbonyl) amino) butanamide yl) acetate were added to the flask, methanol was added IOml dissolved, 30ml36% methanol solution of hydrochloric acid gas, 25 ° C reaction 4h.Evaporated to dryness, and saturated NaHC03 solution, methylene chloride and ethanol (2: 1, volume ratio) was extracted, MgSO4 organic layer was dried and evaporated to dryness to give a yellow oil. This was dissolved in 50ml of dry toluene, was added 1.7g (12.3mmol) of potassium carbonate, 110 ° C reaction 8h. After cooling to room temperature, quenched with saturated NH4Cl solution, 5% Na2CO3 solution is added, methylene chloride and ethanol (2: 1, volume ratio) was extracted organic layers were combined, MgSO4 dried, rotary evaporated to give a white solid (yield 95.78%, mp: 122_123 ° C, [a] 26D = 33.49 (112.87mg / 20ml, MeOH)).

Example 7:

 (R) -4- benzyl-7-methyl-1,4-diaza Synthesis heptane-dione _2,5_

 The 3g (8.2mmol) (R) – methyl _2_ (N_ _ _3 benzyl ((tert-butoxycarbonyl) amino) butanamide yl) acetate were added to the flask, methanol was added IOml dissolved, 30ml of 36% methanol containing hydrochloric acid gas solution, 25 ° C reaction 4h. Evaporated to dryness and saturated NaHCO3 solution, methylene chloride and ethanol (2: 1, volume ratio) was extracted, MgSO4 organic layer was dried and evaporated to dryness to give a yellow oil. Which was dissolved in 30ml of ethyl acetate and dried, was added 0.88g (16.4mmOl) sodium alkoxide, 10 ° C the reaction 6h. Quenched with saturated NH4Cl solution was added 5 ^ Na2CO3 solution, methylene chloride and ethanol (2: 1, volume ratio) was extracted organic layers were combined, MgSO4 dried, rotary evaporated to give a white solid (yield 93%, mp: 122_123 ° C , [a] 26D = 33.49 (112.87mg / 20ml, Me0H)) ο Example 8:

 (R) -4- benzyl-7-methyl-1,4-diaza Synthesis heptane-2,5-dione

 The 3g (8.2mmol) (R) – methyl _2_ (N- benzyl _3_ ((tert-butoxycarbonyl) amino) butanamide yl) acetate were added to the flask, methanol was added IOml dissolved, 30ml hydrochloric acid gas containing 36% methanol solution, 25 ° C reaction 4h. Evaporated to dryness, and saturated NaHC03 solution, methylene chloride and ethanol (2: 1, by volume) to extract, MgS04 organic layer was dried and evaporated to dryness to give a yellow oil. Which was dissolved in 30ml of dry methanol was added 2.07g (20.5mmol) of triethylamine, 60 ° C the reaction 8h. After cooling to room temperature, quenched with saturated NH4Cl solution, 5% Na2CO3 solution is added, methylene chloride and ethanol (2: 1, volume ratio) was extracted organic layers were combined, MgSO4 dried, rotary evaporated to give a white solid (yield 92.68%, mp: 122_123 ° C, [a] 26D = 33.49 (112.87mg / 20ml, MeOH)).

 Example 9:

(R) -4- benzyl-7-methyl-1,4-diaza Synthesis heptane-2,5-dione

The 3g (8.2mmol) (R) – methyl _2_ (N_ _ _3 benzyl ((tert-butoxycarbonyl) amino) butanamide yl) acetate were added to the flask, methanol was added IOml dissolved, 30ml hydrochloric acid gas containing 36% methanol solution, 25 ° C reaction 4h. Evaporated to dryness, and saturated NaHC03 solution, methylene chloride and ethanol (2: 1, by volume) to extract, MgSO4 organic layer was dried and evaporated to dryness to give a yellow oil. Which was dissolved in 30ml of dry acetonitrile was added 1.38g (12.3mmol) of potassium t-butoxide, 30 ° C the reaction 8h. Quenched with saturated NH4Cl solution was added 5 ^ Na2CO3 solution, methylene chloride and ethanol (2: 1, volume ratio) was extracted organic layers were combined, MgSO4 dried, rotary evaporated to give a white solid (yield 89.86%, mp: 122_123 ° C , [a] 26D = 33.49 (112.87mg / 20ml, MeOH)).

Example 10:

 (R) -1- benzyl-5-methyl-1,4-Synthesis diazepan the

 A 1.4g (R) -4- benzyl-7-methyl-diaza heptane _2,5_ _1,4_ dione (6mmol) was dissolved in 60ml dry THF, was added portionwise under ice- 1.35g LiAlH4 (36mmol), 25 ° C was stirred for 4h. Cooled to -10 ° C, was added 1.5mlH2O quenched and then 1.5mll5% NaOH, 4.5ml H20, part MgSO4, stirring lh, filtration, spin dried to give 1.2g oil (yield 97.56%, [a] 29D = -5.87 (200.86mg / 20ml, CHCl 3)). ee> 99%, Chrom Techchiral-AGP150 * 4mm Mobile phase: Ammonium dihydrogen sulfate (IM): acetonitrile = 99: 1, column temperature: 30 ° C, flow rate: 0.5ml / Hiin0 IH NMR (600MHz, DMS0_d6) δ ppm7.32-7.20 (m, 5Η), 3.57 (s, 2Η), 3.48 (bs, 1Η), 2.99-2.95 (m, 1Η), 2.86-2.82 (m, 1Η), 2.72-2.68 (m, 1Η ), 2.65-2.61 (m, 1Η), 2.58-2.49 (m, 3Η), 1.75-1.70 (m, 1Η), 1.46-1.41 (m, 1Η), 1.01-1.00 (d, 3Η); (Figure 3 .) MS (ESI) m / z205.10 ([M + H] +) [0095] Example 11:

(R) -1- benzyl-5-methyl-1,4-Synthesis diazepan the

A 1.4g (R) -4- benzyl-7-methyl-diaza heptane _2,5_ _1,4_ dione (6mmol) was dissolved in 60mlTHF TEMPERATURE dropwise 2 equivalents of borane ( 12mm0l), reflux 8h. Cooled to _10 ° C, quenched by addition of methanol, adjusted pH = 3, stirred for 2h, sodium carbonate adjusted to pH = 10, extracted with methylene chloride three times, the combined organic layer, MgSO4 drying, rotary evaporation. (Yield 95.32%, [a] 29D = -5.87 (200.86mg / 20ml, CHCl 3)). [0098] Example 12:

 (R) -1- benzyl-5-methyl-1,4-Synthesis diazepan the

 The (R) -4- benzyl-7-methyl-1,4-diaza heptane-2,5-dione (5mmol) was dissolved in 15ml dry THF, was added under ice-cooling to a solution of Ig sodium boron (27mmol) in 15ml dry THF hydride was added dropwise a solution of iodine in 20ml THF 12mmol dried under nitrogen, at reflux for 6h. Cooled to (TC, quenched 5ml3N HCl was added, followed by addition of 8ml3NNaOH, liquid separation, the aqueous layer was extracted three times with ether, the combined organic layer was washed with saturated brine, MgSO4 drying, filtration, spin dry (yield 90.34%, [a ] 29D = -5.87 (200.86mg / 20ml, CHC13)).

 Example 13:

(R) – (4_-Benzyl-7-methyl-1,4-diazepan-1-yl) (5-methyl _2_ (2H-1,2,3_ three

Synthesis of 2-yl) phenyl) methyl ketone

 The 3g (R) -1- benzyl-5-methyl-1,4-diazepane (14.7mmol), 3.66g5_ methyl -2- (2Η-1, 2,3- triazol-2-yl) benzoic acid (18.03mmol) was dissolved in DMF, 2.43gHOBt (18.55mmol), 6ml TEA (42.75mmol), 3.45g EDC (17.99mmol), warmed to 50 ° C, the reaction 2h. Was added a saturated NaHCO3 solution and EA, the aqueous layer was washed three times with EA, the combined organic layers. The organic layer was washed with citric acid solution, the product salified fully into the aqueous phase, the aqueous phase was washed with EA after the addition of sodium carbonate to adjust the pH> 9, EA and washed three times, the organic layers combined, washed with water and saturated brine, MgSO4 dried, rotary dried, PE and EA (4: 1) and recrystallized (yield 98.36%, mp: 108-109 ° C, [α] 31D = -58.37 (202.5mg / 20ml, MeOH)). IH NMR (600MHz, DMS0_d6) δ ppm8.00-7.76 (m, 3H), 7.37-7.17 (m, 7H), 4.40-4.09 (m, 1H), 3.63-3.48 (m, 2H), 3.44-3.02 ( m, 3H), 2.82-2.75 (m, 1H), 2.63-2.47 (m, 1H), 2.63-2.14 (m, 5H), 2.02-1.63 (m, 2H), 1.17-0.99 (m, 3H); (Figure 4) MS (ESI) m / z390.30 ([M + H] +) [0105] Example 14:

(R) – (4_-Benzyl-7-methyl-1,4-diazepan-1-yl) (methyl 5_ _2- (2Η_1,2,3_ triazol-2 Synthesis-yl) phenyl) methyl ketone

The 3g (R) -1- benzyl-5-methyl-1,4-diazepane (14.7mmol), 2.98g5_ methyl -2- (2H-1, 2,3- triazol-2-yl) benzoic acid (14.7mmol) was dissolved in methylene chloride, was added 18.55mmolHOAt, 6ml TEA (42.75mmol), 2.86g CDI (17.64mmol), 30 ° C reaction 4h. Was added a saturated NaHC03 solution and EA, the aqueous layer was washed three times with EA, the combined organic layers. The organic layer was washed with citric acid solution, the product salified fully into the aqueous phase, the aqueous phase was washed with EA after the addition of sodium carbonate to adjust the pH> 9, EA and washed three times, the combined organic layer was washed with saturated brine paint, MgS04 drying, spin dry, PE and EA (4: 1) and recrystallized (yield 96.45%, mp = 108-109 ° C, [a J31D = -58.37 (202.5mg / 20ml, MeOH)).

 Example 15:

(R) – (4_-Benzyl-7-methyl-1,4-diazepan-1-yl) (5-methyl _2_ (2H-1,2,3_ triazol – 2- yl) phenyl) -methanone [0110] The 3g (R) -1- benzyl-5-methyl-1,4-diazepane (14.7mmol), 3.28g5_ methyl – 2- (2Η-1,2,3- triazol-2-yl) benzoic acid (16.17mmol) was dissolved in acetone was added 2.43gHOBt (18.55mmol), 6ml TEA (42.75mmol), 3.33gDCC (16.17mmol) After the addition of sodium carbonate, 3 (TC reaction 4h. Saturated NaHCO3 solution was added and EA, the aqueous layer was washed three times with EA, the combined organic layers. The organic layer was washed with citric acid solution, the product salified fully into the aqueous phase, the aqueous phase was washed with EA adjust pH> 9, EA and washed three times, the organic layers combined, washed with water and saturated brine, MgSO4 dried, rotary dried, PE and EA (4: 1) and recrystallized (yield 92.43%, m.ρ .: 108-109 .. , [a J31D = -58.37 (202.5mg / 20ml, MeOH)).

 Example 16:

 (R) – (7- methyl-1,4-diazepan-1-yl) (5-methyl _2_ (2H-1,2,3_ _2_ triazol-yl)

Phenyl) methyl ketone

A 2.08g (R) – (4_ benzyl _7_ methyl _1,4_ two diazepan _1_ yl) (5_-methyl -2- (2Η-1, 2, 3- triazol-2-yl) phenyl) methanone (7.2mmol) was dissolved in 20ml MeOH was added 10% Pd (OH) 2 / C, 25 ° C H2 passed into the reaction 4h.Filtration, rotary evaporation to give the product (yield 98.39%, [a] 26D = -14.36 (199.12mg / 20ml, MeOH)). IH NMR (600MHz, DMS0_d6) δppm8.24-8.02 (m, 2H), 7.88-7.29 (m, 3H), 4.42-2.50 (m, 7H), 2.41 (s, 3H), 2.24-1.98 (m, 2H .), 1.17-0.99 (m, 3H); (FIG. 5) MS (ESI) m / z300.20 ([M + H] +) [0115] Example 17:

 (R) – (7- methyl-1,4-diazepan-1-yl) (5-methyl _2_ (2H-1,2,3_ _2_ triazol-yl) benzene Synthesis yl) methyl ketone

 A 2.08g (R) – (4_ _1,4_ Benzyl-7-methyl-diazepan-1-yl) (5_-methyl -2- (2Η-1, 2, 3- triazol-2-yl) phenyl) methyl ketone (7.2mmol) was dissolved in 20ml THF, 10% of the PdC12,50 ° C through the H2 reaction 2h. Filtration, rotary evaporation to give the product (yield 93.24%, [a] 26D = -14.36 (199.12mg / 20ml, MeOH)).

Example 18:

 (R) – (7- methyl-1,4-diazepan-1-yl) (5-methyl _2_ (2H-1,2,3_ _2_ triazol-yl) benzene Synthesis yl) methyl ketone

 A 2.08g (R) – (4_ _1,4_ Benzyl-7-methyl-diazepan-1-yl) (5_-methyl -2- (2H-1, 2, 3- triazol-2-yl) phenyl) methanone (7.2mmol) was dissolved in 20ml of methanol was added 10% Pd / C, was added ammonium formate (21.6_ο1), the reaction was refluxed for 6h. Filtration, rotary evaporation to give the product (yield 92.68%, [a] 26D = -14.36 (199.12mg / 20ml, MeOH)).

 Example 19

Synthesis Suvorexant of

 To 0.9g (R) – (7- methyl-1,4-diazepan-1-yl) (methyl 5_ _2_ (2H-1,2,3_ triazol-2 yl) phenyl) methanone (3.0lmmol) of IOml DMF was added 0.57g2, 5- dichlorobenzene and oxazole (3.03mmol), 0.91g TEA (9mmol), heated to 75 ° C, the reaction 2h. Cooled to room temperature, EA dispersion, washed with a saturated NaHCO3 solution, saturated brine, MgSO4 dried, rotary evaporated to give a white solid (yield 93.02%, mp: 128-129 ° C, [a] 3C1.9D = -11.7 (199.99 mg / 20ml, MeOH)). IH NMR (600MHz, DMS0_d6) δ ρρm8.05-7.88 (m, 2Η), 7.82-7.78 (m, 1Η), 7.42-7.25 (m, 2Η), ζ, 06-7.00 (m, IH), 4.29- 4.06 (m, 1Η), 4.01-3.72 (m, 2Η), 3.66-3.49 (m, 2Η), 2.10 (s, 3Η), 2.06-2.01 (m, IH), 1.50 (m, 1Η), 1.78- 1.50 (m, 1Η), 1.14-1.13 (d, 3Η); (FIG. 6) MS (ESI) m / z451.20 ([Μ + Η] +).

PATENT

http://www.google.com/patents/WO2013169610A1?cl=en

The compound of the formula I is disclosed as an antagonist of orexin receptors in US Patent 7,951,797, US Patent Application Publication US 2008/0132490, PCT PatentPublication WO 2008/069997, Cox et al, J. Med. Chem. 2010, 53, 5320-5332, Strotman et al, JACS, 2011, 133(21), 8362-8371, and Baxter et al, Org. Process Res. & Dev., 201 1, 15(2) 367- 375.

This compound is disclosed as having activity in antagonizing the human orexin-1 (OX1) receptor with a Ki of 0.55 nM and in antagonizing the human orexin-2 (0X2) receptor with a Ki of 0.35 nM. The processes disclosed in US Patent 7,951,797, US Patent Application Publication US 2008/0132490, PCT Patent Publication WO 2008/069997, Cox et al, J. Med. Chem. 2010, 53, 5320-5332, Strotman et al, JACS, 201 1, 133(21), 8362-8371, and Baxter et al, Org. Process Res. & Dev., 2011, 15(2) 367-375 are lengthy, suffer from low yields, necessitate multiple protecting groups, rely on chiral chromatography to prepare a single isomer and require microwave technology to prepare the acid intermediate. Relative to the processes disclosed in US Patent 7,951,797, US Patent Application Publication US 2008/0132490, PCT Patent Publication WO 2008/069997, Cox et al, J. Med. Chem. 2010, 53, 5320-5332, Strotman et al, JACS, 2011, 133(21), 8362-8371, and Baxter et al, Org. Process Res. & Dev., 201 1, 15(2) 367- 375, the present invention may provide improved processes for the efficient, scalable, chromatography-free and cost-effective preparation of the formula I, to give higher isolated yield of the subject compound.

EXAMPLE 1

2. DMF

5-Chloro-l,3-benzoxazole-2-thiol (9a)

2-Amino-4-chlorophenol (2.50 kg, 17.4 mol) was charged to a vessel and suspended in water (52 L) and methanol (10.4 L). High dilution was required to prevent slow and difficult filtration of the product. The mixture was stirred, cooled to 0 °C, then thiophosgene (2.00 kg, 17.4 mol) was added to the suspension ensuring that the internal temperature remained at 5 °C throughout the addition. Water (8 L) and methanol (2 L) were added to aid stirring and the slurry was warmed to 13 °C for 1 h, followed by aging at 20 °C for a further 1 h. The slurry was then filtered and the solid washed with water (5 L). The batch was repeated and combined to dry in a vacuum oven (T = 40 °C) for 15 h to give 9-a (5.81 kg, 31.3 mol). The data corresponds to the commercially available material. ^XH NMR (400 MHz, d₆-DMSO): δ 7.51 (d, 1 H, J = 9.2 Hz), 7.307.26 (m, 2 H). ¹³C NMR (100.6 MHz, d₆-DMSO): δ 181.2, 147.4, 133.1, 129.7, 123.9, 1 11.6, 110.8. HRMS (ESI): m/z [M⁺ + H] calcd for C₇H₄CINOS: 185.9780; found: 185.9785.

{2-[(5-Chloro-benzooxazol-2-yl)-(3-oxo-butyl)-amino]-ethyl}-carbamic acid tert-butyl ester (10)

Thiol 9a (10.5 kg, 54.6 mol) was added to a vessel and suspended in DCM (141 kg). Oxalyl chloride (10.4 kg, 82.3 mol) was added (slightly endothermic) followed by DMF (40.0 kg, 547 mol) over 1.25 h, such that the batch temperature was≤ 25 °C. The batch was aged at 20 °C for approximately 30 min, HPLC analysis showed reaction to be complete. The batch was cooled to 10 °C then triethylamine (16.64 kg, 164.4 mol) was added via a sub-surface sample line at such a rate as to maintain a batch temperature of≤ 10 °C. A sub-surface addition protocol was required to prevent build up of triethylamine hydrochloride solid on the walls of the vessel. The batch was cooled to 0 °C, then a solution of N-Boc-ethylenediamine (10.5 kg, 61.2 mol) in DCM (10 kg) was added such that the batch temperature was≤ 10 °C. The reaction was warmed to 20 °C and stirred for 2.5 h, HPLC analysis showed the reaction to be complete. Water (63.6 kg) was charged to the batch and the mixture stirred for 5 min. The layers were separated and the aqueous phase re-extracted with DCM (42.2 kg). The organic solutions were then combined and approximately half of the total DCM volume was distilled from the batch under vacuum whilst maintaining a temperature of≤ 40 °C. MeCN (83.3 kg) was then added and the remaining DCM removed by distillation (0.5 mol % DCM left by ^XH NMR wrt MeCN). MVK (4.61 kg, 65.8 mol) was added to the batch followed by DBU (4.17 kg, 27.4 mol) such that the temperature was≤ 20 °C. The batch was aged for 10 h at 20 °C then analyzed by HPLC. The reaction was then diluted with water (42.4 kg) and aged for a further 30 min. The mixture was filtered and the slurry washed with MeCN (33.3 kg). The solid was washed with MeCN (-10 L) then dried in a vacuum oven (T = 60 °C) for 22 h. MVK adduct 10 (15.5 kg) was isolated as an off-white solid, mp 145-148 °C. ¾ NMR (400 MHz, CDC1₃): δ 7.24 (d, 1 H, J = 2.3 Hz), 7.09 (d, 1 H, J = 8.5 Hz), 6.91 (dd, 1 H, J = 8.5, 2.3 Hz), 5.06 (s, 1 H, br), 3.73 (t, 2 H, J = 6.7 Hz), 3.63 (t, 2 H, J = 6.1 Hz), 3.37 (d, 2 H, br), 2.89 (t, 2 H, J = 6.7 Hz), 2.14 (s, 3H), 1.33 (s, 9 H). ¹³C NMR (100.6 MHz, CDC1₃): 8 206.7, 163.0, 156.0, 147.4, 144.6, 129.2, 120.3, 116.6, 109.2, 79.4, 49.3, 44.3, 41.9, 39.1, 30.2, 28.3. HRMS (ESI): m/z [M⁺ + H] calcd for

382.1534; found: 382.1544.

EXAMPLE 2

□ HMDS, THF/hexane (3.6:1.0), -25 to -15 °C; NBS

5-Chlorobenzoxazole (3-2)

To a 250 mL 3-neck round bottom flask equipped with a distillation head, glass stopper, septum, thermocouple and magnetic stir bar was charged 2-amino-4-chlorophenol (20.00 g, 0.139 mol). The solid was dissolved in THF (60 mL) and p-TsOH (0.265 g, 1.39 mmol) was added. The brown solution was warmed to 60 °C over 10 min and aged for 90 min. HPLC assay of the reaction mixture showed 1 LCAP unreacted starting material. The temperature was increased from 60 °C to 74 °C, and at 63 °C solvent distillation began. A total of 58 mL was collected during the first distillation. The mixture was diluted with THF (60 mL) and a total of 67 mL of solvent was removed between 71 and 84 °C. The mixture was again diluted with THF (60 mL) and 61 mL of solvent was removed between 74 and 1 14 °C. The dark brown solution was cooled to room temperature. The final mass of the solution was 27.96 g. Analysis of the crude stream by ^XH NMR showed 0.1 wt% MeOH present in the sample. ^XH NMR (500 MHz, CDC1₃): δ = 8.10 (s, 1H), 7.76 (d, J= 1.5 Hz, 1H), 7.50 (d, J= 8.7 Hz, 1H), 7.36 ppm (dd, J= 8.7, 1.7 Hz, 1H).

2-[(5-Chloro-l,3-benzoxazol-2-yl)amino]ethanol (3-3)

A 500 mL 3-neck round bottom flask equipped with a septum, thermocouple, 125 mL addition funnel, inert gas inlet and magnetic stir bar was purged with nitrogen for 10 min. Hexamethyldisilazane (42 mL, 0.20 mol) and THF (78 mL) were charged against positive nitrogen pressure. The addition funnel was charged with a hexane solution of n-butyllithium (78.0 mL, 195 mmol). The amine solution was cooled to -52 °C and n-butyllithium was added over 84 min, resulting in a temperature increase to 12.5 °C over the course of the addition. The resulting lithium hexamethyldisilazide solution was removed from the cooling bath and aged for 30 minutes. To a 500 mL 3 -neck round bottom flask equipped with a septum, thermocouple, inert gas inlet and magnetic stir bar was charged 5-chlorobenzoxazole (20.00 g, 130 mmol). The gray solid was dissolved in THF (100 mL) and the resulting colorless solution was cooled to -25 °C. The freshly prepared lithium hexamethyldisilazide solution was added via cannula over 80 minutes. The temperature of the anion solution was maintained between -25 and -15 °C during the addition. The resulting dark brown solution was aged for 90 minutes between -25 and -15 °C. To a 1000 mL 3-neck round bottom flask equipped with a Claisen adapter, septum,

thermocouple, inert gas inlet, stir rod bearing, and blade was charged THF (100 mL) and N- bromosuccinimide (34.8 g, 195 mmol). The resulting slurry was cooled to -20 °C and the anion solution was added via cannula over 150 minutes. During the addition the anion solution and reaction mixture were maintained between -25 and -15 °C. The resulting brown slurry was removed from the cooling bath and aged for 50 minutes while warming to room temperature. To the resulting bromide slurry was added a solution of ethanolamine (12.6 mL, 208 mmol) in MeCN (38 mL) via syringe pump over 5 hours. During the addition the reaction temperature was maintained between 20 and 27 °C. The resulting brown slurry was aged at room temperature overnight. The reaction mixture was cooled in an ice water bath and the septum replaced with a 50 mL addition funnel charged with concentrated HC1 (32 mL, 390 mmol). The acid solution was added over 10 min, during which time the addition the temperature increased from 10 to 20 °C. The reaction mixture was removed from the ice water bath and aged for 5 min. A 20% (w/w) solution of K2HPO4 in water (170 mL) was added and the resulting biphasic mixture was transferred to a seperatory funnel. The flask was washed with THF (3x, 10 mL) and the washings were added. The aqueous phase was cut; the organic phase was washed with 20% (w/w) K2HPO4 in water (200 mL), separated and analyzed. The crude reaction stream had a total mass of 396.47 g. By quantitative HPLC assayed 25.81 g of 3-3 in the organic phase. ^XH NMR (500 MHz, DMSO-i¾): δ = 8.17 (t, J= 5.6 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.25 (d, J= 1.8 Hz, 1H), 6.97 (dd, J= 8.4, 1.8 Hz, 1H), 4.81 (t, J= 5.4 Hz, 1H), 3.56 (q, J= 5.7 Hz, 2H), 3.35 pm (q, J= 5.8 Hz, 2H).

Methanesulfonic acid 2-[(5-chloro-benzooxazol-2-yl)-(3-oxo-butyl)-amino]-ethyl ester (3-4)

To a 1000 mL 3-neck round bottom flask equipped with a septum, thermocouple, inert gas inlet and magnetic stir bar was charged 3-3 (25.2 g, 119 mmol). To this flask was added 126 mL DMF, 12.2 mL methyl vinyl ketone (148 mmol) and 0.119 mL 10M NaOH (1.19 mmol). The reaction was then aged for 6 hours, at which time conversion was judged to be complete by HPLC. The solution was diluted with 252 mL iPAc and cooled to 0 °C, then 23.1 mL Et₃ (166 mmol) followed by dropwise addition of 12.0 mL methanesulfonyl chloride (154 mmol) over 45 minutes, maintaining internal temperature less than 10 °C. After a further 30 minutes, conversion was judged to be complete by HPLC. The solution was washed with 3x 63 mL 5 w/w% aqueous aHC0₃ solution, then 66 mL water. After cutting the aqueous layer, the organics were reduced to approximately two volumes or 50 mL iPAc. The organics were then agitated by an overhead stirrer during slow addition of 151 mL n-Heptane over 4 hours. Over this time a crystalline white precipitate developed, and was allowed to stir overnight. At this time there was a thick slurry, which was filtered and washed with 2x 50 mL 90: 10 n- HeptaneTPAc, and after drying with a nitrogen stream over the filter pad, 3-4 was obtained as a white crystalline solid (34.6 g., 96 mmol). ‘H NMR (500 MHz, CDC1₃): δ = 7.29 (s, 1H), 7.16 (d, J= 8.2 Hz, 1H), 6.97 (d, J= 7.8 Hz, 1H), 4.46 (s, 2H), 3.92 (s, 2H), 3.81 (t, J= 5.9 Hz, 2H), 2.98-2.92 (m, 5H), 2.16 (s, 3H).

EXAMPLE 3

5-Chloro-2-((R)-5-methyl-[l,4]diazepan-l-yl)-benzooxazole hydrochloride (R-11) To a 1000 mL 3 -necked flask was charged isopropylamine hydrochloride (25.8 g., 270 mmol) and 525 mL 0.1 M aqueous triethanolamine solution. To this was added 750 mg pyridoxal 5′-phosphate hydrate (PLP) and 3.0 g of the transaminase polypeptide having the amino acid sequence SEQ ID NO: l and the suspension was stirred until all components dissolved. The transaminase polypeptide having the amino acid sequence SEQ ID NO: 1 was obtained as disclosed in US Patent Publication US 2010/0285541 for the identical sequence “SEQ ID NO: 1 10” therein. The solution was heated to 40 °C and the pH of the solution was adjusted to pH 8.5 with an aqueous 4M solution of isopropylamine. Mesylate 3-4 was added as a 225 mL DMSO solution via syringe over 6 hours, and the resulting mixture stirred for a further 5 hours. At this time, the solution was poured into a 3L separatory funnel and extracted with 1.5 L of 1 : 1 iPAc:IPA. The aqueous layer was cut then extracted again with 750 mL 4: 1 iPAc:IPA. The organics were combined, then washed with 750 mL brine. Then the organics were concentrated with IPA flushing to establish a 45 mL solution in IPA which was then treated with 4.6M HC1 in IPA (9.94 mL, 45.7 mmol) via dropwise addition. The resulting solution was stirred vigorously while 52 mL IP Ac was added slowly over 5 hours, creating a slurry of HQ salt 6. The slurry was then slowly cooled to 0 °C and allowed to stir overnight. At this time the slurry was filtered and dried with a nitrogen stream over the filter pad, providing R-11 as a white crystalline solid (7.80 g., 25.8 mmol). ¾ NMR (500 MHz, CD₃OD): δ = 7.13-7.10 (m, 2H), 6.97 (dd, J= 8.2, 1.8 Hz, 1H), 3.99-3.79 (m, 3H), 3.67-3.57 (m, 3H), 3.39-3.33 (m, 1H), 2.24 (s,

1H), 2.12-2.07 (m, 1H), 1.42 (d, J= 6.7 Hz, 3H).

EXAMPLE 4

19 5

5-Methyl-2-[l,2,3]triazol-2-yl-benzoic acid (5) The iodide 19 (6.04 kg, 23.0 mol), THF (45 L) and DMF (9.0 L) were charged to a vessel. Copper iodide (218 g, 1.15 mol) and potassium carbonate (7.94 kg, 57.4 mol) were added and the mixture heated to an internal temperature of 40 °C. 1,2,3-Triazole (3.16 kg, 46.0 mol) was added as a solution in THF (6.0 L) over half an hour (no exotherm) and heating continued to 65 °C (again no exotherm observed) and the reaction monitored by HPLC. Once complete N,N-dimethylethylenediamine (244 mL, 2.30 mol) was added and mixture cooled to RT. Aqueous 3.6 M HC1 (36 L) was added (exotherm) and the mixture extracted twice with ethyl acetate (2 x 30 L). The combined organics were washed with LiCl solution (2 x 20 L). The acid solution assayed for 3.79 kg of 5 (81%) and 4.64 kg of 5 and 20 combined (99%). A solution of acids 5 and 20 (approx. 4.64 kg, 22.9 mol) in THF and EtOAc (approx. 1 10 L) was concentrated to low volume. THF (90 L) was added and the solvent composition checked by ^XH NMR to ensure most ethyl acetate had been removed. Sodium tert-butoxide (2.42 kg, 25.2 mol) was added slowly as a solid over 1-2 h (slight exotherm), allowing the sodium salt to form and stirred overnight at RT. The liquors showed a 45:55 ratio of product: starting material and the solid was collected by filtration, washed with THF (2 x 20 L) and dried in a vacuum oven (T = 40 °C) for 15 h to afford 4.22 kg of crude sodium salt. The crude sodium salt (4.22 kg, 14.9 mol) was charged to a 50 L vessel and 3.6 M HC1 (21.2 L) was added with cooling. The slurry was then stirred at room temperature for 16 h and the off-white solid isolated by filtration. The cake was washed with water (11 L) and iP Ac/Heptane (2 x 5L), then dried in a vacuum oven (T = 35 °C) for 15 h to give 3.10 kg of crude acid 5 (97.9 LCAP, 92 wt%, corrected weight 2.85 kg, 61% yield from 19). The acid 5 (2.85 kg corrected, 14.0 mol) was charged to a 50 L vessel and EtOAc (28 L) and dilute 0.22 M HC1 (14 L) were added and the mixture stirred until two clear phases resulted. The aqueous layer was removed and the organic layer filtered to remove any particulate matter. The ethyl acetate was reduced to about 8 L and then heptane (15.6 L) was added over 1 h and the liquors sampled to check for appropriate losses. The solid was isolated by filtration, washed with heptane:ethyl acetate (3 : 1 , 4 L) and dried on the filter under nitrogen to give 2.81 kg of acid 5. m.p. 167.5 °C. ^XH NMR (400 MHz, d₆-DMSO): δ 12.09 (br s, 1H), 8.04 (s, 1H), 7.62 (d, 1H, J = 8.4 Hz), 7.58 (d, 1H, J = 1.2 Hz), 7.49 (dd, 1H, J = 8.4, 1.2 Hz), 2.41 (s, 3H). ¹³C NMR (100.6 MHz, d₆-DMSO): δ 168.0, 139.2, 136.4, 135.8, 132.5, 130.3, 128.7, 124.8, 20.9. HRMS (ESI): m/z [M⁺ + H] calcd for C1₀H₉N₃O2: 204.0773; found: 204.0781. EXAMPLE 5

[(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 (1)

A round bottom flask was charged 6.86 g of 5-methyl-2-[l,2,3]triazol-2-yl- benzoic acid (5) along with 7.0 vol or 70 mis of dry iPAc (KF < 200 ppm) forming a slurry. To this was charged 0.73 g of DMF then the system was purged thoroughly with nitrogen and temperature was set at 20°C-25°C. 5.04 g of oxalyl chloride was added while maintaining 20°C- 25°C and controlling off-gassing since it is extremely vigorous. With the feed of oxalyl chloride the previous slurry dissolved. The batch was aged for 1 hr, sampled for acid chloride formation (< 1 LCAP) and allowed to proceed to amidation. In a separate vessel a solution of potassium carbonate was prepared in 5.0 vol or 50 mL water (note: exotherm). The solution was cooled to 0 °C. When acid chloride (above) was prepared, added 2.5 vol or 25 mL iPAc to the aqueous solution with overhead stirring, then added 10.0 g. amine hydrochloride salt (R-ll) to solution, and stirred for 15 minutes. Then using a cannula, the acid chloride solution was transferred over from separate vessel over the course of 1 hour, maintaining less than 5°C internal temperature. The vessel was flushed with 2.5 vol or 25 mL iPAc and sampled to determine completion. The slurry was heated to 40 °C. Upon reaching 40 °C, 1.5 vol or 15 mL Acetonitrile was and agitated for 5 minutes, and all material went into solution (98% AY observed). Agitation was stopped. After phase separation, the aqueous layer was cut, the organics were stirred with DARCO (10 wt% 6 basis) at 40°C for 3 hours, then filtered hot and taken through to

crystallization. Additional product was recovered from the carbon with an iPAc flush.

The batch was concentrated in iPAc and flushed to 7.5 vol (L/Kg of 1) and heated to 80-85C until complete dissolution. The solution was cooled to 65 °C linearly over 2 hrs, and the agitation speed was adjusted to high. At 65 °C, the solution was charged with 0.3 wt% seed in n-Heptane and aged for 1 hour. After the age and confirmation of the seed bed, the batch was cooled to 45 °C over 2.5 hrs. At this time a solvent switch was conducted at constant volume to a ratio of 90: 10 n-Heptane: iP Ac. The material was filtered hot at 45 °C, the cake was washed with 3 vol (L/Kg of 1) of 90: 10 n-Heptane :iP Ac twice, followed by 3 vol (L/Kg of 1) of n- Heptane twice. The cake was dried at 70 °C under vacuum to give 14.4 g. 1 (31.8 mmol,) as a crystalline white powder.

EXAMPLE 6

5. Carbon Treatment

6. Seed

7. Solvent switch to IPAcn-Hepatne

8. IKA Milling

[(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 (1)

A reaction vessel was charged with 213.4 g of triazole acid (5) along with 7.4 vol or 2236 mis of dry iPAc (KF < 200 ppm) forming a slurry. To this charge was added 21.93 g of DMF then the system was purged thoroughly with nitrogen and temperature was maintained at 20- 25C. Charged 152.3 g of oxalyl chloride while maintaining 20-25C and control of off-gassing since it is extremely vigorous. With the feed of oxalyl chloride the previous slurry all dissolved. The batch was aged for 1 hr. The reaction was sampled for Acid Chloride formation (< 1 LCAP) and proceeded to distillation. Distillation was conducted down to 11 18 ml or constant volume distillation using 7.4 vol of fresh iPAc under vacuum maintaining less than 30°C.

In a separate vessel prepared a solution of 302.2 g of amine hydrochloride salt (R-ll) in 15.3 vol or 4624 mis of dry iPAc (KF < 200 ppm) to form a slurry. Then transferred the acid chloride solution using a cannula over from a separate vessel followed by flushing the vessel with 6.9 vol or 2085 mis of iPAc. With the amine and acid chloride in the same vessel began addition of 404.8 g of triethylamine. This charge was made over 1 to 4 hrs at a temperature between 20-40C with a desired control of the temperature between 20-30C. Once feed of the TEA was complete, the batch was aged for lhr and then sampled to determine completion.

Once the batch was complete, charged 7.4 vol of water or 2236 mis and then heated the solution to 40C. Once at 40C, the mixture was aged 5 minutes then agitation was stopped. The phases separated but there was an appreciable rag layer so it was allowed to settle and the rag was cut along with the aqueous layer. The aqueous rag was filtered then the aqueous layer was back extracted with 3.5 vol or 1058 ml of iPAc and all iPAc layers were combined.

The batch was recycled in iPAc (~60 g per kg of iPAc) via a Cuno filter (1 bundle per 39 Kg Amine HC1 Salt) for several hours at 40°C. The batch was drummed off through a sparkler filter and additional material was recovered from the carbon with an iPAc flush.

The batch was concentrated in iPAc and flushed to 7.5 vol (L/Kg of product) and heated to 80-85°C until complete dissolution. The mixture was cooled to 65°C linearly over 2 hrs, and agitation speed was adjusted to high from this point forward. At 65°C, the mixture was charged with 0.3 wt% of [(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 seed in n-Heptane and aged for 1-3 hour. After the age and confirmation of the seed bed, the batch was cooled to 45°C over 2.5 hrs. A solvent switch was conducted at constant volume to a ratio of 90: 10 n-Heptane :iP Ac.

The batch was wet milled to a uniform particle size and filter hot at 45C. The cake was washed with 3 vol (L/Kg of product) of 90: 10 n-Heptane :iP Ac twice, followed by 3 vol (L/Kg of product) of n-heptane twice. The cake was dried at 70°C under vacuum.

PAPER

Neil A. Strotman*, Carl A. Baxter, Karel M. J. Brands, Ed Cleator, Shane W. Krska, Robert A. Reamer, Debra J. Wallace, and Timothy J. Wright   

J. Am. Chem. Soc. 2011, 133, 8362–8371

DOI: 10.1021/ja202358f

Suvorexant (MK-4305) is a potent dual Orexin antagonist under development for the treatment of sleep disorders at Merck. The key transformation is an asymmetric Ru-catalyzed transfer hydrogenation (using a modified Noyori RuCl(p-cymene)(DPEN) complex) of an in-situ generated cyclic imine resulting in the formation of the desired chiral diazepane in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO2 (derived from the formic acid) has pronounced effect on reaction outcome.  Studies have determined that the efficiency of the Ru-catalyst, the composition of the resulting amine (via carbamate formation), and the reaction kinetics are mediated by the amount of CO2 generated during the reaction. The efficiency of the reductive-amination can be enhanced by either purging the CO2 or by trapping the newly formed nucleophilic secondary amine.

DOI: 10.1021ja202358f

References:

1) Org. Process Res. Dev., 2011, 15, 367–375  (DOI: 10.1021/op1002853)

2) http://www.kanto.co.jp/english/siyaku/pdf/fuseishokubai_02.pdf

PAPER

Org. Process Res. Dev., 2011, 15 (2), pp 367–375

DOI: 10.1021/op1002853

A new synthetic route to drug candidate 1, a potent and selective dual orexin antagonist for the treatment of sleep disorders, has been developed. The key acyclic precursor 10 was prepared in a one-step process in 75% isolated yield from commercially available starting materials using novel chemistry to synthesize 2-substituted benzoxazoles. A reductive amination was followed by a classical resolution to afford chiral diazepane (R)-11. Finally, coupling of (R)-11 with acid 5 furnished the desired drug candidate 1.

[(R)-4-(5-Chlorobenzoxazol-2-yl)-7-methyl-[1,4]diazepan-1-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)methanone (1)

The amine DBT salt 16 (5.67 kg, 9.09 mol) was charged to a vessel and inerted. DCM (28 L) was added, followed by 4 N sodium hydroxide solution (prepared from 10 N NaOH [22.4 L] and water [36 L]). The slurry was then stirred at ambient temperature for 1 h until a solution was obtained. The layers were separated, and the aqueous phase was treated with sodium chloride solution (10.1 kg in 20 L water). DCM (5 L) was then added and the biphasic mixture stirred for 10 min before separating the layers. The combined organic layers were then concentrated under reduced pressure to a 10 L volume. The solution of the free amine was used directly in the next reaction

The triazole acid 5 (13.25 kg, 65.2 mol), DCM (88 L), and DMF (1.35 L, 17.4 mol) were charged to a vessel, and the resulting suspension was cooled to 0 °C. Oxalyl chloride (8.28 kg, 65.2 mol) was added portionwise, keeping the internal temperature between 5 and 10 °C (the anhydride formed above 10 °C), and then the reaction was aged for 30 min at this temperature. HPLC analysis showed acid 5 remained; an additional charge of oxalyl chloride (160 g, 1.26 mol) was made, and the solution stirred at 5 °C for 30 min. A solution of the amine (R)-11 (16.5 kg, 62.1 mol) and triethylamine (13.19 kg, 130.0 mol) in DCM (∼8 L) was added to the acid chloride over 30 min, keeping the internal temperature less than 15 °C. The resulting slurry was aged for 30 min and then quenched by the addition of water (167 L) over 10 min, keeping the internal temperature <15 °C. The lower organic layer was removed and then concentrated under atmospheric pressure to a volume of 100 L. Assay at this stage showed 27.3 kg 1, 98%. The solution was solvent switched to MeCN (∼560 L, 20 mL/g) by distillation under reduced pressure at <50 °C. The MeCN solution was treated with Ecosorb C-941 (2.8 kg) slurried in MeCN (10 L). The resulting slurry was aged for 30 min and then filtered through a Solka Flok pad and a 0.1 um cartridge filter, washing with MeCN (2 × 30 L). The MeCN filtrate was concentrated under reduced pressure at <50 °C to a final volume of ∼112 L. The slurry was cooled to 25 °C and water (280 L) added over 40 min. The resulting slurry was aged at 20 °C for 1 h and then filtered, washing the cake with 5:1 water/MeCN (60 L) followed by water (40 L). The solid was dried in the vacuum oven with nitrogen purge overnight at 50 °C. The final target 1 was isolated as a white solid, 26.72 kg, 95%, 98.5% ee, 99.6 LCAP, mp 153.1 °C.

The ¹H NMR data for this compound was extremely complicated due to its existence as four rotamers. These rotamers did not coalesce during high-temperature experiments.(4)

[α]²⁵_D −11.8 (c 1.0, MeOH) for a sample of 97.8% ee. HRMS (ESI): m/z [M⁺ + H] calcd for C₂₃H₂₃ClN₆O₂: 451.1649; found: 451.1640.

PAPER

Org. Biomol. Chem., 2013,11, 7830-7833

DOI: 10.1039/C3OB41558A

http://pubs.rsc.org/en/content/articlelanding/2013/ob/c3ob41558a#!divAbstract

A highly regioselective halogenation of 2-substituted-1,2,3-triazoles was developed via sp² C–H activation. This method is compatible with halogen atoms, as well as electron-donating and electron-withdrawing groups. Meanwhile, the strategy is also efficient for the synthesis of a key intermediate of Suvorexant.

PAPER

2.1. Synthesis of (R)-methyl 2-(N-benzyl-3-((tert-butoxycarbonyl)amino)butanamido)acetate (3)

To a solution of methyl 2-(benzylamino)acetate (compound 10, 50.14 g,0.28 mol),(R)-3-((tert-butoxycarbonyl)amino)butanoic acid (50.75 g,0.25 mol),1-hydroxy-1H-benzotriazole (41.88 g, 0.31 mol),and dry triethylamine (37.95 g,0.38 mol) in 320 mL of DMF was added EDC hydrochloride (57.51 g,0.30 mol),and the reaction was stirred for 5 h at room temperature. The reaction was partitioned between EtOAc and 10% aqueous citric acid,the layers were separated and the organic was washed with 5% aqueous Na₂CO₃,then with brine,dried over MgSO₄ and concentrated by rotary evaporation. The residue was recrystallized from a mixture solvent (PE:EtOAc = 2:1) to provide compound 3 as a white solid, 83.01 g in 91% yield. Mp: 107 ℃,[α]D 25 22.0 (c0.52,MeOH). 1H NMR (600 MHz,DMSO-d₆): δ 7.38-7.23 (m,5H),6.73-6.72 (d,1H, J = 6 Hz),4.75-4.43 (m,2H),4.31-3.95 (m,2H),3.89-3.87 (t,1H, J = 12 Hz),3.64-3.62 (d,3H,J = 12 Hz),2.64-2.50 (m,1H),2.37- 2.23 (m,1H),1.38-1.37 (d,9H,J = 6 Hz),1.08-1.06 (m,3H); MS (ESI) m/z: 365.20 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₁₉H₂₈N₂O₅: 365.2071; found: 365.2066.

2.2. Synthesis of (R)-4-benzyl-7-methyl-1,4-diazepane-2,5-dione (4)

A solution of compound 3 (15.93 g,43.74 mmol) in 10 mL EtOAc was added 150 mL 45% HCl/EtOAc and the reaction was stirred for 4 h. The solvents were removed by rotary evaporation,and the residue was basified with saturated aqueous NaHCO₃,and extracted with CH₂Cl₂. The organic extracts were concentrated. The residue was dissolved in 150 mL of dehydrated MeOH, treated with CH₃ONa (2.84 g,52.49 mmol),and stirred at room temperature overnight (N2 protected,slightly exothermic). The reaction was cooled to room temperature and quenched with aqueous NH₄Cl. Most of the solvent was removed and the reaction was then dumped into a separatory funnel containing 5% aqueous Na₂CO₃ and extracted with CH₂Cl₂ three times. The organic layers were combined,dried over MgSO₄,and concentrated to provide compound 4 as a white solid 9.50 g in 94% yield. Analytical HPLC analysis carried out on Chiralpak AD column (4.6 mm × 250 mm) with 60% EtOH in hexanes (containing 0.1% diethylamine as a modifier),flow rate of 1 mL/min,indicated that intermediate (R)-4 was of >99% ee. Mp: 122-123 ℃. [α]D²⁵33.5 (c 0.56,MeOH). ¹H NMR (600 MHz,DMSO-d₆): δ 7.77-7.76 (bd,1H,J = 6 Hz),7.33-7.25 (m,5H),4.59-4.53 (m,2H),4.10- 4.02 (m,2H),3.65-3.62 (m,1H),2.93-2.90 (m,1H),2.76-2.72 (m,1H), 1.14-1.13 (d,3H,J = 6 Hz); ¹³C NMR (150 MHz,DMSO-d₆): δ 171.1, 168.4,138.1,128.9,128.0,127.7,53.1,50.6,46.5,40.5,23.3. MS (ESI) m/z: 233.10 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₁₃H₁₆N₂O₂: 233.1285; found: 233.1289.

2.3. Synthesis of (R)-1-benzyl-5-methyl-1,4-diazepane (6)

A solution of compound 4 (1.40 g,6.0 mmol) in 60 mL THF at 0 ℃ was treated with LiAlH₄ (1.36 g,36.0 mmol) in batches. The reaction was slowly warmed to room temperature and stirred for another 4 h. The reaction was then cooled to -10 ℃ and was carefully quenched with 1.5 mL water,then NaOH (1.5 mL,15%) followed by an additional 4.5 mL of water. A portion of MgSO₄was added and the mixture was stirred for 1 h before filtered. The filtrate was concentrated to provide light yellow oil 1.10 g in 88% yield. [α]D²⁵ -5.9 (c 1.00,CHCl3),ee >99%,Analytical analysis was performed on Chrom Tech chiral-AGP column (150 mm × 4 mm) with 99% 1 mol/L ammonium dihydrogen phosphate and 1% acetonitrile,at flow rate of 0.5 mL/min with column temperature of 40 ℃. ¹H NMR (600 MHz,DMSO-d₆): δ 7.32-7.20 (m,5H),3.57 (s, 2H),3.48 (bs,1H),2.99-2.95 (m,1H),2.86-2.82 (m,1H),2.72-2.68 (m,1H),2.65-2.61 (m,1H),2.58-2.49 (m,3H),1.75-1.70 (m,1H), 1.46-1.41 (m,1H),1.01-1.00 (d,3H,J = 6 Hz); ¹³C NMR (150 MHz, DMSO-d₆): δ 140.1,128.9,128.5,127.1,62.5,58.8,52.7,52.6,47.0, 37.5,23.9. MS (ESI) m/z: 205.10 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₁₃H₂0N₂: 205.1699; found: 205.1692.

2.4. Synthesis of (R)-(4-benzyl-7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (7)

To a solution of compound 6 (2.40 g,11.76 mmol),compound 5 (2.86 g,14.11 mmol),1-hydroxy-1H-benzotriazole (1.90 g, 14.11 mmol),and dry triethylamine (3.56 g,35.28 mmol) in 18 mL of dry DMF was added EDC hydrochloride (2.70 g, 14.11 mmol),and the reaction was stirred 2 h at room temperature. The reaction was partitioned between EtOAc and saturated aqueous NaHCO₃,the layers were separated and the organic was added to aqueous citric acid stirring for 1 h. Water was added and the mixture was partitioned. Combined the water layers and added saturated aqueous Na₂CO₃ to regulate pH > 9,then extracted with three portions of EtOAc. The organic layers were combined,dried over MgSO₄ and concentrated by rotary evaporation to provide compound 7 as a white power 4.30 g in 93% yield. Mp: 108-109 ℃, [α]D²⁵-58.4 (c 1.01,MeOH). 1HNMR(600 MHz,DMSO-d₆): δ 8.00- 7.76 (m,3H),7.37-7.17 (m,7H),4.40-4.09 (m,1H),3.63-3.48 (m, 2H),3.44-3.02 (m,3H),2.82-2.75 (m,1H),2.63-2.47 (m,1H), 2.63-2.14 (m,5H),2.02- 1.63 (m,2H),1.17-0.99 (m,3H); MS (ESI) m/z: 390.30 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₂₃H₂₇N₅O: 390.2288; found: 390.2281.

2.5. Synthesis of (R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (9)

Compound 7 (5.86 g,15.05 mmol) was dissolved in 58 mL MeOH. After a portion of 10% Pd/C was added,the reaction was stirred for 4 h under H2 atmosphere at room temperature. The reaction was filtered through a pad of celite and the filtrate was concentrated to provide compound 9 as a white solid 4.01 g in 89% yield. Mp: 119-121 ℃,^[a]D 26 -14.4 (c 1.00,MeOH)). ¹H NMR (600 MHz,DMSO-d₆): δ 8.24-8.02 (m,2H),7.88-7.29 (m,3H), 4.42-2.50 (m,7H),2.41 (s,3H),2.24-1.98 (m,2H),1.17-0.99 (m, 3H); ¹³C NMR (150 MHz,DMSO-d₆): δ 168.6,138.3,136.9,134.1, 131.1,129.2,128.3,122.5,52.6,49.1,44.4,43.1,37.8,20.8,20.6. MS (ESI)m/z: 300.20 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₁₆H₂₁N₅O: 300.1819; found: 300.1812.

2.6. Synthesis of suvorexant

To compound 8 (0.56 g,3 mmol) in 10 mL dry DMF was added TEA (0.91 g,9 mmol) and compound 9 (0.89 g,3 mmol),the mixture was stirred at 75 ℃ for 2 h. After cooling to room temperature,the reaction was diluted with EtOAc,washed with saturated aqueous NaHCO₃,water,brine and dried over MgSO₄. The residue was recrystallized from i-PrOH/EtOAc to provide a white solid 1.20 g in 90% yield. Mp: 149-150 ℃,[α]D²⁵ -11.6 (c 1.00,MeOH). Analytical HPLC analysis carried out on a Chiralpak AD column (4.6 mm × 250 mm) with 60% EtOH in hexanes (containing 0.1% diethylamine as a modifier) at a flow rate of 1 mL/min,indicated that intermediate (R)-4 was of >99% ee. Mp: 153 ℃,[α]D²⁵ -11.7 (c 1.00,MeOH) ^{[    OPRD REF ]},

¹H NMR (600 MHz, DMSO-d₆): δ 8.05-7.88 (m,2H),7.82-7.78 (m,1H),7.42-7.25 (m, 2H),7.06-7.00 (m,1H),4.29-4.06 (m,1H),4.01-3.72 (m,2H), 3.66-3.49 (m,2H),2.10 (s,3H),2.06-2.01 (m,1H),1.50 (m,1H), 1.78-1.50 (m,1H),1.14-1.13 (d,3H,J = 6 Hz);

¹³C NMR (150 MHz, DMSO-d₆): δ 168.5,163.4,147.8,145.2,138.4,136.6,136.5,134.1, 130.8,129.8,128.6,122.8,120.1,115.6,110.2,52.3,48.3,45.1,43.7, 35.6,20.9,17.2. MS (ESI) m/z: 451.20 [M+H]⁺. HR-MS(ESI): m/z [M+H] calcd. for C₂₃H₂₃C_lN₆O₂: 451.1644; found: 451.1639.

References

Suvorexant

Systematic (IUPAC) name
[(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
Clinical data
Trade names	Belsomra
AHFS/Drugs.com	entry
MedlinePlus	a614046
Pregnancy category	US:C (Risk not ruled out)
Legal status	US:Schedule IV
Routes of administration	By mouth
Pharmacokinetic data
Bioavailability	82% (at 10 mg)
Protein binding	>99%
Metabolism	hepatic, CYP3A,CYP2C19
Biological half-life	~12 hours
Excretion	Feces (66%), urine (23%)
Identifiers
CAS Registry Number	1030377-33-3
ATC code	None
PubChem	CID: 24965990
IUPHAR/BPS	2890
ChemSpider	4589156
UNII	081L192FO9
ChEMBL	CHEMBL1083659
Synonyms	MK-4305
Chemical data
Formula	C23H23ClN6O2
Molecular mass	450.92 g/mol