ChemicalBook CAS DataBase List Suvorexant

Suvorexant synthesis

10synthesis methods

Product Name:Suvorexant
CAS Number:1030377-33-3
Molecular formula:C23H23ClN6O2
Molecular Weight:450.92

Commercially available acid 240 was first subjected to a copper-assisted substitution reaction involving 1,2,3-triazole in DMF at elevated temperatures. Although these conditions resulted in an excellent yield of a triazole-substituted product, an approximate 4:1 ratio of the desired 2-arylated triazole 241 and the undesired 1-arylated triazole byproduct were recovered from the reaction. The mixture was then treated with N,Ndimethylethylenediamine in acid to sequester copper. Next, the mixture of arylated triazoles was carefully subjected to sodium tbutoxide in DMF and ethyl acetate to form the corresponding sodium salts, and interestingly it was found that the desired sodium salt of 241 could be isolated based on its solubility profile under these conditions. Acidification of the desired carboxylate salt using dilute HCl gave rise to acid 241 in 60% yield across the fourstep sequence. Next, subjection of this acid to oxalyl chloride in chilled DMF generated the acid chloride 242 in excellent yield. This crude acid chloride was used immediately in the next step of the synthetic sequence.

For the preparation of the diazepine-containing portion of suvorexant, the synthesis commenced with the condensation of commercial 2-amino-4-chlorophenol (243) with thiophosgene (244) to furnish benzoxazole 245. Next, thiol 245 was converted to the corresponding chloride prior to exposure to Boc-protected ethylenediamine 246 under basic conditions. This was followed by a Michael addition of the resulting aminobenzoxazole and methyl vinyl ketone (MVK). The result of this sequence of reactions delivered aminobenzoxazole ketone 247 in 75% yield over the three steps. Next, subjection of the carbamate to methanesulfonic acid removed the Boc functionality and this was followed by an intramolecular reductive amination sequence to construct the diazaepine ring. Acid–base workup ultimately provided the racemic diazepine 248 in 92% yield from 247. Next, salt formation with a benzoyl tartaric acid and subsequent recrystallization upgrade using isopropyl acetate and methanol at ambient temperature was used to resolve racemic 248 into the tartrate salt 249 in 27% yield and excellent enantiomeric excess. Finally, salt 249 was freebased using sodium hydroxide prior to exposure to the crude acid chloride 242 under basic conditions to ultimately deliver suvorexant (XXX) in 95% yield and 99% ee across the twostep sequence.

956317-36-5 Synthesis

5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

956317-36-5
224 suppliers
$7.00/250mg

1266975-27-2 Synthesis

(R)-5-chloro-2-(5-Methyl-1,4-diazepan-1-yl)benzo[d]oxazole

1266975-27-2
71 suppliers
$374.00/250mg

1030377-33-3
219 suppliers
$39.00/1mg

Yield:1030377-33-3 97%

Reaction Conditions:

with benzotriazol-1-ol;1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;triethylamine in N,N-dimethyl-formamide at 0 - 20;Reagent/catalyst;Solvent;Temperature;

Steps:

1 Example 1:

Diazepane intermediate I (75 mmol) was dissolved in N, N-dimethylformamide (75 ml) followed by reducing body Department of temperature to 0 ~ 5 , was added triazole intermediates II (79mmol),Hydroxybenzotriazole (82.8 mmol), EDCI (82.8 mmol) and triethylamine (188 mmol) were added and the mixture was warmed naturally and stirred at room temperature overnight. Adding 10% citric acid solution, extracting with ethyl acetate, washing the organic layer with 5% sodium carbonate solution, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering and concentrating to obtain 32.8g of suvresol, yield 97%, Purity: 98.1%; the resulting product was further treated with isopropyl acetate and n-propyl acetate Recrystallization from heptane gave 31.8 g of a white solid in 94% yield

References:

CN106916149,2017,A Location in patent:Paragraph 0018; 0019; 0020; 0021; 0022; 0023; 0024-0045

3621-81-6 Synthesis