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Chiral resolution of an intermediate of suvorexant and cocrystals thereof

A technology for producing formulas and derivatives, which can be used in the separation of optically active compounds, organic racemization, nervous system diseases, etc., and can solve problems such as low yield, large amounts of waste, and low enantiomeric excess

Inactive Publication Date: 2019-01-11
ENANTIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, chiral resolution of enantiomers of 1,4-diazepane derivatives ((rac)-(VIIIa)) by chiral HPLC is not suitable for industrial processes and has several disadvantages: moderate Yields, large amounts of solvent, high costs and large amounts of waste
As the enantiomeric excess of these examples remains low, one or more additional recrystallizations should be performed to achieve 98-99% ee, even further reducing the low yield of this resolution

Method used

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  • Chiral resolution of an intermediate of suvorexant and cocrystals thereof
  • Chiral resolution of an intermediate of suvorexant and cocrystals thereof
  • Chiral resolution of an intermediate of suvorexant and cocrystals thereof

Examples

Experimental program
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preparation example Construction

[0097] In a specific embodiment of the method for preparing suvorexan disclosed above, X in compound (IV) is chlorine. In another specific embodiment of the method for preparing Suvorexan, Y in compound (VII) is bromine or chlorine.

[0098] Deprotection of the Cbz group can be achieved, for example, by using H 2 , Pd(OH) 2 , EtOAc hydrogenolysis. The amino protecting group can be introduced and removed by other procedures known in the art (see T.W. Greene and G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, Wiley, N.Y., 1999, pp. 531-535).

[0099]The group PG is a suitable orthogonal amino protecting group. As used herein, the term "suitable orthogonal amino-protecting group" means to cover any amino-protecting group other than the protecting group Cbz to protect other amino groups of compounds of formula (R)-(III), which are sensitive to the selected Cbz cleavage conditions ( such as hydrogenolysis) are stable. Representative protecting groups for amin...

Embodiment 1

[0106] Example 1: Detection of (R)-5-methyl-1,4-diazepane-1-carboxylate benzyl ester hydrochloride and (R)-(+)-1,1,2-tri Phenyl-1,2-ethylene glycol cocrystal form A and (S)-5-methyl-1,4-diazepane-1-carboxylate benzyl ester hydrochloride with (S)-( -)-1,1,2-Triphenyl-1,2-ethanediol co-crystal

[0107] The raw materials used were (rac)-5-methyl-1,4-diazepane-1-carboxylate benzyl ester HCl and (R)-TED (1:1) or (S)-TED ( 1:1).

[0108] (S)-5-Methyl-1,4-diazepane-1-carboxylate benzyl ester hydrochloride and (S)-(-)-1,1,2-triphenyl-1, Co-crystals of 2-ethanediol were obtained by slurrying and wet milling in acetonitrile (ACN).

[0109] (S)-5-Methyl-1,4-diazepane-1-carboxylate benzyl ester hydrochloride and (S)-(-)-1,1,2-triphenyl-1, Co-crystals of 2-ethylene glycol were also slurried by using isopropanol, ethyl acetate, acetone and toluene as solvents and using isopropanol, ethyl acetate, acetone, tetrahydrofuran, tert-butyl methyl ether, dichloromethane and Obtained by wet gri...

Embodiment 2

[0112] Example 2: Preparation of (S)-5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester hydrochloride and (S)-(- )-1,1,2-Triphenyl-1,2-ethanediol co-crystal and (R)-5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester salt Cocrystal A of acid salt and (R)-(+)-1,1,2-triphenyl-1,2-ethanediol

[0113] In an Eppendorf tube, racemic 5-methyl-1,4-diazepane-1-carboxylic acid benzyl ester hydrochloride (19.8 mg, 0.07 mmol) and (S)-1,1, 2-Triphenyl-1,2-ethanediol (20.1 mg, 0.07 mmol) was suspended in acetonitrile (0.2 mL). The resulting suspension was stirred at room temperature for 15 hours (overnight). Then, the solid was recovered by centrifugation and dried under high vacuum at room temperature.

[0114] Can be obtained by the same method starting from (R)-1,1,2-triphenyl-1,2-ethanediol instead of (S)-1,1,2-triphenyl-1,2-ethanediol (R)-5-Methyl-1,4-diazepane-1-carboxylate benzyl ester hydrochloride and (R)-(+)-1,1,2-triphenyl-1, 2-Ethylene glycol type A.

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Abstract

Relating to processes for preparing suvorexant or its pharmaceutically acceptable salts through the formation of a cocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloridewith (R)-(+)-1,1,2-triphenyl-1,2-ethanediol ((R)-TED). This cocrystal provides the resolution of an intermediate of suvorexant, in particular, of(rac)-benzyl5-methyl-1,4-diazepane-1-carboxylateor a hydrochloridesalt thereof. It also relates to a new cocrystal useful in such preparation processes.

Description

[0001] This application claims the benefit of European Patent Application EP16382260.4 filed on June 6, 2016. technical field [0002] The present invention relates to the preparation of suvorexant by resolution of benzyl (rac)-5-methyl-1,4-diazepane-1-carboxylate as an intermediate of suvorexant or its salt method. The invention also relates to new co-crystals that can be used in this preparation method. Background technique [0003] Suvorexant (MK-4305) is [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepane International Nonproprietary Name (INN) of -1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone with CAS number 1030377- 33-3. It is currently marketed as Belsomra and is a selective dual aricilin receptor antagonist for the treatment of insomnia. [0004] The structure of Suvoresan corresponds to the following formula (I). [0005] [0006] Suvoresan has a chiral center of configuration (R). The synthesis of Suvoresan is described in the patent ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/08C07D413/14
CPCA61P25/20C07D243/08C07B57/00C07B2200/07C07B2200/13C07C39/16C07D413/14
Inventor A·C·康姆利N·泰松
Owner ENANTIA
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