Novel routes of synthesis for preparation of suvorexant

一种化合物、组合物的技术，应用在制备苏沃雷生的新合成途径领域，能够解决不适合制备规模等问题

Inactive Publication Date: 2017-04-19
SANDOZ LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, very specific and sensitive enzymes are required, again making the process unsuitable for preparative scale

Method used

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  • Novel routes of synthesis for preparation of suvorexant
  • Novel routes of synthesis for preparation of suvorexant
  • Novel routes of synthesis for preparation of suvorexant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0698]

[0699] In the above table, PG 1 The preferred choice is Boc, PG 2 The preferred choice is Cbz.

[0700] Such as R 1 With R 1a Different, or like R 2 With R 2a Different, or like R 1a And R 2a Respectively with R 1a And R 2a Different, perform step (a4). According to the corresponding group to be replaced, step (a4) includes one or more steps, such deprotection step and / or protection step and / or coupling step with the compound of the following structural formula

[0701]

[0702] And / or the coupling step with the compound of the following structural formula

[0703]

[0704] The compound of structural formula (II) is obtained.

[0705] According to the preferred embodiment, step (a) of the present invention includes, for example:

[0706] (a1) Reaction to form a compound of structural formula (III)

[0707]

[0708] Add the compound of structural formula (IV)

[0709]

[0710] Get the compound of structural formula (V)

[0711]

[0712] Where: R 1a For PG 1 , Where: R 2a For H, PG...

Embodiment 1

[1340] Example 1: Preparation of 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)butan-2-acid (Z)-methyl ester

[1341]

[1342] Take Boc-ethylenediamine (84.3g, 500mmol) and dissolve it in CH 2 Cl 2 (110ml), transfer to 500ml Schmizo, and cool to 10°C. Add silica gel (120g) in portions and use CH 2 Cl 2 (50ml) Dilute the slurry. Methyl acetoacetate (54ml, 500mmol) was added, the reaction mixture was stirred at 20°C, and the progress of the reaction was monitored by GC. After one hour, the reaction was judged to be complete. Filter out the silica gel, use CH 2 Cl 2 (250ml) Wash the filter cake. The pale yellow solution was concentrated under reduced pressure to obtain enamine (127.9 g) as a pale yellow oil.

[1343] 1 H NMR(300MHz, CDCl 3 ): δ=8.57(br s, 1H), 4.84(br s, 1H), 4.47(s, 1H), 3.61(s, 3H), 3.33(m, 2H), 3.23(m, 2H), 1.91( s, 3H), 1.43 (s, 9H). 13 C NMR(75MHz, CDCl 3 ): □=170.9, 162.0, 155.9, 82.7, 79.6, 50.0, 42.8, 41.3, 28.3, 19.3. All data are consistent with the data...

Embodiment 2

[1345] Preparation of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)butyrate by hydrogenation

[1346]

[1347] In the presence of 73 g Pd / C, a solution of enamine (58.7 g, 227 mmol) in MeOH (650 ml) was hydrogenated at 55° C. and a pressure of 3 bar. The reaction was monitored by GC. After complete conversion (about 7 hours), the suspension was filtered through a K150 filter and the solid was washed with MeOH. The solution was concentrated under reduced pressure, dissolved in MeOH (300 ml), and distilled under reduced pressure to obtain β-amino ester (51.6 g, 87%) as an oil.

[1348] 1 H NMR(300MHz, CDCl 3 ): δ = 5.28 (br s, 1H, NH), 3.99 (br s, 1H, NH) 3.66 (s, 3H, OCH3), 3.13-3.25 (overlapping m, 3H, CH 2 +CH), 2.78(m, 2H, CH 2 ), 2.48(m, 2H, CH 2 ), 1.41(s, 9H, C(CH 3 ) 3 ), 1.15(d, J=6.3Hz, 3H, CH 3 ). 13 C NMR(75MHz, CDCl 3 ): δ=172.2, 156.1, 79.2, 51.6, 50.1, 45.9, 40.6, 39.8, 28.3, 19.7.

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Abstract

The present invention relates to a process for the preparation of a compound of formula (A), Further, the present invention relates to the respective compound (A) as such and to its use in the preparation of antifungal agent.

Description

[0001] The present invention relates to a method for preparing a compound of structural formula (A) or a pharmaceutically acceptable salt or solvate thereof, and also relates to compound (A) itself and compound (A) obtained or obtained by the method. [0002] [0003] The present invention also relates to the preparation of intermediate compounds that can be used in the synthesis of the present invention and the intermediate compounds themselves. [0004] Background of the invention [0005] Orexin is a neurotransmitter that regulates wakefulness and appetite. Orexin is an excitatory neuropeptide, which plays a key role in maintaining arousal. The discovery of orexin receptors in the mammalian brain may have many pathological significance, such as depression; anxiety; addiction; obsessive-compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behavioral disorder Mood disorders; dried apricot disorders; psychosexual dysfunction; sexual dis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/04C07C271/20C07D403/06C07D413/14C07C271/22C07D243/08C07C269/06
CPCC07C269/04C07C269/06C07D243/08C07D403/06C07D413/14C07C271/22C07C271/20C07D249/06C07D403/10
Inventor R·巴尔特K·霍弗尔-普兰茨F·里希特G·威德施文特尔
Owner SANDOZ LTD
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