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Continuous flow micro-reaction synthesis method of suvorexant intermediate

A microreactor and reaction technology, applied in organic chemistry and other directions, can solve the problems of high cost and difficult industrial production, and achieve the effects of low cost, simple operation and mild reaction conditions.

Pending Publication Date: 2022-01-14
湖南华腾医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Aiming at the above-mentioned preparation method of Suwo Leisheng intermediate, it has high cost, difficulty in industrial production, highly toxic raw materials used in the reaction, great test and pollution to the environment and production equipment, and many technical problems of safety risks. The invention provides a continuous-flow micro-reaction synthesis method of Suwo Leisheng intermediate compound SM-8, which has the characteristics of easy-to-obtain raw materials, mild reaction conditions, simple operation, low cost, environment-friendly, and suitable for industrial production

Method used

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  • Continuous flow micro-reaction synthesis method of suvorexant intermediate
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  • Continuous flow micro-reaction synthesis method of suvorexant intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Example 1 Preparation of Compound SM-2

[0108]

[0109] Compound SM-1 (800 g), EtOH (5L) and ethylthallate (1.79 kg) (1.79 kg) were added to a 10 l 4 flask; 80 ° C for mechanical stirring 4H; TLC was detected, and after the reaction was complete, the reaction liquid was poured down. The pH was adjusted in 8 L of ice water, and the pH was added dropwise to 7, filtered, and the filter cake was washed with water (6L), and the solid was concentrated to concentrate, resulting in a compound SM-2 (1.117 kg), yield 96.7%, purity 95%.

[0110] Compound SM-2 was detected: 1 H NMR (400 MHz, DMSO) δ: 7.31 (m, 2H), 7.53 (D, J = 8.74 Hz, 1H).

[0111] LC-MS: Calculated MW = 185.63g / mol, Found M / Z [M + 1] + = 186.89.

Embodiment 2

[0112] Example 2 Preparation of Compound SM-3

[0113]

[0114] Precisely weigh the compound SM-2 (1.117 kg), DMF (560 mL) and DCM (11L) thoroughly mixed preparation into uniform liquid spare. The microreactor is disposed and cooled to 5 ° C or less, and the above solution of the compound SM-2, Dichloride SOCL 2 (1120ml) and triethylamine slowly pumped into the microchannel reactor in a set flow (1 ml / min); the reaction liquid flows directly into the 10L NAHCO 3 In the ice aqueous solution, the sedation, the aqueous phase was extracted with DCM (3L), combined with an organic phase, washed once with water (3L), dried over anhydrous sulfate, concentrated under reduced pressure to obtain Compound SM-3 (1.1 kg), yield 97.4%, purity 97%.

[0115] Compound SM-3 was detected: 1 H NMR (400MHz, CDCL 3 δ: 7.67 (D, J = 2.1 Hz, 1H), 7.44 (D, J = 8.8 Hz, 1H), 7.34 (DD, J = 8.8, 2.1 Hz, 1H); 13 C NMR (100MHz, CDCL 3 Δ: 110.9, 12.2, 126.1, 131.0, 142.0, 149.9, 152.34.

[0116] LC-MS: Calcula...

Embodiment 3

[0117] Example 3 Preparation of Compound SM-4

[0118]

[0119] The solvent was prepared as a solvent in DCM, respectively, a solution of 2 mmol / L compound SM-3 (722 g), 2 mmol / L N-BOC-ethylenediamine (650 g) and 2 mmol / L of triethylamine (586 g), the reaction temperature was maintained at Between 5 ° C -10 ° C, three raw materials were pumped into the microreactor system in a set flow (1 ml / min), and the TLC showed that the feedstock was completed; the reaction liquid was directly injected into 15L ice water, and the mixture was allowed to stand after 2min The separation solution, the aqueous phase was extracted once with DCM (3L), combined with the organic phase, washed once with water (5L), dried over anhydrous sulfate, concentrated under reduced pressure to obtain crude, crude EA: PE (400 ml: 2000ml) Ged (4h ), Filtration, filter cake was washed with petroleum ether (1 L), and the concentrated filter cake was concentrated to give compound SM-4 (850 g), yield 71.3%, p...

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Abstract

The invention relates to a continuous flow micro-reaction synthesis method of a suvorexant intermediate, and belongs to the technical field of medicine preparation. According to the preparation method, a key intermediate of a suvorexant bulk drug is technically optimized by adopting a continuous flow microreactor technology, and the suvorexant intermediate is synthesized by taking 2-amino-4-chlorophenol and potassium ethyl xanthate as initial raw materials through cyclization reaction, halogenation reaction, chiral resolution and other reactions. Meanwhile, influences of halogenating reagent types, acid-binding agent types and alkali equivalent factors involved in the technological process on the yield and purity of corresponding intermediates are investigated, and the optimal technological conditions are determined. The optimization process has the advantages of mild reaction conditions, simplicity and convenience in purification, environmental friendliness and the like, and is suitable for industrial large-scale production.

Description

Technical field [0001] The present invention relates to the technical field of medical preparation, and more particularly to a continuous stream microactive synthesis method of Susovalectin. Background technique [0002] SUVOREXANT, CAS: 1030377-33-3 is a new type of hypnotics developed by MERCK, 2014 UN FDA approved for treatment difficult to fall asleep or maintain sleep. Receptor antagonist. Its chemical structural formula is as shown in Formula i: [0003] [0004] There are many challenges in the actual preparation process of Suvola, and their synthetic routes are cumbersome, the overall yield is low, and the separation and purification of multiple core intermediates requires column chromatography or column chromatography, and the production process process tends to involve Dangerous high-risk chemicals and high-risk chemical reactions, while also producing a lot of wastewater and by-products, very likely to cause environmental pollution. [0005] Suvolai Nuclear Intermedi...

Claims

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Application Information

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IPC IPC(8): C07D413/04
CPCC07D413/04
Inventor 许慧张安林彭媛媛金艳娟
Owner 湖南华腾医药有限公司
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