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Method for preparing Suvorexantintermediate and analogue thereof

A technology for analogs and intermediates, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of inconvenient process operation, large environmental pollution, waste of raw materials, etc., achieve simple and feasible process operation, simple and easy operation process, and reduce environmental pollution. Effect

Inactive Publication Date: 2017-06-20
成都美域高制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] (1) Great environmental pollution and inconvenient process operation
[0014] The starting material uses highly toxic compounds, and heavy metal catalysts are also used in the preparation process, which is very polluting to the environment, and operators must wear protective equipment to work, which is extremely inconvenient to operate
[0015] (2) The starting materials and reagents are expensive, and the waste of raw materials is large, resulting in high production costs
[0016] The starting materials and heavy metal catalysts used in the preparation process are all expensive, and the chiral resolution is only in the penultimate step of the synthesis steps, wasting nearly 50% of the raw materials, thereby increasing the production cost
[0017] (3) The total yield of synthesis is too low to be suitable for large-scale production
[0019] Therefore, there is a solution to the problems of using toxic substances, high cost, long route and low yield in the above route

Method used

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  • Method for preparing Suvorexantintermediate and analogue thereof
  • Method for preparing Suvorexantintermediate and analogue thereof
  • Method for preparing Suvorexantintermediate and analogue thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] (a) Synthesis of Compound 2:

[0152]

[0153] In a 5L reaction flask, add absolute ethanol (1.7L), then add p-methoxybenzaldehyde (200g, 1.47mol), anhydrous sodium sulfate (104g, 0.734mol), glacial acetic acid (6g, 0.1mol), continue to stir for 10min after the addition is complete, then add dropwise the mixed solution of Boc-ethylenediamine (282g, 1.763mol) and 300mL ethanol, after the dropwise completion, heat up to 62°C for 2h, then cool down to room temperature, add Sodium triacetoxyborohydride (343g, 1.62mol), stirred for 1h, monitored by HPLC

[0154] After the reaction is complete, add 400 mL of water and stir for 15 minutes, then concentrate the reaction solution under reduced pressure until no solution drops out, add 2 L of water to the residue, stir well, adjust the pH value of the solution to 3 with 2N hydrochloric acid, and extract impurities with diethyl ether. The pH value of the aqueous phase was adjusted to 8 with sodium bicarbonate, and the product ...

Embodiment 2

[0188] (a) Synthesis of Compound 2:

[0189]

[0190] In a 5L reaction flask, add ethanol (1.7L), then add 200g of p-methoxybenzaldehyde, 104g of anhydrous sodium sulfate, and 6g of glacial acetic acid while stirring. The mixture of diamine and 300mL of ethanol was added, and the temperature was raised to 70°C for 2 hours, then cooled to room temperature, 343g of sodium triacetoxyborohydride was added, stirred for 1 hour, and monitored by HPLC.

[0191] After the reaction is complete, add 400 mL of water and stir for 15 minutes, then concentrate the reaction solution under reduced pressure until no solution drops out, add 2 L of water to the residue, and stir evenly; adjust the pH value of the solution to 3 with 2N hydrochloric acid, and extract impurities with MTBE; The pH value was adjusted to 8 with sodium bicarbonate, the product was extracted with EA, the EA phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain...

Embodiment 3

[0218] (a) Synthesis of Compound 2:

[0219]

[0220] In a 10L reaction flask, add ethanol (3.4L), then add 400g of p-methoxybenzaldehyde, 208g of anhydrous sodium sulfate, and 12g of glacial acetic acid while stirring. The mixture of ethylenediamine and 600mL of ethanol was added, and the temperature was raised to 70°C for 2 hours, then cooled to room temperature, 686g of sodium triacetoxyborohydride was added, stirred for 1 hour, and monitored by HPLC.

[0221] After the reaction is complete, add 800 mL of water, stir for 15 min, then concentrate the reaction solution under reduced pressure until no solvent drips out, add 4 L of water to the residue, stir evenly, adjust the pH value of the solution to 3 with 2N hydrochloric acid, extract impurities with MTBE, water The pH value of the phase was adjusted to 8 with sodium bicarbonate, and the product was extracted with EA. The EA phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and conce...

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Abstract

The invention discloses a method for preparing a Suvorexantintermediate as shown in a formula 8A and an analogue thereof, or pharmaceutically acceptable salts and solvates thereof, wherein R is hydrogen or an alkyl group of C1 to C6. The method comprises the following steps of removing an amino protection group of a compound as shown in a formula 3 to obtain a compound as shown in a formula 4A; d, adopting the compound as shown in the formula 4A for preparing to obtain a compound as shown in a formula 5A; e, adopting the formula 5A for preparing to obtain a compound as shown in a formula 6A; f, reacting the compound as shown in the formula 6A and a compound as shown in a formula 10A for preparing to obtain a compound as shown in a formula 7A; g, adopting the compound as shown in the formula 7A for preparing to obtain the compound as shown in the formula 8A. According to the method provided by the invention, the compound 8 is synthesized through a brand new process route, and is then adopted as an intermediate for preparing Suvorexant, so that the problems of the usage of toxic substances, high cost, long route and low yield in an existing method for preparing the Suvorexant are effectively solved, and the method is suitable for industrial application.

Description

technical field [0001] The invention relates to a method for preparing a pharmaceutical intermediate, in particular to a method for preparing a Suvorexant intermediate and analogs thereof. Background technique [0002] Insomnia is the most common sleep disorder, about 30-50% of adults have shown symptoms of insomnia, of which 10-15% have been diagnosed with insomnia. According to statistics, the loss caused by insomnia reaches tens of billions of dollars every year. Although insomnia is associated with many serious physical and mental diseases, people's attention to it is far from enough. For a long time, insomnia is only defined as a symptom of other diseases, so little progress has been made in its understanding and treatment . [0003] Currently, sedative-hypnotics for the treatment of insomnia include the following categories: antidepressant sedatives, benzodiazepine sedative-hypnotics (BZD), new non-benzodiazepine sedative-hypnotics (NBZD), and melatonin receptor Inh...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D413/14
CPCY02P20/55C07D403/06C07D413/14
Inventor 陈志勇王春燕王聪
Owner 成都美域高制药有限公司
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