A kind of synthetic method of Suwo Leisheng intermediate

A synthesis method and intermediate technology, applied in the field of pharmaceutical synthesis, can solve the problems of harsh reaction conditions, complex process routes, poor atom economy and the like, and achieve the effects of fewer reaction steps, high reaction yield and high production safety.

Active Publication Date: 2022-07-05
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

[0010] The above-mentioned technical routes have the following disadvantages: (1) In the technical routes 1 and 2, the highly toxic reagent butenone is required, which has great potential safety hazards and is not friendly to the environment
(2) In the technical route 1, the obtained compound 8 is a racemate, which needs to be resolved, and the atom economy is poor
(3) In the second technical route, it is easy to produce methyl isomerism impurities during splitting, which are similar in structure to the target object and are difficult to remove in the process
(4) The process route is relatively long, and the total yield is not high
[0012] However, the current preparation of the intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic acid tert-butyl ester is mostly complicated and the reaction conditions are harsh

Method used

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  • A kind of synthetic method of Suwo Leisheng intermediate
  • A kind of synthetic method of Suwo Leisheng intermediate
  • A kind of synthetic method of Suwo Leisheng intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Synthesis of Suvorexan intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic acid tert-butyl ester

[0048] Step 1: Compound Suvor-2 Synthesis

[0049] Feeding table 1-1

[0050]

[0051] In the reaction kettle, 400 g of solvent tetrahydrofuran and 50 g of raw material compound Suvor-1 were successively added, and the temperature was lowered to -10 to 0 °C. Add 75g of red aluminum solution in batches, control the temperature at -10 ℃ ~ 0 ℃, after the addition, react until the TLC monitoring raw materials disappear, add 200g 10% potassium sodium tartrate solution and 200g ethyl acetate, stir until the system is clarified, and then separate the liquid, Collect the organic phase. Concentrate under reduced pressure to obtain compound Suvor-2, weighing 41.8 g, HPLC purity 98%, yield 88%.

[0052] Step 2: Synthesis of Compound Suvor-3

[0053] Feeding table 1-2

[0054]

[0055] 26.4 g of compound Suvor-2 was dissolved in 132 g of tetrahydrof...

Embodiment 2

[0068] Example 2 Synthesis of Suvor Lexan intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic acid tert-butyl ester Step 1: Synthesis of compound Suvor-2

[0069] Feeding table 2-1

[0070]

[0071]

[0072] 300 g of solvent tetrahydrofuran and 50 g of raw material compound Suvor-1 were successively added to the reaction kettle, and the temperature was lowered to -10 to 0 °C. Add 50g of red aluminum solution in batches, control the temperature at -10 ℃ ~ 0 ℃, after the addition, react until the TLC monitoring raw materials disappear, add 100g 10% potassium sodium tartrate solution and 100g ethyl acetate, stir until the system is clear, and then separate the liquid, Collect the organic phase. Concentrate under reduced pressure to obtain compound Suvor-2, weighing 40.4 g, HPLC purity 97%, yield 85%.

[0073] Step 2: Synthesis of Compound Suvor-3

[0074] Feeding table 2-2

[0075]

[0076] 26.4 g of compound Suvor-2 was dissolved in 79 g of tetrahydro...

Embodiment 3

[0089] Example 3 Synthesis of (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic acid tert-butyl ester

[0090] Step 1: Compound Suvor-2 Synthesis

[0091] Feeding table 3-1

[0092]

[0093]500 g of solvent tetrahydrofuran and 50 g of raw material compound Suvor-1 were successively added to the reaction kettle, and the temperature was lowered to -10 to 0 °C. Add 100g of red aluminum solution in batches, control the temperature at -10 ℃ ~ 0 ℃, after the addition, react until the TLC monitoring raw materials disappear, add 300g of 10% potassium sodium tartrate solution and 300g of ethyl acetate, stir until the system is clear, and then separate the liquid, Collect the organic phase. Concentrated under reduced pressure to obtain intermediate Suvor-2, weighing 40.6 g, HPLC purity 98%, yield 85%.

[0094] Step 2: Synthesis of Compound Suvor-3

[0095] Feeding table 3-2

[0096]

[0097] 26.4 g of compound Suvor-2 was dissolved in 264 g of tetrahydrofuran, 36 g of gla...

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Abstract

The present invention provides a method for synthesizing Suvorexan intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylate tert-butyl ester, comprising the following steps: (1) compound Suvor-1 reacts with red aluminum solution to obtain compound Suvor-2; (2) compound Suvor-2 reacts with 4,4-dimethoxy-2-butanone to obtain Suvor-3; (3) ) compound Suvor-3 reacts with methanesulfonic acid to obtain compound Suvor-4; (4) compound Suvor-4 reacts with di-tert-butyl dicarbonate to obtain compound Suvor-5; (5) compound Suvor-5 reacts with hydrogen, Obtain Suvorexan intermediates. The method has simple reaction, cheap and easy-to-obtain starting materials, mild reaction conditions, and high production safety; in addition, the method has few reaction steps, high reaction yield, and low production cost; Induced synthesis, the target product obtained after ring closure has high purity, less enantiomeric impurities, and ee% is greater than 97%, which is suitable for commercial scale production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing suvorexan intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic acid tert-butyl ester . Background technique [0002] According to statistics, there are about 1.3 billion people with sleep disorders in my country, and 500 million people with poor sleep. Among the insomniacs, 73% of the patients have never seen a specialist or treated with drugs. Insomnia has become a mental disease that plagues many people. And seriously affect the quality of work and life. [0003] The mechanism by which Suvorexan exerts its therapeutic action in insomnia is hypothesized to be through antagonism of orexin receptors. The orexin neuropeptide signaling system is an arousal central promoter, and blocking the binding of the wake-promoting neuropeptides orexin A and orexin B to the receptors OX1R and OX2R is thought to drive consistent arousal. [0004] In August ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D243/08
Inventor 随裕敏戢颖瑶
Owner 成都美域高制药有限公司
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