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Synthesis method of suvorexant intermediate

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

Active Publication Date: 2019-06-21
成都美域高制药有限公司
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  • Abstract
  • Description
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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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  • Synthesis method of suvorexant intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Synthesis of Suvorexant 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] 400 g of solvent tetrahydrofuran and 50 g of raw material compound Suvor-1 were sequentially added into the reaction kettle, and the temperature was lowered to -10 to 0°C. Add 75g of red aluminum solution in batches, control the temperature at -10°C to 0°C, react until the raw materials are monitored by TLC after the addition is complete, add 200g of 10% potassium sodium tartrate solution and 200g of ethyl acetate, stir until the system is clear, and separate the liquids. Collect the organic phase. Concentrated 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] Dissolve 26.4g of compound Suvor-2 in 132g of tetrahydro...

Embodiment 2

[0068] Example 2 Synthesis of Suvorexant intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic acid tert-butyl ester 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 sequentially added into the reaction kettle, and the temperature was lowered to -10 to 0°C. Add 50g of red aluminum solution in batches, and control the temperature at -10°C to 0°C. After the addition is complete, react until the raw materials monitored by TLC disappear, add 100g of 10% potassium sodium tartrate solution and 100g of ethyl acetate, stir until the system is clear, and separate the liquids. Collect the organic phase. Concentrated 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] Dissolve 26.4g of compound Suvor-2 in 79g of ...

Embodiment 3

[0089] Synthesis of Example 3 (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 into the reaction kettle, and the temperature was lowered to -10 to 0°C. Add 100g of red aluminum solution in batches, and control the temperature at -10°C to 0°C. After the addition is complete, react until the raw materials are monitored by TLC. Add 300g of 10% potassium sodium tartrate solution and 300g of ethyl acetate, stir until the system is clear, and separate the liquids. Collect the organic phase. Concentrate under reduced pressure to obtain the intermediate Suvor-2, weighing 40.6 g, with an HPLC purity of 98% and a yield of 85%.

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

[0095] Feeding table 3-2

[0096]

[0097] Dissolve 26.4g of compound Suvor-2 in 264g of tet...

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Abstract

The invention provides a synthesis method of a suvorexant intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic t-butyl ester. The synthesis method of the suvorexant intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic t-butyl ester comprises the following steps: (1) enabling a compound Suvor-1 to react with vitride solution to obtain a compound Suvor-2; enabling the compound Suvor-2 to react with 4,4-dimethoxy-2-butanone to obtain Suvor-3; (3) enabling the compound Suvor-3 to react with methanesulfonic acid to obtain a compound Suvor-4; (4) enabling the compound Suvor-4 to react with di-tert-butyl dicarbonate to obtain a compound Suvor-5; (5) enabling the compound Suvor-5 to react with hydrogen to obtain the suvorexant intermediate. The synthesis method of the suvorexant intermediate (5S)-hexahydro-5-methyl-1H-1,4-diazepine-1-carboxylic t-butyl ester provided by the invention has the advantages that the reaction is simple, starting materials are cheap and easy to obtain, the reaction condition is mild, and the production safety is high; in addition, the reaction steps are less, the reaction yield is high, and the production cost is lower; moreover, by introducing a chiral functional group, the purity of a target product obtained after induced synthesis and ring closure is high, the amount of impurities in enantiomer is small, the ee% is greater than97%, and the method is suitable for commercial large-scale production.

Description

technical field [0001] The present invention relates to the field of drug synthesis, in particular to a method for synthesizing Suvoraxan 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 patients with sleep disorders in my country, and as many as 500 million people with insomnia. Among the insomniacs, 73% of them have never seen a specialist doctor or been treated with drugs. Insomnia has become a mental illness 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 a central promoter of wakefulness, and blocking the binding of wakefulness-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to drive consistent w...

Claims

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Application Information

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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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