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Preparation method of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol

A technology of methyl vinyl and cyclohexene, which is applied in the field of drug synthesis, can solve the problems of low yield, cumbersome steps, and long process time, and achieve the effects of high yield, simple steps, and high product purity

Active Publication Date: 2021-04-16
ZHEJIANG NHU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the above technology uses a ring-opening catalyst with better stability, it still has the defects of long process time, cumbersome steps and low yield.
[0005] At the same time, in the above-mentioned traditional preparation (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-alcohol technology, all need to go through epoxidation reaction, open There are four steps of cycloaddition reaction, oxidation reaction and elimination reaction. The whole process includes two-step oxidation reaction, which requires high reaction conditions, and there is a large safety risk in industrial production, and there are many steps, which further increases the production cost.

Method used

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  • Preparation method of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol

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preparation example Construction

[0030] The traditional preparation method often uses limonene as a raw material after epoxidation, followed by selective ring opening, and then oxidation and elimination reactions to obtain (1S,4R)-1-methyl-4-(1-methylvinyl)- 2-Cyclohexen-1-ol, this technology has many steps and high production cost, and the whole process includes two-step oxidation reaction, which requires high reaction conditions, and there is a big safety risk in industrialization.

[0031] For example, one of the technical solutions uses expensive oxides such as zirconyl sulfate as catalysts for selective ring-opening reaction. The oxides used in this process, such as zirconyl sulfate, are expensive, resulting in high preparation costs, which is not conducive to industrial production.

[0032] After a large number of experimental investigations, the technicians of the present invention obtained (1S, 4R)-1-methyl-4-(1-methylvinyl) with high yield, simple process and suitable for industrial production in the ...

Embodiment 1

[0084] 1) Preparation of Intermediate 1: In a 500mL three-necked flask, add 81.6g of D-limonene, 100mL of dichloroethane and 100mL of water, 70.0g of sodium hypochlorite, Cu(OAc) 2 ·H 2 O is 1.2g and TMAB is 0.2g, the temperature is raised to 80°C for reflux reaction, the reaction is 6h, and samples are taken for testing. The results show that the content of D-limonene is less than 1%. After ethane, the crude product containing the intermediate 1(1S,4R)-2-chloro-4-(1-methylvinyl)-1-methyl-cyclohexanol was obtained, with a quality of 111.5g, and was further purified under an absolute pressure of 150Pa Distillation under reduced pressure was carried out at ~160Pa, and the fraction at 120°C to 124°C was received to obtain 103.9g of intermediate 1 with a yield of 88.6%. The purity of intermediate 1 obtained by testing was 96.2%.

[0085]2) Preparation of intermediate 2: Add 90.0 g of the above intermediate 1 (1S,4R)-2-chloro-4-(1-methylvinyl)-1-methyl-cyclohexanol to a 250 mL rea...

Embodiment 2

[0090] 1) Preparation of Intermediate 1: In a 500mL three-necked flask, add 81.6g of D-limonene, 100mL of dichloroethane and 100mL of water, 111.8g of sodium hypobromite, Cu(OAc) 2 ·H 2 O is 1.2g, TMAB is 0.2g, the temperature is raised to 80°C for reflux reaction, the reaction is 6h and the sample is taken for testing, the result shows that the content of D-limonene is less than 1%, the reaction is stopped, the layers are separated after cooling, and the organic layer is distilled under reduced pressure to recover dichloro After ethane, 137.5 g of the crude product containing the intermediate 1(1S,4R)-2-chloro-4-(1-methylvinyl)-1-methyl-cyclohexanol was obtained, and further under absolute pressure of 150Pa~160Pa Distillation under reduced pressure was carried out, and the fraction at 126° C. to 129° C. was received to obtain 128.5 g of intermediate 1 with a yield of 88.3%. The purity of intermediate 1 was detected to be 96.1%.

[0091] 2) Preparation of intermediate 2: add ...

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Abstract

The invention relates to a preparation method of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol, and belongs to the technical field of organic solvents. The preparation method comprises the following steps: reacting limonene with a halogenating reagent to obtain an intermediate shown in a formula (1), then reacting the intermediate shown in the formula (1) with a tertiary amine compound to obtain an intermediate shown in a formula (2), and finally carrying out a pyrolysis elimination reaction on the intermediate shown in the formula (2) to obtain (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol. The preparation method has the advantages of mild conditions, no need of an oxidation process of hydrogen peroxide with high preparation condition requirements and high safety risk, no need of an expensive catalyst, high yield, high product purity, simple steps, and suitableness for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a preparation method of (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol. Background technique [0002] Cannabidiol (CBD for short) is the main chemical component in the medicinal plant cannabis. It is extracted from the female cannabis plant and is a non-addictive component in cannabis. It has anti-spasmodic, anti-anxiety, anti-inflammatory, and pain-relieving pharmacological effects. CBD can not only help control the consumption of GABA neurotransmitter, suppress brain excitation, reduce seizures, but also help improve the efficacy of other anti-epileptic drugs. It can even effectively eliminate the hallucinogenic effect of tetrahydrocannabinol (THC) on the human body, known as the "anti-marijuana compound". [0003] (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol is one of the important intermediates for the preparation of CBD, and its traditional preparat...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C215/44C07C29/00C07C35/08C07C29/124C07C35/48
Inventor 贺家伟方向钱洪胜胡瑞君范江涛郭文龙张文志钟鑫
Owner ZHEJIANG NHU CO LTD
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