Preparation method of ketamine and synthesis method of intermediate compound

The technology of a compound, ketamine, is applied in the field of drug synthesis, which can solve the problems of acute poisoning, shock or renal failure, easy pollution of the environment by waste iron powder and acid water, easy explosion of nitrating reagents, etc., to achieve mild conditions and high product quality Improved, low-cost effect

Active Publication Date: 2020-02-21
YICHANG HUMANWELL PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The oxidizing agent used in this route is easy to open the six-membered ring, and the conditions of the oxidation reaction are harsh, difficult to control, and difficult to operate after treatment; the nitrating reagent used is prone to explosion, and the nitric acid used can cause acute poisoning, shock or renal failure Exhaustion, etc., must be very careful during use, and the waste water produced at the same time is easy to pollute the environment; the reducing agent used is a metal reducing agent such as iron powder. Repeated experiments and researches according to the examples of this patent have found that this type of catalyst is particularly It is easy to be poisoned, the storage time is a little long, the catalytic reaction effect is very poor, the total reaction of nitro group is not complete, even if the reducing agent is added, the reaction cannot be completed completely; and the waste iron powder and acid water produced after the reaction are easy to pollute the environment
Therefore, the route and process conditions are also extremely unsuitable for industrialized production

Method used

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  • Preparation method of ketamine and synthesis method of intermediate compound
  • Preparation method of ketamine and synthesis method of intermediate compound
  • Preparation method of ketamine and synthesis method of intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: intermediate compound II: the synthesis of 2-o-chlorophenyl-2-azidocyclohexanone

[0043] Dissolve 1-o-chlorophenylcyclohexene (1.92g) in 30mL of dichloromethane, then add PhI(OAc) at -20°C 2 (3.86g) and TMSN 3 (1.75g), kept at -20°C for 16h. After the reaction was completed, the temperature of the system was raised to room temperature, the reaction solution was washed with water, and extracted with ethyl acetate, the organic phases were combined, and the organic phase was washed with anhydrous Na 2 SO 4 After drying and concentration, column chromatography (petroleum ether: ethyl acetate = 20:1) gave 2-o-chlorophenyl-2-azidocyclohexanone (1.78 g, yield 71%) as a colorless oily liquid. 1 H NMR (400MHz, CDCl3 ):δ=1.76-1.80(m,2H),1.81-1.93(m,2H),2.41-2.44(m,2H),3.01-3.05(m,2H),7.34-7.48(m,4H); 13 C NMR (100MHz, CDCl 3 ): δ=17.18, 23.10, 24.87, 41.87, 119.48, 127.07, 128.76, 130.59, 130.74, 131.85, 139.22, 202.45.

[0044] Compound (II) was detected acc...

Embodiment 2

[0045] Embodiment 2: intermediate compound II: the synthesis of 2-o-chlorophenyl-2-azidocyclohexanone

[0046] Dissolve 1-o-chlorophenylcyclohexene (19.2g) in 300mL of dichloromethane, then add iodosobenzene (26.4g) and 1-(azido)-1,2-benzene at -22°C Iodosyl-3(1H)-one (43.4g) was kept at -22°C for 17h. After the reaction was completed, the temperature of the system was raised to room temperature, the reaction solution was washed with water, and extracted with ethyl acetate, the organic phases were combined, and the organic phase was washed with anhydrous Na 2 SO 4 After drying and concentration, column chromatography (petroleum ether: ethyl acetate = 20:1) gave 2-o-chlorophenyl-2-azidocyclohexanone (20.4 g, yield 82%) as a colorless oily liquid.

Embodiment 3

[0047] Embodiment 3: intermediate compound II: the synthesis of 2-o-chlorophenyl-2-azidocyclohexanone

[0048] Dissolve 1-o-chlorophenylcyclohexene (19.2 g) in 300 mL of dichloromethane, then add bis(trifluoroacetoxy) iodobenzene (58 g) and 1-(azido)- 3,3-Bistrifluoromethyl-1,3-dihydro-1,2-benzoiodooxolane (45.4g) was kept at -18°C for 13h. After the reaction was completed, the temperature of the system was raised to room temperature, the reaction solution was washed with water, and extracted with ethyl acetate, and the organic phases were combined, and the organic phase was washed with anhydrous MgSO 4 After drying and concentration, column chromatography (petroleum ether: ethyl acetate = 20:1) gave 2-o-chlorophenyl-2-azidocyclohexanone (21.6 g, yield 87%) as a colorless oily liquid.

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Abstract

The invention discloses an intermediate compound II for synthesizing ketamine, and the chemical structural formula of the intermediate compound II is disclosed in the invention. The compound II is directly synthesized by one-step reaction of a compound under the action of iodobenzene acetate and azidotrimethylsilane; and ketamine is synthesized from the compound II through two steps: 1) reducing azide into amino; and 2) carrying out aminomethylation reaction. Compared with the prior art, the HPLC purity of the product can reach 97% or above, meanwhile, the ketamine prepared through the methodis high in industrialization degree, the quality of the product is greatly improved, intermediate impurities do not exist, the process route is easy to operate, the cost is low, and conditions are mild.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to an intermediate compound for synthesizing ketamine and a preparation method thereof. Background technique [0002] Ketamine, whose chemical name is 2-o-chlorophenyl-2-methylaminocyclohexanone, is a derivative of phencyclidine. In clinical medicine, it is generally used as an intravenous general anesthetic; it has a bronchodilator effect, and can be used for the treatment of asthma patients and as a dilator for cerebral blood vessels. [0003] At present, the main synthesis method of ketamine is to prepare it through the rearrangement reaction of the N-methylimine hydrochloride of the intermediate 1-hydroxycyclopentyl o-chlorophenyl ketone. However, the rearrangement reaction generally takes place at a high temperature above 160°C, and sometimes microwave radiation is required, which is not conducive to industrial production. [0004] WO2017208031A1 discloses ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C245/24C07C221/00C07C225/20
CPCC07C221/00C07C2601/14C07C247/14C07C225/20Y02W10/37Y02A50/30
Inventor 廖宗权周海峰崔鹏蔡坤张宇吕金良陈雷李莉娥李杰杜文涛田峦鸢雷攀立郭建锋
Owner YICHANG HUMANWELL PHARMA
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