Synthesis method of ketamine, derivative and intermediate thereof

A synthetic method and technology of ketamine, applied in the field of ketamine synthesis, can solve the problems of unfavorable industrial production, difficulty in mass production, low atom economy, etc., and achieve strong industrial prospects, mild reaction conditions, and high equipment requirements.

Inactive Publication Date: 2021-01-08
国药集团工业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route can produce ketamine hydrochloride in three steps, but the high temperature rearrangement in the last step needs to be reacted at 180°C and 35 atm. The high temperature and high pressure conditions greatly increase the energy consumption, that is, the equipment cost, and the yield is only 62%. And this reaction is carried out in microchannel, needs relatively expensive supporting equipment, and daily production capacity is also only 71g, and cost increases greatly, so is unfavorable for its industrialized production
[0017] In summary, the current synthetic route of ketamine and (S)-ketamine has technical problems such as high energy consumption, low atom economy, low yield, and difficulty in mass production, and the current clinical demand for ketamine and (S)-ketamine Larger, so it is urgent to develop a highly efficient synthetic route suitable for industrialized production of ketamine

Method used

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  • Synthesis method of ketamine, derivative and intermediate thereof
  • Synthesis method of ketamine, derivative and intermediate thereof
  • Synthesis method of ketamine, derivative and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Step 1: Dissolve 2-chlorophenylcyclopentyl ketone (4) (10.0g, 0.048mol) in 100mL absolute ethanol solution at room temperature, add potassium hydroxide (2.7g, 0.048mol) and triethyl phosphite The ester (12.0 g, 0.072 mol) was stirred and dissolved, and heated to 30° C. for 48 h under an oxygen atmosphere. After the reaction was completed, about 70 mL of absolute ethanol was concentrated under reduced pressure, 300 mL of water was added dropwise to precipitate a solid, stirred at room temperature for 1 h, filtered with suction, and dried at 50° C. for 10 h to obtain 2-(2-chlorophenyl)-2-hydroxycyclohexyl ketone ( Ⅲ) 8.9g, yield 83.0%, purity 97.15%.

[0085] The HPLC chart of 2-(2-chlorophenyl)-2-hydroxycyclohexyl ketone (Ⅲ) figure 1 shown.

[0086] The H NMR spectrum of compound III is as follows: Figure 6 As shown, the specific data are as follows:

[0087] 1 H NMR (600MHz, CDCl3) δ7.68 (dd, J = 7.8, 1.0Hz, 1H), 7.42–7.33 (m, 2H), 7.28 (ddd, J = 21.5, 10.7, 4.3Hz...

Embodiment 2

[0099] Step 1: Dissolve 2-chlorophenylcyclopentyl ketone (10.0g, 0.048mol) in 100mL absolute ethanol solution at room temperature, add potassium hydroxide (2.7g, 0.048mol) and triethyl phosphite (12.0 g, 0.072mol) was stirred and dissolved, and the temperature was raised to 40° C. for 48 hours under an oxygen atmosphere. After the reaction, concentrate under reduced pressure to remove about 70mL of absolute ethanol, add dropwise 300mL of water to precipitate a solid, filter with suction, and dry at 50°C for 10h to obtain 8.8g of 2-(2-chlorophenyl)-2-hydroxycyclohexylketone (Ⅲ) , yield 82%, purity 98.35%.

[0100] Step 2: Dissolve 2-(2-chlorophenyl)-2-hydroxycyclohexyl ketone (6.0g, 0.027mol) in 50mL tetrahydrofuran solution at room temperature, add triethylamine (9.5g, 0.094mol), -10 Methanesulfonyl chloride (9.2 g, 0.08 mol) was added dropwise at °C for 1 h, then ammonia-methanol solution (40 mL, 0.27 mol) was added and the temperature raised to 15 °C for 3 h. After the rea...

Embodiment 3

[0108] Step 1: Dissolve 2-chlorophenylcyclopentyl ketone (10.0g, 0.048mol) in 100mL absolute ethanol solution at room temperature, add potassium carbonate (6.6g, 0.048mol) and sodium bisulfite (7.5g, 0.072mol) was stirred and dissolved, and the temperature was raised to 40° C. for 24 hours under an oxygen atmosphere. After the reaction, concentrate under reduced pressure to remove about 70mL of absolute ethanol, add dropwise 300mL of water to precipitate a solid, filter with suction, and dry at 50°C for 10h to obtain 6.0g of 2-(2-chlorophenyl)-2-hydroxycyclohexylketone (Ⅲ) , yield 55.7%, purity 98.1%.

[0109] Step 2: Dissolve 2-(2-chlorophenyl)-2-hydroxycyclohexyl ketone (3.0g, 0.013mol) in 25mL tetrahydrofuran solution at room temperature, add triethylamine (4.7g, 0.047mol), -10 Methanesulfonyl chloride (4.6 g, 0.04 mol) was added dropwise at °C for 1 h, then 25%-30% methylamine-ethanol solution (23 mL, 0.13 mol) was added and the temperature was raised to 30 °C for 1.5 h. ...

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Abstract

The invention discloses a synthesis method of ketamine. The synthesis method comprises the following steps: (i) oxidizing and rearranging 2-chlorophenyl cyclopentyl ketone by using an oxidizing agentto generate 2-(2-chlorophenyl)-2-hydroxycyclohexyl ketone, wherein the reaction temperature is 10-80 DEG C; (ii) condensing 2-(2-chlorphenyl)-2-hydroxy cyclohexyl ketone and a sulfonylation reagent ina solvent to form sulfonate, ie., the ketamine intermediate compound is obtained, wherein the reaction temperature is 30-60 DEG C; and (iii) reacting the ketamine intermediate compound with a methylamine reagent to generate ketamine. The invention also discloses a synthetic method of norketamine. The method comprises the steps (i) and (ii), and further comprises the step (iv) of reacting the ketamine intermediate compound with an amination reagent to generate the norketamine. The method is simple, mild in reaction condition, simple and convenient to operate, low in raw material cost and suitable for industrial mass production, and a high-temperature reaction at 180 DEG C is avoided.

Description

technical field [0001] The invention belongs to the technical field of ketamine synthesis, and in particular relates to a synthesis method of ketamine and its derivatives and intermediates. Background technique [0002] Ketamine, whose chemical name is 2-o-chlorophenyl-2-methylaminocyclohexanone, was developed in 1962 by Parke-Davis Pharmaceuticals (now a subsidiary of Pfizer) . Ketamine used clinically is a racemate. Ketamine is an N-methyl-D-aspartate receptor (NMDA) receptor antagonist and belongs to intravenous general anesthetics. It is clinically used as an surgical anesthetic or anesthesia inducer, and has a certain potential for mental dependence. Ketamine has been clinically used since 1962. Because it is the only intravenous anesthetic with analgesic and sedative effects, it can be used for anesthesia induction and anesthesia maintenance. It is widely used in pediatric surgery, cardiac tamponade surgery, and shock patients. And other operations, but also the Chi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/28C07C309/66C07C309/73C07C221/00C07C225/20
CPCC07C45/00C07C303/28C07C221/00C07C49/657C07C309/66C07C225/20C07C309/73
Inventor 张福利高升华杨哲洲李丽平高学智李彩宾林丽娅
Owner 国药集团工业有限公司
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