Method for preparing pentazocine intermediates

An intermediate, benzoazocine technology, applied in the field of drug synthesis, can solve the problems of many route steps and low yield, and achieve the effect of increased total yield, high yield and low cost

Inactive Publication Date: 2018-02-16
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In 2012, Qiang Chen et al. used asa-Prins cyclization and intramolecular Friedel-Crafts reaction to carry out asymmetric synthesis, but this asymmetric synthesis is that the mixture contains enantiomers, and there are many steps in the route, and the yield is low. Dangerous goods such as sodium metal and n-butyllithium are used

Method used

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  • Method for preparing pentazocine intermediates
  • Method for preparing pentazocine intermediates
  • Method for preparing pentazocine intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 1. Preparation of compound 3

[0034]

[0035] In a 100mL reaction flask, add compound 2 (1.86g, 19mmol) and 1.85g (15.3mmol) of anhydrous collidine mixed solution, 3.32g (38.2mmol) of lithium bromide in 40ml of anhydrous ether solution, and control the temperature to below zero From 40°C to minus 50°C, add 1.2ml (12.8mmol) of phosphorus bromide dropwise. After the addition, control the temperature at 0°C and stir for 2h. Add 2ml of collidine. After quenching with water, add n-pentane The solution is extracted with n-pentane, the organic phase is washed with water, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The excess solvent is evaporated under reduced pressure to obtain the crude product, which is slowly added below zero 40°anhydrous zinc bromide (3.75g, 16.7mmol) in ether solution (7ml), the reaction system was heated to 0°C, stirred for 1.5h, and then n-pentane and 50% sodium chloride aqueous s...

Embodiment 2

[0046] 1. Preparation of compound 3

[0047] In a 50mL reaction flask, add compound 2 (0.93g, 9.5mmol) and 0.93g (7.6mmol) of anhydrous collidine mixed solution, 1.7g (19.1mmol) of lithium bromide in 20ml of isopropyl ether solution, control the temperature at From minus 40 degrees to minus 50 degrees, add 0.6ml (6.4mmol) of phosphorus bromide dropwise. After the addition, the temperature is controlled at 0°C and the reaction is stirred for 2h. Add 1ml of collidine. After quenching with water, add positive Heptane, the solution is extracted with n-heptane, the organic phase is washed with water, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the excess solvent is evaporated under reduced pressure to obtain the crude product. Add slowly Anhydrous zinc bromide (1.9g, 8.4mmol) in isopropyl ether solution (4ml) at minus 40°C, the reaction system was heated to 0°C, stirred for 1.5h, and then n-heptane and 50% ...

Embodiment 3

[0055] 1. Preparation of compound 3

[0056] In a 250mL reaction flask, add compound 2 (3.72g, 38mmol) and 3.7g (30.6mmol) of anhydrous collidine mixed solution, 6.64g (76.4mmol) of lithium bromide in 80ml of methyl tert-butyl ether solution, control The temperature is from minus 40 degrees to minus 50 degrees, and 2.4ml (25.6mmol) of phosphorus bromide is added dropwise. After the addition is complete, the temperature is controlled at 0°C, the reaction is stirred for 2h, 4ml of collidine is added, and after quenching by adding water, Add n-pentane, extract the solution with n-pentane, wash the organic phase with water, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dry with anhydrous magnesium sulfate, evaporate excess solvent under reduced pressure to obtain crude product, slowly Add minus 40°C anhydrous zinc bromide (7.5g, 33.4mmol) in methyl tert-butyl ether solution (14ml), the reaction system is heated to 0°C, stirred for 1.5h, then n-pentane...

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Abstract

The invention discloses a method for preparing pentazocine intermediates, and belongs to the field of medicine synthesis. The method includes synthesizing chiral intermediates by the aid of simple synthesis processes; carrying out addition and hydrogenation debenzylation to obtain key intermediates (-)-(2S, [2a, 6a, 11S])-1, 2, 3, 4, 5, 6-hexahydrogen-cis-6, 11-dimethyl-2, 6-methylene-3-benzo azocines-8-alcohol. The method has the advantages that the method is low in cost and high in yield and includes simple processes, and the chiral purity of the pentazocine intermediates which are productsprepared by the aid of the method can reach 98%.

Description

Technical field [0001] The present invention relates to the field of drug synthesis, in particular to the preparation of (-)-(2S,[2a,6a,11S])-1,2,3,4,5,6-hexahydro-cis-6,11- A method for preparing dimethyl-2,6-methylene-3-benzoacrine-8-ol Background technique [0002] Pentazocine, the chemical name is (2R, 6R, 11R)-cis-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl- 2-Butenyl)-2,6-methylene-3-benzoacine-8-ol, its structure is as follows: [0003] [0004] Developed and marketed by the British Sterling Winslob Group in 1967, pentazocine is a derivative of benzomorphane, which has both agonistic and antagonistic effects on opioid receptors, and mainly stimulates opioid κ receptors. Larger doses can excite sigma receptors, and have partial or weak antagonistic effects on mu receptors. Pentazocine is suitable for the analgesia of moderate to severe pain, and has a wide range of clinical applications, such as intraoperative analgesia, postoperative analgesia, chronic pain treatment,...

Claims

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Application Information

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IPC IPC(8): C07D221/26C07D211/70
CPCC07B2200/07C07D211/70C07D221/26
Inventor李文森
OwnerHEADING NANJING PHARMTECH CO LTD