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Method for preparing pentazocine intermediate

A technology of pentazocine and intermediates, which is applied in the field of drug synthesis, can solve the problems of difficult industrial production and low yield, and achieve the effects of short synthesis route, simple operation and high safety factor

Active Publication Date: 2021-02-12
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, the synthetic route of pentazocine uses conditions such as high pressure, the yield is low, and it is difficult to produce industrially

Method used

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  • Method for preparing pentazocine intermediate
  • Method for preparing pentazocine intermediate
  • Method for preparing pentazocine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Synthesis of Compound II

[0057]

[0058] In a 1L three-neck flask, add compound I (53g, 1.0eq), acetone 500mL, K 2 CO 3 (63g, 1.0eq), stirred at room temperature for 10-15min, added dropwise CH 3 I (64.8g, 1.0eq), no obvious exotherm, after dropping, add water (16.4g, 2.0eq) and react overnight at room temperature.

[0059] Post-treatment: Suction filtration, vacuum spin-drying of the filtrate, adding 100mL of water, 200mL of methyl tert-butyl ether (MTBE), stirring, liquid separation, extraction of the aqueous phase with 100mL of methyl tert-butyl ether (MTBE) once, combined organic phase, washed once with water, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to obtain 53g of crude compound II, which was distilled under reduced pressure (oil pump), with an external temperature of 50°C and a top temperature of 34-36°C to obtain 40.6 g of compound II, yield 76%. Compound II 1 H NMR spectrum see figure 1 , see th...

Embodiment 2

[0089] Synthesis of Compound II

[0090]

[0091] In a 100mL three-necked flask, add compound I (5g, 1.0eq), acetone 50mL, K2CO3 (6.37g, 1.2eq), stir at room temperature for 10min, add dimethyl sulfate (5.33g, 1.1eq) dropwise, without obvious exotherm, After dropping, the temperature was raised to reflux for 2 hours.

[0092] Post-processing: suction filtration, vacuum spin-drying of the filtrate, adding water and MTBE, stirring, liquid separation, extracting the aqueous phase once with MTBE, combining the organic phase, washing once with water, washing once with saturated sodium chloride, and drying over anhydrous sodium sulfate , spin-dried to obtain 2 g of the crude product of compound II, and the yield was 36%.

[0093] Synthesis of Compound III

[0094]

[0095] Potassium tert-butoxide (1eq), DMF (3V), add II (4g, 1eq) dissolved in DMF (2V) dropwise at about 0°C, add dropwise for 0.5h, keep warm for 0.5h, then add ethyl chloroacetate (1eq ), added dropwise for 0....

Embodiment 3

[0121] Add compound I (200g, 1.72 mol, 1.0eq), acetone 1500mL, K 2 CO 3 (238g, 1.72mol, 1.0eq), stirred at room temperature for 10-15min, added dropwise CH 3 I (244.5 g, 1.72 mol, 1.0 eq), CH was added dropwise 3 During the I process, there was no obvious exothermic reaction, and the reaction was carried out overnight at room temperature after the drop was completed. Detected by gas chromatography, it was found that the raw material compound I remained 19%, and the conversion of the raw material was incomplete. The temperature was raised to 35-40° C., and the reaction was continued for 3 hours, and detected by gas chromatography, it was found that 15% of the raw material compound I remained. Add 25g CH 3 I continued to react for 3 hours, and detected by gas chromatography, it was found that the raw material compound I still had about 15% remaining. Add 36g K 2 CO 3 And 400mL acetone, continue to react overnight. Next morning, by gas chromatographic detection, it was fo...

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Abstract

The invention belongs to the technical field of chemical synthesis, and provides a method for preparing a pentazocine intermediate, which comprises the following steps: by using low-price methyl acetoacetate as a raw material, carrying out methylation, methoxyformylation and removal of one methoxyformyl group, reducing by using a reducing agent, and reacting the reduction product with alkyl sulfonyl chloride to obtain the pentazocine intermediate; generating a compound with a dialkyl sulfonyl group; reacting a compound with dialkyl sulfonyl with phthalimide potassium salt, removing one alkyl sulfonyl, and grafting phthalimide; carrying out dehydrogenation reaction on the phthalimido product under an alkaline condition to generate a vinyl compound, and reacting the vinyl compound with hydrazine hydrate to obtain the pentazocine intermediate. Cheap compounds are used as initial raw materials, the whole route avoids high-pressure and high-temperature dangerous reactions, and industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing a pentazocine intermediate. Background technique [0002] Pentazocine was successfully developed and marketed in 1967 by the British Stirling Winslob Group. Pentazocine is a derivative of benzomorphinane, which has mixed agonistic and antagonistic effects on opioid receptors, mainly activating opioid κ receptors, and can activate σ receptors in larger doses, and has partial activating effects on μ receptors or weaker antagonism. Pentazocine is suitable for the analgesia of moderate to severe pain and has a wide range of clinical applications. For example, intraoperative auxiliary analgesia, postoperative analgesia, chronic pain treatment, cancer pain treatment, etc. are applicable. Oral pentazocine tablets are currently the only orally available opioid receptor agonist antagonist analgesics. [0003] Existing methods for the preparati...

Claims

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Application Information

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IPC IPC(8): C07C209/28C07C211/21C07D209/48C07C303/28C07C309/65C07C29/147C07C31/20C07C67/343C07C67/32C07C69/716
CPCC07C29/147C07C67/32C07C67/343C07C209/28C07C303/28C07D209/48C07C69/716C07C31/20C07C309/65C07C211/21
Inventor 李文森张文琦田雷
Owner HEADING NANJING PHARMTECH CO LTD
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