A kind of preparation method of pentazocine intermediate

A technology of pentazocine and its intermediates, which is applied in the field of chemical synthesis and can solve the problems of resource waste and low yield

Active Publication Date: 2021-04-23
HEADING NANJING PHARMTECH CO LTD
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Problems solved by technology

[0017] The main purpose of the present invention is in order to provide a kind of preparation method of pentazocine intermediate, solve the problem that the yield of current pentazocine preparation method is low and resource waste is high, obtain key intermediate by simple method, yield High efficiency, simple process, suitable for industrial production, saving resources and reducing production costs

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  • A kind of preparation method of pentazocine intermediate
  • A kind of preparation method of pentazocine intermediate
  • A kind of preparation method of pentazocine intermediate

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preparation example Construction

[0067] The preparation method of the pentazocine intermediate provided in this embodiment, the prepared pentazocine intermediate is shown in formula (1):

[0068]

[0069] The reaction equation of its preparation process is as shown in formula (2):

[0070]

[0071] Its preparation process comprises the following steps:

[0072] Step 1: Methylation reaction

[0073] Add potassium carbonate and methyl iodide to compound 1 in acetone medium, and react at 50°C to obtain compound 2. The molar ratio of compound 1 to methyl iodide is 1:1.3-1.5, and methyl iodide can also be dimethyl sulfate substitute;

[0074] Step 2: Ring opening reaction

[0075] Add concentrated hydrochloric acid and sodium chloride solution to compound 2, and react at 50°C to obtain compound 3, the molar ratio of compound 2 to hydrochloric acid is 1:2.0-2.5, wherein, concentrated hydrochloric acid can be one of phosphoric acid, sulfuric acid and nitric acid an alternative;

[0076] Step 3: Reduction ...

Embodiment 1

[0096]

[0097] Step 1: Add compound 1 (200g), acetone (2L) to a 3L four-neck flask, stir, add potassium carbonate (280.1g, 1.3eq), stir, then add methyl iodide (288.2g, 1.3eq), and heat up To 50°C (micro-reflux), keep warm for 16h, GC sampling detection: raw material <2%; Post-treatment: filter, wash the solid twice with a small amount of acetone (200ml), spin dry the acetone, add water (800ml) + ethyl acetate ( 800ml), stirred, left to stand for layering, the aqueous phase was extracted once with ethyl acetate (800ml), the organic phases were combined, the organic layer was washed once with saturated NaCl (600ml), dried over anhydrous sodium sulfate, and spin-dried to obtain 199g of liquid compound 2; Yield: 90%;

[0098]

[0099] Step 2: Add concentrated hydrochloric acid (286ml, 2.0eq) to compound 2 (200g, 1.0eq), then add 200ml of 15% NaCl solution, heat to 50 degrees to react, take a sample for about 4 hours, send the sample to GC, post-processing: direct distillat...

Embodiment 2

[0117] Step 1: Add compound 1 (2000g), acetone (20L) to a four-neck flask, stir, add potassium carbonate (2801g, 1.3eq), stir, then add methyl iodide (2883g, 1.3eq), and heat up to 50°C (Slight reflux), keep warm for 16h, GC sampling detection,; post-treatment: filter, wash the solid twice with a small amount of acetone (2000ml), spin dry the acetone, add water (8000ml)+ethyl acetate (8000ml), stir, let stand The layers were separated, the aqueous phase was extracted once with ethyl acetate (8000ml), the organic phases were combined, the organic layer was washed once with saturated NaCl (6000ml), dried over anhydrous sodium sulfate, and spin-dried to give 1997g of liquid compound 2; yield: 95% ;

[0118] Step 2: Compound 2 (400g, 1.0eq), add concentrated hydrochloric acid (500ml, 2.0eq), then add 400ml15% NaCl solution, heat to 50 degrees to react, take a sample for about 4h, send the sample to GC, post-processing: direct distillation reaction liquid, distilled water at norma...

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Abstract

The invention discloses a preparation method of a pentazocine intermediate, belonging to the technical field of chemical synthesis, through methylation reaction, ring-opening reaction, reduction reaction, protection reaction, substitution-reduction reaction, esterification reaction, elimination reaction, The hydrazinolysis reaction, the ring-closing reaction and the condensation-demethylation reaction give compound 11, which is the pentazocine intermediate prepared in the present invention. The present invention solves the problems of low yield and waste of resources in the current preparation method of pentazocine, and the current situation that it is difficult to industrialize production under conditions such as using explosive-producing substances and high pressure. The key intermediate is obtained by a simple method with high yield and excellent process. Simple, suitable for industrial production, saving resources and reducing production costs.

Description

technical field [0001] The invention relates to a preparation method of a pentazocine intermediate, which belongs to the technical field of chemical synthesis. Background technique [0002] Pentazocine, chemical name (2R,6R,11R)-cis-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl- 2-butenyl)-2,6-methylene-3-benzazocine-8-ol, its structure is as follows: [0003] [0004] Successfully developed and marketed by Stirling Winslob Group in 1967, pentazocine is a derivative of benzomorphinane, which has both agonistic and antagonistic effects on opioid receptors, mainly activating opioid κ receptors, Larger doses can stimulate σ receptors, and have partial agonistic or weaker antagonistic effects on μ receptors. Pentazocine is suitable for analgesia of moderate to severe pain, and has a wide range of clinical applications, such as auxiliary intraoperative analgesia, postoperative analgesia, chronic pain treatment, cancer pain treatment, etc. Oral pentazocine tablets are curr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/22
CPCC07D221/22
Inventor 李文森张文琦
Owner HEADING NANJING PHARMTECH CO LTD
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