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Preparation method of N-methyl-3-hydroxyl-3-(2-thienyl)-propylamine

A thienyl and methyl technology, applied in the field of duloxetine intermediate preparation, can solve the problems of large amount of methylamine or methylamine hydrochloride, complex operation, high cost, etc., and achieve easy industrial production and simple operation Easy operation and low pollution effect

Active Publication Date: 2013-07-24
浙江丽晶化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the above-mentioned preparation methods, the amount of methylamine or methylamine hydrochloride required by method one is too large, and cannot be recovered, which greatly increases the production cost; Long, complicated operation, demethylation is required, the cost is increased, and more toxic methyl chloride is produced; the Friedel-Crafts reaction yield in method 3 is too low (about 39%), and a chromatographic column is required for separation; method 4 requires a large amount of Sodium borohydride (more expensive) to reduce, increasing the cost

Method used

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  • Preparation method of N-methyl-3-hydroxyl-3-(2-thienyl)-propylamine
  • Preparation method of N-methyl-3-hydroxyl-3-(2-thienyl)-propylamine

Examples

Experimental program
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Effect test

Embodiment 1

[0036] At room temperature (25°C), add 50 g of potassium hydroxide to a 100 ml three-necked flask equipped with a vacuum distillation device and a stirrer, stir under reduced pressure, heat up to a molten state, and dissolve 1.5 g of the polymerization inhibitor catechol Dissolve in 50g of thiophene ethanol and start to add dropwise at 140°C, control the temperature at 160°C for about half an hour to complete the dropwise addition, distill under reduced pressure to 180°C, and dry the distillate over anhydrous magnesium sulfate to obtain a colorless or light yellow liquid. (Weighing 41g, GC relative purity 95%.)

[0037] Add 155.8g of 40% methylamine ethanol solution to a 500ml three-necked flask equipped with a reflux condenser, a stirrer, and a thermometer at room temperature, slowly add 59g of paraformaldehyde below 40°C under stirring, and add 41g of thiopheneethylene after dissolving. 3g, sodium bicarbonate 3g, heat up and reflux after adding, start to add 156g of 50% hydr...

Embodiment 2

[0040] At room temperature (25°C), add 100g of potassium hydroxide to a 100ml three-neck flask equipped with a vacuum distillation device and a stirrer, stir under reduced pressure, heat up to a molten state, and add 1.5g of the polymerization inhibitor catechol Dissolve in 50g of thiophene ethanol and start to add dropwise at 140°C, control the temperature at 160°C for about half an hour to complete the dropwise addition, distill under reduced pressure to 180°C, and dry the distillate over anhydrous magnesium sulfate to obtain a colorless or light yellow liquid. (Weighing 40g, GC relative purity 97%.)

[0041] Add 155.8g of 40% methylamine-methanol solution to a 500ml three-necked flask equipped with a reflux condenser, a stirrer and a thermometer at room temperature, slowly add 59g of paraformaldehyde below 40°C under stirring, add 40g of thiopheneethylene after dissolving, and add a catalyst 3g, sodium bicarbonate 3g, heat up and reflux after adding, start to add 156g of 50...

Embodiment 3

[0044] At room temperature (25°C), add 150g of potassium hydroxide to a 100ml three-necked flask equipped with a vacuum distillation device and a stirrer, stir under reduced pressure, heat up to a molten state, and add 1.5g of polymerization inhibitor catechol Dissolve in 50g of thiophene ethanol and start to add dropwise at 140°C, control the temperature at 160°C for about half an hour to complete the dropwise addition, distill under reduced pressure to 180°C, and dry the distillate over anhydrous magnesium sulfate to obtain a colorless or light yellow liquid. (Weighing 39g, GC relative purity 98%.)

[0045] Add 155.8g of 40% methylamine aqueous solution to a 500ml three-necked flask equipped with a reflux condenser, a stirrer, and a thermometer at room temperature, slowly add 59g of paraformaldehyde below 40°C under stirring, and add 40g of thiopheneethylene and 3g of catalyst after dissolution , sodium bicarbonate 3g, after the addition, the temperature was raised to 60°C, ...

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Abstract

The invention discloses a preparation method of N-methyl-3-hydroxyl-3-(2-thienyl)-propylamine, which belongs to the preparation technology of duloxetine intermediates. The preparation method comprises the following steps of: removing a molecule of water from thiophene alcohol through potassium hydroxide, carrying out reduced pressure distillation to obtain thiophene ethylene, then reacting thiophene ethylene with methanol or alcohol in a methanol or alcohol solvent under the catalysis action of an acid catalyst, dropwise adding hydrogen peroxide, standing still and layering to separate out an organic phase, and distilling to obtain 3-methylamino-1-(2-thienyl)-1-acetone; dissolving 3-methylamino-1-(2-thienyl)-1-acetone in acetic acid, reducing by using iron powder or zinc powder, putting into water for quenching, extracting by using an organic solvent, drying and concentrating to obtain high-purity N-methyl-3-hydroxyl-3-(2-thienyl)-propylamine. The preparation method has the advantages of short path, simple and practical operation, low time consumption, less waste, little pollution and easiness for industrial production.

Description

technical field [0001] The invention belongs to the preparation technology of duloxetine intermediates, and in particular relates to a preparation method of N-methyl-3-hydroxyl-3-(2-thienyl)-propylamine. Background technique [0002] N-methyl-3-hydroxy-3-(2-thienyl)-propylamine is an important intermediate for the synthesis of antidepressant drug duloxetine, and its structural formula is as (1). The literature reports the concentrated preparation method of this intermediate. [0003] [0004] 1. Mannich reaction of 2-acetylthiophene with methylamine hydrochloride or dimethylamine hydrochloride and paraformaldehyde to generate bis-[2-(2-thiophenoyl)-ethyl]amine or 3-dimethylamino-1 -(2-thienyl)-1-propanone, which is then reacted with a large excess of methylamine or methylamine hydrochloride to generate 3-methylamino-1-(2-thienyl)-1-propanone, which is hydroborated Reduction with sodium gives N-methyl-3-hydroxy-3-(2-thienyl)-propylamine. [CA: 2513542; J. Amer.chem. Soc.,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20
Inventor 吕东梁建明潘发金
Owner 浙江丽晶化学有限公司