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Synthesis method for 3-[(1R, 2R)-3-( dimethylamino)-1-ethyl-2-methylpropyl] phenol

A methylpropyl and dimethylamino technology is applied in the field of synthesis of 3-[-3--1-ethyl-2-methylpropyl]phenol, which can solve the problem of increasing the difficulty of industrialized production and the expensive raw materials and other problems, to achieve the effect of high splitting efficiency, simple method and high yield

Active Publication Date: 2014-09-03
HEFEI NEWSTAR PHARMA & CHEM
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Problems solved by technology

[0012] CN102002065A (preparation method of tapentadol and its intermediate) provides a new method for preparing tapentadol hydrochloride, which uses 3-tert-butyldimethylsilyloxybenzaldehyde as the starting material , under the catalysis of R-proline, it undergoes Aldol condensation reaction with propionaldehyde to obtain (2R,3S)-3-hydroxyl-2-methyl-3-(3-tert-butyldimethylsilyloxyphenyl) Propionaldehyde, the compound reacts with dimethylamine hydrochloride to obtain (1S, 2S)-3-(dimethylamino)-2-methyl-1-(3-tert-butyldimethylsilyloxybenzene base)-1-propanol, the obtained compound is reacted with p-toluenesulfonyl chloride to obtain (1S, 2S)-3-(dimethylamino)-2-methyl-1-(3-tert-butyldimethyl Siloxyphenyl) propyl-4-tosylate, and then Grignard reaction to obtain (2R, 3R)-3-(3-tert-butyldimethylsilyloxyphenyl)-2-methyl Amyl-N, N-dimethylamine, and finally tapentadol is obtained through deprotection of trifluoroacetic acid. The starting material of this reaction, 3-tert-butyldimethylsilyloxybenzaldehyde, is not currently commercially available. In the reaction process, harsh conditions such as Grignard reaction are used, which increases the difficulty of industrial production
[0025] In summary, most of the current methods for synthesizing tapentadol use harsh conditions such as Grignard reaction and high-pressure hydrogenation, and use expensive raw materials

Method used

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  • Synthesis method for 3-[(1R, 2R)-3-( dimethylamino)-1-ethyl-2-methylpropyl] phenol
  • Synthesis method for 3-[(1R, 2R)-3-( dimethylamino)-1-ethyl-2-methylpropyl] phenol
  • Synthesis method for 3-[(1R, 2R)-3-( dimethylamino)-1-ethyl-2-methylpropyl] phenol

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Embodiment 1

[0067] (2R, 3R)-3-(3-methoxyphenyl)-2-methylpentanoic acid (Ⅲ) preparation: 3-(3-methoxyphenyl)-2-methylpentanoic acid ( 70g, 0.315mol) (the preparation method of 3-(3-methoxyphenyl)-2-methylpentanoic acid is the same as CN 102557851A) and 400mL methyl tert-butyl ether were added to the reaction flask, and R -(+)-α-(α-naphthyl)ethylamine (cas: 3886-70-2; 27g, 0.158mol), heat (60~70℃) and stir to dissolve, then let cool (10~20℃) Crystallize, filter with suction, wash the filter cake with a small amount of methyl tert-butyl ether, dissolve the obtained solid in water, adjust the pH value to about 14 with 1mol / L sodium hydroxide, extract with ethyl acetate (100mL×2), separate the water layer, the aqueous layer was adjusted to pH 1-2 with dilute hydrochloric acid, extracted with ethyl acetate (100mL×2), the ethyl acetate layer was washed twice with water, dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and the separation steps were repeated ...

Embodiment 2

[0071] (2R, 3R)-3-(3-methoxyphenyl)-2-methylpentanoic acid (III): 3-(3-methoxyphenyl)-2-methylpentanoic acid ( 70g, 0.315mol) and 400mL of isopropyl ether were added to the reaction flask, and R-(+)-α-methylbenzylamine (cas: 3886-69-9; 19.1g, 0.158mol) was added in batches, heated (60 ~70°C) after stirring to dissolve, let cool (10~20°C) to crystallize, filter with suction, wash the filter cake with a small amount of isopropyl ether, add water to dissolve the obtained solid, adjust the pH value to about 14 with 1mol / L sodium hydroxide , extracted with ethyl acetate (100mL×2), separated the aqueous layer, adjusted the pH value of the aqueous layer to 1-2 with dilute hydrochloric acid, extracted with ethyl acetate (100mL×2), washed the ethyl acetate layer twice with water, and anhydrous Magnesium sulfate was dried, concentrated under reduced pressure to dryness, and the splitting step was repeated twice to obtain 12.6g light yellow oil (2R, 3R)-3-(3-methoxyphenyl)-2-methylpentan...

Embodiment 3

[0073] (2R, 3R)-3-(3-methoxyphenyl)-2-methylpentanoic acid (III): 3-(3-methoxyphenyl)-2-methylpentanoic acid ( 70g, 0.315mol) and 400mL of acetonitrile were added to the reaction flask, and R-(+)-N-benzyl-α-phenethylamine (cas: 38235-77-7; 33.3g, 0.158mol) was added in batches, heated (60-70°C) stir to dissolve, let cool (10-20°C) to crystallize, filter with suction, wash the filter cake with a small amount of acetonitrile, add water to dissolve the obtained solid, adjust the pH value to about 14 with 1mol / L sodium hydroxide , extracted with ethyl acetate (100mL×2), separated the aqueous layer, adjusted the pH value of the aqueous layer to 1-2 with dilute hydrochloric acid, extracted with ethyl acetate (100mL×2), washed the ethyl acetate layer twice with water, and anhydrous Magnesium sulfate was dried, concentrated to dryness under reduced pressure, and the splitting step was repeated twice to obtain 11.7g light yellow oil (2R, 3R)-3-(3-methoxyphenyl)-2-methylpentanoic acid (...

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Abstract

The invention provides a synthesis method for 3-[(1R, 2R)-3-( dimethylamino)-1-ethyl-2-methylpropyl] phenol. The 3-[(1R, 2R)-3-( dimethylamino)-1-ethyl-2-methylpropyl] phenol is obtained by performing steps such as resolution, halogenation, amidation, reduction and demethylation on 3-(3-methoxyphenyl)-2-mevalonic acid serving as a starting raw material. The method has the advantages of mild reaction conditions, easiness and convenience in operation, capability of greatly reducing the production cost and high suitability for industrial production. According to the method, high-purity tapentadol can be obtained, the liquid phase purity of tapentadol hydrochloride obtained after salification reaches 99.8 percent, ee (enantiomeric excess) percent is greater than 99.5 percent, and the tapentadol can be directly applied to the field of medicines.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of 3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol. Background technique [0002] 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol (structure shown in formula (I)), also known as tapentadol, It is a new type of central analgesic drug developed by Johnson & Johnson Company of the United States, which has dual action modes of mu opioid receptor (MOR) agonism and norepinephrine (Norepinephrine, NE) reabsorption inhibition (Tzschentke TM, et al ., J.Pharm.Exper.Therap., 2007, 323, 265). On January 23, 2008, the U.S. FDA accepted the new drug listing application for tapentadol hydrochloride immediate-release tablets, which was approved by the U.S. FDA on November 21, 2008. It is clinically used to relieve moderate to severe acute pain in the central nervous system of adults the treatment. [0003] [0004] Tapentadol belongs ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/54C07C213/00
Inventor 徐自奥赵永海李德刚李晓祥
Owner HEFEI NEWSTAR PHARMA & CHEM
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