Preparation method for Rivastigmine midbody 3-hydroxyl-alpha-N, N-dimethyl phenylethylamine

A technology of dimethylphenethylamine and hydroxyacetophenone, which is applied in the field of drug synthesis, can solve problems such as long reaction time, consumption, and influence on product yield and quality, and achieve simple methods, high product purity, and low reaction pollution little effect

Inactive Publication Date: 2009-01-14
SHANGHAI ZHONGXI SUNVE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its disadvantage is that NaBH 4 It is more expensive and difficult to operate, and it will produce a lot of foam when adding materials, which is more dangerous; while demethylation adopts high concentration, long-term high-temperature reaction (145°C) and it is easy to produce by-products, which will affect the yield and quality of the product
The demethylation reaction disclosed in WO 2003 / 101917 uses methionine and sulfuric acid to form a demethylation reagent. The disadvantage is that the reaction time is long, up to 28 hours, and a large amount of methionine is consumed.

Method used

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  • Preparation method for Rivastigmine midbody 3-hydroxyl-alpha-N, N-dimethyl phenylethylamine
  • Preparation method for Rivastigmine midbody 3-hydroxyl-alpha-N, N-dimethyl phenylethylamine
  • Preparation method for Rivastigmine midbody 3-hydroxyl-alpha-N, N-dimethyl phenylethylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1 Preparation of 3-benzyloxyacetophenone (III)

[0017] In a 500ml dry reaction flask, put 50g (0.37mol) of m-hydroxyacetophenone, 300g of DMF and 101.4g (0.73mol) of potassium carbonate, stir, add 60g (0.47mol) of benzyl chloride dropwise, raise the temperature to 70°C, and keep it warm for 2 hours , DMF was recovered under reduced pressure, an appropriate amount of water was added, and extracted with toluene, the aqueous layer and the organic layer were recovered to exhaust the solvent, and 82.5 g of the product was obtained. Yield: 99.28%,. h 1 NMR (δ2.5, s 3H; δ5.05, s 2H; δ7.1-7.69H)

Embodiment 2

[0018] Example 2 Preparation of 3-benzyloxy-α-N, N-dimethylaminophenethylamine (IV)

[0019] In a 1000ml dry reaction bottle, put 250g of absolute ethanol into it, cool it to about 0°C with an ice bath, pass through 60g of dimethylamine, and 2 Under protective condition, drip tetraisopropoxytitanium 190g (0.67mol), then add m-benzyloxyacetophenone 83g (0.37mol) that embodiment 1 makes, keep warm at room temperature for 10 hours, slowly add potassium borohydride, keep warm After 12 hours, add ammonia water, filter, and concentrate the filtrate under reduced pressure, add hydrochloric acid to the residue to make it acidic, extract with toluene, and adjust the pH of the water layer with NaOH solution to 12-14, extract with toluene again, and separate the water layer , and the toluene layer was concentrated under reduced pressure to obtain 80 g of light yellow oil. Yield: 85.42%, H 1 NMR (δ1.3, d3H; δ2.08, s 6H; δ3.1 1H; δ5.0 2H; δ6.8-7.5 9H)

Embodiment 3

[0020] Example 3 3-Hydroxy-α-N, the preparation of N-dimethylphenethylamine (I)

[0021] In a 1000ml dry reaction flask, drop into 700g ethanol, 80g of the product obtained in Example 2, stir and add dropwise 38% 40g hydrochloric acid and 5g palladium-carbon, under normal pressure, feed hydrogen for 6 hours, temperature 35~ 40°C, stop hydrogen flow, filter, concentrate the ethanol to the filtrate under reduced pressure, add 100ml of water, adjust the pH to 9.5 with 10% NaOH, add toluene, separate layers, combine the toluene layers, concentrate the toluene under reduced pressure, and cool the residue to crystallize. Filter and dry to obtain 42 g of light yellow solid. Yield: 81.1%, H 1 NMR (δ 1.4, d 3H; δ 2.21, s 6H; δ 3.3 1H; δ 6.7-7.2 3H). The content detected by HPLC was 99.20%.

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Abstract

The invention relates to a preparation method of an intermediate (R, S)3-oxhydryl-Alpha-N, N-phenpromethamine of rivastigmine. The method takes 3-hydroxyl acetophenone as a raw material, and prepares the target product under the protection of oxhydryl, amination and reduction of carbonyl, and after the dehydroxylation protecting group reaction. The method has advantages of easy taking of materials, simple operation and high product purity.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a preparation method of rivastigmine intermediate (R, S) 3-hydroxyl-α-N, N-dimethylphenethylamine. Background technique [0002] Rivastigmine, also known as rivastigmine tartrate and exelon, is an oral long-acting central AchE inhibitor and an effective drug for the treatment of senile dementia. There are many reports about the synthesis of rivastigmine, wherein m-methoxyacetophenone is used as a starting material to prepare an intermediate for resolution. The resolution agent is cheap and easy to obtain, and the overall cost is low. [0003] [0004] 3-Hydroxy-α-N, N-dimethylphenethylamine (compound I) is the key intermediate in the above route. [0005] WO 2004 / 037771 discloses the use of m-methoxyacetophenone as a starting material to obtain (R, S)-3-hydroxyl-α-N, N-dimethylphenethyl through amination, reduction, and demethylation reactions The method of amine, its synth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/52C07C213/02
CPCY02P20/55
Inventor 李庆毅许大侯金虎
Owner SHANGHAI ZHONGXI SUNVE PHARMA
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