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(S)-3-(1-dimethylaminoethyl)phenol preparation method

A technology of dimethylaminoethyl and dimethylbenzylamine, which is applied in the field of drug synthesis, can solve the problems of non-reuse of R-enantiomer, large loss of raw materials, and high production cost, so as to achieve cheap raw materials and increase yield , cost reduction effect

Active Publication Date: 2009-12-30
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The above-mentioned optical resolution method still has the technical obstacle of low yield, or the defect that the R-enantiomer is not reused after the resolution, resulting in large loss of raw materials and high production cost.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of (S)-m-benzyloxy-α,N-dimethylbenzylamine (III)

[0041] 30.7g of L-tartaric acid, 49.3g of (RS) m-benzyloxy-α,N-dimethylbenzylamine, 320ml of ethanol, stirring and refluxing for 1 hour, cooling to room temperature, standing overnight, precipitation of crystals, and filtration to obtain a crude product. Recrystallize from ethanol to obtain 24.2g of salt, add 100ml of water, adjust pH>10 with 30% NaOH solution, extract with toluene, dry with anhydrous sodium sulfate and evaporate the solvent to obtain 14.9g of residual liquid [α] D -42° (C, 5, MeOH), optical purity>99% e.e., 60.5% of theoretical yield.

[0042] 1 HNMR(CD 3 OD): δ 1.27 (d, 3H), 2.12 (s, 3H), 3.52 (q, 1H), 5.00 (s, 2H), 6.79-6.83 (m, 2H), 6.90-6.91 (t, 1H) ,7.14-7.39 (m, 6H).

Embodiment 2

[0043] Example 2 Resolution of mother liquor, recovery and racemization to prepare (RS) m-benzyloxy-α,N-dimethylbenzylamine (II)

[0044] Example 1 After the resolution of the mother liquor, after recovering ethanol under normal pressure, add 30% NaOH solution to make the pH>10, extract with petroleum ether or ethyl acetate, wash with saturated NaCl solution, anhydrous Na 2 SO 4 After drying, the solvent was recovered to obtain 31 g of residual liquid. Add 24ml of DMSO or toluene, 2.2g of potassium tert-butoxide, and react at 100°C for 2.5 hours. Recover the solvent, extract with petroleum ether or ethyl acetate, wash with saturated NaCl solution, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain (RS) m-benzyloxy-α,N-dimethylbenzylamine 30.2g, [α] D0.00-0.03° (C, 5, MeOH), the recovery rate is 96.8%, the content is 98.6% (GC), which can be used for resolution.

Embodiment 3

[0045] Example 3 Preparation of (S)-3-(1-dimethylaminoethyl)phenol (I)

[0046] (S)-m-benzyloxy-α,N-dimethylbenzylamine 35g, 38% formaldehyde solution 18.34g, methanol 630ml, Reynolds nickel 17.5ml, hydrogenation at room temperature and atmospheric pressure for amine methylation, while hydrogen The benzyl group is decomposed to obtain 23.5g of product, the yield is 98%, recrystallized from ethanol, mp118-119℃, [α] D -55°(C, 5, EtOH), optical purity>99% e.e.

[0047] 1 HNMR(CDCl 3 ): δ 1.39(d, 3H), 2.23(s, 6H), 3.31(q, 1H), 6.72(d, 1H), 6.77(s, 1H), 6.78(d, 1H), 7.12-7.15( t, 1H), 7.5(br, 1H).

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Abstract

The invention relates to a preparation method of key intermediate (S)-3-(1-dimethylaminoethyl)phenol of Rivastigmin for curing presenile dementia, comprising the following steps: adopting (RS)m-benzyloxy-alpha,N-dimethyl benzylamine as raw material and L-(+)-tartaric acid as resolving agent to obtain (S)m-benzyloxy-alpha,N-dimethyl benzylamine, and finally obtaining the target product (S)-3-(1-dimethylaminoethyl)phenol in the presence of aldehyde solution and Raney nickel in alcoholic solution through aminomethylation and hydrogenation by which benzyl can be removed; meanwhile, (R)m-benzyloxy-alpha,N-dimethyl benzylamine and partial (S)m-benzyloxy-alpha,N-dimethyl benzylamine in the separated mother solution are recycled and after racemizing the recycled materials in the present of basic catalyst, (RS)m-benzyloxy-alpha,N-dimethyl benzylamine can be obtained to be used as raw material for repeatedly use and separation. The method of the invention has simple process and cheap raw materials; the separated R-enantiomer can be recycled after the racemization, and compared with the prior art, the yield is greatly improved and the cost is reduced so that the preparation method is applicable to the industrial production.

Description

Technical field [0001] The invention relates to the field of drug synthesis, in particular to the preparation of (S)-3-(1-dimethylaminoethyl)phenol, a key intermediate (S)-3-(1-dimethylaminoethyl)phenol, a drug for the treatment of Alzheimer's disease. Background technique [0002] Rivastigmine is an oral long-acting central AchE inhibitor and an effective drug for the treatment of senile dementia. The inventor discloses in Chinese patent ZL03141995X that optically active (S)-3-(1-dimethylaminoethyl)phenol is used as a raw material and ethylmethylcarbamoyl chloride is esterified to prepare rivastigmine Technology. [0003] There are many reports on the synthesis of (S)-3-(1-dimethylaminoethyl)phenol, mainly focusing on the two ways of chirality-induced asymmetric synthesis and optical resolution. [0004] 1. Chirality induces asymmetric synthesis [0005] (1) Tetrahedron Lett 1991, 32(49): 7175 report [0006] Using m-acetoxyacetophenone as the raw material (see the following for...

Claims

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Application Information

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IPC IPC(8): C07C215/50C07C213/00C07B57/00
Inventor 周宁许杏祥周智善
Owner SHANGAI PHARMA GRP CO LTD
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