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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, high production cost, etc., achieve cheap raw materials and increase yield , cost reduction effect
Active Publication Date: 2013-05-22
SHANGAI PHARMA GRP CO LTD
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[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.
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Embodiment 1
[0040] Embodiment 1 (S)-m-benzyloxy-α, the preparation of N-dimethylbenzylamine (III)
[0041] 30.7g of L-tartaric acid, (RS) m-benzyloxy-α, 49.3g of N-dimethylbenzylamine, 320ml of ethanol, stirred and refluxed for 1 hour, cooled to room temperature, left standing overnight, precipitated crystals, filtered to obtain a crude product, Recrystallize from ethanol to obtain 24.2g of salt, add 100ml of water, adjust the pH to >10 with 30% NaOH solution, extract with toluene, dry with anhydroussodiumsulfate, and evaporate the solvent to obtain 14.9g of residual solution[α] D -42° (C, 5, MeOH), optical purity >99% e.e., 60.5% of theoretical yield.
[0044] Example 1 Split the mother liquor, recover ethanol under normal pressure, add 30% NaOH solution to make pH > 10, extract with petroleumether or ethyl acetate, wash with saturated NaCl solution, anhydrous NaCl 2 SO 4After 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 petroleumether or ethyl acetate, wash with saturated NaCl solution, dry over anhydroussodiumsulfate, evaporate the solvent to obtain (RS) m-benzyloxy-α, N-dimethylbenzylamine 30.2g, [α] D 0.00-0.03° (C, 5, MeOH), recovery rate 96.8%, content 98.6% (GC), for resolution and application.
Embodiment 3
[0045] The preparation of embodiment 3 (S)-3-(1-dimethylaminoethyl)phenol (I)
[0046] (S)-m-benzyloxy-α, N-dimethylbenzylamine 35g, 38% formaldehyde solution 18.34g, methanol 630ml, Reyes nickel 17.5ml, hydrogen under room temperature and pressure for amine methylation, while hydrogen 23.5 g of the product was obtained by removing the benzyl group, with a yield of 98%, recrystallized from ethanol, m.p.118-119°C, [α] D -55° (C, 5, EtOH), optical purity >99% e.e.
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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 a key intermediate (S)-3-(1-dimethylaminoethyl)phenol of rivastigmine, a medicine for treating Alzheimer's disease. Background technique [0002] Rivastigmine is an oral long-acting central AchE inhibitor, which is an effective drug for the treatment of senile dementia. The present inventor disclosed in Chinese patent ZL03141995X that taking optically active (S)-3-(1-dimethylaminoethyl)phenol as a raw material and ethyl methylcarbamoyl chloride for esterification to prepare rivastigmine Technology. [0003] There are many reports on the synthesis of (S)-3-(1-dimethylaminoethyl)phenol, mainly focusing on two approaches: chiral-induced asymmetric synthesis and optical resolution. [0004] 1. Chiral-induced asymmetric synthesis [0005] (1) Reported by Tetrahedron Lett 1991, 32(49): 7175 [0006] Using m-acetoxy acetophenone as raw material (see formula below), i...
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