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Rivastigmine intermediate preparation

An intermediate, the technology of tetraisopropyl titanate, which is applied in the field of preparation of rivastigmine intermediate, can solve the problems of high production cost, low yield, large loss, etc., and achieve low cost, high yield and simple reaction route short effect

Inactive Publication Date: 2009-07-15
SHANGHAI INST OF PHARMA IND +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

DE3805744 reported that rivastigmine was obtained by splitting epispinned rivastigmine with D-DTTA; GB2203040 and WO2005061446 reported in more detail that rivastigmine was obtained by splitting epispinned rivastigmine with D-DTTA. method, but to obtain high-purity rivastigmine requires multiple crystallizations, the yield is only 4.4%; WO20060122417 reported the resolution of 3-(1-aminoethyl)phenol with D(+)-10-camphorsulfonic acid After further preparation of rivastigmine; Bull.Chem.Soc.Jpn., 66,3414-3418 reported further preparation of rivastigmine after the resolution of 1-(3-methoxyphenyl)ethylamine with (S) mandelic acid ; Although the method of splitting is simple and easy, the loss is huge and the yield is low
[0004] WO2007104359 reports the asymmetric synthesis of 3-((S)-1-((S)-1-phenethylamino)ethyl)phenylethyl(methyl)carbamate ( The structural formula is the following formula 1), but it is only a preparation method contained in the general formula, and there is no specific synthetic route and special examples to specifically illustrate its synthetic method
And said synthetic method uses more expensive ytterbium formula Lewis acid, and the production cost is high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Example 1: Preparation of 3-((S)-1-((S)-1-phenethylamino) ethyl) phenylethyl (methyl) carbamate (compound 1)

[0015] In the reactor, drop into 3-acetylphenylethyl (methyl) carbamate 10g (0.05mol), (S)-1-phenethylamine 5.5g (0.05mol), tetraisopropyl titanate 19g ( 0.07mol) and 85ml of ethyl acetate were stirred and reacted at 30°C for 2 hours, 0.5g of 10% palladium carbon was added, hydrogen was passed, and the reaction was carried out at 65°C and 15 atm for 15 hours. TLC monitored that the reaction of compound 1 was complete, cooled and filtered, and poured into the mother liquor Add 100ml of 1N sodium hydroxide solution and stir at room temperature for 1 hour, filter with suction, separate the mother liquor, extract the water layer with 50ml of ethyl acetate x 2 times, combine the ethyl acetate layers, wash with 80ml of saturated saline x 3 times, and anhydrous After drying with sodium sulfate, it was filtered and spin-dried to obtain 13.5 g of a yellow clear liquid w...

Embodiment 2—19

[0017] The specific operation is the same as in Example 1, and the optimized conditions and results are shown in the following tables 1-5.

[0018] Table 1: Effect of Catalyst on Reaction

[0019] Example catalyst Dosage (w / w, %) ee(%) Yield (%) 1 10%Pd / C 1% of substrate 98.2 92.0 2 10%Pd / C 0.5% of substrate 98.0 93.5 3 Raney-Ni(w 2 type, wet product) 50% of substrate 90.2 86.5 4 Raney-Ni (homemade * , wet product) 50% of substrate 92.1 90.6

[0020] * Prepared according to JP44008988. In the present invention, under the same conditions, the reaction time with Raney-Ni is about 4 times longer than that with 10% Pd / C.

[0021] Table 2: Influence of solvents on reactions

[0022] Example solvent ee(%) Yield (%) 5 EtO 98.0 92.0 6 CH 3 Oh 92.5 95.0 7 THF 83.4 81.3 8 CH 3 OH / THF 87.6 91.2

[0023] Table 3: Ti(O i Pr) 4 Effect of Dosage on Response *

[0024] ...

Embodiment 19

[0032] Add 10g (0.03mol) of compound (1) and 100ml of methanol into the reactor, add 0.5g of 10% palladium carbon, stir and pass hydrogen, react at 65°C and 15atm for 8 hours, TLC monitors that compound (1) has reacted completely, and cools Suction filtration, the mother liquor was spin-dried at 40°C, added 100ml of 10% potassium carbonate solution and stirred at room temperature for 1 hour, extracted with 50ml of ethyl acetate x 4 times, combined the ethyl acetate layers, washed with 50ml of saturated brine x 3 times, no After drying with sodium sulfate, the product was filtered and spin-dried to obtain 6.7 g of a yellow clear liquid with a yield of 98.5%.

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Abstract

The invention belongs to the technical field of a method for preparing Rivastigmine intermediate. As is shown above, the Rivastigmine intermediate is obtained by causing the following formula to react with chiral amine under catalysis of tetraisopropyl titanate and then carrying out catalytic hydrogenation. In the method, 3-((S)-1- ((S)-1-phenethylamine group) ethide) phenylethyl (methyl) carbamate is obtained under the catalysis of the tetraisopropyl titanate. As the price of the tetraisopropyl titanate is 10% of the price of the currently used ytterbium acetate, the cost advantage is obvious. In addition, the method has the advantages of simple operation, low cost and high purity and yield of the obtained isomer. By adopting the intermediate to synthesize the Rivastigmine, the reaction route is short and the yield is high; the intermediate is the key intermediate for synthesizing the Rivastigmine.

Description

technical field [0001] The invention belongs to the technical field of the preparation method of intermediate 3-((S)-1-((S)-1-phenethylamino) ethyl) phenylethyl (methyl) carbamate of rivastigmine . Background technique [0002] Rivastigmine bitartrate is a second-generation selective central, reversible, long-acting non-competitive inhibitor of acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) developed by Novartis. It is suitable for treating mild and moderate Alzheimer's dementia (AD), and can be used for treating mild and moderate Parkinson's dementia. It has a more significant curative effect on patients with advanced severe AD, and is currently internationally recognized and the highest-rated drug for improving symptoms of Alzheimer's dementia. With the aging of the global population, the number of patients with senile dementia is also increasing rapidly. The market for this drug is huge. However, due to the high production cost of this drug, the final mark...

Claims

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Application Information

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IPC IPC(8): C07C271/44C07C269/06B01J31/12
Inventor 袁哲东王强沈裕辉俞雄
Owner SHANGHAI INST OF PHARMA IND
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