Chiral synthesis method of ephedrine key intermediate (S)-2-methylamino-1-phenyl-1-acetone

A technology of chiral synthesis and methylamine group, which is applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds. It can solve the problems of not obtaining products, complexity, etc., and achieve improved yield and purity, simplified operations, and Avoid the effect of splitting the course of action

Active Publication Date: 2021-04-13
ZHEJIANG APELOA KANGYU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The author tried various conditions in an attempt to make S-bromide (8) and sodium azide pass through SN 2 The reaction affords the azide R-(9), however, none of the desired products are obtained, or only a set of complex mixtures are obtained

Method used

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  • Chiral synthesis method of ephedrine key intermediate (S)-2-methylamino-1-phenyl-1-acetone
  • Chiral synthesis method of ephedrine key intermediate (S)-2-methylamino-1-phenyl-1-acetone
  • Chiral synthesis method of ephedrine key intermediate (S)-2-methylamino-1-phenyl-1-acetone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The first step reaction: chiral ketalization of the α-position carbonyl of propiophenone

[0046]

[0047] Propiophenone (125mmol), (2S,3S)-(-)-bismethyl tartrate diester (130mmol) and trimethyl orthoformate (250mmol) were mixed and heated to 50°C, then methanesulfonic acid (8mmol) was added . Incubate at 95°C for five days. The post-processing process was completed with reference to J.Chem, Soc.Perkin Trans, I.2759-2765 (2000). Obtain 35 g of oily product (4), with a yield of 95%.

Embodiment 2

[0049] The second step reaction: α-stereoselective bromination of ketal (4)

[0050]

[0051] Ketal (4) (170mmol) was dissolved in 260ml of 1,2-dichloroethane, then cooled to -10°C. Bromine (28.5g, 176mmol) was dissolved in 48mL of 1,2-dichloroethane, and slowly added dropwise to the 1,2-dichloroethane reaction liquid in (4) above, and the post-treatment was completed according to the method provided in the above-mentioned literature . 61.3 g of (4S,5S)-2-[(R)-1-bromoethyl]-2-phenyl-1,3-dioxyethane-4,5-dicarboxylate (2a) was obtained. The ratio is 97%, and the de value of R / S is 93%.

Embodiment 3

[0053] The third step reaction: Walden SN of bromide (2a) 2 Inversion, chiral preparation of methylamine (3a) (absorption of HBr with excess methylamine)

[0054]

[0055] Bromide (2a) (44.8g, 120mmol) was dissolved in anhydrous acetonitrile (447ml), cooled to -15°C with dry ice acetone solution, and the anhydrous dried methylamine gas was slowly passed into the reaction vessel until the solution increased in weight It is 7.5g, that is, the weight of methylamine is 242mmol. Close the reactor, then slowly raise the temperature to 20-30°C, and keep it warm for 14 hours. After the reaction was completed, the reactor was opened to release the pressure. Acetonitrile was distilled off under reduced pressure. 300 ml of dichloromethane was added to the residue, and the layers were washed with water three times (80 ml of water each time) to remove the methylammonium salt of hydrogen bromide. The separated dichloromethane solution was dried over anhydrous magnesium sulfate, and t...

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Abstract

The invention discloses a chiral synthesis method of an ephedrine key intermediate (S)-2-methylamino-1-phenyl-1-acetone. The method comprises the following steps: carrying out nucleophilic substitution reaction on dimethyl-(4S, 5S)-2-[(R)-1-bromoethyl]-2-phenyl-1, 3-dioxyethane-4, 5-dicarboxylate (2a) and methylamine in an SN2 reaction environment to finish Walden inversion to generate dimethyl-(4S, 5S)-2-[(S)-1-methylamino]-2-phenyl-1, 3-dioxyethane-4, 5-dicarboxylate(3a); and then removing a chiral auxiliary agent (2S, 3S)-dimethyl tartrate to obtain (S)-2-methylamino-1-phenyl-1-acetone (1a). The compound can be used as a substrate for potassium borohydride reduction in the ephedrine preparation process, so that traditional complicated physical and chemical coexisting splitting operation of dibenzoyl tartaric acid is avoided, and the method has an important industrial application value.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and in particular relates to a chiral synthesis method of (S)-2-methylamino-1-phenyl-1-acetone, a key intermediate of ephedrine. Background technique [0002] Ephedrine is an important drug, which has been produced by the following process routes for a long time: [0003] [0004] In this process route, the brominated propiophenone generated by bromination is first carried out at the α-position of propiophenone, and the obtained brominated propiophenone is a racemic mixture of S and R. Then carry out the methylation reaction, methylamine nucleophilic substitution of bromine, due to the experience of SN 1 The process of generating methylaminopropiophenone is also a racemic mixture of S and R, the ratio is also 50:50, and the optical rotation is 0°. [0005] However, whether it is ephedrine or pseudoephedrine, the carbon atom connected by the methylamine group is in the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C221/00C07C225/16C07D317/32
CPCC07C221/00C07D317/32C07B2200/07C07C225/16
Inventor 舒理建黄成军卢鑫鑫郭卫锋胡倩应一锋陈华良谭永旺
Owner ZHEJIANG APELOA KANGYU PHARMA
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