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Preparation method for chiral gamma-sec-amino-alcohol

A technology for secondary amino alcohols and secondary amino ketones, which is applied in the synthesis field of preparing chiral γ-secondary amino alcohols, and can solve catalyst deactivation, difficulties in asymmetric hydrogenation of β-secondary amino ketones, long synthesis steps, etc. problems, achieve high enantiomer selectivity, realize industrial synthesis, and improve synthesis efficiency

Active Publication Date: 2016-04-20
SHANGHAI JIAO TONG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, in the prior art, the chiral γ-secondary amino alcohol product is deactivated due to the strong coordination of the N atom and the instability of the β-secondary aminoketone substrate, giving the β-secondary aminoketone Asymmetric hydrogenation poses difficulties
In addition, the synthesis steps of chiral γ-secondary amino alcohols in the prior art are relatively long, and resolution reagents are required for resolution, and the resolution reagents used are expensive and have certain corrosive problems.

Method used

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  • Preparation method for chiral gamma-sec-amino-alcohol
  • Preparation method for chiral gamma-sec-amino-alcohol
  • Preparation method for chiral gamma-sec-amino-alcohol

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preparation example Construction

[0024] The preparation method of the chiral γ-secondary amino alcohol of the present invention can be represented by the following reaction formula.

[0025]

[0026] In the preparation method of the γ-secondary amino alcohol compound of the present invention, Ar and R in the general formula (1) and general formula (2) do not change before and after the reaction.

[0027] In the general formula (1), HY represents an acid. As the acid represented by HY, various acids that form acid addition salts with secondary amino groups can be used, for example, hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, salicylic acid , tetrafluoroboric acid, hexafluorophosphoric acid, hexafluoroantimonate, etc. In other words, in the production method of the present invention, as the acid addition salt of β-secondary aminoketone represented by the general formula (1), hydrochloride, sulfate, phosphate, tartrate, p-toluenesul...

Embodiment 1

[0056]

[0057] Add 1.5mg of [Rh((S,S)-BenzP*)(cod)]SbF to a 50mL reaction tube 6 Catalyst, 803 mg of N-methyl-3-carbonyl-3-phenylpropylamine hydrochloride (substrate 1a), 277 mg of potassium carbonate, 241 mg of magnesium sulfate [ketone:catalyst:base:additive=2000:1:1000:1000 (molar ratio)], put the reaction test tube in the hydrogenation kettle, vacuumize the hydrogen for three times, add 2 mL of degassed ethyl acetate under the protection of hydrogen, finally adjust the hydrogen pressure to 50 bar, and stir vigorously at 50 ° C for 1 hour , stop the reaction, concentrate and evaporate the solvent to dryness, and use basic aluminum oxide column chromatography (dichloromethane V1 / methanol V2=20 / 1) to obtain a light yellow oily product 2a, and the yield of product 2a is 80%.

[0058] The assay data for product 2a are as follows.

[0059] 1 H-NMR (400MHz, CDCl 3 )δ7.38-7.31(m,4H),7.26-7.21(m,1H),4.93(dd,J=3.2Hz,8.4Hz,1H),3.04(brs,2H),2.92-2.81(m,2H ),2.44(s,3H),1.91-1.7...

Embodiment 2

[0068]

[0069] Add 1.5mg of [Rh((S,S)-BenzP*)(cod)]SbF to a 50mL reaction tube 6 Catalyst, 85.5 mg of N-methyl-3-carbonyl-3-(2-methylphenyl)propylamine hydrochloride (substrate 1b), 21.2 mg of sodium carbonate, 73.4 mg of zinc acetate [ketone:catalyst:base: Additive = 200:1:100:200 (molar ratio)], put the reaction test tube in the hydrogenation kettle, vacuumize the hydrogen for three times, add 2 mL of degassed ethyl acetate under the protection of hydrogen, and finally adjust the hydrogen pressure to 50bar , stirred vigorously at -20°C for 24 hours, stopped the reaction, concentrated and evaporated to dryness, and used basic aluminum oxide column chromatography (dichloromethane V1 / methanol V2=20 / 1) to obtain a light yellow oily product 2b, the product The yield of 2b was 75%.

[0070] The NMR measurement data of product 2b are as follows.

[0071] 1 H-NMR (400MHz, CDCl 3 )δ7.55(d, J=7.6Hz, 1H), 7.22(t, J=7.2Hz, 1H), 7.14(td, J=1.2Hz, 7.6Hz, 1H), 7.10(d, J=7.6Hz ,1H),5...

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Abstract

The invention provides a preparation method for chiral gamma-sec-amino-alcohol. The preparation method is characterized in that an acid addition salt of beta-sec-amino-ketone as shown in a general formula (I) which is described in the specification, alkali, a metal salt additive and a bisphosphine-rhodium complex are added into a solvent and a reaction is carried out in a hydrogen atmosphere so as to produce a chiral gamma-sec-amino-alcohol compound as shown in a general formula (II) which is described in the specification; and in the general formula (I) and the general formula (II), Ar represents an aryl group with or without substituent, R represents an alkyl group or aralkyl group, and HY represents acid. The preparation method is simple in synthesis route and process; the metal salt additive substantially improves the technical effect of rhodium in catalysis of asymmetric hydrogenation and enhances reaction yield and optical purity of the product; and production process is simplified, production cost is lowered, and the preparation method is suitable for industrial large-scale production.

Description

technical field [0001] The present invention relates to a method for preparing chiral γ-secondary amino alcohols, specifically a method for preparing chiral γ-amino alcohols by using metal salt additives to improve the catalytic system activity of bisphosphine-rhodium complexes, and using asymmetric catalytic hydrogenation technology to prepare chiral γ-amino alcohols. Synthetic method of secondary amino alcohol. Background technique [0002] The chiral γ-secondary amino alcohol skeleton widely exists in a variety of drug molecules and physiologically active molecules, such as duloxetine, fluoxetine, etc. Duloxetine hydrochloride (Duloxetine), the chemical name is (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-propanamine hydrochloride, produced by the United States A serotonin and norepinephrine reuptake inhibitor developed by Eli Lilly, which is mainly used clinically for the treatment of depression and anxiety. The global sales volume in 2013 is about 5 billion US dolla...

Claims

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Application Information

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IPC IPC(8): C07B41/02B01J31/24C07C213/00C07C215/30C07C217/72C07C231/02C07C233/18C07D317/58C07D333/20C07D307/52
CPCC07B53/00C07B2200/07C07C213/00C07D307/52C07D317/58C07D333/20C07C215/30C07D307/42C07D333/16
Inventor 张万斌张振锋胡秋鹏
Owner SHANGHAI JIAO TONG UNIV