Method for preparing arene beta-amino alcohol of optical voidness

A technology for amino alcohols and aromatic hydrocarbons, applied in the field of preparation of aromatic hydrocarbon β-amino alcohols, can solve the problems of unsuitability for long-term storage, increased production cost, easy racemization of compound 4, etc.

Inactive Publication Date: 2016-06-22
ZHONGSHAN HAIHONG MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although the synthesis method is simple, compound 4 is easy to racemize and is not suitable for long-term storage
And in step 1, a large amount of condensation reagents are used, resulting in a substantial increase in production costs

Method used

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  • Method for preparing arene beta-amino alcohol of optical voidness
  • Method for preparing arene beta-amino alcohol of optical voidness
  • Method for preparing arene beta-amino alcohol of optical voidness

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Synthesis of key intermediates of alogliptin

[0113] 1. Preparation of (4S)-N-Boc-4-propargyl-5-oxazolidinone, namely the compound of formula 22

[0114]

[0115] With 19.9g, 0.1mol (L)-N-BOC-propargylglycine, 6.7g paraformaldehyde and 0.19g, 1mmol p-toluenesulfonic acid monohydrate in 190ml toluene, the reaction solution was suspended; heated to In the reflux state, the produced water is separated by a water separator, and the reaction liquid gradually becomes clear as the reaction progresses. After the reaction was completed, the reaction liquid was cooled to room temperature, an aqueous solution of sodium bicarbonate was added to the reaction liquid for washing, the layers were separated, and the organic layer was washed with saturated brine. The toluene was distilled off under reduced pressure, and the residue was crystallized by cooling and filtered to obtain compound 22, 18.8 g of white crystals, with a yield of 89%.

[0116] 1 H-NMR (CD 3 Cl, 400MHz) δppm...

Embodiment 2

[0138] Synthesis of key intermediates of alogliptin

[0139] 1. Preparation of (4S)-N-Boc-4-propargyl-5-oxazolidinone, namely the compound of formula 22

[0140]

[0141] With 19.9g, 0.1mol of (L)-N-BOC-propargylglycine, 39.8g of paraformaldehyde and 0.38g, 2mmol of p-toluenesulfonic acid monohydrate in 250ml of toluene, the reaction solution was suspended; heating To the state of reflux, use the water separator to divide the produced water. As the reaction progresses, the reaction solution gradually becomes clear. After the reaction was completed, the reaction liquid was cooled to room temperature, an aqueous solution of sodium bicarbonate was added to the reaction liquid for washing, the layers were separated, and the organic layer was washed with saturated brine. Toluene was distilled off under reduced pressure, and the residue was crystallized by cooling and filtered to obtain the title compound 22, 20 g of white crystals, with a yield of 95%.

[0142] 2. Preparation ...

Embodiment 3

[0152] Synthesis of key intermediates of ansertrapib

[0153] 1, the preparation of (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone, namely the compound of formula 24

[0154]

[0155] Put 22.3g, 0.1mol of benzyloxycarbonyl-L-alanine, 8.2g of paraformaldehyde and 0.19g, 1mmol of p-toluenesulfonic acid monohydrate in 220ml of toluene, the reaction solution was suspended; heated to reflux state, use a water separator to divide the produced water, and as the reaction progresses, the reaction solution gradually becomes clear. After the reaction was completed, the reaction solution was cooled to room temperature, 50 ml of aqueous sodium bicarbonate solution was added to the reaction solution for washing, the layers were separated, and the organic layer was washed with saturated brine. The toluene was distilled off under reduced pressure, and the residue was crystallized by cooling and filtered to obtain the title compound 22, 21.6 g of white crystals, with a yield of 92%. Me...

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Abstract

The invention discloses a method for preparing arene beta-amino alcohol of optical voidness. The method is characterized by comprising the following steps that a D or L-amino acid initial material reacts with benzyl chloroformate CBz-Cl or BOC acid anhydride, and a compound I-1 is obtained; the compound I-1 is subjected to reflux dewatering in solvent A through paraformaldehyde, and a compound I-2 is obtained; the compound I-2 is subjected to a Grignard reagent reaction, dilute hydrochloric acid processing is conducted, and a compound I-3 is obtained; the compound I-3 is subjected to catalytic reduction with aluminium isopropoxide, and the arene beta-amino alcohol of the optical voidness can be obtained. The method aims to overcome defects of the prior art, materials are cheap and easy to obtain, it is beneficial to lower cost, the preparation process is simple, and the obtained intermediate is a medical intermediate stable in structure.

Description

technical field [0001] The invention relates to a preparation method of optically pure aromatic hydrocarbon β-amino alcohol, which belongs to the technical field of chemical synthesis. Background technique [0002] The optically pure aromatic hydrocarbon β-aminoalcohol shown in formula 1 and the intermediate of drugs such as DPP-IV inhibitor Omarigliptin, selective CETP inhibitor Anacetrapib and medicine Ipenoxazone are a An important class of pharmaceutical intermediates, widely used in the synthesis of drugs. [0003] [0004] The commonly used synthetic route of substituted optically pure aromatic hydrocarbon β-aminoalcohols has been reported, through the henry reaction, as shown in formula 2, from benzaldehyde (1) as the starting material, nucleophilic substitution reaction with nitroethane to generate β -Nitroalcohol compound (2), compound (2) is reduced to amino, promptly obtains the β-aminoalcohol substituted by aromatic hydrocarbon of racemization, to obtain opti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/16C07C269/06C07D263/22
CPCY02P20/55C07C269/06C07B2200/07C07C269/00C07D263/18C07D263/22C07C271/16C07C271/18
Inventor 杨青海李吉昌朱称水兰小兵
Owner ZHONGSHAN HAIHONG MEDICINE CO LTD
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