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Preparation method of N-carbobenzoxy-3-amino propionaldehyde

A technology of benzyloxycarbonyl and aminopropanal, applied in the field of preparation of N-benzyloxycarbonyl-3-aminopropanal, a drug synthesis intermediate, can solve the problems of inapplicability to large-scale production, unfavorable amplification reaction, unfriendly environment, etc. , to achieve the effect of easy purification, environmental friendliness and simple operation

Inactive Publication Date: 2013-07-24
EAST CHINA NORMAL UNIVERSITY +1
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0004] In the prior art, some literatures have reported the synthesis of N-benzyloxycarbonyl-3-aminopropanal (III). For example, the oxidation condition adopts the acetyl chloride-dimethyl sulfoxide system, and the reaction temperature is -50°C~ -78°C, such as Journal of the American Chemical Society1999, 121(49), 11356-11368; Journal of the American Chemical Society1997, 119(10), 2348-2355; Tetrahedron1997, 53(37), 12391-12404 and Tetrahedron1991, (24), 4089-4100; but the reaction temperature of this method is low, which is not conducive to the amplification reaction, and is not friendly to the environment due to the generation of dimethyl sulfide with a foul smell
For example, useful Dess-Martin oxidants, such as Tetrahedron Letters2001, 42 (2), 183-186; the method reaction conditions are mild, but the cost is relatively high
For example, sodium periodate-2,2,6,6-tetramethylpiperidinium oxide system is also used, such as European Journal of Organic Chemistry2012, (17), 3270-3277, and the cost is also higher
In addition, there are also useful oxidants PCC, PDC, and are not suitable for large-scale production

Method used

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  • Preparation method of N-carbobenzoxy-3-amino propionaldehyde
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  • Preparation method of N-carbobenzoxy-3-amino propionaldehyde

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preparation example Construction

[0021] A kind of preparation method of N-benzyloxycarbonyl-3-aminopropanal of the present invention, take 3-aminopropanol as starting material, obtain 3-(benzyloxycarbonylamino)-1-propanol through amidation reaction; Then , through the oxidation reaction of sodium hypochlorite, 2,2,6,6-tetramethylpiperidine oxide and potassium bromide under the condition of pH 8.0-9.5, to obtain the N-benzyloxycarbonyl-3-aminopropanal. Specifically include the following:

[0022] 1) Amidation reaction: 3-aminopropanol (I) and benzyl chloroformate are placed in triethylamine and methylene chloride solution for amidation reaction to obtain 3-(benzyloxycarbonylamino)-1-propanol (II). The amidation reaction is carried out at 0-10°C. Further, after the amidation reaction is completed, the reaction solution is washed with 1M HCl and brine in sequence, and the obtained organic phase is directly used for the next oxidation reaction.

[0023] 2) Oxidation reaction: the oxidation reaction is carried ...

Embodiment 1

[0024] Embodiment 1 Amidation reaction prepares 3-(benzyloxycarbonylamino)-1-propanol (II)

[0025] 3-Aminopropanol (82.6g), triethylamine (111.3g) and dichloromethane (1L) system was cooled to 0°C, and benzyl chloroformate (170.5g) was slowly added dropwise to the system, and the dropwise addition process Maintain the temperature at 0-10°C; continue to react at this temperature for 2h. After liquid separation, the organic phase was washed with 1M hydrochloric acid and brine in sequence, and was directly used in the next reaction (see Example 2).

Embodiment 2

[0026] Embodiment 2 oxidation reaction prepares N-benzyloxycarbonyl-3-aminopropanal (III)

[0027] A dichloromethane solution of 3-(benzyloxycarbonylamino)-1-propanol prepared in Example 1, 2,2,6,6-tetramethylpiperidine oxide (1.56 g) and dichloromethane ( 600ml) system was cooled to 0°C, and potassium bromide (17.85g) was dissolved in water (100-200ml) and added to the aforementioned reaction system. Then, slowly drop sodium hypochlorite solution (active chlorine 10-14.5%, 2 equivalents) and sodium bicarbonate (46.28g)-aqueous solution (pH8.0-9.5) in the system, and the dropping process control temperature is not high At 10 °C, the reaction was continued at this temperature for 1 h. The liquid was separated, and the organic phase was successively washed with 1M hydrochloric acid-potassium iodide solution, 10% sodium thiosulfate solution, 5% sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Concentration gave an off-white solid (173.8 g, purity ...

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Abstract

The invention discloses a preparation method of N-carbobenzoxy-3-amino propionaldehyde. The method comprises the following steps of: based on 3-amino propyl alcohol as an initial raw material, performing amidation reaction to obtain 3-(carbobenzoxy amino)-1-propyl alcohol; and then, performing oxidation reaction on sodium hypochlorite, 2, 2, 6, 6-tetramethyl piperidine oxide and potassium bromide system at pH of 8.0-9.5 to obtain the N-carbobenzoxy-3-amino propionaldehyde. The method provided by the invention has the advantages of low cost, environment friendliness, easiness in purification, simpleness in operation and high yield, and can realize large-scale industrialized production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and relates to a preparation method of N-benzyloxycarbonyl-3-aminopropanal (III), a drug synthesis intermediate. Background technique [0002] N-benzyloxycarbonyl-3-aminopropanal (III) is an important intermediate for the synthesis of chiral intermediate IV, and IV is a key intermediate for the synthesis of the blood lipid-lowering drug atorvastatin calcium (V). [0003] [0004] In the prior art, some literatures have reported the synthesis of N-benzyloxycarbonyl-3-aminopropanal (III). For example, the oxidation condition adopts the acetyl chloride-dimethyl sulfoxide system, and the reaction temperature is -50°C~ -78°C, such as Journal of the American Chemical Society1999, 121(49), 11356-11368; Journal of the American Chemical Society1997, 119(10), 2348-2355; Tetrahedron1997, 53(37), 12391-12404 and Tetrahedron1991, (24), 4089-4100; but this method has a low reaction temperature, which is no...

Claims

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Application Information

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IPC IPC(8): C07C271/18C07C269/06
Inventor 胡文浩姚文峰李昕侯凯刘顺英赵芸邢栋何正友胡全艮朱高军刘勇王朝东
Owner EAST CHINA NORMAL UNIVERSITY
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