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A kind of preparation method of optically pure (r)-4-polyhalomethyl-2-heterocyclobutanone

A polyhalomethyl, oxetanone technology, applied in the directions of organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve the problem of low optical purity of products, and achieves cheap and easy-to-obtain raw materials, convenient operation, The effect of high stereoselectivity

Inactive Publication Date: 2011-12-07
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Swiss patent CH680588 reported that O-acyl substituted quinidine was used as a chiral catalyst, acetyl chloride and chloral were used as substrates, dimethylisopropylamine was used as an organic base, and at -11°C Preparation of (R)-4-trichloromethyl-2-oxetanone, but the optical purity of the product is not high

Method used

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  • A kind of preparation method of optically pure (r)-4-polyhalomethyl-2-heterocyclobutanone
  • A kind of preparation method of optically pure (r)-4-polyhalomethyl-2-heterocyclobutanone
  • A kind of preparation method of optically pure (r)-4-polyhalomethyl-2-heterocyclobutanone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Chloroacetaldehyde (1.47g, 0.01mol), acetyl chloride (1.58g, 0.02mol), catalyst cinchona alkaloids (R 1 =-CH=CH 2 , R 2 =-CH 3 , R 3 =-OCH 3 ) (86.5mg, 0.256mmol) and methyl tert-butyl ether (30mL) were placed in a dry reaction flask, and triethylamine (2.02g, 0.02mol) in methyl tert-butyl ether ( 20mL) solution. Dropping is completed within 1 hour, and the reaction is continued for 3 hours. After the reaction was completed, the reaction solution was filtered, the organic layer was washed with 4N aqueous HCl solution, and the remaining washing solution was separated, and 20 ml of 4N aqueous HCl solution was used for each washing. After washing three times, the organic layer was dried with anhydrous sodium sulfate. Filtration, filtrate decompression reclaims solvent and obtains white crystalline powder (X 1 =-Cl,X 2 =-Cl,X 3 =-Cl, 1.71g, 90%), mp 51.5-52.8°C, e.e=98%.

[0037] Catalyst recovery: the separated aqueous hydrochloric acid layer was adjusted to pH 9...

Embodiment 2

[0039] Chloroacetaldehyde (1.47g, 0.01mol), acetyl chloride (1.58g, 0.02mol), catalyst cinchona alkaloids (R 1 =-CH=CH 2 , R 2 =-C 2 h 5 , R 3 =-OCH 3) (90.1mg, 0.256mmol) and methyl tert-butyl ether (30mL) were placed in a dry reaction flask, and triethylamine (2.02g, 0.02mol) in methyl tert-butyl ether ( 20mL) solution. Dropping is completed within 1 hour, and the reaction is continued for 3 hours. After the reaction was completed, the reaction solution was filtered, the organic layer was washed with 4N aqueous HCl solution, and the remaining washing solution was separated, and 20 ml of 4N aqueous HCl solution was used for each washing. After washing three times, the organic layer was dried with anhydrous sodium sulfate. Filtration, filtrate decompression reclaims solvent and obtains white crystalline powder (X 1 =-Cl,X 2 =-Cl,X 3 =-Cl, 1.70 g, 90%), mp 51.3-52.6 °C, e.e = 98%.

[0040] The recovery method of catalyst is with embodiment 1.

Embodiment 3

[0042] Chloroacetaldehyde (1.47g, 0.01mol), acetyl chloride (1.58g, 0.02mol), catalyst cinchona alkaloids (R 1 =-CH=CH 2 , R 2 =-CH 2 CH 2 CH 3 , R 3 =-OCH 3 ) (93.7mg, 0.256mmol) and methyl tert-butyl ether (30mL) were placed in a dry reaction flask, and triethylamine (2.02g, 0.02mol) in methyl tert-butyl ether ( 20mL) solution. Dropping is completed within 1 hour, and the reaction is continued for 3 hours. After the reaction was completed, the reaction solution was filtered, the organic layer was washed with 4N aqueous HCl solution, and the remaining washing solution was separated, and 20 ml of 4N aqueous HCl solution was used for each washing. After washing three times, the organic layer was dried with anhydrous sodium sulfate. Filtration, filtrate decompression reclaims solvent and obtains white crystalline powder (X 1 =-Cl,X 2 =-Cl,X 3 =-Cl, 1.72g, 91%), mp 51.7-52.5°C, e.e=99%.

[0043] The recovery method of catalyst is with embodiment 1.

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Abstract

The invention discloses a preparation method of optical voidness (R)-4-trihalomethyl-2-heterocycilic butanone, which includes steps as follows: an enanatioselectivity cyclization reaction is carried out to polyhalogenated acetaldehyde and acyl halide in an organic solvent under the action of a catalyst-quinine alkaloid and organic bases. The molar ratios of components are: polyhalogenated acetaldehyde: acyl halide: quinine alkaloid is equal to 1:1 to 10:1 to 30:0.01 to 1 and the reaction temperature is -50 DEG C to 50 DEG C and the reaction time ranges from 0.5h to 20h; a reaction solution is filtered and an organic layer is washed, dried and filtered, and a solvent is recovered in a vacuum manner from the filtrate to prepare the (R)-4-methyl polyhalide-2-oxetanone; and the pH of a washing solution is adjusted by a NaOH solution to 9 and a white solid is separated out, filtered and dried to obtain the quinine alkaloid. The method has mild reaction conditions, convenient operation, low cost and easy availability of raw materials. The obtained product has high yield and high stereoselectivity, and the catalyst can be recycled in a fixed amount. The method has low cost and is applicable to industrialized production.

Description

technical field [0001] The invention relates to the field of organic chemistry, in particular to a preparation method of optically pure (R)-4-trihalomethyl-2-heterocyclobutanone. Background technique [0002] (R)-4-Trihalo-2-oxetanone is a very important chiral synthetic building block for chiral drugs or natural products. For example, (R)-4-trihalomethyl-2-oxetanone is a synthetic L-carnitine (L-Carnitine, vitamin B T ), (R)-malic acid ((R)-Malic Acid) and γ-amino-β-hydroxy amino acid ((R)-GABOB) are important chiral synthetic building blocks. [0003] The synthesis of 4-polyhalomethyl-2-oxetanone was first reported by Borrmann and Wegler (Chem.Ber, 1966, 99, 1245), under the action of triethylamine, polyhaloacetaldehyde and acetyl chloride, Diethyl ether is used as a solvent, and a [2+2] cycloaddition reaction occurs at 0°C to obtain a racemate. (R)-4-trichloromethyl-2-oxetanone was also first synthesized and reported by them (Chem.Ber, 1967, 100, 1575), using trichloro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/12C07B53/00B01J31/02
CPCY02P20/584
Inventor 陈芬儿李丹赵磊李峰俞雄杰
Owner FUDAN UNIV