Continuous flow synthesis method of (3aS, 6aR)-lactone

A flow synthesis, lactone technology, applied in chemical instruments and methods, organic chemistry, chemical/physical/physical chemical processes, etc., can solve the problems of low enantiomeric selectivity, difficult industrial scale-up, long reaction time, etc. To achieve the effect of shortened reaction time, convenient synthesis and high degree of automation

Pending Publication Date: 2022-05-31
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These methods all have disadvantages such as complicated operation, low enantiomeric selectivity, high cost and difficulty in industrial scale-up.
[0008] In addition, the above methods are all carried out in traditional batch reactors, and there are outstanding problems such as low yield of the target product (3aS,6aR)-lactone (I), complicated operation, long reaction time, low efficiency and high energy consumption.
Therefore, based on the problems existing in the existing preparation method, a kind of reaction time is short, the product (3aS, 6aR)-lactone (I) yield is high, the purity is high, the energy consumption is low, the process efficiency is high and the preparation cost is low. The continuous preparation method is an urgent problem for those skilled in the art

Method used

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  • Continuous flow synthesis method of (3aS, 6aR)-lactone
  • Continuous flow synthesis method of (3aS, 6aR)-lactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The substrate cyclic anhydride (II) (R in formula II 1 is hydrogen, Ar is phenyl, and its full name is cis-1,3-dibenzylimidazolin-2-one-2H-furo[3,4-d]imidazole-2,4,6-trione)( 33.6g, 0.10mol) was dissolved in 200ml of anhydrous toluene and placed in the substrate liquid storage tank 1, and the chiral auxiliary agent (S)-1,1-bis([1,1'-biphenyl]-4-yl )-1,2-propanediol (III) (R in formula III 2 is hydrogen, R 3 Hydrogen) (39.9g, 0.105mol) and newly distilled n-butylamine (23.90ml, 0.10mol) were dissolved in 200ml of anhydrous toluene and placed in the chiral auxiliary agent solution storage tank 3 to prepare a tetrahydrofuran solution of lithium borohydride (1mol / L) is placed in the borohydride solution storage tank 7, and an aqueous hydrochloric acid solution (2mol / L) is prepared and placed in the inorganic mineral acid solution storage tank 11.

[0074] With feed pump 2 and feed pump 4, substrate liquid and chiral auxiliary agent solution are transported respectively i...

Embodiment 2

[0077] This embodiment is the same as Embodiment 1, the only difference is that the micro-mixer 5, the micro-mixer 9 and the micro-mixer 13 in this embodiment are all T-shaped micro-mixers. In this example, the substrate cyclic anhydride (II) was completely converted, the yield of the target product (I) was 92.1%, and the enantioselectivity was 98%.

Embodiment 3

[0079] This embodiment is the same as Embodiment 1, the only difference is that the micro-mixer 5, the micro-mixer 9 and the micro-mixer 13 in this embodiment are all Y-shaped micro-mixers. In this example, the substrate cyclic anhydride (II) was completely converted, the yield of the target product (I) was 87.6%, and the enantioselectivity was 97.6%.

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Abstract

The invention discloses a continuous flow preparation method of (3aS, 6aR)-lactone. The method comprises the following steps: respectively and simultaneously pumping a cyclic anhydride substrate solution and a chiral auxiliary agent propylene glycol solution into a first micro-mixer, mixing, and carrying out a continuous desymmetry reaction in a first micro-channel reactor; after the reactant flows out, the reactant and a hydroboron solution are mixed in a second micro-mixer and then enter a second micro-channel reactor to be subjected to a continuous reduction reaction, the flowing-out mixed reaction material and an inorganic mineral acid solution are mixed in a third micro-mixer and then enter a third micro-channel reactor to be subjected to a continuous ring closing reaction, and the target product (3aS, 6aR)-lactone is prepared. The total product yield is gt; 90%, the enantiomeric excess percentage (ee) gt; 99%. Compared with the prior art, the method is short in reaction time, high in product yield and optical purity, high in automation degree, high in technological process continuous efficiency, low in energy consumption and easy to industrially amplify.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a synthesis method of (3aS, 6aR)-lactone. Background technique [0002] (3aS, 6aR)-lactone is the key intermediate of synthetic (+)-biotin ((+)-Biotin, vitamin H, coenzyme R), and its structural formula is shown in following formula (I): [0003] [0004] In the formula, R 1 hydrogen, C1~C6 alkyl, C3~C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl , 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl or p-chlorophenyl, etc. Ar is phenyl, p-tolyl, p-methoxyphenyl, 3,4 -Dimethylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethylphenyl, 3,4,5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl or naphthyl etc. [0005] Gerecke et al. (Helv.Chim.Acta., 1970,53,991-999) combined cis-1,3-dibenzylimidazolidin-2-one-2H-furo[3,4]imidazole-2,4,6 Monoesterification of ketone (cyclic anhydride II) with cyclohexanol to produce racemic cyc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/048B01J19/00
CPCC07D491/048B01J19/0093Y02P20/584
Inventor 陈芬儿程荡吴迦勒陶媛王佳琦
Owner FUDAN UNIV
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