Method for preparing biotin key intermediate through fixed bed continuous catalytic hydrogenation

Abstract

The invention belongs to the technical field of organic chemical engineering, and particularly relates to a method for preparing a biotin key intermediate through fixed bed continuous catalytic hydrogenation. A solution containing (3aS, 6aR)-1, 3-dibenzyl-tetrahydro-1H-thieno [3, 4-d] imidazol-2 (1H)-ketone-4-enolefine valeric acid (II) and hydrogen are conveyed to a mixer at the same time and then enter a fixed bed reactor filled with Raney nickel to be subjected to a continuous high-stereoselectivity catalytic hydrogenation reaction, an outlet of the fixed bed is connected to a back pressure valve through a pipeline, and then reaction liquid flows out; and (3aS, 6aR)-1, 3-dibenzyl-tetrahydro-1H-thieno [3, 4-d] imidazol-2 (1H)-ketone-4-valeric acid (I) is obtained after purification is carried out. The method provided by the invention overcomes the defects in the prior art, has the advantages of good selectivity, high yield, short reaction time, easy separation and high efficiency, and is suitable for industrial amplification application.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical engineering, and in particular relates to a method for preparing a key intermediate of biotin by continuous catalytic hydrogenation in a fixed bed. Background Art

[0002] (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I) is an important intermediate in the synthesis of biotin, mainly used to regulate body functions, enhance immunity and resistance, and maintain normal growth and development. Its structural formula is shown in formula (I):

[0003]

[0004] European Patent (EP0780392) discloses a method for synthesizing (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I) by palladium acetate-catalyzed hydrogenation. It uses precious metals, has a long reaction time, high pressure, and certain safety hazards. Chinese Patent Publication No. CN109503619A discloses a method for preparing (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I) by palladium-catalyzed hydrogenation. The raw materials of this method are cheap, easy to obtain, and safe, but the catalyst is expensive. International Patent Publication No. WO2023120711A1 discloses a method for preparing compound (I) by nickel-catalyzed hydrogenation. This method has high reaction temperature and high pressure, has safety hazards, and the product separation is cumbersome. Summary of the invention

[0005] In order to overcome the deficiencies of the prior art, the present invention provides a method for preparing a key intermediate of biotin by continuous catalytic hydrogenation in a fixed bed. The method has greatly shortened reaction time, high selectivity, easy product separation, good safety, and is easy for industrial application.

[0006] The method for preparing a key intermediate of biotin by fixed-bed continuous catalytic hydrogenation provided by the present invention uses a reaction system consisting of a mixer, a fixed-bed reactor, and a back-pressure valve connected in sequence, and the specific steps of the method are as follows:

[0007] (1) a solution containing (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazol-2(1H)-one-4-enepentanoic acid (II) and hydrogen are respectively transported to a mixer and then introduced into a fixed bed reactor filled with Raney nickel for continuous catalytic hydrogenation reaction;

[0008] (2) The outlet of the fixed bed is connected to a back pressure valve through a pipeline, and the reaction liquid flowing out after the system back pressure is concentrated and purified to obtain (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I);

[0009] The chemical reaction formula is:

[0010]

[0011] Among them, (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazol-2(1H)-one-4-pentanoic acid is the compound represented by formula (I); (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazol-2(1H)-one-4-enepentanoic acid is the compound represented by formula (II).

[0012] Preferably, the solvent in step (1) is one of alcohol, chlorinated hydrocarbon, ether and ester, more preferably methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, tetrahydrofuran and dichloromethane.

[0013] Preferably, the fixed bed temperature in step (1) is controlled at 20-180°C, and the residence time is 0.1-20 minutes. More preferably, the fixed bed temperature is controlled at 50-120°C, and the residence time is 0.5-5 minutes.

[0014] Preferably, the molar ratio of the compound (II) to hydrogen in step (1) is in the range of 1:1.0 to 1:5.0, and a more preferred molar ratio is 1:1.5 to 1:2.5.

[0015] Preferably, the back pressure in step (2) is controlled within the range of 0 to 100 bar, more preferably within the range of 10 to 30 bar.

[0016] Instruction Manual

[0017] Figure 1 It is a schematic diagram of a reaction system according to a specific embodiment of the present invention. DETAILED DESCRIPTION

[0018] In order to explain the technical content, structural features, achieved purpose and effect of the technical solution in detail, the following is further described in conjunction with specific embodiments and accompanying drawings. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and specific operation process are given, but the protection scope of the present invention is not limited to the following embodiments.

[0019] The structure of the reaction system used in the embodiment is as shown in the attached Figure 1 As shown,

[0020] Its working process is:

[0021] According to the invention, a solution containing (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-enepentanoic acid (II) and hydrogen are respectively and simultaneously transported to a mixer, and then the solution enters a fixed bed reactor filled with Raney nickel for continuous high stereoselective catalytic hydrogenation reaction. The outlet of the fixed bed is connected to a back pressure valve through a pipeline, and then a reaction liquid flows out. After purification, (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-enepentanoic acid (I) is obtained.

[0022] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0023] Example 1

[0024] A method for preparing a key intermediate of biotin by continuous catalytic hydrogenation in a fixed bed, comprising: pre-dissolving a methanol solution of (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-enepentanoic acid (II), and hydrogen (molar ratio of 1:2) are respectively and simultaneously transported to a Y-type three-way for mixing, and then enter a fixed bed reactor pre-filled with Raney nickel (fixed bed temperature is controlled at 100°C, the empty column volume is 20ml, and the volume after filling with Raney nickel is 3ml), the residence time is 3 minutes, and the reaction liquid flowing out of the fixed bed passes through a back pressure valve (the back pressure value is set to 25 bar) and is concentrated to dryness, and is separated and purified to obtain (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I) (yield 93%, purity 99%).

[0025] Example 2

[0026] This example is the same as Example 1, except that the reaction temperature in this example is controlled at 120° C., and (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I) is obtained by separation and purification (yield 95%, purity 99%).

[0027] Example 3

[0028] This example is the same as Example 1, except that the back pressure in this example is controlled to be 30 bar, and (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I) is separated and purified (yield 96%, purity 99%).

[0029] Example 4

[0030] This example is the same as Example 1, except that in this example, the molar ratio of (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-enepentanoic acid (II) to hydrogen is 1:1.5, and (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I) is obtained by separation and purification (yield 92%, purity 99%).

[0031] Example 5

[0032] This example is the same as Example 1, except that the volume of the empty column of the fixed bed reactor in this example is 100 ml, and the volume after filling with Raney nickel is 15 ml. (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I) is separated and purified (yield 95%, purity 98%).

[0033] It should be noted that, although the above embodiments have been described in this article, the scope of patent protection of the present invention is not limited thereby. Therefore, based on the innovative concept of the present invention, changes and modifications made to the embodiments described herein, or equivalent structural or equivalent process transformations made using the contents of the present specification and drawings, directly or indirectly applying the above technical solutions to other related technical fields, are all included in the patent protection of the present invention.

Claims

1. A method for preparing a key intermediate of biotin by continuous catalytic hydrogenation in a fixed bed, characterized in that: A reaction system consisting of a mixer, a fixed bed reactor and a back pressure valve connected in sequence is used, and the method comprises the following specific steps: (1) a solution containing (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazol-2(1H)-one-4-enepentanoic acid (II) and hydrogen are respectively transported to a mixer and then introduced into a fixed bed reactor filled with Raney nickel for continuous catalytic hydrogenation reaction; (2) The outlet of the fixed bed is connected to a back pressure valve through a pipeline, and the reaction liquid flowing out after the system back pressure is concentrated and purified to obtain (3aS, 6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazole-2(1H)-one-4-pentanoic acid (I); The chemical reaction formula is: Among them, (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazol-2(1H)-one-4-pentanoic acid is the compound represented by formula (I); (3aS,6aR)-1,3-dibenzyl-tetrahydro-1H-thieno[3,4-d]imidazol-2(1H)-one-4-enepentanoic acid is the compound represented by formula (II).

2. The method for preparing a key intermediate of biotin by fixed bed continuous catalytic hydrogenation according to claim 1, characterized in that: The solvent described in step (1) is one of alcohol, chlorinated hydrocarbon, ether or ester.

3. The method for preparing a key intermediate of biotin by fixed bed continuous catalytic hydrogenation according to claim 1, characterized in that: The fixed bed temperature in step (1) is controlled to be 20-180° C., and the residence time is 0.1-20 minutes.

4. The method for preparing a key intermediate of biotin by fixed bed continuous catalytic hydrogenation according to claim 1, characterized in that: The molar ratio of the compound (II) to hydrogen in step (1) is in the range of 1:1.0 to 1:5.

0.

5. The method for preparing a key intermediate of biotin by fixed bed continuous catalytic hydrogenation according to claim 1, characterized in that: The back pressure described in step (2) is controlled within the range of 0 to 100 bar.

6. The method for preparing a key intermediate of biotin by fixed bed continuous catalytic hydrogenation according to claim 1, characterized in that: The mixer described in step (1) is any one of a static mixer, a T-type mixer, a Y-type mixer, a cross mixer, a coaxial flow mixer or a flow focusing mixer.

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