CN111116604B

CN111116604B - Process method for preparing fluorescamine

Info

Publication number: CN111116604B
Application number: CN201911345193.3A
Authority: CN
Inventors: 龙韬; 陈丕证; 顾扬; 邹增龙
Original assignee: SUZHOU BAILING WEICHAO FINE MATERIALS CO Ltd
Current assignee: SUZHOU BAILING WEICHAO FINE MATERIALS CO Ltd
Priority date: 2019-12-24
Filing date: 2019-12-24
Publication date: 2021-10-08
Anticipated expiration: 2039-12-24
Also published as: CN111116604A

Abstract

The invention discloses a process method for preparing fluorescamine, which comprises the following steps: the method comprises the following steps: ninhydrin is used as a raw material and reacts with phenylacetaldehyde under the catalysis of a proper amount of catalyst to obtain a tricyclic intermediate; step two: the tricyclic intermediate is used as a raw material and reacts under the oxidation of a proper amount of an oxidant to obtain the fluorescamine. The method has the advantages of short synthetic route, simple process, mild reaction conditions and high reaction yield.

Description

Process method for preparing fluorescamine

Technical Field

The invention relates to the field of biochemical reagents, in particular to a process method for preparing fluorescamine.

Background

Fluorescamine is a non-planar spiro compound that does not fluoresce itself, but can form stable, highly fluorescent compounds upon reaction with primary amines. Due to its property of fluorescence spike after reaction with primary amines, it is used to characterise compounds containing primary amine groups. Is widely applied to the fluorescence measurement of amino acid, protein and proteolytic enzyme at present.

The fluorescence amine has the obvious advantages of low background, high sensitivity and the like for detecting the primary amine compound, and the detection sensitivity can reach 10-12 mol.

Fluoroaniline has only 1 synthetic route reported so far, namely the following route reported in 1976 by Journal of Organic Chemistry,41(2),388-9, 1976:

the method adopts a 7-step synthesis method, and dimethyl phthalate diethyl ester is taken as a starting material, condensed with ethyl acetate, de-esterified with hydrochloric acid, condensed with benzaldehyde, epoxidized with hydrogen peroxide, subjected to ring opening with sodium hydroxide, condensed with N, N-dimethylformamide dimethyl acetal, and subjected to ring closing to obtain the fluorescamine.

This method has two more serious problems: firstly, the reaction route is long, 7 steps of reaction are required, the ring needs to be closed continuously in the whole process, the ring is opened and then closed, and the synthesis operation is very complicated; secondly, the reaction conditions are harsh, the first step, the sixth step and the seventh step need to be carried out under anhydrous conditions, the overall yield is also low, and the overall yield of the reaction in the 7 steps is lower than 10%, so that the product synthesis cost is high. These two problems make it very difficult to scale up the product to the kilogram level and ten kilograms.

In order to solve the problems of long synthetic steps, harsh reaction conditions and complex operation of the existing process route of the fluorescamine, the method for searching the fluorescamine, which has reasonable route design, mild reaction conditions, safety and reliability, has very important significance.

Disclosure of Invention

In order to overcome the defects in the prior art, the embodiment of the invention provides a process method for preparing fluorescamine, which has the advantages of short synthetic route, simple process, mild reaction conditions and high reaction yield.

In order to achieve the above purpose, the embodiment of the present application discloses a process for preparing fluorescamine, which comprises the following steps:

the method comprises the following steps: ninhydrin is used as a raw material and reacts with phenylacetaldehyde under the catalysis of a proper amount of catalyst to obtain a tricyclic intermediate;

step two: the tricyclic intermediate is used as a raw material and reacts under the oxidation of a proper amount of an oxidant to obtain the fluorescamine.

Preferably, the catalyst is acetic acid.

Preferably, the reaction of the ninhydrin with the phenylacetaldehyde is carried out in a solvent under catalysis of a proper amount of catalyst, and the solvent is one or more of the following substances: tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, DMF, DMSO.

Preferably, the dosage of the phenylacetaldehyde is as follows: 0.5 to 3.5 equivalents; the dosage of the catalyst is as follows: 0.01 to 50 equivalents; the reaction temperature in the first step is 50-200 ℃.

Preferably, the oxidant is one or more of the following: sodium periodate, sodium tungstate and potassium permanganate.

Preferably, the reaction of the tricyclic intermediate under oxidation with a suitable amount of an oxidizing agent is carried out in a solvent, wherein the solvent used is one or more of the following: water, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanol, methanol, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, DMF, DMSO.

Preferably, the amount of the oxidant is: 0.1 to 3.5 equivalents; the reaction temperature in the second step is-20-200 ℃.

The invention has the following beneficial effects:

1. the synthetic route is short, only 2 steps of reaction are needed, and the process is simplified;

2. the process is simple, the reaction condition is mild, and extreme reaction conditions are not needed;

3. the reaction yield is high, the product purity is high, the production cost is greatly reduced, and the requirement of large-scale industrial production of the product can be fully met.

In order to make the aforementioned and other objects, features and advantages of the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 shows the nuclear magnetic spectrum of example 1 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In the description of the present invention, it should be noted that the terms "upper", "lower", "bottom", "inner", "outer", and the like indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience of description and simplicity of description, but do not indicate or imply that the referred device or element must have a specific orientation, be constructed in a specific orientation, and be operated, and thus, should not be construed as limiting the present invention. Furthermore, the terms "first", "second", etc. are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first," "second," etc. may explicitly or implicitly include one or more of that feature.

In order to achieve the above object, the present invention provides a process for preparing fluorescamine, comprising the following steps:

Preferably, the catalyst is acetic acid.

Preferably, the dosage of the phenylacetaldehyde is as follows: 0.8 to 1.2 equivalents; the dosage of the catalyst is as follows: 0.1 to 5 equivalents; the reaction temperature in the first step is 50-100 ℃.

Preferably, the amount of the oxidant is: 0.5 to 1.5 equivalents; the reaction temperature of the second step is 20-100 ℃.

Example 1

The method comprises the following steps: preparation of tricyclic intermediates

Under stirring at room temperature, 3.2Kg of ninhydrin, 2.4Kg of phenylacetaldehyde, 2Kg of acetic acid, and 10L of tetrahydrofuran were sequentially added to a 20L glass reaction vessel, and stirred to obtain a reaction solution.

Further, the reaction solution was heated to 70 ℃ and stirred to react for 6 hours, and the reaction was completed.

Further, the reaction solution was distilled under reduced pressure to recover the solvent and the catalyst, the residue was washed with water by beating, recrystallized with ethyl acetate, and finally dried in oven vacuum to obtain 5.3Kg of a yellow solid (tricyclic intermediate) with a yield of 94%.

Step two: preparation of fluorescamine

And under the stirring at room temperature, 5.3Kg of the tricyclic intermediate obtained in the previous step, 4.1Kg of sodium periodate and 20Kg of water are sequentially added into a 50L glass reaction kettle, and the mixture is stirred uniformly to obtain a reaction solution.

Further, the reaction solution was stirred at room temperature for 8 hours to complete the reaction.

Further, the reaction solution is decompressed and filtered, a filter cake is washed by 2Kg of water and then recrystallized by tert-butyl methyl ether, and finally dried in an oven in vacuum to obtain 5.1Kg of yellow solid powdery product with the yield of 96%.

HPLC purity of the product: 99.1 percent.

Melting point of the product: 157 to 158 ℃.

Referring to FIG. 1, the nuclear magnetic data for example 1 is as follows: 1H NMR (400MHz, DMSO-d 6): δ 8.76(s, 1H), 8.03(d, 1H), 7.75(m, 4H), 7.42(m, 4H).

The synthesis route adopted by the embodiment is short, only 2 steps of reaction are needed, and the process is simplified; the process is simple, the reaction condition is mild, and extreme reaction conditions are not needed; the reaction yield is high, the product purity is high, the production cost is greatly reduced, and the requirement of large-scale industrial production of the product can be fully met.

The principle and the implementation mode of the invention are explained by applying specific embodiments in the invention, and the description of the embodiments is only used for helping to understand the method and the core idea of the invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.

Claims

1. A process for preparing fluorescamine, comprising the steps of:

step two: reacting the tricyclic intermediate serving as a raw material under the oxidation of a proper amount of oxidant to obtain the fluorescamine

2. The process of claim 1, wherein said catalyst is acetic acid.

3. The process for preparing fluorescamine according to claim 1, wherein the reaction of ninhydrin with phenylacetaldehyde is carried out in a solvent catalyzed by a suitable amount of catalyst, wherein the solvent is one or more of the following: tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, DMF, DMSO.

4. The process for preparing fluorescamine according to claim 1, wherein the phenylacetaldehyde is used in an amount of: 0.5 to 3.5 equivalents; the dosage of the catalyst is as follows: 0.01 to 50 equivalents; the reaction temperature in the first step is 50-100 ℃.

5. The process for preparing fluorescamine according to claim 1, wherein the oxidizing agent is one or more of the following: sodium periodate, sodium tungstate and potassium permanganate.

6. The process for preparing fluorescamine according to claim 1, wherein the reaction of the tricyclic intermediate under oxidation with a suitable amount of an oxidizing agent is carried out in a solvent, wherein the solvent used is one or more of the following: water, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanol, methanol, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, DMF, DMSO.

7. The process for preparing fluorescamine according to claim 1, wherein the oxidizing agent is used in an amount of: 0.1 to 3.5 equivalents; the reaction temperature in the second step is-20-200 ℃.