A preparation method of 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione

Abstract

The present invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a preparation method of 6-bromo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione. The preparation of 6-bromo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione uses 1-fluoronaphthalene as the starting material, and undergoes selective bromination, Oxone oxidation, and Ac2O dehydration and acid anhydride formation / amidation, a total of three steps of reactions to obtain the finished product. The preparation method provided by the present invention is scientifically and reasonably designed, and can achieve the safe preparation of 6-bromo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione with the characteristics of environmental protection and low cost.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a method for preparing 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione. Background Art

[0002] 6-Bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione is an important pharmaceutical intermediate. No synthetic route has been reported yet. Synthesis methods for its key intermediate dicarboxylic acid have been reported, but both have significant technical disadvantages:

[0003] 1) As shown below:

[0004]

[0005] This synthetic route uses 4-fluoro-2-bromo-6-methylbenzoic acid as the starting material, which has a complex structure, is expensive and difficult to obtain; potassium permanganate, a readily available drug precursor, is used as the oxidant; and the reaction yield is low (18%).

[0006] 2) As shown below:

[0007]

[0008] The literature reports a method for synthesizing the key intermediate dicarboxylic acid: 3-bromo-1-fluoro-7-hydroxynaphthalene is used as the starting material, which has a complex structure and is expensive; potassium permanganate, an easily-made drug reagent, is used as an oxidant.

[0009] 3) As shown below:

[0010]

[0011] This method uses LDA as a base, the reaction requires an anhydrous system and inert gas protection, and carbon dioxide bubbling is required. The operation requirements are high and large-scale preparation is difficult.

[0012] Therefore, there is a need for a new, safe and low-cost method for the preparation of 6-bromo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione. Summary of the invention

[0013] The purpose of the present invention is to overcome the above problems existing in the conventional technology and provide a method for preparing 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione.

[0014] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0015] A method for preparing 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione is characterized in that the preparation of 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione is based on 1-fluoronaphthalene as a starting material, and undergoes three steps of selective bromination, Oxone oxidation, and Ac2O dehydration anhydrification / amidation to obtain a finished product.

[0016] Furthermore, the reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0017] (I)

[0018] Furthermore, the specific steps of the reaction of the first step are: adding trifluoroacetic acid and 1-fluoronaphthalene to a reaction kettle and stirring, adding tribromoisocyanuric acid in batches at room temperature, heating to 80°C, refluxing and stirring to react for a period of time; monitoring the complete reaction of the raw materials by TLC, cooling to room temperature, concentrating under reduced pressure to remove most of the solvent, adding n-hexane and stirring, precipitating a large amount of solid, filtering to remove insoluble matter, washing the filter cake with n-hexane, combining the filtrate, washing twice with a saturated sodium carbonate solution, drying over anhydrous sodium sulfate for a period of time, filtering to remove the desiccant, and concentrating the filtrate under reduced pressure to obtain a crude product, and performing rapid silica gel column chromatography to obtain intermediate A.

[0019] Furthermore, the reaction in the second step is shown in formula (II), and the intermediate B is obtained after the reaction:

[0020] (II)

[0021] Furthermore, the specific steps of the reaction in the second step are: dissolving the intermediate A in acetonitrile and adding it to a reaction kettle, adding water, glacial acetic acid, and tetrabutylammonium chloride, adding potassium peroxymonosulfonate complex salt in batches under stirring at room temperature, and heating the temperature to 80° C. to react for a period of time after the addition; monitoring the complete reaction of the raw materials by TLC, adding ethyl acetate for extraction, extracting the aqueous phase with ethyl acetate again, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to remove the solvent to obtain a crude product, and performing rapid silica gel column chromatography to obtain intermediate B.

[0022] Furthermore, the reaction in the third step is shown in formula (III), and the finished product is obtained after the reaction:

[0023] (III)

[0024] Furthermore, the specific steps of the reaction in the third step are: adding intermediate B to a reactor, adding acetic acid and stirring evenly, adding acetic anhydride in batches, heating to 100°C and reacting for a period of time; monitoring the reaction of the raw materials by TLC, concentrating under reduced pressure and evaporating to remove acetic acid and acetic anhydride, dissolving the concentrate with glacial acetic acid, adding sodium acetate and 3-aminopiperidine-2,6-dione hydrochloride, heating to 100°C and reacting for a period of time, monitoring the reaction of the raw materials by TLC, concentrating under reduced pressure and removing most of the acetic acid, dissolving the concentrate with ethyl acetate, washing with water, saturated sodium bicarbonate aqueous solution, and hydrochloric acid aqueous solution in turn, drying the organic phase with anhydrous magnesium sulfate, filtering, and evaporating to obtain a crude finished product.

[0025] Further, the crude product is purified by column chromatography to obtain a refined product.

[0026] The beneficial effects of the present invention are:

[0027] The preparation method of 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione provided by the present invention is scientifically and reasonably designed, and can realize the safe preparation of 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione with the characteristics of environmental protection and low cost.

[0028] Of course, any product implementing the present invention does not necessarily need to achieve all of the above advantages at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0030] Figure 1 This is a schematic diagram of NMR detection of the finished product of the present invention;

[0031] Figure 2 This is a schematic diagram of NMR detection of the finished product of the present invention;

[0032] Figure 3 This is a schematic diagram of NMR detection of the finished product of the present invention;

[0033] Figure 4 This is a schematic diagram of LCMS detection of the finished product of the present invention;

[0034] Figure 5 It is a schematic diagram of HPLC detection of the finished product of the present invention. DETAILED DESCRIPTION

[0035] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] The specific designations of the abbreviations in this embodiment are as follows:

[0037] SM: 1-Fluoronaphthalene

[0038] TBICA: Tribromoisocyanuric acid

[0039] Oxone: Potassium peroxymonosulfonate complex salt

[0040] TBAC: Tetrabutylammonium chloride

[0041] AcOH: glacial acetic acid

[0042] MeCN: Acetonitrile

[0043] Ac2O: acetic anhydride

[0044] NaOAc: sodium acetate The specific embodiments of the present invention are:

[0045] Example 1

[0046] A method for preparing 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione is characterized in that the preparation of 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione is based on 1-fluoronaphthalene as a starting material, and undergoes three steps of selective bromination, Oxone oxidation, and Ac2O dehydration anhydrification / amidation to obtain a finished product.

[0047] The reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0048] (I)

[0049] The specific steps of the first step are as follows: trifluoroacetic acid (5.0 L) and SM (500.0 g, 1.0 eq.) are added to a reactor and stirred, TBICA (425.4 g, 0.34 eq.) is added in batches at room temperature, the temperature is raised to 80°C, refluxed and stirred for reaction for 8 hours, TLC monitors the reaction of the raw materials to be complete, the temperature is lowered to room temperature, and most of the solvent is removed by vacuum concentration, 3L of n-hexane is added and stirred, a large amount of solid is precipitated, and the insoluble matter is removed by filtration, the filter cake is washed with 1L of n-hexane, the filtrate is combined, washed twice with 4L of saturated sodium carbonate solution, dried over anhydrous sodium sulfate for 2 hours, filtered to remove the desiccant, and the filtrate is concentrated under reduced pressure to obtain a crude product, and rapid silica gel column chromatography is performed to obtain 628.2 g of intermediate A as an oily substance with a yield of 81.6%.

[0050] Mass spectrum: MS-ESI: 227.0 / 225.0 [M+H] + .

[0051] The reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction:

[0052] (II)

[0053] The specific steps of the second step are as follows: dissolve the intermediate A (628.2 g, 1.0 eq.) in acetonitrile (5 L) and add it to the reactor, add water (5 L), AcOH (251.3 g, 1.5 eq.), TBAC (77.6 g, 0.1 eq.), add Oxone (2059.1 g, 1.2 eq.) in batches under stirring at room temperature, and heat to 80°C for 8 hours after addition. TLC monitors the complete reaction of the raw materials, and ethyl acetate (5 L) is added for extraction. The aqueous phase is extracted once more with ethyl acetate (2 L), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to remove the solvent to obtain a crude product, which is quickly chromatographed on a silica gel column to obtain 544.1 g of the intermediate B solid with a yield of 74.1%.

[0054] Mass spectrum: MS-ESI: 264.0 / 262.0 [M+H] + .

[0055] The reaction in the third step is shown in formula (III), and the finished product is obtained after the reaction:

[0056] (III)

[0057] The specific steps of the reaction of the third step are as follows: add intermediate B (544.1 g, 1.0 eq.) into a reactor, add acetic acid (4 L) and stir evenly, add acetic anhydride (1055.0 g, 5 eq.) in batches, heat to 100°C and react for 8 h, monitor the reaction of the raw material by TLC, concentrate under reduced pressure and evaporate to remove acetic acid and acetic anhydride, dissolve the concentrate with 5 L of glacial acetic acid, add sodium acetate (848.1 g, 5.0 eq.) and SM2 (408.6 g, 1.2 eq.), heat to 100°C and react for 12 h, monitor the reaction of the raw material by TLC, concentrate under reduced pressure and remove most of the acetic acid, dissolve the concentrate with 4 L of ethyl acetate, wash with 4 L of water, saturated sodium bicarbonate aqueous solution (4 L), and 1N hydrochloric acid aqueous solution in sequence, dry the organic phase with anhydrous magnesium sulfate, filter, and evaporate to obtain a crude TM product, and obtain 532.6 g of the target product by flash column chromatography with a yield of 72.5%.

[0058] Mass spectrum: MS-ESI: 353.1 / 355.1[MH] - .

[0059] The relevant test results of the finished product are as follows: Figures 1 to 5 shown.

[0060] The preferred embodiments of the present invention disclosed above are only used to help explain the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to specific implementation methods. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing 6-bromo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione, characterized in that: The preparation of 6-bromo-2-(2,6-dioxopiperidin-3-yl)4-fluoroisoindoline-1,3-dione is carried out by using 1-fluoronaphthalene as a starting material, and undergoing three steps of selective bromination, Oxone oxidation, and Ac2O dehydration anhydrification / amidation to obtain the finished product. The reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction: （I） The specific steps of the first step are: adding trifluoroacetic acid and 1-fluoronaphthalene to a reaction kettle and stirring, adding tribromoisocyanuric acid in batches at room temperature, heating to 80°C, refluxing and stirring to react for a period of time; monitoring the reaction of the raw materials to be complete by TLC, cooling to room temperature, concentrating under reduced pressure to remove most of the solvent, adding n-hexane and stirring, precipitating a large amount of solid, filtering to remove insoluble matter, washing the filter cake with n-hexane, combining the filtrate, washing twice with a saturated sodium carbonate solution, drying over anhydrous sodium sulfate for a period of time, filtering to remove the desiccant, concentrating the filtrate under reduced pressure to obtain a crude product, and performing rapid silica gel column chromatography to obtain intermediate A; The reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction: (II) The specific steps of the reaction in the second step are: dissolving the intermediate A in acetonitrile and adding it to a reaction kettle, adding water, glacial acetic acid, and tetrabutylammonium chloride, adding potassium peroxymonosulfonate complex salt in batches under stirring at room temperature, and heating the temperature to 80° C. to react for a period of time after the addition; monitoring the reaction of the raw materials to be complete by TLC, adding ethyl acetate for extraction, extracting the aqueous phase with ethyl acetate again, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to remove the solvent to obtain a crude product, and performing rapid silica gel column chromatography to obtain the intermediate B; The reaction in the third step is shown in formula (III), and the finished product is obtained after the reaction: (III) The specific steps of the reaction in the third step are: adding intermediate B to a reactor, adding acetic acid and stirring evenly, adding acetic anhydride in batches, heating to 100°C and reacting for a period of time; monitoring the reaction of the raw materials by TLC, concentrating under reduced pressure and evaporating to remove acetic acid and acetic anhydride, dissolving the concentrate with glacial acetic acid, adding sodium acetate and 3-aminopiperidine-2,6-dione hydrochloride, heating at 100°C and reacting for a period of time, monitoring the reaction of the raw materials by TLC, concentrating under reduced pressure and removing most of the acetic acid, dissolving the concentrate with ethyl acetate, washing with water, saturated sodium bicarbonate aqueous solution, and hydrochloric acid aqueous solution in turn, drying the organic phase with anhydrous magnesium sulfate, filtering, and evaporating to obtain a crude finished product; The crude product is purified by column chromatography to obtain a refined product.

Images