A preparation method of 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione

Abstract

The present invention belongs to the technical field of pharmaceutical intermediates, and particularly relates to a preparation method of 4-bromo-2-(2,6-dioxopiperidin-3-yl)-7-fluoroisoindoline-1,3-dione. The preparation of 4-bromo-2-(2,6-dioxopiperidin-3-yl)-7-fluoroisoindoline-1,3-dione uses 1-fluoronaphthalene as the starting material and obtains the finished product through three steps of selective bromination, Oxone oxidation, and Ac2O dehydration and acid anhydride formation / amidation. The preparation method provided by the present invention is scientifically and reasonably designed and can realize the safe preparation of 4-bromo-2-(2,6-dioxopiperidin-3-yl)-7-fluoroisoindoline-1,3-dione with the characteristics of environmental protection and easy scale-up production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a method for preparing 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione. Background Art

[0002] 4-Bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione is an important pharmaceutical intermediate. Its corresponding CAS number is 2740657-30-9 and its chemical formula is C 13 H8BrFN2O4, molecular weight is 355.

[0003] After searching, the relevant reports on the preparation method of 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione are as follows:

[0004] 1) As shown below:

[0005]

[0006] The starting materials of the synthesis route of the preparation method have complex structures, are relatively expensive, and are not easy to obtain; LDA is used as a base in step 1, 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; step 2 requires protective gas and high-temperature reflux (130°C), the reaction time is long (24h), and the reaction yield is not ideal (63%).

[0007] 2) As shown below:

[0008]

[0009] This document reports the synthesis method of the key intermediate dicarboxylic acid: Step 1 uses the second type of easily-made drug bromine, which has unsatisfactory aromatic ring selectivity and cumbersome post-processing operations; Step 2 uses chromium trioxide as an oxidant, and large-scale preparation will produce a large amount of chromium-containing waste liquid, which is not conducive to environmental protection.

[0010] Therefore, there is a need for a new, safe, environmentally friendly, and easily scaled-up method for preparing 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione. Summary of the invention

[0011] The purpose of the present invention is to overcome the above problems existing in the conventional technology and provide a method for preparing 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione.

[0012] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0013] A method for preparing 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione. The preparation of 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione takes 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.

[0014] Furthermore, the reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0015] .

[0016] Furthermore, the specific steps of the reaction in the first step are: adding acetonitrile and water into a reaction kettle and stirring, adding 1-fluoronaphthalene, vanadium pentoxide and n-Bu4NBr, adding 30% hydrogen peroxide aqueous solution dropwise at room temperature, stirring at room temperature for a period of time, heating to 50°C and continuing to stir and react for a period of time; TLC monitoring the reaction of the raw materials is complete, cooling to room temperature, adding a saturated sodium thiosulfate solution until the starch potassium iodide test paper no longer turns blue, adding dichloromethane for extraction, extracting the aqueous phase with dichloromethane again, combining the organic phases, 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.

[0017] Furthermore, the reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction:

[0018]

[0019] 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.

[0020] Furthermore, the reaction in the third step is shown in formula (III), and the finished product is obtained after the reaction:

[0021] .

[0022] 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 for a period of time, monitoring the complete reaction of the raw materials by TLC, concentrating under reduced pressure and evaporating to remove acetic anhydride and acetic acid, dissolving the concentrate with 5L of acetic acid, adding sodium acetate and 3-aminopiperidine-2,6-dione hydrochloride, heating to 100°C for a period of time; monitoring the complete reaction of the raw materials by TLC, concentrating under reduced pressure and evaporating to remove most of the solvent, dissolving the condensate with ethyl acetate, washing with water, saturated sodium bicarbonate aqueous solution, and 1N hydrochloric acid aqueous solution in turn, drying the organic phase with anhydrous magnesium sulfate, filtering, and evaporating to obtain a crude finished product.

[0023] Further, the crude product is purified by column chromatography to obtain a refined product.

[0024] The beneficial effects of the present invention are:

[0025] The preparation method provided by the invention is scientifically and reasonably designed, and can realize the safe preparation of 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione with the characteristics of environmental protection and easy scale-up production.

[0026] 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

[0027] 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.

[0028] Figure 1 This is a schematic diagram of NMR detection of the finished product of the present invention;

[0029] Figure 2 This is a schematic diagram of NMR detection of the finished product of the present invention;

[0030] Figure 3 This is a schematic diagram of NMR detection of the finished product of the present invention;

[0031] Figure 4 This is a schematic diagram of LCMS detection of the finished product of the present invention;

[0032] Figure 5 It is a schematic diagram of HPLC detection of the finished product of the present invention. DETAILED DESCRIPTION

[0033] 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.

[0034] The specific designations of the abbreviations in this embodiment are as follows:

[0035] SM: 1-Fluoronaphthalene

[0036] Oxone: Potassium peroxymonosulfonate complex salt

[0037] TBAC: Tetrabutylammonium chloride

[0038] AcOH: glacial acetic acid

[0039] MeCN: Acetonitrile

[0040] Ac2O: acetic anhydride

[0041] NaOAc: Sodium acetate

[0042] The specific embodiments of the present invention are:

[0043] Example 1

[0044] A method for preparing 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione is characterized in that the preparation of 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione is carried out by using 1-fluoronaphthalene as a starting material, and undergoing selective bromination, Oxone oxidation, and Ac2O dehydration anhydrification / amidation to obtain a finished product in three steps.

[0045] The reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0046]

[0047] The specific steps of the first step are as follows: acetonitrile (5.0 L) and water (2.5 L) are added to a reaction kettle and stirred, SM (500.0 g, 1.0 eq.), vanadium pentoxide (310.9 g, 0.5 eq.) and n-Bu4NBr (2203.0 g, 2.0 eq.) are added, 30% hydrogen peroxide aqueous solution (3.9 L, 10 eq.) is added dropwise at room temperature, stirred at room temperature for 30 min, heated to 50° C. and stirred for 6 h. The reaction of the raw material is monitored by TLC, cooled to room temperature, a saturated sodium thiosulfate solution is added until the starch potassium iodide test paper no longer turns blue, dichloromethane (5 L) is added for extraction, the aqueous phase is extracted once more with dichloromethane (3 L), the organic phases are combined, dried over anhydrous sodium sulfate for 2 h, 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 689.7 g of intermediate A as an oily substance with a yield of 89.6%.

[0048] Mass spectrum: MS-ESI: 227.0 / 225.0 [M+H] + .

[0049] The reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction:

[0050]

[0051] The specific steps of the second step are: dissolve the intermediate A (689.7g, 1.0eq.) in acetonitrile (5L) and add it to the reactor, add water (5L), AcOH (275.8g, 1.5eq.), TBAC (84.8g, 0.1eq.), add Oxone (3763.2g, 1.2eq.) in batches under room temperature with stirring, and heat to 80°C for 8 hours after the addition. TLC monitors the complete reaction of the raw materials, and ethyl acetate (5L) is added for extraction. The aqueous phase is extracted once more with ethyl acetate (2L), 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, and rapid silica gel column chromatography is performed to obtain 646.3g of intermediate B solid, with a yield of 80.2%.

[0052] Mass spectrum: MS-ESI: 264.0 / 262.0 [M+H] + .

[0053] The reaction in the third step is shown in formula (III), and the finished product is obtained after the reaction:

[0054]

[0055] The specific steps of the reaction in the third step are: adding intermediate B (646.3 g, 1.0 eq.) to a reactor, adding acetic acid (4 L) and stirring evenly, adding acetic anhydride (1269.0 g, 5 eq.) in batches, heating to 100°C for reaction for 8 h, monitoring the reaction of the raw materials by TLC, concentrating under reduced pressure and evaporating to remove acetic anhydride and acetic acid, dissolving the concentrate with 5 L of acetic acid, adding sodium acetate (1002.7 g, 5.0 eq.) and 3-aminopiperidine-2,6-dione hydrochloride (483.1 g, 1.2 eq.), heating to 100°C for reaction for 12 h, monitoring the reaction of the raw materials by TLC, concentrating under reduced pressure and evaporating to remove most of the solvent, dissolving the concentrate with 4 L of ethyl acetate, washing with water (4 L), saturated sodium bicarbonate aqueous solution (4 L), and 1N hydrochloric acid aqueous solution in turn, drying the organic phase with anhydrous magnesium sulfate, filtering, and evaporating to obtain a crude finished product, and obtaining 665.3 g by flash column chromatography, with a yield of 76.6%.

[0056] Mass spectrum: MS-ESI: 352.9 / 354.9 [MH] - .

[0057] The relevant test results of the finished product are as follows: Figures 1 to 5 shown.

[0058] 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 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-fluoroisoindoline-1,3-dione, characterized in that: The preparation of 4-bromo-2-(2,6-dioxopiperidin-3-yl)7-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: The specific steps of the first step of the reaction are: adding acetonitrile and water into a reaction kettle and stirring, adding 1-fluoronaphthalene, vanadium pentoxide and n-Bu4NBr, adding 30% hydrogen peroxide aqueous solution dropwise at room temperature, stirring at room temperature for a period of time, heating to 50°C and continuing to stir and react for a period of time; monitoring the reaction of the raw materials by TLC, cooling to room temperature, adding a saturated sodium thiosulfate solution until the starch potassium iodide test paper no longer turns blue, adding dichloromethane for extraction, extracting the aqueous phase with dichloromethane again, combining the organic phases, 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; The reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction: 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: The specific steps of the reaction in the third step are: adding intermediate B to a reaction kettle, adding acetic acid and stirring evenly, adding acetic anhydride in batches, heating to 100°C for a period of time, monitoring the reaction of the raw materials by TLC, concentrating under reduced pressure and evaporating to remove acetic anhydride and acetic acid, dissolving the concentrate with 5L acetic acid, adding sodium acetate and 3-aminopiperidine-2,6-dione hydrochloride, heating at 100°C for a period of time; monitoring the reaction of the raw materials by TLC, concentrating under reduced pressure and evaporating to remove most of the solvent, dissolving the concentrate with ethyl acetate, washing with water, saturated sodium bicarbonate aqueous solution, and 1N 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.

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