WO2020131258A1

WO2020131258A1 - Method for the manufacture of 4-nitro-n-(c1-8 alkyl)phthalimide

Info

Publication number: WO2020131258A1
Application number: PCT/US2019/061615
Authority: WO
Inventors: Thomas Link Guggenheim; Ganesan Balakrishnan; Satish Chandra Pandey; Prashil LAKHETE; Sivakumar SREERAMAGIRI
Original assignee: Sabic Global Technologies B.V.
Priority date: 2018-12-21
Filing date: 2019-11-15
Publication date: 2020-06-25
Also published as: CN113396146A

Abstract

A method for the manufacture of 4-nitro-N-(C1-8 alkyl)phthalimide includes providing a first stream having a solution of a N-(C1-8 alkyl)phthalimide and sulfuric acid; and a second stream including nitric acid and sulfuric acid to a microreactor under conditions effective to provide a product stream including 4-nitro-N-(C1-8 alkyl)phthalimide. A method for the manufacture of 4-nitro-N-(C1-8 alkyl)phthalimide can include providing a first stream having a molten N-(C1-8 alkyl)phthalimide; and a second stream consisting of nitric acid; to a microreactor under conditions effective to provide a product stream including 4-nitro-N-(C1-8 alkyl)phthalimide Advantageously, 4-nitro-N-(C1-8 alkyl)phthalimide obtained by the process can have reduced levels of di-nitro byproducts.

Description

METHOD FOR THE MANUFACTURE OF 4-NITRO-N-(Ci-s ALKYL)PHTHALIMIDE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of EP Application No. 18215782.6, filed December 21, 2018, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND

[0001] N-substituted nitrophthalimides are useful starting reactants for making a variety of organic dianhydrides, bisimides, and polyimides. One method for preparing N-substituted nitrophthalimides is by reacting nitrophthalic anhydride and an organic isocyanate in the presence of an alkali carbonate catalyst. See, e.g., U.S. Pat. No. 3,868,389. In another method, a solution of N-alkylphthalimide in a solvent comprising 98-103 wt% concentrated sulfuric acid is contacted with 98-100 wt% concentrated nitric acid within a temperature range of 35-80°C in batch mode, then the reaction product is isolated by methylene chloride extraction. See, e.g., U.S. Pat. No. 3,933,852. Another method is a nitric acid-only process. See, e.g., U.S. Pat. No. 4,902,809.

[0002] In addition to the 3- and 4-isomers of N-alkyl nitrophthalimide produced by the above-described processes, a minor number of di-nitro derivatives of the N-alkyl phthalimide can also be formed, particularly when a combination of nitric acid and sulfuric acid is used. The primary di-nitro derivative formed is 3,5-di-nitro-4-hydroxy-N-alkyl phthalimide (DNPI). The presence of such di-nitro derivatives has generally been regarded as undesirable due to the detrimental effect on subsequent nitro displacement reactions, namely the formation of the desired bisimides in poor yields or the formation of high color bisimides which when converted to polymer, can lead to polymer discoloration. Accordingly, there has been intensive research and development directed to the removal of the di-nitro derivatives formed by various nitration process.

[0003] It would be advantageous to provide a method for manufacturing an N- substituted nitrophthalimide which can desirably reduce the amount of a di-nitro byproduct. It would be further advantageous to provide an improved production method having shorter reaction times.

SUMMARY [0004] A method for the manufacture of 4-nitro-N-(Ci-s alkyl)phthalimide, the method comprising: providing a first stream comprising a solution comprising a N-(Ci-s

alkyl)phthalimide and sulfuric acid; and a second stream comprising nitric acid and sulfuric acid; to a microreactor under conditions effective to provide a product stream comprising 4- nitro-N-(Ci-s alkyl)phthalimide.

[0005] A method for the manufacture of 4-nitro-N-(Ci-s alkyl)phthalimide, the method comprising: providing a first stream comprising a molten N-(Ci-s alkyl)phthalimide; and a second stream consisting of nitric acid; to a microreactor under conditions effective to provide a product stream comprising 4-nitro-N-(Ci-s alkyl)phthalimide.

[0006] The above described method and other features are exemplified by the following figure and detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The following figure represents an exemplary embodiment.

[0008] FIG. 1 shows a schematic illustration of the process according to an embodiment of the present disclosure.

DETAILED DESCRIPTION

[0009] The present inventors have advantageously discovered that 4-nitro-N-(Ci-s alkyl)phthalimides can be prepared using a microreactor. In particular, the present inventors have found that use of a microreactor enables carrying out the nitration reaction as a continuous solution reaction, facile control over highly exothermic reactions, operation at higher temperatures, shorter residence times, and minimization of process equipment and costs.

[0010] Accordingly, an aspect of the present disclosure is a method for the manufacture of 4-nitro-N-(Ci-s alkyl)phthalimide. The method comprises providing a first stream comprising a N-(C_I-8 alkyl)phthalimide and a second stream comprising nitric acid and sulfuric acid to a microreactor under conditions effective to provide a product stream comprising 4-nitro-N-(Ci-s alkyl)phthalimide. The N-(Ci-s alkyl)phthalimide can preferably be N-methylphthalimide.

[0011] The first stream is preferably in liquid form. In an aspect, the first stream comprises a molten N-(Ci-s alkyl)phthalimide. In an aspect, the first stream comprises a solution comprising the N-(Ci-s alkyl)phthalimide), preferably a solution comprising, or consisting of, the N-(C_I-8 alkyl)phthalimide) and sulfuric acid.

[0012] The second stream comprises nitric acid. The particular composition of the second stream can be determined based on the particular nitration process to be used. For example, in an aspect, the method can relate to a nitric acid-only nitration method, wherein the second stream consists of nitric acid. In a specific aspect, the first stream can comprise a molten N-(C_I-8 alkyl)phthalimide, which can be, for example, at a temperature of greater than 135 to 160°C, preferably 150 to 160°C, and the second stream consists of nitric acid. When the second stream comprises only nitric acid, the nitric acid can be present in the second stream so as to provide a molar ratio of nitric acid: N-(Ci-s alkyl)phthalimide of 9:1 to 30:1, preferably 20:1 to 30: 1. Molar ratios of 20: 1 or greater can be preferred in order to obtain a desirable rate of reaction.

[0013] The method described herein can also relate to a mixed acid nitration process. In an aspect, the first stream can comprise a solution comprising the N-(Ci-s alkyl)phthalimide and sulfuric acid, and the first stream is contacted with the second stream comprising nitric acid and sulfuric acid in the microreactor. For example, in an aspect, the second stream comprises, or consists of, a mixture of nitric acid and sulfuric acid. In a specific aspect, the first stream can comprise a solution comprising the N-(Ci-s alkyl)phthalimide and sulfuric acid, and the second stream comprises nitric acid and sulfuric acid. In the mixed acid nitration process, the nitric acid can be present in the second stream so as to provide a molar ratio of nitric acid: N-(Ci-s alkyl)phthalimide of 1.1 : 1 to 4: 1 , preferably greater than 1.1 : 1 to 2: 1. In the mixed acid nitration process, providing the first stream and the second stream to the microreactor can provide a reaction mixture comprising 10 to 50 weight percent, preferably 20 to 40 weight percent, more preferably 25 to 35 weight percent of the N-(Ci-s alkyl)phthalimide, based on the total weight of the first stream and the second stream.

[0014] The first stream and the second stream can be provided to the reactor

simultaneously. The addition of nitric acid to the first stream constitutes an exothermic reaction, which is preferably controlled by cooling the reactor.

[0015] The nitric acid and the sulfuric acid used in the present methods are concentrated nitric acid and concentrated sulfuric acid. The concentrated nitric acid can be 60-100%, or 70- 100%, or 80-100%, or 90-100%, or 95-100%, or 98-100%, or 60-70%, or 60-80%, or 60-90%, or 60-99% by weight concentrated nitric acid. In an aspect, the concentrated nitric acid is 90 to 100%, or 90-99%, or 98 to 100%, or 99 to 100% by weight concentrated nitric acid. The balance can be water. For example, in an aspect, the nitric acid can comprise at least 60% concentrated nitric acid, and up to 40% water. In an aspect, the nitric acid can comprise 99% concentrated nitric acid and 1% water. In an aspect, the nitric acid can also contain impurities including, for example, nitroform, tetranitromethane, trace metals, and the like, or a combination thereof. [0016] The concentrated sulfuric acid can be 70-100%, or 80-100%, or 85-100%, or 90- 100%, or 95-100%, or 98-100%, or 70-80%, or 70-85%, or 70-90%, or 70-95%, or 70-98% by weight concentrated sulfuric acid. In an aspect, the concentrated sulfuric acid is 90-99% by weight concentrated sulfuric acid, or 98-100%, or 98-99% by weight concentrated sulfuric acid. In an aspect, the concentrated sulfuric acid can be greater than 100% concentrated sulfuric acid, e.g., by the addition of oleum, also known as fuming sulfuric acid. Thus, the concentrated sulfuric acid can be up to 130%, for example 70-130%, or 70-105%, or 80-105%, or 85-105%, or 90-105%, or 95-105%, or 98-105%, or 95-103%, or 98-103%, or 99-103%, or 100-103% by weight concentrated sulfuric acid. The balance can be water. For example, in an aspect, the sulfuric acid can comprise at least 70% concentrated sulfuric acid, and up to 30% water. In some embodiments, the sulfuric acid can comprise 99% concentrated sulfuric acid and 1% water. In an aspect, the acid mixture of the second stream can be prepared by combining oleum with 70% nitric acid.

[0017] The microreactor of the present disclosure can be a tubular reactor or can have a coil design. In an aspect, the tubular reactor can accommodate 180-degree bends, affording a long length. The microreactor can have an internal diameter of 1 millimeter to 30 centimeters, or 1 to 10.5 centimeters, or 1 to 2 centimeters. The internal diameter of the microreactor can be selected based on the critical diameter for the particular reaction being carried out, for example based on the energetics of the particular reaction mixture. The microreactor can be made of a silicate glass, corrosion resistant stainless steel or metal alloys or other corrosion-resistant vitreous, ceramic or metal compounds.“Corrosion resistant” as used herein is understood to refer to corrosion resistance in the presence of a nitration agent, optionally under pressure and at elevated temperature. In an aspect, the microreactor can be made of corrosion resistant metal, or can be metal lined with an acid resistant coating, for example an acid resistant fluorinated polymer. The reactor can be designed for efficient heat removal, by adjusting the surface area:volume ratio accordingly. The length and diameter of the reactor is chosen based on required residence time for complete reaction and safety considerations.

[0018] In an aspect, the process and reactor can be configured as shown in Figure 1. As shown in Figure 1, a first stream 1 and a second stream 2 are fed to the continuous microreactor. The first stream comprises N-(Ci-s alkyljphthalimidc in liquid form (e.g., as a solution or in molten form). The second stream comprises nitric acid and sulfuric acid. The first and second streams are pumped to the microreactor. The microreactor can include one or more static mixers along the length of the reactor to facilitate mixing, and when present, the static mixers can be positioned in certain sections of the reactor or can be positioned throughout the reactor. The microreactor can also be contained in an enclosure, wherein heating or cooling media can be supplied to facilitate temperature control of the reactor.

[0019] The conditions effective to provide the product stream can be, for example, a temperature of 30 to 110°C. Within this range, the temperature can be at least 40, or at least 50, or at least 60, or at least 70 or at least 80 or at least 90°C. Also within this range, the temperature can be up to 105, or up to 100, or up to 90, or up to 80, or up to 70, or up to 60, or up to 50, or up to 40°C. In an aspect, the temperature can be less than or equal to 60°C, or 30- 60°C, or 35-60°C, or 40-60°C, or 45-55°C. In an aspect, the temperature can be 60 to 110°C, or 60 to 100°C. Temperatures outside the range of temperatures disclosed above also can be used; however, lower temperatures can result in a reaction rate that is too slow to be cost effective.

[0020] The conditions can also include a particular residence time in the reactor, for example, 1 minute to 3 hours, or 5 minutes to 2 hours, or 10 to 60 minutes, or 10 to 30 minutes. In an aspect, the residence time for the nitric acid-only process (i.e., when the second stream consists of nitric acid) can be 5 minutes to 3 hours, or 5 minutes to 2 hours, or 5 to 60 minutes. In some embodiments, the residence time for the mixed acid nitration process (i.e., when the second stream comprises nitric acid and sulfuric acid) can be 1 to 60 minutes, or 1 to 30 minutes, or 5 to 30 minutes, or 10 to 30 minutes.

[0021] The pressure range under which the nitration process operates can vary from vacuum to above atmospheric pressure. In an aspect, the process can be run at a pressure of 0 to 50 bar (0 to 49.3 atmospheres), or 1 to 20 bar (0.98 to 19.7 atmospheres), or 10 to 20 bar (9.8 to 19.7 atmospheres).

[0022] In an aspect, the first stream comprises N-methylphthalimide and sulfuric acid; the second stream comprises nitric acid and sulfuric acid, wherein the molar ratio of nitric acid to N-methylphthalimide is 1.1:1 to 4:1; the product stream comprises 4-nitro-N- (methyl)phthalimide and 0.0001 to 2 weight percent of 3,5-dinitro-4-hydroxy-N- methylphthalimide; and the conditions effective to provide the product stream comprise a temperature of 30 to 110°C and a residence time of 1 to 30 minutes.

[0023] In an aspect, the present inventors have unexpectedly discovered that in a mixed acid nitration process, the product stream can include significantly reduced amounts of a di-nitro byproduct, specifically 3,5-di-nitro-4-hydroxy-N-alkyl phthalimide, more specifically 3,5- dinitro-4-hydroxy-N-methylphthalimide. In an aspect, particularly when a mixed-acid nitration is used, the product stream can comprise less than 2.5 weight percent, or less than 2 weight percent, or less than 1 weight percent, or less than 0.5 weight percent 3,5-di-nitro-4-hydroxy-N- alkyl phthalimide byproduct. In an aspect, the product stream can comprise less than 0.1 weight percent (1000 ppm) of the di-nitro byproduct. Within this range, the di-nitro byproduct can be present in an amount of 0.0001 to less than 0.1 weight percent (1 to less than 1000 ppm) or 0.001 to less than 0.1 weight percent (10 to less than 1000 ppm), or 0.001 to 0.05 weight percent (10 to 500 ppm). In an aspect, after further purification of the product stream, for example as discussed below, the purified product stream can comprise less than 0.1 weight percent (1000 ppm) of the di-nitro byproduct. Within this range, the di-nitro byproduct can be present in an amount of 0.0001 to less than 0.1 weight percent (1 to less than 1000 ppm) or 0.001 to less than 0.1 weight percent (10 to less than 1000 ppm), or 0.001 to 0.05 weight percent (10 to 500 ppm). In some embodiments, a purified product stream can be substantially free of 4-hydroxy-3,5- dinitro-N-(Ci-s alkyl)phthalimide. The term“substantially free” means that the purified product stream (i.e., the isolated 4-nitro-N-(Ci-s alkyl)phthalamide composition) has less than 10 ppm, or less than 1 ppm of 4-hydroxy-3,5-dinitro-N-(Ci-s alkyl)phthalimide. In some embodiments, any 4-hydroxy-3,5-dinitro-N-(Ci-s alkyl)phthalimide is present in an amount that is not detectable, for example by a high-performance liquid chromatography (HPLC) method after recovery. Without wishing to be bound by theory, it is believed that the reduction in the amounts of 4- hydroxy-3,5-dinitro-N-(Ci-s alkyl)phthalimide is unexpectedly due to the in-situ destruction of 4-hydroxy-3,5-dinitro-N-(Ci-s alkyl)phthalimide during the mixed acid nitration at elevated temperatures that are facilitated by use of the microreactor of the present disclosure.

[0024] In an aspect, the product stream comprises a product mixture comprising the 4- nitro-N-(Ci-s alkyl)phthalimide, a 3-nitro-N-(Ci-s alkyl)phthalimide, and 4-hydroxy-3,5-dinitro- N-(C_I-8 alkyl)phthalimide. The method can optionally further comprise washing the product stream with water to precipitate the product mixture and isolating the precipitated product mixture as a 4-nitro-N-(Ci-s alkyl)phthalimide composition. Isolating the product mixture can be by, for example, filtration or centrifugation. The precipitated product mixture can further optionally be purified using a series of precipitation, washing, and extraction techniques. For example, the isolated precipitated product can be washed with water, which can be

accomplished using a belt filter, centrifuge, an agitated Nutsche filter, or a combination thereof. Washing with water removes the acids used in the nitration process and the more water-soluble 4-hydroxy-3,5-dinitro-N-(Ci-₈ alkyl)phthalimide. Washing is conducted for a time effective to remove the 4-hydroxy-3,5-dinitro-N-(Ci-s alkyl)phthalimide to the desired extent. However, although the 3- and 4-nitro-N-(Ci-s alkyl)phthalimides are less soluble in water, extended washing to remove the 4-hydroxy-3,5-dinitro-N-(Ci-s alkyl)phthalimide can result in an overall lower yield. Advantageously, the present inventors have further unexpectedly discovered that precipitating the product stream of the mixed acid nitration process at low temperature (e.g., 15 to 70°C, preferably 20 to 40°C) can minimize the loss of the desired products, particularly the corresponding 3-nitro-N-(Ci-s alkyl)phthalimide. Accordingly, in an aspect, the method can optionally further comprise adding water to the product stream at a temperature of 15 to 70°C, preferably 20 to 40°C to precipitate the product mixture and isolating the precipitated product mixture as a 4-nitro-N-(Ci-s alkyl)phthalimide composition, wherein the composition comprises a maximum amount of the corresponding 3-nitro-N-(Ci-s alkyl)phthalimide. .

[0025] Thus, in an aspect, the isolated 4-nitro-N-(Ci-s alkyl)phthalimide composition can comprise 4-nitro-N-(Ci-s alkyl)phthalimide; 0.0001 to 2 weight percent of 3,5-dinitro-4- hydroxy-N-(Ci-s alkyl)phthalimide; and 1 to 5 weight percent, preferably 2 to 5 weight percent, more preferably 3 to 5 weight percent of 3-nitro-N-(Ci-s alkyl)phthalimide.

[0026] In an aspect, the process further comprises contacting the washed product mixture with an aqueous alkali metal carbonate or aqueous alkali metal hydrogen carbonate solution, followed by extraction of the 4-nitro-N-(Ci-s alkyl)phthalimide into a solvent, for example as described in US Patent No. 8,080,671. Contacting the washed product mixture is effective to remove residual acid from the product mixture. Contacting the washed product mixture can be by adding the alkali metal carbonate or alkali metal hydrogen carbonate to the precipitated product mixture as a solid or as a solution, to obtain the desired solids content. It is also possible to add any amount of desired additional water at any point in the process. For example, a higher solids wet cake can be diluted with water to form a slurry, and the alkali metal carbonate or alkali metal hydrogen carbonate can be added directly to the slurry to provide the aqueous solution of the alkali metal carbonate or alkali metal hydrogen carbonate. In an aspect, the aqueous alkali metal carbonate comprises sodium carbonate or sodium hydrogen carbonate, preferably sodium hydrogen carbonate.

[0027] After the precipitated product mixture is contacted with the aqueous alkali metal carbonate or aqueous alkali metal hydrogen carbonate solution, an organic solvent is added, for example, toluene, benzene, xylene, chlorobenzene, anisole, or a combination thereof, at a temperature where the desired nitrated product dissolves in the solvent to form a two-phase mixture. The two-phase mixture can be heated, for example to 50-100°C to effect dissolution of the 4-nitro-N-(Ci-s alkyl)phthalimide into the organic solvent, thus providing the N-alkyl nitrophthalimide composition. The two-phase mixture can be separated to provide an aqueous phase and an organic phase, wherein the organic phase comprises the N-alkyl nitrophthalimide composition.

[0028] In an aspect, the washed N-alkyl nitrophthalimide product mixture is optionally first diluted with water, and then contacted with an organic solvent immiscible with water at elevated temperature, as described above, to provide a two-phase mixture. The two phases are separated, to result in the organic solvent phase containing the purified 4-nitro-N-(Ci-s alkyl)phthalimide composition. Or, optionally, after being separated from the water phase, the organic solvent phase can be further contacted with an aqueous alkali metal carbonate solution or an aqueous alkali metal hydrogen carbonate solution.

[0029] Thus, the present inventors have advantageously discovered an improved method for the nitration of N-(Ci-s alkyl)phthalimides using a microreactor. Specifically, the use of the microreactor enables carrying out the nitration reaction as a continuous solution reaction, facile control over highly exothermic reactions, operation at higher temperatures, shorter residence times, and minimization of process equipment and costs. Other unexpected advantages relate to the destruction of 3,5-dinitro-4-hydroxy-N-(Ci-₈ alkyl)phthalimide byproduct in a mixed acid nitration process, and the ability to minimize loss of the corresponding 3-nitro-N-(Ci-s alkyl)phthalimide product through dilution and precipitation of the reaction mixture under specific conditions. Accordingly, a significant improvement is provided by the method of the present disclosure.

[0030] This disclosure is further illustrated by the following examples, which are non limiting.

EXAMPLES

[0031] Materials used for the following examples are described in Table 1.

Table 1

[0032] Equipment Design and Reagent Purity

[0033] The tubular reactor is generally a plug flow reactor, made of a tube or a pipe, having a desired internal diameter, and being made of corrosion resistant metal or a metal lined with an acid resistant fluorinated polymer. The reactor can be of a coil design, or a pipe (or tube) constructed as shown in Figure 1. The reactor can also be equipped with internal static mixing elements to ensure the proper mixing of reactants. The static mixers can be in certain sections of the reactor or throughout the reactor. The reactor is contained within an enclosure, wherein a heating/cooling media can be circulated to achieve the desired temperature for the nitration reaction.

[0034] The PI used has a purity of >99%, wherein the major impurities comprise phthalic anhydride, phthalic acid, and the di-N-methylamide of phthalic acid. Other organic impurities in the PI are known to negatively affect the quality of the desired 4-nitro-N- methylphthalimide product. The sulfuric acid is >99 wt% H2SO4 with the balance being water. The nitric acid is 99 wt% HNO3, with the balance being water. The nitric acid can also contain substantial amounts of tetranitromethane.

[0035] PI (molten or dissolved in 98% sulfuric acid) is conveyed (pumped) to the tubular reactor along with 99% nitric acid or 99% nitric acid dissolved in 98% sulfuric acid, at the desired flow rates and temperature. The reactor can be equipped with a back-pressure control valve to provide the desired internal pressure of the reactor (0 to 50 bar). The back-pressure was generally controlled to 10 to 20 bar.

[0036] The effluent from the reactor contains the desired product dissolved in concentrated sulfuric acid in the presence of residual nitric acid, or the desired product dissolved in concentrated nitric acid. The extent of nitration is important in terms of material usage and purity of the product. The product is isolated via conveying the effluent to a vessel, equipped with cooling capacity, containing water or weak sulfuric acid (<20 wt% sulfuric acid). The product precipitates from solution at the desired temperature. The temperature of dilution can be selected so as to maximize the recovery of 3-NPI with the 4-NPI and can be, for example 15 to 40°C, preferably 20 to 30°C. The resulting slurry is then conveyed to equipment capable of removing the mother liquor, such as a continuous belt filter, a centrifuge, or an agitated Nutsche filter. In each case the precipitated product is washed with water, dilute sulfuric acid, or dilute nitric to remove residual acid and unwanted byproducts. The precipitate is then washed with water to complete the purification process. The temperature of the washing is controlled to minimize the loss of 3-NPI and 4-NPI, while maximizing the removal of DNPI and other impurities. Finally the purified product, containing from 0.01 to 5 wt% of 3-NPI and <3000 ppm of DNPI can be dried to a powder containing <70 wt% water, or stored in water and manipulated as a slurry in water at 5 to 25 wt% solids.

Example 1

[0037] A vessel was charged with 80 grams of 99% sulfuric and 20 grams of PI was slowly added with stirring at 30 to 40 °C. Another vessel was charged with 100 grams of 99% nitric acid and 100 grams of 99% sulfuric acid. The materials were conveyed to a coiled tubular micro-reactor made of a fluorinated polymer resistant to strong sulfuric acid and nitric acid, with an internal diameter of 1 mm, with a total volume of 10 mL. The feed rate of the Pl/sulfuric acid mixture was 2.1 mL/min, and the flow of the acid solution was 0.4 mL/min. The residence time in the reactor was 4 minutes. The molar ratio of nitric acid and PI was 1.2:1. The reactor was enclosed in a cavity (e.g., an appropriately designed oven) capable of being heated, wherein the temperature of the cavity and reactor was controlled to within 1°C. In this example, the temperature was controlled to 70 °C. The exit of the reactor was equipped with a back-pressure control valve. The back-pressure was controlled to 10 to 20 bar. The effluent was directed to a vessel containing the desired dilution media, which in all examples was water.

[0038] The effluent from the back-pressure control valve (prior to being diluted in water) was diluted in the appropriate solvent and analyzed by HPLC for the extent of reaction (i.e., PI consumption) and the yields of 3-NPI, 4-NPI, and DNPI were determined. In this example the extent of reaction was 87.7% (i.e., 87.7% of the PI was converted to products). The recovered solids included 82.94 wt% 4-NPI, 2.707 wt% 3-NPI, and 2.49 wt% DNPI. The specifics of this example are shown in Table 2.

Examples 2 and 3

[0039] The reactor as described in Example 1 was fed PI diluted in 99% sulfuric acid at 20 wt% solids at 1.23 mL/min, and 99 wt% nitric acid at 0.44 mL/min. The residence time in the reactor was 6 minutes and the molar ratio of nitric acid to PI was 2:1, with an oven temperature of either 60 °C or 80 °C. The extent of conversion at 60 °C was 76% and 89% at 80 °C. In Example 2 (at 60°C), the recovered solids included 1.85 wt% DNPI and in Example 3 (at 80°C), the recovered solids included 1.96 wt% DNPI.

Examples 4 and 5

[0040] The reactor as described in Example 1 was fed PI diluted in 99% sulfuric acid at 15 wt% solids and a 50/50 (wt/wt) mixture of 99 wt% nitric acid and 99% sulfuric acid. The residence time in the reactor was 6 minutes and the molar ratio of nitric acid to PI was either 1.4:1 (Example 4) or 2.2:1 (Example 5), with an oven temperature of 80 °C. The extent of conversion at a molar ratio of 1.4:1 was 88% and 100% at a molar ratio of 2.2:1. In Example 4, the recovered solids included 1.68 wt% DNPI and in Example 5, the recovered solids included 0.53 wt% DNPI

Examples 6 and 7

[0041] The reactor as described in Example 1 was fed PI diluted in 99% sulfuric acid at 20 wt% solids at 1.85 mL/min, and a 50/50 (wt/wt) mixture of 99 wt% nitric acid and 99% sulfuric acid 0.65 mL/min. The residence time in the reactor was 4 minutes and the molar ratio of nitric acid to PI was 2.2:1, with an oven temperature of either 60 °C or 70 °C. The extent of conversion at 60 °C was 99.2% (Example 6) and 99.6% at 70 °C (Example 7). The reaction at 70 °C showed that a significant amount of the DNPI produced had been destroyed under these reaction conditions. In Example 6 (at 60°C), the recovered solids included 1.84 wt% DNPI and in Example 7 (at 70°C), the recovered solids included 1.4 wt% DNPI.

Examples 8-11

[0042] The reactor as described in Example 1 was fed PI diluted in 99% sulfuric acid at 15 wt% solids and a 50/50 (wt/wt) mixture of 99 wt% nitric acid and 99% sulfuric acid. The flow rates of each were adjusted to provide residence times in the reactor of 4, 6, 8 and 10 minutes (Examples 8-11, respectively) and the molar ratio of nitric acid to PI was 2.2: 1 in all cases, with an oven temperature of 70 °C. The extent of conversion at 4 minutes residence time was 98.6%, 99.1% at 6 minutes, 100% at 8 minutes, and 99% at 10 minutes. In example 8, the recovered solids included 0.3 wt% DNPI; in example 9, the recovered solids included 4.43 wt% DNPI; in example 10, the recovered solids included 3.6 wt% DNPI; and in example 11, the recovered solids included 3.2 wt% DNPI.

Examples 12-14

[0043] The reactor as described in Example 1 was fed PI diluted in 99% sulfuric acid at 15 wt% solids at 1.31 mL/min and 99 wt% nitric acid at 0.36 mL/min. The residence time in the reactor was 6 minutes and the molar ratio of nitric acid to PI was 4:1, with an oven temperature of either 90, 98 or 108°C (Examples 12-14, respectively). The extent of conversion at 90°C was 99.9%, 99.8% at 98 °C, and 100% at 108 °C. The DNPI was nearly all destroyed under the reaction conditions at 100 °C. In example 12, the recovered solids included 0.19 wt% DNPI; in example 13, the recovered solids included 0.287 wt% DNPI; and in example 14, the recovered solids included 0.058 wt% DNPI.

[0044] Table 2 summarizes the reaction conditions and results for each of Examples 1- 14 as discussed above.

Table 2

*DNPI amount diminished

[0045] For comparison, Comparative Example 1 was conducted as a batch reaction. The reaction conditions for the batch reaction were as shown in Table 3.

Table 3

[0046] The batch experiment was performed by adding HNO3 dropwise to the round bottom flask containing the PI in H2SO4. At various time intervals, samples were withdrawn for analysis. The samples were quenched with water to provide a slurry, which was filtered and the solids washed with water. The wet solid was dried in an oven and analyzed using HPLC. Table 4 below show the composition of the recovered solids at 2, 4, 120 and 180 minutes. 12.5% of unreacted PI was observed after 180 minutes residence time in the batch reaction (i.e., the batch reaction reached a conversion of 87.5 %).

Table 4

[0047] This disclosure further encompasses the following aspects.

[0048] Aspect 1: A method for the manufacture of 4-nitro-N-(Ci-s alkyl)phthalimide, the method comprising: providing a first stream comprising a solution comprising a N-(Ci-s alkyl)phthalimide and sulfuric acid; and a second stream comprising nitric acid and sulfuric acid; to a microreactor under conditions effective to provide a product stream comprising 4- nitro-N-(Ci-s alkyl)phthalimide.

[0049] Aspect 2: A method for the manufacture of 4-nitro-N-(Ci-s alkyl)phthalimide, the method comprising: providing a first stream comprising a molten N-(Ci-s alkyl)phthalimide; and a second stream consisting of nitric acid; to a microreactor under conditions effective to provide a product stream comprising 4-nitro-N-(Ci-s alkyl)phthalimide.

[0050] Aspect 3: The method of aspect 1 or 2, wherein the first stream and the second stream are provided simultaneously to the microreactor.

[0051] Aspect 4: The method of any one or more of aspects 1 to 3, wherein the first stream and the second stream are provided to the microreactor at a temperature of 30 to 110°C.

[0052] Aspect 5: The method of any one or more of aspects 1 to 4, wherein the N-(Ci-s alkyl)phthalimide is N-methylphthalimide.

[0053] Aspect 6: The method of aspect 1, wherein the nitric acid is present in the second stream in a molar ratio 1.1:1 to 4:1 of nitric acid: N-(Ci-s alkyl)phthalimide.

[0054] Aspect 7: The method of aspect 2, wherein the nitric acid is present in the stream in a molar ratio of 20:1 to 30:1 of nitric acid: N-(Ci-s alkyl)phthalimide.

[0055] Aspect 8: The method of any one or more of aspects 1 to 7, wherein providing the first stream and the second stream to the microreactor provides a reaction mixture comprising 10 to 50 weight percent, preferably 20 to 40 weight percent, more preferably 25 to 35 weight percent of the N-(Ci-s alkyl)phthalimide, based on the total weight of the first stream and the second stream.

[0056] Aspect 9: The method of any one or more of aspects 1 to 8, wherein the microreactor has an internal diameter of 1 millimeter to 30 centimeters, or 1 to 10.5 centimeters, or 1 to 2 centimeters. [0057] Aspect 10: The method of any one or more of aspects 1 to 9, wherein providing the first stream and the second stream to the microreactor to provide the product stream is at: a temperature of 70 to 110°C; a residence time of 1 minute to 3 hours, or 5 minutes to 20 hours, or 10 to 60 minutes, or 1 to 30 minutes; or both.

[0058] Aspect 11: The method any one or more of aspects 1 or 3 to 10, wherein the product stream comprises less than 2 weight percent a di-nitro byproduct.

[0059] Aspect 12: The method of aspect 11, wherein the di-nitro byproduct comprises 3,5-dinitro-4-hydroxy-N-methylphthalimide.

[0060] Aspect 13: The method of aspect 1, wherein the first stream comprises N- methylphthalimide and sulfuric acid; the second stream comprises nitric acid and sulfuric acid, wherein the molar ratio of nitric acid to N-methylphthalimide is 1.1:1 to 4:1; the product stream comprises 4-nitro-N-(methyl)phthalimide and 0.001 to 2 weight percent of 3,5-dinitro-4- hydroxy-N-methylphthalimide; and the conditions effective to provide the product stream comprise a temperature of 30 to 110°C and a residence time of 1 to 30 minutes.

[0061] Aspect 14: The method of any one or more of aspects 1 to 13, wherein the product stream comprises a product mixture comprising the 4-nitro-N-(Ci-s alkyl)phthalimide, a 3-nitro-N-(Ci-s alkyl)phthalimide, and 3,5-dinitro-4-hydroxy-N-methylphthalimide, and the method further comprises: adding water to the product stream at a temperature of 15 to 70°C, preferably 20 to 40°C to precipitate the product mixture; and isolating the product mixture to provide a of 4-nitro-N-(Ci-s alkyl)phthalimide composition; wherein the 4-nitro-N-(Ci-s alkyl)phthalimide composition comprises 4-nitro-N-(Ci-s alkyl)phthalimide; 0.001 to 2 weight percent of 3,5-dinitro-4-hydroxy-N-methylphthalimide; and 1 to 5 weight percent, preferably 2 to 5 weight percent, more preferably 3 to 5 weight percent of 3-nitro-N-(Ci-s alkyl)phthalimide.

[0062] The methods can alternatively comprise, consist of, or consist essentially of, any appropriate materials, steps, or components herein disclosed. The methods can additionally, or alternatively, be formulated so as to be devoid, or substantially free, of any materials (or species), steps, or components, that are otherwise not necessary to the achievement of the function or objectives of the compositions, methods, and articles.

[0063] All ranges disclosed herein are inclusive of the endpoints, and the endpoints are independently combinable with each other. “Combinations” is inclusive of blends, mixtures, alloys, reaction products, and the like. The terms“first,”“second,” and the like, do not denote any order, quantity, or importance, but rather are used to distinguish one element from another. The terms“a” and“an” and“the” do not denote a limitation of quantity, and are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. “Or” means“and/or” unless clearly stated otherwise. Reference throughout the specification to“some embodiments,”“an embodiment,” and so forth, means that a particular element described in connection with the embodiment is included in at least one embodiment described herein, and may or may not be present in other embodiments. The term “combination thereof’ as used herein includes one or more of the listed elements, and is open, allowing the presence of one or more like elements not named. In addition, it is to be

understood that the described elements may be combined in any suitable manner in the various embodiments.

[0064] Unless specified to the contrary herein, all test standards are the most recent standard in effect as of the filing date of this application, or, if priority is claimed, the filing date of the earliest priority application in which the test standard appears.

[0065] Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this application belongs. All cited patents, patent applications, and other references are incorporated herein by reference in their entirety. However, if a term in the present application contradicts or conflicts with a term in the incorporated reference, the term from the present application takes precedence over the conflicting term from the incorporated reference.

[0066] Compounds are described using standard nomenclature. For example, any position not substituted by any indicated group is understood to have its valency filled by a bond as indicated, or a hydrogen atom. A dash

that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CHO is attached through carbon of the carbonyl group.

[0067] Unless substituents are otherwise specifically indicated, each of the foregoing groups can be unsubstituted or substituted, provided that the substitution does not significantly adversely affect synthesis, stability, or use of the compound.“Substituted” means that the compound, group, or atom is substituted with at least one (e.g., 1, 2, 3, or 4) substituents instead of hydrogen, where each substituent is independently nitro (-NO₂), cyano (-CN), hydroxy (-OH), halogen, thiol (-SH), thiocyano (-SCN), Ci-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, Ci-6 haloalkyl, C_1-9 alkoxy, Ci-6 haloalkoxy, C_3-12 cycloalkyl, C_5-18 cycloalkenyl, C_6-12 aryl, C_7-13 arylalkylene (e.g., benzyl), C_7-12 alkylarylene (e.g, toluyl), C_4-12 heterocycloalkyl, C_3-12 heteroaryl, Ci-6 alkyl sulfonyl (-S(=0)₂-alkyl), C_6-12 arylsulfonyl (-S(=0)₂-aryl), or tosyl (CH₃C₆H₄SO₂-), provided that the substituted atom’s normal valence is not exceeded, and that the substitution does not significantly adversely affect the manufacture, stability, or desired property of the compound. When a compound is substituted, the indicated number of carbon atoms is the total number of carbon atoms in the compound or group, including those of any substituents.

[0068] While particular embodiments have been described, alternatives, modifications, variations, improvements, and substantial equivalents that are or may be presently unforeseen may arise to applicants or others skilled in the art. Accordingly, the appended claims as filed and as they may be amended are intended to embrace all such alternatives, modifications variations, improvements, and substantial equivalents.

Claims

CLAIMS What is claimed is:

1. A method for the manufacture of 4-nitro-N-(Ci-s alkyl)phthalimide, the method comprising:

providing

a first stream comprising a solution comprising a N-(Ci-s alkyl)phthalimide and sulfuric acid; and

a second stream comprising nitric acid and sulfuric acid;

to a microreactor under conditions effective to provide a product stream comprising 4- nitro-N-(Ci-s alkyl)phthalimide.

2. A method for the manufacture of 4-nitro-N-(Ci-s alkyl)phthalimide, the method comprising:

providing

a first stream comprising a molten N-(Ci-s alkyl)phthalimide; and a second stream consisting of nitric acid;

to a microreactor under conditions effective to provide a product stream comprising 4-nitro-N- (C 1 -₈ alkyl)phthalimide .

3. The method of claim 1 or 2, wherein the first stream and the second stream are provided simultaneously to the microreactor.

4. The method of any one or more of claims 1 to 3, wherein the first stream and the second stream are provided to the microreactor at a temperature of 30 to 110°C.

5. The method of any one or more of claims 1 to 4, wherein the N-(Ci-s

alkyl)phthalimide is N-methylphthalimide.

6. The method of claim 1, wherein the nitric acid is present in the second stream in a molar ratio 1.1:1 to 4:1 of nitric acid: N-(Ci-s alkyl)phthalimide.

7. The method of claim 2, wherein the nitric acid is present in the stream in a molar ratio of 20:1 to 30:1 of nitric acid: N-(Ci-s alkyl)phthalimide.

8. The method of any one or more of claims 1 to 7, wherein providing the first stream and the second stream to the microreactor provides a reaction mixture comprising 10 to 50 weight percent, preferably 20 to 40 weight percent, more preferably 25 to 35 weight percent of the N-(C_I-8 alkyl)phthalimide, based on the total weight of the first stream and the second stream.

9. The method of any one or more of claims 1 to 8, wherein the microreactor has an internal diameter of 1 millimeter to 30 centimeters, or 1 to 10.5 centimeters, or 1 to 2 centimeters.

10. The method of any one or more of claims 1 to 9, wherein providing the first stream and the second stream to the microreactor to provide the product stream is at:

a temperature of 70 to 110°C;

a residence time of 1 minute to 3 hours, or 5 minutes to 20 hours, or 10 to 60 minutes, or 1 to 30 minutes;

or both.

11. The method any one or more of claims 1 or 3 to 10, wherein the product stream comprises less than 2 weight percent a di-nitro byproduct.

12. The method of claim 11, wherein the di-nitro byproduct comprises 3,5-dinitro-4- hydroxy-N-methylphthalimide .

13. The method of claim 1, wherein

the first stream comprises N-methylphthalimide and sulfuric acid;

the second stream comprises nitric acid and sulfuric acid, wherein the molar ratio of nitric acid to N-methylphthalimide is 1.1:1 to 4:1;

the product stream comprises 4-nitro-N-(methyl)phthalimide and 0.001 to 2 weight percent of 3,5-dinitro-4-hydroxy-N-methylphthalimide; and

the conditions effective to provide the product stream comprise a temperature of 30 to 110°C and a residence time of 1 to 30 minutes.

14. The method of any one or more of claims 1 to 13, wherein the product stream comprises a product mixture comprising the 4-nitro-N-(Ci-s alkyl)phthalimide, a 3-nitro-N-(Ci-s alkyl)phthalimide, and 3,5-dinitro-4-hydroxy-N-methylphthalimide, and the method further comprises:

adding water to the product stream at a temperature of 15 to 40°C, preferably 20 to 30°C to precipitate the product mixture; and

isolating the product mixture to provide a of 4-nitro-N-(Ci-s alkyl)phthalimide composition;

wherein the 4-nitro-N-(Ci-s alkyl)phthalimide composition comprises

4-nitro-N - (C i -s alkyl)phthalimide ;

0.001 to 0.1 weight percent of 3,5-dinitro-4-hydroxy-N-methylphthalimide; and 1 to 5 weight percent, preferably 2 to 5 weight percent, more preferably 3 to 5 weight percent of 3-nitro-N-(Ci-s alkyl)phthalimide.