Intermediates for synthesis of iprotecan mesylate

Abstract

The compound can be used for preparing an intermediate and related compounds of iprotecan mesylate. Further provided are methods for preparing these compounds. Also provided are improved, scalable synthesis of iprotecan mesylate using the provided intermediates. The synthesis of iprotecan mesylate utilizes a convergent pathway, includes fewer steps and utilizes fewer reagents and improves efficiency.

Description

[0001] Cross-references to related applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 516,024, filed July 27, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Exatecan mesylate is a sought-after payload for antibody-drug conjugates (ADCs). Enhertu is a commercial ADC therapy utilizing derutincan, which is synthesized from exatecan mesylate. In addition, several experimental ADCs utilizing exatecan-based payloads exist.

[0003] The commercial supply of ixenocarb is tightly controlled, with high entry costs and challenging synthetic routes for its production. Current prior art methods for synthesizing ixenocarb mesylate rely on the linear assembly of a bicyclic core followed by low-yield amination. Such methods are described in published patent applications such as US20200384121 and WO2022000868.

[0004] New synthetic methods are needed to overcome significant supply issues that limit the research and commercialization of icotinamide-based ADCs. Such routes should offer improved yields, be scalable for manufacturing, and eliminate the need for chromatographic purification. Summary of the Invention

[0005] This provides a novel intermediate that can be used to synthesize ixotecan mesylate and related synthesis.

[0006] The first intermediate provided is a compound of formula I: I.

[0007] The other intermediates provided include those of formulas II, III, and IV: II III IV.

[0008] A further method for preparing compounds of formula I is provided, the method comprising the steps of: providing N-(3-fluoro-5-iodo-4-methylphenyl)acetamide, and respectively (a) reacting 3-bromo-2-oxotetrahydrofuran with potassium phthalimide to provide 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione; and (b) reacting 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione with trimethyliodosilane (TMSI) to form the corresponding carboxylic acid (IV). IV; (c) React the carboxylic acid of (c) with indium powder and copper iodide (I) to form indium intermediate (III). III; (d) React indium intermediate (III) with N-(3-fluoro-5-iodo-4-methylphenyl)acetamide to form intermediate (II). II; (e) Perform ring closure to produce a compound of formula (I). I. Attached Figure Description

[0009] The accompanying drawings are provided to illustrate one or more versions of the invention and should not be construed as limiting the scope of the claims.

[0010] Figure 1 The preparation of the intermediates provided herein is illustrated.

[0011] Figure 2 The synthesis of iciticon mesylate from the provided intermediates is shown. Detailed Implementation

[0012] This article provides new intermediates for the preparation of ixenocarb mesylate and methods for synthesizing these intermediates, thus providing new and efficient routes for the synthesis of ixenocarb mesylate and other ixenocarb-based payloads.

[0013] The improved synthesis is shown in Figure 1 The use of a bromolactone arm in the synthesis provides a key improvement over existing methods. By introducing the amine protected as phthalimide into the palladium coupling coupler, a shorter, longest linear route compared to conventional synthetic routes is achieved. Furthermore, as shown in the examples, the route provided herein does not utilize or require column chromatography. Moreover, this route is scalable for manufacturing.

[0014] like Figure 1 As shown, significant improvements in synthesis were achieved by utilizing an indium-based palladium cross-coupling reaction in the preparation of the cyclization intermediate: .

[0015] In addition, the cyclization intermediate is protected as phthalimide, compound I I, This approach offers significant advantages in streamlining the synthesis of ixenocarbam mesylate. Furthermore, it allows for alternative, scalable routes for ixenocarbam mesylate, offering a significant advantage by shortening the longest linear synthetic route, which in turn reduces the amount of starting materials required. By utilizing a more convergent pathway, individual reactions are smaller in scale and more efficient in synthesis.

[0016] Preparation of intermediates N-(3-fluoro-5-iodo-4-methylphenyl)acetamide is prepared according to the route described below, or it can be obtained from commercial sources.

[0017] Preparation of 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione In the presence of a catalyst (preferably tetrabutylammonium bromide (TBAB)) and a base (preferably cesium carbonate), 3-bromo-2-oxotetrahydrofuran is reacted with potassium phthalimide in acetone to form 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione.

[0018] 4-(5-acetamido-3-fluoro-2-methylphenyl)-2-(1,3-dioxoisoindololin-2-yl)butyric acid was prepared by compounds (III) and (IV), and compound (II) was prepared by compound (IV). In a first reactor, 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione was reacted with excess trimethyliodosilane in dichloromethane to produce the corresponding terminal iodocarboxylic acid. The resulting carboxylic acid was isolated, and then copper iodide (I) and indium powder were added sequentially. The resulting suspension was purged with nitrogen, and N,N-dimethylacetamide (DMAc) was added. The mixture was heated to allow the reaction to proceed, and then cooled to form an indium-containing intermediate. Fluoro-5-iodo-4-methylphenyl)acetamide and dried lithium chloride were added to a second reactor, and the organic matter from the first reactor was filtered into the second reactor. Palladium(II) chloride was added, and the reaction mixture was heated to 110°C and stirred vigorously for a sufficient time to allow the reaction to complete. The mixture was then cooled to 80°C to remove volatiles, and then cooled to 40°C. Methyl ethyl ketone was added, and the suspension was stirred, and then filtered. The filtrate was heated to 60°C and concentrated to remove methyl ethyl ketone. The resulting solution was cooled to 15°C, and a solution of phosphoric acid in water was slowly added with stirring. The mixture was cooled to 5°C, and the product was allowed to precipitate. This precipitate was then filtered, washed, and concentrated. The product was further purified in nitromethane and MTBE, and then dried.

[0019] Ring closure and aniline deprotection to form compound (I). 4-(5-acetamido-3-fluoro-2-methylphenyl)-2-(1,3-dioxoisoindoline-2-yl)butyric acid and methanesulfonic anhydride were combined, and the reaction was heated to reflux and stirred until complete. The reaction was cooled to 15°C, methanol was added, and the mixture was stirred for 10 h. The mixture was then concentrated, cooled to 5°C, and water was slowly added, with the temperature not exceeding 30°C. The product was then washed, filtered, and dried to provide 2-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)isoindoline-1,3-dione.

[0020] Preparation of EXA-aniline An aqueous solution of HCl in 2-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)isoindoline-1,3-dione and acetic acid were added sequentially to a reactor, followed by purging with nitrogen and heating to reflux. The reaction was allowed to proceed to completion, and then cooled to allow the phthalic acid byproduct to form a white precipitate. The reactants were filtered, concentrated, and dried. A solvent (preferably THF, EtOAc, or acetone), isopropanol, and a base (preferably an aqueous solution of KHCO3 or K2CO3) were added to the resulting residue under stirring. The reaction was cooled to 5°C under nitrogen bubbling, and acetic anhydride was carefully added with stirring; the reaction was stirred for another 30 min. Methanol was added, and the reactor was stirred for another 15 min, then the volatiles were removed. Water was added, and the mixture was heated to 40°C and stirred vigorously for 15 min. The aqueous layer was filtered off, and the solid was washed with an aqueous solution of water and ethanol and dried. Acetone was added, and the resulting suspension was heated to 50°C and stirred for 3 h, then cooled. The crystals were filtered again and dried to provide EXA-aniline.

[0021] Iciticon mesylate was prepared using EXA-aniline.

[0022] In the first step, EXA-aniline is reacted with (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1 H -pyrano[3,4- f Indazine-3,6,10(4) H )-trione (EXA-trione) condensation.

[0023] This condensation step is carried out in toluene containing o-cresol in the presence of an acid catalyst (preferably pyridinium p-toluenesulfonate (PPTS)). The acid catalyst can be used in an amount sufficient to carry out the reaction, preferably 0.03 to 0.3 equivalents based on EXA-aniline. The reaction is carried out at a temperature in the range of 90 to 130°C for a duration sufficient to complete the reaction, typically 16 hours or longer.

[0024] The resulting compound was deprotected using methanesulfonic acid (MsOH) to produce icetane mesylate. Example

[0025] The following examples are illustrative in nature and are not intended to limit the scope of the invention as defined by the claims.

[0026] Example 1. Preparation of 1-fluoro-3-iodo-2-methyl-5-nitrobenzene.

[0027] Sulfuric acid (8 volumes) was added to a stirred reactor in air. The reactor was cooled to 5°C, and sodium iodide (0.96 equivalents) was added in one go, followed by a slight exothermic reaction. The reactor was cooled back to 5°C, and sodium periodate (0.32 equivalents) was added in one go. The resulting dark brown liquid was stirred at 5°C for another 30 min. 2-Fluoro-1-methyl-4-nitrobenzene (100.0 g, 1 equivalent) was added in a single part, and the reactor temperature was raised to 15°C. The viscous mixture was stirred vigorously for 22 h, after which less than 5% of the starting material remained. The reactants were slowly poured into ice (1200 g) stirred at 0°C over 1 h. The quenched reactants were then warmed to 15°C with continuous stirring. The reactants were vacuum filtered to produce a slightly reddish solid, which was then washed twice with water (2 x 8 volumes). Toluene (12 volumes) was added, followed by an aqueous solution of sodium sulfite (0.8 M, 8 volumes). The two-phase suspension was heated to 40°C for 30 min under vigorous stirring. Stirring was stopped, and the suspension was allowed to separate at 40°C for 10 min. The aqueous layer was removed, and additional toluene (4 volumes) was added. The two-phase mixture was stirred at 40°C for another 5 min, then separated, and the depleted aqueous layer was again removed and discarded. The combined organic layers were washed sequentially with an aqueous solution of sodium carbonate (ReagentPlus® grade, MilliporeSigma, St. Louis, Missouri, 0.75 M, 3 volumes) and an aqueous solution of sodium chloride (2.0 M, 3 volumes). The resulting pale yellow mixture was filtered through a celite pad and washed with a very small amount of toluene (2 volumes). The filtrate was concentrated under vacuum to give a yellow residue. The residue was crystallized from boiling MeCN / water (based on crude material, 5 volumes / 2 volumes) according to the following procedure: The stirred suspension was heated to boiling, aged for 30 min, and cooled back to 5°C over 5 hours with very gentle stirring (approximately 10 rpm), precipitating pale yellow crystals. The mother liquor was filtered off, and the crystals were washed twice with 50% MeCN aqueous solution (2 x 4 volumes) and concentrated under vacuum to obtain pale yellow crystals (92.5 g, 50% yield).

[0028] Example 2. N Preparation of 3-(3-fluoro-5-iodo-4-methylphenyl)acetamide.

[0029] Under nitrogen (N2), iron powder (4.4 equivalents) and acetic acid (6 volumes) were added sequentially in a single batch to a stirred reactor. The reactor was heated to 85°C, and a pre-prepared solution of 1-fluoro-3-iodo-2-methyl-5-nitrobenzene (56.2 g, 1 equivalent) in toluene (8 volumes) was slowly added dropwise with vigorous stirring, ensuring the temperature did not exceed 100°C. After complete addition, the reaction was cooled to 50°C, and acetic anhydride (1.77 equivalents) was added over 10 min. The reaction was stirred vigorously for another 30 min, and then the solvent was evaporated (75 mBar, 50°C). The resulting solid was azeotropically dried twice with additional toluene (2 x 6 volumes). The reactor temperature was set to 30°C, and acetone (5 volumes) was added. The mixture was stirred vigorously for 10 min, and the organic matter containing the product was filtered into a stirred aqueous solution of sodium carbonate (Reagent Plus® grade, MilliporeSigma, St. Louis, Missouri, 2.0 M, 4 volumes). Following the same procedure, the reactor vessel was washed four more times with acetone (4 x 2 volumes). The resulting filtrate suspension was stirred for 10 min and allowed to stand for 30 min, during which time a two-phase mixture formed. The dark (bottom) aqueous layer was discarded, and the light yellow organic layer was treated with activated carbon (10 g). The suspension was stirred vigorously for 15 min and then filtered through a diatomaceous earth mat. The diatomaceous earth mat was washed with a very small amount of acetone (3 volumes), and the collected organic filtrate was concentrated under vacuum to 8 volumes. Water (8 volumes) was added with stirring, and the remaining acetone was evaporated. Methanol (2 volumes) was added with stirring, and the suspension was filtered under vacuum. The resulting white solid was washed twice with a 25% MeOH aqueous solution. The white solid was thoroughly dried under vacuum to give a chalky white solid product (53.0 g, 90% yield).

[0030] Example 3. Preparation of 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione Tetrabutylammonium bromide (0.05 equivalents), cesium carbonate (0.075 equivalents), and 1H-isoindole-1,3(2H)-diketone potassium salt (100.0 g, 1 equivalent) were added sequentially to the reactor. The reactor was purged with nitrogen, and acetone (7 volumes) was added all at once. Stirring was started, and the temperature was lowered to 10°C. Then, 3-bromotetrahydrofuran-2-one (1.3 equivalents) was added dropwise, keeping the internal temperature below 15°C (approximately 1 drop / second). After the addition was complete, the reaction was stirred at 15°C for 2 h, and then at 20°C for 10 h. Subsequently, the temperature was lowered to 5°C, and water (7 volumes) was added at a rate that kept the temperature below 20°C. After stirring for another 15 min, acetone was removed under vacuum at 20°C. Methanol (2 volumes) was added, and the mixture was stirred vigorously for another 5 min. The mixture was filtered under vacuum, and the solids were washed three times with a 2 / 1 H₂O / MeOH solution (3 x 6 volumes). The filtrate was thoroughly dried in a vacuum at 50°C for several days to obtain a chalky white solid (98.0 g, 79% yield).

[0031] Example 4. Preparation of 4-(5-acetamido-3-fluoro-2-methylphenyl)-2-(1,3-dioxoisoindoline-2-yl)butyric acid In a stirred reactor, 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione (13.41 g, 1.7 equivalents, 58.00 mmol), dichloromethane (38.83 g, 29.42 mL, 13.4 equivalents, 457.2 mmol), and trimethyl iodosilane (14.68 g, 9.985 mL, 2.15 equivalents, 73.36 mmol) were added sequentially in single portions. The reaction was stirred at ambient temperature for 16 h, and then concentrated under vacuum at 40 °C to obtain a viscous brown residue. Copper(I) iodide (11.70 g, 1.8 equivalents, 61.42 mmol) and indium powder (13.32 g, 1.824 mL, 3.4 equivalents, 116.0 mmol) were added sequentially in single portions. The suspension was purged with N2, and N,N-dimethylacetamide (25.18 g, 26.8 mL, 8.47 equivalents, 289.0 mmol) was added. The mixture was heated to 70 °C and stirred for 20 h, then cooled to 20 °C. Simultaneously, N-(3-fluoro-5-iodo-4-methylphenyl)acetamide (10.00 g, 1 equivalent, 34.12 mmol) and dried lithium chloride (5.785 g, 4.0 equivalents, 136.5 mmol) were added in single portions to a second reactor. The organic matter containing the product from the first reactor was filtered into reactor 2. Reactor 1 was washed with another N,N-dimethylacetamide (25.18 g, 26.8 mL, 8.47 equivalents, 289.0 mmol), and the filtrate was washed into reactor 2 using the washing solution. Palladium(II) chloride (605 mg, 0.1 equivalents) was added in a single dose, and the reaction product turned black. The reactants were heated to 110°C (approximately reflux) and stirred vigorously for 26 h, then cooled to 80°C. Volatile substances were removed under vacuum, and the mixture was cooled to 40°C. 100 mL of fluoro-5-iodo-4-methylphenylacetamide was added, and the suspension was stirred for 5 min. The reactants were filtered through a diatomaceous earth mat and washed with a very small amount of methyl ethyl ketone (20 mL). The filtrate was heated to 60°C and concentrated again under vacuum to remove the methyl ethyl ketone. The resulting red solution was cooled to 15°C, and a solution of phosphoric acid (5.0 g, 85 wt%, 1.5 equivalents) in water (125 mL) was added dropwise over 30 min with stirring. The mixture was cooled to 5°C, and the dark product was allowed to precipitate out as an oil at the bottom of the container with gentle stirring for 2 h. The light-colored, opaque supernatant was removed using a filter rod, and the dark, oily residue was washed several times with water (3 x 100 mL) in a similar manner. The resulting brown residue was concentrated thoroughly under vacuum and dried azeotropically with toluene if necessary. Nitromethane (approximately 15 volumes based on the theoretical yield) was added with gentle stirring, during which a fine white precipitate formed.The mixture was heated to 45°C and aged for 3 h with vigorous stirring, then cooled to 10°C for another hour with gentle stirring. The suspension was filtered, and the collected solids were washed sequentially with cold nitromethane (2 x 2 volumes) and MTBE (2 x 2 volumes). The solids were dried under vacuum to give a cross-coupled product (8.3 g, 61% yield) as a grayish-white powder.

[0032] Example 5. Preparation of 2-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)isoindoline-1,3-dione 4-(5-acetamido-3-fluoro-2-methylphenyl)-2-(1,3-dioxoisoindoline-2-yl)butyric acid (3.0 g), methanesulfonic anhydride (4.5 equivalents), and 1,2-dichloroethane (10 volumes) were added sequentially to the reactor. The reaction was heated to reflux and stirred until complete conversion was observed (approximately 24 h). The reaction was cooled to 15 °C, and methanol (10 volumes) was added all at once. The mixture was stirred for 10 h and then concentrated to 5 volumes. Further methanol (15 volumes) was added with stirring, and the suspension was concentrated again to 5 volumes. Finally, methanol (15 volumes) was added and the suspension was concentrated to 5 volumes. The suspension was then cooled to 5 °C, and water (15 volumes) was slowly added over 20 min, ensuring the temperature did not exceed 30 °C. After stirring for another 5 min, the resulting solid was filtered off and washed twice with water (2 x 8 volumes) and twice with methanol (2 x 8 volumes). After drying, the resulting solid was aged in boiling ethanol (8 volumes) for 15 min with stirring. After cooling to 15°C, the suspension was filtered and dried to obtain a product in the form of grayish-white crystals (1.85 g, 73% yield).

[0033] Example 6. N Preparation of 8-amino-6-fluoro-1,2,3,4-tetrahydro-5-methyl-1-oxo-2-naphthyl)acetamide (EXA-aniline) 2-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)isoindoline-1,3-dione (1 equivalent), aqueous HCl solution (6 M, 12 volumes), and acetic acid (6 volumes) were added sequentially to the reactor. The reaction mixture was purged with nitrogen and then heated to reflux until complete conversion was observed (approximately 24 h). The reaction mixture was cooled to 15 °C and gently stirred for another 6 h, during which time a white precipitate (phthalic acid byproduct) formed. The reaction mixture was filtered without washing, and the filtrate was concentrated under vacuum. The residue was azeotropically dried with isopropanol (2 x 4 volumes) to obtain a residue of satisfactory purity for use in the next step.

[0034] While stirring, solvent (THF or EtOAC or acetone; 5-8 volumes), isopropanol (0.3 equivalents), and base (KHCO3 aqueous solution or K2CO3 aqueous solution, approximately 3.5 equivalents) were added sequentially to the resulting residue. The reaction was cooled to 5°C under N2 bubbling for 30 min, and acetic anhydride (approximately 1.2 equivalents) was added after 30 min. The reaction was stirred for another 30 min.

[0035] Methanol (5 volumes) was added, and the reactor was stirred for 15 min. Volatile substances were removed under vacuum, and water (10 volumes) was added to the resulting residue. The mixture was heated to 40°C for 15 min under vigorous stirring. The aqueous layer was filtered off, and the solid was washed twice, successively, with water (2 x 5 volumes) and a cold 60% aqueous ethanol solution (10 volumes). The solid was dried under vacuum to obtain dark crystals. Acetone (10 volumes) was added to the crystals, and the resulting suspension was heated to 50°C for 3 h under stirring. After cooling to ambient temperature, the crystals were filtered again and washed with another acetone (5 volumes). The crystals were dried under vacuum to obtain EXA-aniline as grayish-white crystals.

[0036] The above procedure can then be used to convert EXA-aniline into icitidine mesylate.

Claims

1. A compound of formula I I。 2. A compound of formula II II。 3. A compound of formula III III。 4. A compound of formula IV IV。 5. A method for preparing a compound of formula I, the method comprising the following steps: N-(3-fluoro-5-iodo-4-methylphenyl)acetamide is provided. separately a. Reaction of 3-bromo-2-oxotetrahydrofuran with potassium phthalimide to provide 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione b. Reaction of 2-(2-oxotetrahydrofuran-3-yl)isoindoline-1,3-dione with trimethyliodosilane (TMSI) to form the corresponding carboxylic acid (IV). IV; c. React the carboxylic acid of (c) with indium powder and copper iodide (I) to form indium intermediate (III). III; d. React the indium intermediate (III) with N-(3-fluoro-5-iodo-4-methylphenyl)acetamide to form intermediate (II). II; e. Perform ring closure to produce the compound of formula (I). I。

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