Preparation method of Fosmanogepix intermediate

Abstract

The invention relates to a preparation method of a Fosmanogepix intermediate, and belongs to the technical field of organic chemistry. The preparation route is as follows. Comprising the following steps: (1) reacting 2-pyridinol with 4-bromomethylbenzaldehyde to obtain a compound as shown in a formula IV; (2) obtaining a compound as shown in a formula III from the compound as shown in the formula IV and hydroxylamine sulfate under the action of sodium hydroxide; (3) carrying out chlorination reaction on the compound shown in the formula III to obtain a compound shown in a formula II; and (4) reacting the compound as shown in the formula II with 3-acetylene pyridine-2-amine by taking triethylamine as a solvent to obtain the compound as shown in the formula I. The preparation method of the Fosmanogepix intermediate provided by the invention is mild in reaction condition, high-explosive and high-toxicity reagents such as nitromethane and titanium tetrachloride are not used, and meanwhile, high-risk processes such as hydrogenation reaction are avoided. Meanwhile, the product yield is increased, and when isoxazole is prepared through cyclization, triethylamine is adopted as a solvent, so that the single-step reaction yield is greatly increased.

Description

Technical Field

[0001] This invention relates to the technical field of organic chemistry, and specifically to a method for preparing a Fosmanogepix intermediate. Background Technology

[0002] Fosmanogepix (APX001) is a water-soluble phosphate prodrug that can be administered intravenously or orally and is metabolized by systemic alkaline phosphatase into its active form, Manogepix (APX001A, E1210). This drug inhibits the fungal enzyme Gwt1, which is crucial for the attachment of mannose proteins to the fungal cell wall. By targeting this enzyme, Fosmanogepix disrupts the integrity of the fungal cell wall, leading to cell death.

[0003] The intermediate Manogepix is ​​a precursor to Fosmanogepix and the active form of Fosmanogepix in vivo. Its structure is as follows: .

[0004] The preparation method of the aforementioned intermediate Manogepix is ​​disclosed in patent CN101668767A. Patent CN101668767A discloses the following method: .

[0005] The above method uses 4-(pyridin-2-yloxymethyl)benzaldehyde as a raw material. It requires first preparing a nitro compound containing a C=C double bond using nitromethane, then reducing the C=C double bond with sodium borohydride, followed by preparing a chlorooxime compound using lithium or methyllithium, and finally reacting with 3-ethynyl-pyridin-2-ylamine to prepare the intermediate Manogepix. It can be seen that this method uses many high-risk reagents, such as nitromethane, sodium borohydride, and titanium tetrachloride. Nitromethane is an easily explosive hazardous chemical and is listed as a Group 2B carcinogen. In the reduction reaction using sodium borohydride as a reducing agent, the presence of a small amount of water inevitably leads to the generation of a small amount of hydrogen gas. The minimum explosive limit for hydrogen is 4%, therefore, the reaction conditions must be strictly controlled when using sodium borohydride. Furthermore, the solvent DMSO used is a high-boiling-point solvent, which can easily lead to excessive solvent residues in subsequent processing. Titanium tetrachloride is a highly toxic substance, classified as a Class 1 inorganic acidic corrosive. Its solution is highly irritating to skin and mucous membranes, and it decomposes violently upon contact with moisture, producing hydrochloric acid fumes. Furthermore, in the final cyclization reaction step, the yield of patent CN101668767A is only 58%. Summary of the Invention

[0006] To address the problems of excessive use of hazardous chemicals and low product yield in existing methods for preparing the intermediate Manogepix, this invention provides a method for preparing the Fosmanogepix intermediate to solve the aforementioned technical problems.

[0007] The technical solution of this invention is as follows: A method for preparing a Fosmanogepix intermediate, the preparation route is as follows: ; Includes the following steps: (1) 2-Pyridinol reacts with 4-bromomethylbenzaldehyde to obtain compound IV; (2) Compound IV reacts with hydroxylamine sulfate in the presence of sodium hydroxide to obtain compound III; (3) Compound III undergoes a chlorination reaction to yield compound II; (4) Compound II of Formula II reacts with 3-acetylenypyridine-2-amine in triethylamine solvent to obtain compound I of Formula I.

[0008] The names of the compounds in the reaction equation are as follows: The compound of formula I is: 3-{3-[4-(pyridin-2-yloxymethyl)benzyl]-isoxazol-5-yl}-pyridin-2-ylamine; The compound of formula II is: 2-[4-(pyridin-2-oxomethyl)-phenyl]-1-chloroacetaldehyde oxime; Compound III is: [4-(pyridin-2-yloxymethyl)-phenyl]-acetaldehyde oxime; The compound of formula IV is: 4-(pyridine-2-oxomethyl)-benzaldehyde.

[0009] Further, step (1) is as follows: 2-pyridinol is added to DMF and stirred until dissolved, then potassium carbonate and potassium iodide are added and stirred evenly; then 4-bromomethylbenzaldehyde is added, stirred and heated to 75~80℃, and after the reaction of 4-bromomethylbenzaldehyde is complete by TLC monitoring, the temperature is reduced to 20~30℃, filtered, water is added to the filtrate to crystallize, filtered, and dried to obtain compound IV.

[0010] Furthermore, the molar ratio of 4-bromomethylbenzaldehyde, 2-pyridinol, potassium carbonate, and potassium iodide is 1:(1.1~1.2):(2~3):(0.1~0.15).

[0011] Further, step (2) is as follows: add compound IV to methanol, stir to dissolve, and control the temperature of the reaction system to 10~20℃; add hydroxylamine hydrochloride to water, add sodium hydroxide and stir evenly, and then drop it into the methanol solution of compound IV; after the drop is completed, keep the reaction at the temperature, monitor the reaction of compound IV by TLC until it is complete, filter, and dry the filter cake to obtain compound III.

[0012] Furthermore, the molar ratio of the compound of formula IV to hydroxylamine hydrochloride is 1:1.1~1.5. Further, step (3) is as follows: add compound III to ethyl acetate or dichloromethane, add NCS while stirring, react at 40~45℃ for 1 hour, add water after the reaction is completed, stir and let stand, separate the liquid, wash the organic phase with saturated brine, and concentrate to obtain compound II.

[0013] Furthermore, the molar ratio of the compound of formula III to NCS is 1:1.1~1.3.

[0014] Further, step (4) is as follows: add compound II to triethylamine, add anhydrous zinc chloride or anhydrous lithium chloride at 20~30℃ with stirring, keep warm and stir for 0.5 hours, then add 3-acetylenypyridine-2-amine, heat to 40~45℃ to react, monitor the reaction of 3-acetylenypyridine-2-amine by TLC until the reaction is complete, cool down to 20~25℃, filter, concentrate the filtrate, then add ethyl acetate to the concentrate, stir to dissolve, add n-heptane to crystallize, filter, and obtain compound I.

[0015] Furthermore, the amount of triethylamine used is 10~12 ml / g based on the amount of compound II fed; the molar ratio of compound II to 3-acetylenyl-2-amine is 1.1~1.2:1; and the molar ratio of anhydrous zinc chloride or anhydrous lithium chloride to 3-acetylenyl-2-amine is 2~3:1.

[0016] The method for preparing Fosmanogepix intermediates provided by this invention employs mild reaction conditions, avoiding the use of highly explosive and toxic reagents such as nitromethane and titanium tetrachloride, and also avoiding high-risk processes such as hydrogenation reactions. Furthermore, this invention improves product yield; by using triethylamine as a solvent in the cyclization preparation of isoxazole, the yield of the single-step reaction is significantly increased. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 This is the MS spectrum of the product prepared in Example 1.

[0019] Figure 2 This is the HNMR spectrum of the product prepared in Example 1.

[0020] Figure 3 This is the HPLC chromatogram of the product prepared in Example 1.

[0021] Figure 4 This is the HPLC chromatogram of the product prepared in Example 2.

[0022] Figure 5 This is the HPLC chromatogram of the product prepared in Example 3. Detailed Implementation

[0023] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention. Example

[0024] A method for preparing a Fosmanogepix intermediate, the specific steps of which are as follows: (1) Add 3L of DMF to a 10L five-necked flask, then add 210.0g (2.2mol) of 2-pyridinol under stirring. After stirring until dissolved, add 345.5g (2.5mol) of potassium carbonate and 41.5g (0.25mol) of potassium iodide and stir until homogeneous. The potassium carbonate was pulverized beforehand to make the granules into powder. Then add 398.0g (2.0mol) of 4-bromomethylbenzaldehyde, stir and heat to 80℃. Monitor the reaction of 4-bromomethylbenzaldehyde by TLC until it is complete. Cool the reaction system to 25℃, filter, add 3L of water to the filtrate to crystallize. After the water is added, continue stirring for 30min, filter, wash the filter cake with ice water, and dry to obtain 349.7g of compound IV, with a yield of 82.0% and an HPLC purity of 98.12%.

[0025] (2) Add 341.2 g (1.6 mol) of compound IV to a 10 L five-necked flask, then add 3.5 L of methanol, stir until dissolved, and control the temperature of the reaction system at 10~20 °C; separately add 122.3 g (1.76 mol) of hydroxylamine hydrochloride to 3 L of water, then add 128 g (3.2 mol) of sodium hydroxide and stir until homogeneous, then add dropwise to the methanol solution of compound IV; after the addition is complete, keep the reaction at the temperature. As the reaction proceeds, solids gradually precipitate out. After the reaction of compound IV is complete by TLC monitoring, filter the solution, wash the filter cake with water until the pH of the filtrate is neutral, and dry the filter cake to obtain 331.4 g of compound III, with a yield of 85.5% and an HPLC purity of 97.86%.

[0026] (3) Add 327.4 g (1.35 mol) of compound III to a 10 L five-necked flask, then add 3 L of ethyl acetate, and add 198.3 g (1.485 mol) of NCS while stirring. Control the temperature at 45 °C and react for 1 hour. After the reaction is completed, cool to room temperature, then add 3 L of water, stir and let stand, separate the liquid and organic phase, wash twice with 3 L × 2 of saturated brine, dry with anhydrous sulfuric acid, concentrate the organic phase to obtain 331.4 g of compound II, with a yield of 88.7% and an HPLC purity of 98.66%.

[0027] (4) Add 3.3 L of triethylamine to a 5 L three-necked flask, then add 304.4 g (1.1 mol) of compound II, add 106 g (2.5 mol) of anhydrous lithium chloride while stirring at 20-30 °C, keep warm and stir for 0.5 hours, then add 118.1 g (1.0 mol) of 3-acetylenypyridine-2-amine, heat to 45 °C under nitrogen protection, monitor the reaction of 3-acetylenypyridine-2-amine by TLC until the reaction is complete, cool down to 20-25 °C, filter, concentrate the filtrate, recover the distilled triethylamine, then add 1.5 L of ethyl acetate to the concentrate, stir to dissolve, add 1.5 L of n-heptane to crystallize for 1 hour, filter, dry the filter cake to obtain 294.2 g of compound I, yield 82.1%, HPLC purity 99.872%. Example

[0028] A method for preparing a Fosmanogepix intermediate, using triethylamine recovered in step (4) of Example 1, is described below: Take 10g (36.1mmol) of compound II prepared in step (3) of Example 1, add 120ml of triethylamine recovered in step (4) of Example 1, add 3.5g (82.6mmol) of anhydrous lithium chloride under stirring, keep warm and stir for 0.5 hours, then add 3.9g (32.9mmol) of 3-acetylypyridine-2-amine, heat to 45℃ under nitrogen protection, monitor the reaction of 3-acetylypyridine-2-amine by TLC until the reaction is complete, cool down to 20~25℃, filter, concentrate the filtrate and add 100ml of ethyl acetate, stir to dissolve and add 100ml of n-heptane dropwise, crystallize for 1 hour, filter, dry the filter cake to obtain 9.6g of compound I, yield 81.4%, HPLC purity 99.859%.

[0029] As can be seen from the results of Example 2, when using the recovered triethylamine as the reaction solvent in step (4), good product purity and yield can still be obtained. This provides an experimental basis for the subsequent recycling and use of the solvent, which can significantly reduce the cost of materials. Example

[0030] A method for preparing a Fosmanogepix intermediate, the specific steps of which are as follows: (1) Add 15L of DMF to a 50L glass reactor, then add 1050g (11mol) of 2-pyridinol under stirring. After stirring until dissolved, add 1728g (12.5mol) of powdered potassium carbonate and 208g (1.25mol) of potassium iodide and stir until homogeneous. Then add 1990g (10mol) of 4-bromomethylbenzaldehyde, stir and heat to 80℃. Monitor the reaction of 4-bromomethylbenzaldehyde by TLC until complete. Cool the reaction system to 25℃, filter, add 15L of water to the filtrate to crystallize. After the water is added, continue stirring for 1 hour, filter, rinse the filter cake with ice water, and dry to obtain 1744g of compound IV, with a yield of 81.8% and HPLC purity of 98.03%.

[0031] (2) Add 1706 g (8 mol) of compound IV to a 50 L glass reactor, then add 17.5 L of methanol, stir until dissolved, and control the temperature of the reaction system at 10~20 °C; separately add 611 g (8.8 mol) of hydroxylamine hydrochloride to 15 L of water, then add 640 g (16 mol) of sodium hydroxide and stir until homogeneous, then slowly add to the methanol solution of compound IV; after the addition is complete, keep the reaction at the temperature. As the reaction proceeds, solids gradually precipitate out. After the reaction of compound IV is complete by TLC monitoring, filter the solution, wash the filter cake with water until the pH of the filtrate is neutral, and dry the filter cake to obtain 1655 g of compound III, with a yield of 85.4% and an HPLC purity of 97.71%.

[0032] (3) Add 1635g (6.75mol) of compound III to a 50L glass reactor, then add 15L of ethyl acetate, and add 1000g (7.49mol) of NCS while stirring. Control the temperature at 45℃ and react for 1 hour. After the reaction is completed, cool to room temperature, then add 15L of water, stir and let stand, separate the liquid and wash the organic phase twice with 15L × 2 of saturated brine, dry with anhydrous sulfuric acid, concentrate the organic phase to obtain 1647g of compound II, with a yield of 88.2% and an HPLC purity of 98.88%.

[0033] (4) Add 16.5 L of triethylamine to a 30 L glass reactor, then add 1522 g (5.5 mol) of compound II, add 530 g (12.5 mol) of anhydrous lithium chloride under stirring at 20-30 °C, keep warm and stir for 1 hour, then add 590 g (5.0 mol) of 3-acetylenypyridine-2-amine, heat to 45 °C under nitrogen protection, monitor the reaction of 3-acetylenypyridine-2-amine by TLC until the reaction is complete, cool down to 20-25 °C, filter, concentrate the filtrate, recover the distilled triethylamine, then add 7 L of ethyl acetate to the concentrate, stir to dissolve, add 7 L of n-heptane to crystallize for 1 hour, filter, dry the filter cake to obtain 1490 g of compound I, yield 83.1%, HPLC purity 99.875%.

[0034] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the invention should also be covered within the protection scope of the invention. Therefore, the protection scope of the invention should be determined by the scope defined in the claims.

Claims

1. A method for preparing a Fosmanogepix intermediate, characterized in that, The preparation route is as follows: Includes the following steps: (1) 2-pyridinol reacts with 4-bromomethylbenzaldehyde to obtain compound IV; (2) Compound IV reacts with hydroxylamine sulfate in the presence of sodium hydroxide to obtain compound III; (3) Compound III undergoes a chlorination reaction to yield compound II; (4) Compound II of Formula II reacts with 3-acetylenypyridine-2-amine in triethylamine solvent to obtain compound I of Formula I.

2. The method for preparing a Fosmanogepix intermediate as described in claim 1, characterized in that, Step (1) is as follows: 2-pyridinol is added to DMF and stirred until dissolved, then potassium carbonate and potassium iodide are added and stirred evenly; 4-bromomethylbenzaldehyde is added and stirred and heated to 75-80°C. After the reaction of 4-bromomethylbenzaldehyde is complete, the temperature is lowered to 20-30°C by TLC monitoring. The mixture is filtered, water is added to the filtrate to crystallize, filtered, and dried to obtain compound IV.

3. The method for preparing a Fosmanogepix intermediate as described in claim 2, characterized in that, The molar ratio of 4-bromomethylbenzaldehyde, 2-pyridinol, potassium carbonate, and potassium iodide is 1:(1.1-1.2):(2-3):(0.1-0.15).

4. The method for preparing a Fosmanogepix intermediate as described in claim 1, characterized in that, Step (2) is as follows: Add compound IV to methanol, stir until dissolved, and control the temperature of the reaction system to 10-20℃; separately add hydroxylamine hydrochloride to water, add sodium hydroxide and stir evenly, and then drop it into the methanol solution of compound IV; after the drop is completed, keep the reaction at the temperature, monitor the reaction of compound IV by TLC until it is complete, filter, and dry the filter cake to obtain compound III.

5. The method for preparing a Fosmanogepix intermediate as described in claim 4, characterized in that, The molar ratio of the compound of formula IV to hydroxylamine hydrochloride is 1:1.1 to 1.

5.

6. The method for preparing a Fosmanogepix intermediate as described in claim 1, characterized in that, Step (3) is as follows: Add the compound of formula III to ethyl acetate or dichloromethane, add NCS while stirring, react at 40-45℃ for 1 hour, add water after the reaction is completed, stir and let stand, separate the liquids, wash the organic phase with saturated brine, and concentrate to obtain the compound of formula II.

7. The method for preparing a Fosmanogepix intermediate as described in claim 6, characterized in that, The molar ratio of the compound of formula III to NCS is 1:1.1 to 1.

3.

8. The method for preparing a Fosmanogepix intermediate as described in claim 1, characterized in that, Step (4) is as follows: Add the compound of formula II to triethylamine, add anhydrous zinc chloride or anhydrous lithium chloride at 20-30°C with stirring, keep warm and stir for 0.5 hours, then add 3-acetylenypyridine-2-amine, heat to 40-45°C to react, monitor the reaction of 3-acetylenypyridine-2-amine by TLC until the reaction is complete, cool down to 20-25°C, filter, concentrate the filtrate, then add ethyl acetate to the concentrate, stir to dissolve, add n-heptane to crystallize, filter, and obtain the compound of formula I.

9. The method for preparing a Fosmanogepix intermediate as described in claim 8, characterized in that, The amount of triethylamine used is 10-12 ml / g based on the amount of compound II added; the molar ratio of compound II to 3-acetylenepyridine-2-amine is 1.1-1.2:1; The molar ratio of anhydrous zinc chloride or anhydrous lithium chloride to 3-acetylenypyridine-2-amine is 2 to 3:1.

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