A method for synthesizing the immunological dermatitis drug deguelin

Abstract

The application provides a synthesis method of digitevirine, wherein compound 1 is used as a starting material, reacts with compound 2 to obtain compound 3, then obtains compound 4, and then obtains compound 5, and then removes a protective group and obtains a key chiral spiro intermediate compound 6 in the form of a salt, and finally, compound 6 is condensed with compound 7 to obtain compound 8; compound 8 is condensed with compound 7 to obtain the target product digitevirine compound 13 through two ways, the route is simple to operate, the total yield is high, the purity of the obtained product is high, the route is suitable for scale-up production, and the route is as follows:

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical engineering, and specifically relates to a method for synthesizing digotinib, a JAK inhibitor and an immune dermatitis drug. Background Technology

[0002] Delgocitinib is a topical JAK inhibitor cream developed by LEO Pharma, primarily used to treat atopic dermatitis and moderate to severe chronic hand eczema (CHE). This drug simultaneously inhibits four enzymes: JAK1, JAK2, JAK3, and TYK2, blocking the JAK-STAT inflammatory signaling pathway, reducing the release of inflammatory mediators, and specifically modulating the immune system to significantly relieve eczema symptoms. The brand name of delgocitinib ointment is Anzupgo. It was approved for marketing in the EU in September 2023 and by the US FDA in July 2025 for the treatment of adult patients with moderate to severe chronic hand eczema who have an inadequate response to topical corticosteroids or are unsuitable for corticosteroid use, indicating a significant market potential.

[0003] The chemical name of digotinib is: 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3,4]octane-1-yl]-3-oxopropionitrile, and its structural formula is as follows:

[0004] The earliest reported synthetic route for digotinib was described in patent WO2011013785A1 of Japan Tobacco International Co., Ltd.: Di-tert-butyl-3-methylazacyclobutane-1,2-dicarboxylic acid ester was alkylated with isopentenyl bromide under the action of LiHMDS. Following this, the double bond was cleaved using ozone, and an aldehyde intermediate was generated under the action of triphenylphosphine. The aldehyde intermediate was then reductively amination reaction with benzylamine under the action of sodium borohydride acetate. The Boc protecting group and the tert-butyl protecting group of the carboxylic acid were removed by acid elution with hydrochloric acid. Subsequently, an intramolecular condensation reaction of the amino and carboxylic acids was completed using HATU condensing agent to obtain a spirocyclic lactam intermediate. The amide carbonyl group was then reduced using lithium aluminum hydride, and the exposed amino group was protected with Boc anhydride after treatment. Finally, hydrogenation reduction under palladium hydroxide catalysis yielded the key spirocyclic intermediate of digotinib. The key spirocyclic intermediate of digotinib was condensed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine in the presence of potassium carbonate. Then, the Boc protecting group was removed by hydrochloric acid. Finally, it was condensed with the digotinib branched intermediate 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile in the presence of an organic base to obtain the target product digotinib.

[0005]

[0006] The journal *Org. Process Res. Dev.* 2021, 25, pp. 342-348 reported an alternative synthetic method for digotinib, whose core technology improved the process route for the key chiral spirocyclic intermediate derivative. The method involved condensing 3-bromodihydrofuran-2(3H)-one with benzylamine and separating it as a hydrochloride salt. This was followed by condensation with (R)-2-chloropropionyl chloride in the presence of the acid-binding agent 2,6-dimethylpyridine. Intramolecular cyclization was then performed using LiHMDS to obtain a spirocyclic lactone intermediate. The lactone ring was then opened with potassium phthalimide and the carboxyl group was ethylated with iodoethane. Subsequently, the phthalimide cofactor was removed and intramolecular amidation was completed with diethylenetriamine. Finally, the amide carbonyl group was reduced with lithium aluminum hydride in the presence of trimethylchlorosilane to obtain the key chiral spirocyclic intermediate of digotinib, which was then separated as an oxalate salt. Finally, the intermediate was condensed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, followed by hydrogenation to remove the benzyl group under palladium-carbon catalysis, and finally condensed with the digotinib branched intermediate 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropionitrile to obtain the target product digotinib.

[0007]

[0008] In general, the existing technical route has disadvantages such as low overall yield, high cost of scaling up production, and high levels of waste, so there is an urgent need to improve the process. Summary of the Invention

[0009] To address the shortcomings of existing technologies, the purpose of this invention is to provide a synthetic method for digotinib that is characterized by a short synthetic route, simple operation, high yield, high selectivity, and suitability for industrial production.

[0010] To achieve the purpose of this invention, the method for synthesizing digotinib provided by this invention adopts the following technical solution: One of the objectives of this invention is to provide various compounds for the synthesis of digotinib.

[0011] The intermediate compounds used in the synthesis of digotinib include compounds 6, 9, and 10, with the following structural formulas:

[0012] In compound 6, HA is a pharmaceutically acceptable acid, preferably hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, fumaric acid, maleic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, L-tartaric acid, D-tartaric acid, L-DBTA, D-DBTA, L-DTTA, D-DTTA, or L-camphorsulfonic acid.

[0013] The second objective of this invention is to provide a method for synthesizing digotinib intermediate compound 6, which adopts the following technical solution: A method for synthesizing digotinib intermediate compound 6 includes the following steps: (1) Compound 3 was obtained by intramolecular cyclization of the intermediate state of compound 1 and compound 2 after condensation under the action of base under acid catalysis.

[0014] (2) Compound 3 was reduced by a boron reducing agent to obtain compound 4;

[0015] (3) Compound 4 was cyclized by reacting the intermediate state of compound 4 after the dihydroxyl group was activated by the acylating agent with the amination agent to obtain compound 5;

[0016] (4) Selectively remove PG from compound 5 under appropriate conditions. 2 The protecting group yields an intermediate free base or a resalting compound to obtain its pharmaceutically acceptable salt compound 6;

[0017] In compound 1, R is methyl, ethyl or tert-butyl; When PG 1 When it is benzyl or benzyloxycarbonyl, PG 2 It is 4-methoxybenzyl, tert-butyl, or triphenylmethyl; when PG 1 When it is tert-butyloxycarbonyl, PG 2 It is benzyl.

[0018] Preferably, in the condensation reaction of step (1), the base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, n-butyllithium, LDA, LiHMDS, NaHMDS, or KHMDS; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, or NMP, or any two of them forming a mixed solvent system; the ring-closed acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid; and the reaction temperature is -80~80℃.

[0019] Preferably, in step (2) the reduction reaction, the boron reducing agent is selected from sodium borohydride, lithium borohydride, potassium borohydride or borane; the agent with or without a accelerator is selected from boron trifluoride ether, boron trifluoride acetic acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid; the reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, 1,4-dioxane, water or a mixture of any two of them; the reaction temperature is -20~110℃.

[0020] Preferably, in step (3) the cyclization reaction, the acylating agent is selected from hydrogen chloride, thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl anhydride; the amination reagent is selected from benzylamine, 4-methoxybenzylamine, tert-butylamine, or triphenylmethylamine; the reagent with or without alkali is selected from sodium carbonate, potassium carbonate, cesium carbonate, pyridine, 2,6-dimethylpyridine, triethylamine, diisopropylethylamine, DABCO, or DBU; the reaction solvent is selected from DMF, DMAC, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, acetonitrile, 1,4-dioxane, or a mixture of any two of them; the reaction temperature is -20~110℃.

[0021] Preferably, in the deprotection reaction of step (4), when PG 1 = tert-butyl, triphenylmethyl, or tert-butyloxycarbonyl, PG 2 =For benzyl groups, palladium catalysis is used to remove PG under the action of a reducing agent. 2 Protecting group; the palladium catalyst is selected from palladium on carbon or palladium hydroxide; the reducing agent is selected from hydrogen, formic acid or ammonium formate; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, acetic acid or water, or any two of them forming a mixed solvent system; the reaction temperature is 0~60℃.

[0022] The third objective of this invention is to provide a method for synthesizing digotinib intermediate compound 9, which adopts the following technical solution: A method for synthesizing digotinib intermediate compound 9 includes the following steps: (1) Compound 6 and compound 7 were condensed under alkaline conditions to obtain compound 8;

[0023] Compound 8 was deprotected by reduction with a reducing agent under the action of a palladium catalyst to obtain compound 9;

[0024] Preferably, in the condensation reaction of step (1), the base is selected from triethylamine, diisopropylethylamine, dimethylaniline, pyridine, DBU, DABCO, DMAP, potassium carbonate, sodium carbonate, or potassium phosphate; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, or NMP, or any two of them forming a mixed solvent system; the reaction temperature is -30~100℃.

[0025] In the deprotection reaction of step (2), palladium catalysis is used to remove PG under the action of a reducing agent. 1 The protecting group is selected from palladium on carbon or palladium hydroxide as the palladium catalyst, and hydrogen, formic acid or ammonium formate as the reducing agent. The reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, acetic acid or water, or any two of them forming a mixed solvent system. The reaction temperature is 0~60℃.

[0026] The fourth objective of this invention is to provide a method for synthesizing digotinib, which adopts the following technical solution: A method for synthesizing digotinib, comprising the following steps: (1) Compound 8 was deprotected under acid to give compound 11;

[0027] (2) Compound 11 was condensed with compound 12 under alkaline conditions to obtain the target product, digotinib compound 13;

[0028] Among them, PG 1 It is tert-butyl, benzyloxycarbonyl, or triphenylmethyl.

[0029] Preferably, in the deprotection reaction of step (1), the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, methyl tert-butyl ether, toluene, acetone, butanone, MIBK, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, water, or NMP, or any two of them forming a mixed solvent system; the reaction temperature is -30~100℃.

[0030] Preferably, in the condensation reaction of step (2), the base is selected from DBU or DABCO; the reaction solvent is selected from one or any two of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC or NMP to form a mixed solvent system; the reaction temperature is -30~100℃.

[0031] The fifth objective of this invention is to provide another method for synthesizing digotinib, which adopts the following technical solution: A method for synthesizing digotinib, comprising the following steps: (1) Compound 9 was condensed with compound 12 or 12b under alkaline conditions to obtain compound 10;

[0032] (2) Compound 10 was deprotected to obtain the target product, digotinib compound 13;

[0033] Among them, PG 1 It is benzyl or benzyloxycarbonyl.

[0034] Preferably, in step (1) the condensation reaction, the base is selected from triethylamine, diisopropylethylamine, dimethylaniline, pyridine, DBU, DABCO, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC or NMP or any two of them forming a mixed solvent system; the reaction temperature is -30~100℃.

[0035] Preferably, in the deprotection reaction of step (2), no acid is added or the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, methyl tert-butyl ether, toluene, acetone, butanone, MIBK, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, water or NMP or any two of them forming a mixed solvent system; the reaction temperature is -30~130℃.

[0036] More specifically, the present invention provides a method for synthesizing digotinib, which adopts the following technical solution: A method for synthesizing digotinib, starting with compound 1, involves first undergoing ring-opening condensation and intramolecular esterification with vinyl sulfate compound 2 under alkaline conditions to obtain spirocyclic lactone compound 3. Then, the ester group is reduced using a boron reducing agent to obtain diol compound 4. Next, the hydroxyl group is activated using an acylation reagent, followed by condensation with an amine reagent to obtain spirocyclic compound 5. The protecting group is then removed, and the compound is presented as a salt to obtain the key chiral spirocyclic intermediate compound 6 of digotinib. Finally, compound 6 is condensed with digotinib intermediate compound 7 to obtain digotinib intermediate compound 8. Compound 8 yields the target product digotinib through two pathways. In method one, compound 6 is selectively deprotected to obtain compound 9, which then reacts with a branched digotinib compound to obtain compound 10, and finally, the Boc protecting group is removed to obtain digotinib compound 13. In method two, two protecting groups are removed in one step to obtain compound 11, which then undergoes an aminotransfer reaction with a branched digotinib compound 12 to obtain the final product digotinib compound 13. The route is as follows: .

[0037] This invention relates to a method for synthesizing digotinib. It optimizes the introduction of the leaving group into the key Boc protecting intermediate 8 and its use in the synthesis of digotinib, resulting in better selectivity of the condensation reaction. The salt formation of the key chiral spirocyclic intermediate of digotinib is also optimized, improving the stereoselectivity of the reaction and significantly increasing the optical purity of the product, while shortening the synthetic steps. This method improves synthetic efficiency and overall yield, greatly reducing process costs. The route is simple to operate, yields a high overall yield, and produces a high-purity product, making it suitable for scale-up production. Detailed Implementation

[0038] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0039] Example 1

[0040]

[0041] In a three-necked flask, add tetrahydrofuran (136 mL) and compound 1a (27.14 g, 100 mmol), cool to 0–5 °C, slowly add 1 M LiHMDS tetrahydrofuran solution (110 mL, 110 mmol), maintain temperature and stir for 1 hour, then slowly add compound 2 (13.03 g, 105 mmol) in tetrahydrofuran solution, maintaining temperature at 0–5 °C. oStir for 4–6 hours. After the reaction is complete, slowly add 274 mL of 10% ammonium chloride solution to quench the reaction. Extract twice with ethyl acetate (136 mL), combine the organic phases, wash once with water, transfer the organic phase to a reaction flask, add acetic acid (7.21 g, 120 mmol), stir at room temperature for 3–4 hours, concentrate to a small volume, slowly add n-heptane (274 mL), slowly cool to 0–10 °C to crystallize, filter, collect the solid and dry to give product 3a (21.40 g, 88.7%).

[0042] In Example 1, the base LiHMDS can be replaced by sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, n-butyllithium, LDA, NaHMDS, or KHMDS; the reaction solvent tetrahydrofuran can be replaced by one or any two of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, or NMP, or a mixed solvent system formed by any two of them; the cyclic acid acetic acid can be replaced by hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, or p-toluenesulfonic acid.

[0043] Example 2

[0044]

[0045] In a three-necked flask, tetrahydrofuran (136 mL) and compound 1b (30.54 g, 100 mmol) were added. The mixture was cooled to 0–5 °C, and a 1 M LiHMDS tetrahydrofuran solution (110 mL, 110 mmol) was slowly added. The mixture was stirred at this temperature for 1 hour. Then, a tetrahydrofuran solution of compound 2 (13.03 g, 105 mmol) was slowly added, and the mixture was stirred at 0–5 °C for 4–6 hours. After the reaction was complete, 274 mL of 10% ammonium chloride solution was slowly added to quench the reaction. The mixture was extracted twice with ethyl acetate (136 mL), and the organic phases were combined and washed once with water. The organic phase was transferred to a reaction flask, and acetic acid (7.21 g, 120 mmol) was added. The mixture was stirred at room temperature for 3–4 hours and concentrated to a small volume. Heptane (274 mL) was slowly added, and the mixture was slowly cooled to 0–10 °C to crystallize. The crystals were filtered, and the solid was collected and dried to give product 3b (25.44 g, 92.4%).

[0046] In Example 2, the base LiHMDS can be replaced by sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, n-butyllithium, LDA, NaHMDS, or KHMDS; the reaction solvent tetrahydrofuran can be replaced by one or any two of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, or NMP, or a mixed solvent system formed by any two of them; the cyclic acid acetic acid can be replaced by hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, or p-toluenesulfonic acid.

[0047] Example 3

[0048]

[0049] In a three-necked flask, add 121 mL of tetrahydrofuran (compound formula 3a, 24.13 g, 100 mmol), stir well, then add 6.41 g of methanol (200 mmol). Heat to 55–60 °C, then add sodium borohydride (9.46 g, 250 mmol) in five portions. After the addition is complete, maintain the reaction temperature for 6–8 hours. After the reaction is complete, cool to room temperature, slowly add 241 mL of 0.5% dilute hydrochloric acid, and extract three times with 121 mL of ethyl acetate. Combine the organic phases, wash once with water, concentrate to dryness, and directly proceed to the next reaction step.

[0050] In Example 3, the boron reducing agent sodium borohydride can be replaced by lithium borohydride, potassium borohydride, or borane.

[0051] Example 4

[0052]

[0053] Toluene (245 mL) and compound 4a (24.53 g, 100 mmol) were added to a three-necked flask and stirred until dissolved. Triethylamine (40.48 g, 400 mmol) was then added, and the mixture was stirred until homogeneous. The mixture was cooled to 0–10 °C, and methanesulfonyl chloride (27.49 g, 240 mmol) was slowly added. The mixture was stirred at 0–10 °C for 2–3 hours. After the reaction was complete, 207 mL of water was slowly added, and the mixture was separated by stirring. The organic phase was collected and transferred to a reaction flask. Benzylamine (53.58 g, 500 mmol) was added, and the mixture was heated to 75–80 °C for 6–8 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (245 mL) was added. The mixture was stirred and separated by stirring. The organic phase was collected and heated to 55–60 °C. Column chromatography was used to separate product 5a (33.49 g, 82.4% yield in two steps).

[0054] In Example 4, the acylating agent methanesulfonyl chloride can be replaced by hydrogen chloride, thionyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl anhydride; the amination agent benzylamine can be replaced by 4-methoxybenzylamine, tert-butylamine, or triphenylmethylamine; triethylamine can be replaced by sodium carbonate, potassium carbonate, cesium carbonate, pyridine, 2,6-dimethylpyridine, diisopropylethylamine, DABCO, or DBU; and the reaction solvent toluene can be replaced by DMF, DMAC, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, acetonitrile, 1,4-dioxane, or a mixture of any two of them.

[0055] Example 5

[0056]

[0057] Compound 5a (31.64 g, 100 mmol) was added to a hydrogenation reaction flask and dissolved in methanol (155 mL). 5% palladium on carbon (20 mg) was added, and the hydrogen gas was switched three times under vacuum. The hydrogenation reaction was carried out at room temperature for 16–18 hours under pressure using a hydrogen balloon. After the reaction was complete, the palladium on carbon was filtered off, and the filtrate was collected and concentrated under reduced pressure to remove some methanol. Ethyl acetate (316 mL) was added, and the mixture was heated to 50–55 °C with stirring. Oxalic acid (9.00 g, 100 mmol) was added, and the mixture was slowly cooled to 0–5 °C and stirred. The mixture was filtered, and the filter cake was washed with a small amount of cold ethyl acetate. The solid was collected and dried to give compound 6a (29.16 g, yield 92.2%).

[0058] MS(ESI) m / z = 227.2 [M+H] + 1 H NMR (500 MHz, DMSO) δ 3.84 (dt, J = 35.6, 7.8 Hz, 1H), 3.52 - 3.33(m, 2H), 3.32 - 3.08 (m, 3H), 2.58 (d, J = 6.5 Hz, 1H), 2.40 (dt, J = 13.2,6.5 Hz, 1H), 2.13 - 2.01 (m, 1H), 1.40 (s, 9H), 1.13 (d, J = 6.1 Hz, 3H). In Example 5, palladium on carbon can be replaced by palladium hydroxide; hydrogen as a reducing agent can be replaced by formic acid or ammonium formate; methanol as a reaction solvent can be replaced by one or any two of the following solvents: ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, acetic acid, or water, or a mixed solvent system formed by any two of them.

[0059] Example 6

[0060]

[0061] Acetonitrile (316 mL) was added to a three-necked flask, followed by compound 6a (31.64 g, 100 mmol) and compound 7 (26.64 g, 105 mmol). After thorough mixing, triethylamine (30.36 g, 300 mmol) was added, and the mixture was stirred at room temperature for 6–8 hours. After the reaction was complete, the mixture was concentrated and distilled to a small volume, kept at 55–60 °C with stirring, and 316 mL of water was slowly added. The mixture was then slowly cooled to 0–10 °C to induce crystallization. The crystals were filtered, and the solid was collected and dried to obtain product 8a (41.22 g, 93.0%).

[0062] In Example 6, the base triethylamine can be replaced by diisopropylethylamine, dimethylaniline, pyridine, DBU, DABCO, DMAP, potassium carbonate, sodium carbonate, or potassium phosphate; the reaction solvent acetonitrile can be replaced by one or any two of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, 1,4-dioxane, DMF, DMAC, or NMP to form a mixed solvent system.

[0063] Example 7

[0064]

[0065] In a three-necked flask, tetrahydrofuran (350 mL) was added, followed by compound 6a (35.04 g, 100 mmol) and compound 7 (26.64 g, 105 mmol). After thorough mixing, DIPEA (38.77 g, 300 mmol) was added, and the mixture was stirred at room temperature for 6–8 hours. After the reaction was complete, the mixture was concentrated and distilled to a small volume, kept at 55–60 °C with stirring, and 316 mL of water was slowly added. The mixture was then slowly cooled to 0–10 °C to induce crystallization. The crystals were filtered, and the solid was collected and dried to obtain product 8b (44.08 g, 92.3%).

[0066] In Example 7, the base diisopropylethylamine can be replaced by triethylamine, dimethylaniline, pyridine, DBU, DABCO, DMAP, potassium carbonate, sodium carbonate, or potassium phosphate; the reaction solvent tetrahydrofuran can be replaced by one or any two of the following to form a mixed solvent system: acetonitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, 1,4-dioxane, DMF, DMAC, or NMP.

[0067] Example 8

[0068]

[0069] Ethanol (443 mL) and compound 8a (44.35 g, 100 mmol) were added to a three-necked flask and stirred until homogeneous. Then, 33% hydrochloric acid solution (36.46 g, 330 mmol) was slowly added, and the mixture was stirred at room temperature for 4–5 hours. After the reaction was complete, the mixture was concentrated to remove most of the solvent. Water (443 mL) and methyl tert-butyl ether (222 mL) were added, and the mixture was stirred and separated. The aqueous phase was collected, and 10% sodium hydroxide solution (200 mL, 500 mmol) was slowly added. The mixture was slowly cooled to 0–5 °C to crystallize. The crystals were filtered, washed with water, and the solid was collected and dried to give product 11 (22.97 g, 94.4%).

[0070] In Example 8, hydrochloric acid can be replaced by sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid; ethanol can be replaced by methanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, methyl tert-butyl ether, toluene, acetone, butanone, MIBK, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, water, or NMP, or any two of them forming a mixed solvent system.

[0071] Example 9

[0072]

[0073] In a three-necked flask, add NMP (122 mL), compound 11 (24.33 g, 100 mmol), and compound 12 (12.44 g, 110 mmol). After stirring until homogeneous, add DBU (30.45 g, 200 mmol) and stir at room temperature for 6–8 hours. After the reaction is complete, add water (243 mL) to quench the reaction, extract three times with ethyl acetate (122 mL), combine the organic phases, wash once with water, concentrate and distill to a small volume, add isopropanol (72 mL), keep warm at 55–60 °C with stirring, slowly add 365 mL of water, slowly cool to 0–10 °C to crystallize, filter, collect the solid and dry to obtain product 13 (28.61 g, 92.2%).

[0074] In Example 9, DBU can be replaced by DABCO; NMP can be replaced by a mixed solvent system formed by one or any two of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, or DMAC.

[0075] Example 10

[0076]

[0077] Compound 8b (47.76 g, 100 mmol) was added to a hydrogenation reaction flask and dissolved in methanol (239 mL). 5% palladium on carbon (20 mg) was added, and the hydrogen gas was switched three times under vacuum. The hydrogenation reaction was carried out at 40–45 °C for 6–8 hours. After the reaction was complete, the palladium on carbon was filtered off, and the filtrate was collected and concentrated under reduced pressure to remove some methanol. Water was slowly added with stirring at 50–55 °C, and the mixture was slowly cooled to 0–10 °C and slurried. The mixture was filtered, and the filter cake was washed with a small amount of cold water. The solid was collected and dried to obtain compound 9 (32.73 g, yield 95.3%).

[0078] MS(ESI) m / z = 344.2 [M+H] + 1 H NMR (500 MHz, CDCl3) δ 8.49(s, 1H), 7.34(d, J=4.0Hz, 1H), 6.59(d, J=4.0Hz, 1H), 4.09-3.95(m, 2H), 3.84-3.82(m, 3H), 3.71-3.69(m, 1H), 3.20-3.18(m, 1H), 2.78-2.77(m, 1H), 2.21-2.14(m, 2H), 1.66(s, 9H), 1.21(d, J=7.0Hz, 3H). In Example 10, palladium on carbon can be replaced by palladium hydroxide, hydrogen can be replaced by formic acid or ammonium formate, and the reaction solvent methanol can be replaced by one or any two of ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, acetic acid, or water, or a mixed solvent system formed by any two of them.

[0079] Example 11

[0080]

[0081] Acetonitrile (343 mL) was added to a three-necked flask, followed by compound 9 (34.34 g, 100 mmol) and compound 12b (17.95 g, 110 mmol). After thorough mixing, DIPEA (25.85 g, 200 mmol) was added, and the mixture was stirred at room temperature for 6–8 hours. After the reaction was complete, 5% sodium bicarbonate solution (343 mL) was added, followed by extraction three times with ethyl acetate (172 mL). The combined organic phases were washed once with water, concentrated, and distilled to a small volume. The mixture was stirred at 55–60 °C, and 343 mL of n-heptane was slowly added. The mixture was slowly cooled to 0–10 °C to crystallize. The crystals were filtered, and the solid was collected and dried to give product 13 (38.38 g, 93.5%).

[0082] MS(ESI) m / z = 411.1 [M+H] + 1 H NMR (500 MHz, DMSO) δ 8.27(s, 1H), 7.48(d, J=4.0Hz, 1H), 6.83(d, J=4.0Hz, 1H), 4.17-4.08(m, 2H), 3.98-3.78(m, 3H), 3.72-3.64(m, 2H), 3.59-3.54(m,1H), 2.69-2.62(m, 2H), 2.20-2.12(m, 1H), 1.60(s, 9H), 1.14(d, J=7.0Hz, 3H ) In Example 11, diisopropylethylamine can be replaced by triethylamine, diisopropylethylamine, dimethylaniline, pyridine, DBU, DABCO, potassium carbonate, sodium carbonate, or potassium phosphate; the reaction solvent acetonitrile can be replaced by one or any two of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, 1,4-dioxane, DMF, DMAC, or NMP to form a mixed solvent system.

[0083] Example 12

[0084]

[0085] In a three-necked flask, 410 mL of n-butanol was added, followed by compound 11 (41.05 g, 100 mmol). The mixture was stirred until homogeneous and then heated to 85–90 °C with stirring for 5–6 hours. After the reaction was complete, the mixture was concentrated and distilled to a small volume. The mixture was then kept at 55–60 °C with stirring, and 328 mL of n-heptane was slowly added. The mixture was then slowly cooled to 0–10 °C to induce crystallization. The crystals were filtered, and the solid was collected and dried to obtain product 13 (29.45 g, 94.9%).

[0086] In Example 12, the reaction solvent n-butanol can be replaced by a mixture of methanol, ethanol, n-propanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, methyl tert-butyl ether, toluene, acetone, butanone, MIBK, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, water, or NMP, or any two of them, forming a mixed solvent system.

Claims

1. An intermediate compound for the synthesis of digotinib, characterized in that... Compounds 6, 9, and 10 are included, with the following structural formulas: In compound 6, HA is a pharmaceutically acceptable acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, fumaric acid, maleic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, L-tartaric acid, D-tartaric acid, L-DBTA, D-DBTA, L-DTTA, D-DTTA, or L-camphorsulfonic acid.

2. A method for synthesizing digotinib intermediate compound 6, characterized in that, Includes the following steps: (1) Compound 3 was obtained by intramolecular cyclization of the intermediate state of compound 1 and compound 2 after condensation under the action of base under acid catalysis. (2) Compound 3 was reduced by a boron reducing agent to obtain compound 4; (3) Compound 4 was cyclized by reacting the intermediate state of compound 4 after the dihydroxyl group was activated by the acylating agent with the amination agent to obtain compound 5; (4) Selectively remove PG from compound 5 under appropriate conditions. 2 The protecting group yields an intermediate free base or a resalting compound to obtain its pharmaceutically acceptable salt compound 6; In compound 1, R is methyl, ethyl or tert-butyl; When PG 1 When it is benzyl or benzyloxycarbonyl, PG 2 It is 4-methoxybenzyl, tert-butyl, or triphenylmethyl; when PG 1 When it is tert-butyloxycarbonyl, PG 2 It is benzyl.

3. The method for synthesizing digotinib intermediate compound 6 according to claim 2, characterized in that, In step (1) the condensation reaction, the base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, n-butyllithium, LDA, LiHMDS, NaHMDS, or KHMDS; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, or NMP, or any two of them forming a mixed solvent system; the ring-closed acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid; in step (2) the reduction reaction, the boron reducing agent is selected from sodium borohydride, lithium borohydride, potassium borohydride, or borane; the agent with or without a accelerator is selected from boron trifluoride ether, boron trifluoride acetic acid, trifluoroacetic acid, etc. Acetic acid, methanesulfonic acid, or trifluoromethanesulfonic acid; the reaction solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, acetonitrile, 1,4-dioxane, water, or a mixture of any two of them; in step (3) the cyclization reaction, the acylating agent is selected from hydrogen chloride, thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl anhydride; the amination agent is selected from benzylamine, 4-methoxybenzylamine, tert-butylamine, or triphenylmethylamine; with or without alkali, the acylating agent is selected from sodium carbonate, potassium carbonate, cesium carbonate, pyridine, 2,6-dimethylpyridine, triethylamine, diisopropylethylamine, DABCO, or DBU; the reaction solvent is selected from DMF, DMAC, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, acetonitrile, 1,4-dioxane, or a mixture of any two of them.

4. The method for synthesizing digotinib intermediate compound 6 according to claim 2, characterized in that, In the deprotection reaction of step (4), when PG 1 =Benzyl or benzyloxycarbonyl, PG 2 When 4-methoxybenzyl, tert-butyl, or triphenylmethyl is used, a strong acid hydrolysis method is selected to remove PG. 2 The protecting group, wherein the strong acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, methyl tert-butyl ether, toluene, acetone, butanone, MIBK, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, water, or NMP, or any two of them forming a mixed solvent system; or, in the deprotection reaction of step (1), when PG 1 = tert-butyl, triphenylmethyl or tert-butyloxycarbonyl, PG 2 =For benzyl groups, palladium catalysis is used to remove PG under the action of a reducing agent. 2 Protecting group; wherein the palladium catalyst is palladium on carbon or palladium hydroxide; the reducing agent is selected from hydrogen, formic acid or ammonium formate; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, acetic acid or water, or any two of them forming a mixed solvent system.

5. A method for synthesizing digotinib intermediate compound 9, characterized in that, Includes the following steps: (1) Compound 6 and compound 7 were condensed under the action of a base to obtain compound 8; (2) Compound 8 was reduced and deprotected by a reducing agent under the action of palladium catalyst to obtain compound 9.

6. The method for synthesizing digotinib intermediate compound 9 according to claim 4, characterized in that, In step (1) the condensation reaction, the base is selected from triethylamine, diisopropylethylamine, dimethylaniline, pyridine, DBU, DABCO, DMAP, potassium carbonate, sodium carbonate, or potassium phosphate; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, or NMP, or any two of them forming a mixed solvent system; in step (2) the deprotection reaction, palladium catalysis is used to remove PG under the action of a reducing agent. 1 The protecting group is selected from palladium on carbon or palladium hydroxide as the palladium catalyst, and hydrogen, formic acid or ammonium formate as the reducing agent. The reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, acetic acid or water, or any two of them forming a mixed solvent system.

7. A method for synthesizing digotinib, characterized in that... Includes the following steps: (1) Compound 8 was deprotected under acid to give compound 11; (2) Compound 11 was condensed with compound 12 under alkaline conditions to obtain the target product, digotinib compound 13; Among them, PG 1 It is tert-butyl, benzyloxycarbonyl, or triphenylmethyl.

8. The method for synthesizing digotinib according to claim 7, characterized in that, In the deprotection reaction of step (1), the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, methyl tert-butyl ether, toluene, acetone, butanone, MIBK, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, water, or NMP. One or any two of them form a mixed solvent system; in the condensation reaction of step (2), the base is selected from DBU or DABCO; the reaction solvent is selected from one or any two of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC or NMP to form a mixed solvent system.

9. A method for synthesizing digotinib, characterized in that, Includes the following steps: (1) Compound 9 was condensed with compound 12 or 12b under alkaline conditions to obtain compound 10; (2) Compound 10 was deprotected to obtain the target product, digotinib compound 13; Among them, PG 1 It is benzyl or benzyloxycarbonyl.

10. A method for synthesizing digotinib according to claim 9, characterized in that, In step (1) of the condensation reaction, the base is selected from triethylamine, diisopropylethylamine, dimethylaniline, pyridine, DBU, DABCO, potassium carbonate, sodium carbonate, or potassium phosphate; the reaction solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, toluene, chlorobenzene, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, or NMP, or any two of them forming a mixed solvent system; in step (2) In the deprotection reaction, the acid may be selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid, with or without acid; the reaction solvent may be selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, tert-butyl acetate, n-butyl acetate, methyl tert-butyl ether, toluene, acetone, butanone, MIBK, dichloromethane, acetonitrile, 1,4-dioxane, DMF, DMAC, water, or NMP, or any two of them forming a mixed solvent system.

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