Novel preparation method of cupanicilib

Abstract

The invention relates to the technical field of preparation of cupanicilib, and discloses a novel preparation method of cupanicilib, which comprises the following steps: by taking vanillic acid as an initial raw material, carrying out methyl esterification, nitration, alkylation reaction with N-3-chloropropylmorpholine hydrochloride, ester group hydrolysis, condensation with urea, nitro reduction, intramolecular condensation and condensation with chloroethylamine hydrochloride to obtain cupanicilib. According to the synthetic scheme, the synthetic route is short, the raw materials are easy to obtain, the yield is high, no dangerous reaction process exists in the reaction process, a highly toxic reagent is not used, and the synthetic scheme is green and efficient.

Description

Technical Field

[0001] The present invention relates to the technical field of copanlisib preparation, and specifically to a new preparation method of copanlisib. Background Art

[0002] Copanlisib, chemically named 2-amino-N-[2,3-dihydro-7-methoxy-8-[3-(4-morpholinyl)propoxy]-imidazo[1,2-c]quinazolin-5-yl]-5-pyrimidinecarboxamide, is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor developed by Bayer AG, Germany. It mainly inhibits the PI3K-α and PI3K-δ subtypes expressed on malignant B cells. It was acceleratedly approved by the US FDA for marketing in September 2017 and obtained orphan drug status, with the trade name Aliqopa, and is used for the treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least two systemic therapies.

[0003] There are mainly three current synthetic schemes for copanlisib. One scheme uses acetylvanillin as the starting material, the second uses 7-benzyloxy-8-methoxyquinazoline-2,4-diol as the starting material, and the third uses 2-amino-3-methoxy-4-[3-(4-morpholinyl)propoxy]-benzonitrile as the starting material, such as PCT patent W02008070150, Chinese Journal of Pharmaceuticals, 2019, 50(2): 158-163.

[0004] The first synthetic scheme of copanlisib: There are two synthetic methods using acetylvanillin as the starting material: Method 1: Using acetylvanillin as the starting material, through nitration, acetyl group hydrolysis, phenolic hydroxyl benzyl protection, condensation and dehydration to form nitrile, nitro reduction, reaction with ethylenediamine under the action of sulfur powder to form dihydroimidazole, reaction with highly toxic reagent cyanogen bromide, deprotection with trifluoroacetic acid, alkylation, and acylation to obtain copanlisib. The yield of this synthetic scheme is low. For example, the yields of the nitration reaction step, alkylation reaction step, and acylation reaction step are less than 50%, resulting in a low overall reaction yield and increased costs.

[0005] The synthetic route of Method 1 is as follows:

[0006] Method 2: Using acetylvanillin as the starting material, nitrating with a mixed acid, directly performing an alkylation reaction, directly reacting with ethylenediamine to form an imidazole structure, then performing nitro reduction, reacting with cyanogen bromide, and finally condensing to obtain copanlisib. The yield of this scheme is greatly improved compared to Method 1, but it still uses the highly toxic reagent cyanogen bromide, and this reagent is relatively expensive, increasing the synthesis cost.

[0007] The synthetic route of Method 2 is as follows:

[0008] The second synthetic scheme of copanlisib: Using 7-benzyloxy-8-methoxyquinazoline-2,4-diol as the starting material, copanlisib is prepared through chlorination, nucleophilic substitution, chlorination, intramolecular nucleophilic substitution cyclization, deprotection, alkylation, and acylation reactions. The yield of this synthetic scheme is relatively low, and the starting material is difficult to obtain, resulting in a high cost.

[0009]

[0010] The third synthetic scheme of copanlisib: Using 2-amino-3-methoxy-4-[3-(4-morpholinyl)propoxy]-benzonitrile as the starting material, there are two synthetic methods: Method 1: Reacting 2-amino-3-methoxy-4-[3-(4-morpholinyl)propoxy]-benzonitrile with guanidine hydrochloride to obtain 2-aminoquinazolin-4-one, followed by condensation, chlorination, nucleophilic substitution, and intramolecular cyclization to prepare copanlisib. Although the synthetic steps of this scheme are short, the raw materials are difficult to obtain, the yield of each step is not high, and the cost is high.

[0011] The synthetic route of Method 1 is as follows:

[0012] Method 2: Reacting 2-amino-3-methoxy-4-[3-(4-morpholinyl)propoxy]-benzonitrile with benzoyl isocyanurate, followed by alkylation, intramolecular cyclization, chlorination, amination, and condensation to obtain it. The synthetic route is short, but the yield of each step is also not high, and the raw material cost is high, which is not suitable for industrial production.

[0013] The synthetic route of Method 2 is as follows: Summary of the Invention

[0014] (I) Technical problems to be solved To solve the existing technical problems of low yield and high raw material cost, the present invention provides a new preparation method for copanlisib.

[0015] (II) Technical solution The present invention is realized by the following technical solution: A new preparation method for copanlisib, the method comprising the following: S1: Synthesis of methyl 4-hydroxy-3-methoxybenzoate (1); Among them, under an ice bath, thionyl chloride is added dropwise to methanol, and then vanillic acid is added and refluxed for 12 h to obtain methyl 4-hydroxy-3-methoxybenzoate with a yield of 97%. The specific reaction is as follows: (1) S2: Synthesis of 2-nitro-3-methoxy-4-hydroxybenzoic acid (2); Among them, methyl 4-hydroxy-3-methoxybenzoate is dissolved in glacial acetic acid and dropped into a mixed acid of nitric acid and sulfuric acid at 0 °C, and reacted for 8 h to obtain methyl 2-nitro-3-methoxy-4-hydroxybenzoate with a yield of 84%. The specific reaction is as follows: (2) S3: Synthesis of methyl 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoate (3); Among them, methyl 2-nitro-3-methoxy-4-hydroxybenzoate reacts with N-(3-chloropropyl)morpholine hydrochloride under the action of potassium carbonate powder to obtain methyl 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoate with a yield of 92%. The specific reaction is as follows: (3) S4: Synthesis of 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoic acid (4); Among them, methyl 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoate is dissolved in methanol, and 30% sodium hydroxide solution is added, and hydrolyzed at room temperature to obtain 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoic acid with a yield of 97%. The specific reaction is as follows: (4) S5: Synthesis of 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoylurea (5); Among them, 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoic acid is dissolved in dichloromethane, and oxalyl chloride is dropped under an ice bath. After the dropping is completed, the reaction is carried out at room temperature for 5 h to obtain 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoyl chloride. Then the reaction solution is dropped into a DMF solution of urea and triethylamine. After the dropping is completed, the temperature is raised to 40 °C and the reaction is carried out for 4 h to obtain 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoylurea with a yield of 81%. The specific reaction is as follows: (5) S6: Synthesis of 2-amino-3-methoxy-4-(3-morpholinopropoxy)benzoylurea (6); Among them, 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoylurea is dissolved in absolute ethanol, and Pd / C is added, and catalytic hydrogenation is carried out to obtain 2-amino-3-methoxy-4-(3-morpholinopropoxy)benzoylurea with a yield of 98%. The specific reaction is as follows: (6) S7: Synthesis of 2-amino-8-methoxy-7-(3-morpholinopropoxy) quinazolinone (7); Among them, 2-amino-3-methoxy-4-(3-morpholinopropoxy) benzoyl urea was dissolved in absolute ethanol, and intramolecular cyclization was carried out under the action of sodium acetate to obtain 2-amino-8-methoxy-7-(3-morpholinopropoxy) quinazolinone with a yield of 94%. The specific reaction is as follows: (7) S8: Synthesis of 2-amino-4-(2-chloroethylimino)-8-methoxy-7-(3-morpholinopropoxy) quinazoline (8); Among them, 2-amino-8-methoxy-7-(3-morpholinopropoxy) quinazolinone was dissolved in absolute ethanol, and condensed with 2-chloroethylamine hydrochloride under the action of sodium acetate to obtain 2-amino-4-(2-chloroethylimino)-8-methoxy-7-(3-morpholinopropoxy) quinazoline with a yield of 98%. The specific reaction is as follows: (8) S9: Synthesis of 5-amino-7-methoxy-8-(3-morpholinopropoxy)[1,2-c]dihydroimidazoquinazoline (9); Among them, 2-amino-4-(2-chloroethylimino)-8-methoxy-7-(3-morpholinopropoxy) quinazoline was dissolved in a solution of sodium methoxide, and heated under reflux for 7 h to obtain 5-amino-7-methoxy-8-(3-morpholinopropoxy)[1,2-c]dihydroimidazoquinazoline with a yield of 94%. The specific reaction is as follows: (9) S10: Synthesis of copanlisib (10); Among them, 5-amino-7-methoxy-8-(3-morpholinopropoxy)[1,2-c]dihydroimidazoquinazoline and 2-aminopyrimidine-4-carboxylic acid were used to prepare copanlisib (X) under the action of a condensing agent with a yield of 95%. The specific reaction is as follows: (10).

[0016] (III) Beneficial effects Compared with the prior art, the beneficial effects of the present invention are as follows: In the present invention, starting from vanillic acid, through methylation, nitration, alkylation reaction with N-3-chloropropylmorpholine hydrochloride, hydrolysis of the ester group, condensation with urea, reduction of the nitro group, intramolecular condensation, condensation with 2-chloroethylamine hydrochloride, intramolecular alkylation, and acylation with 2-aminopyrimidinecarboxylic acid, copanlisib is prepared. This synthesis scheme has a short synthesis route, easily available raw materials, a high yield, no dangerous reaction processes during the reaction, no use of highly toxic reagents, and is green and efficient. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a flow chart of the synthesis steps of a new preparation method of copanlisib of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0018] Next, in combination with the drawings and the specific embodiments, the present invention will be further described. It should be noted that, on the premise of no conflict, the following-described embodiments or technical features can be arbitrarily combined to form new embodiments.

[0019] Please refer to Figure 1 , a new preparation method of copanlisib in this embodiment includes Example 1: S1: Synthesis of methyl 4-hydroxy-3-methoxybenzoate (1); Among them, 300 ml of methanol was measured, and under ice bath, 50 ml of thionyl chloride was added dropwise, and the addition was completed in 30 minutes. After the addition was completed, stirring was continued for 30 minutes under ice bath, then 168 g of vanillic acid was added, and the system was stirred at room temperature for 1 h, and then heated to reflux for 12 h. After the reaction was completed, most of the solvent was recovered under reduced pressure. The residue was poured into an ice-saturated sodium bicarbonate solution, extracted with 400 ml of ethyl acetate, washed with water until neutral, dried over anhydrous magnesium sulfate, filtered, and the solvent was recovered from the filtrate under reduced pressure. The residue was recrystallized from absolute ethanol to obtain 176.5 g of white solid crystals, with a yield of 97%. The specific reaction is as follows: (1) S2: Synthesis of 2-nitro-3-methoxy-4-hydroxybenzoic acid (2); Among them, 100 ml of concentrated sulfuric acid was measured, and under ice bath, 200 ml of concentrated nitric acid was added dropwise while stirring. During the addition, the temperature of the system was controlled not to exceed 5 °C, and the addition was completed in 30 minutes. After the addition was completed, the system was stirred for another 10 minutes. Under ice bath, an acetic acid solution of methyl 4-hydroxy-3-methoxybenzoate (182 g of methyl 4-hydroxy-3-methoxybenzoate and 300 ml of glacial acetic acid) was added dropwise. During the addition, the temperature of the system was controlled not to exceed 15 °C, and the addition was completed in 1 h. After the addition was completed, the reaction was continued for 1 h under ice bath, and then the system was heated to room temperature and continued to react for 7 h. After the reaction was completed, the reaction solution was slowly poured into 500 ml of ice water, and white solid was precipitated. The solid was filtered, washed with water until neutral, dried in vacuo, and recrystallized twice from absolute ethanol to obtain 190.7 g of white solid, with a yield of 84%. The specific reaction is as follows: (2) S3: Synthesis of methyl 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoate (3); Among them, 227 g of 2-nitro-3-methoxy-4-hydroxybenzoic acid and 220 g of N-chloropropylmorpholine hydrochloride were dissolved in 1500 mL of DMF. 600 g of potassium carbonate powder was added, and the temperature of the system was raised to 90 °C for reaction for 12 h. After the reaction was completed, the reaction solution was slowly poured into ice water, extracted with 800 mL of ethyl acetate, the organic layer was washed twice with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, the solvent in the filtrate was recovered under reduced pressure, and the residue was recrystallized from methanol to obtain 325.7 g of a white solid powder with a yield of 92%. The specific reaction is as follows: (3) S4: Synthesis of 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoic acid (4); Among them, 177 g of methyl 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoate was dissolved in 300 mL of methanol. 300 mL of 30% sodium hydroxide solution was added, and the reaction was stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was slowly poured into 1 mol / L dilute hydrochloric acid to adjust the pH to 2-3, and then the system was adjusted to about pH 8 with ice-saturated sodium carbonate solution, extracted with 500 mL of ethyl acetate, the organic layer was washed twice with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, the solvent in the filtrate was recovered under reduced pressure, and the residue was recrystallized from acetone to obtain 164.9 g of a white solid powder with a yield of 97%. The specific reaction is as follows: (4) S5: Synthesis of 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoylurea (5); Among them, 34 g of 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoic acid was dissolved in 100 mL of dichloromethane, cooled to 0 °C in an ice bath, and 15 g of oxalyl chloride was added dropwise. The addition was completed in 30 minutes. After the addition was completed, the reaction continued in the ice bath for 1 h, and then the temperature was raised to room temperature and the reaction continued for 5 h. After the reaction was completed, it was transferred to a constant pressure dropping funnel and dropped into a DMF solution of urea (7 g of urea, 12 g of triethylamine, 120 mL of DMF, in an ice bath). The addition was completed in 30 minutes. After the addition was completed, the reaction solution continued to react in the ice bath for 2 h, and then the temperature of the system was slowly raised to 40 °C and the reaction continued for 4 h. After the reaction was completed, the reaction solution was slowly poured into a saturated aqueous sodium bicarbonate solution, extracted with 300 mL of ethyl acetate, the organic layer was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, the solvent in the filtrate was recovered under reduced pressure, and the residue was recrystallized from absolute ethanol to obtain 30.9 g of a pale yellow solid powder with a yield of 81%. The specific reaction is as follows: (5) S6: Synthesis of 2-amino-3-methoxy-4-(3-morpholinopropoxy)benzoylurea (6); Among them, 38.2 g of 2-nitro-3-methoxy-4-(3-morpholinopropoxy) benzoylurea was dissolved in 200 mL of absolute ethanol, 10 g of 5% Pd / C was added, hydrogen was introduced, the temperature was raised to reflux, the system pressure was maintained at 2 atmospheres, and the reaction was carried out for 8 h. After the reaction was completed, the catalyst Pd / C was filtered off, half of the solvent in the filtrate was recovered, and the solution was cooled and crystallized to obtain 34.5 g of light yellow crystals with a yield of 98%. The specific reaction is as follows: (6) Synthesis of 2-amino-8-methoxy-7-(3-morpholinopropoxy) quinazolinone (7); Among them, 35.2 g of 2-amino-3-methoxy-4-(3-morpholinopropoxy) benzoylurea was dissolved in 150 mL of absolute ethanol, 10 g of anhydrous sodium acetate was added, and the temperature was raised to reflux for 12 h. After the reaction was completed, most of the solvent was recovered under reduced pressure. The residue was poured into ice water, extracted with 300 mL of dichloromethane, the organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, the solvent in the filtrate was recovered under reduced pressure, and the residue was recrystallized from petroleum ether:ethyl acetate = 1:1 to obtain 31.4 g of yellow solid powder with a yield of 94%. The specific reaction is as follows: (7) S8: Synthesis of 2-amino-4-(2-chloroethylimino)-8-methoxy-7-(3-morpholinopropoxy) quinazoline (8); Among them, 33.4 g of 2-amino-8-methoxy-7-(3-morpholinopropoxy) quinazolinone and 12 g of 2-chloroethylamine hydrochloride were dissolved in 200 mL of absolute ethanol, 10 g of anhydrous sodium acetate was added, and the mixture was refluxed for 4 h. After the reaction was completed, the solvent was recovered under reduced pressure. 200 mL of ethyl acetate was added to the system, stirred and dissolved, and slowly poured into ice water. The layers were separated, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, the solvent in the filtrate was recovered under reduced pressure, and the residue was recrystallized from petroleum ether:ethyl acetate = 1:1 to obtain 38.7 g of yellow solid powder with a yield of 98%. The specific reaction is as follows: (8) S9: Synthesis of 5-amino-7-methoxy-8-(3-morpholinopropoxy)[1,2-c]dihydroimidazoquinazoline (9); Among them, 39.6 g of 2-amino-4-(2-chloroethylimino)-8-methoxy-7-(3-morpholinopropoxy) quinazoline was added to 200 mL of 30% sodium methoxide in methanol solution, and the mixture was refluxed for 7 h. After the reaction was completed, most of the methanol was recovered under reduced pressure. The residue was slowly poured into 300 mL of ice water, extracted with 300 mL of ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, the solvent in the filtrate was recovered under reduced pressure, and the residue was recrystallized from dichloromethane to obtain 33.7 g of light yellow solid with a yield of 94%. The specific reaction is as follows: (9) Example 10: S10: Synthesis of copanlisib (10); Among them, take 35.9 g of 5-amino-7-methoxy-8-(3-morpholinopropoxy)[1,2-c]dihydroimidazoquinazoline, 15 g of 2-aminopyrimidine-4-carboxylic acid, and 2.5 g of DMAP, dissolve them in 200 mL of DMF, add 20 g of EDCI and 15 g of HOBt, react at room temperature for 8 h. After the reaction is completed, slowly pour the reaction solution into ice water, extract with 300 mL of ethyl acetate, wash with water, dry the organic layer with anhydrous magnesium sulfate, filter, recover the solvent under reduced pressure from the filtrate, and recrystallize the residue with absolute ethanol to obtain 45.2 g of white solid, with a yield of 95%. The specific reaction is as follows: (10).

[0020] The overall synthesis route of the present invention is as follows:

[0021] Working principle: Starting from vanillic acid, through methylation, nitration, alkylation reaction with N-3-chloropropylmorpholine hydrochloride, hydrolysis of the ester group, condensation with urea, reduction of the nitro group, intramolecular condensation, condensation with chloroethylamine hydrochloride, intramolecular alkylation, and acylation with 2-aminopyrimidinecarboxylic acid to prepare copanlisib. This synthesis scheme has a short synthesis route, easily available raw materials, high yield, no dangerous reaction processes during the reaction, no use of highly toxic reagents, and is green and efficient.

[0022] The above embodiments are only the preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by those skilled in the art based on the present invention fall within the scope of protection required by the present invention.

Claims

1. A new preparation method of copanlisib, characterized in that, The method includes the following: S1: Synthesis of methyl 4-hydroxy-3-methoxybenzoate (1); Among them, under an ice bath, thionyl chloride was added dropwise to methanol, and then vanillic acid was added and refluxed for 12 h to obtain methyl 4-hydroxy-3-methoxybenzoate with a yield of 97%. The specific reaction is as follows: （1） S2: Synthesis of 2-nitro-3-methoxy-4-hydroxybenzoic acid (2); Among them, methyl 4-hydroxy-3-methoxybenzoate was dissolved in glacial acetic acid and added dropwise to a mixed acid of nitric acid and sulfuric acid at 0 °C, and reacted for 8 h to obtain methyl 2-nitro-3-methoxy-4-hydroxybenzoate with a yield of 84%. The specific reaction is as follows: （2） S3: Synthesis of methyl 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoate (3); Among them, methyl 2-nitro-3-methoxy-4-hydroxybenzoate and N-3-chloropropylmorpholine hydrochloride were reacted under the action of potassium carbonate powder to obtain methyl 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoate with a yield of 92%. The specific reaction is as follows: （3） S4: Synthesis of 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoic acid (4); Among them, methyl 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoate was dissolved in methanol, and 30% sodium hydroxide solution was added, and hydrolyzed at room temperature to obtain 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoic acid with a yield of 97%. The specific reaction is as follows: （4） S5: Synthesis of 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoylurea (5); Among them, 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoic acid was dissolved in dichloromethane, and oxalyl chloride was added dropwise under an ice bath. After the addition was completed, the reaction was carried out at room temperature for 5 h to obtain 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoyl chloride. Then the reaction solution was added dropwise to a DMF solution of urea and triethylamine. After the addition was completed, the temperature was raised to 40 °C and reacted for 4 h to obtain 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoylurea with a yield of 81%. The specific reaction is as follows: （5） S6: Synthesis of 2-amino-3-methoxy-4-(3-morpholinopropoxy)benzoylurea (6); Among them, 2-nitro-3-methoxy-4-(3-morpholinopropoxy)benzoylurea was dissolved in absolute ethanol, and Pd / C was added, and catalytic hydrogenation was carried out to obtain 2-amino-3-methoxy-4-(3-morpholinopropoxy)benzoylurea with a yield of 98%. The specific reaction is as follows: （6） S7: Synthesis of 2-amino-8-methoxy-7-(3-morpholinopropoxy)quinazolinone (7); Among them, 2-amino-3-methoxy-4-(3-morpholinopropoxy)benzoylurea was dissolved in absolute ethanol, and intramolecular cyclization was carried out under the action of sodium acetate to obtain 2-amino-8-methoxy-7-(3-morpholinopropoxy)quinazolinone with a yield of 94%. The specific reaction is as follows: （7） S8: Synthesis of 2-amino-4-(2-chloroethylimino)-8-methoxy-7-(3-morpholinopropoxy)quinazoline (8); Among them, 2-amino-8-methoxy-7-(3-morpholinopropoxy) quinazolinone is dissolved in absolute ethanol and condensed with 2-chloroethylamine hydrochloride under the action of sodium acetate to obtain 2-amino-4-(2-chloroethylimino)-8-methoxy-7-(3-morpholinopropoxy) quinazoline, with a yield of 98%. The specific reaction is as follows: （8） S9: Synthesis of 5-amino-7-methoxy-8-(3-morpholinopropoxy)[1,2-c]dihydroimidazoquinazoline (9); Among them, 2-amino-4-(2-chloroethylimino)-8-methoxy-7-(3-morpholinopropoxy) quinazoline is dissolved in a solution of sodium methoxide and heated under reflux for 7 h to obtain 5-amino-7-methoxy-8-(3-morpholinopropoxy)[1,2-c]dihydroimidazoquinazoline, with a yield of 94%. The specific reaction is as follows: （9） S10: Synthesis of copanlisib (10); Among them, 5-amino-7-methoxy-8-(3-morpholinopropoxy)[1,2-c]dihydroimidazoquinazoline and 2-aminopyrimidine-4-carboxylic acid are used to prepare copanlisib (X) under the action of a condensing agent, with a yield of 95%. The specific reaction is as follows: （10）。

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