KR102104957B1 - Manufacturing method of copanriship - Google Patents

Abstract

The present invention is a known starting compound 2-amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile as a starting material, heterocyclization, condensation cyclization, halogenated amination and amidation The method of preparing copanlisib (BAY80-6946), which produces a target compound copanlisib through a single step reaction, etc., is published. In the above manufacturing method, the raw material can be easily obtained, the process is simple, economical and eco-friendly, and suitable for industrial production.

Description

Manufacturing method of copanriship

The present invention belongs to the field of organic synthetic route design, raw material and intermediate manufacturing technology, and more particularly, to a method of manufacturing a drug copanriship for the treatment of leukemia.

Copanlisib is a new oral phosphoinositide 3-kinase (PI3K) inhibitor developed by Bayer, Germany. As a result of existing clinical studies, the drug suppresses cancer cell growth in the body of leukemia and lymphoma patients by blocking the PI3K signaling pathway. To further demonstrate the prospects of the drug, in 2015 Bayer also conducted two phase III clinical trials, either alone or in combination with Rituxan, to treat rare non-Hodgkin's lymphoma (NHL) and Rituxan alone. It was compared with the effect used. In addition, Bayer also conducted a Phase II clinical study in which Copanlisib treats diffuse giant B cell lymphoma (a type of malignant NHL subtype). Since the drug does not yet have a standard Chinese translation name, the applicant has transliterated it as "Kopariship" in the text.

The chemical name of Copanlisib (I) is 2-amino-N- [2, 3-dihydro-7-methoxy-8- [3- (4-morpholino) propoxy] imidazo [1, 2-C] quinazolin-5-yl] -5-pyrimidinecarboxamide, and the structural formula is as follows.

The original research company's PCT patent WO2008070150 discloses a method for producing copanlisib and analogs thereof, and the following five possible synthetic routes are proposed in the above documents.

Synthetic route 1 ：

Synthetic route 2 ：

Synthetic route 3:

Synthetic route 4 ：

Synthetic route 5 ：

Analyzing the above 5 synthetic routes, the first 4 pathways are vanillin (3-methoxy-4-hydroxybenzaldehyde) as the main raw material, protecting and deprotecting hydroxy groups, nitrification, reduction, nitrification, cyclization , Through the cyclization and the reaction of the propyl morpholine side chain and the link of the aminopyrimidine side chain, the production of copanriship was realized. The difference is mainly that the order of each single step reaction is different, whereby the steps of the reaction, the selection of protecting groups and the number and method of deprotection are different from each other, and the reaction conditions and the total yield are also different. However, regardless of which synthetic route is selected, the above reaction process is related to the parental protection and deprotection reaction, and all of them use non-conventional reagents such as cyanide bromide, in addition, there are many reaction steps, and the total yield is low, resulting in industrial production. Not good for The fifth synthetic route is a starting material for a compound containing a quinazolinone structure, and analogs of copanrichip are prepared through reactions such as chlorination, substitution, cyclization, deprotection, and condensation with a side chain. As can be seen in the process of designing the reaction path, there are two chlorine atoms in the quinazoline ring after chlorination, and the substitution reaction causes side reactions competing at different positions, and adversely affects the mass and purification process of the product.

Considering the existing process defects, developing a manufacturing technology that is simple, economical, eco-friendly, and excellent in mass, and exploring process technology suitable for industrial production, in particular, is of great practical significance in improving the economic and social efficiency of the drug. I can have it.

An object of the present invention is to provide a method of manufacturing Copanlisib (I), which can easily obtain raw materials, has a simple process, is economical and eco-friendly, and is suitable for industrial production.

In order to realize the object of the present invention, the present invention uses the following main technical methods. In the manufacturing method of copanriship (I),

2-Amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile (II) and cyclization reagents chloroformate isocyanate, chlorosulfonyl isocyanate, benzoyl isocyanate or urea heterocyclization reaction This produces 4-amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) -one (III), 4-amino-7- (3- Morpholine-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) -one (III) and 2-halogen ethanol are 7-methoxy-8- by condensation cyclization reaction under the action of an acid binder. (3-morpholin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5 (6H) -one (IV), 7-methoxy-8 -(3-morpholin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5 (6H) -one (IV) undergoes halogenation and amination reactions, followed by 7 -Methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5-amine (V), and 7-meth Thoxy-8- (3-mo Folin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5-amine (V) and 2-aminopyrimidine-5-carboxylic acid act as condensing and alkali accelerators And a step of generating copanrisib (I) by amidation.

Halogen in the 2-halogen ethanol is fluorine, chlorine, bromine or iodine.

In addition, the present invention also provides additional technical solutions as follows.

The cyclization reagent of the heterocyclization reaction is chloro formic acid isocyanate, chloro sulfonyl isocyanate, benzoyl isocyanate or urea, and benzoyl isocyanate is preferred.

The solvent for the heterocyclization reaction is dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane, and dioxane or tetrahydrofuran is preferred.

The temperature of the heterocyclization reaction is 0 to 120 ° C, and 20 to 90 ° C is preferable.

Addition molar ratio of 4-amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) -one (III) and 2-halogen ethanol as raw materials for the condensation cyclization reaction Is 1: 1.0 to 2.0, and 1: 1.0 to 1.5 is preferred.

Halogen in the raw material 2-halogen ethanol of the condensation cyclization reaction is fluorine, chlorine, bromine or iodine, and chlorine or bromine is preferred.

The acid binder of the condensation cyclization reaction is triethylamine, pyridine, N-methylmorpholine, diisopropyl ethylamine, 4-dimethylamino pyridine, potassium carbonate, lithium carbonate, cesium carbonate or potassium t-butoxide, carbonic acid Cesium or potassium t-butoxide is preferred.

The solvent of the condensation cyclization reaction is tetrahydrofuran, dioxane, 1,2-dichloroethane, acetonitrile, toluene, dimethyl carbonate, N, N-dimethylformamide or dimethyl sulfoxide, and N, N-dimethylformamide Or dimethyl sulfoxide is preferred.

The temperature of the condensation cyclization reaction is 25 to 150 ° C, preferably 80 to 90 ° C.

The halogenating agent of the halogenation reaction is phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, oxalyl chloride or carbonyl chloride, phosphorus oxychloride is preferred.

The temperature of the halogenation reaction is 50 to 150 ° C, preferably 90 to 105 ° C.

The amination agent of the amination reaction is ammonia water or ammonia gas.

The temperature of the amination reaction is 50 to 150 ° C, preferably 90 to 105 ° C.

The condensation agent of the amidation reaction is N, N, -dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), N, N'-diisopropyl carbodiimide (DIC), 1-hydr Oxy-benzotriazole (HOBt), O-benzotriazole-N, N, N ', N'-tetramethyluronium tetrafluoro borate (TBTU), O- (7-azobenzotriazole) -N, N, N ', N'-tetramethyluronium hexafluoro borate (HATU), benzotriazole-N, N, N', N'-tetramethyluronium hexafluoro borate (HBTU) or benzotriazole- 1-yl oxy tris (dimethyl amino) phosphonium hexafluoro phosphate (BOP), benzotriazole-N, N, N ', N'-tetramethyluronium hexafluoro borate (HBTU) or benzotriazole- 1-yl oxy tris (dimethyl amino) phosphonium hexafluoro phosphate (BOP) is preferred.

The alkali accelerator of the amidation reaction is triethylamine (TEA), pyridine, 2, 6-dimethylpyridine, 4-dimethylamino pyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM) , Diisopropyl ethylamine (DIEA), 1, 5-diazabicyclo [4.3.0] -nonane-5-ene (DBN), 1, 8-diazabicyclo [5.4.0] -undes-7- Yen (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO), 1, 8-diazabicyclo [5.4.0] -undec-7-ene (DBU) or 1,5- Diazabicyclo [4.3.0] -nonane-5-ene (DBN) or 1,4-diazabicyclo [2.2.2] octane (DABCO) is preferred.

The solvent of the amidation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, dimethyl sulfoxide, N, N-dimethylformamide or acetonitrile, and acetonitrile is preferred.

The temperature of the amidation reaction is 0 to 120 ° C, preferably 50 to 60 ° C.

Compared to the existing technology, the method of manufacturing the copanriship (I) according to the present invention can easily acquire raw materials, has a simple process, has economical and eco-friendly characteristics, and is advantageous for industrial production of the raw materials and develops economic technology. Can promote.

Hereinafter, the present invention is combined with a number of preferred embodiments to provide a non-limiting detailed description of the technical solution of the present invention. Here, the production of raw materials 2-amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile (II) and side chain 2-aminopyrimidine-5-carboxylic acid was published in 2008. A method for preparing the same compound in international patent WO2008070150, named June 12, entitled "Preparation of substituted 2, 3-dihydroimidazo [1, 2-c] quinazoline derivatives for treating hyper-proliferative disorders and diseases associated with angiogenesis" Please refer.

Example 1:

Under a nitrogen atmosphere, 2-amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile (II) (5.82g, 20mmol) and dioxane 50mL were added to the drying reactor, and benzoyl Isocyanate (3.23 g, 22 mmol) was added at room temperature and stirred at room temperature for 20 hours, and the completion of the reaction was detected by TLC. The solution was filtered while standing, and the filter cake was washed with a mixed solvent of normal hexane and ethyl acetate (4: 1), and dried under vacuum to give a white solid 4-amino-7- (3-morpholin-4-ylpro). Foxy) -8-methoxyquinazolin-2 (1H) -one (III) 4.55g is obtained, the yield is 68.1%, and the mass spectrometry (EI) result is m / z 335 (M + H).

Example 2:

Under a nitrogen atmosphere, 2-amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile (II) (5.82 g, 20 mmol) and 50 mL of tetrahydrofuran were added to the drying reactor, A 15 mL solution of tetrahydrofuran of chloro sulfonyl isocyanate (3.25 g, 23 mmol) is added dropwise at 0-5 ° C. After completion of dropping, the temperature was raised to room temperature, followed by stirring for 6 to 8 hours, and the completion of the reaction was detected by TLC. The pH is adjusted to neutral with 5% sodium hydroxide and extracted three times with dichloromethane. The organic phases are combined and washed with water and saturated brine. Concentrated under reduced pressure, the residue was washed with a mixed solvent of normal hexane and ethyl acetate (4: 1), and dried under vacuum to give a white solid 4-amino-7- (3-morpholin-4-ylpropoxy) -8-me 5.10 g of oxyquinazoline-2 (1H) -one (III) was obtained, the yield was 76.3%, and the mass spectrometry (EI) result was m / z 335 (M + H).

Example 3:

Under nitrogen atmosphere, 4-amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) -one (III) (3.3g, 10mmol), 2- Chloroethanol (0.97 g, 12 mmol), potassium t-butoxide (1.68 g, 15 mmol) and 25 mL of N, N-dimethylformamide are added, heated to 80 to 90 ° C, and stirred for 4 to 6 hours. After cooling to room temperature, the reaction solution is poured into a sodium hydroxide solution having a weight percent of 5%, heated to 60 ° C., kept warm for 2 hours, cooled to room temperature, precipitated solid, filtered, washed with water, and normal hexane. Light yellow solid 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5 (6H) by washing and vacuum drying ) -On (IV) 2.12g is obtained, the yield is 58.9%, and the mass spectrometry (EI) result is m / z 361 (M + H).

Example 4:

Under a nitrogen atmosphere, 4-amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (6H) -one (III) (3.3g, 10mmol), 2- Bromine ethanol (1.50 g, 12 mmol), cesium carbonate (3.57 g, 11 mmol) and dimethyl sulfoxide 35 mL are added, heated to 80 to 90 ° C., and stirred for 4 to 6 hours. After cooling to room temperature, the reaction solution is poured into a sodium hydroxide solution having a weight percent of 5%, heated to 60 ° C., kept warm for 2 hours, cooled to room temperature, precipitated solid, filtered, washed with water, and normal hexane. Light yellow solid 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5 (6H) by washing and vacuum drying ) -On (IV) 2.30g is obtained, the yield is 63.9%, and the mass spectrometry (EI) result is m / z 361 (M + H).

Example 5:

Under nitrogen atmosphere, 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5 (6H) -one in the reactor (IV) (1.8 g, 5 mmol), 10 mL of phosphorus oxychloride and 1 mL of N, N-dimethylformamide are added, heated to 90 to 105 ° C, stirred for 4 to 5 hours, and reacted with stirring for 4 to 5 hours to complete the consumption of raw materials by TLC. To detect. After cooling to room temperature, the reaction solution is poured into 50 mL of ice water to precipitate a solid. Filter. The filter cake is washed twice with water, and the obtained wet product need not be treated, and 20 mL of ammonia water having a weight percent of 30% is added, placed in a sealed tube, heated to 100 ° C. and reacted for 12 to 16 hours. Cool to room temperature, filter, and wash the filter cake with water. Vacuum-dried to light yellow solid 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5-amine (V) 1.32g is obtained, the yield is 73.5%, the mass spectrometry (EI) result is m / z 360 (M + H), and the hydrogen spectrum ¹ H NMR (DMSO- d ₆ ) result is δ 1.88 (m, 2H). , 2.36 (m, 4H), 2.44 (m, 2H), 3.56 (m, 4H), 3.70 (s, 3H), 3.89 (m, 4H), 4.04 (t, 2H), 6.74 (m, 3H), 7.43 (m, 1H).

Example 6:

Under a nitrogen atmosphere, 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5-amine (V) was added to the reactor. (0.36 g, 1 mmol), 2-aminopyrimidine-5-carboxylic acid (0.15 g, 1.1 mmol) and 25 mL of acetonitrile are added, and the condensing agent benzotriazol-1-yl oxy tris (dimethyl amino) phosphonium hexafluor Low phosphate (0.49 g, 1.1 mmol) and base catalyst 1, 5-diazabicyclo [4.3.0] -nonane-5-ene (0.50 g, 4 mmol) are added and reacted at room temperature for 12 hours. The temperature was raised to 50-60 ° C again, followed by stirring for 6-8 hours, and the completion of the reaction was detected by TLC. The solvent is evaporated under reduced pressure, cooled to room temperature, and ethyl acetate is added to precipitate a solid. Filtration, the filter cake was washed with cold methanol, and vacuum dried to obtain 0.27 g of a white solid copansiri (I), the yield was 56.3%, and the EI-MS m / z result was 481 [M + H] ⁺ And ¹ H NMR (CDCl ₃ ) results are δ 2.05 (m, 2H), 2.48 (m, 4H), 2.56 (m, 2H), 3.72 (t, 4H), 4.02 (s, 3H), 4.16 (m , 7H), 5.36 (s, 2H), 6.84 (d, 1H), 7.08 (d, 1H), 9.10 (s, 2H).

Specifically, the above embodiments are merely for explaining the technical spirit and features of the present invention, the purpose of which is to enable those skilled in the art to understand and implement the contents of the present invention, thereby protecting the scope of the present invention Is not limited. All equivalent changes or modifications substantially carried out in accordance with the spirit of the present invention fall within the protection scope of the present invention.

Claims (10)

In the manufacturing method of the copanriship,

2-Amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile and cyclization reagent chloro formic acid isocyanate, chloro sulfonyl isocyanate, benzoyl isocyanate or urea is 4 by heterocyclization reaction. -Amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) -one, and 4-amino-7- (3-morpholine-4- Ilpropoxy) -8-methoxyquinazolin-2 (1H) -one and 2-halogen ethanol are 7-methoxy-8- (3-morpholin-4-yl by condensation cyclization reaction under the action of an acid binder. Propoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5 (6H) -one, which produces the 7-methoxy-8- (3-morpholin-4-ylpro Foxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5 (6H) -one undergoes a halogenated amination reaction to give 7-methoxy-8- (3-morpholin-4-yl Propoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5-amine, and the 7-methoxy-8- (3-morpholine-4- Propoxy) -2, 3-dihydro imidazo [1, 2-c] quinazolin-5-amine and 2-aminopyrimidine-5-carboxylic acid are copanri by amidation reaction under the action of condensing agent and alkali accelerator. It includes the step of producing ten, wherein the halogen in the 2-halogen ethanol is fluorine, chlorine, bromine or iodine, characterized in that the production method of copanriship. The method according to claim 1,
The solvent of the heterocyclization reaction is dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane, and the temperature of the heterocyclization reaction is 0 to 120 ° C. Characterized by the manufacturing method of the copanriship. The method according to claim 1,
The molar ratio of the addition of 4-amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) -one and 2-halogen ethanol as the condensation cyclization raw material is 1: 1.0. The method of manufacturing copanriship, characterized in that ~ 2.0. The method according to claim 1,
The acid binder of the condensation cyclization reaction is triethylamine, pyridine, N-methylmorpholine, diisopropyl ethylamine, 4-dimethylamino pyridine, potassium carbonate, lithium carbonate, cesium carbonate or potassium t-butoxide Manufacturing method of copanriship. The method according to claim 1,
The solvent of the condensation cyclization reaction is tetrahydrofuran, dioxane, 1,2-dichloroethane, acetonitrile, toluene, dimethyl carbonate, N, N-dimethylformamide or dimethyl sulfoxide, the temperature of the condensation cyclization reaction The method of manufacturing a copanriship, characterized in that 25 ~ 150 ℃. The method according to claim 1,
The halogenating agent of the halogenated amination reaction is phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, oxalyl chloride or carbonyl chloride, and the amidating agent of the halogenated amination reaction is ammonia water Or a method of manufacturing a copanriship, characterized in that ammonia gas. The method according to claim 1,
The temperature of the halogenated amination reaction is 50 ~ 150 ℃ copanrisip manufacturing method. The method according to claim 1,
The condensation agent of the amidation reaction is N, N, -dicyclohexylcarbodiimide, carbonyldiimidazole, N, N'-diisopropyl carbodiimide, 1-hydroxy-benzotriazole, O-benzo Triazole-N, N, N ', N'-tetramethyluronium tetrafluoroborate, O- (7-azobenzotriazole) -N, N, N', N'-tetramethyluronium hexafluoro A nose characterized by being a borate, benzotriazole-N, N, N ', N'-tetramethyluronium hexa fluoro borate or benzotriazol-1-yl oxy tris (dimethyl amino) phosphonium hexafluoro phosphate Method of manufacturing a fanship. The method according to claim 1,
The alkali accelerator of the amidation reaction is triethylamine, pyridine, 2, 6-dimethylpyridine, 4-dimethylamino pyridine, N-methylmorpholine, N-ethylmorpholine, diisopropyl ethylamine, 1, 5-dia It is characterized by Xavicyclo [4.3.0] -nonane-5-ene, 1, 8-diazabicyclo [5.4.0] -undec-7-ene or 1,4-diazabicyclo [2.2.2] octane Manufacturing method of copanriship. The method according to claim 1,
The solvent of the amidation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, dimethyl sulfoxide, N, N-dimethylformamide or acetonitrile, and the temperature of the amidation reaction is 0 to 120 ° C. Method of manufacturing a copanriship, characterized in that.