KR20180096572A - Manufacturing method of copari - Google Patents

Abstract

The present invention is based on the already known compound 2-amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile as a starting material for heterocyclic, condensation cyclization, halogenated amination and amidation (Copanlisib, BAY 80-6946), which manufactures the target compound cornolysin. In the above production method, the raw material can be easily obtained, the process is simple, economical, eco-friendly, and suitable for industrial production.

Description

Manufacturing method of copari

The present invention belongs to the field of organic synthesis pathway design, raw materials and intermediates production technology, and more particularly, to a method for producing a drug cochineal drug for the treatment of leukemia.

Copanlisib is a novel oral phosphoinositide 3-kinase (PI3K) inhibitor developed by Bayer, Germany. Based on existing clinical studies, the drug inhibits cancer cell growth in leukemic and lymphoma patients through blocking the PI3K signaling pathway. To further advance the prospect of the drug, Bayer also conducted two Phase III trials in 2015 and used either alone or combined with Rituxan to treat rare non-Hodgkin's lymphoma (NHL), and Rituxan alone As opposed to the effects used by. In addition, Bayer has also conducted clinical Phase II studies in which Copanlisib treats diffuse large B-cell lymphoma (a malignant NHL subtype). Since the drug has not yet been given a standard Chinese translation designation, the applicant has translated it into the word " Kofanrisi " in the text.

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

PCT Patent WO2008070150 of the original research company has published a process for the preparation of co-orientalis and its analogs, all of which are described in the following five possible synthetic routes.

Synthetic route 1:

Synthetic route 2:

Synthesis Route 3:

Synthetic route 4:

Synthesis Route 5:

Analysis of the five synthetic routes showed that the first four routes were all based on vanillin (3-methoxy-4-hydroxybenzaldehyde) as the main raw material, protecting and deprotecting the hydroxy group, nitrifying, reducing, nitrating, , Bicyclization and linkage of propylmorpholine side chain and aminopyrimidine side chain. The difference in the order of the respective single step reactions is different from each other, whereby the steps of the reaction, the number of times of selection and deprotection of the protecting group and the method are different from each other, and the reaction conditions and the total number of steps are also different. However, whichever synthesis route is selected, the reaction process is related to the protection of the mother protection and the deprotection reaction. In addition, all of the unrecognized reagents such as cyanogen bromide are used. Moreover, the reaction step is also extensive and the total yield is low, . The fifth synthetic route is to prepare analogs of coporgid with the compounds containing the quinazolinone structure as starting materials through reactions such as chlorination, substitution, cyclization, deprotection and condensation with side chains. As can be seen from the designing process of the reaction pathway, there are two chlorine atoms in the quinazoline ring after the chlorination, and the substitution reaction causes a side reaction which competing at different positions, which adversely affects the mass of the product and the purification process.

Considering existing process defects, developing a manufacturing process that is simple, economical, eco-friendly, and massive in process, and exploring process technology that is particularly suitable for industrial production, has a significant realistic significance in improving the economic and social efficiency of the drug You can have it.

An object of the present invention is to provide a method for producing Copanlisib (I) which can easily obtain a raw material, is simple in process, economical, environmentally friendly and suitable for industrial production.

In order to realize the object of the present invention, the present invention uses the following main technical scheme. In the process for the preparation of the co-operon I,

(II) and the cyclizing reagent chloroformic acid isocyanate, chlorosulfonyl isocyanate, benzoyl isocyanate or urea is subjected to a heterocyclic reaction (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) -one (III) 8-methoxyquinazolin-2 (1H) -one (III) and 2-halogenated ethanol are condensed under the action of acid coupling agent to give 7-methoxy-8- Dihydroimidazo [1,2-c] quinazolin-5 (6H) -one (IV), and 7-methoxy-8 - (3-morpholin-4-ylpropoxy) -2,3-dihydroimidazo [1,2- c] quinazolin-5 (6H) -one (IV) was halogenated and aminated to give 7 2-c] quinazolin-5-amine (V), which is converted to the 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2,3-dihydroimidazo [ Ethoxy-8- (3- (V) and 2-aminopyrimidine-5-carboxylic acid are used in combination with a condensing agent and an alkali promoter action (I) < / RTI > by an amidation reaction.

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

The present invention also provides the following additional technical solutions.

The cyclization reagent of the above heterocyclic reaction is chloroformic acid isocyanate, chlorosulfonyl isocyanate, benzoyl isocyanate or urea, and benzoyl isocyanate is preferred.

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

The temperature of the heterocyclic reaction is 0 to 120 ° C, preferably 20 to 90 ° C.

The addition molar ratio of the raw material 4-amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) Is 1: 1.0 to 2.0, and 1: 1.0 to 1.5 is preferable.

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

The acid binding agent in the condensation cyclization reaction may be triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, lithium carbonate, cesium carbonate or potassium t- Cesium or potassium t-butoxide is preferred.

The solvent for the condensation cyclization reaction may be tetrahydrofuran, dioxane, 1,2-dichloroethane, acetonitrile, toluene, dimethyl carbonate, N, N-dimethylformamide or dimethylsulfoxide, and N, N-dimethylformamide Or dimethylsulfoxide is preferable.

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

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

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

The aminating agent for 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 condensing agent for the amidation reaction may be at least one selected from the group consisting of N, N, -dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), N, N'-diisopropylcarbodiimide Benzotriazole-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), O- (7-azobenzotriazole) -N, (HATU), benzotriazole-N, N, N ', N'-tetramethyluronium hexafluoroborate (HBTU) or benzotriazole- (BOP) which is 1-yl oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and which is selected from the group consisting of benzotriazole-N, N, N ', N'-tetramethyluronium hexafluoroborate (HBTU) 1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) is preferred.

The alkali promoter of the amidation reaction may be selected from the group consisting of triethylamine (TEA), pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM) Diisopropylethylamine (DIEA), 1,5-diazabicyclo [4.3.0] -nonan-5-ene (DBN), 1,8-diazabicyclo [5.4.0] Diazabicyclo [5.4.0] -undec-7-ene (DBU) or 1, 5- diazabicyclo [2.2.2] octane (DABCO) Diazabicyclo [4.3.0] -nonan-5-ene (DBN) or 1,4-diazabicyclo [2.2.2] octane (DABCO) are preferable.

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

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

Compared with the existing technology, the process for producing corpolysate (I) according to the present invention is characterized in that it can easily obtain the raw material, and the process is simple, economical and environmentally friendly. . ≪ / RTI >

BRIEF DESCRIPTION OF THE DRAWINGS The above and other features and advantages of the present invention will be more apparent from the following detailed description taken in conjunction with the accompanying drawings, in which: FIG. The preparation of the starting 2-amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile (II) and the side chain 2-aminopyrimidine- The preparation method for the same compound in International Patent No. WO2008070150, entitled " Preparation of substituted 2,3-dihydroimidazo [1,2-c] quinazoline derivatives for treating hyper-proliferative disorders and diseases associated with angiogenesis & See also.

Example 1:

(5.82 g, 20 mmol) of 2-amino-3-methoxy-4- (3-morpholin-4-ylpropoxy) benzonitrile (II) and 50 mL of dioxane were added to a dry reactor under a nitrogen atmosphere, 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 checked by TLC. The filtrate cake was washed with a mixed solvent of n-hexane and ethyl acetate (4: 1) and vacuum dried to obtain white solid 4-amino-7- (3-morpholin- The mass spectrometry (EI) gave m / z 335 (M + H). The yield was 68.1%.

Example 2:

(3-morpholin-4-ylpropoxy) benzonitrile (II) (5.82 g, 20 mmol) and 50 mL of tetrahydrofuran were added to a dry reactor under a nitrogen atmosphere, 15 mL of tetrahydrofuran solution of chlorosulfonyl isocyanate (3.25 g, 23 mmol) is added dropwise at 0 to 5 ° C. After completing the dropwise addition, the temperature is raised to room temperature, stirred for 6 to 8 hours, and the completion of the reaction is checked by TLC. Adjust the pH to neutral with 5% sodium hydroxide and extract three times with dichloromethane. The organic phase is combined and washed with water and saturated brine. The residue was washed with a mixed solvent of n-hexane and ethyl acetate (4: 1) and vacuum dried to obtain white solid 4-amino-7- (3-morpholin-4-ylpropoxy) -8- (III) (yield: 76.3%, mass spectrometry (EI): m / z 335 (M + H).

Example 3:

(3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) -one (III) (3.3 g, 10 mmol), 2- (1.68 g, 15 mmol) and 25 mL of N, N-dimethylformamide were added, and the mixture was heated to 80-90 DEG C and stirred for 4 to 6 hours. After cooling to room temperature, the reaction solution was poured into a sodium hydroxide solution having a weight percentage of 5%, heated to 60 DEG C, kept warm for 2 hours and cooled to room temperature to precipitate a solid, which was then filtered, washed with water, Washed and vacuum dried to give pale yellow solid 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2,3-dihydroimidazo [1,2- c] quinazolin- ) -One (IV), the yield is 58.9% and the mass spectrometry (EI) result is m / z 361 (M + H).

Example 4:

(3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (6H) -one (III) (3.3 g, 10 mmol), 2- Bromine ethanol (1.50 g, 12 mmol), cesium carbonate (3.57 g, 11 mmol) and 35 mL of dimethylsulfoxide were added, the temperature was raised to 80 to 90 ° C and the reaction was stirred for 4 to 6 hours. After cooling to room temperature, the reaction solution was poured into a sodium hydroxide solution having a weight percentage of 5%, heated to 60 DEG C, kept warm for 2 hours and cooled to room temperature to precipitate a solid, which was then filtered, washed with water, Washed and vacuum dried to give pale yellow solid 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2,3-dihydroimidazo [1,2- c] quinazolin- ) -One (IV), the yield is 63.9% and the mass spectrometry (EI) result is m / z 361 (M + H).

Example 5:

(3H) -quinazolin-5 (6H) -one was obtained in a reactor under a nitrogen atmosphere. (IV) (1.8 g, 5 mmol), 10 mL of phosphorus oxychloride and 1 mL of N, N-dimethylformamide were added, the temperature was raised to 90 to 105 ° C, the reaction was stirred for 4 to 5 hours, Check. The reaction mixture was cooled to room temperature and 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 does not need to be treated. Add 20 mL of ammonia water having a weight percentage of 30%, add the solution to a sealed tube, raise the temperature to 100 캜, and react for 12 to 16 hours. Cool to room temperature, filter, and wash the filter cake with water. 2-c] quinazolin-5-amine (V) as an off-white solid. obtains the 1.32g, yield is 73.5%, the mass analysis (EI) results m / z 360 (M + H ) , and the hydrogen spectrum ¹ H NMR (DMSO- d ₆₎ results δ 1.88 (m, 2H) 2H), 6.74 (m, 3H), 2.36 (m, 4H), 2.44 7.43 (m, 1H).

Example 6:

(3-morpholin-4-ylpropoxy) -2,3-dihydroimidazo [1,2-c] quinazolin-5-amine (V) Aminopyrimidine-5-carboxylic acid (0.15 g, 1.1 mmol) and 25 mL of acetonitrile were added and the condensation product benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoro (0.49 g, 1.1 mmol) and base catalyst 1, 5-diazabicyclo [4.3.0] -nonan-5-ene (0.50 g, 4 mmol) were added and reacted at room temperature for 12 hours. The temperature is raised again to 50 to 60 ° C, stirred for 6 to 8 hours, and the completion of the reaction is checked by TLC. The solvent is evaporated under reduced pressure, cooled to room temperature, and ethyl acetate is added to precipitate a solid. The filtrate cake was washed with cold methanol and vacuum dried to yield 0.27 g of white solid co-phenylacetate (I), yield 56.3%, EI-MS m / z yield 481 [M + H] ⁺ and, ¹ H NMR (CDCl ₃₎ results 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, IH), 7.08 (d, IH), 9.10 (s, 2H).

It is to be understood that the foregoing embodiments are merely illustrative of the technical ideas and features of the present invention and that the objects of the present invention are to be understood by those skilled in the art to implement the present invention, Is not limited. All equivalents or modifications practiced substantially in accordance with the teachings of the invention are within the scope of the present invention.

Claims (10)

In the method for producing corn masa,

Benzoyl chloride and cyclization reagent chloroformic acid isocyanate, chlorosulfonyl isocyanate, benzoyl isocyanate or urea is reacted with 4 (3-morpholin-4-yl-propoxy) Amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) (3-morpholin-4-yl) -8-methoxyquinazolin-2 (1H) -one and 2-halogen ethanol were prepared by condensation- Propoxy) -2,3-dihydroimidazo [1,2-c] quinazolin-5 (6H) -one and the 7-methoxy-8- (3-morpholin- (3-morpholin-4-yl) -2,3-dihydroimidazo [1,2- c] quinazolin-5 (6H) -one was obtained via a halogenated amination reaction to give 7-methoxy- Propoxy) -2,3-dihydroimidazo [1,2-c] quinazolin-5-amine, wherein the 7-methoxy-8- (3-morpholin- Propoxy) -2,3-dihydroimidazo [1,2-c] quinazolin-5-amine and 2-aminopyrimidine-5-carboxylic acid are prepared by amidation reaction under the action of a condensing agent and an alkali promoter, Wherein the halogen in said 2-halogen ethanol is fluorine, chlorine, bromine or iodine. ≪ RTI ID = 0.0 > 8. < / RTI > The method according to claim 1,
The solvent for the heterocyclic reaction is dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane, and the temperature for the heterocyclic reaction is 0 to 120 ° C ≪ / RTI > The method according to claim 1,
The molar ratio of the condensation-cycled raw material 4-amino-7- (3-morpholin-4-ylpropoxy) -8-methoxyquinazolin-2 (1H) To 2.0. ≪ / RTI > The method according to claim 1,
The acid binding agent of the condensation cyclization reaction is characterized by being triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, lithium carbonate, cesium carbonate or potassium t- By weight. 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 dimethylsulfoxide, Is 25 to < RTI ID = 0.0 > 150 C. < / RTI > The method according to claim 1,
Wherein 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 aminating agent of the halogenated amination reaction is ammonia water Or an ammonia gas. The method according to claim 1,
Wherein the temperature of the halogenated amination reaction is 50 to 150 ° C. The method according to claim 1,
The condensing agent for the amidation reaction may be at least one selected from the group consisting of N, N, -dicyclohexylcarbodiimide, carbonyldiimidazole, N, N'-diisopropylcarbodiimide, 1 -hydroxy-benzotriazole, N, N, N ', N'-tetramethyluronium tetrafluoroborate, O- (7-azobenzotriazole) -N, Characterized in that it is a borate, a borate, a benzotriazole-N, N, N ', N'-tetramethyluronium hexafluoroborate or a benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate Process for the preparation of. The method according to claim 1,
The alkali promoter of the amidation reaction may be selected from the group consisting of triethylamine, pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, N-methylmorpholine, N- ethylmorpholine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] -undec-7-ene or 1,4-diazabicyclo [2.2.2] octane. By weight. The method according to claim 1,
The amidation reaction may be carried out in a solvent such as toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, dimethyl sulfoxide, N, N-dimethylformamide or acetonitrile, ≪ / RTI >