Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/10—Spiro-condensed systems

Definitions

• the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of a drug Copannisi which can be used for treating leukemia.
• Copanlisib is a novel oral phosphoinositide 3-kinase (PI3K) inhibitor developed by Bayer, Germany.
• PI3K oral phosphoinositide 3-kinase
• Bayer launched two clinical Phase III studies in 2015: treatment of a rare non-Hodgkin's lymphoma (NHL) by use alone or in combination with Rituxan, and with separate use The effects of Rituxan are compared.
• Bayer plans to conduct a Phase II clinical study of Copanlisib in the treatment of diffuse large B-cell lymphoma, a malignant NHL subtype. Since the drug does not yet have a standard Chinese translation, the applicant hereby transliterates it as "Kuppanisi".
• Copanlisib (I) 2-amino-N-[2,3-dihydro-7-methoxy-8-[3-(4-morpholinyl)propoxy] Imidazo[1,2-c]quinazolin-5-yl]-5-pyrimidinecarboxamide having the structural formula:
• the first four routes are through vanillin (3-methoxy-4-hydroxybenzaldehyde) as the main raw material, through the protection and deprotection of hydroxyl groups, nitrification, reduction, nitrilation, cyclization
• the preparation of kupanixi is achieved by a reaction such as bicyclization and linking of a propylmorpholine side chain and an aminopyrimidine side chain.
• the difference is mainly manifested in the different order of reaction of the above units, so that the steps of the reaction, the selection of the protecting group and the number and method of deprotection are different, and the reaction conditions and the total yield are also different.
• the reaction process involves protection and deprotection reactions, and it is also very useful to use such as brominated nitrile.
• the reagents, plus many reaction steps and low total yield, are not favorable for industrial production.
• the fifth synthetic route is based on a compound containing a quinazolinone structure as a starting material, which is similar to the preparation of Kupanisi by chlorination, substitution, cyclization, deprotection and condensation with side chains. Things. It can be seen from the design process of the reaction route that there are two chlorine atoms on the quinazoline ring after chlorination, which will cause the substitution reaction to produce competitive side reactions at different positions, which will bring about the quality of the product and the purification process. Negative Effects.
• the object of the present invention is to provide a preparation method of Copanlisib (I) which is easy to obtain raw materials, simple in process, economical and environmentally friendly, and suitable for industrial production.
• the present invention adopts the following main technical solutions: a preparation method of Kupanisi (I),
• the preparation steps include: 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (II) and cyclizing reagent isocyanate chloroformate, isocyanate chlorosulfonate, benzoic acid Heterocyclic reaction of acylate isocyanate or urea to form 4-amino-7-(3-morpholin-4-ylpropoxy)-8-methoxyquinazoline-2(1H)-one (III); -Amino-7-(3-morpholin-4-ylpropoxy)-8-methoxyquinazoline-2(1H)-one (III) and 2-haloethanol occur under the action of an acid binding agent Condensation cyclization to give 7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazoline-5 (6H) -keto(IV); 7-methoxy-8-(3-morpholin-4-ylpropoxy
• halogen in the 2-haloethanol is fluorine, chlorine, bromine or iodine.
• the cyclizing agent for the heterocyclic reaction is chloroformic acid isocyanate, chlorosulfonic acid isocyanate, benzoyl isocyanate or urea, preferably benzoic acid isocyanate.
• the solvent for the heterocyclic reaction is dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane, preferably dioxane or tetrahydrofuran.
• the temperature of the heterocyclic reaction is from 0 to 120 ° C, preferably from 20 to 90 ° C.
• the starting material of the condensation cyclization reaction is 4-amino-7-(3-morpholin-4-ylpropoxy)-8-methoxyquinazoline-2(1H)-one (III) and 2-halogen
• the molar ratio of the substituted ethanol is from 1:1.0 to 2.0, preferably from 1:1.0 to 1.5.
• the halogen in the raw material of the condensation cyclization reaction in 2-haloethanol is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
• the acid binding agent of the condensation cyclization reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, lithium carbonate, cesium carbonate or tert-butanol. Potassium, preferably cesium carbonate or potassium t-butoxide.
• the solvent for the condensation cyclization reaction is tetrahydrofuran, dioxane, 1,2-dichloroethane, acetonitrile, toluene, dimethyl carbonate, N,N-dimethylformyl or dimethyl sulfoxide, preferably N,N-dimethylformamide or dimethyl sulfoxide.
• the temperature of the condensation cyclization reaction is from 25 to 150 ° C, preferably from 80 to 90 ° C.
• the halogenating agent of the halogenation reaction is phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, phosphorus oxybromide, dichlorosulfoxide, oxalyl chloride or phosgene, preferably phosphorus oxychloride.
• the temperature of the halogenation reaction is from 50 to 150 ° C, preferably from 90 to 105 ° C.
• the aminating agent of the amination reaction is ammonia or ammonia.
• the temperature of the amination reaction is from 50 to 150 ° C, preferably from 90 to 105 ° C.
• the condensing agent for the amidation reaction is N,N,-dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), N,N'-diisopropylcarbodiimide (DIC), 1 -hydroxy-benzotriazole (HOBt), O-benzotriazine azole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azobenzotriazole)-N,N,N',N'-four Methylurea hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or benzotriazol-1-yloxy Tris(dimethylamino)phosphonium hexafluorophosphate (BOP), preferably benzotriazole-N,N,N',N
• the alkali promoter of the amidation reaction is triethylamine (TEA), pyridine, 2,6-lutidine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), N- Ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN), 1,8-diazabicyclo ring [5.4.0]-11-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO), preferably 1,8-diazabicyclo[5.4.0] -11-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or 1,4-diazabicyclo[2.2.2] octane Alkane (DABCO).
• TAA triethylamine
• DBU 1,8-diaza
• the solvent for the amidation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile, preferably acetonitrile.
• the temperature of the amidation reaction is from 0 to 120 ° C, preferably from 50 to 60 ° C.
• the preparation method of Kupanisi (I) according to the invention has the characteristics of easy raw materials, simple process and economical environmental protection, so that it is beneficial to the industrial production of the raw material medicine and promotes its economic technology. development of.
• Embodiment 1 is a diagrammatic representation of Embodiment 1:
• Embodiment 2 is a diagrammatic representation of Embodiment 1:
• Embodiment 3 is a diagrammatic representation of Embodiment 3
• reaction solution was poured into a 5% by weight sodium hydroxide solution, heated to 60 ° C, kept for 2 hours, cooled to room temperature, solid precipitated, filtered, washed with water, washed with n-hexane, dried in vacuo.
• Embodiment 4 is a diagrammatic representation of Embodiment 4:
• Embodiment 5 is a diagrammatic representation of Embodiment 5:

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• 2015
  • 2015-09-25 CN CN201510618067.6A patent/CN105130998B/zh active Active
• 2016
  • 2016-07-01 KR KR1020187011225A patent/KR102104957B1/ko active IP Right Grant
  • 2016-07-01 WO PCT/CN2016/088091 patent/WO2017049983A1/zh active Application Filing

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