CN105130998B - Ku Pannixi preparation method - Google Patents

Ku Pannixi preparation method Download PDF

Info

Publication number
CN105130998B
CN105130998B CN201510618067.6A CN201510618067A CN105130998B CN 105130998 B CN105130998 B CN 105130998B CN 201510618067 A CN201510618067 A CN 201510618067A CN 105130998 B CN105130998 B CN 105130998B
Authority
CN
China
Prior art keywords
pannixi
preparation
propoxyl group
reaction
bases
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201510618067.6A
Other languages
Chinese (zh)
Other versions
CN105130998A (en
Inventor
许学农
王喆
包志坚
张文件
苏健
顾新禹
薛佳
袁玉环
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SUZHOU LIXIN PHARMACEUTICAL Co.,Ltd.
Original Assignee
SUZHOU LIXIN PHARMACY CO Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SUZHOU LIXIN PHARMACY CO Ltd filed Critical SUZHOU LIXIN PHARMACY CO Ltd
Priority to CN201510618067.6A priority Critical patent/CN105130998B/en
Publication of CN105130998A publication Critical patent/CN105130998A/en
Priority to KR1020187011225A priority patent/KR102104957B1/en
Priority to PCT/CN2016/088091 priority patent/WO2017049983A1/en
Application granted granted Critical
Publication of CN105130998B publication Critical patent/CN105130998B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Inks, Pencil-Leads, Or Crayons (AREA)

Abstract

Present invention is disclosed a kind of Ku Pannixi (Copanlisib；BAY80 6946) preparation method, it is initiation material by 2 amino of known compound 3 methoxyl group 4 (the base propoxyl group of 3 morpholine 4) cyanophenyl, through unit processes such as jeterocyclic chemistry, condensation and cyclization, halo amination and amidatioons, target compound Ku Pannixi is made.The preparation method raw material is easy to get, and concise in technology is economic and environment-friendly, is adapted to industrialized production.

Description

Ku Pannixi preparation method
Technical field
It is more particularly to a kind of the invention belongs to organic synthetic route design and its bulk drug and intermediate preparing technical field Preparation method available for the drug reservoir Pan Nixi for the treatment of leukaemia.
Background technology
Ku Pannixi (Copanlisib) is the novel oral phosphoinositide of one kind developed by Bayer Bitterfeld GmbH (Bayer) company 3 kinases (PI3K) inhibitor.Existing clinical research shows, the medicine be by blocking PI3K signal paths, suppress leukaemia and Growth of cancer cells in Lymphoma body.In order to further prove the prospect of this medicine, Beyer Co., Ltd deploys again within 2015 Two clinic III phases are studied：By being used alone or treating a kind of rare NHL with Rituxan combinations (NHL), and with exclusive use Rituxan effect contrasted.In addition, Beyer Co., Ltd's also program launched one on A kind of clinical II phases of Copanlisib treatment diffusivity large B cell lymphoid tumors (pernicious NHL hypotypes) are studied.Because the medicine does not have also There is the Chinese translation of standard, therefore its transliteration is herein " Ku Pannixi " by the applicant.
Ku Pannixi's (Copanlisib, I) is chemical entitled：2- amino-N- [2,3- dihydro -7- methoxyl groups -8- [3- (4- Morpholinyl) propoxyl group] imidazo [1,2-C] quinazoline -5- bases] -5- pyrimidine carboxamides, its structural formula is：
The PCT Patent WO2008070150 of Yuan Yan companies discloses Ku Pannixi and the like preparation method, this article Offer and refer to following five synthetic routes that may be used altogether.
Synthetic route one：
Synthetic route two：
Synthetic route three：
Synthetic route four：
Synthetic route five：
Above-mentioned five synthetic routes are analyzed, wherein preceding four routes are all by vanillic aldehyde (3- methoxyl group -4- hydroxy benzenes first Aldehyde) it is primary raw material, protection and deprotection, nitrification, reduction, itrile group, cyclisation, bicyclicization and propylmorpholin through perhydroxyl radical Link of side chain and aminopyrimidine side chain etc. reacts to realize Ku Pannixi preparation.Its difference is mainly manifested in above-mentioned each unit The order of reaction is different, so that the number of times and method of the step of reaction, the selection of protection group and deprotection are different, also makes Obtain reaction condition different with total recovery.But any bar synthetic route no matter is selected, it is anti-with deprotection that its course of reaction all refers to protection Should, such as unconventional reagent of bromination nitrile also can be all used, adds that reactions steps are more, total recovery is low, thus is not conducive to its work Industry metaplasia is produced.Article 5 synthetic route be then using a kind of compound containing quinazolinone structure as initiation material, by chlorination, Substitution, cyclisation, deprotection reaction and the analog that Ku Pannixi is prepared with the reaction such as the condensation of side chain.From the reaction scheme Design process, which can be seen that, two chlorine atoms on the quinazoline ring after chlorination, substitution reaction can be made to produce the competing of diverse location The side reaction of striving property, quality and purifying process to product can bring adverse effect.
For existing defective workmanship, concise in technology is developed, the economic and environment-friendly and technology of preparing that has good quality, especially Seek to can adapt to the technology of industrialized production, the economic and social benefit of the medicine, which is improved, has important reality to anticipate Justice.
The content of the invention
Be easy to get it is an object of the invention to provide a kind of raw material, concise in technology, economic and environment-friendly and suitable industrialized production Ku Pannixi (Copanlisib, I) preparation method.
For achieving the above object, present invention employs following main technical schemes：A kind of preparation of Ku Pannixi (I) Method,
Its preparation process includes：2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyls (II) are tried with cyclisation Agent chloro-carbonic acid isocyanates, chlorosulfonic acid isocyanate, benzoyl isocyanate or urea generation heterocyclization generation 4- amino- 7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 (1H) -one (III)；4- amino -7- (3- morpholine -4- the third oxygen of base Base) -8- methoxyquinazoline hydrochlorides -2 (1H) -one (III) with 2- ethylene halohydrins give birth to by the generation condensation and cyclization reaction under acid binding agent effect Into 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5 (6H) -one (IV)；7- Methoxyl group -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5 (6H) -one (IV) through halo and Aminating reaction generates 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- amine (V)；7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- amine (V) and 2- ammonia Yl pyrimidines -5- formic acid occurs amidation process under condensing agent and the effect of alkali accelerator and Ku Pannixi (I) is made.
Halogen in wherein described 2- ethylene halohydrins is fluorine, chlorine, bromine or iodine.
In addition, the present invention also proposes following attached technical scheme：
The cyclization reagent of the heterocyclization is chloro-carbonic acid isocyanates, chlorosulfonic acid isocyanate, benzoyl isocyanic acid Ester or urea, preferably benzoic acid isocyanates.
The solvent of the heterocyclization be dichloromethane, chloroform, 1,2- dichloroethanes, acetonitrile, toluene, tetrahydrofuran, Dimethyl carbonate or dioxane, preferably dioxane or tetrahydrofuran.
The temperature of the heterocyclization is 0-120 DEG C, preferably 20-90 DEG C.
Raw material 4- amino -7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 of the condensation and cyclization reaction The molar ratio of (1H) -one (III) and 2- ethylene halohydrins is 1: 1.0-2.0, preferably 1: 1.0-1.5.
Halogen in the raw material 2- ethylene halohydrins of the condensation and cyclization reaction is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
The acid binding agent of the condensation and cyclization reaction is triethylamine, pyridine, N- methylmorpholines, diisopropylethylamine, 4- bis- Methylamino pyridine, potassium carbonate, lithium carbonate, cesium carbonate or potassium tert-butoxide, preferably cesium carbonate or potassium tert-butoxide.
The solvent of the condensation and cyclization reaction is tetrahydrofuran, dioxane, 1,2- dichloroethanes, acetonitrile, toluene, carbonic acid Dimethyl ester, N, N- dimethyl formyl or dimethyl sulfoxide, preferably DMF or dimethyl sulfoxide.
The temperature of the condensation and cyclization reaction is 25-150 DEG C, preferably 80-90 DEG C.
The halogenating agent of the halogenating reaction is phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, POCl3, tribromo oxygen phosphorus, two Chlorine sulfoxide, oxalyl chloride or phosgene, preferably POCl3.
The temperature of the halogenating reaction is 50-150 DEG C, preferably 90-105 DEG C.
The aminating agent of the aminating reaction is ammoniacal liquor or ammonia.
The temperature of the aminating reaction is 50-150 DEG C, preferably 90-105 DEG C.
The condensing agent of the amidation process be N, N ,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N, N '-DIC (DIC), 1- hydroxyls-BTA (HOBt), O- BTAs-N, N, N ', N '-tetramethyl Base urea tetrafluoro boric acid ester (TBTU), O- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or (dimethylamino of BTA -1- bases epoxide three Base) phosphorus hexafluorophosphate (BOP), preferably BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or benzene And (dimethylamino) the phosphorus hexafluorophosphate (BOP) of triazole -1- bases epoxide three.
The alkali accelerator of the amidation process is triethylamine (TEA), pyridine, 2,6- lutidines, 4- dimethylaminos Pyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DlEA), 1,5- diazabicylos [4.3.0]-nonyl- 5- alkene (DBN), -7- alkene (DBU) of 1,8- diazabicyclos [5.4.0]-ten one or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO), -7- alkene (DBU) of preferably 1,8- diazabicyclos [5.4.0]-ten one or 1,5- diazabicylo [4.3.0]-nonyl- 5- alkene (DBN) or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO).
The solvent of the amidation process is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butyl acetate, diformazan Asia Sulfone, DMF or acetonitrile, preferably acetonitrile.
The temperature of the amidation process is 0-120 DEG C, preferably 50-60 DEG C.
Compared to prior art, Ku Pannixi (I) involved in the present invention preparation method is easy to get, technique with raw material Succinct and economic and environment-friendly the features such as, so beneficial to the industrialized production of the bulk drug, promote the development of its economic technology.
Embodiment
Technical solution of the present invention is further non-limitingly described in detail below in conjunction with several preferred embodiments.Wherein The system of raw material 2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyls (II) and side chain 2- aminopyrimidine -5- formic acid Standby is on June 12nd, 2008 and entitled " Preparation of substituted2,3- referring to publication date Dihydroimidazo [1,2-c] quinazoline derivatives for treating hyper-proliferative Disorders and diseases associated with angiogenesis " WO2008070150 pairs of international monopoly The preparation method of identical compound.
Embodiment one：
In blanket of nitrogen, 2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyl is added in dry reaction bottle (II) (5.82g, 20mmol) and dioxane 50mL, add benzoyl isocyanate (3.23g, 22mmol) room temperature and stir at room temperature Mix 20 hours, TLC detection reactions are completed.Stand, filtering, filter cake is washed with n-hexane and ethyl acetate (4: 1) mixed solvent, very Empty dry off-white powder 4- amino -7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 (1H) -one (III) 4.55g, yield 68.1%；Mass spectrum (EI)：m/z 335(M+H).Embodiment two：
In blanket of nitrogen, 2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyl is added in dry reaction bottle (II) (5.82g, 20mmol) and tetrahydrofuran 50mL, are added dropwise the four of chlorosulfonic acid isocyanate (3.25g, 23mmol) at 0-5 DEG C Hydrogen furans 15mL solution.Drop finishes, and is warmed to room temperature, stirring reaction 6-8 hours, and TLC detection reactions are completed.Adjusted with 5% sodium hydroxide PH is saved to neutrality, dichloromethane is extracted three times.Merge organic phase, water, saturated common salt water washing are used with this.It is concentrated under reduced pressure, it is remaining Thing is washed with n-hexane and ethyl acetate (4: 1) mixed solvent, is dried in vacuo to obtain off-white powder 4- amino -7- (3- morpholines -4- Base propoxyl group) -8- methoxyquinazoline hydrochlorides -2 (1H) -one (III) 5.10g, yield 76.3%；Mass spectrum (EI)：m/z 335(M+H).
Embodiment three：
In blanket of nitrogen, 4- amino -7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 are added in reaction bulb (1H) -one (III) (3.3g, 10mmol), ethylene chlorhydrin (0.97g, 12mmol), potassium tert-butoxide (1.68g, 15mmol) and N, N- Dimethylformamide 25mL, is warming up to 80-90 DEG C, stirring reaction 4-6 hours.Room temperature is down to, reaction solution is inclined to weight percent Than in the sodium hydroxide solution for 5%, being heated to 60 DEG C, 2 hours are incubated, room temperature is cooled to, there is solid precipitation, filtered, washing, N-hexane wash, be dried in vacuo faint yellow solid 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine is simultaneously [1,2-c] quinazoline -5 (6H) -one (IV) 2.12g, yield 58.9%；Mass spectrum (EI)：m/z 361(M+H).
Example IV：
In blanket of nitrogen, 4- amino -7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 are added in reaction bulb (6H) -one (III) (3.3g, 10mmol), ethylene bromohyrin (1.50g, 12mmol), cesium carbonate (3.57g, 11mmol) and and diformazan Sulfoxide 35mL, is warming up to 80-90 DEG C, stirring reaction 4-6 hours.Room temperature is down to, it is 5% that reaction solution, which is inclined to percentage by weight, In sodium hydroxide solution, 60 DEG C are heated to, 2 hours is incubated, is cooled to room temperature, there is solid precipitation, is filtered, washing, n-hexane is washed Wash, be dried in vacuo to obtain faint yellow solid 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinoline Oxazoline -5 (6H) -one (IV) 2.30g, yield 63.9%；Mass spectrum (EI)：m/z 361(M+H).
Embodiment five：
In blanket of nitrogen, -2,3- glyoxalidine is simultaneously by addition 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) in reaction bulb [1,2-c] quinazoline -5 (6H) -one (IV) (1.8g, 5mmol), POCl3 10mL and N, N- dimethyl formyl 1mL, are warming up to 90-105 DEG C, stirring reaction 4-5 hours, TLC detection consumption of raw materialss are completed.Room temperature is down to, reaction solution is inclined into frozen water 50mL, There is solid precipitation.Filtering.Filter cake is washed with water 2 times, and gained wet product adds the ammoniacal liquor of percentage by weight 30% without processing 20mL, is placed in seal pipe, is warming up to 100 DEG C, reacts 12-16 hours.Room temperature is down to, is filtered, filter cake is washed with water.Vacuum is done It is dry to obtain faint yellow solid 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- Amine (V) 1.32g, yield 73.5%；Mass spectrum (EI)：m/z 360(M+H)；Hydrogen is composed1H NMR(DMSO-d6) 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).
Embodiment six：
In blanket of nitrogen, -2,3- glyoxalidine is simultaneously by addition 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) in reaction bulb [1,2-c] quinazoline -5- amine (V) (0.36g, 1mmol), 2- aminopyrimidine -5- formic acid (0.15g, 1.1mmol) and acetonitrile 25mL, adds (dimethylamino) the phosphorus hexafluorophosphate (0.49g, 1.1mmol) of condensing agent BTA -1- bases epoxide three With base catalyst 1,5- diazabicylos [4.3.0]-nonyl- 5- alkene (0.50g, 4mmol) are reacted at room temperature 12 hours.It is warming up to again 50-60 DEG C, stirring reaction 6-8 hours, TLC detection reactions are completed.Decompression steams solvent, is down to room temperature, adds ethyl acetate, has Solid is separated out.Filtering, filter cake is washed with cold methanol, is dried in vacuo to obtain off-white powder Ku Pannixi (I) 0.27g, yield 56.3%；EI-MS m/z：481[M+H]+,1H NMR(CDCl3) 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).
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, ripe its object is to allow Present disclosure can be understood and implement according to this by knowing the personage of technique, and the protection model of the present invention can not be limited with this Enclose.Any equivalent change or modification in accordance with the spirit of the invention, should all be included within the scope of the present invention.

Claims (10)

1. a kind of Ku Pannixi preparation method,
Its preparation process includes：2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyls and cyclization reagent chloro-carbonic acid Heterocyclization generation 4- amino -7- (3- occur for isocyanates, chlorosulfonic acid isocyanate, benzoyl isocyanate or urea Quinoline -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 (1H) -one；4- amino -7- (3- morpholine -4- bases the propoxyl group) -8- first With 2- ethylene halohydrins condensation and cyclization reaction generation 7- methoxyl groups -8- occurs under acid binding agent effect for (1H) -one of epoxide quinazoline -2 (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5 (6H) -one；7- methoxyl groups -8- (the 3- Quinoline -4- bases propoxyl group) simultaneously [1,2-c] quinazoline -5 (6H) -one generates 7- methoxies to -2,3- glyoxalidine through halo aminating reaction Base -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- amine；7- methoxyl groups -8- (the 3- Morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- amine and 2- aminopyrimidine -5- formic acid in condensing agent Ku Pannixi is made with the lower generation amidation process of alkali accelerator effect；Halogen in wherein described 2- ethylene halohydrins is fluorine, chlorine, Bromine or iodine.
2. Ku Pannixi as claimed in claim 1 preparation method, the solvent of the heterocyclization is dichloromethane, chloroform, 1,2- dichloroethanes, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane；The temperature of the heterocyclization is 0- 120℃。
3. Ku Pannixi as claimed in claim 1 preparation method, the condensation and cyclization reaction raw materials 4- amino -7- (3- morpholines - 4- bases propoxyl group) molar ratio of (1H) -one of -8- methoxyquinazoline hydrochlorides -2 and 2- ethylene halohydrins is 1:1.0-2.0.
4. Ku Pannixi as claimed in claim 1 preparation method, the acid binding agent of the condensation and cyclization reaction is triethylamine, pyrrole Pyridine, N- methylmorpholines, diisopropylethylamine, DMAP, potassium carbonate, lithium carbonate, cesium carbonate or potassium tert-butoxide.
5. Ku Pannixi as claimed in claim 1 preparation method, the solvent of the condensation and cyclization reaction is tetrahydrofuran, dioxy Six rings, 1,2- dichloroethanes, acetonitrile, toluene, dimethyl carbonate, N,N-dimethylformamide or dimethyl sulfoxide；The condensed ring The temperature for changing reaction is 25-150 DEG C.
6. Ku Pannixi as claimed in claim 1 preparation method, the halogenating agent of the halo aminating reaction is phosphorus trichloride, three Phosphonium bromide, phosphorus pentachloride, POCl3, tribromo oxygen phosphorus, thionyl chloride, oxalyl chloride or phosgene；The halo aminating reaction Aminating agent is ammoniacal liquor or ammonia.
7. Ku Pannixi as claimed in claim 1 preparation method, the temperature of the halo aminating reaction is 50-150 DEG C.
8. Ku Pannixi as claimed in claim 1 preparation method, the condensing agent of the amidation process is N, N ,-dicyclohexyl Carbodiimide, carbonyl dimidazoles, N, N '-DIC, 1- hydroxyl-BTA, O- BTA-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester, O- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester, benzene And triazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester or (dimethylamino) phosphorus of BTA -1- bases epoxide three Hexafluorophosphate.
9. Ku Pannixi as claimed in claim 1 preparation method, the alkali accelerator of the amidation process is triethylamine, pyrrole Pyridine, 2,6- lutidines, DMAP, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5- phenodiazines Miscellaneous two ring [4.3.0]-nonyl- 5- the alkene, -7- alkene of 1,8- diazabicyclos [5.4.0]-ten one or 1,4- diazabicylos [2.2.2] Octane.
10. Ku Pannixi as claimed in claim 1 preparation method, the solvent of the amidation process is toluene, dimethylbenzene, second Acetoacetic ester, isopropyl acetate, butyl acetate, dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile；The temperature of the amidation process Spend for 0-120 DEG C.
CN201510618067.6A 2015-09-25 2015-09-25 Ku Pannixi preparation method Active CN105130998B (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201510618067.6A CN105130998B (en) 2015-09-25 2015-09-25 Ku Pannixi preparation method
KR1020187011225A KR102104957B1 (en) 2015-09-25 2016-07-01 Manufacturing method of copanriship
PCT/CN2016/088091 WO2017049983A1 (en) 2015-09-25 2016-07-01 Preparation method of copanlisib

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510618067.6A CN105130998B (en) 2015-09-25 2015-09-25 Ku Pannixi preparation method

Publications (2)

Publication Number Publication Date
CN105130998A CN105130998A (en) 2015-12-09
CN105130998B true CN105130998B (en) 2017-07-28

Family

ID=54716625

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510618067.6A Active CN105130998B (en) 2015-09-25 2015-09-25 Ku Pannixi preparation method

Country Status (3)

Country Link
KR (1) KR102104957B1 (en)
CN (1) CN105130998B (en)
WO (1) WO2017049983A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105130998B (en) * 2015-09-25 2017-07-28 苏州立新制药有限公司 Ku Pannixi preparation method
AU2017214230A1 (en) * 2016-02-01 2018-08-09 Bayer Pharma Aktiengesellschaft Copanlisib biomarkers

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE110071T1 (en) * 1988-01-23 1994-09-15 Kyowa Hakko Kogyo Kk PYRIDAZINONE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM.
JP2003252875A (en) * 2002-03-04 2003-09-10 Lotte Co Ltd Novel purine derivative
ES2312843T3 (en) * 2002-09-30 2009-03-01 Bayer Healthcare Ag CONDENSED AZOLPIRIMIDINE DERIVATIVES.
AR064106A1 (en) * 2006-12-05 2009-03-11 Bayer Schering Pharma Ag DERIVATIVES OF 2,3-DIHYDROIMIDAZO [1,2-C] SUBSTITUTED QUINAZOLINE USEFUL FOR THE TREATMENT OF HYPER-PROLIFERATIVE DISEASES ASSOCIATED WITH ANGIOGENESIS
JP5210558B2 (en) * 2007-07-12 2013-06-12 株式会社ブリヂストン Vibration isolator
EP3018131A1 (en) * 2014-11-07 2016-05-11 Bayer Pharma Aktiengesellschaft Synthesis of copanlisib and its dihydrochloride salt
CN105130997B (en) * 2015-09-25 2017-12-05 苏州明锐医药科技有限公司 A kind of Ku Pannixi preparation method
CN105130998B (en) * 2015-09-25 2017-07-28 苏州立新制药有限公司 Ku Pannixi preparation method

Also Published As

Publication number Publication date
WO2017049983A1 (en) 2017-03-30
KR102104957B1 (en) 2020-04-28
KR20180096572A (en) 2018-08-29
CN105130998A (en) 2015-12-09

Similar Documents

Publication Publication Date Title
ES2432647T3 (en) Procedure for the preparation of telmisartan
CN106966947B (en) A kind of preparation method of vildagliptin
CN106366072B (en) A kind of preparation method of AZD9291
JP6681922B2 (en) Ibrutinib manufacturing method
CN103342704B (en) A kind of preparation method of antithrombotic reagent Eliquis
CN109912624A (en) A kind of synthetic method of Ba Luoshawei ester key parent nucleus intermediate
CN104098553B (en) The preparation method of intermediate of ticagrelor and preparation method thereof and ticagrelor
CN105130998B (en) Ku Pannixi preparation method
CN104774194B (en) deuterated hepatitis c virus inhibitors
CN106749259A (en) A kind of synthetic method of cyclopenta pyrimido azoles
CN103923080A (en) Method for preparing antithrombotic drug apixaban
CN105358529B (en) A kind of new method of synthesis Eliquis important intermediate
CN107814804A (en) The preparation method of Buddhist nun is replaced according to Shandong
CN105130997B (en) A kind of Ku Pannixi preparation method
CN104030958B (en) A kind of (S)-1-(2-chloracetyl) synthetic method of pyrrolidine-2-formonitrile HCN
CN110143951A (en) Synthetic method of pazopanib hydrochloride raw material trimer impurity
CN104725292A (en) Preparation method of (S)(-)-amisulpride
CN109020977B (en) Preparation method of Acaraburtinib
CN101602707A (en) One class naphthalene lactam derivatives and the application on tumor cell proliferation suppresses thereof
EP3257851B1 (en) Salt form and crystal form of 1,2,5 thiadiazolidin-1,1-dioxide, preparation method thereof and intermediate
CN104860888B (en) The synthetic method of Alcaftadine intermediate and Alcaftadine
CN107722007A (en) The preparation method of Eliquis impurity
CA2207464A1 (en) Crystal of n-{(quinolin-2-yl)phenylsulfonamides and process for producing the same
CN106317060A (en) Preparation method of conivaptan hydrochloride
CN104447899B (en) A kind of intermediate of the compound for preparing renin angiotensin aldosterone system double inhibitor

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20200714

Address after: Hu Suzhou high tech Zone of Jiangsu province 215151 City Road No. 21 Tang Guan District

Patentee after: SUZHOU LIXIN PHARMACEUTICAL Co.,Ltd.

Address before: 215151 No. 21 West Tong Road, hi tech Development Zone, Jiangsu, Suzhou

Co-patentee before: Xu Xuenong

Patentee before: SUZHOU LIXIN PHARMACEUTICAL Co.,Ltd.