CN105130998A - Preparation method for copanlisib - Google Patents
Preparation method for copanlisib Download PDFInfo
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- CN105130998A CN105130998A CN201510618067.6A CN201510618067A CN105130998A CN 105130998 A CN105130998 A CN 105130998A CN 201510618067 A CN201510618067 A CN 201510618067A CN 105130998 A CN105130998 A CN 105130998A
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The invention discloses a preparation method for copanlisib (BAY80-6946). An unknown compound 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy) cyanophenyl is taken as a starting material, and elementary reactions such as heterocyclization, condensation and cyclization, halogenated amination and amidation are carried out to obtain a target compound namely the copanlisib. The preparation method is environmentally-friendly and suitable for industrial production, the raw material is easily obtained, and the process is simple.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind ofly can be used for the preparation method treating leukemic drug reservoir Pan Nixi.
Background technology
Ku Pannixi (Copanlisib) is novel oral Phosphoinositide-3 kinase (PI3K) inhibitor of one developed by Bayer Bitterfeld GmbH (Bayer) company.Existing clinical study shows, this medicine is by blocking PI3K signal path, suppresses the growth of cancer cells in leukemia and Lymphoma body.In order to prove the prospect of this medicine further, Beyer Co., Ltd in 2015 expands again two clinical III phases and studies: by being used alone or treating a kind of rare non-Hodgkin lymphoma (NHL) with Rituxan coupling, and contrast with the effect being used alone Rituxan.In addition, Beyer Co., Ltd is studied the clinical II phase that also program launched one treats diffuse large B cell lymphoma (a kind of pernicious NHL hypotype) about Copanlisib.Because this medicine does not also have the Chinese translation of standard, therefore its transliteration is " Ku Pannixi " at this by the applicant.
Ku Pannixi (Copanlisib, I) chemistry is called: 2-amino-N-[2,3-dihydro-7-methoxyl group-8-[3-(4-morpholinyl) propoxy-] imidazo [1,2-C] quinazoline-5-base]-5-pyrimidine carboxamide, its structural formula is:
The PCT patent WO2008070150 of Yuan Yan company discloses the preparation method of Ku Pannixi and analogue thereof, and the document refer to altogether following five synthetic routes that may use.
Synthetic route one:
Synthetic route two:
Synthetic route three:
Synthetic route four:
Synthetic route five:
Analyze above-mentioned five synthetic routes; wherein front four routes are all be main raw material by Vanillin (Vanillin), and the reaction such as link through the protection of perhydroxyl radical and deprotection, nitrated, reduction, itrile group, cyclisation, dicyclo and propylmorpholin side chain and aminopyrimidine side chain realizes the preparation of Ku Pannixi.The order that its difference is mainly manifested in above-mentioned each unit process is different, thus makes the step of reaction, the number of times of the selection of protecting group and deprotection and method different, also makes reaction conditions different with total recovery.But no matter select which bar synthetic route, its reaction process all relates to protection and deprotection reaction, and also all can use as unconventional reagent such as bromination nitriles, add that reactions steps is many, total recovery is low, is not thus conducive to its suitability for industrialized production.Article 5 synthetic route is then with a kind of compound containing quinazolinone structure for starting raw material, by chlorination, replacement, cyclisation, deprotection reaction and react with the condensation etc. of side chain the analogue preparing Ku Pannixi.As can be seen from the design process of this reaction scheme, the quinazoline ring after chlorination there are two chlorine atoms, substitution reaction can be made to produce the competitive side reaction of different positions, all can bring disadvantageous effect to the quality of product and purifying process.
For existing defective workmanship, develop concise in technology, economic environmental protection and the technology of preparing had good quality, especially seek the Technology that can adapt to suitability for industrialized production, improving the economic and social benefit of this medicine has important realistic meaning.
Summary of the invention
The object of the present invention is to provide that a kind of raw material is easy to get, concise in technology, economic environmental protection and be applicable to the preparation method of the Ku Pannixi (Copanlisib, I) of suitability for industrialized production.
For achieving the above object, present invention employs following main technical schemes: the preparation method of a kind of Ku Pannixi (I),
Its preparation process comprises: 2-amino-3-methoxyl group-4-(3-morpholine-4-base propoxy-) cyanophenyl (II) and cyclization reagent chloroformic acid isocyanic ester, chlorosulfonic acid isocyanate, benzoyl isocyanate or urea generation heterocyclization generate 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one (III); Condensation and cyclization is there is and reacts and generate 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2 in 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one (III) and 2-ethylene halohydrin under acid binding agent effect, 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-one (IV) also; 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2,3-glyoxalidine also [1,2-c] quinazoline-5 (6H)-one (IV) generates 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2 through halo and amination reaction, 3-glyoxalidine is [1,2-c] quinazoline-5-amine (V) also; 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2, amidate action is there is and obtains Ku Pannixi (I) in 3-glyoxalidine also [1,2-c] quinazoline-5-amine (V) and 2-aminopyrimidine-5-formic acid under condensing agent and alkali promotor act on.
Halogen in wherein said 2-ethylene halohydrin is fluorine, chlorine, bromine or iodine.
In addition, the present invention also proposes following attached technical scheme:
The cyclization reagent of described heterocyclization is chloroformic acid isocyanic ester, chlorosulfonic acid isocyanate, benzoyl isocyanate or urea, preferred phenylformic acid isocyanic ester.
The solvent of described heterocyclization is methylene dichloride, chloroform, 1,2-ethylene dichloride, acetonitrile, toluene, tetrahydrofuran (THF), methylcarbonate or dioxane, preferred dioxane or tetrahydrofuran (THF).
The temperature of described heterocyclization is 0-120 DEG C, preferred 20-90 DEG C.
Raw material 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one (III) of described condensation and cyclization reaction is 1: 1.0-2.0 with the molar ratio of 2-ethylene halohydrin, preferably 1: 1.0-1.5.
Halogen in the raw material 2-ethylene halohydrin of described condensation and cyclization reaction is fluorine, chlorine, bromine or iodine, preferred chlorine or bromine.
The acid binding agent of described condensation and cyclization reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, DMAP, salt of wormwood, Quilonum Retard, cesium carbonate or potassium tert.-butoxide, preferred cesium carbonate or potassium tert.-butoxide.
The solvent of described condensation and cyclization reaction is tetrahydrofuran (THF), dioxane, 1,2-ethylene dichloride, acetonitrile, toluene, methylcarbonate, N, N-dimethyl formyl or methyl-sulphoxide, preferred DMF or methyl-sulphoxide.
The temperature of described condensation and cyclization reaction is 25-150 DEG C, preferred 80-90 DEG C.
The halogenating agent of described halogenating reaction is phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, tribromo oxygen phosphorus, thionyl chloride, oxalyl chloride or carbonyl chloride, preferred phosphorus oxychloride.
The temperature of described halogenating reaction is 50-150 DEG C, preferred 90-105 DEG C.
The aminating agent of described amination reaction is ammoniacal liquor or ammonia.
The temperature of described amination reaction is 50-150 DEG C, preferred 90-105 DEG C.
The condensing agent of described amidate action is N, N,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N, N '-DIC (DIC), 1-hydroxyl-benzotriazole (HOBt), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), preferred benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).
The alkali promotor of described amidate action is triethylamine (TEA), pyridine, 2, 6-lutidine, DMAP (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DlEA), 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN), 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 4-diazabicylo [2.2.2] octane (DABCO), preferably 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN) or 1, 4-diazabicylo [2.2.2] octane (DABCO).
The solvent of described amidate action is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, methyl-sulphoxide, DMF or acetonitrile, preferred acetonitrile.
The temperature of described amidate action is 0-120 DEG C, preferred 50-60 DEG C.
Compared to prior art, the preparation method of Ku Pannixi (I) involved in the present invention, has that raw material is easy to get, the feature such as concise in technology and economic environmental protection, so be beneficial to the suitability for industrialized production of this bulk drug, promotes the development of its economic technology.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.The preparation of its Raw 2-amino-3-methoxyl group-4-(3-morpholine-4-base propoxy-) cyanophenyl (II) and side chain 2-aminopyrimidine-5-formic acid is on June 12nd, 2008 see publication date and name is called that the international monopoly WO2008070150 of " Preparationofsubstituted2; 3-dihydroimidazo [1,2-c] quinazolinederivativesfortreatinghyper-proliferativediso rdersanddiseasesassociatedwithangiogenesis " is to the preparation method of same compound.
Embodiment one:
In nitrogen atmosphere, 2-amino-3-methoxyl group-4-(3-morpholine-4-base propoxy-) cyanophenyl (II) (5.82g is added in dry reaction bottle, 20mmol) with dioxane 50mL, benzoyl isocyanate (3.23g is added under room temperature, 22mmol) stirring at room temperature 20 hours, TLC detection reaction completes.Leave standstill, filter, filter cake normal hexane and the washing of ethyl acetate (4: 1) mixed solvent, vacuum-drying obtains off-white color solid 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one (III) 4.55g, yield 68.1%; Mass spectrum (EI): m/z335 (M+H).Embodiment two:
In nitrogen atmosphere, 2-amino-3-methoxyl group-4-(3-morpholine-4-base propoxy-) cyanophenyl (II) (5.82g is added in dry reaction bottle, 20mmol) with tetrahydrofuran (THF) 50mL, the tetrahydrofuran (THF) 15mL solution of chlorosulfonic acid isocyanate (3.25g, 23mmol) is dripped at 0-5 DEG C.Drip and finish, rise to room temperature, stirring reaction 6-8 hour, TLC detection reaction completes.Regulate pH to neutral with 5% sodium hydroxide, dichloromethane extraction three times.Merge organic phase, use water, saturated common salt water washing with this.Concentrating under reduced pressure, resistates normal hexane and the washing of ethyl acetate (4: 1) mixed solvent, vacuum-drying obtains off-white color solid 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one (III) 5.10g, yield 76.3%; Mass spectrum (EI): m/z335 (M+H).
Embodiment three:
In nitrogen atmosphere, 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one (III) (3.3g is added in reaction flask, 10mmol), ethylene chlorhydrin (0.97g, 12mmol), potassium tert.-butoxide (1.68g, 15mmol) and N, dinethylformamide 25mL, is warming up to 80-90 DEG C, stirring reaction 4-6 hour.Be down to room temperature, being inclined by reaction solution to weight percent is in the sodium hydroxide solution of 5%, is heated to 60 DEG C, be incubated 2 hours, be cooled to room temperature, have solid to separate out, filter, washing, n-hexane, vacuum-drying obtains faint yellow solid 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2,3-glyoxalidine also [1,2-c] quinazoline-5 (6H)-one (IV) 2.12g, yield 58.9%; Mass spectrum (EI): m/z361 (M+H).
Embodiment four:
In nitrogen atmosphere, 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (6H)-one (III) (3.3g is added in reaction flask, 10mmol), ethylene bromohyrin (1.50g, 12mmol), cesium carbonate (3.57g, 11mmol) and and methyl-sulphoxide 35mL, be warming up to 80-90 DEG C, stirring reaction 4-6 hour.Be down to room temperature, being inclined by reaction solution to weight percent is in the sodium hydroxide solution of 5%, is heated to 60 DEG C, be incubated 2 hours, be cooled to room temperature, have solid to separate out, filter, washing, n-hexane, vacuum-drying obtains faint yellow solid 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2,3-glyoxalidine also [1,2-c] quinazoline-5 (6H)-one (IV) 2.30g, yield 63.9%; Mass spectrum (EI): m/z361 (M+H).
Embodiment five:
In nitrogen atmosphere, 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2 is added in reaction flask, 3-glyoxalidine also [1,2-c] quinazoline-5 (6H)-one (IV) (1.8g, 5mmol), phosphorus oxychloride 10mL and N, N-dimethyl formyl 1mL, be warming up to 90-105 DEG C, stirring reaction 4-5 hour, TLC detect raw material consumption and complete.Be down to room temperature, reaction solution inclined in frozen water 50mL, have solid to separate out.Filter.Filter cake washes 2 times with water, and gained wet product, without the need to process, adds the ammoniacal liquor 20mL of weight percent 30%, is placed in sealed tube, be warming up to 100 DEG C, reaction 12-16 hour.Be down to room temperature, filter, filter cake washes with water.Vacuum-drying obtains faint yellow solid 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2,3-glyoxalidine also [1,2-c] quinazoline-5-amine (V) 1.32g, yield 73.5%; Mass spectrum (EI): m/z360 (M+H); Hydrogen is composed
1hNMR (DMSO-d
6) 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 nitrogen atmosphere, 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2 is added in reaction flask, 3-glyoxalidine also [1,2-c] quinazoline-5-amine (V) (0.36g, 1mmol), 2-aminopyrimidine-5-formic acid (0.15g, 1.1mmol) with acetonitrile 25mL, add condensing agent benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (0.49g, 1.1mmol) with alkaline catalysts 1,5-diazabicylo [the 4.3.0]-ninth of the ten Heavenly Stems-5-alkene (0.50g, 4mmol), room temperature reaction 12 hours.Be warming up to 50-60 DEG C again, stirring reaction 6-8 hour, TLC detection reaction completes.Decompression steams solvent, is down to room temperature, adds ethyl acetate, have solid to separate out.Filter, filter cake cold methanol washs, and vacuum-drying obtains off-white color solid Ku Pannixi (I) 0.27g, yield 56.3%; EI-MSm/z:481 [M+H]
+,
1hNMR (CDCl
3) 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 above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. the preparation method of Yi Zhong Ku Pannixi,
Its preparation process comprises: 2-amino-3-methoxyl group-4-(3-morpholine-4-base propoxy-) cyanophenyl and cyclization reagent chloroformic acid isocyanic ester, chlorosulfonic acid isocyanate, benzoyl isocyanate or urea generation heterocyclization generate 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one; Condensation and cyclization is there is and reacts and generate 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2 in described 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one and 2-ethylene halohydrin under acid binding agent effect, 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-one also; Described 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2,3-glyoxalidine also [1,2-c] quinazoline-5 (6H)-one generates 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2 through halo amination reaction, 3-glyoxalidine is [1,2-c] quinazoline-5-amine also; Amidate action is there is and obtains Ku Pannixi in described 7-methoxyl group-8-(3-morpholine-4-base propoxy-)-2,3-glyoxalidine also [1,2-c] quinazoline-5-amine and 2-aminopyrimidine-5-formic acid under condensing agent and alkali promotor act on; Halogen in wherein said 2-ethylene halohydrin is fluorine, chlorine, bromine or iodine.
2. the preparation method of Ku Pannixi as claimed in claim 1, the solvent of described heterocyclization is methylene dichloride, chloroform, 1,2-ethylene dichloride, acetonitrile, toluene, tetrahydrofuran (THF), methylcarbonate or dioxane; The temperature of described heterocyclization is 0-120 DEG C.
3. the preparation method of Ku Pannixi as claimed in claim 1, the molar ratio of described condensation and cyclization reaction raw materials 4-amino-7-(3-morpholine-4-base propoxy-)-8-methoxyquinazoline hydrochloride-2 (1H)-one and 2-ethylene halohydrin is 1: 1.0-2.0.
4. the preparation method of Ku Pannixi as claimed in claim 1, the acid binding agent of described condensation and cyclization reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, DMAP, salt of wormwood, Quilonum Retard, cesium carbonate or potassium tert.-butoxide.
5. the preparation method of Ku Pannixi as claimed in claim 1, the solvent of described condensation and cyclization reaction is tetrahydrofuran (THF), dioxane, 1,2-ethylene dichloride, acetonitrile, toluene, methylcarbonate, N, N-dimethyl formyl or methyl-sulphoxide; The temperature of described condensation and cyclization reaction is 25-150 DEG C.
6. the preparation method of Ku Pannixi as claimed in claim 1, the halogenating agent of described halo amination reaction is phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, tribromo oxygen phosphorus, thionyl chloride, oxalyl chloride or carbonyl chloride; The aminating agent of described halo amination reaction is ammoniacal liquor or ammonia.
7. the preparation method of Ku Pannixi as claimed in claim 1, the temperature of described halo amination reaction is 50-150 DEG C.
8. the preparation method of Ku Pannixi as claimed in claim 1, the condensing agent of described amidate action is N, N,-dicyclohexylcarbodiimide, carbonyl dimidazoles, N, N '-DIC, 1-hydroxyl-benzotriazole, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester, O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate.
9. the preparation method of Ku Pannixi as claimed in claim 1, the alkali promotor of described amidate action is triethylamine, pyridine, 2,6-lutidine, DMAP, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [the 4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-ten one-7-alkene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane.
10. the preparation method of Ku Pannixi as claimed in claim 1, the solvent of described amidate action is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, methyl-sulphoxide, DMF or acetonitrile; The temperature of described amidate action is 0-120 DEG C.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510618067.6A CN105130998B (en) | 2015-09-25 | 2015-09-25 | Ku Pannixi preparation method |
| PCT/CN2016/088091 WO2017049983A1 (en) | 2015-09-25 | 2016-07-01 | Preparation method of copanlisib |
| KR1020187011225A KR102104957B1 (en) | 2015-09-25 | 2016-07-01 | Manufacturing method of copanriship |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510618067.6A CN105130998B (en) | 2015-09-25 | 2015-09-25 | Ku Pannixi preparation method |
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| Publication Number | Publication Date |
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| CN105130998A true CN105130998A (en) | 2015-12-09 |
| CN105130998B CN105130998B (en) | 2017-07-28 |
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| CN201510618067.6A Active CN105130998B (en) | 2015-09-25 | 2015-09-25 | Ku Pannixi preparation method |
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| KR (1) | KR102104957B1 (en) |
| CN (1) | CN105130998B (en) |
| WO (1) | WO2017049983A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017049983A1 (en) * | 2015-09-25 | 2017-03-30 | 苏州立新制药有限公司 | Preparation method of copanlisib |
| CN108884496A (en) * | 2016-02-01 | 2018-11-23 | 拜耳制药股份公司 | COPANLISIB biomarker |
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| EP0326307A2 (en) * | 1988-01-23 | 1989-08-02 | Kyowa Hakko Kogyo Co., Ltd. | Novel pyridazinone derivatives and pharmaceutical preparations containing them |
| JP2003252875A (en) * | 2002-03-04 | 2003-09-10 | Lotte Co Ltd | Novel purine derivative |
| CN1688582A (en) * | 2002-09-30 | 2005-10-26 | 拜尔药品公司 | Fused azole-pyrimidine derivatives |
| CN101631464A (en) * | 2006-12-05 | 2010-01-20 | 拜耳先灵医药股份有限公司 | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN105130998B (en) * | 2015-09-25 | 2017-07-28 | 苏州立新制药有限公司 | Ku Pannixi preparation method |
| 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 |
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2015
- 2015-09-25 CN CN201510618067.6A patent/CN105130998B/en active Active
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- 2016-07-01 WO PCT/CN2016/088091 patent/WO2017049983A1/en active Application Filing
- 2016-07-01 KR KR1020187011225A patent/KR102104957B1/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0326307A2 (en) * | 1988-01-23 | 1989-08-02 | Kyowa Hakko Kogyo Co., Ltd. | Novel pyridazinone derivatives and pharmaceutical preparations containing them |
| JP2003252875A (en) * | 2002-03-04 | 2003-09-10 | Lotte Co Ltd | Novel purine derivative |
| CN1688582A (en) * | 2002-09-30 | 2005-10-26 | 拜尔药品公司 | Fused azole-pyrimidine derivatives |
| CN101631464A (en) * | 2006-12-05 | 2010-01-20 | 拜耳先灵医药股份有限公司 | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017049983A1 (en) * | 2015-09-25 | 2017-03-30 | 苏州立新制药有限公司 | Preparation method of copanlisib |
| CN108884496A (en) * | 2016-02-01 | 2018-11-23 | 拜耳制药股份公司 | COPANLISIB biomarker |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105130998B (en) | 2017-07-28 |
| KR102104957B1 (en) | 2020-04-28 |
| WO2017049983A1 (en) | 2017-03-30 |
| KR20180096572A (en) | 2018-08-29 |
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