WO2023139125A1 - Improved process for preparation of copanlisib - Google Patents
Improved process for preparation of copanlisib Download PDFInfo
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- WO2023139125A1 WO2023139125A1 PCT/EP2023/051132 EP2023051132W WO2023139125A1 WO 2023139125 A1 WO2023139125 A1 WO 2023139125A1 EP 2023051132 W EP2023051132 W EP 2023051132W WO 2023139125 A1 WO2023139125 A1 WO 2023139125A1
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229950002550 copanlisib Drugs 0.000 title claims abstract description 17
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000012453 solvate Substances 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 27
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 238000006476 reductive cyclization reaction Methods 0.000 claims description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 230000001131 transforming effect Effects 0.000 claims description 3
- 229940086542 triethylamine Drugs 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- LRPIQBVXZKUKTR-UHFFFAOYSA-N potassium sodium butan-1-olate Chemical compound [O-]CCCC.[K+].[Na+].[O-]CCCC LRPIQBVXZKUKTR-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- -1 alkali metal alkoxide Chemical class 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 239000007822 coupling agent Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- KWHDQPVGKVPPPS-UHFFFAOYSA-N quinazolin-5-amine Chemical compound C1=NC=C2C(N)=CC=CC2=N1 KWHDQPVGKVPPPS-UHFFFAOYSA-N 0.000 description 4
- GWLAEBPGTQVKBA-UHFFFAOYSA-N 3-methoxy-2-nitro-4-phenylmethoxybenzaldehyde Chemical compound C1=CC(C=O)=C([N+]([O-])=O)C(OC)=C1OCC1=CC=CC=C1 GWLAEBPGTQVKBA-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000002360 explosive Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- LNNRQIKKDKDFRV-UHFFFAOYSA-N quinazolin-8-ol Chemical compound N1=CN=C2C(O)=CC=CC2=C1 LNNRQIKKDKDFRV-UHFFFAOYSA-N 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CBRLWSXYXSFYSP-UHFFFAOYSA-N 2-aminopyrimidine-5-carboxylic acid Chemical compound NC1=NC=C(C(O)=O)C=N1 CBRLWSXYXSFYSP-UHFFFAOYSA-N 0.000 description 1
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- PQECODMSWJOUAT-UHFFFAOYSA-N 4-(3-chloropropyl)morpholine;hydrochloride Chemical compound [Cl-].ClCCC[NH+]1CCOCC1 PQECODMSWJOUAT-UHFFFAOYSA-N 0.000 description 1
- PHCNQUJHXJQLQR-UHFFFAOYSA-N 4-hydroxy-3-methoxy-2-nitrobenzaldehyde Chemical compound COC1=C(O)C=CC(C=O)=C1[N+]([O-])=O PHCNQUJHXJQLQR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010549 co-Evaporation Methods 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof:
- Copanlisib 2-Amino-N-[7-methoxy-8-[3-(4-morpholinyl)propoxy]-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, is a phosphatidylinositol 3- kinase (PI3K) inhibitor, launched as dihydrochloride salt for the treatment for adults with relapsed follicular lymphoma who have received at least two prior therapy regimens.
- PI3K phosphatidylinositol 3- kinase
- Copanlisib was first disclosed in W02008070150 by Bayer. Processes for preparation of Copanlisib are disclosed in W02008070150 or WO2016071435 by Bayer. The disadvantages of the processes described in prior art is use of hazardous, toxic and explosive reagents in processes for Copanlisib preparation. W02008070150 describes a process that uses I2/NH3 that yield explosive I3N. Process described in WO2016071435 uses highly toxic BrCN for Copanlisib production.
- the presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof, , comprising: a. Reacting compound of formula (2) with cyanamide (NH2CN) in methanol in a presence of a base to provide compound of formula (3);
- Prot means a protective group
- the presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof, , comprising: a. Reacting compound of formula (2) with cyanamide (NH2CN) in methanol in a presence of a base to provide compound of formula (3);
- Prot means a protective group
- the reaction step a. is preferably performed under a protecting atmosphere, for example under argon or nitrogen atmosphere.
- the protective group, Prot can be a suitable hydroxyl protective group, for example a hydroxyl protective group disclosed in Protective groups in organic synthesis, Theodora W. Greene and Petr G.M.Wuts, 3rd Ed., John Wiley & Sons Inc.
- the protective group is preferably benzylic group.
- the base in step a. can be for example an alkali metal alkoxide such as sodium or potassium methoxide or sodium or potassium ethoxide or sodium or potassium butoxide sodium or potassium tert-butoxide.
- the concentration of compound of formula (2) in the solvent can be between 0.010 and 0.020 g/ml.
- the concentration of cyanamide (NH2CN) in the solvent can be between 0.005 g/ml and 0.015 g/ml.
- the molar ratio between compound of formula (2) and the cyanamide (NH2CN) can be between 1:3 and 1:6, preferably it is between 1:4 and 1:5.
- the molar ratio between the compound of formula (2) and the base can be between 1:3 and 1:6, preferably it is between 1:4 and 1:5.
- the reaction step a. is performed in a presence ofN-bromo- succinimide.
- Compound of formula (2) and cyanamide (NH2CN) are mixed with the solvent.
- the mixture is cooled to 0-5°C.
- the base is added.
- the base can be added in solid form or can be added in form of a solution, for example as a solution in the solvent used in step a.
- the base can be added portion wise, for example in 2 or 3 or 4 or 5 or 6 or 8 or 10 or 12 or 14 or 16 portions.
- the mixture is heated to room temperature (between 20°C and 25°C) and stirred at this temperature for between 25 and 60 minutes.
- the mixture is cooled to 0-5°C and to the mixture N-bromosuccinimide is added in the course of 30-180 minutes.
- the mixture is heated to a temperature between 45°C and 55°C and stirred at this temperature for between 15-60 minutes.
- the reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC.
- the mixture is cooled to room temperature (20-25°C) and stirred at this temperature for between 1 and 6 hours.
- the mixture can be optionally cooled to a temperature between 0-5°C and stirred at this temperature for between 1 and 10 hours.
- Obtained solid compound of formula (3) can be isolated by any suitable technique, for example using filtration and optionally dried.
- compound of formula (3) is reacted with compound of formula (4) or a salt thereof in a presence of a base to provide compound of formula (5).
- the reaction is preferably performed under a protecting atmosphere, for example under argon or nitrogen atmosphere.
- the reaction is performed in a suitable solvent selected for example from an alcohol such as methanol or ethanol or propanol or isopropanol, preferably methanol is used.
- the concentration of compound of formula (3) in the solvent can be between 0.08 and 0.2 g/ml.
- Compound of formula (4) can be used in a form of a salt, for example HC1 salt.
- the molar ratio between compound of formula (3) and compound of formula (4) or a salt thereof can be between 1:0.9 and 1:1, preferably it is 1:0.95.
- an organic amine for example N,N-diisopropylethyl amine or triethyl amine or dimethyl amine or diethyl amine, preferably N,N-diisopropylethyl amine is used.
- the molar ratio between compound of formula (3) and the base can be between 1:2.5 and 1:5, preferably it is between 1:3 and 1:3.5.
- Compound of formula (3) and compound of formula (4) or a salt thereof are mixed with the solvent.
- the base is added and the mixture is heated to a temperature between 50°C and the reflux temperature of used solvent and stirred at this temperature for between 2 and 10 hours.
- the reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC.
- the mixture is then cooled to room temperature (20°C- 25°C) and stirred at this temperature for between 30-180 minutes to obtain a suspension.
- Obtained solid compound of formula (5) can be isolated by any suitable technique, for example using filtration and optionally dried.
- an alcohol preferably methanol
- the compound of formula (5) can be isolated directly from reaction mixture in good yield and purity. There is no need for work-up of the reaction mixture that is often time consuming, can decrease the yield of the isolated compound and produce by product waste and significant amount of solvents.
- the compound of formula (5) can be transformed into compound of formula (1) for example by a process comprising: a.
- the reductive cyclization step a can be done for example by H2 (hydrogen) in a solvent selected from for example tetrahydrofurane or dimethylformamide or an alcohol such as methanol or ethanol.
- the reductive cyclization step is done in a presence of a catalyst selected for example from Pt or Pd or SnCL, preferably it is Pt on carbon (Pt/C) or Pd on carbon (Pd/C), more preferably it is Pt/C dopped by Fe is used.
- the reductive cyclization is done in a presence of organic base selected for example from an amine such as N,N- diisopropylethyl amine or triethylamine.
- the concentration of compound (5) in the solvent can be between 0.015 g/ml and 0.05 g/ml.
- Molar ratio between compound of formula (5) and the catalyst can be between 90: 1 and 110:1.
- Compound of formula (5) is mixed with the solvent and the catalyst is added. The mixture is reduced by H2 at a temperature between 35°C - 50°C for between 15 and 30 hours at for example between 3-80 bars.
- the reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC.
- the mixture is filtered and the filtrate is evaporated to provide compound of formula (6A).
- Compound of formula (6A) is deprotected to obtain compound of formula (6). Conditions for deprotection of compound of formula (6 A) depend on the protective group Prot and are described in prior art (Protective groups in organic synthesis, Theodora W.
- Compound of formula (6A), wherein Prot group can be cleaved by an acid can be deprotected for example using trifluoroacetic acid.
- the reaction is preferably performed under a protective atmosphere, for example argon or nitrogen atmosphere.
- the molar ratio between compound of formula (6A) and trifluoroacetic acid can be between 1:100 and 1:200. Reaction is preferably done in trifluoroacetic acid used also as a solvent.
- Compound of formula (6A) is added to trifluoroacetic acid, preferably at a temperature between 0-5°C.
- Compound of formula (6A) is added preferably in portions, for example in 2 or 3 or 4 or 5 or 6 or 7 or 8 portions.
- the mixture is heated to a temperature between 55°C and 65°C and stirred at this temperature for between 10 and 24 hours.
- the reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC.
- the mixture is cooled to room temperature (20-25°C).
- Trifluoroacetic acid is removed by co-evaporation with solvents (di chloromethane or heptane or methanol) and obtained solid is dried under vacuum (100 mbar, 30 °C, overnight).
- Compound of formula (6) is reacted with compound (7) in a presence of a base in a suitable solvent.
- Compound of formula (7) can be used in a form of a salt, for example HC1 salt.
- the solvent can be selected from an alcohol such as methanol or ethanol or propanol or butanol or isopropanol or isobutanol or N,N-dimethylformamide or the mixture of the solvents with water.
- the molar ratio between compound of formula (6) and compound of formula (7) or a salt thereof can be between 1:1.5 and 1:2.
- the molar ratio between compound of formula (6) and the base can be between 1 :2 and 1:6.
- Compound of formula (6) is mixed with the solvent or solvent mixture, the base and compound of formula (7).
- the mixture is heated to a temperature between 80°C and 100°C and stirred at this temperature for between 3 and 8 hours.
- the reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC.
- the mixture is cooled to room temperature (20°C-25°C).
- To the mixture water is added.
- the volume ratio between the solvent used in step a. and the added water can be between 1:0.3 and 1:0.7.
- the mixture is stirred at room temperature for between 10 and 60 minutes.
- the phases are separated and water phase is extracted with n-butanol.
- the volume ratio between n-butanol and water added previously can be between 1.2:1 and 1.7:1. Phases are separated and the mixed organic phases are concentrated to approximately 40% of the original volume.
- the mixture is heated to 50°C.
- tert-butylmethyl ether is added.
- the volume ratio between added tertbutylmethyl ether and the solvent to which tert-butylmethyl ether is added is approximately 1:1.
- the mixture is cooled to a temperature between -5°C and 5°C and stirred at this temperature for between 30 and 180 minutes. Obtained suspension was filtered off to provide compound (8).
- Compound of formula (8) is reacted with compound of formula (9) to provide compound of formula (1),
- the reaction is performed in a suitable solvent, for example N,N-dimethylformamide in a presence of coupling agent, for example N,N-dimethylaminopyridine and N-[l-(dimethyl- amino)propyl]-N’ -ethylcarbodiimine.
- a suitable solvent for example N,N-dimethylformamide
- coupling agent for example N,N-dimethylaminopyridine and N-[l-(dimethyl- amino)propyl]-N’ -ethylcarbodiimine.
- Concentration of compound of formula (8) in the solvent can be between 0.03 g/ml and 0.08 g/ml.
- the molar ratio between compound of formula (8) and compound of formula (9) can be between 1:0.7 and 1:1.3. Concentration of the coupling agent and molar ratio between compound of formula (8) and the coupling agent depends on used coupling agent.
- the compound of formula (8) is mixed with the solvent, compound of formula (9)
- the mixture is stirred at room temperature (20°C-25°C) for between 15 and 24 hours.
- the reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC.
- obtained suspension is filtered off and obtained solid compound of formula (1) is washed and optionally dried. It can be converted into a salt, for example 2.HC1 salt or a hydrate thereof, by contacting compound of formula (1) with corresponding acid.
- Obtained Copanlisib or a salt thereof can be used for preparation of a pharmaceutically acceptable composition and can be used for the treatment of conditions treatable by Copanlisib or a salt thereof.
- Example 7 Preparation of Copanlisib 1.4 g of 5-amino-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-8-ol was mixed with 14 ml of butanol, 1.4 ml of N,N-dimethylformamide and 1.4 ml of water. To the mixture 2.5 g of K2CO3 was added. To the mixture 1.57 g of 4-(3-chloropropyl)morpholine hydrochloride was added. The resulting mixture was heated to 90°C and stirred for 5 hours. The mixture was cooled to room temperature (20-25°C). To the mixture 8.4 g of water was added and the mixture was stirred for 15 minutes.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof comprising:.
Description
IMPROVED PROCESS FOR PREPARATION OF COPANLISIB
BACKGROUND OF THE PRESENT INVENTION The presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof:
Copanlisib, 2-Amino-N-[7-methoxy-8-[3-(4-morpholinyl)propoxy]-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, is a phosphatidylinositol 3- kinase (PI3K) inhibitor, launched as dihydrochloride salt for the treatment for adults with relapsed follicular lymphoma who have received at least two prior therapy regimens.
Copanlisib was first disclosed in W02008070150 by Bayer. Processes for preparation of Copanlisib are disclosed in W02008070150 or WO2016071435 by Bayer. The disadvantages of the processes described in prior art is use of hazardous, toxic and explosive reagents in processes for Copanlisib preparation. W02008070150 describes a process that uses I2/NH3 that yield explosive I3N. Process described in WO2016071435 uses highly toxic BrCN for Copanlisib production.
There is still a need for improved process for preparation of Copanlisib that uses no explosive or toxic reagents.
SUMMARY OF THE INVENTION
The presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof,
, comprising: a. Reacting compound of formula (2) with cyanamide (NH2CN) in methanol in a presence of a base to provide compound of formula (3);
Prot means a protective group;
Reacting compound of formula (3) with compound of formula (4) or a salt thereof in a presence of a base to provide compound of formula (5):
c. Transforming compound of formula (5) into compound of formula (1).
DETAILED DESCRIPTION OF THE INVENTION
The presented invention relates to a process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof,
, comprising: a. Reacting compound of formula (2) with cyanamide (NH2CN) in methanol in a presence of a base to provide compound of formula (3);
(2) (3)
Prot means a protective group;
Reacting compound of formula (3) with compound of formula (4) or a salt thereof in a presence of a base to provide compound of formula (5):
c. Transforming compound of formula (5) into compound of formula (1).
The reaction step a. is preferably performed under a protecting atmosphere, for example under argon or nitrogen atmosphere. The protective group, Prot, can be a suitable hydroxyl protective group, for example a hydroxyl protective group disclosed in Protective groups in organic synthesis, Theodora W. Greene and Petr G.M.Wuts, 3rd Ed., John Wiley & Sons Inc.
The protective group is preferably benzylic group. The base in step a. can be for example an alkali metal alkoxide such as sodium or potassium methoxide or sodium or potassium ethoxide or sodium or potassium butoxide sodium or potassium tert-butoxide. The concentration of compound of formula (2) in the solvent can be between 0.010 and 0.020 g/ml. The concentration of cyanamide (NH2CN) in the solvent can be between 0.005 g/ml and 0.015 g/ml. The molar ratio between compound of formula (2) and the cyanamide (NH2CN) can be between 1:3 and 1:6, preferably it is between 1:4 and 1:5. The molar ratio between the compound of formula (2) and the base can be between 1:3 and 1:6, preferably it is between 1:4 and 1:5. The reaction step a. is performed in a presence ofN-bromo- succinimide. The molar ratio between compound of formula (2) and N-bromosuccinimide 1:3 and 1:6, preferably it is between 1:4 and 1:5.
Compound of formula (2) and cyanamide (NH2CN) are mixed with the solvent. The mixture is cooled to 0-5°C. To the mixture the base is added. The base can be added in solid form or can be added in form of a solution, for example as a solution in the solvent used in step a. The base can be added portion wise, for example in 2 or 3 or 4 or 5 or 6 or 8 or 10 or 12 or 14 or 16 portions. The mixture is heated to room temperature (between 20°C and 25°C) and stirred at this temperature for between 25 and 60 minutes. The mixture is cooled to 0-5°C and to the mixture N-bromosuccinimide is added in the course of 30-180 minutes. The mixture is heated to a temperature between 45°C and 55°C and stirred at this temperature for between 15-60 minutes. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is cooled to room temperature (20-25°C) and stirred at this temperature for between 1 and 6 hours. The mixture can be optionally cooled to a temperature between 0-5°C and stirred at this temperature for between 1 and 10 hours. Obtained solid compound of formula (3) can be isolated by any suitable technique, for example using filtration and optionally dried.
In the step b. compound of formula (3) is reacted with compound of formula (4) or a salt thereof in a presence of a base to provide compound of formula (5). The reaction step b. is preferably performed under a protecting atmosphere, for example under argon or nitrogen atmosphere. The reaction is performed in a suitable solvent selected for example from an alcohol such as methanol or ethanol or propanol or isopropanol, preferably methanol is used. The concentration of compound of formula (3) in the solvent can be between 0.08 and 0.2 g/ml. Compound of formula (4) can be used in a form of a salt, for example HC1 salt. The molar ratio between compound of formula (3) and compound of formula (4) or a salt thereof can be between 1:0.9 and 1:1, preferably it is 1:0.95. As a base an organic amine for example N,N-diisopropylethyl amine or triethyl amine or dimethyl amine or diethyl amine, preferably N,N-diisopropylethyl amine is used. The molar ratio between compound of formula (3) and the base can be between 1:2.5 and 1:5, preferably it is between 1:3 and 1:3.5. Compound of formula (3) and compound of formula (4) or a salt thereof are mixed with the solvent. To the mixture the base is added and the mixture is heated to a temperature between 50°C and the reflux temperature of used solvent and stirred at this temperature for between 2 and 10 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is then cooled to room temperature (20°C- 25°C) and stirred at this temperature for between 30-180 minutes to obtain a suspension. Obtained solid compound of formula (5) can be isolated by any suitable technique, for example using filtration and optionally dried. As a result of use of an alcohol, preferably methanol, as a solvent in reaction step b. the compound of formula (5) can be isolated directly from reaction mixture in good yield and purity. There is no need for work-up of the reaction mixture that is often time consuming, can decrease the yield of the isolated compound and produce by product waste and significant amount of solvents.
In the step c. the compound of formula (5) can be transformed into compound of formula (1) for example by a process comprising: a. Reductive cyclization of the compound of formula (5) to obtain compound of formula (6A) and deprotecting compound of formula (6A) to obtain compound of formula (6),
b. Reacting compound of formula (6) with compound of formula (7) to obtain compound of formula (8),
c. Reacting compound of formula (8) with compound of formula (9) to obtain compound of formula (1),
The reductive cyclization step a. can be done for example by H2 (hydrogen) in a solvent selected from for example tetrahydrofurane or dimethylformamide or an alcohol such as
methanol or ethanol. The reductive cyclization step is done in a presence of a catalyst selected for example from Pt or Pd or SnCL, preferably it is Pt on carbon (Pt/C) or Pd on carbon (Pd/C), more preferably it is Pt/C dopped by Fe is used. The reductive cyclization is done in a presence of organic base selected for example from an amine such as N,N- diisopropylethyl amine or triethylamine. The concentration of compound (5) in the solvent can be between 0.015 g/ml and 0.05 g/ml. Molar ratio between compound of formula (5) and the catalyst can be between 90: 1 and 110:1. Compound of formula (5) is mixed with the solvent and the catalyst is added. The mixture is reduced by H2 at a temperature between 35°C - 50°C for between 15 and 30 hours at for example between 3-80 bars. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is filtered and the filtrate is evaporated to provide compound of formula (6A). Compound of formula (6A) is deprotected to obtain compound of formula (6). Conditions for deprotection of compound of formula (6 A) depend on the protective group Prot and are described in prior art (Protective groups in organic synthesis, Theodora W.
Greene and Petr G.M.Wuts, 3rd Ed., John Wiley & Sons Inc.). Compound of formula (6A), wherein Prot group can be cleaved by an acid, can be deprotected for example using trifluoroacetic acid. The reaction is preferably performed under a protective atmosphere, for example argon or nitrogen atmosphere. The molar ratio between compound of formula (6A) and trifluoroacetic acid can be between 1:100 and 1:200. Reaction is preferably done in trifluoroacetic acid used also as a solvent. Compound of formula (6A) is added to trifluoroacetic acid, preferably at a temperature between 0-5°C. Compound of formula (6A) is added preferably in portions, for example in 2 or 3 or 4 or 5 or 6 or 7 or 8 portions. The mixture is heated to a temperature between 55°C and 65°C and stirred at this temperature for between 10 and 24 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is completed the mixture is cooled to room
temperature (20-25°C). Trifluoroacetic acid is removed by co-evaporation with solvents (di chloromethane or heptane or methanol) and obtained solid is dried under vacuum (100 mbar, 30 °C, overnight).
Compound of formula (6) is reacted with compound (7) in a presence of a base in a suitable solvent. Compound of formula (7) can be used in a form of a salt, for example HC1 salt. The solvent can be selected from an alcohol such as methanol or ethanol or propanol or butanol or isopropanol or isobutanol or N,N-dimethylformamide or the mixture of the solvents with water. The molar ratio between compound of formula (6) and compound of formula (7) or a salt thereof can be between 1:1.5 and 1:2. The molar ratio between compound of formula (6) and the base can be between 1 :2 and 1:6. Compound of formula (6) is mixed with the solvent or solvent mixture, the base and compound of formula (7). The mixture is heated to a temperature between 80°C and 100°C and stirred at this temperature for between 3 and 8 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, the mixture is cooled to room temperature (20°C-25°C). To the mixture water is added. The volume ratio between the solvent used in step a. and the added water can be between 1:0.3 and 1:0.7. The mixture is stirred at room temperature for between 10 and 60 minutes. The phases are separated and water phase is extracted with n-butanol. The volume ratio between n-butanol and water added previously can be between 1.2:1 and 1.7:1. Phases are separated and the mixed organic phases are concentrated to approximately 40% of the original volume. The mixture is heated to 50°C. To the mixture tert-butylmethyl ether is added. The volume ratio between added tertbutylmethyl ether and the solvent to which tert-butylmethyl ether is added is approximately 1:1. The mixture is cooled to a temperature between -5°C and 5°C and stirred at this temperature for between 30 and 180 minutes. Obtained suspension was filtered off to provide compound (8). Compound of formula (8) is reacted with compound of formula (9) to provide
compound of formula (1),
The reaction is performed in a suitable solvent, for example N,N-dimethylformamide in a presence of coupling agent, for example N,N-dimethylaminopyridine and N-[l-(dimethyl- amino)propyl]-N’ -ethylcarbodiimine. Concentration of compound of formula (8) in the solvent can be between 0.03 g/ml and 0.08 g/ml. The molar ratio between compound of formula (8) and compound of formula (9) can be between 1:0.7 and 1:1.3. Concentration of the coupling agent and molar ratio between compound of formula (8) and the coupling agent depends on used coupling agent. The compound of formula (8) is mixed with the solvent, compound of formula (9) and the coupling agent. The mixture is stirred at room temperature (20°C-25°C) for between 15 and 24 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, obtained suspension is filtered off and obtained solid compound of formula (1) is washed and optionally dried. It can be converted into a salt, for example 2.HC1 salt or a hydrate thereof, by contacting compound of formula (1) with corresponding acid.
Obtained Copanlisib or a salt thereof can be used for preparation of a pharmaceutically acceptable composition and can be used for the treatment of conditions treatable by Copanlisib or a salt thereof.
The invention will be further illustrated by the following examples.
EXAMPLES
50 g of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde and 52.6 g of potassium carbonate were mixed with 350 ml of anhydrous DMF under argon. To the mixture 36.2 ml of benzyl bromide was added and the mixture was stirred for 12 hours. The reaction mixture was poured into 3500 ml of water to obtain a suspension. Solid product was filtered off and dried under vacuum (100 mbar, overnight, 35 - 50 °C) to provide 4-(benzyloxy)-3-methoxy-2- nitrobenzaldehyde in almost 100% yield.
40 g of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde and 23.42 g of cyanamide (NH2CN) were mixed with 3000 ml of methanol under argon atmosphere. The mixture was cooled to 0-5°C and to the mixture 53.5 g of sodium tert-butoxide was added in the course of 30 minutes portion wise (in 10 portions). The mixture was heated to room temperature (20- 25°C) and stirred at this temperature for 30 minutes. The mixture was cooled to 0-5°C and to the mixture 99 g of N-bromosuccinimide was added slowly, in the course of 60 minutes. The mixture was heated to 50°C. The mixture was cooled to room temperature (20-25°C) and stirred at this temperature for 3 hours. The mixture was then left at 0-5°C for 10 hours.
Obtained suspension was filtered off and obtained solid was dried under vacuum (30°C, 100 mbar, 1 hour) to provide methyl (Z)-4-(benzyloxy)-N-cyano-3-methoxy-2-nitrobenzimidate in 65% yield and 99.6% purity (HPLC IN).
Example 3: Preparation of 2-(4-(benzyloxy)-3-methoxy-2-nitrophenyl)-lH-imidazole-
5 g of methyl (Z)-4-(benzyloxy)-N-cyano-3-methoxy-2-nitrobenzimidate and 1.614 g of 2-chloroethylamine hydrochloride was mixed with 50 ml of methanol under argon atmosphere. To the mixture 7.65 ml of N,N-diisopropylethylamine was added and the mixture was heated to reflux (65°C) and stirred at this temperature for 3 hours. The mixture was cooled to room temperature (20-25°C) and filtered. Obtained solid was dried under vacuum at room temperature for 12 hours to obtain 2-(4-(benzyloxy)-3-methoxy-2- nitrophenyl)-lH-imidazole-l -carbonitrile in 73% yield and 98.4% purity (HPLC IN).
250 mg of 2-(4-(benzyloxy)-3-methoxy-2-nitrophenyl)-lH-imidazole-l-carbonitrile was mixed with 9 ml of tetrahydrofurane and 66.9 mg of 5% platinum on activated carbon, paste, type 163, 0.1% Fe doped. To the mixture 0.989 ml of N,N-diisopropylethylamine was
added. Mixture was placed in miniclave under nitrogen and heated to 40°C. Nitrogen was replaced by H2 (5 bars). Reaction was carried over for 24 hours, then the mixture was filtered and the filtrate was evaporated under reduced pressure (300 mbar, 40°C). The residue was dissolved in 4 ml of acetone and sonicated until white suspension appeared. The solid was collected by filtration to produce essentially pure (98%, HPLC IN) 2-(2-amino-4- (benzyloxy)-3-methoxyphenyl)-lH-imidazole-l -carbonitrile.
Example 5: Preparation of 5-amino-7-methoxy-2.3-dihydroimidazo[1.2-clquinazolin-
2 g of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-amine was mixed with 0.2 g of 5% Pd/C and 33.7 ml of N,N-dimethylformamide. The mixture was heated to 60°C. The mixture was hydrogenated under 3 bars of H2 for 18 hours. The mixture was filtered and the filtrate was concentrated to approximately 30-35% of original volume. The rest was cooled to room temperature (20-25°C) and 14 ml of water was added during 10 minutes to obtain a suspension. The mixture was stirred at room temperature and filtered to provide 5-amino-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-8-ol in yield 58%.
Example 6: Preparation of 5-amino-7-methoxy-2.3-dihydroimidazo|T.2-c]quinazohn-
0.322 g of 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-5-amine was added portion wise (in 3 portions) in the course of 10 minutes to 10.03 ml of trifluoroacetic acid precooled with an ice bath to 0-5°C. The reaction mixture was heated to 60 °C, stirred at this temperature for 17 hours and then cooled to 20-25°C. The mixture was evaporated to approximately 60% of original volume. To the rest 4 ml of a mixture dichloromethane/ heptane (1:1, vol: vol) was added. The mixture was evaporated to approximately 60% of original volume. To the rest 4 ml of a mixture dichloromethane/methanol (1:1, vol:vol) was added. The mixture was evaporated and the rest was dried under vacuum (100 mbar, 30 °C, overnight).
Product 5-amino-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-8-ol.( trifluoroacetic acid)2 was prepared in 87% of yield.
Example 7: Preparation of Copanlisib
1.4 g of 5-amino-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin-8-ol was mixed with 14 ml of butanol, 1.4 ml of N,N-dimethylformamide and 1.4 ml of water. To the mixture 2.5 g of K2CO3 was added. To the mixture 1.57 g of 4-(3-chloropropyl)morpholine hydrochloride was added. The resulting mixture was heated to 90°C and stirred for 5 hours. The mixture was cooled to room temperature (20-25°C). To the mixture 8.4 g of water was added and the mixture was stirred for 15 minutes. The phases were separated and the water phase was extracted with 12 ml of butanol. The organic phases were mixed and evaporated to approximately 50-55% of original volume. The mixture was heated to 45°C. To the mixture 11 ml of tert-butyl methyl ether was added. The mixture was cooled to -5°C and stirred at this temperature for 30 minutes. The mixture was filtered off to provide 7-methoxy-8-[3- (morphohn-4-yl)-propoxy]-2,3-dihydroimidazo[l,2-c]quinazolin-5-amine in yield 80%.
1.3 g of 7-methoxy-8-[3-(morpholin-4-yl)-propoxy]-2,3-dihydroimidazo[l,2- c]quinazolin-5-amine was mixed with 21.5 ml of N,N, -dimethylformamide, 0.5 g of 2- aminopyrimidine-5 -carboxylic acid, 0.4 g of N,N-dimethylaminopyridine and 1 g of N-[3- (dimethylamino)propyl]-N’-ethylcarbodiimide hydrochloride. The mixture was stirred at 20- 25°C for 15 hours. The mixture was filtered. Obtained solid was dried to provide Copanlisib in 95% yield.
Claims
A process for preparation of Copanlisib, compound of formula (1), or a salt or a solvate thereof,
, comprising:
Reacting compound of formula (2) with cyanamide (NH2CN) in methanol in a presence of a base to provide compound of formula (3);
(2) (3)
Prot means a protective group b. Reacting compound of formula (3) with compound of formula (4) or a salt thereof in a presence of a base to provide compound of formula (5);
Transforming compound of formula (5) into compound of formula (1).
2. The process according to claim 1 wherein the Prot is benzyl.
The process according to claim 1 or 2 wherein the base in step a. is an alkoxide.
4. The process according to claim 3 wherein the base is selected from sodium or potassium methoxide or sodium or potassium ethoxide or sodium or potassium butoxide sodium or potassium tert-butoxide.
5. The process according to any one of claims 1 to 4 wherein the base in step b. is selected from an organic amine.
6. The process according to claim 5 wherein the base is selected from N,N- diisopropylethyl amine or triethyl amine or dimethyl amine or diethyl amine.
7. The process according to any one of claims 1 to 6 wherein the step b. is performed in an alcohol solvent.
8. The process according to claim 7 wherein the solvent is selected from methanol or ethanol or propanol or isopropanol.
9. The process according to step 8 wherein the solvent is methanol.
10. The process according to any one of claims 7 to 9 wherein the compound of formula (5) is isolated directly from reaction mixture.
11. The process according to anyone of previous claims wherein the step c. comprises: a. Reductive cyclization of compound of formula (5) to obtain compound of formula (6A) and deprotecting compound of formula (6A) to obtain compound of formula (6),
b. Reacting compound of formula (6) with compound of formula (7) to obtain compound of formula (8),
c. Reacting compound of formula (8) with compound of formula (9) to obtain compound of formula (1),
The process according to claim 11 wherein the compound of formula 1 is transformed into a salt or a solvate.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2008070150A1 (en) | 2006-12-05 | 2008-06-12 | Bayer Schering Pharma Aktiengesellschaft | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
WO2016071435A2 (en) | 2014-11-07 | 2016-05-12 | Bayer Pharma Aktiengesellschaft | Synthesis of copanlisib and its dihydrochloride salt |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008070150A1 (en) | 2006-12-05 | 2008-06-12 | Bayer Schering Pharma Aktiengesellschaft | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
WO2016071435A2 (en) | 2014-11-07 | 2016-05-12 | Bayer Pharma Aktiengesellschaft | Synthesis of copanlisib and its dihydrochloride salt |
Non-Patent Citations (2)
Title |
---|
PING YIN ET AL: "Synthesis of 2,4-Diaminoquinazolines and Tricyclic Quinazolines by Cascade Reductive Cyclization of Methyl N -Cyano-2-nitrobenzimidates", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 77, no. 6, 16 March 2012 (2012-03-16), pages 2649 - 2658, XP055287925, ISSN: 0022-3263, DOI: 10.1021/jo2023697 * |
THEODORA W. GREENEPETR G.M.WUTS: "Protective groups in organic synthesis", JOHN WILEY & SONS INC. |
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