WO2016016769A1 - A process for the preparation of palbociclib - Google Patents
A process for the preparation of palbociclib Download PDFInfo
- Publication number
- WO2016016769A1 WO2016016769A1 PCT/IB2015/055528 IB2015055528W WO2016016769A1 WO 2016016769 A1 WO2016016769 A1 WO 2016016769A1 IB 2015055528 W IB2015055528 W IB 2015055528W WO 2016016769 A1 WO2016016769 A1 WO 2016016769A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- trimethylsilyl
- dimethylsilyl
- butyldimethylsilyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 37
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229960004390 palbociclib Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- -1 silyl-protected crotonic acid Chemical class 0.000 claims abstract description 18
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 11
- 229910052763 palladium Inorganic materials 0.000 claims description 11
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical class C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- BSKNQSYIDZUXQT-UHFFFAOYSA-N 2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7-one Chemical compound C12=NC(Cl)=NC=C2C(C)=CC(=O)N1C1CCCC1 BSKNQSYIDZUXQT-UHFFFAOYSA-N 0.000 abstract description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- DIVUXBABVYOIOT-UHFFFAOYSA-N 5-bromo-2-chloro-n-cyclopentylpyrimidin-4-amine Chemical compound ClC1=NC=C(Br)C(NC2CCCC2)=N1 DIVUXBABVYOIOT-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- BFMGZABSMGSRKM-UHFFFAOYSA-N CC(c(cn1)c(N2C3CCCC3)nc1Cl)=CC2O Chemical compound CC(c(cn1)c(N2C3CCCC3)nc1Cl)=CC2O BFMGZABSMGSRKM-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- DAGQYUCAQQEEJD-UHFFFAOYSA-N tris(2-methylpropyl)phosphane Chemical compound CC(C)CP(CC(C)C)CC(C)C DAGQYUCAQQEEJD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Definitions
- the present invention relates to a process for the preparation of palbociclib.
- Palbociclib chemically is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(l-piperazinyl)-2- pyridinyl]amino]pyrido 2,3-d]pyrimidin-7(8H)-one, represented by the Formula I.
- U.S. Patent No. 6,936,612 discloses palbociclib and a process for the preparation of its hydrochloride salt.
- U.S. Patent No. 7,781,583 discloses a process for the preparation of palbociclib, wherein 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Formula II
- U.S. Patent No. 7,863,278 discloses polymorphs of various salts of palbociclib and processes for their preparation.
- the present invention relates to a process for the preparation of palbociclib.
- room temperature refers to a temperature in the range of 25°C to 35°C.
- a first aspect of the present invention provides a process for the preparation of a compound of Formula IV,
- R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl
- R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl
- a second aspect of the present invention provides a process for the preparation of palbociclib of Formula I,
- R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III
- R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) converting the compound of Formula IV to palbociclib of Formula I.
- a third aspect of the present invention provides a process for the preparation of a compound of Formula II
- R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III
- R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) intramolecular cyclization of the compound of Formula IV to give a
- a fourth aspect of the present invention provides a process for the preparation of palbociclib of Formula I
- R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III
- R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl
- the compound of Formula V may be prepared by any method known in the art, for example, the method described in U.S. Patent No. 7, 126,025, or by the method as described herein.
- the compound of Formula III may be prepared by any method known in the art, for example, the method described in U.S. Patent No. 7,781,583.
- the compound of Formula III is reacted with the compound of Formula V in the presence of the palladium catalyst, the base, and optionally the ligand to give the compound of Formula IV in a solvent.
- the compound of Formula V may be reacted with the compound of Formula III after isolation from the reaction mixture in which it is formed.
- the reaction mixture containing the compound of Formula V may be used for the reaction with the compound of Formula III.
- the base is an organic base or an inorganic base.
- organic bases include triethylamine, diisopropylethylamine, and tributylamine.
- inorganic bases include potassium carbonate, sodium carbonate, and lithium carbonate.
- the palladium catalyst is selected from the group consisting of
- the ligand is selected from the group consisting of tri-o-tolylphosphine, triphenylphosphine, and tri-i-butylphosphine.
- the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and esters.
- ether solvents include tetrahydrofuran, 1,4-dioxane, diisopropylether, and methyl fert-butyl ether.
- halogenated hydrocarbon solvents include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
- Examples of alcohol solvents include methanol, ethanol, n-propanol, isopropanol, and n-butanol.
- ester solvents include ethyl acetate and butyl acetate.
- the reaction of the compound of Formula III with the compound of Formula V is carried out for from about 15 hours to about 30 hours, for example, from about 18 hours to about 24 hours.
- the reaction of the compound of Formula III with the compound of Formula V is carried out at a temperature of from about 50°C to about 90°C, for example, from about 70°C to about 80°C.
- the compound of Formula IV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
- the compound of Formula IV may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
- the intramolecular cyclization of the compound of Formula IV to give the compound of Formula II is carried out in the presence of an acid anhydride or an acid chloride.
- acid anhydrides include acetic anhydride, propionic anhydride, butyric anhydride, trifluoroacetic anhydride, and trifluoromethanesulfonic anhydride.
- acid chlorides include acetyl chloride and ethanoyl chloride.
- the intramolecular cyclization of the compound of Formula IV may be carried out after isolation from the reaction mixture in which it is formed. Alternatively, the reaction mixture containing the compound of Formula IV may be used for this step.
- the intramolecular cyclization of the compound of Formula IV is carried out for from about 1 hour to about 6 hours, for example, from about 2 hours to about 3 hours.
- the intramolecular cyclization of the compound of Formula IV is carried out at a temperature of from about 50°C to about 90°C, for example, from about 70°C to about 80°C.
- the compound of Formula II may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
- the compound of Formula II may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
- the compound of Formula II is converted to palbociclib of Formula I by processes known in the art, for example, as disclosed in U.S. Patent No. 7,781,583. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
- Step a Preparation of trimethylsilyl (2£)-but-2-enoate (Formula V, when R is trimethylsilyl)
- Crotonic acid (18.68 g) was taken in dichloromethane (80 mL) at room temperature
- Trimethylsilyl (2£)-but-2-enoate (obtained from step a) and diisopropylethylamine (52 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (20 g, Formula III) in tetrahydrofuran (100 mL) at room temperature under a nitrogen atmosphere.
- the reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times.
- Trans- dichlorobis(acetonitrile) palladium (II) (0.970 g) followed by the addition of tri-o- tolylphosphine (0.770 g) was added to the reaction mixture under a nitrogen atmosphere.
- reaction system was again degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times.
- the reaction mixture was heated at 75°C to 80°C overnight.
- the progress of the reaction was monitored by thin layer chromatography (TLC) (60% ethyl acetate/toluene).
- TLC thin layer chromatography
- Trans-dichlorobis(acetonitrile) palladium (II) (0.725 g) was again added followed by the addition of tri-o-tolylphosphine (0.725 g) was again added followed by the addition of tri-o-tolylphosphine (0.725 g) to the reaction mixture at 75°C to 80°C.
- the reaction mixture was heated at 75°C to 80°C for 4 hours.
- Trimethylsilyl (2£)-but-2-enoate (obtained from step a) and diisopropylethylamine (26.5 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (Formula III, 10 g) in tetrahydrofuran (50 mL) at room temperature under a nitrogen atmosphere.
- the reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times.
- Trans- dichlorobis(acetonitrile) palladium (II) (1.39 g) followed by the addition of tri-o- tolylphosphine (1.1 g) was added to the reaction mixture under a nitrogen atmosphere.
- the reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times.
- the reaction mixture was heated at 75 °C to 80°C overnight.
- acetic anhydride (20 mL) was added, and then the mixture was stirred at 75°C to 80°C for 3 hours.
- the reaction mixture was cooled to room temperature.
- Dichloromethane (50 mL) and IN hydrochloric acid (50 mL) were added, and then the mixture was stirred for 10 minutes.
- the layers were separated and the aqueous layer was re-extracted with dichloromethane (20 mL) and separated.
- the combined organic layers were washed with a 5% sodium bicarbonate solution (200 mL) at room temperature.
- the organic layer was separated and activated carbon (1 g) was added to the mixture. The mixture was stirred for 20 minutes at room temperature. The mixture was filtered through a Hyflo ® bed and then washed with dichloromethane (20 mL). The organic layer was evaporated under vacuum to obtain a residue. Isopropyl alcohol (40 mL) was added to the residue and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. Isopropyl alcohol (20 mL) was again added to the mixture and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. The mixture was stirred for 3 hours at room temperature. The product was filtered and washed with isopropyl alcohol (10 mL), and then dried under vacuum at 45°C to obtain the title compound.
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- Chemical & Material Sciences (AREA)
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Abstract
The present invention relates to a process for the preparation of palbociclib utilizing a silyl-protected crotonic acid derivative to produce a silyl-protected 5-(1-methyl-3 carboxy-prop-1-en-1-yl)-2-chloro-piperazine followed by intramolecular cyclization of the compound the piperazine intermediate to produce 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one which is then converted to palbociclib.
Description
A PROCESS FOR THE PREPARATION OF PALBOCICLIB
Field of the Invention
The present invention relates to a process for the preparation of palbociclib.
Background of the Invention
Palbociclib chemically is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(l-piperazinyl)-2- pyridinyl]amino]pyrido 2,3-d]pyrimidin-7(8H)-one, represented by the Formula I.
Formula I
U.S. Patent No. 6,936,612 discloses palbociclib and a process for the preparation of its hydrochloride salt.
U.S. Patent No. 7,781,583 discloses a process for the preparation of palbociclib, wherein 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Formula II
Formula II
prepared by reacting 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine of Formula III
Formula III
with crotonic acid.
U.S. Patent No. 7,863,278 discloses polymorphs of various salts of palbociclib and processes for their preparation.
Summary of the Invention
The present invention relates to a process for the preparation of palbociclib.
Detailed Description of the Invention
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "room temperature," as used herein, refers to a temperature in the range of 25°C to 35°C.
A first aspect of the present invention provides a process for the preparation of a compound of Formula IV,
Formula IV
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl
Formula III
in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV.
A second aspect of the present invention provides a process for the preparation of palbociclib of Formula I,
Formula I
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III
Formula III
in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV
Formula IV
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) converting the compound of Formula IV to palbociclib of Formula I.
A third aspect of the present invention provides a process for the preparation of a compound of Formula II
Formula II
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III
Formula III
in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV,
Formula IV
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) intramolecular cyclization of the compound of Formula IV to give a
compound of Formula II.
A fourth aspect of the present invention provides a process for the preparation of palbociclib of Formula I
Formula I
comprising:
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III
Formula III
in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV
Formula IV
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl;
intramolecular cyclization of the compound of Formula IV to give a compound of Formula II; and
Formula II
converting the compound of Formula II to palbociclib of Formula I.
The compound of Formula V may be prepared by any method known in the art, for example, the method described in U.S. Patent No. 7, 126,025, or by the method as described herein.
The compound of Formula III may be prepared by any method known in the art, for example, the method described in U.S. Patent No. 7,781,583.
The compound of Formula III is reacted with the compound of Formula V in the presence of the palladium catalyst, the base, and optionally the ligand to give the compound of Formula IV in a solvent.
The compound of Formula V may be reacted with the compound of Formula III after isolation from the reaction mixture in which it is formed. Alternatively, the reaction mixture containing the compound of Formula V may be used for the reaction with the compound of Formula III.
The base is an organic base or an inorganic base. Examples of organic bases include triethylamine, diisopropylethylamine, and tributylamine. Examples of inorganic bases include potassium carbonate, sodium carbonate, and lithium carbonate.
The palladium catalyst is selected from the group consisting of
tetrakis(triphenylphosphine)palladium (0), palladium acetate, palladium chloride, and trans-dichlorobis(acetonitrile)palladium (II) .
The ligand is selected from the group consisting of tri-o-tolylphosphine, triphenylphosphine, and tri-i-butylphosphine.
The solvent is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and esters. Examples of ether solvents include tetrahydrofuran, 1,4-dioxane, diisopropylether, and methyl fert-butyl ether. Examples of halogenated hydrocarbon solvents include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride. Examples of alcohol solvents include methanol, ethanol, n-propanol, isopropanol, and n-butanol. Examples of ester solvents include ethyl acetate and butyl acetate.
The reaction of the compound of Formula III with the compound of Formula V is carried out for from about 15 hours to about 30 hours, for example, from about 18 hours to about 24 hours.
The reaction of the compound of Formula III with the compound of Formula V is carried out at a temperature of from about 50°C to about 90°C, for example, from about 70°C to about 80°C.
The compound of Formula IV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula IV may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The intramolecular cyclization of the compound of Formula IV to give the compound of Formula II is carried out in the presence of an acid anhydride or an acid chloride.
Examples of acid anhydrides include acetic anhydride, propionic anhydride, butyric anhydride, trifluoroacetic anhydride, and trifluoromethanesulfonic anhydride. Examples of acid chlorides include acetyl chloride and ethanoyl chloride.
The intramolecular cyclization of the compound of Formula IV may be carried out after isolation from the reaction mixture in which it is formed. Alternatively, the reaction mixture containing the compound of Formula IV may be used for this step.
The intramolecular cyclization of the compound of Formula IV is carried out for from about 1 hour to about 6 hours, for example, from about 2 hours to about 3 hours.
The intramolecular cyclization of the compound of Formula IV is carried out at a temperature of from about 50°C to about 90°C, for example, from about 70°C to about 80°C.
The compound of Formula II may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. The compound of Formula II may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, air drying, or agitated thin film drying.
The compound of Formula II is converted to palbociclib of Formula I by processes known in the art, for example, as disclosed in U.S. Patent No. 7,781,583.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
Method
Chromatographic purity was determined by HPLC using an Agilent® Model 1200; the column used was an ACE® C18-PFP (150 x 4.6 nm).
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Preparation of 2-chloro-8 -cyclopentyl-5 -methyl-8H-pyrido Γ2.3 - lpyrimidin-7-one (Formula II)
Step a: Preparation of trimethylsilyl (2£)-but-2-enoate (Formula V, when R is trimethylsilyl)
Crotonic acid (18.68 g) was taken in dichloromethane (80 mL) at room
temperature to obtain a solution. Hexamethyldisilazane (HMDS) (21 g) followed by imidazole (0.4 g) was added to the solution at room temperature under stirring. The reaction mixture was refluxed for 2 hours. Dichloromethane was recovered completely under vacuum at 45°C. Dichloromethane (200 mL) was again added to the reaction mixture, and then recovered completely under vacuum at 45°C. The colorless liquid obtained was taken as such for next step.
Step b: Preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-i/|pyrimidin-7- one (Formula II)
Method A
Trimethylsilyl (2£)-but-2-enoate (obtained from step a) and diisopropylethylamine (52 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (20 g, Formula III) in tetrahydrofuran (100 mL) at room temperature under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. Trans- dichlorobis(acetonitrile) palladium (II) (0.970 g) followed by the addition of tri-o- tolylphosphine (0.770 g) was added to the reaction mixture under a nitrogen atmosphere.
The reaction system was again degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. The reaction mixture was heated at 75°C to 80°C overnight. The progress of the reaction was monitored by thin layer chromatography (TLC) (60% ethyl acetate/toluene). Trans-dichlorobis(acetonitrile) palladium (II) (0.725 g) was again added followed by the addition of tri-o-tolylphosphine (0.725 g) to the reaction mixture at 75°C to 80°C. The reaction mixture was heated at 75°C to 80°C for 4 hours. After completion of the reaction, acetic anhydride (17 mL) was added, and then the mixture was stirred at 75°C to 80°C for 3 hours. The reaction mixture was cooled to room temperature. Dichloromethane (100 mL) and IN hydrochloric acid (100 mL) were added and then the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was re-extracted with dichloromethane (40 mL) and separated. The combined organic layers were washed with a 5% sodium bicarbonate solution (200 mL) at room temperature. The organic layer was separated and activated carbon (2 g) was added to the mixture. The mixture was stirred for 20 minutes at room temperature. The mixture was filtered through a Hyflo® bed and then washed with dichloromethane (40 mL). The organic layer was evaporated under vacuum to obtain a residue. Isopropyl alcohol (80 mL) was added to the residue and the solvent was evaporated under reduced pressure until 40 mL of isopropyl alcohol remained. Isopropyl alcohol (40 mL) was again added to the mixture, and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. The mixture was stirred for 3 hours at room temperature. The product was filtered, thenwashed with isopropyl alcohol (20 mL), and then dried under vacuum at 45°C to obtain the title compound.
Yield: 0.535% w/w
Chromatographic purity: 99.51%
Method B
Trimethylsilyl (2£)-but-2-enoate (obtained from step a) and diisopropylethylamine (26.5 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (Formula III, 10 g) in tetrahydrofuran (50 mL) at room temperature under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. Trans- dichlorobis(acetonitrile) palladium (II) (1.39 g) followed by the addition of tri-o-
tolylphosphine (1.1 g) was added to the reaction mixture under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. The reaction mixture was heated at 75 °C to 80°C overnight. After completion of the reaction, acetic anhydride (20 mL) was added, and then the mixture was stirred at 75°C to 80°C for 3 hours. The reaction mixture was cooled to room temperature. Dichloromethane (50 mL) and IN hydrochloric acid (50 mL) were added, and then the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was re-extracted with dichloromethane (20 mL) and separated. The combined organic layers were washed with a 5% sodium bicarbonate solution (200 mL) at room temperature. The organic layer was separated and activated carbon (1 g) was added to the mixture. The mixture was stirred for 20 minutes at room temperature. The mixture was filtered through a Hyflo® bed and then washed with dichloromethane (20 mL). The organic layer was evaporated under vacuum to obtain a residue. Isopropyl alcohol (40 mL) was added to the residue and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. Isopropyl alcohol (20 mL) was again added to the mixture and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. The mixture was stirred for 3 hours at room temperature. The product was filtered and washed with isopropyl alcohol (10 mL), and then dried under vacuum at 45°C to obtain the title compound.
Yield: 0.46% w/w
Chromatographic purity: 98.1%
Claims
We Claim:
1. A process for the preparation of a compound of Formula IV
Formula IV
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl
with a compound of Formula III
Formula III
in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV.
A process for the reparation of palbociclib of Formula I,
Formula I
comprising:
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III
Formula III
in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV
Formula IV
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) converting the compound of Formula IV to palbociclib of Formula I.
A process for the preparation of a compound of Formula II
Formula II
comprising:
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or fer -butyldimethylsilyl with a compound of Formula III
Formula III
in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV
Formula IV
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) intramolecular cyclization of the compound of Formula IV to give a compound of Formula II.
A process for the reparation of palbociclib of Formula I
Formula I
comprising:
Formula V
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III
Formula III
in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV
Formula IV
wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl;
b) intramolecular cyclization of the compound of Formula IV to give a
compound of Formula II; and
Formula II
c) converting the compound of Formula II to palbociclib of Formula I.
5. The process according to claim 1, 2, 3, or 4, wherein the compound of Formula III is reacted with the compound of Formula V to give the compound of Formula IV in a solvent.
6. The process according to claim 1, 2, 3, or 4, wherein the palladium catalyst is selected from the group consisting of tetrakis(triphenylphosphine) palladium (0), palladium acetate, palladium chloride, and trans-dichlorobis(acetonitrile) palladium (II).
7. The process according to claim 1, 2, 3, or 4, wherein the base is an organic base or an inorganic base.
8. The process according to claim 7, wherein the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, and tributylamine, and the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, and lithium carbonate.
9. The process according to claim 1, 2, 3, or 4, wherein the ligand is selected from the group consisting of tri-o-tolylphosphine, triphenylphosphine, and tri-7-butylphosphine. 10. The process according to claim 5, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, alcohols, and esters.
11. The process according to claim 3 or 4, wherein the intramolecular cyclization of the compound of Formula IV to give the compound of Formula II is carried out in the presence of an acid anhydride or an acid chloride.
12. The process according to claim 11, wherein the acid anhydride is selected from the group consisting of acetic anhydride, propionic anhydride, butyric anhydride, trifluoroacetic anhydride, and trifluoromethanesulfonic anhydride, and the acid chloride is selected from the group consisting of acetyl chloride and ethanoyl chloride.
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EP15826397.0A EP3174878A4 (en) | 2014-07-31 | 2015-07-21 | A process for the preparation of palbociclib |
US15/500,616 US20170217962A1 (en) | 2014-07-31 | 2015-07-21 | A process for the preparation of palbociclib |
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IN2154DE2014 | 2014-07-31 | ||
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Cited By (2)
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CN108017630A (en) * | 2016-10-31 | 2018-05-11 | 上海创诺制药有限公司 | A kind of preparation method of small specific surface product Pa Boxini free alkalis |
WO2019224194A1 (en) | 2018-05-24 | 2019-11-28 | Synthon B.V. | A process for making palbociclib |
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WO2022091001A1 (en) | 2020-10-29 | 2022-05-05 | Pfizer Ireland Pharmaceuticals | Process for preparation of palbociclib |
Citations (4)
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US20030149001A1 (en) * | 2002-01-22 | 2003-08-07 | Mark Barvian | 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
US20080021037A1 (en) * | 2003-07-11 | 2008-01-24 | Pfizer Inc. | Isethionate salt of a selective cdk4 inhibitor |
WO2008032157A2 (en) * | 2006-09-08 | 2008-03-20 | Pfizer Products Inc. | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
CN104447739A (en) * | 2014-11-07 | 2015-03-25 | 郑州泰基鸿诺药物科技有限公司 | Deuterated palbociclib derivative, and preparation method and application thereof |
-
2015
- 2015-07-21 EP EP15826397.0A patent/EP3174878A4/en not_active Withdrawn
- 2015-07-21 WO PCT/IB2015/055528 patent/WO2016016769A1/en active Application Filing
- 2015-07-21 US US15/500,616 patent/US20170217962A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US20030149001A1 (en) * | 2002-01-22 | 2003-08-07 | Mark Barvian | 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
US20080021037A1 (en) * | 2003-07-11 | 2008-01-24 | Pfizer Inc. | Isethionate salt of a selective cdk4 inhibitor |
WO2008032157A2 (en) * | 2006-09-08 | 2008-03-20 | Pfizer Products Inc. | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
CN104447739A (en) * | 2014-11-07 | 2015-03-25 | 郑州泰基鸿诺药物科技有限公司 | Deuterated palbociclib derivative, and preparation method and application thereof |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108017630A (en) * | 2016-10-31 | 2018-05-11 | 上海创诺制药有限公司 | A kind of preparation method of small specific surface product Pa Boxini free alkalis |
CN108017630B (en) * | 2016-10-31 | 2022-10-11 | 上海创诺制药有限公司 | Preparation method of small-specific-surface-area palbociclib free base |
WO2019224194A1 (en) | 2018-05-24 | 2019-11-28 | Synthon B.V. | A process for making palbociclib |
EP4289844A2 (en) | 2018-05-24 | 2023-12-13 | Synthon B.V. | A process for making palbociclib |
US11858928B2 (en) | 2018-05-24 | 2024-01-02 | Synthon B.V. | Process for making palbociclib |
Also Published As
Publication number | Publication date |
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EP3174878A1 (en) | 2017-06-07 |
US20170217962A1 (en) | 2017-08-03 |
WO2016016769A8 (en) | 2016-03-24 |
EP3174878A4 (en) | 2017-12-27 |
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