WO2019166987A1 - A process for the preparation of ribociclib and its intermediates - Google Patents
A process for the preparation of ribociclib and its intermediates Download PDFInfo
- Publication number
- WO2019166987A1 WO2019166987A1 PCT/IB2019/051625 IB2019051625W WO2019166987A1 WO 2019166987 A1 WO2019166987 A1 WO 2019166987A1 IB 2019051625 W IB2019051625 W IB 2019051625W WO 2019166987 A1 WO2019166987 A1 WO 2019166987A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- process according
- palladium
- copper
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000008569 process Effects 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 title abstract description 14
- 229950003687 ribociclib Drugs 0.000 title abstract description 14
- 239000000543 intermediate Substances 0.000 title abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 15
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims description 15
- 230000008878 coupling Effects 0.000 claims description 14
- 238000010168 coupling process Methods 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 14
- 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 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 5
- NHANOMFABJQAAH-UHFFFAOYSA-N butanedioic acid;7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound OC(=O)CCC(O)=O.N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 NHANOMFABJQAAH-UHFFFAOYSA-N 0.000 claims description 5
- 239000003426 co-catalyst Substances 0.000 claims description 5
- 229950010518 ribociclib succinate Drugs 0.000 claims description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 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
- 239000002904 solvent Substances 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
- 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 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 108091008039 hormone receptors Proteins 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-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
- 238000007605 air drying Methods 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 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
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- 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
Definitions
- ambient temperature refers to the temperature in the range of 25°C to 35°C.
- a second aspect of the present invention provides a process of the preparation of ribociclib of Formula la,
- the solvent is selected from ethers, esters, water or mixture thereof.
- ether solvents include tetrahydrofiiran, 2-methy tetrahydrofiiran, l,4-dioxane,
- ester solvents include ethyl acetate, and butyl acetate.
- the coupling of the compound of Formula III with propargyl alcohol is carried out at a temperature from about ambient temperature to about 70°C. In an embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out at a temperature from about 40°C to about 65 °C. In another embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out at a temperature from about 45°C to about 60°C. In another embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out at a temperature from about 50°C to about 55°C.
- the compound of Formula II may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and 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.
- ribociclib of Formula la is converted to ribociclib succinate of Formula I by general processes known in the art, for example, as disclosed in Handbook of
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a process for the preparation of ribociclib and its intermediates.
Description
A PROCESS FOR THE PREPARATION OF RIBOCICLIB AND ITS
INTERMEDIATES
Field of the Invention
The present invention relates to a process for the preparation of ribociclib and its intermediates.
Background of the Invention
Ribociclib succinate chemically is butanedioic acid-7-cyclopentyl-/V. /V-di methyl - 2- { [5 -(piperazin- 1 -yl) pyridin-2-yl]amino } -7//-pyrrolo [2,3 -d]pyrimidine-6-carboxamide (1/1), represented by Formula I.
Formula I
Ribociclib is a kinase inhibitor indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)- negative advanced or metastatic breast cancer.
U.S. Patent No. 8,415,355 describes a process for the preparation of ribociclib.
U.S. Patent No. 9,193,732 allegedly discloses crystalline forms of ribociclib succinate and processes thereof.
PCT Publication No. WO2016192522 describes a process for the preparation of ribociclib.
Summary of the Invention
The present invention relates to the processes for the preparation of ribociclib and its intermediates. The present invention provides an environmentally friendly, cost- effective, and industrially advantageous process for the preparation of ribociclib and its intermediates. The present invention provides the compound of Formula II in high purity.
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“ambient temperature,” as used herein, refers to the 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 II,
Formula II
comprising coupling of a compound of Formula III
Formula III
with propargyl alcohol in the presence of a palladium catalyst, a ligand, a copper (I) co catalyst and a base.
A second aspect of the present invention provides a process of the preparation of ribociclib of Formula la,
Formula la
compnsmg
a) coupling a compound of Formula III
Formula III
with propargyl alcohol in the presence of a palladium catalyst, a ligand, a copper (I) co catalyst and a base to obtain a compound of Formula II; and
Formula II
b) converting the compound of Formula II to ribociclib of Formula la.
In an embodiment, the ribociclib of Formula la can be converted to ribociclib succinate of Formula I.
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.
In an embodiment, the coupling of the compound of Formula III with propargyl alcohol to obtain the compound of Formula II is carried out in the presence of a palladium catalyst, a ligand, a copper (I) co-catalyst and a base in a solvent.
The palladium catalyst is selected from palladium on carbon (Pd/C),
tetrakis(triphenylphosphine)palladium (0), palladium acetate, palladium chloride, trans- dichlorobis(acetonitrile)palladium (II), tris(dibenzylideneacetone)dipalladium(0) and [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane complex.
The ligand is selected from bis-[2-(diphenylphosphino)phenyl]ether, [1,1'- bis(diphenylphosphino)ferrocene], triphenylphosphine, and tri(o-tolyl)phosphine.
The copper catalyst is selected from copper (I) iodide, copper (I) bromide, and copper (I) chloride.
The base is an organic base or an inorganic base. Examples of organic bases include triethylamine, diisopropylethylamine, and n-butylamine. Examples of inorganic bases include potassium carbonate, sodium carbonate, and lithium carbonate.
The solvent is selected from ethers, esters, water or mixture thereof. Examples of ether solvents include tetrahydrofiiran, 2-methy tetrahydrofiiran, l,4-dioxane,
diisopropylether, and methyl tert- butyl ether. Examples of ester solvents include ethyl acetate, and butyl acetate.
The coupling of the compound of Formula III with propargyl alcohol is carried out for about one hour to about 10 hours. In an embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out for about 1.5 hours to about 8 hours. In another embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out for about 2 hours to about 7 hours. In another embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out for about 4 hours to about 6 hours.
The coupling of the compound of Formula III with propargyl alcohol is carried out at a temperature from about ambient temperature to about 70°C. In an embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out at a temperature from about 40°C to about 65 °C. In another embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out at a temperature from about 45°C to about 60°C. In another embodiment, the coupling of the compound of Formula III with propargyl alcohol is carried out at a temperature from about 50°C to about 55°C.
The compound of Formula II may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and 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 III is converted to ribociclib of Formula la by method known in the art, for example, the method described in U.S. Patent No. 8,415,355.
The ribociclib of Formula la is converted to ribociclib succinate of Formula I by general processes known in the art, for example, as disclosed in Handbook of
Pharmaceutical Salts Properties, Selection and Use, By P.H. Stahl and C.G. Wermuth (Eds.),VHCA, Zurich 2002.
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.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
Methods
Chromatographic purity was determined by HPLC using an Agilent® Model 1200; the column used was an ACE® C18-PFP (150 x 4.6 nm).
EXAMPLES
Example 1: Preparation of 3-r2-chloro-4-(cvclopentylaminotpyrimidin-5-yl1prop-2-vn-l- ql
5-Bromo-2-chloro-/V-cyclopentylpyrimidin-4-amine (50 g) was added to tetrahydrofuran (THF) (350 mL) under nitrogen atmosphere to obtain a solution. Bis-[2- (diphenylphosphino)phenyl] ether (DPE-Phos) (14.6 g) was added to the solution followed by diisopropylethylamine (DIPEA), palladium on carbon (Pd/C) (2.5 loading, dry weight 71.6 g), cuprous iodide (Cul) (5.16 g) with THF (50 mL) to obtain a reaction mixture. The reaction mixture was stirred for 10 minutes at room temperature. Propargyl alcohol (20 g)
was added to the reaction mixture and then heated to reflux for 5.5 hours. DPE-Phos (4.8 g) was again added to the reaction mixture and then heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and then filtered over Hyflo® bed. The Hyflo® bed was washed with THF and ethyl acetate (1 : 1; 200 mL) to obtain a filtrate. The filtrate was stirred with 5% bisulphite solution (200 mL) and then concentrated hydrochloric acid was added until the pH was 2. The organic layer was stirred with activated carbon (10 g) and filtered over Hyflo® bed. The Hyflo® bed was washed with THF and ethyl acetate (1 : 1; 150 mL) to obtain a filtrate. The filtrate was concentrated to a brown residue and taken into ethyl acetate (150 mL). The residue was stirred at 0°C to 5°C for 30 minutes and then filtered to obtain a solid. The solid was washed with cold ethyl acetate (30 mL) and then dried under vacuum to obtain the title compound.
Yield: 74.5 %
HPLC Purity: 98.36 %
Claims
1. A process for the preparation of a compound of Formula II,
Formula II
comprising coupling of a compound of Formula III
Formula III
with propargyl alcohol in the presence of a Palladium catalyst, a ligand, a Copper (I) co catalyst and a base.
2. The process according to claim 1, wherein the palladium catalyst is selected from palladium on carbon (Pd/C), tetrakis(triphenylphosphine)palladium (0), palladium acetate, palladium chloride, trans-dichlorobis(acetonitrile)palladium (II),
tris(dibenzylideneacetone)dipalladium(0) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane complex.
3. The process according to claim 1, wherein the ligand is selected from bis- [2- (dipheny lphosphino)pheny 1] ether, [1,1 '-bis(diphenylphosphino)ferrocene] ,
triphenylphosphine, and tri(o-tolyl)phosphine.
4. The process according to claim 1, wherein the copper (I) co-catalyst is selected from copper (I) iodide, copper (I) bromide, and copper (I) chloride.
5. The process according to claim 1, wherein the base is selected from an organic base or an inorganic base.
6. The process according to claim 5, wherein the organic base is selected from triethylamine, diisopropylethylamine, and n-butylamine.
7. The process according to claim 1, wherein the coupling of the compound of Formula II with propargyl alcohol is carried out in the presence of a solvent.
8. The process according to claim 7, wherein the solvent is selected from ethers, esters, water or mixture thereof.
9. The process according to claim 1, wherein the coupling of the compound of Formula II with propargyl alcohol is carried out at ambient temperature to a temperature of about 70°C.
10. The process according to claim 1, wherein the compound of Formula II is further converted to ribociclib succinate of Formula I.
Formula I
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201811007525 | 2018-02-28 | ||
| IN201811007525 | 2018-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2019166987A1 true WO2019166987A1 (en) | 2019-09-06 |
Family
ID=67804885
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2019/051625 WO2019166987A1 (en) | 2018-02-28 | 2019-02-28 | A process for the preparation of ribociclib and its intermediates |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2019166987A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024201299A1 (en) | 2023-03-27 | 2024-10-03 | Novartis Ag | Method of treating early breast cancer with ribociclib in combination with an aromatase inhibitor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160039832A1 (en) * | 2010-11-10 | 2016-02-11 | Novartis Ag | Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| CN106478641A (en) * | 2016-10-09 | 2017-03-08 | 杭州科巢生物科技有限公司 | New synthetic method of Ribociclib intermediate |
-
2019
- 2019-02-28 WO PCT/IB2019/051625 patent/WO2019166987A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160039832A1 (en) * | 2010-11-10 | 2016-02-11 | Novartis Ag | Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| CN106478641A (en) * | 2016-10-09 | 2017-03-08 | 杭州科巢生物科技有限公司 | New synthetic method of Ribociclib intermediate |
Non-Patent Citations (2)
| Title |
|---|
| GELMAN ET AL.: "Efficient Palladium-Catalyzed Coupling of Aryl Chlorides and Tosylates with Terminal Alkynes: Use of a Copper Cocatalyst Inhibits the Reaction", ANGEW. CHEM., vol. 42, 2003, pages 5993 - 5996, XP002387107, doi:10.1002/anie.200353015 * |
| LI ET AL.: "Tetrabutylammonium Fluoride", ENCYCLOPEDIA OF REAGENTS FOR ORGANIC SYNTHESIS, 2007 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024201299A1 (en) | 2023-03-27 | 2024-10-03 | Novartis Ag | Method of treating early breast cancer with ribociclib in combination with an aromatase inhibitor |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105503867B (en) | The method for being used to prepare the fluoro- 1H- pyrazolo-pyridines of substituted 5- | |
| CN111386272B (en) | Improved preparation method of Riboxib and salt thereof | |
| US20040162442A1 (en) | Synthesis of 4-(amino)-2-butenoyl chlorides and their use in the preparation of 3-cyano quinolines | |
| WO2016110224A1 (en) | Preparation method for bemaciclib | |
| CN107936029B (en) | Method for synthesizing Ribociclib | |
| CN110606842A (en) | Process for producing pyridylamino pyrimidine derivative and intermediate thereof | |
| WO2019166987A1 (en) | A process for the preparation of ribociclib and its intermediates | |
| US20160039759A1 (en) | Process for the preparation of perampanel | |
| CN113135840B (en) | Synthetic method of conjugated alkenyl amidine compound | |
| CN115448848A (en) | Preparation method of antifungal compound | |
| CN105294657B (en) | A kind of preparation method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine | |
| CN107759596A (en) | A kind of synthesis Pa Boxini method | |
| WO2024017150A1 (en) | Method for synthesizing deucravacitinib | |
| CA2491464A1 (en) | Process for preparation of 1,3-benzodioxole-2-spiro- cycloalkane derivatives | |
| US20130123501A1 (en) | Process for the preparation of the compound osi-906 | |
| MX2011003529A (en) | Thiazolyl-pyrazolopyrimidine compounds as synthetic intermediates and related synthetic processes. | |
| KR20140042805A (en) | Intermediate for synthesizing caspofungin and preparation method therefor | |
| CN115141180A (en) | Preparation method of ruxotinib intermediate | |
| US20170217962A1 (en) | A process for the preparation of palbociclib | |
| CN106008499B (en) | A kind of method for preparing CDK46 kinase inhibitors Pa Boxini | |
| WO2023151359A1 (en) | Tetrahydrocarbazole derivative as well as preparation method therefor and use thereof | |
| CN103896889B (en) | Lapatinib intermediate and its preparation method and application | |
| JPH038330B2 (en) | ||
| KR20210131374A (en) | Method for preparing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide | |
| CN118930551B (en) | Process for preparing beta-aminopyrazine acetate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19761457 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 19761457 Country of ref document: EP Kind code of ref document: A1 |