CN108314686A - A kind of novel Ribociclib preparation methods - Google Patents
A kind of novel Ribociclib preparation methods Download PDFInfo
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- CN108314686A CN108314686A CN201710033354.XA CN201710033354A CN108314686A CN 108314686 A CN108314686 A CN 108314686A CN 201710033354 A CN201710033354 A CN 201710033354A CN 108314686 A CN108314686 A CN 108314686A
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- 0 CN(C)C(c([n]1C2CCCC2)cc2c1nc(Nc(cc1)ncc1N1CC*CC1)nc2)=O Chemical compound CN(C)C(c([n]1C2CCCC2)cc2c1nc(Nc(cc1)ncc1N1CC*CC1)nc2)=O 0.000 description 1
- RHXHGRAEPCAFML-UHFFFAOYSA-N CN(C)C(c([n]1C2CCCC2)cc2c1nc(Nc(cc1)ncc1N1CCNCC1)nc2)=O Chemical compound CN(C)C(c([n]1C2CCCC2)cc2c1nc(Nc(cc1)ncc1N1CCNCC1)nc2)=O RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 1
- TXPSNWJFOBWSCB-UHFFFAOYSA-N Cc(nc1)nc(Cl)c1Br Chemical compound Cc(nc1)nc(Cl)c1Br TXPSNWJFOBWSCB-UHFFFAOYSA-N 0.000 description 1
- UZMLULJYXUSYGQ-UHFFFAOYSA-N Cc(nc1)nc(NC2CCCC2)c1Br Chemical compound Cc(nc1)nc(NC2CCCC2)c1Br UZMLULJYXUSYGQ-UHFFFAOYSA-N 0.000 description 1
- LXXICMDQPANETK-UHFFFAOYSA-N Cc1nc([n](C2CCCC2)c(CO)c2)c2cn1 Chemical compound Cc1nc([n](C2CCCC2)c(CO)c2)c2cn1 LXXICMDQPANETK-UHFFFAOYSA-N 0.000 description 1
- XGJZMLQVYTXTTN-UHFFFAOYSA-N Cc1ncc(CO)c(NC2CCCC2)n1 Chemical compound Cc1ncc(CO)c(NC2CCCC2)n1 XGJZMLQVYTXTTN-UHFFFAOYSA-N 0.000 description 1
- UCXGDRAQDIIHEF-UHFFFAOYSA-N Cc1ncc(cc(C(N(C)C)=O)[n]2C3CCCC3)c2n1 Chemical compound Cc1ncc(cc(C(N(C)C)=O)[n]2C3CCCC3)c2n1 UCXGDRAQDIIHEF-UHFFFAOYSA-N 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N NC1CCCC1 Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- VBBGHNGROGZGHG-UHFFFAOYSA-N Nc(cc1)ncc1N1CCNCC1 Chemical compound Nc(cc1)ncc1N1CCNCC1 VBBGHNGROGZGHG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of synthetic method of Ribociclib, specific reaction route is as follows:
Description
Technical field
The present invention relates to the preparation methods of cyclin-dependent kinase (CDK) inhibitor Ribociclib a kind of.
Background technology
Breast cancer is one of the most common malignant tumors in women, and incidence accounts for the 7%~10% of the various malignant tumours of whole body,
It is only second to uterine cancer, it has also become threaten the Etiological of WomanHealth.Its morbidity is often related with heredity, and 40~60 years old exhausted
Women's incidence before and after menstrual period is higher.It is that one kind being usually happened at breast galandular epithelium tissue, and it is strong to seriously affect women's body and mind
Health even one of the malignant tumour of threat to life.
Breast cancer cell period G1/S nodes are it occur frequently that imbalance Pa Bosaibu is a kind of oral CDK4/6 selectively suppressions
Preparation prevents the synthesis of DNA by preventing the cell cycle from from 1 phases of G proceeding to the S phases, can selective depression CDK4/6, it is extensive
Multiple cell cycle control, blocks tumor cell proliferation.Tumor growth stagnation time lengthening can be made to original twice --- by
Original median is increased to median 20 months in 10 months.
Ribociclib, No. CAS:1211441-98-3, chemical name are:7-cyclopentyl-N, N-dimethyl-
2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-d] pyrimidine-6-
Carboxamide, structural formula are as follows:
Ribociclib belongs to the double inhibitor of high degree of specificity Cyclin dependent kinase 4/6, can targeted inhibition D1/
CDK4, D3/CDK6 cell cycle have potential antitumor activity.In vitro test shows that ribociclib can be significantly inhibited
12 kinds of growth in 17 kinds of Human Neuroblastoma Cell Lines, average IC50 are 307nmol/L.The daily gavage of mouse is given
Ribociclib 200mg/kg can significantly postpone the growth of BE2C in Mice Body, 1643 cells, but not influence weight
Variation.On August 3rd, 2016, U.S. FDA authorize CDK4/6 inhibitor Ribociclib and break through sex therapy identification, can combine next bent
Azoles is used for first-line treatment late period or metastatic hormone receptor positive, HER2 negative breast cancers.
For Ribociclib synthesis there are mainly two types of method, first, the route of Novartis enters WO
Described in 2012064805A1:
Pyrimidine compound A1 and cyclopenta amine A2 obtain compound A-13 by nucleophilic aromatic substitution reaction, pass through
Sonogashira reacts, and obtains compound A4, and then cyclisation obtains compound A-45 under alkaline condition, then in MnO2 and
A6 is obtained under conditions of NaCN.Compound A6 and side chain compound A7 obtain chemical combination by Buchwald-Hartwig aminating reactions
Object A8 removes Boc protecting groups in the presence of HCl, obtains compound 1.
Second is that the synthetic route of Suzhou Ming Yue Pharmaceutical Technology Co., Ltd CN201510300181:
Amide compound B1 bromos obtain B2 later, and intermediate B 3 is obtained by the reaction in B2 and the third dicyan, and cyclization obtains pyrrole to B3 again
It coughs up derivative B4, B4 and obtains nitrogen substituted compound B5, B5 again with side chain guanidine derivatives B6 cyclizations up to mesh through alkylated reaction
Mark product 1.
Invention content
Few, high yield that the present invention provides a kind of steps, the preparation method of safety and environmental protection.
Technical solution of the present invention is as follows:
Formula (2) compound and formula (3) compound are dissolved in tetrahydrofuran, benzene,toluene,xylene, dimethylformamide, second
Nitrile, dioxane the solvent that is formed of one or more in after in sodium hydroxide, potassium hydroxide, sodium tert-butoxide, tertiary fourth
Potassium alcoholate, sodium carbonate, sodium bicarbonate, triethylamine, 1,8- diazabicylos [5.4.0], 11 carbon -7- alkene (DBU), piperidines, pyridine,
Formula (4) compound is obtained under the organic bases such as quinoline, inorganic base effect, and reaction temperature is -20-160 DEG C, preferably 60-120 DEG C, formula
(2) molar ratio of compound and formula (3) compound is 0.1-10: 1, preferably 0.5-2: 1, and the alkali and formula (3) compound are rubbed
You are than being 0.1-10: 1, preferably 0.5-2: 1.
Formula (4) compound is dissolved in tetrahydrofuran, methanol, ethyl alcohol, benzene,toluene,xylene, dimethylformamide, acetonitrile, two
After in the solvent that one or more of oxinane is formed sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide,
Potassium tert-butoxide, sodium carbonate, sodium bicarbonate, butyl lithium, diisopropylamine lithium, triethylamine, 1,8- diazabicylos [5.4.0] 11
The organic bases such as carbon -7- alkene (DBU), piperidines, pyridine, quinoline, inorganic base effect are lower that formula (5) compound, reaction temperature are -20-
105 DEG C, preferably 20-60 DEG C.
Formula (5) compound be dissolved in chloroform, dichloromethane, acetonitrile, dioxane one or more formed it is molten
After agent (6) compound is obtained under the effect of the oxidants such as first chloroperoxybenzoic acid, hydrogen peroxide, manganese dioxide, periodic acid.Reaction
Temperature is -20-160 DEG C, preferably 60-120 DEG C.
Formula (6) compound is dissolved in benzene,toluene,xylene, dimethylformamide, dimethyl sulfoxide, glycol dimethyl ether, diethyl
Glycol dimethyl ether, acetonitrile, dioxane, tetrahydrofuran the solvent that is formed of one or more after in sodium hydroxide, hydrogen
Potassium oxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, triethylamine, 1,8- diazabicylos [5.4.0], 11 carbon-
The organic bases such as 7- alkene (DBU), piperidines, pyridine, quinoline, inorganic base effect is lower and formula (8) chemical combination is made in side chain compound (7) coupling
Object, reaction temperature are -20-160 DEG C;It is preferred that 60-120 DEG C, the molar ratio of formula (5) compound and side chain compound is 0.1-10:
1, preferably 0.5-2: 1.
Formula (8) compound is dissolved in methanol, ethyl alcohol, n-butanol, benzene,toluene,xylene, dimethylformamide, acetonitrile, dioxy
After the solvent that the one or more of azacyclohexane are formed hydrochloric acid, acetic acid, the trifluoracetic acid the effects that under target compound is made
(1), reaction temperature is -20-50 DEG C.
According to the technique and scheme of the present invention, the amount ratio of preferred processing condition and substance is as follows in each step:
Preferably, in step (1):The solvent be tetrahydrofuran, benzene,toluene,xylene, dimethylformamide, acetonitrile,
The solvent that the one or more of dioxane are formed.It is preferred that tetrahydrofuran;
The alkali be sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, triethylamine, 1,
11 carbon -7- alkene (DBU) of 8- diazabicylos [5.4.0], piperidines, pyridine, quinoline, preferably sodium hydroxide, potassium tert-butoxide, three second
Amine;
Reaction temperature is -20-160 DEG C, preferably 60-120 DEG C, and the molar ratio of formula (2) compound and formula (3) compound is
The molar ratio of 0.1-10: 1, preferably 0.5-2: 1, the alkali and formula (3) compound is 0.1-10: 1, preferably 0.5-2: 1;
Preferably, in step (2), the solvent is tetrahydrofuran, methanol, ethyl alcohol, benzene,toluene,xylene, dimethyl methyl
The solvent that one or more of amide, acetonitrile, dioxane are formed, preferably methanol, ethyl alcohol;
The catalyst is sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, bicarbonate
Sodium, butyl lithium, diisopropylamine lithium, triethylamine, 1,8- diazabicylos [5.4.0], 11 carbon -7- alkene (DBU), piperidines, pyrrole
Pyridine, quinoline, preferably sodium methoxide, sodium ethoxide;Reaction temperature is -20-140 DEG C, preferably 20-80 DEG C;
Preferably, in step (3), the solvent is one kind or several of chloroform, dichloromethane, acetonitrile, dioxane
The formed solvent of kind.Preferably dichloromethane, acetonitrile;
The oxidant is first chloroperoxybenzoic acid, hydrogen peroxide, manganese dioxide, periodic acid, preferably first chlorine peroxide benzene first
Acid, hydrogen peroxide;
The molar ratio of oxidant and formula (5) compound is 0.1-10: 1, preferably 0.5-2: 1;
Reaction temperature is -20-160 DEG C, preferably 0-60 DEG C.
Preferably, in step (4), the solvent is benzene,toluene,xylene, dimethylformamide, dimethyl sulfoxide, second two
The solvent that is formed of one or more of diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, dioxane, tetrahydrofuran.It is excellent
It is selected as dimethyl sulfoxide, toluene;
The alkali be sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, triethylamine, 1,
Organic bases, the inorganic bases such as 11 carbon -7- alkene (DBU) of 8- diazabicylos [5.4.0], piperidines, pyridine, quinoline;
Formula (6) compound is 0.1-10: 1, preferably 0.5-2: 1 with side chain compound (7) molar ratio
Reaction temperature is -20-160 DEG C, preferably 20-120 DEG C.
Preferably, in step (5), the solvent is methanol, ethyl alcohol, n-butanol, benzene,toluene,xylene, dimethyl formyl
The solvent that is formed of one or more of amine, acetonitrile, dioxane, preferably methanol, toluene;
The acid is hydrochloric acid, acetic acid, trifluoracetic acid etc., preferably hydrochloric acid;
Reaction temperature is -78-160 DEG C, preferably -20-120 DEG C.
The technical characterstic and excellent beneficial effect of the present invention:
The present invention obtains target product using simple reagent as starting material, by cyclization, oxidation, coupling, deprotection reaction
(1), it is involved in the present invention to synthesis strategy have raw material is easy to get, step is short, high income, easy to operate, safety and environmental protection, be conducive to
Industrialized production reduces production cost.
Specific implementation mode
The example in detail present invention is once combined, but the present invention is not only limited to this.Its object is to allow be familiar with this
The personage of item technology can understand present disclosure, and it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent change or modification that Spirit Essence is done should be all included within the scope of the present invention.
Case study on implementation is raw materials used and reagent is commercial product." % " described in embodiment is matter unless otherwise specified
Measure percentage.
Embodiment 1:2-(cyclopentyl(5-formyl-2-(methylthio)pyrimidin-4-yl)amino)-
The preparation of N, N-dimethylacetamide (compound 4)
18.8 g of compound 2 (100mmol), 18.7 g of compound 3 (110mmol) are added into 1000ml round-bottomed flasks,
500ml anhydrous tetrahydro furans, 10.1 grams of triethylamines (100mmol), react at room temperature.TLC detects raw material compound 2, and the reaction was complete
Stop reaction afterwards, solvent is recovered under reduced pressure and obtains yellow solid, petrol ether/ethyl acetate recrystallizes to obtain 28.0 grams of faint yellow solids, receives
Rate 90%.
Embodiment 2:7-cyclopentyl-N, N-dimethyl-2- (methylthio) -7H-pyrrolo [2,3-d]
The preparation of pyrimidine-6-carboxamide (compound 5)
Be added 16 g of compound 4 (50mmol) into 500ml round-bottomed flasks, 6.8 grams of sodium ethoxides (100mmol), 200ml without
Water-ethanol, back flow reaction, TLC, which is detected after raw material disappears, stops reaction, depressurizes the grease of lower recycling design, adds water, acetic acid
Each 1500ml extractions of ethyl ester, are extracted twice combined ethyl acetate layer, depressurize lower recycling ethyl acetate and obtain faint yellow product, oil
Ether/re-crystallizing in ethyl acetate obtains 12 g of compound 5, yield 80%.
Embodiment 3:7-cyclopentyl-N, N-dimethyl-2- (methylsulfonyl) -7H-pyrrolo [2,3-
D] pyrimidine-6-carboxamide (compound 6) preparation
15.2 g of compound 5 (50mmol), 13.2 gram of 65% metachloroperbenzoic acid are added into 500ml round-bottomed flasks
(100mmol), 200ml dichloromethane, reacts at room temperature.TLC detection compounds (5) stop reaction after disappearing.Add water 100ml
It is extracted twice, combined dichloromethane layer, recycling design obtains yellow solid petrol ether/ethyl acetate recrystallization and must produce twice under depressurizing
11 grams of object (compound 6), yield 80%.
Embodiment 4:tert-butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-
Pyrrolo [2,3-d] pyrimidin-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate (chemical combination
Object 8) preparation
It is added 16.8 g of compound 6 (50mmol) into 500ml round-bottomed flasks, 15.3 grams of side chain compounds 7 (55mmol),
5.5 grams of triethylamines are dissolved in 300 milliliters of tetrahydrofurans, back flow reaction.TLC detection compounds (6) stop reaction after disappearing.It depressurizes back
Solvent is received, each 200ml of water, ethyl acetate is added to be extracted twice, combined ethyl acetate layer, the yellow for depressurizing lower recycling ethyl acetate is consolidated
Body, petrol ether/ethyl acetate recrystallize to obtain 18 grams of product (compound 8), yield 65%.
Claims (6)
1. a kind of synthetic method of Ribociclib (compound 1), which is characterized in that the specific route of the synthetic method is such as
Under:
Reaction step is as follows:
1) formula (2) compound and formula (3) compound be dissolved in tetrahydrofuran, benzene,toluene,xylene, dimethylformamide, acetonitrile,
In sodium hydroxide, potassium hydroxide, sodium tert-butoxide, the tert-butyl alcohol after in the solvent that the one or more of dioxane are formed
Potassium, sodium carbonate, sodium bicarbonate, triethylamine, 1,8- diazabicylos [5.4.0], 11 carbon -7- alkene (DBU), piperidines, pyridine, quinoline
Formula (4) compound is obtained under the action of quinoline etc., reaction temperature is -20-120 DEG C;
2) formula (4) compound is dissolved in tetrahydrofuran, methanol, ethyl alcohol, benzene,toluene,xylene, dimethylformamide, acetonitrile, dioxy
In sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, uncle after in the solvent that one or more of azacyclohexane is formed
Butanol potassium, sodium carbonate, sodium bicarbonate, butyl lithium, diisopropylamine lithium, triethylamine, 1,8- diazabicylos [5.4.0] 11
Formula (5) compound is obtained under the effects that carbon -7- alkene (DBU), piperidines, pyridine, quinoline, reaction temperature is -78-140 DEG C;
3) formula (5) compound is dissolved in the solvent that is formed of one or more of chloroform, dichloromethane, acetonitrile, dioxane
(6) compound is obtained under first chloroperoxybenzoic acid, hydrogen peroxide, manganese dioxide, periodic acid effect afterwards, reaction temperature is -20-
160 DEG C, reaction temperature is -20-160 DEG C;
4) formula (6) compound is dissolved in benzene,toluene,xylene, dimethylformamide, dimethyl sulfoxide, glycol dimethyl ether, diethyl two
Diethylene glycol dimethyl ether, acetonitrile, dioxane the solvent that is formed of one or more after be made with side chain compound (7) coupling
Formula (8) compound, reaction temperature are -20-160 DEG C;
5) formula (8) compound is dissolved in methanol, ethyl alcohol, n-butanol, benzene,toluene,xylene, dimethylformamide, acetonitrile, dioxa
After the solvent that the one or more of hexamethylene are formed hydrochloric acid, acetic acid, the trifluoracetic acid the effects that under target compound is made
(1), reaction temperature is -20-50 DEG C.
2. the synthetic method of Ribociclib according to claim 1 a kind of, it is characterised in that step 1) Chinese style (2) chemical combination
The molar ratio of object and formula (3) compound is 0.1-10: 1, and the molar ratio of the alkali and formula (3) compound is 0.1-10: 1.
3. the synthetic method of Ribociclib according to claim 1 a kind of, which is characterized in that the step 2) solvent is
One kind or several in tetrahydrofuran, methanol, ethyl alcohol, benzene,toluene,xylene, dimethylformamide, acetonitrile, dioxane
Kind formed solvent, used catalyst be sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate,
Sodium bicarbonate, butyl lithium, diisopropylamine lithium, triethylamine, 1,8- diazabicylos [5.4.0], 11 carbon -7- alkene (DBU), piperazine
The molar ratio of pyridine, pyridine, quinoline etc., the alkali and formula (4) compound is 0.1-10: 1.
4. the synthetic method of Ribociclib according to claim 1 a kind of, which is characterized in that the step 3) solvent is
The solvent that is formed of one or more of chloroform, dichloromethane, acetonitrile, dioxane, the oxidant are first chlorine peroxide
The molar ratio of benzoic acid, hydrogen peroxide, manganese dioxide, periodic acid etc., the oxidant and formula (5) compound is 0.1-10: 1.
5. the synthetic method of Ribociclib according to claim 1 a kind of, which is characterized in that the step 4) solvent
Benzene,toluene,xylene, dimethylformamide, dimethyl sulfoxide, glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, dioxa
The molar ratio of the solvent that the one or more of hexamethylene are formed, side chain compound (7) and formula (6) compound is 0.1-10: 1.
6. the synthetic method of Ribociclib according to claim 1 a kind of, which is characterized in that the step 5) solvent is
One or more of institutes of methanol, ethyl alcohol, n-butanol, benzene,toluene,xylene, dimethylformamide, acetonitrile, dioxane
The solvent of composition, the acid are hydrochloric acid, acetic acid, trifluoracetic acid etc..
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Cited By (1)
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US10723739B2 (en) | 2018-05-14 | 2020-07-28 | Apotex Inc. | Processes for the preparation of Ribociclib and intermediates thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101945867A (en) * | 2007-12-19 | 2011-01-12 | 安姆根有限公司 | Fused pyridine, pyrimidine and triazine compounds as cell cycle inhibitors |
CN103201275A (en) * | 2010-11-10 | 2013-07-10 | 诺华有限公司 | 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 |
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2017
- 2017-01-18 CN CN201710033354.XA patent/CN108314686A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101945867A (en) * | 2007-12-19 | 2011-01-12 | 安姆根有限公司 | Fused pyridine, pyrimidine and triazine compounds as cell cycle inhibitors |
CN103201275A (en) * | 2010-11-10 | 2013-07-10 | 诺华有限公司 | 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 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US10723739B2 (en) | 2018-05-14 | 2020-07-28 | Apotex Inc. | Processes for the preparation of Ribociclib and intermediates thereof |
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