ChemicalBook CAS DataBase List Ribociclib

Ribociclib synthesis

10synthesis methods

Product Name:Ribociclib
CAS Number:1211441-98-3
Molecular formula:C23H30N8O
Molecular Weight:434.54

Ribociclib Free Base, also known as LEE011, is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. CDK4/6 inhibitor LEE011 specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation. Synthetic Description Reference: Reddy, Peddireddy Subba; Kumar, Kottur Mohan; Oruganti, Srinivas; Kandagatla, Bhaskar; Das Gupta, Shirshendu. Process for preparation of Ribociclib and its acid addition salts. WO 2018051280. (PCT Int. Appl. (2018)) Synthetic Description Reference: Xu, Xuenong. Process for preparation of Ribociclib intermediate. WO 2016192522. (PCT Int. Appl. (2016)) Synthetic Description Reference: Calienni, John Vincent; Chen, Guang-Pei; Gong, Baoqing; Kapa, Prasad Koteswara; Saxena, Vishal. 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. US 20160039832. (U.S. Pat. Appl. Publ. (2016)) Synthetic Description Reference: Calienni, John Vincent; Chen, Guang-Pei; Gong, Baoqing; Kapa, Prasad Koteswara; Saxena, Vishal. 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. US 20120115878 (U.S. Pat. Appl. Publ. (2012)) Synthetic Description Reference: Borland, Maria; Brain, Christopher Thomas; Doshi, Shivang; Kim, Sunkyu; Ma, Jianguo; Murtie, Josh; Zhang, Hong. Combination comprising a cyclin dependent kinase 4 or cyclin dependent kinase (cdk4/6) inhibitor and an Mtor inhibitor for treating cancer. WO 2011130232. (PCT Int. Appl. (2011)) Synthetic Description Reference: Besong, Gilbert; Brain, Christopher Thomas; Brooks, Clinton A.; Congreve, Miles Stuart; Dagostin, Claudio; He, Guo; Hou, Ying; Howard, Steven; Li, Yue; Lu, Yipin; et al. Preparation of pyrrolopyrimidine compounds as CDK inhibitors. WO 2010020675. (PCT Int. Appl. (2010))

Synthetic Routes

ROUTE 1

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ROUTE 6

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ROUTE 8

ROUTE 9

ROUTE 10

Reference: Reddy, Peddireddy Subba; Kumar, Kottur Mohan; Oruganti, Srinivas; Kandagatla, Bhaskar; Das Gupta, Shirshendu. Process for preparation of Ribociclib and its acid addition salts. WO 2018051280. (PCT Int. Appl. (2018))

1-Piperazinecarboxylic acid, 4-[6-[[7-cyclopentyl-6-[(diMethylaMino)carbonyl]-7H-pyrrolo[2,3-d]pyriMidin-2-yl]aMino]-3-pyridinyl]-, 1,1-diMethylethyl ester

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1211441-98-3
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Yield:1211441-98-3 98.8%

Reaction Conditions:

with phosphoric acid in dichloromethaneReagent/catalyst;

Steps:

1.6 (6) Preparation of Ribociclib (X)
The above-obtained intermediate 7-cyclopentyl-N,N-dimethyl-2-{[5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazolePyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (IX) (5.353 g, 10 mmol) is dissolved in 30 ml of dichloromethanThe alkane solution was added with 15 ml of hydrochloric acid (2 mol/L) and stirred at room temperature for 1 h. The reaction was stopped and then distilled under reduced pressure. The resulting concentrate was dissolved in 5 ml of ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate to pH. 7-8, the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The resulting concentrate was recrystallized with n-hexane and vacuum dried to give Rebsini (a white solid product). X) 4.26 g; Yield 98.0%; Purity 99.8% (HPLC area normalization method); (6) Preparation of Rebocini (X)The difference with Example 1 is that the acid used is phosphoric acid.The final white solid product, rebamizin (X) 4.32 g; yield 98.8%; purity 99.8% (HPLC areaNormalization);

References:

Nanjing Qike Pharmaceutical Co., Ltd.;Wu Xueping;Xing Jigang;Chu Yijie;Yan Dongyang CN107936029, 2018, A Location in patent:Paragraph 0047; 0061-0062; 0078-0079; 0094-0096

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1003-03-8 Synthesis