Synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines
Inventors
Smith, Alexander • White, Hannah S. • Tavares, Francis Xavier • Krasutsky, Sergiy • Chen, Jian-Xie • Dorrow, Roberta L. • Zhong, Hua
Assignees
Pharma Advance Inc • Pharmacosmos Holding AS • Pharmacosmos AS • Kalexsyn Inc • Curia Global Inc
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Publication Number
US-11629150-B2
Publication Date
2023-04-18
Expiration Date
Abstract
This invention is in the area of synthesizing pyrimidine-based compounds useful in the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
Core Innovation
The patent describes compounds of Formula II that include a lactam ring bearing a spiro-connected carbocycle of 3 to 8 carbons. The structure is further characterized by substituent groups R1, R2, and R5 selected from enumerated chemical classes, and the disclosure includes related Formula IIA to IID examples and spirocyclic lactam scaffolds such as 1,4-diazaspiro[5.5]undecan-3-one.
The disclosure provides synthetic routes for producing lactam-pyrrolo[2,3-d]pyrimidine derivatives and related intermediates, including 2'-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[2,3-d]pyrimidines and 2'-(heteroaryl)-lactam-pyrrolo[2,3-d]pyrimidines. It describes transformations among Formula I to IV and related formula-based linkages, including hydroxy-to-leaving-group conversion, leaving-group displacement, dehydration, intramolecular cyclization, and optional oxidation or deoxidation.
The patent also describes preparation of diazaspiro[5.5]undecan-3-ones via cyano-to-amine reduction and cyclization and via an alkyl 2-oxoacetate route. It states that illustrative compounds can be synthesized, includes general analytical characterization references such as HPLC, NMR, and mass spectrometry, and references use in synthesis of CDK inhibitors.
Claims Coverage
The consolidated claim coverage centers on one independent compound class, Formula II, with a spiro-fused 3 to 8 carbon carbocycle connected to a lactam ring and three defined substituent positions. Dependent claims further narrow the scope to specific depicted alternative chemical structures referenced in the claim images (CHEM-US-00084).
Spiro-fused lactam with 3 to 8 carbon carbocycle
A compound of Formula II wherein a carbocycle of 3 to 8 carbons is connected in a spiro-fashion to the lactam ring.
Restricted R1 substituent class
R1 is selected from alkyl, aryl, haloalkyl, and arylalkyl.
Restricted R2 substituent class
R2 is selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl.
Restricted R5 substituent class
R5 is selected from hydrogen, halogen, —N(alkyl)(alkoxy), —NCH3OMe, alkoxy, aryloxy, —OCH2aryl, —OC(O)alkyl, —OC(O)aryl, and —OC(O)arylalkyl.
Selection from depicted chemical alternatives
The compound of Formula II is selected from the specific compound structures shown in the claim images (CHEM-US-00084).
Overall, the claim set focuses on a spiro-fashion lactam scaffold with a 3 to 8 carbon carbocycle and tightly enumerated substituent classes at R1, R2, and R5, and further restricts the covered compounds to specific depicted chemical alternatives referenced as CHEM-US-00084.
Stated Advantages
Improved crystallization/purification behavior in the ester route versus the aldehyde route.
Ester route avoids need for column chromatography described as necessary in the aldehyde route.
Reduced impurity formation in the ester route as compared to the aldehyde route.
Improved yield by reducing nitrile prior to glycinate addition.
Limits di-Boc formation by performing Boc protection at −270 °C.
Demonstrated kilogram scale for the Ti(Oi-Pr)4/TMSCN step and conversion from compound 24 to spirolactam.
Crystallization-based isolations without silica chromatography for scalability.
Workup purges residual palladium, with a reduction in reported residual palladium from an earlier intermediate to the final spirolactam salt form.
Documented Applications
The compounds are used in synthesis of CDK inhibitors.
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