Orforglipron Intermediate N-8

I. Core Chemical Information

Project Details Chemical Name (1S,2S)-1-Cyano-2-methylcyclopropyl-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-N-methyl-N-phenyl-1H-indole-2-carboxamide Common Synonyms HR2331-N08; Orforglipron N-8; Orforglipron Intermediate N-8 CAS Number 2212021-81-1 Molecular Formula Molecular Weight 441.56 g/mol Structural Features Contains (1S,2S)-cyanomethylcyclopropyl, (4S)-2,2-dimethyltetrahydropyran-4-yl, and N-methyl-N-phenylcarboxamide side chains; the indole core has a tetrahydropyran chiral side chain at the C5 position and a chiral cyclopropyl cyano fragment at the C1 position, with three chiral centers synergistically stabilizing the GLP-1R binding conformation of the final product. Core Function As a key precursor in the synthesis of the final product, it introduces the cyanocyclopropyl-indole core pharmacophore through condensation with an oxadiazolone fragment, and is the last chiral building block for constructing the tricyclic heterocyclic scaffold of Orforglipron.

II. Physical and Quality Control Parameters

Appearance: White to off-white crystalline powder, odorless, non-irritating.

Solubility: Easily soluble in dichloromethane, tetrahydrofuran, and ethyl acetate; soluble in methanol and ethanol; sparingly soluble in n-hexane and water; purification is achieved by recrystallization using ethyl acetate/n-hexane, achieving a purity of over 99.5%.

Stability: Store in a sealed container, protected from light, at 2-8℃, avoiding high temperature, humidity, strong acids, and strong bases; the cyano group is easily hydrolyzed to form an amide, and the cyclopropyl ring is easily opened under strongly acidic conditions; shelf life is approximately 12 months; solutions require nitrogen protection. Key Quality Control Indicators

Chemical Purity: ≥99.5% (HPLC area normalization method, detection wavelength 254 nm)

Chiral Purity: ≥99.5% ee (Chiral HPLC, Chiralpak IC column)

Moisture Content: ≤0.3% (Karl Fischer method)

Heavy Metals (Pb, Cd, Hg, As): ≤5 ppm (ICP-MS)

Residual Solvents: Complies with ICH Q3C standards

III. Synthesis Route and Process Highlights

N-8 is synthesized starting from M-6 through the following steps:

Chiral cyclopropyl group introduction: M-6 undergoes nucleophilic substitution with (S,S)-cyanomethylcyclopropylamine under triethylamine catalysis to generate an indole N1-substituted intermediate. The reaction temperature is controlled at 0-5℃, and the reaction time is approximately 4 hours to avoid racemization.

Tetrahydropyran side chain coupling: The intermediate undergoes Suzuki coupling with (4S)-2,2-dimethyltetrahydropyran-4-boronic acid pinacol ester to introduce the chiral tetrahydropyran side chain.  Pd(dppf)Cl₂ is used as the catalyst, the reaction temperature is 80-90℃, and the yield is approximately 78%.

Formylation and purification: The coupling product undergoes acylation with N-methyl-N-phenylformyl chloride in pyridine to produce crude N-8.  Recrystallization with ethyl acetate/n-hexane yields a product with a purity of ≥99.5% and a chiral purity of ≥99.5% ee.