Orforglipron Intermediate N-4

Appearance: Off-white to light yellow crystalline powder; slight yellow discoloration may occur when purity is below 99.0%; chiral impurities can affect crystal regularity.

Solubility: Easily soluble in dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), soluble in ethyl acetate and tetrahydrofuran (THF), slightly soluble in methanol and ethanol, and poorly soluble in water and n-hexane; purification is achieved by ethyl acetate-n-hexane gradient recrystallization, which effectively removes diastereomeric impurities.

Stability: Store in a sealed container, protected from light, at 2-8℃; shelf life is 12 months; the carboxylic acid group is prone to acylation reactions, the cyano group is easily hydrolyzed to form an amide under strongly alkaline conditions, and the cyclopropyl group has a risk of ring opening in strong acids; solutions require nitrogen protection to prevent oxidation leading to indole ring degradation. Key Quality Control Indicators

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

Chiral Purity: ≥99.8% ee (Chiral SFC, Chiralpak IA column)

Moisture Content: ≤0.3% (Karl Fischer method)

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

Residual Solvents: Complies with ICH Q3C Class 2 solvent limits (ethyl acetate ≤0.5%)

III. Synthesis Route and Process Highlights

The synthesis of N-4 starts with the intermediate M-6 of ofloxacin, prepared through two core reaction steps. The specific route is as follows:

Indole N-Chiral Cyclopropylation: The indole N-H of M-6 undergoes a nucleophilic substitution reaction with (1S,2S)-1-cyano-2-methylcyclopropyl bromide under alkaline conditions; Cs₂CO₃ is used as the base (weak alkalinity to avoid deprotonation of the carboxylic acid group), the reaction solvent is anhydrous DMF, the temperature is controlled at 25-30℃, and the reaction time is 6-8 hours; this step is critical for chiral control and requires strict control of the cyclopropyl bromide feed ratio (1.05 eq) to avoid the formation of polysubstituted impurities.

Ester Hydrolysis to Carboxylic Acid: The methyl ester group of the intermediate is hydrolyzed in a LiOH/THF-H₂O system (volume ratio 3:1) at 0-5℃ for 2 hours; the solid is precipitated by acidification to pH=2-3, filtered, and recrystallized; this step requires avoiding high temperatures to prevent cyclopropyl ring opening and racemization of the chiral center.

Post-treatment and Purification: The crude product is dissolved in ethyl acetate, washed with saturated saline solution, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then recrystallized with ethyl acetate-n-hexane (1:4). The yield is approximately 68%-75% (laboratory process), and the chiral purity is ≥99.8% ee.