Orforglipron Intermediate M-2

II. Physical and Quality Control Parameters

Appearance: White to off-white needle-shaped crystals; crystal form purity significantly affects the solubility and selectivity of subsequent reactions.

Solubility: Easily soluble in dichloromethane (DCM) and tetrahydrofuran (THF), soluble in ethyl acetate and toluene, sparingly soluble in n-hexane and water; purification is achieved by recrystallization using ethyl acetate/n-hexane (volume ratio 1:5), with a single recrystallization increasing purity to over 99.5%.

Stability: Store in a sealed container, protected from light, at 2-8℃, avoiding high temperatures and strongly alkaline environments; the oxazolidinone ring is prone to ring-opening hydrolysis at pH > 10, with a shelf life of approximately 18 months; in solution, nitrogen protection is required to prevent oxidation and discoloration.

Key Quality Control Indicators

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

Chiral Purity: ≥99.5% ee (Chiral HPLC, Chiralcel OD-H column)

Moisture Content: ≤0.3% (Karl Fischer method)

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

III. Synthesis Route and Process Highlights

The synthesis of M-2 uses industrial-grade (S)-valine as the starting material, employing the classic Evans chiral auxiliary synthesis process, with the following steps:

Preparation of the chiral oxazolidinone core: (S)-valine reacts with ethyl chloroformate to form a mixed anhydride, which then condenses with N-methylhydroxylamine to form a hydroxamic acid.  Dehydration and ring closure with trifluoroacetic anhydride yields (S)-4-isopropyl-2-oxazolidinone, with a yield of approximately 85%.

Acylation to introduce the brominated benzene ring: Under low temperature (-78℃) and nitrogen protection, the oxazolidinone is deprotonated with n-butyllithium (n-BuLi), followed by nucleophilic addition with 4-bromophenylacetyl chloride. The reaction temperature is controlled to not exceed -60℃ to avoid racemization. Post-processing and purification: The reaction mixture was quenched with saturated ammonium chloride solution, extracted with DCM, and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by recrystallization, yielding a final product with approximately 72% yield and a chiral purity of ≥99.5% ee.