Orforglipron Intermediate N-1 HCl salt

Physical and Quality Control Parameters

Appearance: White crystalline powder, odorless; a slight yellow color may appear if the chiral purity is below 99.9% ee; excessive free acid impurities can lead to increased hygroscopicity.

Solubility: Easily soluble in methanol, ethanol, and ethyl acetate, soluble in water, slightly soluble in diethyl ether; purification is achieved by recrystallization (solvent system: ethyl acetate - petroleum ether = 1:3), achieving a purity of over 99.9%.

Stability: Stable for 36 months when stored sealed and dry at room temperature; significantly more stable than free N-1; decomposes into (S)-lactic acid and ethanol at high temperatures (>120℃), with chloride ion elimination; avoid contact with strong oxidizing agents and strong bases to prevent structural damage and chiral racemization.

Key Quality Control Indicators

Chemical Purity: ≥99.9% (HPLC area normalization method, C18 column)

Chiral Purity: ≥99.95% ee (Chiral HPLC, Chiralpak AD-H column)

Moisture Content: ≤0.05% (Karl Fischer method)

Specific Rotation: [α]D20 = -22.0°~-23.5° (c=10, methanol)

Isomer Impurity [(R)-ethyl lactate hydrochloride]: ≤0.05% (Chiral HPLC external standard method)

Free Hydrochloric Acid: ≤0.1% (Potentiometric titration method)

Heavy Metals (Pb, Cd, Hg, As): ≤1 ppm (ICP-MS)

III. Synthesis Route and Process Highlights

N-1 HCl salt is prepared from **(S)-ethyl lactate (N-1)** as the raw material through a salt formation reaction. The specific route and key processes are as follows:

Raw Material Pre-treatment: N-1 (purity ≥99.9%, chiral purity ≥99.95% ee) is dehydrated by vacuum distillation, controlling the moisture content to ≤0.03% to prevent water from affecting the crystallinity of the salt during the salt formation reaction. Salt Formation Reaction: Dissolve the pre-treated N-1 in anhydrous ethyl acetate, and slowly bubble dry hydrogen chloride gas into the solution at 0-5℃ until the solution is saturated (pH=2-3).  Stirring and temperature control are necessary during the reaction to prevent local overheating and subsequent racemization, resulting in the formation of a white crystalline precipitate.

Crystallization and Drying:

Continue stirring the reaction mixture for 1-2 hours to ensure complete crystallization, then filter to collect the solid.

Wash the crystals 2-3 times with cold anhydrous ethyl acetate to remove residual free N-1 and hydrochloric acid.

Dry the crystals in a vacuum drying oven at 40℃ for 8 hours. The final yield is approximately 90%, with a chiral purity of ≥99.95% ee.