Orforglipron Intermediate N-1

Physical and Quality Control Parameters

Appearance: Colorless, transparent, and clear liquid with a slight fruity odor; slight turbidity may occur when the chiral purity is below 99.9% ee.

Solubility: Miscible with organic solvents such as ethanol, ethyl acetate, tetrahydrofuran (THF), and dichloromethane (DCM); soluble in water (solubility approximately 15 g/100 mL, 25℃); purification is achieved by precision fractional distillation (theoretical plates ≥50), collecting the 154-155℃ atmospheric pressure fraction, achieving a purity of over 99.9%.

Stability: Stable for 24 months when stored sealed at room temperature and protected from light; the hydroxyl group is easily oxidized to ethyl pyruvate, and the ester group can be hydrolyzed to (S)-lactic acid under strongly alkaline conditions; avoid contact with strong oxidizing agents, strong acids, and strong bases to prevent racemization of the chiral center or structural damage.

Key Quality Control Indicators

Chemical Purity: ≥99.9% (GC area normalization method, FID detector)

Chiral Purity: ≥99.95% ee (Chiral GC, Cyclodex β-236M-19 column)

Moisture Content: ≤0.03% (Karl Fischer method)

Optical Rotation: [α]D20 = -25.0°~-26.5° (c=10, ethanol)

Isomer Impurities [(R)-ethyl lactate]: ≤0.05% (Chiral GC external standard method)

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

III. Synthesis Route and Process Highlights

The synthesis of N-1 ((S)-ethyl lactate) uses L-lactic acid prepared by biomass fermentation as the raw material, followed by an esterification reaction. The specific route and key processes are as follows:

Raw Material Pretreatment: L-lactic acid prepared by fermentation (purity ≥99.0%) is dehydrated by vacuum distillation, controlling the moisture content to ≤0.1% to avoid yield reduction due to ethanol dilution during the esterification reaction. Catalytic Esterification Reaction: Dehydrated L-lactic acid is mixed with anhydrous ethanol in a molar ratio of 1:1.2. Concentrated sulfuric acid (0.5% of the total mass of reactants) is added as a catalyst, and the reaction is carried out at reflux temperature (78-80°C) for 4-6 hours.  The water produced during the reaction is removed using a water separator to drive the reaction forward.

Neutralization and Purification:

After the reaction solution cools to room temperature, it is neutralized with a 10% sodium carbonate solution to a pH of 7-8 to remove the sulfuric acid catalyst and unreacted lactic acid.

The organic phase is separated and washed twice with saturated saline solution, then dried with anhydrous magnesium sulfate.

Excess ethanol is recovered by atmospheric distillation, followed by fractional distillation to collect the fraction at 154-155°C. The final yield is approximately 85%-90%, with a chiral purity of ≥99.95% ee.

Key Process Considerations:

The amount of catalyst used in the esterification reaction must be strictly controlled. Excess concentrated sulfuric acid can lead to carbonization of lactic acid, racemization of the chiral center, and the formation of byproducts.

During fractional distillation, the heating rate needs to be controlled (1-2°C/min) to avoid rapid heating that could lead to impurities in the distillate; the initial fraction (approximately 5%) should be discarded before collecting the target product to ensure its purity.