Orforglipron Intermediate N-2

Physical and Quality Control Parameters

Appearance: Colorless to pale yellow transparent liquid; colorless when chiral purity is ≥99.9% ee; the color deepens to light brown if (1R,2R) isomer impurities are present.

Solubility: Easily soluble in dichloromethane (DCM), tetrahydrofuran (THF), and ethyl acetate; soluble in methanol and ethanol; sparingly soluble in water; purification is achieved by vacuum distillation (distillation column with ≥30 theoretical plates), collecting the 65-68℃/5 mmHg fraction, achieving a purity of over 99.8%.

Stability: Stable for 6 months when stored sealed and protected from light at room temperature; the cyclopropyl ring is prone to ring opening at high temperatures (>100℃) or under strong alkaline conditions, and the bromine atom is prone to elimination reactions, generating cyclopropenecarbonitrile impurities; it should be stored separately from strong bases and strong reducing agents to avoid dehydrobromination reactions.

Key Quality Control Indicators

Chemical Purity: ≥99.8% (GC area normalization method, FID detector)

Chiral Purity: ≥99.9% ee (chiral GC, Cyclodex B column)

Moisture Content: ≤0.05% (Karl Fischer method)

Free Bromide Ions: ≤0.01% (silver nitrate titration method)

Isomer Impurities [(1R,2R)-configuration]: ≤0.1% (chiral GC external standard method)

III. Synthesis Route and Key Process Points

The synthesis of N-2 uses **(S)-ethyl lactate** as the starting material and is prepared through an asymmetric cyclization reaction. The specific route and key processes are as follows:

Chiral Precursor Construction: (S)-ethyl lactate reacts with 2-bromopropionyl bromide under triethylamine catalysis to produce (S)-2-bromopropionic acid-1-ethoxyethyl ester. The reaction temperature is controlled at 0-5℃ to avoid racemization, with a yield of approximately 88%. Asymmetric Cyclization: The above product undergoes a Reformatsky reaction with zinc powder in anhydrous THF, generating a chiral cyclopropyl ester intermediate. The reaction needs to be carried out under nitrogen protection, and the zinc powder needs to be activated (washed with dilute hydrochloric acid and then dried) to enhance reactivity. This step is crucial for chiral control; the reaction temperature is controlled at -10-0℃, and the diastereoselectivity is dr≥99:1.

Cyanation and Deprotection: The cyclopropyl ester intermediate is converted to an amide via ammonolysis, then dehydrated with a dehydrating agent (trifluoroacetic anhydride) to form a cyano-substituted cyclopropyl ester. Finally, the ester group is removed and brominated to produce the crude N-2 product. NBS (N-bromosuccinimide) is used as the brominating agent to avoid the formation of isomeric impurities caused by the use of liquid bromine.

Purification: The crude product is purified by vacuum distillation, and the target fraction is collected. The final yield is approximately 35% (laboratory process), with a chiral purity of ≥99.9% ee.