Orforglipron Intermediate M-1

II. Physical and Quality Control Parameters

Appearance: White to off-white crystalline powder, odorless, irritating.

Solubility: Easily soluble in ethanol, diethyl ether, and dichloromethane; slightly soluble in water; sparingly soluble in n-hexane; purification can be achieved by recrystallization or vacuum distillation.

Stability: Stable at room temperature; avoid high temperature, humidity, and strong oxidizing agents; the carboxyl group readily undergoes esterification with alcohols; store in a sealed, moisture-proof container; shelf life is approximately 24 months.

Key Quality Control Indicators

Chemical Purity: ≥99.0% (HPLC area normalization method)

Moisture Content: ≤0.5% (Karl Fischer method)

Heavy Metals (Pb, Cd, Hg, As): ≤10 ppm (ICP-MS)

Free Bromide Ions: ≤0.1% (silver nitrate titration method)

III. Synthesis Route and Process Highlights

M-1 is synthesized from 4-bromotoluene as the starting material through the following steps:

Introduction of the side-chain carboxyl group: 4-bromotoluene undergoes a Friedel-Crafts alkylation reaction with chloroacetic acid under anhydrous aluminum trichloride catalysis to produce 4-bromophenylacetic acid. The reaction temperature is controlled at 80-90℃, and the reaction time is approximately 6 hours.

Post-treatment and purification: After cooling, the reaction solution is poured into ice water, acidified with hydrochloric acid to pH=2-3, and the solid is precipitated. After filtration, it is recrystallized with ethanol. The yield is approximately 75%-80%, and the purity is ≥99.0%.

Process Key Points

Anhydrous aluminum trichloride should be finely ground and added in batches to avoid excessive local concentration, which can lead to the formation of polyalkylation byproducts.

The reaction temperature must be strictly controlled; excessively high temperatures can easily produce tar-like polymers, affecting product purity and yield. IV. Uses and Application Scenarios

Core Use: As a starting material for the total synthesis of ofloxacin, it undergoes an acylation reaction to produce 4-bromophenylacetyl chloride, which is used in the nucleophilic addition reaction with (S)-4-isopropyl oxazolidinone in the synthesis of M-2. It is a key building block for constructing the bromobenzoylmethyl side chain of M-2.

Application Scenarios: Suitable for laboratory and industrial production. High-purity product can be purchased directly or synthesized in-house; purity and free bromide ion content must be checked before use to avoid affecting the synthesis efficiency and quality of M-2.