Orforglipron Base

II. Physical and Quality Control Parameters

Appearance: White to off-white crystalline powder, odorless; the crystal form is the thermodynamically stable Form I, and the crystal form purity directly affects the dissolution rate and bioavailability of the preparation.

Solubility: Easily soluble in dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF), soluble in ethyl acetate and methanol, slightly soluble in water (solubility approximately 0.8 mg/mL, 25℃); water solubility can be increased to over 50 mg/mL by forming a phosphate salt.

Stability:

Stable in solid form when sealed, protected from light, and stored at 2-8℃ for 24 months; sensitive to light, easily undergoing indole ring oxidation and degradation under light exposure, requiring storage in brown glass bottles.

In solution, it is stable at pH 4.0-7.0; under strong acid conditions (pH < 2.0), the pyran ring is easily opened, and under strong alkaline conditions (pH > 10.0), the oxadiazolone ring is easily hydrolyzed. Key Quality Control Indicators (API Level)

Chemical Purity: ≥99.8% (HPLC area normalization method, detection wavelength 254 nm)

Chiral Purity: ≥99.9% ee (Chiral SFC, Chiralpak IA column)

Crystalline Purity: Form I ≥99.5% (XRPD detection)

Moisture Content: ≤0.2% (Karl Fischer method)

Residual Solvents: Complies with ICH Q3C limits (Ethyl acetate ≤0.5%, DCM ≤0.06%)

Heavy Metals: ≤1 ppm (ICP-MS)

Related Substances: Single impurity ≤0.05%, total impurities ≤0.2%

III. Synthesis Route and Key Processes

The synthesis of Olaparib is based on the intermediate N-8 as the core precursor, prepared through a one-step cyclization reaction. The complete synthesis route and cyclization steps are as follows:

Precursor Activation: The cyano group of N-8 reacts with hydroxylamine under alkaline conditions to form an amidine intermediate. Anhydrous potassium carbonate is used as the catalyst, anhydrous ethanol as the solvent, the reaction temperature is 60-65℃, and the reaction time is 4 hours.

Oxadiazolone Cyclization: The amidine intermediate undergoes a cyclization reaction with triphosgene to construct the 5-oxo-1,2,4-oxadiazolone pharmacophore; the reaction needs to be carried out under nitrogen protection, controlling the triphosgene dropping rate (0.5 mL/min) to avoid the formation of polymer impurities due to excessively high local concentration.

Refinement and Purification

The crude product is recrystallized with ethyl acetate-n-hexane (volume ratio 1:4) to remove cyclization by-products.

A dynamic hydrothermal crystal form transformation process is used to convert the crude product crystal form into the stable Form I, improving the stability of the formulation.

Yield: The total yield of cyclization and purification is approximately 65% ​​(based on N-8), and the final product has a chemical purity of ≥99.8% and a chiral purity of ≥99.9% ee. Key Process Considerations

The cyclization reaction requires strict control of moisture content; the ethanol solvent must be dried using molecular sieves (moisture content ≤ 0.05%), otherwise, the cyclization efficiency will be reduced.

The crystal form transformation step requires precise control of temperature (45℃) and stirring speed (200 rpm) to avoid the formation of the metastable Form II.

IV. Pharmacological and Application Characteristics

Pharmacological effects: Highly selective activation of GLP-1 receptors, promoting insulin secretion, inhibiting glucagon release, delaying gastric emptying, and increasing satiety; compared with peptide GLP-1 agonists (such as semaglutide), oral bioavailability is increased to 15%-20%, and the dosing frequency can be reduced to once daily.

Application Scenarios

Used as an API in the production of formulations for the treatment of type 2 diabetes and obesity, and can be prepared into various dosage forms such as ordinary tablets and sustained-release capsules.

Used in preclinical pharmacological research, such as receptor binding experiments and pharmacokinetic evaluation.

V. Precautions

The synthesis process involves highly toxic reagents such as triphosgene; operations must be carried out in a dedicated fume hood, and operators must wear gas masks and protective gloves.

When stored as an API, it must be stored separately from oxidizing agents, strong acids, and strong bases to prevent structural degradation; after opening, it needs to be protected with nitrogen gas and used within 7 days.

During formulation processing, if increased water solubility is required, it can be converted into a phosphate salt under mild conditions. After salt formation, the crystal form and related substances need to be re-tested to ensure compliance with API standards.