Orforglipron Intermediate N-3

Physical and Quality Control Parameters

Appearance: White to off-white crystalline powder; forms regular prismatic crystals when purity is ≥99.5%; powder clumping and slight yellowing may occur if ester hydrolysis impurities are present.

Solubility: Easily soluble in dichloromethane (DCM), tetrahydrofuran (THF), and ethyl acetate; soluble in methanol and ethanol; sparingly soluble in n-hexane and water; purification uses methanol-water gradient recrystallization, which effectively separates ester hydrolysis impurities and diastereoisomers.

Stability: Stable when stored sealed, protected from light, and refrigerated at 2-8℃ for 12 months; the methyl ester group is stable under weakly alkaline conditions, but strong bases (such as NaOH concentration > 1 mol/L) easily induce hydrolysis; the cyano and cyclopropyl structures are stable under neutral/weakly acidic conditions; solutions require nitrogen protection to prevent oxidation of the indole ring to form quinone impurities.

Key Quality Control Indicators

Chemical Purity: ≥99.5% (HPLC area normalization method, detection wavelength 254 nm)

Chiral Purity: ≥99.85% ee (Chiral SFC, Chiralpak IB column)

Moisture Content: ≤0.2% (Karl Fischer method)

Ester Hydrolysis Impurities: ≤0.1% (HPLC external standard method)

Heavy Metals (Pb, Cd, Hg, As): ≤5 ppm (ICP-MS)

Residual Solvents: Complies with ICH Q3C limits (methanol ≤0.3%, DCM ≤0.06%)

III. Synthesis Route and Process Highlights

The synthesis of N-3 uses the intermediate M-6 methyl ester as the starting material, prepared through a one-step indole N-chiral cyclopropylation reaction. The specific route and key process are as follows:

Raw Material Pretreatment: The carboxylic acid group of M-6 undergoes esterification with methanol under concentrated sulfuric acid catalysis to produce M-6 methyl ester, with a yield of approximately 92% and purity ≥99.0%; this step requires strict temperature control (60-65℃) to avoid excessive formation of dimethyl ether impurities. Indole N-Cyclopropylation: M-6 methyl ester reacts with (1S,2S)-1-cyano-2-methylcyclopropyl bromide in anhydrous DMF solvent; a weak base is used (to avoid methyl ester hydrolysis), and tetrabutylammonium bromide (TBAB) is used as a phase transfer catalyst to increase the reaction rate; the reaction temperature is controlled at 20-25℃, the reaction time is 4-6 hours, and the cyclopropyl bromide is added at a ratio of 1.02 eq (to reduce polysubstituted impurities).

Post-treatment and purification: The reaction solution is quenched with water, extracted with ethyl acetate, the organic phase is washed three times with saturated brine, and dried with anhydrous magnesium sulfate; after concentration under reduced pressure, it is recrystallized with methanol-water (volume ratio 3:1), filtered, and vacuum dried (40℃, -0.09 MPa), with a final yield of approximately 72%-78% and a chiral purity of ≥99.85% ee.

Key Process Points

The cyclopropylation reaction requires anhydrous operation throughout. DMF must be dried with molecular sieves (moisture content ≤0.05%), otherwise, it will reduce the activity of the phase transfer catalyst, leading to incomplete reaction.

During recrystallization, the temperature should be lowered slowly (from 50℃ to 5℃, at a rate of 1℃/h) to promote regular crystal growth and reduce impurity inclusion.

IV. Uses and Application Scenarios

Core Use: As a direct precursor of N-4 in the synthesis of Olaparib, it is converted into (1S,2S)-1-cyano-2-methylcyclopropyl-5-[(4S)-2,2-dimethyltetrahydropyran-4-yl]-1H-indole-2-carboxylic acid (i.e., intermediate N-4) through selective ester hydrolysis; the presence of the methyl ester protecting group ensures high selectivity of the upstream cyclopropylation reaction, avoiding interference from the carboxylic acid group. Application scenario: Suitable for commercial production under cGMP conditions, and can serve as a critical quality control point for intermediate purity; the ester hydrolysis impurity content must be tested by HPLC before charging the materials to avoid the transfer of impurities to N-4, which would affect the subsequent condensation efficiency with the oxadiazolone fragment.