Larotrectinib

1.Core Larotrectinib Intermediates

Key Chiral Building Block

(2R)-2-(2,5-difluorophenyl)pyrrolidine

- CAS No.: 1218935-59-1

- Molecular Formula: C₁₀H₁₁F₂N

- Role: The most critical chiral intermediate of larotrectinib, determining the stereochemical configuration and biological activity of the final active pharmaceutical ingredient (API); an essential component in all industrial synthetic routes.

Core Coupling Intermediate

5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine

- Status: Patent-protected intermediate (no public CAS No.)

- Role: Key intermediate formed by the coupling of chiral pyrrolidine and pyrazolopyrimidine core skeleton, laying the foundation for the final API structure.

Final Precursor

(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide

- Role: Direct precursor of larotrectinib sulfate (Vitrakvi); salt formation with sulfuric acid yields the marketed drug.

2.Brief Industrial Synthetic Route

Start with 2,5-difluorobromobenzene and N-Boc-L-pyroglutamate → prepare key chiral intermediate via coupling, deprotection, cyclization and reduction → couple with pyrazolopyrimidine core to form core intermediate → generate larotrectinib sulfate through nitration, reduction, amidation and salification.

3.Major Industrial & Technical News

1. 2022 Biocatalytic Breakthrough (ACS Catalysis)

Directed evolved imine reductase (IRED) realizes green kilogram-scale synthesis of the key chiral intermediate, with space-time yield of 352 g/L/day, enantiomeric excess (ee) >99.5% and yield of 82.5%, realizing high-efficiency and high-purity production.

2. 2025 Chinese Supply Chain Upgrade

Domestic pharmaceutical enterprises and research institutes developed optimized synthetic and fermentation processes, cutting intermediate production costs by about 30% and improving process yield, realizing independent control of the domestic high-quality intermediate supply chain.

3. 2025 Global Supply Optimization

Bayer cooperated with global CDMOs to optimize Intermediate Synthesis routes, increasing the total process yield by approximately 25%, ensuring stable global supply and supporting the drug's market expansion and volume growth after being included in China's National Reimbursement Drug List.

4. 2021-2025 Domestic Patent Layout

Chinese research institutions (Shanghai Institute of Pharma, Chongqing Medical University, etc.) published a number of patents, focusing on short-route synthesis, chiral resolution and green production processes of core intermediates, promoting industrialized large-scale manufacturing.

4.Core Key Data

Product/Intermediate CAS No. Core Indicator

(2R)-2-(2,5-difluorophenyl)pyrrolidine 1218935-59-1 ee >99.5%

Larotrectinib Sulfate 1223405-08-0 Marketed API (Vitrakvi)

Industrial Process Optimization - Total yield +25%, Cost -30%