1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is a key pharmaceutical intermediate and process impurity in the industrial synthesis of baricitinib (Olumiant®), a selective Janus kinase (JAK1/JAK2) inhibitor approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata [1†L14-L16][4†L11-L12]. As a boronic ester, 1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole participates in palladium‑catalyzed Suzuki–Miyaura cross‑coupling reactions with aryl and heteroaryl halides, enabling the installation of diverse aromatic substituents onto the pyrazole scaffold during baricitinib API assembly. The acid‑labile EE protecting group on the pyrazole nitrogen of 1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole allows orthogonal deprotection under mild acidic conditions, facilitating sequential functionalization of the pyrazole ring without compromising the integrity of sensitive boronic ester moieties. Moreover, 1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is officially designated as baricitinib impurity 24 (Baricitinib Impurity 24), making it an indispensable reference standard for analytical method development, method validation (AMV), quality control (QC) applications for Abbreviated New Drug Applications (ANDA), and commercial production processes of baricitinib

Product Parameters

Synthetic Route

Preparation via Metal‑Halogen Exchange and Borylation

The synthesis of 1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole proceeds via directed metal‑halogen exchange of 4‑bromo‑1-(1-ethoxyethyl)-1H‑pyrazole, followed by trapping with a boron electrophile.

Procedure (from ChemicalBook protocol):

1.In an inert atmosphere (nitrogen or argon), charge a pre‑dried reaction vessel with isopropylmagnesium chloride lithium chloride complex (i‑PrMgCl·LiCl, 1.0 M in THF, 6.32 mL, 8.22 mmol) at room temperature.

2.Slowly add 4‑bromo‑1-(1-ethoxyethyl)-1H‑pyrazole (1.00 g, 4.56 mmol) dropwise to the stirred solution.

3..Stir the reaction mixture at room temperature for 16 hours to ensure complete metal‑halogen exchange.

4.Cool the reaction mixture to −20 °C.

5.Add 2‑methoxy‑4,4,5,5‑tetramethyl‑1,3,2‑dioxaborolane (1.73 g, 10.95 mmol) via syringe.

6.Slowly warm the reaction mixture to room temperature and stir for an additional 2 hours.

7.Quench the reaction by adding saturated aqueous ammonium chloride solution (15 mL). A white precipitate forms.

8.Dilute the mixture with additional water (20 mL) and extract with hexane (2 × 140 mL).

9.Combine the organic phases and wash sequentially with saturated aqueous sodium bicarbonate solution and brine.

10. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.

FAQ

Q1:Is 1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole the same as baricitinib?

A: No. 1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is a boronic ester intermediate used in the synthesis of baricitinib (Olumiant®), not the final API. Baricitinib is the completed drug substance formed after Suzuki cross‑coupling, EE group deprotection, and further functionalization steps.

Q2:Is this compound intended for human consumption?

A: No. 1-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is supplied as a chemical intermediate and analytical reference standard for research and pharmaceutical manufacturing use only. It is not intended for human consumption, therapeutic administration, or in vivo applications.

Application Scenarios

1.Baricitinib API Intermediate

As the key boronic ester building block, this compound participates in the Suzuki–Miyaura cross‑coupling reaction that installs the pyrazole side chain onto the baricitinib core. Generic manufacturers and CMOs require consistent, high‑purity material to ensure API equivalence and regulatory compliance.

2.Baricitinib Impurity 24 Reference Standard

This compound is the designated Baricitinib Impurity 24. Analytical laboratories, CROs, and generic manufacturers use it as a certified reference standard for analytical method development, method validation (AMV), quality control (QC) testing, forced degradation studies, ANDA filing, and commercial production of baricitinib.

3.Pyrazole‑4‑boronic Acid Pinacol Ester Scaffold

The boronic ester at the 4‑position enables Suzuki–Miyaura cross‑coupling with aryl and heteroaryl halides to generate diverse 4‑substituted pyrazole derivatives. This scaffold is used to build compound libraries targeting JAK kinases and other pyrazole‑binding enzymes.

4.Suzuki–Miyaura Cross‑Coupling Methodology

The compound serves as a model substrate for developing and optimizing Suzuki–Miyaura cross‑coupling conditions — including catalyst screening (Pd(PPh₃)₄, PdCl₂(dppf), XPhos Pd G3), base optimization (K₂CO₃, Cs₂CO₃, K₃PO₄), and solvent selection (dioxane/water, THF/water, DMF).

5.EE Protecting Group Chemistry

The 1-(1-ethoxyethyl) group provides a case study for orthogonal protecting group strategies in heterocyclic chemistry. Researchers use this compound to demonstrate selective EE deprotection under mild acidic conditions in the presence of base‑stable Bpin functionality.

6.ANDA / NDA Regulatory Filing Support

For generic manufacturers filing ANDA for baricitinib, this impurity reference standard is a critical component of the analytical method validation package — used in system suitability testing, specificity studies, and impurity profiling as part of ICH Q2(R1)-compliant method validation.

7.Analytical Method Development & Validation

Used for developing, validating, and transferring HPLC and UPLC methods for baricitinib drug substance and drug product. Supports selectivity assessment, LOD/LOQ determination, accuracy and precision studies, and robustness testing.

8.Forced Degradation Studies

Used as an impurity marker in forced degradation studies (oxidative, thermal, photolytic, hydrolytic, and basic/acidic stress conditions) to monitor the formation of process‑related impurities and to confirm the stability‑indicating power of analytical methods for baricitinib formulations.

9.Process Development & Scale‑Up

Pharmaceutical process chemists use this intermediate for reaction optimization, impurity mapping, and development of scalable commercial manufacturing routes for baricitinib. Cosperpharm provides characterization data and process support for seamless scale‑up from laboratory to pilot plant.

Contact us

Whatever your application — baricitinib intermediate manufacturing, impurity reference standard qualification, or custom synthesis — Cosperpharm is ready to support you with quality material and responsive service.