1428243-26-8

Usage

Uses

Used in Pharmaceutical Industry:
(3R,4S)-3-(2-Bromoacetyl)-4-ethyl-1-pyrrolidinecarboxylic acid phenylmethyl ester is used as a reagent for the preparation of imidazopyrrolopyrazine derivatives and analogs. These derivatives are of significant interest due to their potential as protein kinase modulators, which play a crucial role in various cellular processes and are often targeted in the development of therapeutic agents for various diseases, including cancer and inflammatory disorders.
Used in Chemical Research:
In addition to its pharmaceutical applications, (3R,4S)-3-(2-Bromoacetyl)-4-ethyl-1-pyrrolidinecarboxylic acid phenylmethyl ester can also be utilized in chemical research as a starting material or intermediate for the synthesis of other complex organic molecules. Its unique structure and functional groups make it a valuable compound for exploring new chemical reactions and developing novel synthetic pathways.

Upstream product

• 51814-19-8 1-Benzyloxycarbonyl-4-ethoxycarbonyl-3-oxopyrrolidine 
• 27805-84-1 (cis)-2-pentenoic acid ethyl ester 
• 55314-57-3 ethyl pent-2-ynoate 

Downstream Products

• 1428243-27-9 (3R,4S)-benzyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-ethylpyrrolidine-1-carboxylate 
• 1310726-60-3 (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide 
• 1428243-28-0 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine 

Relevant academic research and scientific papers

Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib

Process development of a six-stage synthesis of upadacitinib, a JAK1 inhibitor, is described. It is highlighted by an enantioselective and diastereoselective hydrogenation of a tetrasubstituted olefin to set the two pyrrolidine stereocenters. Preparation of the main fragments and strategies to link them together, optimization of the imidazole cyclization, and in-depth understanding of the formation of the urea moiety at the final stage are discussed.

PROCESS AND INTERMEDIATES FOR THE PREPARATION OF UPADACITINIB

The invention relates to a process for the preparation of compounds of formula (I), which are useful intermediates in the synthesis of Upadacitinib and structurally related compounds, by using Weinreb amide (III), or an equivalent thereof, as key intermediate.

Preparation method and application of 1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid

The invention relates to a preparation method and application of 1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid. The preparation method comprises the following steps: carrying out hydrogenation reaction on a compound I-1 to obtain a compound II, and carrying out reaction on the compound II to obtain the 1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid. Compared with the prior art, the synthesis method is simple in route, convenient to operate, safe and reliable; the method is environment-friendly; efficiency is high and cost is low; and the synthesis method has good chemical selectivity and enantioselectivity, and the product purity and optical purity are high. The 1-((benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic acid prepared by the method can be further used for preparing a compound benzyl 3-(2-bromoacetyl)-4-ethylpyrrolidine-1-formate which is an important intermediate for preparing a selective JAK1 inhibitor; and therefore, the synthetic route provided by the invention also has important significance on the production of the selective JAK1 inhibitor.

Method for synthesizing upatinib chiral intermediate by using microchannel reaction technology

The invention provides a micro-channel reaction synthesis method of a key chiral intermediate (3R, 4S)-benzyl 3-(2-bromoacetyl)-4-ethyl pyrrolidinyl-1-formic ether of upatinib. The method comprises the following steps: 1) mixing an N-methyl-N-nitroso p-toluene sulfonamide solution and a potassium hydroxide aqueous solution, and then carrying out diazo reaction in a micro-channel reactor to obtain diazomethane; (2) carrying out a diazo absorption reaction on the (3R, 4S)-1-((benzyloxy) carbonyl)-4-ethyl pyrrolidine-3-formyl chloride solution and diazomethane in the micro-channel reactor; and (3) carrying out bromination reaction on the product obtained in the step (2) and a hydrobromic acid aqueous solution in a micro-channel reactor to obtain a target product. According to the microchannel reaction technology capable of realizing continuous production, diazomethane can be applied to enlarged production, the risk of diazomethane and diazo intermediates can be greatly reduced, the recarburization bromination reaction can be stably and quantitatively carried out, and the route efficiency is improved.

THE PROCESS FOR THE PREPARATION OF UPADACITINIB AND ITS INTERMEDIATES

The present invention provides an improved process for the preparation Upadacitinib by using novel intermediates. The present invention also provides processes for the preparation of novel intermediates of Upadacitinib.

Synthetic method of (by machine translation)

The synthesis method takes compound 1 as a starting raw material, is subjected to chlorination, coupling, hydrolysis and hydrogenation into a salt to obtain compound 4, and then derivatized with erucic acid and halogenated to obtain the intermediate compound 6. Next, we utilize 2 - bromo -5 - p tosyl - 555H-pyrrolo [2, 3 - b] pyrazine compound 7 as starting materials for aminolysis and amino protection to obtain the intermediate compound 9. Of Compound 6 and Compound 9 A Chemical Formula 10 was obtained, and then a key mother nucleus 11 was obtained by using trifluoroacetic anhydride to form a ring. Finally, the butt reaction of triethylamine is optimized, and the product is obtained by two methods. To the improvement, the route efficiency is greatly improved, the process steps of using the noble metal catalyst are reduced, the process cost is reduced, the generation of the auxiliary chiral products is greatly reduced, and the final product purity is improved. Route is : (by machine translation)

Two compounds, preparation methods thereof, and application thereof for synthesis of upadacitinib

The application provides the compounds as the formulas II and III and preparation methods thereof, and provides the compounds as the formulas II and III and a synthesis method for synthesizing upadacitinib. The raw materials of the methods in the application are easy to obtain and low in cost. The methods are simple in operation, is energy-saving and environment-friendly and is beneficial to industrial production.

ALTERNATE PROCESSES FOR THE PREPARATION OF PYRROLIDINE DERIVATIVES

Aspects of the present application relate to process for the preparation of Pyrrolidine derivatives useful as key intermediates for active ingredients. Specific aspects relate to alternate process for the preparation of Upadacitinib intermediate, 4-ethylpyrrolidine-3-carboxylic acid, its ester or a salt thereof. Processes disclosed here in are cost effective and industrially viable as compared to known processes.

Synthesis method of JAK (Janus Kinase) inhibitor

The invention discloses a synthesis method of a JAK (Janus Kinase) inhibitor. The synthesis method comprises the following steps: carrying out condensation on an intermediate A-8 and an intermediate B-3 to obtain an intermediate AB-1; carrying out deprotection on the intermediate AB-1 to obtain an intermediate AB-2; carrying out cyclization on the AB-2 to obtain an intermediate AB-3; carrying outthe deprotection on the intermediate AB-3 to obtain an intermediate AB-4; carrying out the deprotection on the AB-4 again to obtain an intermediate AB-5; carrying out condensation reaction on the AB-5to obtain the JAK inhibitor 1. The synthesis method disclosed by the invention has the main advantages that the intermediate A-8 is prepared through a chiral catalysis method in a high-yield and high-chiral-purity manner, and the intermediate B-3 and the JAK inhibitor 1 are prepared in a high-yield manner. Useless enantiomers are nearly not generated so that the pressure on the environment is reduced; meanwhile, the reaction yield is high, the operation is simple and the post-treatment is simple and convenient. According to the synthesis method, reaction conditions also can be applied to large-batch preparation and are suitable for industrial production, so that the synthesis method has relatively high practical value and social and economic benefits.

Upadacitinib tartrate: Tyrosine-protein kinase JAK1 inhibitor Treatment of autoimmune inflammatory diseases Treatment of rheumatoid arthritis

Upadacitinib tartrate (ABT-494) is a potent and selective tyrosine-protein kinase JAK1 inhibitor being developed for the treatment of systemic autoimmune inflammatory diseases, including rheumatoid arthritis (RA), Crohn's disease, ulcerative colitis and psoriatic arthritis. In vitro, upadacitinib demonstrated higher selectivity for inhibiting JAK1 over JAK2 and JAK3, suggesting a potentially improved therapeutic profile in treating patients with inflammatory diseases compared to nonselective JAK inhibitors. Upadacitinib has demonstrated safety and efficacy in phase II trials in patients with RA and inflammatory bowel disease, and is currently in phase III development for these indications.