Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3

Summary

Here, we present a protocol for the scaled-up synthesis of the intermediate tert-butyl (5-toluenesulfonyl-5h-pyrrole [2,3-b] pyrazine-2-yl) carbamate (ACT051-3) of Upatinib.

Abstract

Upatinib, a Janus kinase inhibitor drug, was developed by a biotech company to treat immune diseases. The compound tert-butyl (5-toluenesulfonyl-5h-pyrrole [2,3-b] pyrazine-2-yl) carbamate (ACT051-3) is an important intermediate of Upatinib. To date, the steady industrial production of this intermediate compound (ACT051-3) has not been reported. In this study, we described the specific synthesis method and process of the compound ACT051-3 in terms of laboratory synthesis, pilot scale-up, and industrial production. During the exploration of the process route for ACT051-3, many appropriate adjustments and improvements were made to the reaction conditions, finally leading to the successful development of the optimal industrial production process for ACT051-3. The reaction time was nearly doubled by changing the state of the potassium carbonate involved in the reaction, which greatly improved the reaction efficiency. Additionally, by introducing N,N-diisopropylethylamine (DIPEA) to the reaction, the amount of the expensive catalyst Pd(OAc)₂ was reduced 2.5-fold, significantly lowering production costs, confirming the feasibility of this process route and the industrial production of ACT051-3, and satisfying market demand for this important intermediate.

Introduction

Upatinib has become a globally popular Janus kinase 1 (JAK1) inhibitor for treating immune disorders in recent years^1,2. This drug has demonstrated significant therapeutic effects on psoriaticarthritis (PsA)^3,4, rheumatoid arthritis (RA)^5,6,7, and atopic dermatitis (AD)^8,9. Additionally, due to its high selectivity¹⁰, Upatinib has a wide range of clinical applications. Tert-buty....

Protocol

1. Pilot scale synthesis of compounds ACT051-2 and ACT051-3

1. Synthesis of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (ACT051-2)
   1. In a round-bottom flask, dissolve 50.0 g of the compound 2-bromo-5H-pyrrolo[2,3-b]pyrazine (ACT051-1; 0.25 M) in 15 mL of N,N-dimethylformamide (DMF; 3 V).
   2. Add 65.3 g of diisopropylethylamine (DIPEA; 0.51 M) to the reaction solution under nitrogen protection (provide a gas and moisture barrier) and cool the temperature to 0-5 °C through a cool water bath. For nitrogen protection, pump the pressure of the reactor to -0.75--0.8 MPa, then pass N₂ to balance the pressure at 0.1 MPa....

Results

This study provides the scaled-up synthesis process for the important intermediate ACT051-3 of Upatinib (Figure 1 and Figure 2). The protocol section (steps 1-3) specifically shows the gram-grade synthesis, pilot-scale kilogram-grade synthesis, and scale-up production step of the compound ACT051-2 and the intermediate ACT051-3.

In the course of exploring the optimal route for the compound ACT051-2, as shown in

Discussion

The reaction conditions of synthesis, including reaction temperature, time, the selection of reaction reagents, and the ratio of materials, affect the feasibility of the reaction, yields, purity, and production cost, especially for scale-up production.

In the laboratory synthesis of ACT051-2, TsCl in liquid form (dissolved in DMF; step 1.1.3) can be used to in the reaction; however, it is not suitable for pilot scale-up synthesis or industrial production, as using liquid TsCl for this reaction.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
2-bromo-5H-pyrrolo[2,3-b]pyrazine	Nanjing Cook Biotechnology Co., Ltd.	19120110
1,4-dioxane	Liaoning cook Biotechnology Co., Ltd	General Reagent
1H NMR		Bruker AVIII 500
37% chloride acid molecular grade	NEON	02618 NEON
4-toluenesulfonyl chloride (TsCl)	Nanjing Cook Biotechnology Co., Ltd.	AR A2010137
Anti-Chicken IgY (H+L), highly cross-adsorbed, CF 488A antibody produced in donkey	Sigma-Aldrich	SAB4600031
Anti-mouse IgG (H+L), F(ab′)2	Sigma-Aldrich	SAB4600388
BD FACSCanto II	BD Biosciences	BF-FACSC2
BD FACSDiva CS&T research beads (CS&T research beads)	BD Biosciences	655050
BD FACSDiva software 7.0	BD Biosciences	655677
Bovine serum albumin	Sigma-Aldrich	A4503
Centrifuge 5702 R	Eppendorf	Z606936
Circulating water vacuum pump	Guangzhou Zhiyan Instrument Co., Ltd	SHZ-D()
CML latex, 4% w/v	Invitrogen	C37253
Diatomite	Guangzhou Qishuo Chemical Co., Ltd.	/
Double cone rotary vacuum dryer	Jiangsu Yang-Yang Chemical Equipment Plant Inc	SZE-500T
enamel kettle	Jiangsu Yang-Yang Chemical Equipment Plant Inc	CS-03-002	1000L / 2000L
heptane	Nanjing Cook Biotechnology Co., Ltd.	General Reagent
HPLC	Guangzhou aoyi Technology Trading Co., Ltd	LC-2030C 3D
Large scale rotary evaporators	Guangzhou Xingshuo Instrument Co.,Ltd.	RE-2002
Low temperature and constant temperature stirring reaction bath	Guangzhou Yuhua Instrument Co., Ltd	XHDHJF-3005
Low temperature coolant circulating pump	Guangzhou Jincheng Scientific Instrument Co., Ltd	XHDLSB-5/25
Megafuge 8R	Thermo Scientific	TS-HM8R
N, N-Diisopropyl ethylamine (DIPEA)	Apicci Pharm	General Reagent
N-dimethylformamide (DMF)	Guangzhou bell Biotechnology Co., Ltd	General Reagent
Octanoid acid	Sigma-Aldrich	O3907
Pd(OAc)2	Xi'an Catalyst New Materials Co.,ltd.	200704
Phosphate buffered saline	Sigma-Aldrich	1003335620
Potassium carbonate (K2CO3)	Guangzhou Zhonghua Trade Co.,Ltd.	General Reagent
Tert amyl alcohol	Nanjing Cook Biotechnology Co., Ltd.	General Reagent
tert-Butyl carbamate	Nanjing Cook Biotechnology Co., Ltd.	General Reagent
Thermo Mixer Heat/Cool	KASVI	K80-120R
toluene	Liaoning cook Biotechnology Co., Ltd	General Reagent
Vacuum drying oven	Guangzhou Yuhua Instrument Co., Ltd	DZF-6090
Water	/	/
Xantphos	Liaoning cook Biotechnology Co., Ltd	Asp20-44892