Name: scaled-up preparation of an intermediate of upatinib, act051-3
Uploaded: 2023-04-07T14:00:00
Description: Watch this Scientific Journal Video about Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3 at JoVE.com

There are no acknowledgments to mention here.

1. Pilot scale synthesis of compounds ACT051-2 and ACT051-3
<ol>
	<li>Synthesis of 2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (ACT051-2)
	<ol>
		<li>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).</li>
		<li>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 &#176;C through a co...

<ol>
	<li>Kerschbaumer, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Points+to+consider+for+the+treatment+of+immune-mediated+inflammatory+diseases+with+Janus+kinase+inhibitors:+a+systematic+literature+research.">Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a systematic literature research.</a> RMD Open. 6 (3), e001374 (2020).</li><li>Fragoulis, G. E., Brock, J., Basu, N., McInnes, I. B., Siebert, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+role+for+JAK+inhibitors+in+the+treatment+of+immune-+mediated+rheumatic+and+related+conditions.">The role for JAK inhibitors in the treatment of immune- mediated rheumatic and related conditions.</a> The Journal of Allergy and Clinical Immunology. 148 (4), 941-952 (2021).</li><li>Shaw, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=P220+Long-term+safety+profile+of+upadacitinib+in+patients+with+rheumatoid+arthritis,+psoriatic+arthritis,+or+ankylosing+spondylitis.">P220 Long-term safety profile of upadacitinib in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.</a> Rheumatology. 61, 133 (2022).</li><li>Keeling, S., Maksymowych, W. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=JAK+inhibitors,+psoriatic+arthritis,+and+axial+spondyloarthritis:+a+critical+review+of+clinical+trials.">JAK inhibitors, psoriatic arthritis, and axial spondyloarthritis: a critical review of clinical trials.</a> Expert Review of Clinical Immunology. 17 (7), 701-715 (2021).</li><li>Fleischmann, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Safety+and+efficacy+of+elsubrutinib+or+upadacitinib+alone+or+in+combination+(ABBV-599)+in+patients+with+rheumatoid+arthritis+and+inadequate+response+or+intolerance+to+biological+therapies:+a+multicentre,+double-blind,+randomised,+controlled,+phase+2+trial.">Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial.</a> The Lancet Rheumatology. 4 (6), e395-e406 (2022).</li><li>Stamatis, P., Bogdanos, D. P., Sakka, L. I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Upadacitinib+tartrate+in+rheumatoid+arthritis.">Upadacitinib tartrate in rheumatoid arthritis.</a> Drugs of Today. 56 (11), 723-732 (2020).</li><li>Rubbert-Roth, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Trial+of+upadacitinib+or+abatacept+in+rheumatoid+arthritis.">Trial of upadacitinib or abatacept in rheumatoid arthritis.</a> The New England Journal of Medicine. 383 (16), 1511-1521 (2020).</li><li>Asfour, L., Getsos Colla, T., Moussa, A., Sinclair, R. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Concurrent+chronic+alopecia+areata+and+severe+atopic+dermatitis+successfully+treated+with+upadacitinib.">Concurrent chronic alopecia areata and severe atopic dermatitis successfully treated with upadacitinib.</a> International Journal of Dermatology. 61 (11), e416-e417 (2022).</li><li>Cantelli, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Upadacitinib+improved+alopecia+areata+in+a+patient+with+atopic+dermatitis:+A+case+report.">Upadacitinib improved alopecia areata in a patient with atopic dermatitis: A case report.</a> Dermatologic Therapy. 35 (4), e15346 (2022).</li><li>Traves, P. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=JAK+selectivity+and+the+implications+for+clinical+inhibition+of+pharmacodynamic+cytokine+signalling+by+filgotinib,+upadacitinib,+tofacitinib+and+baricitinib.">JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib.</a> Annals of the Rheumatic Diseases. 80 (7), 865-875 (2021).</li><li>Rozema, M. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+scalable+enantioselective+synthesis+of+JAK+inhibitor+upadacitinib.">Development of a scalable enantioselective synthesis of JAK inhibitor upadacitinib.</a> Organic Process Research &amp; Development. 26 (3), 949-962 (2022).</li><li>Wynn, J. P., Hanchar, R., Kleff, S., Senyk, D., Tiedje, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Biobased+technology+commercialization:+the+importance+of+lab+to+pilot+scale-up.">Biobased technology commercialization: the importance of lab to pilot scale-up.</a> Metabolic Engineering for Bioprocess Commercialization. , 101-119 (2016).</li><li>Tang, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Influenza virus replication inhibitor and use thereof. , (2020).</li><li>Ren, Q., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Inhibitors+of+influenza+virus+replication+and+uses+thereof.">Inhibitors of influenza virus replication and uses thereof.</a> Center for Biotechnology Information. , (2020).</li><li>Van Epps, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Design+and+synthesis+of+tricyclic+cores+for+kinase+inhibition.">Design and synthesis of tricyclic cores for kinase inhibition.</a> Bioorganic &amp; Medicinal Chemistry Letters. 23 (3), 693-698 (2013).</li><li>Paul, F., Patt, J., Hartwig, J. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Palladium-catalyzed+formation+of+carbon-nitrogen+bonds.+Reaction+intermediates+and+catalyst+improvements+in+the+hetero+cross-coupling+of+aryl+halides+and+tin+amides.">Palladium-catalyzed formation of carbon-nitrogen bonds. Reaction intermediates and catalyst improvements in the hetero cross-coupling of aryl halides and tin amides.</a> Journal of the American Chemical Society. 116 (13), 5969-5970 (1994).</li><li>Zhou, T., Ji, C. L., Hong, X., Szostak, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Palladium-catalyzed+decarbonylative+Suzuki-Miyaura+cross-coupling+of+amides+by+carbon-nitrogen+bond+activation.">Palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of amides by carbon-nitrogen bond activation.</a> Chemical Science. 10 (42), 9865-9871 (2019).</li><li>Sain, S., Jain, S., Srivastava, M., Vishwakarma, R., Dwivedi, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Application+of+palladium-catalyzed+cross-coupling+reactions+in+organic+synthesis.">Application of palladium-catalyzed cross-coupling reactions in organic synthesis.</a> Current Organic Synthesis. 16 (8), 1105-1142 (2019).</li><li>Takale, B. S., Kong, F. Y., Thakore, R. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+applications+of+Pd-catalyzed+Suzuki-Miyaura+and+Buchwald-Hartwig+couplings+in+pharmaceutical+process+chemistry.">Recent applications of Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig couplings in pharmaceutical process chemistry.</a> Organics. 3 (1), 1-21 (2021).</li></ol>

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...

Upatinib has become a globally popular Janus kinase 1 (JAK1) inhibitor for treating immune disorders in recent years1,2. 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-butyl (5-tosyl-5h-pyrolo [2,3-b] pyrazin-2-yl) carbamate (ACT051-3) is an important intermediate of Upatinib. Its main structural components are the pyrrole ring and the pyrazine ring, which can be used in the preparation of new nitrogen-containing tricyclic kinase inhibitors for the treatment of immune and tumor diseases11.
Pilot scale-up is a medium-sized scale-up (50x-100x) of the process route and conditions determined by the laboratory pilot study, followed by process testing, industrial investigation, and optimization to determine the best industrial production and operating conditions12.
At present, the lab synthesis routes for this intermediate compound (ACT051-3) have been reported, but they have only been performed on a small scale due to problems of low yield, complex reactions, and high equipment requirements, which still have a lot of room to be optimized11,13,14,15. However, no process route has been reported for pilot scale-up and industrial production of the intermediate compound ACT051-3 at present.
Therefore, in this study, we investigated the pilot scale-up and production route of the compound ACT051-3, with reference to the better reported laboratory synthetic routes. Compared with the original laboratory synthesis route, many appropriate adjustments and improvements were made to the reaction conditions, and other factors that may affect the reaction results were investigated. Finally, the most suitable process parameters for the optimal route were identified, and we obtained a process route that is simple to operate, low cost, and environmentally friendly, which is suitable for the pilot scale-up and production of ACT051-3.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>2-bromo-5H-pyrrolo[2,3-b]pyrazine</td>
			<td>Nanjing Cook Biotechnology Co., Ltd.</td>
			<td>19120110</td>
			<td></td>
		</tr>
		<tr>
			<td>1,4-dioxane</td>
			<td>Liaoning cook Biotechnology Co., Ltd</td>
			<td>General Reagent</td>
			<td></td>
		</tr>
		<tr>
			<td>1H NMR</td>
			<td></td>
			<td>Bruker AVIII 500</td>
			<td></td>
		</tr>
		<tr>
			<td>37% chloride acid molecular grade</td>
			<td>NEON</td>
			<td>02618 NEON</td>
			<td></td>
		</tr>
		<tr>
			<td>4-toluenesulfonyl chloride (TsCl)</td>
			<td>Nanjing Cook Biotechnology Co., Ltd.</td>
			<td>AR A2010137</td>
			<td></td>
		</tr>
		<tr>
			<td>Anti-Chicken IgY (H+L), highly cross-adsorbed, CF&#160;488A antibody produced in donkey</td>
			<td>Sigma-Aldrich</td>
			<td>SAB4600031</td>
			<td></td>
		</tr>
		<tr>
			<td>Anti-mouse IgG (H+L), F(ab&#8242;)2</td>
			<td>Sigma-Aldrich</td>
			<td>SAB4600388</td>
			<td></td>
		</tr>
		<tr>
			<td>BD FACSCanto II</td>
			<td>BD Biosciences</td>
			<td>BF-FACSC2</td>
			<td></td>
		</tr>
		<tr>
			<td>BD FACSDiva CS&#38;T research beads (CS&#38;T research beads)</td>
			<td>BD Biosciences</td>
			<td>655050</td>
			<td></td>
		</tr>
		<tr>
			<td>BD FACSDiva software 7.0</td>
			<td>BD Biosciences</td>
			<td>655677</td>
			<td></td>
		</tr>
		<tr>
			<td>Bovine serum albumin</td>
			<td>Sigma-Aldrich</td>
			<td>A4503</td>
			<td></td>
		</tr>
		<tr>
			<td>Centrifuge 5702 R</td>
			<td>Eppendorf</td>
			<td>Z606936</td>
			<td></td>
		</tr>
		<tr>
			<td>Circulating water vacuum pump</td>
			<td>Guangzhou Zhiyan Instrument Co., Ltd</td>
			<td>SHZ-D(<img alt="Equation 1" src="/files/ftp_upload/64514/64514eq01.jpg" style="margin: auto;" />)</td>
			<td></td>
		</tr>
		<tr>
			<td>CML latex, 4% w/v</td>
			<td>Invitrogen</td>
			<td>C37253</td>
			<td></td>
		</tr>
		<tr>
			<td>Diatomite</td>
			<td>Guangzhou Qishuo Chemical Co., Ltd.</td>
			<td>/</td>
			<td></td>
		</tr>
		<tr>
			<td>Double cone rotary vacuum dryer</td>
			<td>Jiangsu Yang-Yang Chemical Equipment Plant Inc</td>
			<td>SZE-500T</td>
			<td></td>
		</tr>
		<tr>
			<td>enamel kettle</td>
			<td>Jiangsu Yang-Yang Chemical Equipment Plant Inc</td>
			<td>CS-03-002</td>
			<td>1000L / 2000L</td>
		</tr>
		<tr>
			<td>heptane</td>
			<td>Nanjing Cook Biotechnology Co., Ltd.</td>
			<td>General Reagent</td>
			<td></td>
		</tr>
		<tr>
			<td>HPLC</td>
			<td>Guangzhou aoyi Technology Trading Co., Ltd</td>
			<td>LC-2030C 3D</td>
			<td></td>
		</tr>
		<tr>
			<td>Large scale rotary evaporators</td>
			<td>Guangzhou Xingshuo Instrument Co.,Ltd.</td>
			<td>RE-2002</td>
			<td></td>
		</tr>
		<tr>
			<td>Low temperature and constant temperature stirring reaction bath</td>
			<td>Guangzhou Yuhua Instrument Co., Ltd</td>
			<td>XHDHJF-3005</td>
			<td></td>
		</tr>
		<tr>
			<td>Low temperature coolant circulating pump</td>
			<td>Guangzhou Jincheng Scientific Instrument Co., Ltd</td>
			<td>XHDLSB-5/25</td>
			<td></td>
		</tr>
		<tr>
			<td>Megafuge 8R</td>
			<td>Thermo Scientific</td>
			<td>TS-HM8R</td>
			<td></td>
		</tr>
		<tr>
			<td>N, N-Diisopropyl ethylamine (DIPEA)</td>
			<td>Apicci Pharm</td>
			<td>General Reagent</td>
			<td></td>
		</tr>
		<tr>
			<td>N-dimethylformamide (DMF)</td>
			<td>Guangzhou bell Biotechnology Co., Ltd</td>
			<td>General Reagent</td>
			<td></td>
		</tr>
		<tr>
			<td>Octanoid acid</td>
			<td>Sigma-Aldrich</td>
			<td>O3907</td>
			<td></td>
		</tr>
		<tr>
			<td>Pd(OAc)2</td>
			<td>Xi&#39;an Catalyst New Materials Co.,ltd.</td>
			<td>200704</td>
			<td></td>
		</tr>
		<tr>
			<td>Phosphate buffered saline</td>
			<td>Sigma-Aldrich</td>
			<td>1003335620</td>
			<td></td>
		</tr>
		<tr>
			<td>Potassium carbonate (K2CO3)</td>
			<td>Guangzhou Zhonghua Trade Co.,Ltd.</td>
			<td>General Reagent</td>
			<td></td>
		</tr>
		<tr>
			<td>Tert amyl alcohol</td>
			<td>Nanjing Cook Biotechnology Co., Ltd.</td>
			<td>General Reagent</td>
			<td></td>
		</tr>
		<tr>
			<td>tert-Butyl carbamate</td>
			<td>Nanjing Cook Biotechnology Co., Ltd.</td>
			<td>General Reagent</td>
			<td></td>
		</tr>
		<tr>
			<td>Thermo Mixer Heat/Cool</td>
			<td>KASVI</td>
			<td>K80-120R</td>
			<td></td>
		</tr>
		<tr>
			<td>toluene</td>
			<td>Liaoning cook Biotechnology Co., Ltd</td>
			<td>General Reagent</td>
			<td></td>
		</tr>
		<tr>
			<td>Vacuum drying oven</td>
			<td>Guangzhou Yuhua Instrument Co., Ltd</td>
			<td>DZF-6090</td>
			<td></td>
		</tr>
		<tr>
			<td>Water</td>
			<td>/</td>
			<td>/</td>
			<td></td>
		</tr>
		<tr>
			<td>Xantphos</td>
			<td>Liaoning cook Biotechnology Co., Ltd</td>
			<td>Asp20-44892</td>
			<td></td>
		</tr>
	</tbody>
</table>

scaled-up preparation of an intermediate of upatinib, act051-3

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.

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 <strong...

Watch this Scientific Journal Video about Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3 at JoVE.com

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

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.

Upatinib, a Janus kinase inhibitor drug, was developed by a biotech company to treat immune diseases. The compound tert-butyl ...

Here, a protocol for the scaled-up synthesis of an intermediate of upatinib, ACT051-3, is presented. This method is simple to operate, low cost, and environmentally friendly. To begin, prepare ACT051-2 by dissolving 50 grams of the compound 2-bromo-5-tosyl-5H-pyrrolo[2, 3-b]pyrazine in 15 milliliters of N, N-dimethylformamide, or DMF in a round-bottom flask.Add 65.3 grams of diisopropylethylamine to the reaction solution under nitrogen protection, and cool the temperature to 0 to 5 degrees Celsius through a cool water bath. Add 60.2 grams of para-toluene sulphonyl chloride, or TsCL, dissolved in 12 milliliters of DMF, and raise the temperature to 20 to 30 degrees Celsius through the warm water bath. Stir for about 1 hour.Add 600 milliliters of cool water to the mixture, and stir for another 1 hour. Filter the product under a vacuum using a glass funnel with a sanding board padded with filter paper. Wash with 200 milliliters of water several times, and dry, using an electric thermostatic drying oven to obtain pale yellow solid ACT051-2 with a yield of 78%For the synthesis of ACT051-3, dissolve 176.11 grams of ACT051-2 in 366.31 grams of 1, 4-dioxane in a three-port round-bottom flask, and add 65.75 grams of tert-butyl carbamate, 138.21 grams of granular potassium carbonate, 11.57 grams of Xantphos, and 2.25 grams of palladium acetate to the solution.Heat the mixture to 105 degrees Celsius, and stir for 7 hours under a nitrogen atmosphere. After cooling the mixture to room temperature, filter the product with a Buchner funnel. Wash the filter residue with 200 milliliters of ethyl acetate.Use a circulating water vacuum pump to concentrate the product under reduced pressure at 50 to 60 degrees Celsius, with a pressure value of minus 0.095 megapascal. Keep the pump working to maintain the pressure and obtain a dark brown oil. Purify the crude product with column chromatography, eluting with petroleum ether and ethyl acetate to obtain the target compound as a white solid with a yield of 93.5%For the pilot scale-up synthesis of ACT051-2, add one kilogram of 5.05 molar ACT051-1 and 1.305 kilograms of 10.1 molar DIPEA to a four-port round-bottom flask.Add 3 liters of DMF to the flask, and dissolve the solid. Heat the reaction mixture to 35 degrees Celsius. Add 1.203 kilograms of 6.31 molar TsCL to the reaction solution and stir for 1 hour.Stir the mixture until the completion of the reaction is confirmed by thin-layer chromatography, or TLC, and HPLC. Pour in 8.4 liters of cool water, and stir for another half an hour. Filter all liquids with a Buchner funnel, and rinse the crude product with 600 milliliters of water.Dry the resulting product at 70 degrees Celsius overnight using an electric thermostatic drawing oven, and obtain a product with a yield of 94.9%For the pilot scale-up synthesis of ACT051-3, add 3.31 liters of tert-amyl alcohol and 4.97 liters of toluene to the reaction kettle, and then add 1.66 kilograms of ACT051-2, 0.83 kilograms of tert-butyl carbamate, 1.301 kilograms of powdered potassium carbonate, 0.11 kilograms of Xantphos, and 0.31 kilograms of DIPEA to the solution. After evacuating nitrogen three times, as shown earlier, add 10 grams of palladium acetate to the reaction solution under nitrogen protection. Heat the reaction mixture to 90 degrees Celsius and stir for 4 hours.After that, cool the mixture to 40 degrees Celsius or below. Filter the reaction solution with a Buchner funnel using diatomite as a filter aid, and wash the filter cake with toluene. Collect and concentrate the filtrate using a circulating water vacuum pump, as shown earlier.Add 300 milliliters of heptane and stir for 20 minutes. After filtering the reaction solution again with a Buchner funnel, rinse the crude product with 50 milliliters of heptane. Dry and obtain the product with a yield of 96.3%The reaction route and conditions of the intermediate ACT051-3 before optimization and after optimization are presented in this figure.The effect of different forms of TsCL on the synthetic compound ACT051-2 is shown here. The results show that solid TsCL is more conducive to industrial production. The effect of adding TsCL at different temperatures on the synthesis of ACT051-2 is shown here.The product yield was increased from 97.49%to 98.44%when TsCL was added from 0 to 5 degrees Celsius to 23 to 35 degrees Celsius. The effect of different post-treatment water consumption on the synthesis of ACT051-2 is presented here. The optimal conditions were achieved at a post-treatment water volume of 6 milliliters per gram ACT051-2.This data shows the effect of adding DIPEA to the reaction for the synthesis of ACT051-3. The introduction of DIPEA reduced the amount of palladium acetate by a factor of 2.5. The effect of different states of potassium carbonate and different reaction solvents on the reaction of the synthetic compound ACT051-3 are presented here.The results show that by changing the state of potassium carbonate involved in the reaction, the reaction time was reduced from 7 hours to 3.5 hours. Additionally, by switching from tert-amyl alcohol/1, 4-dioxane to tert-amyl alcohol/toluene, the reaction time was shortened to 3 hours, and the product peak area increased from 84.22%to 88.52%The addition of DIPEA is critical for the pilot scale-up synthesis and industrial production of compound ACT051-3.

Research

JoVE Journal

Chemistry

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

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Real-time Monitoring of Reactions Performed Using Continuous-flow Processing: The Preparation of 3-Acetylcoumarin as an Example

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Preparation of Carbon Nanosheets at Room Temperature

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A reliable, intermediate scale preparation of 1,2,3,4,5-pentamethylcyclopentadiene (Cp*H) is presented, based on modifications of existing protocols that ...

Preparation and Characterization of C60/Graphene Hybrid Nanostructures

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Physical thermal deposition in a high vacuum environment is a clean and controllable method for fabricating novel molecular nanostructures on graphene. We ...

An Efficient Sample Preparation Method to Enhance Carbohydrate Ion Signals in Matrix-assisted Laser Desorption/Ionization Mass Spectrometry

Sample preparation is a critical process in mass spectrometry (MS) analysis of carbohydrates. Although matrix-assisted laser desorption/ionization (MALDI) ...

Microfluidic Preparation of Liquid Crystalline Elastomer Actuators

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