Development of a Scalable Route for a Key Benzothiazole Building Block via a Pd-Catalyzed Migita Coupling with a Nonsmelly Thiol Surrogate

Abstract

2-Methylbenzo[d]thiazole-6-carbonitrile was internally identified as an important building block and therefore, kg amounts of it needed to be urgently supplied. As the desired benzothiazole was only available in small quantities for a high price (∼1000 USD/g), a robust and scalable route needed to be rapidly developed. The key to success was the use of a 2-iodophenyl N-acetamide precursor to construct the 2-methylbenzo[d]thiazole core via a Pd-catalyzed Migita coupling followed by subsequent intramolecular condensation of the intermediate thiophenol onto the N-acetyl group. To avoid the use of malodorous thiols on scale, 2-ethylhexyl 3-mercaptopropionate was used as a nonsmelly, inexpensive thiol surrogate. The Migita coupling was extensively optimized and allowed the reaction to be performed in a dose-controlled manner with regard to the addition of the thiol surrogate at 40 °C, by using only 0.1 mol % Pd2dba3. The subsequent intramolecular cyclization step was promoted by the one-pot addition of DBU. After aqueous workup and crystallization, 2-methylbenzo[d]thiazole-6-carbonitrile was obtained in 81% yield and excellent purity (99.7% a/a) on a 2.0 kg scale.

Practical One Pot Synthesis of 2-Alkyl-substituted Benzothiazoles from Bis-(2-nitrophenyl)-disulfides.

“…p. 41-45°C. 1 H NMR (500 MHz, DMSO-d6) δ 7.92 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.28 (dd, J = 8.4, 1.9 Hz, 1H), 2.76 (s, 3H), 2.53 (s, 3H). 13…”

“…The residue was dried in vacuo (1.0 mm Hg) and distilled (1.0 mm Hg) to afford the product 5c (24.8 g, 78%) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 3.12 (q, J = 7.5 Hz, 2H), 1.37 (t, J = 7.5 Hz, 3H). 13…”

“…Working many years in CRO we observed it rather frequently. The inspiration of this current paper was Idorsia publication in OPRD directed on optimization of the chemical route to sole compound, 2-methylbenzothiazole-6-carbonitrile as valuable building block for its drug discovery program [ 1 ]. After reading of the paper we decided to publish "our story" about another 2-methylbenzothiazole: 2-methyl-5-(methylthio)benzothiazole 1a.…”

Development of a Scalable Route toward an Alkylated 1,2,4-Triazol, a Key Starting Material for CXCR3 Antagonist ACT-777991

“…Hence, we investigated nonsmelly alternatives such as octyl-thioacetimidate and Me-acetimidate (Chart 1, entries 4 and 5). 16 Even though the desired condensation also worked with octyl-thioacetimidate, we focused our efforts on Meacetimidate due to its straightforward synthesis from two bulk solvents (MeOH and MeCN). In addition, the formed MeOH byproduct from the reaction of Me-acetimidate with hydrazine 16-HCl can be easily removed, which is an advantage compared to the high boiling 1-octanethiol from octylthioacetimidate.…”

“…During our optimization efforts, we realized that the reaction with Me-thioacetimidate caused an unpleasant odor, especially during workup. Hence, we investigated nonsmelly alternatives such as octyl-thioacetimidate and Me-acetimidate (Chart , entries 4 and 5) . Even though the desired condensation also worked with octyl-thioacetimidate, we focused our efforts on Me-acetimidate due to its straightforward synthesis from two bulk solvents (MeOH and MeCN).…”