4,4,5,5-Tetramethyl-1,3,2-dioxaborolane; Pinacolborane -Drug Synthesis Database

【结构式】

【分子编号】55457

【品名】4,4,5,5-Tetramethyl-1,3,2-dioxaborolane; Pinacolborane

【CA登记号】25015-63-8

【分子式】C₆H₁₃BO₂

【分子量】127.97902

【元素组成】C 56.31% H 10.24% B 8.45% O 25%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

The intermediate boronic ester (IV) has been obtained as follows: the silylation of pent-2-en-4-yn-1-ol (I) with Tbdps-Cl and imidazole gives the silyl ether (II), which is condensed with pinacolborane (III) by means of a Rh catalyst tricyclohexyl phosphine and TEA in cyclohexane to afford the target boronic ester intermediate (IV).

参考文献中间体

合成目标

【1】 Falck, J.R.; Reddy, Y.K.; Asymmetric total synthesis of (+)-fostriecin. Org Lett 2002, 4, 6, 969.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	55455	(E)-2-penten-4-yn-1-ol	5557-88-0	C₅H₆O	详情	详情
(II)	55456	tert-butyl(diphenyl)silyl (E)-2-penten-4-ynyl ether; tert-butyl[(E)-2-penten-4-ynyloxy]diphenylsilane		C₂₁H₂₄OSi	详情	详情
(III)	55457	4,4,5,5-Tetramethyl-1,3,2-dioxaborolane; Pinacolborane	25015-63-8	C₆H₁₃BO₂	详情	详情
(IV)	55458	tert-butyl(diphenyl){[(2E,4Z)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-pentadienyl]oxy}silane; tert-butyl(diphenyl)silyl (2E,4Z)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-pentadienyl ether		C₂₇H₃₇BO₃Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

Condensation of indole-6-carboxylic acid (VI) with cyclopentanone (VII) in the presence of aqueous NaOH and glycerol at 100 °C or KOH in aqueous MeOH at 75 °C yields the cyclopentene derivative (VIII), which is reduced to the corresponding cyclopentane (IX) by catalytic hydrogenation over Pd/C in THF or Pd(OH)2 in MeOH . Simultaneous esterification and N-methylation of the indole-carboxylic acid (IX) with CO(OMe)2 by means of K2CO3 in NMP at 130 °C , or sequential esterification with MeI and K2CO3 in DMF, followed by Nmethylation of the resultant indolyl-carboxylate with MeI using NaH in DMF , affords methyl 3-cyclopentyl-1-methylindole-6-carboxylate (X) . Bromination of intermediate (X) with Br2, optionally in the presence of NaOAc in acetonitrile or i-PrOAc, gives the 2-bromoindole derivative (XI) , which is then condensed with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XII) in the presence of Pd(OAc)2, TFP and Et3N in DME at 68 °C to provide boronate (XIIIa) . In an alternative procedure, transesterification of the methyl ester (X) with i-PrOLi in i-PrOH at 65 °C produces the more stable isopropyl ester (XIV), which is then brominated with Br2 in acetonitrile or i-PrOAc to afford the bromoindole derivative (XV). Condensation of bromide (XV) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XII) using Pd(TFP)2Cl2 or Pd(OAc)2, TFP and Et3N in acetonitrile at 82 °C yields boronate (XIIIb) . Finally, Suzuki coupling of pinacol boronates (XIIIa) or (XIIIb) with 5-bromo-2-iodopyrimidine (XVI) in the presence of K3PO4 at 76 °C, followed by ester hydrolysis of the resulting adducts (XVIIa) or (XVIIb) with NaOH in NMP, DMSO or i-PrOH , affords carboxylic acid (I) .

参考文献中间体

合成目标

【1】 Boecher, W., Haefner, C., Kukolj, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Combination therapy for treating HCV infection. CN 103228278, EP 2621495, JP 2013540112, KR 2013116245, US 2012135949, WO 2012041771.
【2】 Brickl, R.-S., Chen, S., Chung, J. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Solid state forms of a potent HCV inhibitor. CN 103153987, EP 2621921, JP 2013543495, KR 2013108326, US 2012122887, US 8598183, US 2014057928, WO 2012044520.
【3】 Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749.
【4】 Mensa, F. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient sub-population. WO 2013147750.
【5】 LaPlante, S.R., Boes, M., Brochu, C. et al. Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors. Discovery of deleobuvir (BI 207127). J Med Chem 2014, 57(5): 1845-54.
【6】 Tsantrizos, Y.S., Chabot, C., Beaulieu, P. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Viral polymerase inhibitors. CN 102911161, CN 103304541, CN 103319464, CN 103333162, EP 1718608, EP 2626354, JP 2007523094, JP 2010195818, JP 2010280740, KR 2012091276, US 2005222236, US 8030309, WO 2005080388.
【7】 Khodabocus, A., Lu, Z.-H., Senanayake, C.H., Wei, H., Zhang, Y. (Boehringer Ingelheim Pharma GmbH & Co. KG). Process for preparing 2,3-disubstituted indoles. CN 103524495, EP 1853589, EP 2530082, JP 2008530117, KR 2014022796, US 2006183752, US 7642352, WO 2006086657.
【8】 Fazal, G., Kukolj, G., Tsantrizos, Y.S. et al. (Boehringer Ingelheim (Canada) Ltd.). Viral polymerase inhibitors. CN 102424680, EP 1414797, EP 1891951, EP 2335700, JP 2004537564, JP 2009275037, US 2004024190, US 7141574, WO 2003010141.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIIIa)	67776	methyl 3-cyclopentyl-1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate		C₂₂H₃₀BNO₄	详情	详情
(XIIIb)	67777	isopropyl 3-cyclopentyl-1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate		C₂₄H₃₄BNO₄	详情	详情
(XVIIa)	67781	methyl 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate		C₂₀H₂₀BrN₃O₂	详情	详情
(XVIIb)	67780	isopropyl 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate		C₂₂H₂₄BrN₃O₂	详情	详情
(I)	67763	2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acid		C₁₉H₁₈BrN₃O₂	详情	详情
(VI)	67771	indole-6-carboxylic acid	1670-82-2	C₉H₇NO₂	详情	详情
(VII)	15113	cyclopentanone	120-92-3	C₅H₈O	详情	详情
(VIII)	67772	3-(cyclopent-1-en-1-yl)-1H-indole-6-carboxylic acid		C₁₄H₁₃NO₂	详情	详情
(IX)	67773	3-cyclopentyl-1H-indole-6-carboxylic acid		C₁₄H₁₅NO₂	详情	详情
(X)	67774	methyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate		C₁₆H₁₉NO₂	详情	详情
(XI)	67775	methyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate		C₁₆H₁₈BrNO₂	详情	详情
(XII)	55457	4,4,5,5-Tetramethyl-1,3,2-dioxaborolane; Pinacolborane	25015-63-8	C₆H₁₃BO₂	详情	详情
(XIV)	67778	isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate		C₁₈H₂₃NO₂	详情	详情
(XV)	67779	isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate		C₁₈H₂₂BrNO₂	详情	详情
(XVI)	67782	5-bromo-2-iodopyrimidine	183438-24-6	C₄H₂BrIN₂	详情	详情

Extended Information