N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide -Drug Synthesis Database

【结构式】

【分子编号】67686

【品名】N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide

【CA登记号】　

【分子式】C₁₇H₂₂BNO₄S

【分子量】347.243

【元素组成】C 58.80% H 6.38% B 3.11% N 4.03% O 18.43% S 9.23%

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：(XI)

Iodination of 2-tert-butylphenol (I) with excess NaI and NaOCl in the presence of NaOH in MeOH gives 2-tert-butyl-4,6-diiodophenol (II), which is O-alkylated with Me2SO4 and K2CO3 or with MeI and NaOH in refluxing acetone to yield 1-tert-butyl-3,5-diiodo-2-methoxybenzene (III). goldberg reaction of aryl iodide (III) with uracil (Iv) by means of CuI, K3PO4 and N-(2-cyanophenyl)picolinamide in DMSO at 60 °C affords 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)uracil (v) (1-4), which by Suzuki coupling with 6-hydroxy-2-naphthylboronic acid (vI) in the presence of Pd2dba3, K3PO4 and meCgPPh (1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.113,7]decane) in THF provides adduct (vII). Condensation of naphthol (vII) with perfluoro-butanesulfonyl fluoride (vIII) and K2CO3 in acetonitrile/DMF produces sulfonate (IX), which is finally condensed with methanesulfonamide (X) using Pd2dba3, K3PO4 and t-BuBrettPhos in t-amyl alcohol at 60 °C, THF, 2-MeTHF or EtOAc .
In a related procedure, dasabuvir is obtained by Suzuki coupling of aryl iodide (v) with pinacol 6-(methylsulfonamido)-2-naphth-ylboronate (XI) using K3PO4, Pd2dba3 and meCgPPh in THF/H2O at 50 °C .

参考文献中间体

合成目标

【1】 Pratt, J.K., Betebenner, D., Flentge, C. et al. Aryl 1-uracil inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase: Uracil ring replacements. 244th ACS Natl Meet (August 19-23, Philadelphia) 2012, Abst MEDI 146.
【3】 Flentge, C.A., Hutchinson, D.K., Betebenner, D.A. et al. (Abbott Laboratories). Anti-infective pyrimidines and uses thereof. CN 101842360, CN 102746240, EP 2203431, EP 2368882, EP 2639226, JP 2010539187, US 8188104, US 2012244119, US 8501238, WO 2009039134.
【4】 Shekhar, S., Franczyk, T.S., Barnes, D.M., Dunn, T.B., Haight, A.R., Chan, v.S. (Abbvie, Inc.) Process for preparing antiviral compounds. CN 103097360, EP 2593439, JP 2013532636, KR 2013043195, US 2012014913, WO 2012009699.
【2】 Wagner, R., Tufano, M.D., Stewart, K.D. et al. (Abbvie Bahamas Ltd.). Uracil or thymine derivative for treating hepatitis C. CN 101801935, CN 102746239, EP 2222646, JP 2010539186, US 2012213733, WO 2009039127.

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)	67678	2-tert-butylphenol；o-t-Butylphenol；o-tert-Butylphenol；2-tert-Butyl-1-hydroxybenzene；2-(1,1-Dimethylethyl)phenol	88-18-6	C₁₀H₁₄O	详情	详情
(II)	67679	2-tert-butyl-4,6-diiodophenol		C₁₀H₁₂I₂O	详情	详情
(III)	67680	1-tert-butyl-3,5-diiodo-2-methoxybenzene		C₁₁H₁₄I₂O	详情	详情
(IV)	30921	2,4(1H,3H)-pyrimidinedione; Uracil	66-22-8	C₄H₄N₂O₂	详情	详情
(V)	67681	1-(3-tert-butyl-5-iodo-4-methoxyphenyl)uracil		C₁₅H₁₇IN₂O₃	详情	详情
(VI)	67682	6-hydroxy-2-naphthylboronic acid	173194-95-1	C₁₀H₉BO₃	详情	详情
(VII)	67683	1-(3-(tert-butyl)-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione		C₂₅H₂₄N₂O₄	详情	详情
(VIII)	67684	perfluoro-butanesulfonyl fluoride	375-72-4	C₄F₁₀O₂S	详情	详情
(IX)	67685	6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate		C₂₉H₂₃F₉N₂O₆S	详情	详情
(X)	39701	methanesulfonamide	3144-09-0	CH₅NO₂S	详情	详情
(XI)	67686	N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide		C₁₇H₂₂BNO₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

The boronate intermediate (XI) is prepared by hydrolysis of methyl 6-bromo-2-naphthoate (XII) with LiOH in H2O/THF to give 6-bromo-2-naphthoic acid (XIII), which by Curtius rearrangement with DPPA and Et3N in DMF at 100 °C yields 6-bromo-2-naphthylamine (XIv). Sulfonylation of amine (XIv) with mesyl chloride (Xv) in pyridine provides the sulfonamido naphthalene (XvI), which finally undergoes borylation with bis(pinacolato)diboron in the presence of KOAc and combiPhos-Pd6 catalyst in refluxing toluene .

参考文献中间体

合成目标

【1】 Pratt, J.K., Betebenner, D., Flentge, C. et al. Aryl 1-uracil inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase: Uracil ring replacements. 244th ACS Natl Meet (August 19-23, Philadelphia) 2012, Abst MEDI 146.
【2】 Wagner, R., Tufano, M.D., Stewart, K.D. et al. (Abbvie Bahamas Ltd.). Uracil or thymine derivative for treating hepatitis C. CN 101801935, CN 102746239, EP 2222646, JP 2010539186, US 2012213733, WO 2009039127.
【3】 Flentge, C.A., Hutchinson, D.K., Betebenner, D.A. et al. (Abbott Laboratories). Anti-infective pyrimidines and uses thereof. CN 101842360, CN 102746240, EP 2203431, EP 2368882, EP 2639226, JP 2010539187, US 8188104, US 2012244119, US 8501238, WO 2009039134.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	67686	N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide		C₁₇H₂₂BNO₄S	详情	详情
(XII)	59539	6-Bromo-2-naphthoic acid methyl ester; Methyl 6-bromo-2-naphthoate	33626-98-1	C₁₂H₉BrO₂	详情	详情
(XIII)	42564	6-Bromo-2-naphthoic acid；(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid	5773-80-8	C₁₁H₇BrO₂	详情	详情
(XIV)	55631	6-bromo-2-naphthalenamine; 6-bromo-2-naphthylamine	7499-66-3	C₁₀H₈BrN	详情	详情
(XV)	13467	Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride	124-63-0	CH₃ClO₂S	详情	详情
(XVI)	67687	N-(5-bromonaphthalen-1-yl)methanesulfonamide		C₁₁H₁₀BrNO₂S	详情	详情

Extended Information