6-Bromo-2-naphthoic acid；(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】42564

【品名】6-Bromo-2-naphthoic acid；(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid

【CA登记号】5773-80-8

【分子式】C₁₁H₇BrO₂

【分子量】251.07938

【元素组成】C 52.62% H 2.81% Br 31.82% O 12.74%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Chlorination of 6-bromo-2-naphthoic acid (I) with SOCl2 , optionally in the presence of DMF in THF , affords the corresponding acid chloride (II), which by reaction with (i-Pr)2NH , optionally in the presence of Et3N in THF , provides amide (III). Metalation of 6-bromo-N,N-diisopropyl-2-naphthamide (III) with BuLi in THF followed by condensation with 1-tritylimidazole-4-carbaldehyde (IV) gives the diarylcarbinol (V), which by oxidation with MnO2 in CH2Cl2 yields the corresponding ketone (VI) . Compound (VI) can also be obtained directly by condensation of lithiated naphthamide (III) (by means of BuLi in THF) with N-methoxy-N-methyl-1-tritylimidazole-4-carboxamide (VII) . Asymmetric Reformatsky reaction of ketone (VI) with either bromo (2-ethoxy-2-oxoethyl)zinc (VIIIa) or bromo (2-tert-butoxy-2-oxoethyl)zinc (VIIIb) [prepared in situ by reaction of tert-butyl bromoacetate (IX) with Zn and TMSCl ] by means of cinchonine, and optionally pyridine, in THF provides the 3(S)-hydroxy-3-(4-imidazolyl)-3-(2-naphthyl)propionic acid ethyl and tert-butyl esters (Xa) and (Xb) , respectively. Reduction of esters (Xa) or (Xb) by means of Red-Al in toluene yields the propane-1,3-diol derivative (XI), which by activation with MsCl in the presence of DIEA in THF followed by cyclization with MeOH in the presence of DIEA in acetonitrile affords the 7(S)-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol derivative (XII). Finally, the N,N-diisopropylnaphthamide derivative (XII) is treated with CH3NH2 in the presence of BuLi in THF .

参考文献中间体

合成目标

【1】 Kaku, T., Hitaka, T., Ojida, A. et al. Discovery of TAK-700, a naphthylmethylimidazole derivative, as a highly selective, orally active 17, 20 lyase inhibitor for prostate cancer. 240th ACS Natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 96.
【2】 Hitaka, T., Kusaka, M., Aoki, I., Ojida, A., Matsunaga, N., Adachi, M., Tasaka, A. (Takeda Pharmaceutical Co., Ltd.). Novel imidazole derivatives, production method thereof and use thereof. EP 1334106, EP 1681290, JP 2003201282, JP 2006045239, US 7141598, WO 2002040484.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIa)	68259	bromo (2-ethoxy-2-oxoethyl)zinc;(2-ethoxy-2-oxoethyl)zinc bromide		C₄H₇BrO₂Zn	详情	详情
(VIIIb)	68260	bromo (2-tert-butoxy-2-oxoethyl)zinc;(2-(tert-butoxy)-2-oxoethyl)zinc bromide		C₆H₁₁BrO₂Zn	详情	详情
(Xa)	68262	3(S)-hydroxy-3-(4-imidazolyl)-3-(2-naphthyl)propionic acid ethyl		C₄₄H₄₅N₃O₄	详情	详情
(Xb)	68263	(S)-tert-butyl 3-(6-(diisopropylcarbamoyl)naphthalen-2-yl)-3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate		C₄₆H₄₉N₃O₄	详情	详情
(I)	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
(II)	68255	6-bromo-2-naphthoyl chloride		C₁₁H₆BrClO	详情	详情
(III)	68256	6-bromo-N,N-diisopropyl-2-naphthamide		C₁₇H₂₀BrNO	详情	详情
(IV)	27712	1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde	33016-47-6	C₂₃H₁₈N₂O	详情	详情
(V)	68257	6-(hydroxy(1-trityl-1H-imidazol-4-yl)methyl)-N,N-diisopropyl-2-naphthamide		C₄₀H₃₉N₃O₂	详情	详情
(VI)	68258	N,N-diisopropyl-6-(1-trityl-1H-imidazole-4-carbonyl)-2-naphthamide		C₄₀H₃₇N₃O₂	详情	详情
(VII)	68261	N-methoxy-N-methyl-1-trityl-1H-imidazole-4-carboxamide		C₂₅H₂₃N₃O₂	详情	详情
(IX)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(XI)	68264	(S)-6-(1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl)-N,N-diisopropyl-2-naphthamide		C₄₂H₄₃N₃O₃	详情	详情
(XII)	68265	7(S)-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol;(S)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N,N-diisopropyl-2-naphthamide		C₂₃H₂₇N₃O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Reagent (XI) can be prepared as follows: Reduction of carboxylic acid (IX) with LiAlH4 in Et2O or BH3 in THF followed by alcohol protection with TBDMSCl in CH2Cl2 in the presence of TEA and DMAP yields silyl ether (X). Derivative (X) is finally converted into Grignard reagent (XI) by means of Mg in THF or, alternatively, by treatment with t-BuLi in THF followed by MgBr2 in CH2Cl2 in the presence of TEA.

参考文献中间体

合成目标

【1】 Greenlee, M.L.; et al.; 2-Naphthylcarbapenems: Broad spectrum antibiotics with enhanced potency against MRSA. Bioorg Med Chem Lett 1999, 9, 19, 2893.
【2】 DiNinno, F.P.; Greenlee, M.L. (Merck & Co., Inc.); 2-Naphthyl-carbapenem antibacterial agents. EP 0466254; JP 1992253980; US 5032587 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	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
(X)	42565	(6-bromo-2-naphthyl)methyl tert-butyl(dimethyl)silyl ether; [(6-bromo-2-naphthyl)methoxy](tert-butyl)dimethylsilane		C₁₇H₂₃BrOSi	详情	详情
(XI)	42559	bromo[6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-naphthyl]magnesium		C₁₇H₂₃BrMgOSi	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

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