1,3,5-tribromobenzene -Drug Synthesis Database

【结构式】

【分子编号】26991

【品名】1,3,5-tribromobenzene

【CA登记号】626-39-1

【分子式】C₆H₃Br₃

【分子量】314.80182

【元素组成】C 22.89% H 0.96% Br 76.15%

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：(I)

The reaction of 1,3,5-tribromobenzene (I) with 4-fluorobenzaldehyde (II) by means of BuLi in ethyl ether gives the benzhydrol (III), which is condensed with ethyl acrylate (IV) by means of palladium acetate and tri o-tolylphosphine in refluxing acetonitrile yielding the phenylenebisacrylate (V). The acetylation of (V) with acetic anhydride and DMAP in dichloromethane affords the acetate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate providing the bispropanoate (VII). Selective hydrolysis of (VII) with NaOH in ethanol gives the monoacid (VIII), which is treated with oxalyl chloride in dichloromethane yielding the monoacyl chloride (IX). The reaction of (IX) with NH4OH affords the corresponding amide (X), which is treated with NaOCl and NaOH to perform degradation of the amide group and simultaneous hydrolysis of the ester group providing the amino acid (XI). Finally, this compound is sulfonated with 4-chlorophenylsulfonyl chloride (XII) and NaOH.

参考文献中间体

合成目标

【1】 Dack, K.N.; Dickinson, R.P.; Long, C.J.; Steele, J.; Thromboxane modulating agents. 4. Design and synthesis of 3-(2-[((4-chlorophenyl)sulfonyl)amino]ethyl)benzenepropanoic acid derivatives as potent thromboxane receptor antagonists. Bioorg Med Chem Lett 1998, 8, 16, 2061.

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)	26991	1,3,5-tribromobenzene	626-39-1	C₆H₃Br₃	详情	详情
(II)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(III)	26992	(3,5-dibromophenyl)(4-fluorophenyl)methanol		C₁₃H₉Br₂FO	详情	详情
(IV)	10164	ethyl acrylate	140-88-5	C₅H₈O₂	详情	详情
(V)	26993	ethyl (E)-3-[3-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-[(4-fluorophenyl)(hydroxy)methyl]phenyl]-2-propenoate		C₂₃H₂₃FO₅	详情	详情
(VI)	26994	ethyl (E)-3-[3-[(acetoxy)(4-fluorophenyl)methyl]-5-[(E)-3-ethoxy-3-oxo-1-propenyl]phenyl]-2-propenoate		C₂₅H₂₅FO₆	详情	详情
(VII)	26995	ethyl 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate		C₂₃H₂₇FO₄	详情	详情
(VIII)	26996	3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propionic acid		C₂₁H₂₃FO₄	详情	详情
(IX)	26997	ethyl 3-[3-(3-chloro-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate		C₂₁H₂₂ClFO₃	详情	详情
(X)	26998	ethyl 3-[3-(3-amino-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate		C₂₁H₂₄FNO₃	详情	详情
(XI)	26999	3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propionic acid		C₁₈H₂₀FNO₂	详情	详情
(XII)	15787	4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride	98-60-2	C₆H₄Cl₂O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The condensation of 1,3,5-tribromobenzene (VII) with benzaldehyde (VIII) by means of BuLi in ethyl ether gives 3,5-dibromodiphenylmethanol (IX), which is reduced with Tes-H and BF3/Et2O to yield 3,5-dibromodiphenylmethane (X). The carbonylation of (X) with BuLi and DMF in THF affords the benzaldehyde (XI), which is reduced by means of NaBH4 in methanol to provide the benzyl alcohol (XII). The reaction of (XII) with CBr4 and PPh3 in dichloromethane gives the bromomethyl derivative (XIII), which is condensed with 1,3-propanesultam (XIV) by means of K2CO3 in refluxing acetonitrile to yield the adduct (XV). The reaction of (XV) with thalium acetate and palladium acetate in DMF affords the acetyl derivative (XVI), which is brominated with Br2 and AlCl3 in dioxane to provide the bromoacetyl compound (XVII). The condensation of (XVII) with the intermediate amine (VI) by means of TEA in acetonitrile gives the secondary amine (XVIII), which is protected with benzyl chloroformate (XIX) to yield the carbamate (XX). The carboxylation of (XX) by means of CO, EtOH, TEA and PdCl2(PPh3)2 in ethyl acetate affords the pyridine-2-carboxylate derivative (XXI), which is finally cyclized by means of NaOMe in THF to provide the target naphthyridine derivative.

参考文献中间体

合成目标

【1】 Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J Med Chem 2003, 46, 4, 453.
【2】 Young, S.D.; Guare, J.P.; Wai, J.S.; Payne, L.S.; Fisher, T.E.; Zhuang, L.; Embrey, M. (Merck & Co., Inc.); Aza- and polyaza-naphthalenyl ketones useful as HIV integrase inhibitors. WO 0236734 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	61832	(2-chloro-3-pyridinyl)methanamine; (2-chloro-3-pyridinyl)methylamine		C₆H₇ClN₂	详情	详情
(VII)	26991	1,3,5-tribromobenzene	626-39-1	C₆H₃Br₃	详情	详情
(VIII)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(IX)	61833	(3,5-dibromophenyl)(phenyl)methanol		C₁₃H₁₀Br₂O	详情	详情
(X)	61834	1-benzyl-3,5-dibromobenzene		C₁₃H₁₀Br₂	详情	详情
(XI)	61835	3-benzyl-5-bromobenzaldehyde		C₁₄H₁₁BrO	详情	详情
(XII)	61836	(3-benzyl-5-bromophenyl)methanol		C₁₄H₁₃BrO	详情	详情
(XIII)	61837	1-benzyl-3-bromo-5-(bromomethyl)benzene		C₁₄H₁₂Br₂	详情	详情
(XIV)	61838	1lambda~6~-isothiazolidine-1,1-dione		C₃H₇NO₂S	详情	详情
(XV)	61839	2-(3-benzyl-5-bromobenzyl)-1lambda~6~-isothiazolidine-1,1-dione		C₁₇H₁₈BrNO₂S	详情	详情
(XVI)	61840	2-(3-acetyl-5-benzylbenzyl)-1lambda~6~-isothiazolidine-1,1-dione		C₁₉H₂₁NO₃S	详情	详情
(XVII)	61841	2-[3-benzyl-5-(2-bromoacetyl)benzyl]-1lambda~6~-isothiazolidine-1,1-dione		C₁₉H₂₀BrNO₃S	详情	详情
(XVIII)	61842	2-[3-benzyl-5-(2-{[(2-chloro-3-pyridinyl)methyl]amino}acetyl)benzyl]-1lambda~6~-isothiazolidine-1,1-dione		C₂₅H₂₆ClN₃O₃S	详情	详情
(XIX)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(XX)	61843	benzyl 2-{3-benzyl-5-[(1,1-dioxo-1lambda~6~-isothiazolidin-2-yl)methyl]phenyl}-2-oxoethyl[(2-chloro-3-pyridinyl)methyl]carbamate		C₃₃H₃₂ClN₃O₅S	详情	详情
(XXI)	61844	ethyl 3-({(2-{3-benzyl-5-[(1,1-dioxo-1lambda~6~-isothiazolidin-2-yl)methyl]phenyl}-2-oxoethyl)[(benzyloxy)carbonyl]amino}methyl)-2-pyridinecarboxylate		C₃₆H₃₇N₃O₇S	详情	详情

Extended Information