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【结 构 式】 
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【分子编号】40934 【品名】3-nitrophenylboronic acid 【CA登记号】13331-27-6 |
【 分 子 式 】C6H6BNO4 【 分 子 量 】166.92898 【元素组成】C 43.17% H 3.62% B 6.48% N 8.39% O 38.34% |
合成路线1
该中间体在本合成路线中的序号：(IV)Reaction of 3-(cyanomethyl)pyridine-N-oxide (I) with cyanotrimethylsilane and dimethylcarbamoyl chloride provided dinitrile (II). Subsequent cyclization of (II) in the presence of HBr gave rise to 6-amino-8-bromo-1,7-naphthyridine (III). Attachment of a 3-nitrophenyl group to (III) to afford (V) was carried out by Suzuki coupling of (III) with 3-nitrophenylboronic acid (IV) in the presence of bis(dibenzylideneacetone)palladium and triphenylphosphine. The required triflate (VI) was then obtained by nitrosation of aminonaphthyridine (V) in trifluromethanesulfonic acid/DMF. Finally, a second Suzuki coupling of (VI) with 4-carboxyphenylboronic acid (VII) provided the title 6,8-diarylnaphthyridine.
| 【1】 Bray-French, K.; Hersperger, R.; Müller, T.; Mazzoni, L.; Palladium-catalyzed cross-coupling reactions for the synthesis of 6,8-disubstituted 1,7-naphthyridines: A novel class of potent and selective phosphodiesterase type 4D inhibitors. J Med Chem 2000, 43, 4, 675. |
| 【2】 Hersperger, R. (Novartis AG); Naphtyridine derivs.. EP 0934320; US 6136821; WO 9818796 . |
| 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) | 40931 | 3-(cyanomethyl)-1-pyridiniumolate | C7H6N2O | 详情 | 详情 | |
| (II) | 40932 | 3-(cyanomethyl)-2-pyridinecarbonitrile | C8H5N3 | 详情 | 详情 | |
| (III) | 40933 | 8-bromo[1,7]naphthyridin-6-ylamine; 8-bromo[1,7]naphthyridin-6-amine | C8H6BrN3 | 详情 | 详情 | |
| (IV) | 40934 | 3-nitrophenylboronic acid | 13331-27-6 | C6H6BNO4 | 详情 | 详情 |
| (V) | 40935 | 8-(3-nitrophenyl)[1,7]naphthyridin-6-ylamine; 8-(3-nitrophenyl)[1,7]naphthyridin-6-amine | C14H10N4O2 | 详情 | 详情 | |
| (VI) | 40936 | 8-(3-nitrophenyl)[1,7]naphthyridin-6-yl trifluoromethanesulfonate | C15H8F3N3O5S | 详情 | 详情 | |
| (VII) | 32841 | 4-(dihydroxyboryl)benzoic acid；4-Boronobenzoic acid；4-carboxyphenylboronic acid;4-(Dihydroxyboryl)benzoic acid | 14047-29-1 | C7H7BO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Formylation of methyl 4-hydroxyphenylacetate (I) by reaction with MgCl2 and formaldehyde in acetonitrile yields aldehyde (II), which is then brominated by means of NBS in DMF to provide bromo derivative (III). Treatment of (III) with methoxyethoxymethyl chloride and DIEA furnishes O-protected derivative (IV), which is then subjected to Suzuki reaction with boronic acid (V) catalyzed by Pd(PPh3)4 in refluxing toluene in the presence of Na2CO3 to afford biphenyl (VI). Treatment of (VI) with dimethyl-1-diazo-2-oxopropylphosphonate (VII) in MeOH in the presence of K2CO3 furnishes alkyne (VIII), which is then coupled with the iodo-benzonitrile (IX) by means of catalytic Pd(PPh3)2Cl2, CuI and Et3N in acetonitrile to provide indole (X). Saponification of the methyl ester group of (X) with NaOH in THF, followed by hydrolysis with HCl in EtOH, gives carboxylic acid (XI), which is finally converted into the desired product by transformation of the nitrile moiety into an amidine via standard Pinner/aminolysis conditions with NH3 in EtOH followed by treatment with refluxing HCl.
| 【1】 Young, W.B.; Kolesnikov, A.; Rai, R.; et al.; Optimization of a screening lead for factor VIIa/TF. Bioorg Med Chem Lett 2001, 11, 17, 2253. |
| 【2】 Young, W.B.; Kakimura, H.; Nakaike, S.; Taniguchi, K.; Kobayashi, Y.; Ishii, T.; Amada, H.; Miyata, N.; Kametani, S.; Optimization of a screening lead for factor VIIIA/TF. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 48. |
| 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) | 15822 | Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate | 14199-15-6 | C9H10O3 | 详情 | 详情 |
| (II) | 48883 | methyl 2-(3-formyl-4-hydroxyphenyl)acetate | C10H10O4 | 详情 | 详情 | |
| (III) | 48884 | methyl 2-(3-bromo-5-formyl-4-hydroxyphenyl)acetate | C10H9BrO4 | 详情 | 详情 | |
| (IV) | 48885 | methyl 2-[3-bromo-5-formyl-4-[(2-methoxyethoxy)methoxy]phenyl]acetate | C14H17BrO6 | 详情 | 详情 | |
| (V) | 40934 | 3-nitrophenylboronic acid | 13331-27-6 | C6H6BNO4 | 详情 | 详情 |
| (VI) | 48886 | methyl 2-[5-formyl-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate | C20H21NO8 | 详情 | 详情 | |
| (VII) | 32432 | 1-Diazo-2-oxopropylphosphonic acid dimethyl ester | C5H9N2O4P | 详情 | 详情 | |
| (VIII) | 48887 | methyl 2-[5-ethynyl-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate | C21H21NO7 | 详情 | 详情 | |
| (IX) | 48888 | N-(4-cyano-2-iodophenyl)methanesulfonamide | C8H7IN2O2S | 详情 | 详情 | |
| (X) | 48889 | methyl 2-[5-[5-cyano-1-(methylsulfonyl)-1H-indol-2-yl]-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate | C29H27N3O9S | 详情 | 详情 | |
| (XI) | 48890 | 2-[5-(5-cyano-1H-indol-2-yl)-6-hydroxy-3'-nitro[1,1'-biphenyl]-3-yl]acetic acid | C23H15N3O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The title compound was synthesized within a combinatorial library on a Wang polystyrene resin. Attachment of N-Fmoc-(R)-beta-phenylalanine (I) to the solid support was achieved via activation with 2,6-dichlorobenzoyl chloride to afford the aminoacid-bound resin (II). After conventional Fmoc group deprotection with piperidine in DMF, the resultant amine resin (III) was acylated with 5-bromo-2-methoxybenzenesulfonyl chloride (IV) yielding sulfonamide (V). Mitsunobu coupling between aryl bromide (V) and 3-nitrobenzeneboronic acid (VI) gave rise to the biphenyl derivative (VII). Reduction of the nitro group of (VII) to the corresponding aniline (VIII) was then performed by treatment with stannous chloride in N-methylpyrrolidone. Alternatively, the aminobiphenyl resin (VIII) was directly prepared by coupling between aryl bromide (V) and 3-aminobenzeneboronic acid (IX). Reaction of amine (VIII) with p-nitrophenyl chloroformate (X) produced the nitrophenyl carbamate resin (IX), which was further reacted with 2-aminobenzimidazole (XII) to furnish urea (XIII). Final resin cleavage was effected by treatment with trifluoroacetic acid in CH2Cl2.
| 【1】 Gerdes, C.; Albers, M.; Schmidt, D.; Stelte-Ludwig, B.; Bruggemeier, U.; Vaupel, A.; Harter, M.; Urbahns, K.; Biphenyls as potent vitronectin receptor antagonists. Bioorg Med Chem Lett 2002, 12, 2, 205. |
| 【2】 Schmidt, D.; Urbahns, K.; Gerdes, C.; Keldenich, J.; Härter, M.; Stahl, E.; Albers, M.; Vaupel, A.; Stelte-Ludwig, B.; Brüggemeier, U.; Lustig, K. (Bayer AG); New biphenyl and biphenyl-analogous cpds. as integrin antagonists. EP 1140809; JP 2002532465; US 6420396; WO 0035864 . |
| 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),(II) | 56271 | Fmoc-(R)-3-amino-3-phenylpropionic acid | C24H21NO4 | 详情 | 详情 | |
| (III) | 56272 | (3R)-3-amino-3-phenylpropanoic acid | C9H11NO2 | 详情 | 详情 | |
| (IV) | 56273 | 5-Bromo-2-methoxybenzenesulfonyl chloride | 23095-05-8 | C7H6BrClO3S | 详情 | 详情 |
| (V) | 56274 | (3R)-3-{[(5-bromo-2-methoxyphenyl)sulfonyl]amino}-3-phenylpropanoic acid | C16H16BrNO5S | 详情 | 详情 | |
| (VI) | 40934 | 3-nitrophenylboronic acid | 13331-27-6 | C6H6BNO4 | 详情 | 详情 |
| (VII) | 56275 | (3R)-3-{[(4-methoxy-3'-nitro[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid | C22H20N2O7S | 详情 | 详情 | |
| (VIII) | 56276 | (3-Aminophenyl)dihydroxyborane; 3-Aminobenzeneboronic acid; 3-Aminophenylboronic acid | 30418-59-8 | C22H22N2O5S | 详情 | 详情 |
| (IX) | 56277 | 3-aminophenylboronic acid | C6H8BNO2 | 详情 | 详情 | |
| (X) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XI) | 56278 | (3R)-3-{[(4-methoxy-3'-{[(4-nitrophenoxy)carbonyl]amino}[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid | C29H25N3O9S | 详情 | 详情 | |
| (XII) | 48437 | 2-Aminobenzimidazole; 2-Amino-1H-benzimidazol; 1H-Benzimidazol-2-amine; 2-Benzimidazolamine | 934-32-7 | C7H7N3 | 详情 | 详情 |
| (XIII) | 56279 | (3R)-3-{[(3'-{[(1H-benzimidazol-2-ylamino)carbonyl]amino}-4-methoxy[1,1'-biphenyl]-3-yl)sulfonyl]amino}-3-phenylpropanoic acid | C30H27N5O6S | 详情 | 详情 |