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【结 构 式】 
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【分子编号】17163 【品名】N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione 【CA登记号】5394-18-3 |
【 分 子 式 】C12H12BrNO2 【 分 子 量 】282.13682 【元素组成】C 51.09% H 4.29% Br 28.32% N 4.96% O 11.34% |
合成路线1
该中间体在本合成路线中的序号：(VII)The selective mesylation of 2'-O-acetyl-3-des(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A (I) with methanesulfonic anhydride in pyridine gives the expected 11-O-methanesulfonyl derivative (II), which is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to yield the 10,11-didehydro derivative (III). The acylation of (III) with carbonyl diimidazole (IV) by means of NaH in THF affords the 12-O-acyl derivative (V), which is finally cyclocondensed with 4-[4-(3-pyridyl)imidazol-1-yl]butylamine (VI) in hot acetonitrile. The intermediate compound 4-[4-(3-pyridyl)imidazol-1-yl]butylamine (VI) is obtained as follows: The condensation of N-(4-bromobutyl)phthalimide (VII) with 4-(3-pyridyl)imidazole (VIII) by means of NaH in DMF gives N-[4-[4-(3-pyridyl)imidazol-1-yl]butyl]phthalimide (IX), which is then treated with hydrazine in refluxing ethanol.
| 【1】 Castañer, J.; Graul, A.; HMR-3647. Drugs Fut 1998, 23, 6, 591. |
| 【2】 Agouridas, C.; Denis, A.; Auger, J.-M.; et al.; Synthesis and antibacterial activity of HMR 3647 a new ketolide highly potent against erythromycin-resistant and susceptible pathogens. Bioorg Med Chem Lett 1999, 9, 21, 3075. |
| 【3】 Agouridas, C.; Chantot, J.-F.; Denis, A.; Gouin d'Ambrieres, S.; Le Martret, O. (Aventis Pharma SA); Novel erythromycin derivs., method for their preparation and their use as drugs. EP 0680967; FR 2719587; JP 1996053489; JP 1999152296; US 5635485; WO 9529929 . |
| 【4】 Agouridas, C.; Chantot, J.F.; Denis, A.; Gouin d'Ambrieres, S.; Le Martret, O. (Aventis Pharma SA); Novel erythromycin derivs., their process of preparation and their application as medicines. FR 2732684 . |
| 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) | 17157 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C32H55NO11 | 详情 | 详情 | |
| (II) | 17158 | (2S,3R,4S,6R)-4-(dimethylamino)-2-([(3R,5R,6R,7R,9R,11R,12R,13R,14R)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-12-[(methylsulfonyl)oxy]-2,4,10-trioxooxacyclotetradecanyl]oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate | C33H57NO13S | 详情 | 详情 | |
| (III) | 17159 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,13S,14R)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxa-11-cyclotetradecen-6-yl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C32H53NO10 | 详情 | 详情 | |
| (IV) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (V) | 17161 | (2R,3S,7R,9R,10R,11R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C36H55N3O11 | 详情 | 详情 | |
| (VI) | 17162 | 4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylamine; 4-[4-(3-pyridinyl)-1H-imidazol-1-yl]-1-butanamine | 173838-63-6 | C12H16N4 | 详情 | 详情 |
| (VII) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (VIII) | 17164 | 3-(1H-imidazol-4-yl)pyridine | C8H7N3 | 详情 | 详情 | |
| (IX) | 17165 | 2-[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]-1H-isoindole-1,3(2H)-dione | 173838-67-0 | C20H18N4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Dichlorophenylpiperazine (III) was prepared from aniline (I) by dehydrative cyclization with diethanolamine (II) in the presence of P2O5 and Et3N-HCl at 200 C. Alkylation of piperazine (III) with N-(4-bromobutyl) phthalimide (IV) gave (V), and subsequent hydrazinolysis of the phthalimide provided the (4-aminobutyl)piperazine (VI). Finally, condensation of (VI) with fluorene-2-carboxylic acid (VII) yielded the target amide.
| 【1】 Yuan, J.; Chen, X.; Brodbeck, R.; Primus, R.; Braun, J.; Wasley, W.F.; Thurkauf, A.; NGB 2904 and NGB 2849: Two highly selective dopamine D3 receptor antagonists. Bioorg Med Chem Lett 1998, 8, 19, 2715. |
| 【2】 Yuan, J.; Chen, X. (Neurogen Corp.); Novel N-aminoalkylfluorenecarboxamides; a new class of dopamine receptor subtype specific ligands. EP 0873329; JP 1998511114; US 5659033; WO 9710229 . |
| 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) | 28562 | 2,3-dichlorophenylamine | 608-27-5 | C6H5Cl2N | 详情 | 详情 |
| (II) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (III) | 13943 | 1-(2,3-Dichlorophenyl)piperazine | 41202-77-1 | C10H12Cl2N2 | 详情 | 详情 |
| (IV) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (V) | 28563 | 2-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)-dione | C22H23Cl2N3O2 | 详情 | 详情 | |
| (VI) | 28564 | 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butylamine | C14H21Cl2N3 | 详情 | 详情 | |
| (VII) | 28566 | 9H-fluorene-2-carboxylic acid | C14H10O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Dichlorophenylpiperazine (III) was prepared from aniline (I) by dehydrative cyclization with diethanolamine (II) in the presence of P2O5 and Et3N-HCl at 200 C. Alkylation of piperazine (III) with N-(4-bromobutyl) phthalimide (IV) gave (V), and subsequent hydrazinolysis of the phthalimide provided the (4-aminobutyl)piperazine (VI). Finally, condensation of (VI) with biphenylene-2-carboxylic acid (VII) yielded the target amide.
| 【1】 Yuan, J.; Chen, X.; Brodbeck, R.; Primus, R.; Braun, J.; Wasley, W.F.; Thurkauf, A.; NGB 2904 and NGB 2849: Two highly selective dopamine D3 receptor antagonists. Bioorg Med Chem Lett 1998, 8, 19, 2715. |
| 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) | 28562 | 2,3-dichlorophenylamine | 608-27-5 | C6H5Cl2N | 详情 | 详情 |
| (II) | 24273 | 2-[(2-hydroxyethyl)amino]-1-ethanol | 111-42-2 | C4H11NO2 | 详情 | 详情 |
| (III) | 23943 | 2-methoxyisonicotinonitrile | C7H6N2O | 详情 | 详情 | |
| (IV) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (V) | 28563 | 2-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)-dione | C22H23Cl2N3O2 | 详情 | 详情 | |
| (VI) | 28564 | 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butylamine | C14H21Cl2N3 | 详情 | 详情 | |
| (VII) | 28565 | 2-biphenylenecarboxylic acid | C13H8O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The primary amino group of 4-(aminomethyl)piperidine (I) was protected by conversion to the phthalimide (III) upon heating with phthalic anhydride (II). After coupling of piperidine (III) with 1-naphthylacetic acid (IV) to give amide (V), hydrazinolysis of the phthalimido group of (V) liberated the primary amine (VI). Alkylation of (VI) with N-(4-bromobutyl)phthalimide (VII) furnished the secondary amine (VIII), which was further protected with a tert-butoxycarbonyl group to provide (IX). The phthaloyl group of (IX) was then removed by hydrazinolysis, yielding amine (X). This was subjected to reductive alkylation with cyclohexanecarboxaldehyde (XI) in the presence of NaBH4 to afford the cyclohexylmethyl amine (XII). After purification as the di-Boc derivative, acid cleavage of the tert-butyl carbamate groups provided the title compound.
| 【1】 Yoneda, Y.; et al.; Synthesis of diaminobutane derivatives as potent Ca2+-permeable AMPA receptor antagonists. Bioorg Med Chem Lett 2001, 11, 19, 2663. |
| 【2】 Ito, M.; Yoneda, Y.; Kawagoe, K.; Yasukouchi, T.; Kito, F.; Mimura, T.; Kawajiri, S.; Sugimura, M.; Saito, M.; Tatematu, T.; Discovery of diaminobutane derivatives as Ca2+ -permeable AMPA receptor antagonists. Bioorg Med Chem 2002, 10, 5, 1347. |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (III) | 51132 | 2-(4-piperidinylmethyl)-1H-isoindole-1,3(2H)-dione | C14H16N2O2 | 详情 | 详情 | |
| (IV) | 51133 | Planofix; alpha-Naphthylacetic acid; 1-Naphthaleneacetic acid; 1-Naphthylacetic acid; alpha-Naphthaleneacetic acid; Naphthalene-1-acetic acid | 86-87-3 | C12H10O2 | 详情 | 详情 |
| (V) | 51134 | 2-([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)-1H-isoindole-1,3(2H)-dione | C26H24N2O3 | 详情 | 详情 | |
| (VI) | 51135 | 1-[4-(aminomethyl)-1-piperidinyl]-2-(1-naphthyl)-1-ethanone | C18H22N2O | 详情 | 详情 | |
| (VII) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (VIII) | 51136 | 2-[4-[([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)amino]butyl]-1H-isoindole-1,3(2H)-dione | C30H33N3O3 | 详情 | 详情 | |
| (IX) | 51137 | tert-butyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)carbamate | C35H41N3O5 | 详情 | 详情 | |
| (X) | 51138 | tert-butyl 4-aminobutyl([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)carbamate | C27H39N3O3 | 详情 | 详情 | |
| (XI) | 33694 | cyclohexanecarbaldehyde | 2043-61-0 | C7H12O | 详情 | 详情 |
| (XII) | 51139 | tert-butyl 4-[(cyclohexylmethyl)amino]butyl([1-[2-(1-naphthyl)acetyl]-4-piperidinyl]methyl)carbamate | C34H51N3O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The condensation of 3-ethylphenol (I) with 4-piperidone (II) by means of gaseous HCl in acetic acid gives 5-ethyl-2-(1,2,3,6-tetrahydropyridin-4-yl)phenol (III), which is treated with acetic anhydride in pyridine to yield the diacetyl derivative (IV). The selective hydrolysis of the O-acetyl group of (IV) by means of K2CO3 in methanol affords the phenol derivative (V), which is hydrogenated with H2 over Pd/C in methanol to provide the acetyl piperidine (VI). The alkylation of the phenolic group of (VI) with ethyl iodide and Cs2CO3 in refluxing acetone gives 1-acetyl-4-(2-ethoxy-4-ethylphenyl)piperidine (VII), which is deacetylated by means of NaOH in refluxing methanol to yield 4-(2-ethoxy-4-ethylphenyl)piperidine (VIII). The alkylation of the piperidine (VIII) with N-(4-bromobutyl)phthalimide (IX) by means of Cs2CO3 in refluxing acetone affords the adduct (X), which is cleaved with hydrazine in hot methanol to provide 1-(4-aminobutyl)-4-(2-ethoxy-4-ethylphenyl)piperidine (XI). Finally, this amine is condensed with 4-(4-chlorobenzamido)benzoic acid (XII) by means of EDC, HOBT and TEA in DMF to give the target diamide. The intermediate 4-(4-chlorobenzamido)benzoic acid (XII) is obtained as follows: The condensation of 4-aminobenzoic acid ethyl ester (XIV) with 4-chlorobenzoyl chloride (XIII) by means of TEA and DMAP gives 4-(4-chlorobenzamido)benzoic acid ethyl ester (XV), which is finally hydrolyzed with NaOH to afford the target benzoic acid intermediate (XII).
| 【1】 Grand-Perret, T.A.R.; Issandou, M. (GlaxoSmithKline plc); Binding competition of SREBP-cleavage activating protein (SCAP) antagonists. WO 0106261 . |
| 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) | 53495 | 3-Ethyl phenol; m-Ethyl phenol | 620-17-7 | C8H10O | 详情 | 详情 |
| (II) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (III) | 53496 | 5-ethyl-2-(1,2,3,6-tetrahydro-4-pyridinyl)phenol | n/a | C13H17NO | 详情 | 详情 |
| (IV) | 53497 | 2-(1-acetyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-ethylphenyl acetate | n/a | C17H21NO3 | 详情 | 详情 |
| (V) | 53498 | 1-[4-(4-ethyl-2-hydroxyphenyl)-3,6-dihydro-1(2H)-pyridinyl]-1-ethanone | n/a | C15H19NO2 | 详情 | 详情 |
| (VI) | 53499 | 1-[4-(4-ethyl-2-hydroxyphenyl)-1-piperidinyl]-1-ethanone | n/a | C15H21NO2 | 详情 | 详情 |
| (VII) | 53500 | 1-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]-1-ethanone | n/a | C17H25NO2 | 详情 | 详情 |
| (VIII) | 53501 | 4-(2-ethoxy-4-ethylphenyl)piperidine; ethyl 5-ethyl-2-(4-piperidinyl)phenyl ether | n/a | C15H23NO | 详情 | 详情 |
| (IX) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (X) | 53502 | 2-{4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]butyl}-1H-isoindole-1,3(2H)-dione | n/a | C27H34N2O3 | 详情 | 详情 |
| (XI) | 53503 | 4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]-1-butanamine; 4-[4-(2-ethoxy-4-ethylphenyl)-1-piperidinyl]butylamine | n/a | C19H32N2O | 详情 | 详情 |
| (XII) | 53504 | 4-[(4-chlorobenzoyl)amino]benzoic acid | n/a | C14H10ClNO3 | 详情 | 详情 |
| (XIII) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (XIV) | 16498 | Benzocaine; ethyl 4-aminobenzoate | 94-09-7 | C9H11NO2 | 详情 | 详情 |
| (XV) | 53505 | Ethyl 4-(4-chlorobenzamido)benzoate | n/a | C16H14ClNO3 | 详情 | 详情 |