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【结 构 式】 
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【分子编号】13463 【品名】o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene 【CA登记号】1493-27-2 |
【 分 子 式 】C6H4FNO2 【 分 子 量 】141.1017032 【元素组成】C 51.07% H 2.86% F 13.46% N 9.93% O 22.68% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 5-carboxyphthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives the lactol (III), which is treated with 3-(dimethylamino)propylmagnesium chloride in the same solvent to yield the dihydroxylated intermediate (V). The cyclization of (V) by means of conc. HCl affords the isobenzofuran derivative (VI), which is finally treated with sulfamide and thionyl chloride in sulfolane at 130 C in order to convert the carboxy group of (VI) into the target 5-cyano group of citalopram.
| 【1】 Petersen, H.; Dancer, R.; Ahmadian, H. (H. Lundbeck A/S); Method for the preparation of citalopram. WO 0216341; WO 0216342 . |
| 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) | 37594 | 1-oxo-1,3-dihydro-2-benzofuran-5-carboxylic acid | C9H6O4 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 55293 | 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydro-2-benzofuran-5-carboxylic acid | C15H11FO4 | 详情 | 详情 | |
| (IV) | 12587 | Chloro[3-(dimethylamino)propyl]magnesium | C5H12ClMgN | 详情 | 详情 | |
| (V) | 55294 | 4-[4-(dimethylamino)-1-hydroxy-1-(4-methylphenyl)butyl]-3-(hydroxymethyl)benzoic acid | C21H27NO4 | 详情 | 详情 | |
| (VI) | 55295 | 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carboxylic acid | C20H22FNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of 2-fluoronitrobenzene (I) with cyclohexanol (II) by means of NaH gives 2-(cyclohexyloxy)nitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 2-(cyclohexyloxy)aniline (IV). The acylation of (IV) with methanesulfonyl chloride (V) in pyridine affords N-(2-cyclohexyloxy phenyl)methanesulfonamide (VI), which is finally nitrated with concentrated HNO3 in hot acetic acid.
| 【1】 Yoshikawa, K.; Ohuchi, Y.; Sekiuchi, K.; Saito, S.; Hatayama, K.; Sota, K. (Taisho Pharmaceutical Co., Ltd.); Sulfoanilide cpds. EP 0317332; JP 1990000268 . |
| 【2】 Yoshikawa, K.; Ohuchi, H.; Saito, H.; Nakajima, Y.; Hatayama, K.; Soda, H. (Taisho Pharmaceutical Co., Ltd.); Antiinflammatories, analgesics and antipyretics. JP 1990300122 . |
| 【3】 Prous, J.; Castaner, J.; Mealy, N.; NS-398. Drugs Fut 1993, 18, 7, 603. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (III) | 13465 | Cyclohexyl 2-nitrophenyl ether; 1-(Cyclohexyloxy)-2-nitrobenzene | C12H15NO3 | 详情 | 详情 | |
| (IV) | 13466 | 2-(Cyclohexyloxy)aniline; 2-(Cyclohexyloxy)phenylamine | C12H17NO | 详情 | 详情 | |
| (V) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (VI) | 13468 | N-[2-(Cyclohexyloxy)phenyl]methanesulfonamide | C13H19NO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The synthesis of some metabolites of olanzapine have been described: 1) Synthesis of 4'-N-desmethyl olanzapine: The condensation of 2-fluoronitrobenzene (I) with 5-methylthiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III), which is cyclized by means of SnCl2 in ethanol yielding 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine-4-amine (IV). Finally, this compound is condensed with piperazine (V) in toluene/DMSO affording the metabolite 2-methyl-4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.
| 【1】 Calligaro, D.O.; Moore, N.A.; Tupper, D.E.; Fairhurst, J.; Hotten, T.M.; The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053). Bioorg Med Chem Lett 1997, 7, 1, 25. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 15249 | 5-Amino-4-cyano-2-methylthiophene; 2-amino-5-methyl-3-thiophenecarbonitrile | 138564-58-6 | C6H6N2S | 详情 | 详情 |
| (III) | 15250 | 5-methyl-2-(2-nitroanilino)-3-thiophenecarbonitrile | C12H9N3O2S | 详情 | 详情 | |
| (IV) | 15255 | 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-ylamine; 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine | C12H11N3S | 详情 | 详情 | |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)2) Synthesis of olanzapine 4'-N-oxide: The condensation of 2-fluoronitrobenzene (I) with 5-methylthiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III), which is cyclized by means of SnCl2 in ethanol yielding 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine-4-amine (IV). The condensation of (IV) with N-methylpiperazine (V) in toluene/DMSO affords 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepin e (olanzapine) (VI), which is finally oxidized with m-chloroperbenzoic acid (m-CPBA) in dichloromethane to give the metabolite 2-methyl-4-(4-methyl-4-oxidopiperazinyl-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine.
| 【1】 Calligaro, D.O.; Moore, N.A.; Tupper, D.E.; Fairhurst, J.; Hotten, T.M.; The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053). Bioorg Med Chem Lett 1997, 7, 1, 25. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 15249 | 5-Amino-4-cyano-2-methylthiophene; 2-amino-5-methyl-3-thiophenecarbonitrile | 138564-58-6 | C6H6N2S | 详情 | 详情 |
| (III) | 15250 | 5-methyl-2-(2-nitroanilino)-3-thiophenecarbonitrile | C12H9N3O2S | 详情 | 详情 | |
| (IV) | 15255 | 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-ylamine; 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine | C12H11N3S | 详情 | 详情 | |
| (V) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (VI) | 15262 | 2-methyl-4-(4-methylpiperazino)-10H-thieno[2,3-b][1,5]benzodiazepine | C17H20N4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)3) Synthesis of 2-hydroxymethyl olanzapine: The condensation of 2-fluoronitrobenzene (I) with thiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III), which is formylated with DMF by means of POCl3 yielding the aldehyde (IV). The reducticyclization of (IV) with SnCl2 in ethanol affords 4-amino-10H-thieno[2,3-b][1,5]benzodiazepine-2-carbaldehyde (V), which is reduced with NaBH4 in ethanol to the corresponding hydroxymethyl derivative (VI). Finally, this compound is condensed with N-methylpiperazine (VII) in toluene/DMSO to give the metabolite 2-(hydroxymethyl)-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benz odiazepine.
| 【1】 Calligaro, D.O.; Moore, N.A.; Tupper, D.E.; Fairhurst, J.; Hotten, T.M.; The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053). Bioorg Med Chem Lett 1997, 7, 1, 25. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 15263 | 2-amino-3-thiophenecarbonitrile | 4651-82-5 | C5H4N2S | 详情 | 详情 |
| (III) | 15264 | 2-(2-nitroanilino)-3-thiophenecarbonitrile | C11H7N3O2S | 详情 | 详情 | |
| (IV) | 15265 | 5-formyl-2-(2-nitroanilino)-3-thiophenecarbonitrile | C12H7N3O3S | 详情 | 详情 | |
| (V) | 15266 | 4-amino-10H-thieno[2,3-b][1,5]benzodiazepine-2-carbaldehyde | C12H9N3OS | 详情 | 详情 | |
| (VI) | 15267 | (4-amino-10H-thieno[2,3-b][1,5]benzodiazepin-2-yl)methanol | C12H11N3OS | 详情 | 详情 | |
| (VII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound.
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound. The intermediate 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) has been obtained as follows: The reaction of benzylmalonic acid (XI) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XII), which is condensed with O-benzylhydroxylamine (XIII) in refluxing ethanol yielding 2-benzyl-3-(benzyloxyamino)propionic acid (XIV). Finally, this compound is N-formylated with formic acid/acetic anhydride to afford the desired intermediate (IX).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Condensation of 1-fluoro-2-nitrobenzene (I) with cis-4-hydroxy-D-proline methyl ester (II) in hot acetonitrile provided the N-(2-nitrophenyl)proline derivative (III). The stereochemical inversion of the hydroxyl group of (III) was achieved by Mitsunobu coupling with acetic acid, followed by basic hydrolysis of the resulting acetate ester (IV) to acid (V). The nitro acid (V) obtained was then hydrogenated over Pd/C to form the tricyclic lactam (VI). Further reduction of the lactam carbonyl group by means of NaBH4 in refluxing THF gave pyrroloquinoxaline (VII). This was finally coupled with 4-(4'-methyl-2-biphenylcarboxamido)benzoyl chloride (VIII) to furnish the target amide.
| 【1】 Naito, A.; Ohtake, Y.; Hasegawa, H.; et al.; Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives. Bioorg Med Chem 1999, 7, 6, 1247. |
| 【2】 Matsukawa, H.; Toyofuku, H.; Naito, A.; Ohtake, Y.; Saito, Y.; Naito, K. (Wakamoto Pharmaceutical Co., Ltd.); Biphenyl derivs. and medicinal compsns.. EP 0987266; WO 9843976 . |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 36815 | methyl (2R,4R)-4-hydroxy-2-pyrrolidinecarboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 36816 | methyl (2R,4R)-4-hydroxy-1-(2-nitrophenyl)-2-pyrrolidinecarboxylate | C12H14N2O5 | 详情 | 详情 | |
| (IV) | 36817 | methyl (2R,4S)-4-(acetoxy)-1-(2-nitrophenyl)-2-pyrrolidinecarboxylate | C14H16N2O6 | 详情 | 详情 | |
| (V) | 36818 | (2R,4S)-4-hydroxy-1-(2-nitrophenyl)-2-pyrrolidinecarboxylic acid | C11H12N2O5 | 详情 | 详情 | |
| (VI) | 36819 | (2S,3aR)-2-hydroxy-1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxalin-4(5H)-one | C11H12N2O2 | 详情 | 详情 | |
| (VII) | 36820 | (2S,3aR)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxalin-2-ol | C11H14N2O | 详情 | 详情 | |
| (VIII) | 36821 | 4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl chloride | C21H16ClNO2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)The condensation of 2-fluoronitrobenzene (I) with acetone oxime (II) by means of NaH in DMF gives acetone O-(2-nitrophenyl)oxime (III), which is cyclized to 2-methyl-7-nitrobenzofuran (IV) by means of H2SO4. The Friedel Crafts acylation of (IV) with acetyl chloride and AlCl3 in dichloromethane affords 3-acetyl-2-methyl-7-nitrobenzofuran (V), which is reduced to the corresponding amino derivative (VI) with Fe and HCl in ethanol. The condensation of (VI) with 2,6-dichlorobenzoyl chloride (VII) by means of triethylamine in dichloroethane yields N-(3-acetyl-2-methylbenzofuran-7-yl)-2,6-dichlorobenzamide (VIII), which is finally submitted to a Grignard reaction with methylmagnesium bromide in THF.
| 【1】 Yamazaki, H.; et al.; Synthesis and pharmacological activities of novel benzofuran derivatives as vacuolar type H+-ATPase inhibitors. Symp Med Chem 1998, Abst 2-P-32. |
| 【2】 Kawai, Y.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K.; Yatabe, T.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Benzofuran derivs. useful as inhibitors of bone resorption. EP 0757682; JP 1997512795; US 5858995; WO 9529907 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 17791 | acetone oxime; Acetoxime | 127-06-0 | C3H7NO | 详情 | 详情 |
| (III) | 25083 | acetone O-(2-nitrophenyl)oxime | C9H10N2O3 | 详情 | 详情 | |
| (IV) | 25084 | 2-methyl-7-nitro-1-benzofuran | C9H7NO3 | 详情 | 详情 | |
| (V) | 25086 | 1-(7-amino-2-methyl-1-benzofuran-3-yl)-1-ethanone | C11H11NO2 | 详情 | 详情 | |
| (VI) | 24086 | benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetate | C25H25N3O6S | 详情 | 详情 | |
| (VII) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (VIII) | 25088 | N-(3-acetyl-2-methyl-1-benzofuran-7-yl)-2,6-dichlorobenzamide | C18H13Cl2NO3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VI)Reductive alkylation of ethyl 4-oxopiperidine-3-carboxylate (I) with cyclooctane carboxaldehyde (II) in the presence of sodium triacetoxy borohydride provided the cyclooctylmethyl piperidine (III). Treatment of (III) with ammonium acetate gave the unstable enamine (IV), which was reduced to amine (V) with NaBH3CN and subsequently coupled with 2-fluoronitrobenzene (VI) in refluxing MeOH to furnish nitroaniline (VIIa-b) as a mixture of trans- and cis-isomers. After separation by silica gel column chromatography, the desired trans-isomer was hydrogenated in the presence of Pd/C to afford phenylenediamine (VIII). Cyclization of (VIII) with carbonyldiimidazole produced benzimidazolone (IX), which was N-alkylated with ethyl iodide and NaH to give (X). Reduction of the ester group of (X) with LiAlH4 yielded the corresponding alcohol as a racemate. Optical resolution was achieved using a Chiralpak AD column.
| 【1】 Kawamoto, H.; et al.; Discovery and synthesis of the first potent and selective small molecule ORL1 receptor antagonist: J-113397. 20th Symp Med Chem (Dec 6 2000, Tokyo) 2000, Abst 1P-14. |
| 【2】 Miyaji, M.; Nakashima, H.; Arai, S.; Kawamoto, H.; Ohta, H.; Itoh, Y.; Iwasawa, Y.; Kato, T.; Ozaki, S.; Discovery of the first potent and selective small molecule opioid receptor-like (ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]3-ethyl-1,3-dihydro-2H-benzimidazol-2-one(J-113397). J Med Chem 1999, 42, 25, 5061. |
| 【3】 Ozaki, S.; Kawamoto, H.; Hirano, K.; Ito, Y.; Hayashi, K.; Iwasawa, Y. (Banyu Pharmaceutical Co., Ltd.); 2-Oxoimidazole derivs.. EP 0990653; WO 9854168 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 38005 | ethyl (3R,4R)-1-(cyclooctylmethyl)-4-(2-nitroanilino)-3-piperidinecarboxylate | C23H35N3O4 | 详情 | 详情 | |
| (VIIb) | 38006 | ethyl (3S,4R)-1-(cyclooctylmethyl)-4-(2-nitroanilino)-3-piperidinecarboxylate | C23H35N3O4 | 详情 | 详情 | |
| (I) | 38000 | ethyl 4-oxo-3-piperidinecarboxylate | 4644-61-5 | C8H13NO3 | 详情 | 详情 |
| (II) | 38001 | cyclooctanecarbaldehyde | 6688-11-5 | C9H16O | 详情 | 详情 |
| (III) | 38002 | ethyl 1-(cyclooctylmethyl)-4-oxo-3-piperidinecarboxylate | C17H29NO3 | 详情 | 详情 | |
| (IV) | 38003 | ethyl 4-amino-1-(cyclooctylmethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C17H30N2O2 | 详情 | 详情 | |
| (V) | 38004 | ethyl 4-amino-1-(cyclooctylmethyl)-3-piperidinecarboxylate | C17H32N2O2 | 详情 | 详情 | |
| (VI) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (VIII) | 38007 | ethyl (3R,4R)-4-(2-aminoanilino)-1-(cyclooctylmethyl)-3-piperidinecarboxylate | C23H37N3O2 | 详情 | 详情 | |
| (IX) | 38008 | ethyl (3R,4R)-1-(cyclooctylmethyl)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-3-piperidinecarboxylate | C24H35N3O3 | 详情 | 详情 | |
| (X) | 38009 | ethyl (3R,4R)-1-(cyclooctylmethyl)-4-(3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-3-piperidinecarboxylate | C26H39N3O3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)The condensation of the mono-protected 2,3-diaminopropionic acid (I) with 2-fluoronitrobenzene (II) produced the nitro acid (III). After catalytic hydrogenation of the nitro group of (III), the resulting amino acid (IV) was cyclized to the benzodiazepinone (V) upon refluxing in toluene. Alkylation of (V) with cyclohexenyl bromide (VI) afforded the 5-cyclohexenyl benzodiazepinone (VII), which was further hydrogenated to the cyclohexyl derivative (VIII). Acid cleavage of the Boc protecting group of (VIII) furnished the aminobenzodiazepinone (IX).
| 【1】 Murata, M.; Shinozaki, K.; Yoneta, T.; Miura, N.; Maeda, K. (Zeria Pharmaceutical Co., Ltd.); 1,5-Benzodiazepine derivs.. EP 0945445; US 6239131; WO 9825911 . |
| 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) | 49763 | Boc-D-diaminopropionic acid | C8H16N2O4 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 49764 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitroanilino)propionic acid | C14H19N3O6 | 详情 | 详情 | |
| (IV) | 49765 | (2R)-3-(2-aminoanilino)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H21N3O4 | 详情 | 详情 | |
| (V) | 49766 | tert-butyl (3R)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-ylcarbamate | C14H19N3O3 | 详情 | 详情 | |
| (VI) | 30800 | 3-bromo-1-cyclohexene | 1521-51-3 | C6H9Br | 详情 | 详情 |
| (VII) | 49767 | tert-butyl (3R)-1-(2-cyclohexen-1-yl)-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-ylcarbamate | C20H27N3O3 | 详情 | 详情 | |
| (VIII) | 49768 | tert-butyl (3R)-1-cyclohexyl-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-ylcarbamate | C20H29N3O3 | 详情 | 详情 | |
| (IX) | 49769 | (3R)-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C15H21N3O | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)o-Fluoronitrobenzene (I) is converted into (III) by an aromatic nucleophilic substitution with N-Ac-Cysteine (II) in EtOH in the presence of NaHCO3. Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and in the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (Scheme 28946801a).
| 【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 39365 | (2S)-2-(acetamido)-3-sulfanylpropionic acid | 616-91-1 | C5H9NO3S | 详情 | 详情 |
| (III) | 43244 | (2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid | C11H12N2O5S | 详情 | 详情 | |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 43245 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid | C17H16N2O6S | 详情 | 详情 | |
| (VI) | 43246 | (2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid | C17H18N2O4S | 详情 | 详情 | |
| (VII) | 43247 | benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate | C17H16N2O3S | 详情 | 详情 | |
| (VIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IX) | 43248 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C21H22N2O5S | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(I)Aromatic nucleophilic substitution of o-fluoronitrobenzene (I) with N-Ac-cysteine (II) in EtOH in the presence of NaHCO3 yields (III). Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (1) (Scheme 28947001a). Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH, Boc-Gly-OH, Boc-Hyp-OH, Boc-Pro-OH, Boc Arg(Tos)-OH, Boc-Lys(COOCH2Ph)-OH (x2)) with BOP/DIEA, providing derivative (XIV), which is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole (2,3) (Scheme 28947001[b-d]).
| 【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 39365 | (2S)-2-(acetamido)-3-sulfanylpropionic acid | 616-91-1 | C5H9NO3S | 详情 | 详情 |
| (III) | 43244 | (2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid | C11H12N2O5S | 详情 | 详情 | |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 43245 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid | C17H16N2O6S | 详情 | 详情 | |
| (VI) | 43246 | (2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid | C17H18N2O4S | 详情 | 详情 | |
| (VII) | 43247 | benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate | C17H16N2O3S | 详情 | 详情 | |
| (VIII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IX) | 43248 | ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate | C21H22N2O5S | 详情 | 详情 |