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【结 构 式】 
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【分子编号】13505 【品名】N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione 【CA登记号】524-38-9 |
【 分 子 式 】C8H5NO3 【 分 子 量 】163.13264 【元素组成】C 58.9% H 3.09% N 8.59% O 29.42% |
合成路线1
该中间体在本合成路线中的序号：(V)The bromination of 3,4-diacetoxyphenylacetic acid with N-bromosuccinimide (NBS) and SOCl2 gives the corresponding bromoacetic acid (II), which is esterified with diphenyldiazomethane (III) in acetone affording the diphenylmethyl ester (IV). The reaction of (IV) with N-hydroxyphthalimide (V) by means of triethylamine in acetonitrile yields diphenylmethyl-2-phthalimidooxy-2-(3,4-diacetoxy phenyl)acetate (VI), which is treated witb methyl hydrazine in dichloromethane to give diphenylmethyl-2-aminooxy-2-(3,4-diacetoxyphenyl)acetate (VII). The condensation of (VII) with (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (VIII) in methanol affords 2-(2-triphenylmethylamino-4-thiazolyl)-2-[(Z)-(diphenyl)methoxyimino]acetic acid (IX), which is condensed with 7beta-amino-3-[2-(diphenylmethoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ylthiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester (X) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane giving the protected final product (XI). Finally, this compound is deprotected by treatment first with trifluoroacetic acid and then with NaHCO3 in water.
| 【1】 Ohnishi, H.; Kosuzume, H.; Mizota, M.; Suzuki, Y.; Mochida, E. (Mochida Pharmaceutical Co., Ltd.); Cephalosporin derivs.. AU 8654876; AU 8655860; EP 0197409; EP 0359291; JP 1987077392; JP 1987161793; JP 1987167784; US 4840945; US 5001121; WO 8605786 . |
| 【2】 Prous, J.; Castaner, J.; M-14659. Drugs Fut 1988, 13, 12, 1047. |
| 【3】 Kusakabe, S.; Kosuzume, H.; Kato, K.; Shiihara, T.; Murakami, K.; Yamada, H.; Ishigura, J.; Oikawa, Y.; Mochizuki, H.; Antibacterial and pharmacokinetic properties of M1. J Antibiot 1988, 41, 3, 377. |
| 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) | 23001 | 2-[3,4-bis(acetoxy)phenyl]acetic acid | C12H12O6 | 详情 | 详情 | |
| (II) | 23002 | 2-[3,4-bis(acetoxy)phenyl]-2-bromoacetic acid | C12H11BrO6 | 详情 | 详情 | |
| (III) | 23003 | Diphenyldiazomethane | C13H10N2 | 详情 | 详情 | |
| (IV) | 23004 | benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-bromoacetate | C25H21BrO6 | 详情 | 详情 | |
| (V) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (VI) | 23006 | benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate | C33H25NO9 | 详情 | 详情 | |
| (VII) | 23007 | benzhydryl 2-(aminooxy)-2-[3,4-bis(acetoxy)phenyl]acetate | C25H23NO7 | 详情 | 详情 | |
| (VIII) | 23008 | 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C24H18N2O3S | 详情 | 详情 | |
| (IX) | 23009 | 2-([2-(benzhydryloxy)-1-[3,4-bis(acetoxy)phenyl]-2-oxoethoxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C49H39N3O9S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The alkylation of 5-hydroxy-2-(hydroxymethyl)-4-pyrone (I) with diphenyldiazomethane in ethanol gives 5-(diphenylmethoxy)-2-(hydroxymethyl)-4-pyrone (II), which is treated with hydroxylamine in hot ethanol - water to afford 5-(diphenylmethoxy)-1-hydroxy-2-(hydroxymethyl)-4-pyridone (III). The alkylation of (III) with diphenylmethyl chloride, K2CO3 and NaI in DMSO yields 1,5-bis(diphenylmethoxy)-2-(hydroxymethyl)-4-pyridone (IV), which is condensed with N-hydroxyphthalimide (V) by means of triphenylphosphine in THF to give 1,5-bis(diphenylmethoxy)-2-(phthalimidooxymethyl)-4-pyridone (VI). The reaction of (VI) with hydrazine in ethanol affords the corresponding aminooxy derivative (VII), which is condensed with 2-[2-(triphenylmethylamino)thiazol-4-yl]glyoxylic acid (VIII) in CHCl3 - ethanol to yield 2(Z)-[1,5-bis(diphenylmethoxy)-4-oxo-1,4-dihydropyridin-2-ylmethoxyimino]-2-[2-(triphenylmethylamino)thiazol-4-yl]acetic acid (IX). The condensation of (IX) with (6R,7R)-7-amino-3-(chloromethyl)-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (X) by means of NaHCO3, 1-hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DDC) in ethyl acetate - water gives the corresponding 7-acetamide derivative (XI), which by a new condensation with sodium 1,2,3-thiadiazole-5-thiolate (XII) in DMF - ethanol affords the fully protected final product (XIII). Finally, this compound is deprotected by a treatment with trifluoroacetic acid and anisole, the sodium salt being obtained by treatment with HaHCO3 in water.
| 【1】 Zama, Y.; Ishiyama, N.; Saita, T.; Naito, T.; Hirose, M.; Yokoyama, M.; Asano, T.; Senda, H.; Sekine, H.; Sanai, S. (Kaken Pharmaceutical Co., Ltd.); Cephalosporin cpds., processes for their preparation and antibacterial agents. EP 0251299; JP 1988146887; JP 1988152386; JP 1990288884; US 4822786; US 4883879 . |
| 【2】 Prous, J.; Castaner, J.; KP-736. Drugs Fut 1990, 15, 5, 457. |
| 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) | 13501 | Kojic acid; 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one | 501-30-4 | C6H6O4 | 详情 | 详情 |
| (II) | 13502 | 5-(Benzhydryloxy)-2-(hydroxymethyl)-4H-pyran-4-one | C19H16O4 | 详情 | 详情 | |
| (III) | 13503 | 5-(Benzhydryloxy)-1-hydroxy-2-(hydroxymethyl)-4(1H)-pyridinone | C19H17NO4 | 详情 | 详情 | |
| (IV) | 13504 | 1,5-Bis(benzhydryloxy)-2-(hydroxymethyl)-4(1H)-pyridinone | C32H27NO4 | 详情 | 详情 | |
| (V) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (VI) | 13506 | 2-[[1,5-Bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]-1H-isoindole-1,3(2H)-dione | C40H30N2O6 | 详情 | 详情 | |
| (VII) | 13507 | 2-[(Aminooxy)methyl]-1,5-bis(benzhydryloxy)-4(1H)-pyridinone | C32H28N2O4 | 详情 | 详情 | |
| (VIII) | 13508 | 2-[2-(Benzhydrylamino)-1,3-thiazol-4-yl]-2-oxoacetic acid | C18H14N2O3S | 详情 | 详情 | |
| (IX) | 13509 | 2-[2-(Benzhydrylamino)-1,3-thiazol-4-yl]-2-([[1,5-bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]imino)acetic acid | C50H40N4O6S | 详情 | 详情 | |
| (X) | 13510 | 4-methoxybenzyl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H17ClN2O4S | 详情 | 详情 | |
| (XI) | 13511 | 4-methoxybenzyl (6R,7R)-7-[[2-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-2-([[1,5-bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]imino)acetyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C66H55ClN6O9S2 | 详情 | 详情 | |
| (XII) | 13512 | Sodium 1,2,3-thiadiazol-5-ylsulfide | 75849-83-1 | C2HN2NaS2 | 详情 | 详情 |
| (XIII) | 13513 | 4-methoxybenzyl (6R,7R)-7-[[2-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-2-([[1,5-bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]imino)acetyl]amino]-8-oxo-3-[(1,2,3-thiadiazol-5-ylsulfanyl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxyl | C68H56N8O9S4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 1(R)-phenylethane-1,2-diol (I) with N-hydroxyphthalimide (II) by means of DEAD and PPh3 gives the N-alcoxyphthalimide (III) with(S)-configuration. The hydrazinolysis of (III) with hydrazine hydrate affords the O-alkylhydroxylamine (IV), which is condensed with benzaldehyde (V) to provide the alkylated benzaldoxime (VI). The alkylation of the oxime (VI) with vinyl lithium (VII) in toluene gives the N, O dialkylated hydroxylamine (VIII), which is treated with Zn and AcOH to yield 1(R)-phenylallylamine (IX). The protection of the amine (IX) with Boc2O and NaOH affords the carbamate (X), which is oxidized at the vinyl double bond by means of OsO4 and NaIO4 to provide the acetaldehyde (XI). The reaction of aldehyde (XI) with allylmagnesium bromide (XII) in ethyl ether gives the aminoalcohol (XIII), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (XIV).
| 【1】 Yamazaki, N.; et al.; Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue. Tetrahedron Lett 2001, 42, 30, 5029. |
| 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) | 56141 | (R)-(-)-1-Phenyl-1,2-ethanediol; (R)-(-)-alpha,beta-Dihydroxyethylbenzene; (R)-(-)-Phenyl-1,2-ethanediol; (R)-(-)-Styrene glycol; (-)-Styrene glycol | 16355-00-3 | C8H10O2 | 详情 | 详情 |
| (II) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (III) | 56142 | 2-{[(1S)-2-hydroxy-1-phenylethyl]oxy}-1H-isoindole-1,3(2H)-dione | C16H13NO4 | 详情 | 详情 | |
| (IV) | 56143 | (2S)-2-(aminooxy)-2-phenyl-1-ethanol | C8H11NO2 | 详情 | 详情 | |
| (V) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VI) | 62256 | benzaldehyde O-[(1S)-2-hydroxy-1-phenylethyl]oxime | C15H15NO2 | 详情 | 详情 | |
| (VII) | 42368 | vinyllithium | 917-57-7 | C2H3Li | 详情 | 详情 |
| (VIII) | 62257 | (2S)-2-phenyl-2-({[(1R)-1-phenyl-2-propenyl]amino}oxy)-1-ethanol | C17H19NO2 | 详情 | 详情 | |
| (IX) | 62258 | (1R)-1-phenyl-2-propenylamine; (1R)-1-phenyl-2-propen-1-amine | C9H11N | 详情 | 详情 | |
| (X) | 62259 | tert-butyl (1R)-1-phenyl-2-propenylcarbamate | C14H19NO2 | 详情 | 详情 | |
| (XI) | 45428 | tert-butyl (1S)-2-oxo-1-phenylethylcarbamate | C13H17NO3 | 详情 | 详情 | |
| (XII) | 61128 | C4H8 | 详情 | 详情 | ||
| (XIII) | 62260 | tert-butyl (1S)-2-hydroxy-1-phenyl-4-pentenylcarbamate | C16H23NO3 | 详情 | 详情 | |
| (XIV) | 62261 | tert-butyl (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-4-pentenylcarbamate | C22H37NO3Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)A new procedure for the asymmetric synthesis of amine (III) was reported. Mitsunobu coupling of N-hydroxyphthalimide (V) with the chiral auxiliary (R)-phenylglycol (IV) yielded the (S)-alkoxyphthalimide (VI). Hydrazinolysis of (VI) provided the free alkoxyamine (VII), which was condensed with 3-methoxybenzaldehyde (VIII) to afford oxime (IX). Diastereoselective addition of methyllithium to the oxime ether (IX) led to the methyl adduct (X) as the major isomer. Then, reductive N-O bond cleavage to furnish amine (III) was carried out by using zinc-acetic acid or, with an improved yield, using molybdenum hexacarbonyl.
| 【1】 Yamazaki, N.; et al.; Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue. Tetrahedron Lett 2001, 42, 30, 5029. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56140 | (R)-1-(3-Methoxyphenyl)ethylamine; (R)-3-Methoxy-alpha-methylbenzylamine; (R)-m-Methoxy-alpha-methylbenzylamine | 88196-70-7 | C9H13NO | 详情 | 详情 |
| (IV) | 56141 | (R)-(-)-1-Phenyl-1,2-ethanediol; (R)-(-)-alpha,beta-Dihydroxyethylbenzene; (R)-(-)-Phenyl-1,2-ethanediol; (R)-(-)-Styrene glycol; (-)-Styrene glycol | 16355-00-3 | C8H10O2 | 详情 | 详情 |
| (V) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (VI) | 56142 | 2-{[(1S)-2-hydroxy-1-phenylethyl]oxy}-1H-isoindole-1,3(2H)-dione | C16H13NO4 | 详情 | 详情 | |
| (VII) | 56143 | (2S)-2-(aminooxy)-2-phenyl-1-ethanol | C8H11NO2 | 详情 | 详情 | |
| (VIII) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (IX) | 56144 | 3-methoxybenzaldehyde O-[(1S)-2-hydroxy-1-phenylethyl]oxime | C16H17NO3 | 详情 | 详情 | |
| (X) | 56145 | (2S)-2-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}oxy)-2-phenyl-1-ethanol | C17H21NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIV)The reaction of ethyl 2-sulfanylacetate (I) with 2-bromoacetonitrile (II) by means of NaOEt in ethanol gives ethyl 2-(cyanomethylsulfanyl)acetate (III), which is cyclized with diethyl oxalate (IV) by means of NaOEt in ethanol yielding 5-cyano-3,4-dihydroxythiophene-2-carboxylic acid ethyl ester (V). The protection of the hydroxyl groups of (V) with 2-methoxyethoxymethyl chloride (Mem-Cl) and DIEA in dichloromethane affords the protected thiophene (VI), which is reduced with (t-BuO)2AlH in THF providing the carbinol (VII). The oxidation of (VII) with MnO2 in dichloromethane yields the carbaldehyde (VIII), which is condensed with malonodinitrile (IX) by means of piperidine in dioxane giving the alkylidenemalonodinitrile (X). The epoxidation of (X) with tert-butyl hydroperoxide and TEA in dioxane yields the epoxide (XI), which is treated with HCl in THF to afford 2-chloro-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy) thiophen-2-yl]acetic acid (XII). The esterification of (XII) with diphenyldiazomethane affords the corresponding diphenylmethyl ester (XIII), which is condensed with N-hydroxyphthalimide (XIV) and NaHCO3 in dichloromethane providing the adduct (XV). The cleavage of the phthalimido group of (XV) with hydrazine in methanol gives 2-(aminooxy)-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy)thiophen-2-yl]acetic acid diphenylmethyl ester (XVI), which is condensed with 2-oxo-2-[2-(tritylamino)thiazol-4-yl]acetic acid (XVII) yielding the corresponding alcoxyimino derivative (XVIII).
| 【1】 Aszodi, J.; Dini, C.; Fauveau, P. (Aventis Pharma SA); Cephalosporins having in position 7 as substd. axymino radical, intermediates, processes for their preparation and their use as medicaments. CA 2111164; EP 0628562; JP 1994345776 . |
| 【2】 Dini, C.; Aszodi, J.; Synthesis of a dihydroxythiophene analogue of catechosporines. Bioorg Med Chem Lett 2000, 10, 4, 349. |
| 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) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (II) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (III) | 35506 | ethyl 2-[(cyanomethyl)sulfanyl]acetate | C6H9NO2S | 详情 | 详情 | |
| (IV) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (V) | 35507 | ethyl 5-cyano-3,4-dihydroxy-2-thiophenecarboxylate | C8H7NO4S | 详情 | 详情 | |
| (VI) | 35508 | ethyl 5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarboxylate | C16H23NO8S | 详情 | 详情 | |
| (VII) | 35509 | 5-(hydroxymethyl)-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile | C14H21NO7S | 详情 | 详情 | |
| (VIII) | 35510 | 5-formyl-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile | C14H19NO7S | 详情 | 详情 | |
| (X) | 35511 | 2-([5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]methylene)malononitrile | C17H19N3O6S | 详情 | 详情 | |
| (XI) | 35512 | 3-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2,2-oxiranedicarbonitrile | C17H19N3O7S | 详情 | 详情 | |
| (XII) | 35513 | 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetic acid | C15H20ClNO8S | 详情 | 详情 | |
| (XIII) | 35514 | benzhydryl 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate | C28H30ClNO8S | 详情 | 详情 | |
| (XIV) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XV) | 35515 | benzhydryl 2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate | C36H34N2O11S | 详情 | 详情 | |
| (XVI) | 35516 | benzhydryl 2-(aminooxy)-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate | C28H32N2O9S | 详情 | 详情 | |
| (XVII) | 23008 | 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C24H18N2O3S | 详情 | 详情 | |
| (XVIII) | 35517 | 2-[(2-(benzhydryloxy)-1-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-oxoethoxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C52H48N4O11S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XI)Nitration of 5-bromoisoquinoline (I) using KNO3 in H2SO4 gave 5-bromo-8-nitroisoquinoline (II), which upon methylation with dimethyl sulfate was converted to the isoquinolinium salt (III). Subsequent reduction of (III) with NaBH4 in AcOH provided tetrahydroisoquinoline (IV). This was coupled with phenylboronic acid (V) in the presence of Pd(PPh3)4 and NaHCO3 to yield the 5-phenylisoquinoline (VI). Further reduction of the nitro group of (VI) by catalytic hydrogenation over Pd/C afforded amine (VII). The pyrroloisoquinoline (VIII) was then formed by condensation of (VII) with chloral and hydroxylamine in boiling water, followed by cyclization of the intermediate (oxymino)acetamide in methanesulfonic acid at 120 C. After chlorosulfonation of (VIII), the sulfonyl chloride (IX) was condensed with dimethylamine in THF to afford sulfonamide (X). Hydroxylamine derivative (XIV) was prepared by O-alkylation of N-hydroxyphthalimide (XI) with alpha-bromo-gamma-butyrolactone (XII), followed by hydrolysis of the phthalimide (XIII) in boiling 1 M HCl. Hydroxylamine derivative (XIV) was then condensed with sulfonamide (X) to furnish oxime (XV). Finally, hydrolysis of the butyrolactone group of (XV) with aqueous NaOH gave the title compound.
| 【1】 Watjen, F.; Drejer, J. (NeuroSearch A/S); Novel indole-2,3-dione-3-oxime derivs.. EP 0869958; JP 2000501432; US 6124285; WO 9814447 . |
| 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) | 22811 | 5-bromoisoquinoline | C9H6BrN | 详情 | 详情 | |
| (II) | 22812 | 5-bromo-8-nitroisoquinoline | C9H5BrN2O2 | 详情 | 详情 | |
| (III) | 22813 | 5-bromo-2-methyl-8-nitro-2lambda(5)-isoquinoline | C10H8BrN2O2 | 详情 | 详情 | |
| (IV) | 22814 | 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline | C10H11BrN2O2 | 详情 | 详情 | |
| (V) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (VI) | 22816 | 2-methyl-8-nitro-5-phenyl-1,2,3,4-tetrahydroisoquinoline | C16H16N2O2 | 详情 | 详情 | |
| (VII) | 22817 | 2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinylamine; 2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinamine | C16H18N2 | 详情 | 详情 | |
| (VIII) | 22818 | 8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione | C18H16N2O2 | 详情 | 详情 | |
| (IX) | 22819 | 4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonyl chloride | C18H15ClN2O4S | 详情 | 详情 | |
| (X) | 22820 | N,N-dimethyl-4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide | C20H21N3O4S | 详情 | 详情 | |
| (XI) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XII) | 22822 | 3-bromodihydro-2(3H)-furanone | 5061-21-2 | C4H5BrO2 | 详情 | 详情 |
| (XIII) | 22823 | 2-[(2-oxotetrahydro-3-furanyl)oxy]-1H-isoindole-1,3(2H)-dione | C12H9NO5 | 详情 | 详情 | |
| (XIV) | 22824 | 3-(aminooxy)dihydro-2(3H)-furanone | C4H7NO3 | 详情 | 详情 | |
| (XV) | 22825 | N,N-dimethyl-4-(8-methyl-2-oxo-3-[[(2-oxotetrahydro-3-furanyl)oxy]imino]-1,2,6,7,8,9-hexahydro-3H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide | C24H26N4O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Mitsunobu coupling of geranylgeraniol (I) with N-hydroxyphthalimide (II) in the presence of diethyl azodicarboxylate and triphenylphosphine produced the N-alkoxyphthalimide (III). Subsequent hydrazinolysis of the phthaloyl group of (III) gave rise to the O-alkyl hydroxylamine (IV). (2-Diethylphosphono)butyric acid (VI), prepared by partial hydrolysis of triethyl ester (V), was then coupled with hydroxylamine (IV) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl and 1-hydroxybenzotriazole to furnish the N-alkoxyamide (VII). The phosphonate ester groups were finally cleaved by treatment with bromotrimethylsilane and 2,4,6-collidine.
| 【1】 Balsamo, A.; Macchia, B.; Macchia, M.; Baldacci, M.; Danesi, R.; Del Tacca, M. (Laboratori Baldacci SpA); Novel geranylgeranyl-derivs., process for the preparation thereof and related pharmaceutical compsns.. EP 0862575; JP 2000500758; WO 9719091 . |
| 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) | 34476 | (2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol | C20H34O | 详情 | 详情 | |
| (II) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (III) | 34477 | 2-[[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]oxy]-1H-isoindole-1,3(2H)-dione | C28H37NO3 | 详情 | 详情 | |
| (IV) | 34478 | O-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]hydroxylamine; (2E,6E,10E)-1-(aminooxy)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene | C20H35NO | 详情 | 详情 | |
| (V) | 20274 | ethyl 2-(diethoxyphosphoryl)butanoate | 17145-91-4 | C10H21O5P | 详情 | 详情 |
| (VI) | 34479 | 2-(diethoxyphosphoryl)butyric acid | C8H17O5P | 详情 | 详情 | |
| (VII) | 34480 | diethyl 1-[([[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]oxy]amino)carbonyl]propylphosphonate | C28H50NO5P | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)N-(2-Butynyloxy)phthalimide (III) was obtained by the Mitsunobu coupling between 2-butyn-1-ol (II) and N-hydroxyphthalimide (I). Subsequent hydrazinolysis of (III) gave the O-alkynyl hydroxylamine (IV). This was finally condensed with quinuclidin-3-one (V) in methanol to furnish the corresponding oxime.
| 【1】 Go, M.-L.; Loke, W.-K.; Sim, M.-K.; Somanadhan, B.; Quinuclidinone O-alkynyloximes with muscarinic agonist activity. Bioorg Med Chem 2002, 10, 1, 207. |
| 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) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (II) | 42514 | 2-butyn-1-ol | 764-01-2 | C4H6O | 详情 | 详情 |
| (III) | 59686 | 2-(2-butynyloxy)-1H-isoindole-1,3(2H)-dione | C12H9NO3 | 详情 | 详情 | |
| (IV) | 59687 | 1-(aminooxy)-2-butyne; O-(2-butynyl)hydroxylamine | C4H7NO | 详情 | 详情 | |
| (V) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XIV)Nitration of 2,3,4-trifluorobenzoic acid (I) using HNO3 and H2SO4 gives 2,3,4-trifluoro-5-nitrobenzoic acid (II), which by displacement with NH4OH in H2O at 0 °C yields 4-amino-2,3-difluoro-5-nitrobenzoic acid (III). Fisher esterification of acid (III) with Me3SiCHN2 in THF/MeOH at 0 °C affords 4-amino-2,3-difluoro-5-nitrobezoic acid methyl ester (IV), which is condensed with 2-fluoroaniline (V) in xylene at 140 °C to provide methyl 4-amino-3-fluoro-2-(2-fluorophenylamino)-5-nitrobenzoic acid methyl ester (VI). Reduction and cyclization of intermediate (VI) using formic acid and Pd(OH)2/C in EtOH at 95 °C generates methyl 4-fluoro-5-(2-fluorophenylamino)-benzimidazole-6-carboxylate (VII), which by bromination with NBS and p-TsOH in DMF produces the bromo derivative (VIII). N-Methylation of compound (VIII) with methyl iodide by means of K2CO3 in DMF at 75 °C gives compound (IX), which is hydrolyzed with NaOH in THF/H2O to yield the free carboxylic acid (X). Condensation of carboxylic acid (X) with O-[2-(vinyloxy)ethyl]hydroxylamine (XI) using HOBt, Et3N and EDC in DMF affords amide (XII), which is finally treated with HCl in EtOH (1).
Intermediate O-[2-(vinyloxy)ethyl]hydroxylamine (XI) is prepared by Mitsnoubu reaction of 2-(vinyloxy)ethanol (XIII) with N-hydroxy - phthalimide (XIV) using PPh3 and DEAD in THF at 0 °C to give 2-[2-(vinyloxy)ethoxy]-1H-isoindole-1,3(2H)-dione (XV), which is finally treated with MeNHNH2 in CH2Cl2 .
| 【1】 Barrett, S.D., Biwersi, C., Warmus, J.S., Tecle, H., Kaufman, M. (Pfizer, Inc.). Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids. WO 2002006213; EP 1301472; CA 2416685; US 2004054172; US 6960614. |
| 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) | 34622 | 2,3,4-trifluorobenzoic acid | 61079-72-9 | C7H3F3O2 | 详情 | 详情 |
| (II) | 67510 | 2,3,4-trifluoro-5-nitrobenzoic acid | C7H2F3NO4 | 详情 | 详情 | |
| (III) | 67511 | 4-amino-2,3-difluoro-5-nitrobenzoic acid | C7H4F2N2O4 | 详情 | 详情 | |
| (IV) | 67512 | 4-amino-2,3-difluoro-5-nitrobezoic acid methyl ester | 284030-58-6 | C8H6F2N2O4 | 详情 | 详情 |
| (V) | 22296 | 2-fluorophenylamine; 2-fluoroaniline | 348-54-9 | C6H6FN | 详情 | 详情 |
| (VI) | 67513 | methyl 4-amino-3-fluoro-2-(2-fluorophenyl-amino)-5-nitrobenzoic acid methyl ester | C15H13F2N3O4 | 详情 | 详情 | |
| (VII) | 67514 | methyl 4-fluoro-5-(2-fluorophenylamino)-benzimidazole-6-carboxylate | C15H11F2N3O2 | 详情 | 详情 | |
| (VIII) | 67515 | methyl 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate | C15H10BrF2N3O2 | 详情 | 详情 | |
| (IX) | 67516 | methyl 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate | C16H12BrF2N3O2 | 详情 | 详情 | |
| (X) | 67517 | 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid | C15H10BrF2N3O2 | 详情 | 详情 | |
| (XI) | 67518 | O-[2-(vinyloxy)ethyl]hydroxylamine | 391212-29-6 | C4H9NO2 | 详情 | 详情 |
| (XII) | 67519 | 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-N-(2-(vinyloxy)ethoxy)-1H-benzo[d]imidazole-6-carboxamide | C19H17BrF2N4O3 | 详情 | 详情 | |
| (XIII) | 67520 | 2-(vinyloxy)ethanol | 764-48-7 | C4H8O2 | 详情 | 详情 |
| (XIV) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XV) | 67521 | 2-[2-(vinyloxy)ethoxy]-1H-isoindole-1,3(2H)-dione | C12H11NO4 | 详情 | 详情 |