|
【结 构 式】 
|
【分子编号】16601 【品名】ethyl chloroacetate; ethyl 2-chloroacetate 【CA登记号】105-39-5 |
【 分 子 式 】C4H7ClO2 【 分 子 量 】122.55108 【元素组成】C 39.2% H 5.76% Cl 28.93% O 26.11% |
合成路线1
该中间体在本合成路线中的序号：(XIX)The reaction of 3-trifluoromethylphenol (XVIII) with ethyl chloroacetate (XIX) by means of NaI and K2CO3 in acetone gives ethyl-(3-trifluoromethylphenoxy)acetate (XX), which is then condensed with dimethyl methylphosphonate (C) by means of butyllithium in THF to afford dimethyl 2-oxo-3-(3-trifluoromethylphenoxy)propylphosphonate (II).
| 【1】 Hayashi, M.; et al.; US 4065632 . |
| 【2】 Castaner, J.; Riberos, J.; ONO-995. Drugs Fut 1980, 5, 10, 499. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 32121 | dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonate | C12H14F3O5P | 详情 | 详情 | |
| (XVIII) | 33504 | 3-(trifluoromethyl)phenol | 98-17-9 | C7H5F3O | 详情 | 详情 |
| (XIX) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (XX) | 39185 | ethyl 2-[3-(trifluoromethyl)phenoxy]acetate | C11H11F3O3 | 详情 | 详情 | |
| (C) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The cyclization of 2-chlororesorcine (I) with ethyl alpha-(beta-diethylaminoethyl) acetoacetate (II) by means of p-toluenesulfonic acid and polyphosphoric acid gives 8-chloro-3-(beta-diethylaminoethyl)-4-methyl-7-hydroxycoumarin (III), which is then condensed with ethyl chloroacetate (IV) by means of K2CO3 in refluxing acetone.
| 【1】 Della Valle, F.; Selected process for producing monohalogenated derivatives of 7-hydroxy-coumarin. BE 0871315; DE 2846083; ES 474445; FR 2412541; FR 2412542; GB 2008109; JP 54079282; US 4296039 . |
| 【2】 Castaner, J.; Hillier, K.; Serradell, M.N.; Blancafort, P.; AD-6. Drugs Fut 1979, 4, 10, 701. |
| 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) | 33375 | 2-chloro-1,3-benzenediol | C6H5ClO2 | 详情 | 详情 | |
| (II) | 33376 | ethyl 2-[2-(diethylamino)ethyl]-3-oxobutanoate | C12H23NO3 | 详情 | 详情 | |
| (III) | 33377 | 8-chloro-3-[2-(diethylamino)ethyl]-7-hydroxy-4-methyl-2H-chromen-2-one | C16H20ClNO3 | 详情 | 详情 | |
| (IV) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 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 dl-l-phenylethylamine (I) with ethyl chloroacetate (II) by means of triethylamine in DMF gives dl-N-[(ethoxycarbonyl)methyl]-1-phenylethylamine (III), which is then treated with formic acid in refluxing xylene yielding dl-N-formyl-N-[(ethoxycarbonyl)methyl]-1-phenylethylamine (IV). The reaction of (IV) with sodium ethoxide and ethyl formate (A) in THF affords dl-N-formyl-N-[(ethoxycarbonyl)-2-hydroxyvinyl]-1-phenylethylamine (V), which, without purification, is treated with potassium thiocyanate and HCl in diisopropyl ether to give dl-l-(phenylethyl)-2-mercapto-5-ethoxycarbonylimidazole (VI). This product is finally treated with nitric acid and sodium nitrate at room temperature. The optical active drugs can be obtained starting the synthesis with the optically active amine (I).
| 【1】 Godefroi, E.F.; et al.; Imidazole carboxylates. BE 0662474; DE 1545988; FR 4499M; GB 1064531; US 3354173 . |
| 【2】 Roberts, P.J.; Castaner, J.; Etomidate. Drugs Fut 1976, 1, 10, 461. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (I) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 34103 | ethyl 2-[[(1R)-1-phenylethyl]amino]acetate | C12H17NO2 | 详情 | 详情 | |
| (IV) | 34104 | ethyl 2-[formyl[(1R)-1-phenylethyl]amino]acetate | C13H17NO3 | 详情 | 详情 | |
| (V) | 34105 | ethyl (Z)-2-[formyl[(1R)-1-phenylethyl]amino]-3-hydroxy-2-propenoate | C14H17NO4 | 详情 | 详情 | |
| (VI) | 34106 | ethyl 1-[(1R)-1-phenylethyl]-2-sulfanyl-1H-imidazole-5-carboxylate | C14H16N2O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：The key intermediate (XXI) was also prepared by several related procedures. Chlorination of aminoalcohol (XVI) gave chloro amine (XXIV), which was condensed with 2-aminobenzyl alcohol (X) to afford diamine (XXV). Then, alkylation of diamine (XXV) with dibromoethane (XIII) in hot pyridine gave rise to the target piperazine (XXI). Alternatively, diamine (XXV) was condensed with ethyl chloroacetate or with diethyl oxalate to produce the mono- or dioxopiperazines (XXVII) and (XXVI), respectively, which were then reduced to (XXI) by means of LiAlH4. Cyclization of alcohol (XXI) to the title compound was achieved by treatment with concentrated sulfuric acid
| 【1】 Olivié, J.; Synthesis for the preparation of tetracyclic cpds.. US 4217452 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 | |
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XIII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XVI) | 62404 | 2-(methylamino)-1-phenyl-1-ethanol | C9H13NO | 详情 | 详情 | |
| (XXI) | 62407 | [2-(4-methyl-2-phenyl-1-piperazinyl)phenyl]methanol | C18H22N2O | 详情 | 详情 | |
| (XXIV) | 62410 | C10H16ClN | 详情 | 详情 | ||
| (XXV) | 62411 | (2-{[2-(methylamino)-1-phenylethyl]amino}phenyl)methanol | C16H20N2O | 详情 | 详情 | |
| (XXVI) | 62413 | 4-[2-(hydroxymethyl)phenyl]-1-methyl-5-phenyl-2,3-piperazinedione | C18H18N2O3 | 详情 | 详情 | |
| (XXVII) | 62412 | 1-[2-(hydroxymethyl)phenyl]-4-methyl-6-phenyl-2-piperazinone | C18H20N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)In an alternative method, condensation of semicarbazide hydrochloride (I) with cyclohexanone (II) yields the semicarbazone (III). Subsequent reaction of (III) with ethyl chloroacetate (IV) in the presence of NaOMe gives rise to the cyclohexylidene aminohydantoin (V). Treatment of (V) with 5-(p-nitrophenyl)furfural (VI) under acidic conditions affords the furfurylidene aminohydantoin (VII). This is finally converted into the corresponding sodium salt employing methanolic NaOMe (3).
| 【1】 Martin-Escudero Perez, U.; Izquierdo Sanjose, M.; Process for obtaining 1-[(5-(p-nitrophenyl)furfuryliden)amino]hydantoin and its sodium salt. ES 458000 . |
| 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) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
| (II) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (III) | 63587 | 2-cyclohexylidene-1-hydrazinecarboxamide | C7H13N3O | 详情 | 详情 | |
| (IV) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (V) | 63588 | 1-(cyclohexylideneamino)-2,4-imidazolidinedione | C9H13N3O2 | 详情 | 详情 | |
| (VI) | 63583 | 5-(4-nitrophenyl)-2-furaldehyde | C11H7NO4 | 详情 | 详情 | |
| (VII) | 63586 | 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione | C14H10N4O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(A)Treatment of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid (I) with thionyl chloride yields the dichloride (II). Compound (II) is treated with acetoxyacetyl chloride to give compound (III), which is methylated with iodomethane. Condensation with 3-amino-1,2-propanediol of the N-methyl derivative (IV) thus obtained, followed by deacetylation with alkali metal hydroxide, yields iomeprol.
| 【1】 Felder, E.; Musu, C.; Fumagalli, L.; Uggeri, F. (Bracco SpA); Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivs.. WO 8809328 . |
| 【2】 Davies, A.; Felder, E.; Tirone, P.; IOMEPROL < Rec INN; BAN; USAN >. Drugs Fut 1990, 15, 11, 1074. |
| 【3】 Musu, C.; Felder, E.; Fumagalli, L.; Piva, R.; Uggeri, F.; Smiles rearrangement, a new synthetic pathway to the synthesis of 5-(hydroxyacyl)-amino-2,4,6-triiodoisophthalamides. Invest Radiol 1990, 25, Suppl. 1, S100-1. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 12979 | 3-Amino-1,2-propanediol；3-aminopropane-1,2-diol | 616-30-8 | C3H9NO2 | 详情 | 详情 |
| (A) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (I) | 22006 | 5-amino-2,4,6-triiodoisophthalic acid | 35453-19-1 | C8H4I3NO4 | 详情 | 详情 |
| (II) | 31194 | 5-amino-2,4,6-triiodoisophthaloyl dichloride | 37441-29-5 | C8H2Cl2I3NO2 | 详情 | 详情 |
| (III) | 31195 | 2-[3,5-bis(chlorocarbonyl)-2,4,6-triiodoanilino]-2-oxoethyl acetate | C12H6Cl2I3NO5 | 详情 | 详情 | |
| (IV) | 31196 | 2-[3,5-bis(chlorocarbonyl)-2,4,6-triiodomethylanilino]-2-oxoethyl acetate | C13H8Cl2I3NO5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(A)5-Hydroxy-1,3-benzenedicarboxylic acid dimethyl ester (I) is treated with 3-amino-1,2-propanediol to give the corresponding bisamide (II), which is then iodinated with iodine monochloride. The reaction of the triiodinated compound thus obtained (III) with sodium methoxide and chloroacetic acid ethyl ester yields N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[2-ethoxy-2-oxoethoxy]-1,3-benzenedicarboxamide (IV), which is treated with methylamine to give the 5-[2-(methylamino)-2-oxoethoxy] derivative (V). Iomeprol is obtained through a Smiles-type intramolecular rearrangement of (V) in aqueous alkaline medium.
| 【1】 Felder, E.; Pitre, D. (Bracco SpA); Derivs. of 2,4,6-triiodo-isophthalic acid, processes for their synthesis and x-ray contrasting materials containing these. EP 0026281; US 4352788 . |
| 【2】 Davies, A.; Felder, E.; Tirone, P.; IOMEPROL < Rec INN; BAN; USAN >. Drugs Fut 1990, 15, 11, 1074. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 12979 | 3-Amino-1,2-propanediol；3-aminopropane-1,2-diol | 616-30-8 | C3H9NO2 | 详情 | 详情 |
| (A) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (I) | 31197 | dimethyl 5-hydroxyisophthalate | 13036-02-7 | C10H10O5 | 详情 | 详情 |
| (II) | 31198 | N(1),N(3)-bis(2,3-dihydroxypropyl)-5-hydroxyisophthalamide | C14H20N2O7 | 详情 | 详情 | |
| (III) | 31199 | N(1),N(3)-bis(2,3-dihydroxypropyl)-5-hydroxy-2,4,6-triiodoisophthalamide | C14H17I3N2O7 | 详情 | 详情 | |
| (IV) | 31200 | ethyl 2-(3,5-bis[[(2,3-dihydroxypropyl)amino]carbonyl]-2,4,6-triiodophenoxy)acetate | C18H23I3N2O9 | 详情 | 详情 | |
| (V) | 31201 | N(1),N(3)-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[2-(methylamino)-2-oxoethoxy]isophthalamide | C17H22I3N3O8 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XVII)The thiazolyl carbonate (XI) has been synthesized as follows: The reaction of formamide (XIV) with P2S5 in ethyl ether gives thioformamide (XV), which is cyclized with 2-chloro-3-oxopropionic acid ethyl ester (XVI) [obtained by condensation of ethyl chloroacetate (XVII) with ethyl formate (XVIII) by means of t-BuOK in THF] yielding thiazol-5-carboxylic acid ethyl ester (XIX). The reduction of (XIX) with LiAlH4 in THF affords 5-thiazolylmethanol (XX), which is then esterified with 4-nitrophenyl chloroformate (XXI) by means of 4-methylmorpholine (MPH) in dichloromethane to give the desired product (XI).
| 【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700. |
| 【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 . |
| 【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 . |
| 【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 16595 | 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate | 144163-97-3 | C11H8N2O5S | 详情 | 详情 |
| (XIV) | 16598 | Formamide | 75-12-7 | CH3NO | 详情 | 详情 |
| (XV) | 16599 | Thioformamide | CH3NS | 详情 | 详情 | |
| (XVI) | 16600 | ethyl 2-chloro-3-oxopropanoate | C5H7ClO3 | 详情 | 详情 | |
| (XVII) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (XVIII) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (XIX) | 16603 | ethyl 1,3-thiazole-5-carboxylate | 32955-22-9 | C6H7NO2S | 详情 | 详情 |
| (XX) | 16604 | 1,3-thiazol-5-ylmethanol;5-thiazolylmethanol;Thiazole-5-methanol | 38585-74-9 | C4H5NOS | 详情 | 详情 |
| (XXI) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：The reaction of 2,6-di(tert-butyl)phenol (I) with CS2 and ethyl chloroacetate gives the dithiobenzoate (II), which is treated with hydrazine in ethanol yielding the thiobenzoyl hydrazide (III). The cyclization of (III) with CS2 in refluxing ethanol affords the thiadiazolethione (IV), which is finally condensed with ethyl iodide and NaOH in THF.
| 【1】 Sercel, A.D.; Connor, D.T.; Song, Y.; et al.; Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 2. 1,3,4- and 1,2,4-thiadiazole series. J Med Chem 1999, 42, 7, 1161. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 | |
| 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 | |
| (I) | 25925 | 2,6-di(tert-butyl)phenol | 128-39-2 | C14H22O | 详情 | 详情 |
| (II) | 25926 | ethyl 2-[[3,5-di(tert-butyl)-4-hydroxybenzothioyl]sulfanyl]acetate | C19H28O3S2 | 详情 | 详情 | |
| (III) | 25927 | 3,5-di(tert-butyl)-4-hydroxybenzenecarbothiohydrazide | C15H24N2OS | 详情 | 详情 | |
| (IV) | 25928 | 5-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione | C16H22N2OS2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The condensation of 1-(4-methoxyphenyl)piperazine (I) with ethyl chloroacetate (II) gives the expected condensation product (III), which by treatment with hydrazine in converted into the corresponding hydrazide (IV). The cyclization of (IV) with benzimidate (V) by heating at 180 C affords the triazole (VI), which is finally condensed with 4-fluorobenzyl chloride (VII) by means of NaH in DMF.
| 【1】 Chytiroglou-Lada, A.; Filippatos, E.C.; Papakonstantinou-Garoufalias, S.S.; Papadaki-Valiraki, A.E.; Todoulou, O.G.; Synthesis, antifungal activity and antibacterial evaluation of some 3-piperazinylmethyl-5-aryl-1H-1,2,4-triazoles. Arzneim-Forsch Drug Res 1998, 48, 10, 1019. |
| 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) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 25573 | ethyl 2-[4-(4-methoxyphenyl)-1-piperazinyl]acetate | C15H22N2O3 | 详情 | 详情 | |
| (IV) | 25574 | 2-[4-(4-methoxyphenyl)-1-piperazinyl]acetohydrazide | C13H20N4O2 | 详情 | 详情 | |
| (V) | 14225 | ethyl benzenecarboximidoate | C9H11NO | 详情 | 详情 | |
| (VI) | 25575 | 1-(4-methoxyphenyl)-4-[(5-phenyl-1H-1,2,4-triazol-3-yl)methyl]piperazine; methyl 4-[4-[(5-phenyl-1H-1,2,4-triazol-3-yl)methyl]-1-piperazinyl]phenyl ether | C20H23N5O | 详情 | 详情 | |
| (VII) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 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 1-(4-methoxyphenyl)piperazine (I) with ethyl chloroacetate (II) gives the expected condensation product (III), which by treatment with hydrazine in converted into the corresponding hydrazide (IV). The cyclization of (IV) with 4-methylbenzimidate (V) by heating at 180 C affords the triazole (VI), which is finally condensed with 4-fluorobenzyl chloride (VII) by means of NaH in DMF.
| 【1】 Chytiroglou-Lada, A.; Filippatos, E.C.; Papakonstantinou-Garoufalias, S.S.; Papadaki-Valiraki, A.E.; Todoulou, O.G.; Synthesis, antifungal activity and antibacterial evaluation of some 3-piperazinylmethyl-5-aryl-1H-1,2,4-triazoles. Arzneim-Forsch Drug Res 1998, 48, 10, 1019. |
| 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) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 25573 | ethyl 2-[4-(4-methoxyphenyl)-1-piperazinyl]acetate | C15H22N2O3 | 详情 | 详情 | |
| (IV) | 25574 | 2-[4-(4-methoxyphenyl)-1-piperazinyl]acetohydrazide | C13H20N4O2 | 详情 | 详情 | |
| (V) | 25576 | ethyl 4-methylbenzenecarboximidoate | C10H13NO | 详情 | 详情 | |
| (VI) | 25577 | methyl 4-(4-[[5-(4-methylphenyl)-1H-1,2,4-triazol-3-yl]methyl]-1-piperazinyl)phenyl ether; 1-(4-methoxyphenyl)-4-[[5-(4-methylphenyl)-1H-1,2,4-triazol-3-yl]methyl]piperazine | C21H25N5O | 详情 | 详情 | |
| (VII) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)Darzen’s condensation of 4,4'-dichlorobenzophenone (I) with ethyl chloroacetate (II) produced the glycidic ester (III), which was subsequently converted to aldehyde (IV) upon treatment with KOH. Diol (V) was then obtained by Tollens’ reaction of aldehyde (IV) with formaldehyde. Ethyl 4-chlorophenylglyoxylate (VII) was prepared by addition of the Grignard reagent prepared from 1-bromo-4-chlorobenzene (VI) to diethyl oxalate. The condensation between diol (V) and keto ester (VII) in the presence of boron trifluoride furnished the cyclic ketal (VIII). Finally, saponification of the ethyl ester group gave rise to the target carboxylic acid.
| 【1】 Al Hazaa, A.; et al.; ZD1839 (Iressa(TM)), an EGFR-TKI, and cisplatin have an additive effect on programmed cell death in human head and neck squamous carcinoma cells in vitro. Clin Cancer Res 2000, 6, Suppl., Poster Nº 308. |
| 【2】 Zeiller, J.-J.; Raspé, E.; Guerrier, D.; Berthelon, J.-J. (Merck Patent GmbH); Cyclic cpds. useful in the treatment of dyslipidaemia, atherosclerosis and diabetes, pharmaceutical compsns. and preparation process. EP 1098893; FR 2781222; WO 0004011 . |
| 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) | 47449 | bis(4-chlorophenyl)methanone | 90-98-2 | C13H8Cl2O | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 47450 | ethyl 3,3-bis(4-chlorophenyl)-2-oxiranecarboxylate | C17H14Cl2O3 | 详情 | 详情 | |
| (IV) | 47451 | 2,2-bis(4-chlorophenyl)acetaldehyde | C14H10Cl2O | 详情 | 详情 | |
| (V) | 47452 | 2,2-bis(4-chlorophenyl)-1,3-propanediol | C15H14Cl2O2 | 详情 | 详情 | |
| (VI) | 14733 | 4-Bromochlorobenzene; 1-bromo-4-chlorobenzene | 106-39-8 | C6H4BrCl | 详情 | 详情 |
| (VII) | 47453 | ethyl 2-(4-chlorophenyl)-2-oxoacetate | C10H9ClO3 | 详情 | 详情 | |
| (VIII) | 47454 | ethyl 2,5,5-tris(4-chlorophenyl)-1,3-dioxane-2-carboxylate | C25H21Cl3O4 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(II)Alkylation of phenothiazine (I) by ethyl chloroacetate (II) in the presence of K2CO3 affords the ester (III). Subsequent condensation of (III) with thiosemicarbazide (IV) gives the acyl thiosemicarbazide (V), which is cyclized to the thiadiazole derivative (VI) in concentrated H2SO4. Finally, Mannich condensation of aminothiadiazole (VI) with thiobarbituric acid (VII) and formaldehyde furnishes the desired compound.
| 【1】 Archana; Rani, P.; Bajaj, K.; Srivastava, V.K.; Chandra, R.; Kumar, A.; Synthesis of newer indolyl/phenothiazinyl substituted 2-oxo/thiobarbituric acid derivatives as potent anticonvulsant agents. Arzneim-Forsch Drug Res 2003, 53, 5, 301. |
| 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) | 57751 | 10H-Phenothiazine; 2,3,5,6-Dibenzo-1,4-thiazine; Dibenzo-1.4-thiazine; Dibenzothiazine; Phenothiazine; Thiodiphenylamine | 92-84-2 | C12H9NS | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 64835 | ethyl 2-(10H-phenothiazin-10-yl)acetate | C16H15NO2S | 详情 | 详情 | |
| (IV) | 12954 | 1-Hydrazinecarbothioamide; Thiosemicarbazide | 79-19-6 | CH5N3S | 详情 | 详情 |
| (V) | 64836 | 2-[2-(10H-phenothiazin-10-yl)acetyl]-1-hydrazinecarbothioamide | C15H14N4OS2 | 详情 | 详情 | |
| (VI) | 64837 | 5-(10H-phenothiazin-10-ylmethyl)-1,3,4-thiadiazol-2-amine; 5-(10H-phenothiazin-10-ylmethyl)-1,3,4-thiadiazol-2-ylamine | C15H12N4S2 | 详情 | 详情 | |
| (VII) | 64838 | 2-thioxodihydro-4,6(1H,5H)-pyrimidinedione | C4H4N2O2S | 详情 | 详情 |