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【结 构 式】 
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【分子编号】12354 【品名】4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene 【CA登记号】352-11-4 |
【 分 子 式 】C7H6ClF 【 分 子 量 】144.5757432 【元素组成】C 58.15% H 4.18% Cl 24.52% F 13.14% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reaction of 1-isothiocyanato-2-nitrobenzene (I) with ethyl 4-aminopiperidine-1-carboxylate (II) in ethanol gives N-(2-nitrophenyl)-N'-(1-ethoxycarbonyl-4-piperidyl)thiourea (III), which is reduced with H2 over Pd/C in methanol saturated with NH3 to afford N-(2-aminophenyl)-N'-(1-ethoxycarbonyl-4-piperidyl)thiourea (IV). The cyclization of (IV) with iodomethane in refluxing ethanol yields 2-(1-ethoxycarbonyl-4-piperidylamino)benzimidazole (V), which is then condensed with 4-fluorobenzyl chloride (VI) by means of Na2CO3 in hot DMF to yield 1-(fluorobenzyl)-2-(1-ethoxycarbonyl-4-piperidylamino)benzimidazole (VII). The decarboxylative hydrolysis of (VII) with 48% HBr in refluxing acetic acid gives 1-(p-fluorobenzyl)-2-(4-piperidylamino)benzimidazole (VIII), which is finally condensed with p-methoxyphenylethyl methanesulfonate (IX) by means of Na2CO3 - KI in hot DMF.
| 【1】 Janssens, F.; Stokbroekx, R.; Torremans, J.; Luyckx, M. (Janssen Pharmaceutica NV); N-Heterocyclyl-4-piperidinamines. EP 0005318 . |
| 【2】 Blancafort, P.; Hillier, K.; Serradell, M.N.; Castaner, J.; Astemizole. Drugs Fut 1982, 7, 1, 10. |
| 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) | 37061 | 1-isothiocyanato-2-nitrobenzene; 2-nitrophenyl isothiocyanate | 2719-30-4 | C7H4N2O2S | 详情 | 详情 |
| (II) | 37062 | 4-amino-N-carbethoxypiperidine; ethyl 4-amino-1-piperidinecarboxylate | 58859-46-4 | C8H16N2O2 | 详情 | 详情 |
| (III) | 37063 | ethyl 4-[[(2-nitroanilino)carbothioyl]amino]-1-piperidinecarboxylate | C15H20N4O4S | 详情 | 详情 | |
| (IV) | 37064 | ethyl 4-[[(2-aminoanilino)carbothioyl]amino]-1-piperidinecarboxylate | C15H22N4O2S | 详情 | 详情 | |
| (V) | 37065 | ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate | C15H20N4O2 | 详情 | 详情 | |
| (VI) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (VII) | 37066 | ethyl 4-[[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate | C22H25FN4O2 | 详情 | 详情 | |
| (VIII) | 37067 | 1-(4-fluorobenzyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine; N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-N-(4-piperidinyl)amine | C19H21FN4 | 详情 | 详情 | |
| (IX) | 37068 | [(4-methoxyphenethyl)oxy](methyl)dimethylene-lambda(6)-sulfane; methyl 4-(2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)phenyl ether | C12H18O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)The chiral sulfonate [(R)-IX] has been obtained in a different way: The cyclization of 2(S)-(benzyloxymethyl)oxirane (XII) with 2-aminoethyl hydrogen sulfate sodium salt (XIII) by means of NaOH in methanol gives 2(R)-(benzyloxymethyl)morpholine (XIV), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to the chiral alcohol (XV). The condensation of (XV) with 4-fluorobenzyl chloride (XVI) by means of K2CO3 and NaI in refluxing butanone affords 4-(4-fluorobenzyl)-2(R)-(hydroxymethyl)morpholine (XVII), which is finally tosylated with tosyl chloride as before to afford [(R)-IX], already obtained.
| 【1】 Morie, T.; Kato, S.; Harada, H.; Yoshida, N.; Matsumoto, J.; Synthesis and biological activities of the optical isomers of (±)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride). Chem Pharm Bull 1994, 42, 4, 877. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 12346 | [(2R)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate | C19H22FNO4S | 详情 | 详情 | |
| (XII) | 12350 | Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane | 14618-80-5 | C10H12O2 | 详情 | 详情 |
| (XIII) | 12351 | Sodium 1-amino-2-(sulfonatooxy)ethane | C2H6NNaO4S | 详情 | 详情 | |
| (XIV) | 12352 | Benzyl (2R)-1,4-oxazinan-2-ylmethyl ether; (2R)-2-[(Benzyloxy)methyl]-1,4-oxazinane | C12H17NO2 | 详情 | 详情 | |
| (XV) | 12353 | (2R)-1,4-Oxazinan-2-ylmethanol | C5H11NO2 | 详情 | 详情 | |
| (XVI) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (XVII) | 12344 | [4-(4-fluorobenzyl)-2-morpholinyl]methyl 4-methylbenzenesulfonate | C19H22FNO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Elgodipine can be obtained in three main steps: The alkylation of N-methyl-2-aminoethanol (I) with 4-fluorobenzyl chloride (II) gives 2-[N-(4-fluorobenzyl)-N-methylamino]ethanol (III), which is esterified with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (IV) yielding the corresponding acetoacetic ester (V). The condensation of (V) with 2,3-methylenedioxybenzaldehyde (VI) affords 2-[N-(4-fluorobenzyl)-N-methylamino]ethyl 2-(2,3-methylenedioxybenzylidene]acetoacetate (VII), which is finally cyclized with isopropyl 3-aminocrotonate (VIII). The intermediate aldehyde (VI) is obtained starting from 2,3-dimethoxybenzaldehyde (X), which by demethylation with HCl or HBr yields 2,3-dihydroxybenzaldehyde (XI). Finally, this compound is converted into (VI) in the usual way. The intermediate crotonate (VIII) is obtained by reaction of isopropyl acetoacetate (IX) with ammonia.
| 【1】 Galiano, A.; Elgodipine Hydrochloride. Drugs Fut 1995, 20, 3, 231. |
| 【2】 Fernandez Torija, C.; Galiano Ramos, J.A. (IIDQB (Madrid)); 1,4-Dihydropyridines, process for their preparation and their use as medicaments. AU 8820330; BE 1001055; CH 675999; EP 0302980; GB 2208861; JP 1989294675; US 4952592 . |
| 【3】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Oxodipine. Drugs Fut 1987, 12, 7, 633. |
| 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) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (III) | 13333 | 2-[(4-Fluorobenzyl)(methyl)amino]-1-ethanol | C10H14FNO | 详情 | 详情 | |
| (IV) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (V) | 13328 | 2-[(4-fluorobenzyl)(methyl)amino]ethyl 3-oxobutanoate | C14H18FNO3 | 详情 | 详情 | |
| (VI) | 13329 | 2,3-(Methylenedioxy)benzaldehyde; 1,3-Benzodioxole-4-carbaldehyde | 7797-83-3 | C8H6O3 | 详情 | 详情 |
| (VII) | 13330 | 2-[(4-fluorobenzyl)(methyl)amino]ethyl (Z)-2-acetyl-3-(1,3-benzodioxol-4-yl)-2-propenoate | C22H22FNO5 | 详情 | 详情 | |
| (VIII) | 13331 | isopropyl (E)-3-amino-2-butenoate | 143093-33-8 | C7H13NO2 | 详情 | 详情 |
| (IX) | 13332 | isopropyl 3-oxobutanoate; Isopropyl acetoacetate | 542-08-5 | C7H12O3 | 详情 | 详情 |
| (X) | 17615 | 2,3-Dimethoxybenzaldehyde | 86-51-1 | C9H10O3 | 详情 | 详情 |
| (XI) | 12380 | 2,3-Dihydroxybenzaldehyde | 24677-78-9 | C7H6O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Indolylacetic acid (I) was esterified with ethanolic HCl, and the resulting ethyl ester (II) was alkylated with 4-fluorobenzyl chloride (III) in the presence of NaH to afford the N-fluorobenzyl indole (IV). Subsequent saponification of (IV) provided carboxylic acid (V). This was finally coupled with 4-aminopyridine (VI) by means of activation with 2-chloro-1-methylpyridinium iodide.
| 【1】 Menciu, C.; Duflos, M.; Fouchard, F.; et al.; New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents. J Med Chem 1999, 42, 4, 638. |
| 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) | 25657 | Indole-3-acetic acid; 2-(1H-Indol-3-yl)acetic acid; 3-Indoleacetic acid | 87-51-4 | C10H9NO2 | 详情 | 详情 |
| (II) | 25658 | 2-(1H-Indol-3-yl)acetic acid ethyl ester | 778-82-5 | C12H13NO2 | 详情 | 详情 |
| (III) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (IV) | 25659 | ethyl 2-[1-(4-fluorobenzyl)-1H-indol-3-yl]acetate | C19H18FNO2 | 详情 | 详情 | |
| (V) | 25660 | 2-[1-(4-fluorobenzyl)-1H-indol-3-yl]acetic acid | C17H14FNO2 | 详情 | 详情 | |
| (VI) | 25661 | 4-pyridinamine; 4-aminopyridine | 5044-74-5 | C5H6N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：The reaction of 5-methoxyindol (I) with 4-fluorobenzyl chloride in DMF gives 5-methoxy-1-(4-fluorobenzyl)indol (II). This compound is acylated with oxalyl chloride, yielding 5-methoxy-[1-(4-fluorobenzyl)indol-3-yl]glyoxylic acid chloride (III), which is transformed with 4-amino-3,5-dichloropyridine into the corresponding amide (IV). The reaction of (IV) with borontribromide in toluene cleaves the methoxy group, yielding AWD 12-281.
| 【1】 Hofgen, N.; Schupke, H.; Marx, D.; Gasparic, A.; Kronbach, T.; Hartenhauer, H.; Szelenyi, I.; Krone, D.; Hempel, R.; Kiss, H.; Berthold, K.; Egerland, U.; Olbrich, M.; Heer, S.; Rundfelt, C.; AWD 12-281. Drugs Fut 2002, 27, 2, 111. |
| 【2】 Höfgen, N.; Kronbach, T.; Plymeropoulos, E.; Marx, D.; Heer, S.; Szelenyi, S.; Egerland, U.; Poppe, H. (Arzneimittelwerk Dresden GmbH); New hydroxyindoles, their use as phosphodiesterase 4 inhibitors and method for producing same. CA 2270301; DE 19818964; WO 9955696 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 | |
| 25135 | 3,5-dichloro-4-pyridinamine; 4-amino-3,5-dichloropyridine | 22889-78-7 | C5H4Cl2N2 | 详情 | 详情 | |
| (I) | 25902 | 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole | 1006-94-6 | C9H9NO | 详情 | 详情 |
| (II) | 51711 | 1-(4-fluorobenzyl)-1H-indol-5-yl methyl ether; 1-(4-fluorobenzyl)-5-methoxy-1H-indole | C16H14FNO | 详情 | 详情 | |
| (III) | 51712 | 2-[1-(4-fluorobenzyl)-5-methoxy-1H-indol-3-yl]-2-oxoacetyl chloride | C18H13ClFNO3 | 详情 | 详情 | |
| (IV) | 31732 | N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-methoxy-1H-indol-3-yl]-2-oxoacetamide | C23H16Cl2FN3O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The reaction of 2-chlorobenzimidazole (I) with N,N'-dimethylprolylene-1,3-diamine (II) by heating at 130 C gives N-(1H-benzimidazol-2-yl)-N,N'-dimethylpropylene-1,3-diamine (III), which is treated with tert-butoxycarbonyl anhydride yielding the carbamate (IV). The condensation of (IV) with 4-fluorobenzyl chloride (V) by means of K2CO3 in DMF affords N-(benzyloxycarbonyl)-N'-[1-(4-fluorobenzyl)benzimidazol-2-yl)-N,N'-dimethylpropylene-1,3-diamine (VI), which is deprotected with trifluoroacetic acid providing the secondary amine (VII). Finally, this compound is condensed with phenyl N-[3,5-bis(trifluoromethyl)benzyl]carbamate (VIII) by heating at 120 C.
| 【1】 Kamikawaji, Y.; Tanikawa, K.; Yamamoto, A.; Hirotsuka, M.; Iwama, T.; Fujita, Y. (Nissan Chemical Industry, Ltd.); Benzimidazole deriv.. EP 0980359; JP 1999315071; US 6114369; WO 9850368 . |
| 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) | 26761 | 2-chloroimidazo[1,2-a]pyridine; 2-chlorobenzimidazole; 2-Amino-4'-chlorodiphenylether; 2-Aminodiphenylether; 2-chloro-1H-benzimidazole | 4857-06-1 | C7H5ClN2 | 详情 | 详情 |
| (II) | 26762 | N-methyl-N-[3-(methylamino)propyl]amine | 111-33-1 | C5H14N2 | 详情 | 详情 |
| (III) | 26763 | N(1)-(1H-benzimidazol-2-yl)-N(1),N(3)-dimethyl-1,3-propanediamine | C12H18N4 | 详情 | 详情 | |
| (IV) | 26764 | tert-butyl 3-[1H-benzimidazol-2-yl(methyl)amino]propyl(methyl)carbamate | C17H26N4O2 | 详情 | 详情 | |
| (V) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (VI) | 26765 | tert-butyl 3-[[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl](methyl)amino]propyl(methyl)carbamate | C24H31FN4O2 | 详情 | 详情 | |
| (VII) | 26766 | N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-N-methyl-N-[3-(methylamino)propyl]amine | C19H23FN4 | 详情 | 详情 | |
| (VIII) | 26767 | phenyl 3,5-bis(trifluoromethyl)benzylcarbamate | C16H11F6NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)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8
该中间体在本合成路线中的序号：(VII)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9
该中间体在本合成路线中的序号：(II)Alkylation of 5-fluoroindole (I) with 4-fluorobenzyl chloride (II) provided the N-benzyl indole (III). Subsequent reaction of (III) with oxalyl chloride furnished the indolylglyoxylic acid chloride (IV). This was finally coupled with 4-amino-3,5-dichloropyridine (V) to afford the corresponding amide.
| 【1】 Egerland, U.; Kronbach, T.; Höfgen, N.; Poppe, H.; Küsters, S.; szelenyi, S.; AWD 12-343, a new orally active PDE 4 inhibitor - Synthesis and comparison with SB 207499, rolipram and AWD 12-281. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-79. |
| 【2】 Hofgen, N.; et al.; AWD 12-343, a new orally active PDE 4 inhibitor - Synthesis and comparison with SB 207499, rolipram and AWD 12-281. 27th Natl Med Chem Symp (June 13 2000, Kansas City) 2000, Abst B-19. |
| 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) | 32388 | 5-Fluoroindole; 5-Fluoro-1H-indole | 399-52-0 | C8H6FN | 详情 | 详情 |
| (II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (III) | 44312 | 5-fluoro-1-(4-fluorobenzyl)-1H-indole | C15H11F2N | 详情 | 详情 | |
| (IV) | 44313 | 2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetyl chloride | C17H10ClF2NO2 | 详情 | 详情 | |
| (V) | 25135 | 3,5-dichloro-4-pyridinamine; 4-amino-3,5-dichloropyridine | 22889-78-7 | C5H4Cl2N2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)The Knoevenagel condensation of 1-methylpyrazole-4-carboxaldehyde (I) with malonic acid afforded the pyrazolylacrylic acid (II), which was further esterified with methanol and sulfuric acid, yielding ester (III). Catalytic hydrogenation of the unsaturated ester (III) in the presence of Pd/C gave the pyrazolylpropionate (IV). Claisen condensation of ester (IV) with methyl formate by using potassium tert-butoxide produced the (hydroxymethylene)propionate (V), which was subsequently cyclized with thiourea (VI) to furnish the thiouracil derivative (VII). Alkylation of (VII) with 4-fluorobenzyl chloride (VIII) gave rise to the thioether (IX). Regioselective alkylation of pyrimidine (IX) with tert-butyl iodoacetate produced the pyrimidinylacetate (X). The tert-butyl ester of (X) was then cleaved with trifluoroacetic acid yielding carboxylic acid (XI).
| 【1】 Smith, S.A.; Inhibition of lipoprotein-associated phospholipase A2 - A novel approach for the treatment of atherosclerosis. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst . |
| 【2】 Ife, R.J.; Leach, C.A.; Smith, S.A.; Pinto, I.L.; Hickey, D.M.B.; Fenwick, A.E. (GlaxoSmithKline plc); Pyrimidinone cpds.. EP 1175408; WO 0066567 . |
| 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) | 53042 | 1-methyl-1H-pyrazole-4-carbaldehyde | n/a | C5H6N2O | 详情 | 详情 |
| (II) | 53043 | (E)-3-(1-methyl-1H-pyrazol-4-yl)-2-propenoic acid | n/a | C7H8N2O2 | 详情 | 详情 |
| (III) | 53044 | methyl (E)-3-(1-methyl-1H-pyrazol-4-yl)-2-propenoate | n/a | C8H10N2O2 | 详情 | 详情 |
| (IV) | 53045 | methyl 3-(1-methyl-1H-pyrazol-4-yl)propanoate | n/a | C8H12N2O2 | 详情 | 详情 |
| (V) | 53046 | methyl (Z)-3-hydroxy-2-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-propenoate | n/a | C9H12N2O3 | 详情 | 详情 |
| (VI) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VII) | 53047 | 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | n/a | C9H10N4OS | 详情 | 详情 |
| (VIII) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (IX) | 53048 | 2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4(1H)-pyrimidinone | n/a | C16H15FN4OS | 详情 | 详情 |
| (X) | 53049 | tert-butyl 2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetate | n/a | C22H25FN4O3S | 详情 | 详情 |
| (XI) | 53050 | 2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetic acid | n/a | C18H17FN4O3S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)Condensation between ethyl 2-oxocyclopentanecarboxylate (I) and thiourea (II) gives rise to the thiouracil derivative (III) (1,2). This is then alkylated with 4-fluorobenzyl chloride (IV) to yield thioether (V). Subsequent alkylation of (V) with tert-butyl iodoacetate (VI) furnishes adduct (VII). Further acidic cleavage of the tert-butyl ester group of (VII) leads to carboxylic acid (VIII) (2,3). Alternatively, intermediate (VIII) is prepared by alkylation of (V) with triflate (IX), followed by alkaline hydrolysis of the resultant methyl ester (X)
| 【1】 The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003, 13, 6, 1067. |
| 【2】 Ife, R.J.; Leach, C.A.; Hickey, D.M.B.; Pinto, I.L.; Smith, S.A.; Stanway, S.J. (GlaxoSmithKline plc); Pyrimidine-4-one derivs. as LDL-PLA 2 inhibitors. EP 1263740; JP 2003523335; US 2002103213; US 6649619; WO 0160805 . |
| 【3】 Mulholland, K.R.; Ross, A.R.; Smith, G.E.; Slater, G.R. (GlaxoSmithKline plc); Novel processes. WO 0316287 . |
| 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) | 29947 | ethyl 2-oxocyclopentanecarboxylate | 611-10-9 | C8H12O3 | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 63490 | 2-sulfanyl-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one | C7H8N2OS | 详情 | 详情 | |
| (IV) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (V) | 63491 | 2-{[(4-fluorophenyl)methyl]sulfanyl}-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one | C14H13FN2OS | 详情 | 详情 | |
| (VI) | 24735 | tert-Butyl 2-iodoacetate | C6H11IO2 | 详情 | 详情 | |
| (VII) | 63492 | 1,1-dimethylethyl 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate | C20H23FN2O3S | 详情 | 详情 | |
| (VIII) | 63494 | 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid | C16H15FN2O3S | 详情 | 详情 | |
| (IX) | 63493 | methyl 2-{[(trifluoromethyl)sulfonyl]oxy}acetate | C4H5F3O5S | 详情 | 详情 | |
| (X) | 63495 | methyl 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate | C17H17FN2O3S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(IV)Condensation of 4-amino-5-cyanoimidazole (I) with pentanamide (II) upon heating at 210 C produced the 2-butyladenine (III). Subsequent alkylation of (III) with 4-fluorobenzyl chloride (IV) yielded the 9-fluorobenzyl adenine (V). This was brominated at position 8 using Br2 and NaOAc in HOAc. The resultant 8-bromo adenine (VI) was finally hydrolyzed under acidic conditions to the title 8-hydroxy derivative.
| 【1】 Matsui, H.; Takaku, H.; Isobe, Y.; Ogita, H.; Tobe, M.; Tomizawa, H. (Japan Energy Corp.); Type 2 helper T cell-selective immune response suppressors. EP 1043021; US 6376501; WO 9932122 . |
| 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) | 52898 | 4(5)-Amino-1H-imidazole-5(4)-carbonitrile; 4(5)-Amino-5(4)-cyanoimidazole | 5098-11-3 | C4H4N4 | 详情 | 详情 |
| (II) | 52899 | Pentanamide; Valeramide; n-Valeramide | 626-97-1 | C5H11NO | 详情 | 详情 |
| (III) | 52900 | 2-butyl-9H-purin-6-amine; 2-butyl-9H-purin-6-ylamine | C9H13N5 | 详情 | 详情 | |
| (IV) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (V) | 52901 | 2-butyl-9-(4-fluorobenzyl)-9H-purin-6-amine; 2-butyl-9-(4-fluorobenzyl)-9H-purin-6-ylamine | C16H18FN5 | 详情 | 详情 | |
| (VI) | 52902 | 8-bromo-2-butyl-9-(4-fluorobenzyl)-9H-purin-6-ylamine; 8-bromo-2-butyl-9-(4-fluorobenzyl)-9H-purin-6-amine | C16H17BrFN5 | 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 2-pyridin-4-ylethanol (I) with 4-fluorobenzyl chloride (II), followed by reduction of the resultant pyridinium salt (III) with NaBH4 leads to the tetrahydropyridine (IV). Acid-catalyzed condensation of alcohol (IV) with benzhydrol (V) then provides the benzhydryl ether (VI) (1). Hydroboration of tetrahydropyridine (VI) and subsequent oxidative work up gives rise to the racemic trans piperidinol rac-(VII) (1,2). Resolution of (VII) is accomplished via esterification with (-)-camphanic chloride (VIII), followed by HPLC separation of the resulting diastereoisomers. The desired isomer (IX) is finally hydrolyzed employing K2CO3 in MeOH to provide the target enantiomer
| 【1】 Ghorai, S.K.; Cook, C.; Davis, M.; Venkataraman, S.K.; George, C.; Beardsley, P.M.; Reith, M.E.A.; Dutta, A.K.; High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: Stereospecific interactions in vitro and in vivo. J Med Chem 2003, 46, 7, 1220. |
| 【2】 Dutta, A.K. (Wayne State University); N- and O-substd. 4-[2-(diphenylmethoxy)-ethyl]-1-[(phenyl)methyl]piperidine analogs and methods of treating CNS disorders therewith. WO 0198266 . |
| 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) | 52533 | 2-(4-Pyridinyl)-1-ethanol; 2-Pyridin-4-ylethanol | C7H9NO | 详情 | 详情 | |
| (II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (III) | 63533 | 1-[(4-fluorophenyl)methyl]-4-(2-hydroxyethyl)pyridinium chloride | C14H15ClFNO | 详情 | 详情 | |
| (IV) | 63534 | 2-{1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1-ethanol | C14H18FNO | 详情 | 详情 | |
| (V) | 11845 | Diphenylmethanol; Benzhydrol | 91-01-0 | C13H12O | 详情 | 详情 |
| (VI) | 63535 | diphenylmethyl 2-{1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydro-4-pyridinyl}ethyl ether; 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-1,2,3,6-tetrahydropyridine | C27H28FNO | 详情 | 详情 | |
| (VII) | 63536 | 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-3-piperidinol | C27H30FNO2 | 详情 | 详情 | |
| (VIII) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
| (IX) | 63537 | 4-{2-[(diphenylmethyl)oxy]ethyl}-1-[(4-fluorophenyl)methyl]-3-piperidinyl 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate | C37H42FNO5 | 详情 | 详情 |