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【结 构 式】

【分子编号】10252

【品名】1,2-Dibromoethane; Ethylene dibromide

【CA登记号】106-93-4

【 分 子 式 】C2H4Br2

【 分 子 量 】187.86176

【元素组成】C 12.79% H 2.15% Br 85.07%
与该中间体有关的原料药合成路线共 29 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26合成路线27合成路线28合成路线29

合成路线1

该中间体在本合成路线中的序号：(II)

The condensation of 4-fluorophenol (I) with 1,2-dibromoethane (II) in basic medium gives 2-(4-fluorophenyl)ethyl bromide (III), which by reaction with N-benzoyl-2-hydroxyglycine (IV) in methanesulfonic acid yields N-benzoyl-2-[2-(2-bromoethoxy)-5-fluorophenyl]glycine (V). The cyclization of (V) with acetic anhydride and triethylamine at 50 C affords 6-fluoro-2'-phenylspiro[2,3-dihydro-4H-1-benzopyran-4,4'-oxazolidine]-5'-one (VI), which is hydrolyzed with refluxing formic acid-HCl giving the amino acid (VII). The esterification of (VII) with SOCl2 and methanol in the usual way yields the methyl ester (VIII), which is submitted to optical resolution by selective hydrolysis with alpha-chymotrypsine affording methyl 4(S)-amino-6-fluoro-2,3-dihydro-4H-1-benzopyrano-4-carboxylate (IX). Finally, this compound is converted into sorbinil by cyclization with sodium cyanate in acetic acid at room temperature.

参考文献 中间体
合成目标
【1】 Dirlam, N.L.; Moore, B.S.; Urban, F.J.; Novel synthesis of the aldose reductase inhibitor sorbinil via amidoalkylation, intramolecular oxazolidin-5-one alkylation, and chymotrypsin resolution. J Org Chem 1987, 52, 16, 3587-91.
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) 19369 2-iodopropane 75-30-9 C3H7I 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 20830 1-(2-bromoethoxy)-4-fluorobenzene; 2-bromoethyl 4-fluorophenyl ether 332-48-9 C8H8BrFO 详情 详情
(IV) 20606 2-(benzoylamino)-2-hydroxyacetic acid 16555-77-4 C9H9NO4 详情 详情
(V) 20832 2-(benzoylamino)-2-[2-(2-bromoethoxy)-5-fluorophenyl]acetic acid C17H15BrFNO4 详情 详情
(VI) 20833 6-Fluoro-2'-phenyl-3,4,4',5'-tetrahydro-2H-spiro[1-benzopyran-4,4'-oxazol]-5'-one C17H12FNO3 详情 详情
(VII) 20834 4-amino-6-fluoro-4-chromanecarboxylic acid C10H10FNO3 详情 详情
(VIII) 20835 methyl 4-amino-6-fluoro-4-chromanecarboxylate C11H12FNO3 详情 详情
(IX) 20836 [(4S)-4-amino-6-fluoro-3,4-dihydro-2H-chromen-4-yl]methyl formate C11H12FNO3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

A new synthesis of dazoxiben has been described: The condensation of methyl 4-hydroxybenzoate (I) with 1,2-dibromoethane (II) by means of NaOH gives methyl 4-(2-bromoethoxy)benzoate (III), which is hydrolyzed with H2SO4 to the corresponding free acid (IV). Finally, this compound is condensed with imidazole (V) in refluxing butanol.

参考文献 中间体
合成目标
【1】 Palei, R.M.; Kochergin, P.M.; Balandina, L.V.; Govorukhina, E.I.; Persanova, L.V.; Frolova, M.A.; Kravchenko, A.N.; Kharitonova, A.E.; A simplified synthesis of dazoxibene. Khim Farm Zh 1995, 29, 2, 56.
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) 10251 methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate 99-76-3 C8H8O3 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 10253 methyl 4-(2-bromoethoxy)benzoate 56850-91-0 C10H11BrO3 详情 详情
(IV) 10254 4-(2-bromoethoxy)benzoic acid 51616-09-2 C9H9BrO3 详情 详情
(V) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

By condensation of 4-(4-fluorobenzoyl)piperidine (IX) with 6-(2-bromo ethyl)-7-methyl-2,3-dihydro-5H-thiazolo[2,3-a]pyrimidin-5-one (IV) by means of Na2CO3 in refluxing 4-methyl-2-pentanone. The starting products are obtained as follows: The cyclization of 4-hydroxy-5-(2-hydroxyethyl)-6-methyl-2-mercaptopyrimidine (I) with 1,2-dibromo ethane (II) by means of K2CO3 in hot dimethylacetamide gives 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (II), which by reaction with HBr in refluxing acetic acid is converted to the corresponding 6-(2-bromoethyl) derivative (IV). The Grignard reaction of 4-bromofluorobenzene (V) with N benzyl-4 cyanopiperidine (VI) by means of Mg in dimethoxyethane gives 4-(4-fluorobenzoyl)-N-benzylpiperidine (VII), which is treated with ethyl chlorocarbo-nate in refluxing toluene to afford ethyl 4-(4-fluorobenzoyl)piperidine-1-carboxylate (VIII). Finally, this compound is treated with HBr in refluxing 48% HBr to give (IX).

参考文献 中间体
合成目标
【1】 Kennis, L.; Mertens, J.C. (Janssen Pharmaceutica NV); Bicyclic pyrimidin-5-one derivatives. DD 215553; EP 0070053; US 4443451 .
【2】 Serradell, M.N.; Castaner, J.; Setoperone. Drugs Fut 1985, 10, 1, 40.
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) 29009 5-(2-hydroxyethyl)-6-methyl-2-sulfanyl-4-pyrimidinol C7H10N2O2S 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 29010 6-(2-hydroxyethyl)-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one C9H12N2O2S 详情 详情
(IV) 29011 6-(2-bromoethyl)-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one C9H11BrN2OS 详情 详情
(V) 29012 1-bromo-4-fluorobenzene 460-00-4 C6H4BrF 详情 详情
(VI) 29013 1-benzyl-4-piperidinecarbonitrile C13H16N2 详情 详情
(VII) 29014 (1-benzyl-4-piperidinyl)(4-fluorophenyl)methanone C19H20FNO 详情 详情
(VIII) 29015 ethyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate C15H18FNO3 详情 详情
(IX) 21497 (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine 56346-57-7 C12H14FNO 详情 详情

合成路线4

该中间体在本合成路线中的序号：(X)

The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with tetrazolone derivative (VIII) by means of KI in refluxing acetonitrile (or propionitrile) yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (XII). Finally, this compound is acylated with propionyl chloride (XIII) in chloroform to provide the target compound. The intermediate tetrazolone derivative (VIII) has been obtained by reaction of 1-ethyl-4,5-dihydro-1H-tetrazol-5-one (IX) with 1,2-dibromoethane (X) by means of TEA in acetonitrile.

参考文献 中间体
合成目标
【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .
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) 13486 Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone 29976-53-2 C8H13NO3 详情 详情
(II) 49678 ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate C9H13Cl2NO3 详情 详情
(III) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(IV) 49679 ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate C21H25N3O3 详情 详情
(V) 49680 ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate C22H27N3O3 详情 详情
(VI) 49681 4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide C19H23N3O 详情 详情
(VII) 49682 (4-anilino-4-piperidinyl)methanol C12H18N2O 详情 详情
(VIII) 14721 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one C5H9BrN4O 详情 详情
(IX) 32218 1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one 69048-98-2 C3H6N4O 详情 详情
(X) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(XI) 49683 1-[2-[4-anilino-4-(hydroxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one C17H26N6O2 详情 详情
(XII) 49684 1-[2-[4-anilino-4-(methoxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one C18H28N6O2 详情 详情
(XIII) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XIII)

Treatment of alpha-chlorophenylacetyl chloride (VIII) with methylamine provided the corresponding chloro amide (IX), which was subsequently condensed with 2-aminobenzyl alcohol (X) to afford amino alcohol (XI). Cyclization of (XI) in the presence of AlCl3 led to the dibenzoazepine (XII). This was converted to the tetracyclic compound (XIV) by reaction with dibromoethane (XIII) in the presence of Na2CO3. Reduction of the amide carbonyl group of (XIV) by means of LiAlH4 furnished the title compound. In a related strategy, amide (XII) was initially reduced to diamine (VI) by using LiAlH4. Subsequent condensation of (VI) with dibromoethane (XIII) led to the target tetracyclic derivative

参考文献 中间体
合成目标
【1】 Haider, A.; Bollinger, H.; Fischer, A. (Sochinaz SA); Process for the preparation of a tetracyclic compound and application of this process for the preparation of 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin. FR 2647114 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 62397 6,11-dihydro-5H-dibenzo[b,e]azepin-6-yl-N-methylmethanamine; N-(6,11-dihydro-5H-dibenzo[b,e]azepin-6-ylmethyl)-N-methylamine C16H18N2 详情 详情
(VIII) 62399 2-chloro-2-phenylacetyl chloride C8H6Cl2O 详情 详情
(IX) 62400 2-chloro-N-methyl-2-phenylacetamide C9H10ClNO 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
(XI) 62401 2-[2-(hydroxymethyl)anilino]-N-methyl-2-phenylacetamide C16H18N2O2 详情 详情
(XII) 62402 N-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine-6-carboxamide C16H16N2O 详情 详情
(XIII) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(XIV) 62403 2-methyl-3,4,10,14b-tetrahydrodibenzo[c,f]pyrazino[1,2-a]azepin-1(2H)-one C18H18N2O 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XIII)

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

参考文献 中间体
合成目标
【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7

该中间体在本合成路线中的序号：(II)

The alkylation of succinimide (I) with 1,2-dibromoethane (II) by means of K2CO3 in refluxing butanone gives N-(2-bromoethyl)succinimide (III), which is condensed with 4-hydroxythiophenol (IV) by means of K2CO3 in refluxing ethanol to afford 4-hydroxyphenyl 2-succinimidoethyl sulfide (V). Finally, this compound is esterified with 4-guanidinobenzoyl chloride in pyridine, and treated with methanesulfonic acid in methanol.

参考文献 中间体
合成目标
【1】 Hishinuma, I.; Kawashima, H.; Kawata, T.; Miyamoto, K.; Miyazawa, S.; Nagakawa, J.; Nagaoka, J.; Nagaoka, N.; Shimomura, N.; Souda, S.; Ueda, N.; Wakabayashi, T.; Yamanaka, T. (Eisai Co., Ltd.); Guanidinobenzoic ester deriv., a process for preparing same and pharmaceutical compsns. containing same. EP 0229370; JP 1987155253; JP 1994298730; US 4801603; US 5075335 .
【2】 Prous, J.; Castaner, J.; E-3123. Drugs Fut 1988, 13, 7, 613.
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) 22543 2,5-pyrrolidinedione 123-56-8 C4H5NO2 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 22545 1-(2-bromoethyl)-2,5-pyrrolidinedione C6H8BrNO2 详情 详情
(IV) 22546 4-sulfanylphenol 637-89-8 C6H6OS 详情 详情
(V) 22547 1-[2-[(4-hydroxyphenyl)sulfanyl]ethyl]-2,5-pyrrolidinedione C12H13NO3S 详情 详情
(VI) 22548 4-[[amino(imino)methyl]amino]benzoyl chloride C8H8ClN3O 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XXXII)

b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 1) The cyclopropanation of ethyl acetoacetate (XXXI) with 1,2-dibromoethane (XXXII) by means of K2CO3 in DMF gives 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII), which is brominated with Br2 in ethanol yielding the bromoacetyl derivative (XXXIV). The cyclization of (XXXI) with (R)-alpha-methylbenzylamine (XIII) by means of triethylamine affords 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), which by reaction with hydroxylamine is converted into the monooxime (XXXVI). The reduction of (XXXVI) with H2 over RaNi in methanol affords 7-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one as a diastereomeric mixture (XXXVII) + (XXXVIII), which is separated by column chromatography. The reduction of the (7S)-isomer (XXXVIII) with LiAlH4 in THF gives 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXXIX), which is protected in the usual way to the tert-butoxycarbonyl derivative (XL). Finally, this compound is debenzylated to (VII) by hydrogenation with H2 over Pd/C in ethanol.

参考文献 中间体
合成目标
【1】 Hayakawa, I.; Kimura, Y. (Daiichi Pharmaceutical Co., Ltd.); Optically active pyridone carboxylic acid derivs. AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127 .
【2】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIX)) 15177 (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine C14H20N2 详情 详情
(VII) 15131 N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamic acid tert-butyl ester 127199-45-5 C11H20N2O2 详情 详情
(XIII) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(XXXI) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(XXXII) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(XXXIII) 15171 ethyl 1-acetylcyclopropanecarboxylate C8H12O3 详情 详情
(XXXIV) 15172 ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate C8H11BrO3 详情 详情
(XXXV) 15173 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione C14H15NO2 详情 详情
(XXXVI) 15174 5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime C14H16N2O2 详情 详情
(XXXVII) 15175 (7R)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one C14H18N2O 详情 详情
(XXXVIII) 15176 (7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one C14H18N2O 详情 详情
(XL) 15178 N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamic acid C15H20N2O2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(V)

An efficient synthesis of 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XI), a key intermediate in the synthesis of DU-6859a, via an asymmetric microbial reduction has been described: The reaction of N-benzylglycine (I) with tert-butoxycarbonyl anhydride gives N-benzyl-N-(tert-butoxycarbonyl)glycine (II), which is condensed with the potassium salt of ethyl hydrogen malonate (III) by means of carbonyldiimidazole (CDI) in THF yielding 4-[N-benzyl-N-(tert-butoxycarbonyl)amino]-3-oxobutyric acid ethyl ester (IV). The cyclopropanation of (IV) with 1,2-dibromoethane (V) by means of K2CO3 in refluxing acetone affords the cyclopropane derivative (VI), which is cyclized by means of trifluoroacetic acid in dichloromethane to give 5-benzyl-5-azaspiro[2.4]heptane-4,7-dione (VII). The enantioselective microbial reduction of (VII) by means of Phaeocreopsis sp. JCM 1880 in a complex medium containing glucose and polypeptone yields 5-benzyl-7(R)-hydroxy-5-azaspiro[2.4]heptan-4-one (VIII), which by reaction with triphenylphosphine, diethyl azodicarboxylate and diphenylphosphoryl azide (DPPA) followed by reduction with LiAlH4, is converted into 7(S)-amino-5-benzyl-5-azaspiro[2.4]heptane (IX). The protection of (IX) with tert-butoxycarbonyl anhydride as usual gives the protected amine (X), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol affording the desired 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XI).

参考文献 中间体
合成目标
【1】 Yukimoto, Y.; Imura, A.; Satoh, K.; Kanai, K.; Miyadera, A.; An efficient synthesis of a key intermediate of DU-6859a via asymmetric microbial reduction. Chem Pharm Bull 1998, 46, 4, 587.
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) 27895 N-(benzylamino)acetic acid; N-Benzylglycine; 2-(benzylamino)acetic acid 17136-36-6 C9H11NO2 详情 详情
(II) 27846 2-[benzyl(tert-butoxycarbonyl)amino]acetic acid C14H19NO4 详情 详情
(III) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(IV) 27896 ethyl 4-[benzyl(tert-butoxycarbonyl)amino]-3-oxobutanoate C18H25NO5 详情 详情
(V) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(VI) 27897 ethyl 1-[2-[benzyl(tert-butoxycarbonyl)amino]acetyl]cyclopropanecarboxylate C20H27NO5 详情 详情
(VII) 27898 5-benzyl-5-azaspiro[2.4]heptane-4,7-dione C13H13NO2 详情 详情
(VIII) 27899 (7R)-5-benzyl-7-hydroxy-5-azaspiro[2.4]heptan-4-one C13H15NO2 详情 详情
(IX) 27900 (7S)-5-benzyl-5-azaspiro[2.4]hept-7-ylamine C13H18N2 详情 详情
(X) 27901 tert-butyl (7S)-5-benzyl-5-azaspiro[2.4]hept-7-ylcarbamate C18H26N2O2 详情 详情
(XI) 15193 tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate C11H20N2O2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XXII)

The bromination of 1-acetyl-5-propionylindoline (I) with pyrrolidone hydrotribromide (PTBr) and sulfuric acid in THF gives the alpha-bromo derivative (II), which is reduced with triethylsilane in TFA yielding the 2-bromopropyl compound (III). Nitration of (III) with HNO3 in HOAc affords the 7-nitroindoline (IV), which is reduced to the corresponding amine derivative (V) with H2 over PtO2 in ethanol. The reaction of amine (V) with NaNO2/HCl, followed by treatment with CuCN, provides 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (VI), which is treated with NaN3 in hot ethylene glycol monomethyl ether/water to yield the 2-azidopropyl derivative (VII). Reduction of (VII) with H2 over Pd/BaSO4 in ethanol affords the expected 2-aminopropyl compound (VIII), which is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) by means of NaHCO3 in ethanol to provide the secondary amine (X). The intermediate 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) has been obtained as follows: Alkylation of 2-methoxyphenol (XVIII) with 2,2,2-trifluoroethyl iodide (XIX) by means of K2CO3 in hot DMF gives 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (XX), which is demethylated by means of BBr3 in dichloromethane to yield the corresponding phenol (XXI). Finally, this compound is alkylated with 1,2-dibromoethane (XXII) and NaOH in water at 120 C (1,2).

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; KMD-3213. Drugs Fut 2001, 26, 6, 553.
【2】 Kitazawa, M.; Ban, M.; Okazaki, K.; Ozawa, M.; Yazaki, T.; Yamagishi, R. (Kissei Pharmaceutical Co., Ltd.); Indoline cpds. for the treatment of dysuria. EP 0600675; JP 1994220015; US 5387603 .
【3】 Kitazawa, M.; Ozawa, M.; Okazaki, K.; Yamagishi, R.; Yazaki, T.; Saka, M. (Kissei Pharmaceutical Co., Ltd.); Indole derivs.. JP 1995330726 .
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) 47548 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-1-propanone C13H15NO2 详情 详情
(II) 47549 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-bromo-1-propanone C13H14BrNO2 详情 详情
(III) 47550 1-[5-(2-bromopropyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone C13H16BrNO 详情 详情
(IV) 47551 1-[5-(2-bromopropyl)-7-nitro-2,3-dihydro-1H-indol-1-yl]-1-ethanone C13H15BrN2O3 详情 详情
(V) 47552 1-[7-amino-5-(2-bromopropyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone C13H17BrN2O 详情 详情
(VI) 47553 1-acetyl-5-(2-bromopropyl)-7-indolinecarbonitrile C14H15BrN2O 详情 详情
(VII) 47554 1-acetyl-5-(2-azidopropyl)-7-indolinecarbonitrile C14H15N5O 详情 详情
(VIII) 47555 1-acetyl-5-(2-aminopropyl)-7-indolinecarbonitrile C14H17N3O 详情 详情
(IX) 47556 1-(2-bromoethoxy)-2-(2,2,2-trifluoroethoxy)benzene; 2-(2-bromoethoxy)phenyl 2,2,2-trifluoroethyl ether C10H10BrF3O2 详情 详情
(X) 47557 1-acetyl-5-[2-([2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino)propyl]-7-indolinecarbonitrile C24H26F3N3O3 详情 详情
(XVIII) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情
(XIX) 18806 1,1,1-trifluoro-2-iodoethane 353-83-3 C2H2F3I 详情 详情
(XX) 47558 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene; 2-methoxyphenyl 2,2,2-trifluoroethyl ether C9H9F3O2 详情 详情
(XXI) 47559 2-(2,2,2-trifluoroethoxy)phenol C8H7F3O2 详情 详情
(XXII) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

Alkylation of phenol (I) with 1,2-dibromoethane (II) in the presence of K2CO3 in DMF yielded bromoethyl ether (III), which was further, condensed with amine (IV) to afford tertiary amine (V). The nitro group of (V) was then reduced by either catalytic hydrogenation in the presence of Pd/C or by treatment with SnCl2 in aqueous HCl, and the resulting aniline (VI) was condensed with methanesulfonyl chloride in pyridine to give sulfonamide (VII). Finally, acid hydrolysis of the acetamido group provided the title compound.

参考文献 中间体
合成目标
【1】 Kim, D.-I.; Kim, H.Y.; Kwon, L.S.; Park, S.D.; Jeon, G.H.; Jung, K.Y.; Min, J.K.; Nam, W.H.; Lee, K.; Chung, Y.S.; Tanabe, S.; Kozono, T.; Synthesis and biological activity of KCB-328 and its analogues: Novel class III antiarrhythmic agents with little reverse frequency dependence. Bioorg Med Chem Lett 1999, 9, 1, 85.
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) 19881 N-(2-hydroxy-5-nitrophenyl)acetamide C8H8N2O4 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 18938 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine 3490-06-0 C11H17NO2 详情 详情
(III) 19883 N-[2-(2-bromoethoxy)-5-nitrophenyl]acetamide C10H11BrN2O4 详情 详情
(V) 19885 N-(2-[2-[(3,4-dimethoxyphenethyl)(methyl)amino]ethoxy]-5-nitrophenyl)acetamide C21H27N3O6 详情 详情
(VI) 19886 N-(5-amino-2-[2-[(3,4-dimethoxyphenethyl)(methyl)amino]ethoxy]phenyl)acetamide C21H29N3O4 详情 详情
(VII) 19887 N-[2-[2-[(3,4-dimethoxyphenethyl)(methyl)amino]ethoxy]-5-[(methylsulfonyl)amino]phenyl]acetamide C22H31N3O6S 详情 详情

合成路线12

该中间体在本合成路线中的序号：

Reaction of 4-amino-5-chloro-2-methoxybenzoic acid (I) with 1,2-dibromoethane in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene afforded bromoethyl ester (II). This was then condensed with a mixture of cis and trans 3,5-dimethylpiperidines (III), and the resulting mixture of amines was finally separated by column chromatogaphy to provide the target cis compound.

参考文献 中间体
合成目标
【1】 Sicsic, S.; Soulier, J.-L.; Yang, D.; et al.; New esters of 4-amino-5-chloro-2-methoxybenzoic acid as potent agonists and antagonists for 5-HT4 receptors. J Med Chem 1997, 40, 4, 608.
【2】 Langlois, M.; Guzzi, U.; Cecchi, R.; Croci, T. (Midy SpA); Esters of 4-amino-5-chloro-2-methoxybenzoic acid, process for their preparation and pharmaceutical compsns. containing them. EP 0683161 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(I) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(II) 26533 2-bromoethyl 4-amino-5-chloro-2-methoxybenzoate C10H11BrClNO3 详情 详情
(III) 26534 3,5-dimethylpiperidine 35794-11-7 C7H15N 详情 详情

合成路线13

该中间体在本合成路线中的序号：(B)

Activation of butyric acid derivative (I) with isobutyl chloroformate (II) by means of Et3N in THF, followed by coupling with ethylamine (III) in THF in the presence of Et3N, yields butyramide derivative (IV). Reduction of (IV) by means of (-)-B-chlorodiisopinocampheylborane (Ipc2BCl) in THF, followed by reaction with diethanolamine (A), affords hydroxy derivative (V), whose carbonyl group is removed by means of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in toluene/THF, followed by treatment with H2SO4 to provide compound (VI) . Separately, the synthesis of intermediate (XIV) is performed as follows: condensation of pentamethylene chlorohydrin (VII) with 3,4-dihydro-2H-pyran (VIII) by means of p-toluenesulfonic acid in Et2O furnishes 5-chloropentyl-2-tetrahydropyranyl ether (IX), which is then subjected to reaction with acetone (X) in THF by means of Mg in the presence of 1,2-dibromoethane (B) to provide tetrahydropyranyl ether (XI). Conversion of hydroxy derivative (XI) into the corresponding fluoro derivative (XII) is performed by reaction with diethylaminosulfur trifluoride (DAST) in CH2Cl2, and posterior reaction of (XII) with pyridinium p-toluenesulfonate in EtOH furnishes 6-fluoro-6-methyl-1-heptanol (XIII). Finally, intermediate (XIV) is obtained by reaction of (XIII) with NBS and PPh3 in benzene. Condensation of secondary amine (VI) with intermediate (XIV) by means of NaHCO3 in refluxing acetonitrile provides methanesulfonamide (XV), which is finally converted into the target product by formation of the hemifumarate salt by treatment with fumaric acid (XVI) in acetone.

参考文献 中间体
合成目标
【1】 Hester, J.B.; Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: Synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential. J Med Chem 2001, 44, 7, 1099.
【2】 Hester, J.B. Jr.; Gibson, J.K. (Pharmacia Corp.); Antiarrhythmic (S)-enantiomers of methanesulfonamides. EP 0802900; JP 1999500418; WO 9621643 .
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) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(A) 24273 2-[(2-hydroxyethyl)amino]-1-ethanol 111-42-2 C4H11NO2 详情 详情
(I) 14625 4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutyric acid C11H13NO5S 详情 详情
(II) 14932 isobutyryl chloride; 2-methylpropanoyl chloride 79-30-1 C4H7ClO 详情 详情
(III) 10928 Ethanamine 75-04-7 C2H7N 详情 详情
(IV) 48114 N-ethyl-4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutanamide C13H18N2O4S 详情 详情
(V) 48115 (4S)-N-ethyl-4-hydroxy-4-[4-[(methylsulfonyl)amino]phenyl]butanamide C13H20N2O4S 详情 详情
(VI) 48116 N-[4-[(1S)-4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide C13H22N2O3S 详情 详情
(VII) 48117 5-chloro-1-pentanol C5H11ClO 详情 详情
(VIII) 13684 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran 110-87-2 C5H8O 详情 详情
(IX) 48118 2-[(5-chloropentyl)oxy]tetrahydro-2H-pyran; 5-chloropentyl tetrahydro-2H-pyran-2-yl ether C10H19ClO2 详情 详情
(X) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(XI) 48119 2-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-2-hexanol C12H24O3 详情 详情
(XII) 48120 5-fluoro-5-methylhexyl tetrahydro-2H-pyran-2-yl ether; 2-[(5-fluoro-5-methylhexyl)oxy]tetrahydro-2H-pyran C12H23FO2 详情 详情
(XIII) 48121 6-fluoro-6-methyl-1-heptanol C8H17FO 详情 详情
(XIV) 48122 1-bromo-6-fluoro-6-methylheptane C8H16BrF 详情 详情
(XV) 48123 N-(4-[(1S)-4-[ethyl(6-fluoro-6-methylheptyl)amino]-1-hydroxybutyl]phenyl)methanesulfonamide C21H37FN2O3S 详情 详情
(XVI) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情

合成路线14

该中间体在本合成路线中的序号：(X)

The condensation of 3,4-dimethylbenzyl chloride (I) with diethyl malonate (II) by means of sodium ethoxide ethanol gives the diethyl 2-(3,4-dimethylbenzyl)malonate (III), which by treatment with aqueous refluxing NaOH and the with refluxing aqueous sulfuric acid yields 3-(3,4-dimethylphenyl)propionic acid (IV). The reaction of (IV) with refluxing SOCl2 affords the corresponding acyl chloride (V), which is treated with ammonia providing the amide (VI). The reduction of (VI) with LiAlH4 in refluxing THF gives 3-(3,4-dimethylphenyl)propylamine (VII), which by condensation with 2-(4-hydroxy-3-methoxyphenyl)acetic acid (VIII) by heating at 150 C yields the corresponding amide (IX). The alkylation of the phenolic group of (IX) with 1,2-dibromoethane (X) and NaH in refluxing THF affords the 2-bromoethoxy derivative (XI), which by treatment with NaN3 and Bu4NBr in refluxing benzene gives the 2-azidoethoxy derivative (XII). Finally, this compound is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.

参考文献 中间体
合成目标
【1】 Lee, J.-C.; Lee, K.-S.; Han, M.-S.; Jung, Y.S.; Choi, J.; Park, N.-S.; Ha, D.-C.; Seong, C.-M.; Lim, H.-J.; Choi, S.W.; Synthesis of homovanillic amide derivatives and their analgesic activity. Arch Pharmacal Res 1996, 19, 3, 246.
【2】 Lim, H.-J.; Park, N.-S.; Choi, J.-K.; Ha, D.-C.; Kim, H.-S.; Lee, B.-Y.; N-Aralkylated 4-(2-aminoethoxy)phenylacetamide derivatives as potent analgesic and antiinflammatory agents. Korean Journal of Medicinal Chemistry 1991, 1, 1, 36.
【3】 Lee, K.S.; Choi, J.K.; Hong, M.S.; Kim, H.S.; Lim, H.J.; Ha, D.C.; Park, N.S. (Korea Research Institute of Chemical Technology); Novel phenylacetamide derivs. and processes for the preparation thereof. EP 0525360; US 5242944 .
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) 40283 4-(chloromethyl)-1,2-dimethylbenzene 102-46-5 C9H11Cl 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 40284 diethyl 2-(3,4-dimethylbenzyl)malonate C16H22O4 详情 详情
(IV) 40285 3-(3,4-dimethylphenyl)propionic acid C11H14O2 详情 详情
(V) 40286 3-(3,4-dimethylphenyl)propanoyl chloride C11H13ClO 详情 详情
(VI) 40287 3-(3,4-dimethylphenyl)propanamide C11H15NO 详情 详情
(VII) 40288 3-(3,4-dimethylphenyl)-1-propanamine; 3-(3,4-dimethylphenyl)propylamine C11H17N 详情 详情
(VIII) 40289 4-Hydroxy-3-methoxyphenylacetic acid; Homovanillic acid; 2-(4-hydroxy-3-methoxyphenyl)acetic acid 306-08-1 C9H10O4 详情 详情
(IX) 40290 N-[3-(3,4-dimethylphenyl)propyl]-2-(4-hydroxy-3-methoxyphenyl)acetamide C20H25NO3 详情 详情
(X) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(XI) 40291 2-[4-(2-bromoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide C22H28BrNO3 详情 详情
(XII) 40292 2-[4-(2-azidoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide C22H28N4O3 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XX)

Synthesis of morpholine intermediate (I): Treatment of 4-fluorophenyl acetic acid (X) with trimethylacetyl chloride (XI) and Et3N in Et2O followed by reaction with 4-(S)-benzyl-2-oxazolidinone (XII) in THF and n-BuLi in hexane affords oxazolidinone derivative (XIII). Conversion of (XIII) into azido derivative (XV) is achieved by first treatment of (XIII) in THF with a potassium bis(trimethylsilyl)amide solution in toluene followed by treatment with 2,4,6-triisopropylphenylsulfonyl azide (XIV) in THF. Hydrolysis of azido-oxazolidinone derivative (XV) by means of LiOH in THF/H2O yields azido acetic acid derivative (XVI), which is then hydrogenated over Pd/C in H2O/HOAc to afford (S)-(4-fluorophenyl)glycine (XVII). Treatment of (S)-(4-fluorophenyl)glycine (XVII) with benzaldehyde (XVIII), NaOH and NaBH4 in MeOH yields N-benzyl (S)-(4-fluorophenyl)glycine (XIX), which is then cyclized with 1,2-dibromoethane (XX) in the presence of DIEA in DMF to furnish morpholine intermediate (I).

参考文献 中间体
合成目标
【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211.
【2】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G. (Merck & Co., Inc.); Prodrugs of morpholine tachykinin receptor antagonists. EP 0748320; JP 1997509935; US 5691336; WO 9523798 .
【3】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G.; Ladduwahetty, T.; Shah, S.K. (Merck & Co., Inc.); Morpholine and thiomorpholine tachykinin receptor antagonists. EP 0577394; JP 1994172178; US 5719147; WO 9400440; WO 9516679 .
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) 18288 (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone C17H16FNO2 详情 详情
(X) 18999 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid 405-50-5 C8H7FO2 详情 详情
(XI) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XII) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XIII) 44186 (4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one C18H16FNO3 详情 详情
(XIV) 44187 2,4,6-triisopropylbenzenesulfonyl azide C15H23N3O2S 详情 详情
(XV) 44188 (4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one C18H15FN4O3 详情 详情
(XVI) 44189 (2S)-2-azido-2-(4-fluorophenyl)ethanoic acid C8H6FN3O2 详情 详情
(XVII) 43098 (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid 7292-73-1 C8H8FNO2 详情 详情
(XVIII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XIX) 44190 (2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid C15H14FNO2 详情 详情
(XX) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情

合成路线16

该中间体在本合成路线中的序号：

Alkylation of diphenylacetonitrile (I) with dibromoethane provided bromide (II). This was condensed with 2-methylimidazole (III) in the presence of Et3N in DMF to afford the substituted imidazole (IV). Finally, hydrolysis of the cyano group of (IV) with 70% sulfuric acid produced the target amide.

参考文献 中间体
合成目标
【1】 Miyachi, H.; et al.; Synthesis and antimuscarinic activity of a series of 4-(1-imidazolyl)-2,2-diphenylbutyramides: Discovery of potent and subtype-selective antimuscarinic agents. Bioorg Med Chem 1999, 7, 6, 1151.
【2】 Miyachi, H.; Okazaki, K.; Kiyota, H.; Segawa, M. (Kyorin Pharmaceutical Co., Ltd.); Novel imidazole deriv. and process for producing the same. EP 0733621; US 5932607; US 6103747; WO 9515951 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(I) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(II) 26217 4-Bromo-2,2-diphenylbutyronitrile; 4-Bromo-2,2-diphenylbutanenitrile 39186-58-8 C16H14BrN 详情 详情
(III) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(IV) 26218 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanenitrile C20H19N3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

The intermediate fluoropyrrolidine (XIV) was obtained as follows: Alkylation of ethyl acetoacetate (I) with 1,2-dibromoethane (II) led to the cyclopropane derivative (III). Bromination of (III) provided bromo ketone (IV), which was condensed with (S)-1-phenylethylamine (V), yielding amino ketone (VI). Acylation of amine (VI) with (diethylfosfonyl)fluoroacetyl chloride (VII) gave amide (VIII). Intramolecular Wadsworth-Emmons condensation of keto phosphonate (VIII) in the presence of potassium tert-butoxide produced the pyrrolinone (IX). Catalytic hydrogenation of the pyrroline double bond of (IX), followed by separation of the resultant diastereomeric mixture, furnished pyrrolidinone (X). After saponification of the ethyl ester group of (X), the resulting acid (XI) was subjected to Curtius rearrangement in the presence of DPPA and t-BuOH, giving rise to carbamate (XII). Lactam (XII) reduction by means of borane in THF afforded pyrrolidine (XIII). The N-phenylethyl group of (XIII) was then removed by hydrogenation over Pd/C to furnish the required intermediate pyrrolidine (XIV) (See scheme no. 27170201a, intermediate (IX)).

参考文献 中间体
合成目标
【1】 Takahashi, H.; et al.; DQ-113 (D61-1113), a potent fluoroquinolone against multi-drug resistance Gram-positive bacteria: Practical synthesis, and in vitro and in vivo activities. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-550.
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) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 15171 ethyl 1-acetylcyclopropanecarboxylate C8H12O3 详情 详情
(IV) 15172 ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate C8H11BrO3 详情 详情
(V) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(VI) 55739 ethyl 1-(2-{[(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate C16H21NO3 详情 详情
(VII) 55740 diethyl 2-chloro-1-fluoro-2-oxoethylphosphonate C6H11ClFO4P 详情 详情
(VIII) 55741 ethyl 1-(2-{[2-(diethoxyphosphoryl)-2-fluoroacetyl][(1S)-1-phenylethyl]amino}acetyl)cyclopropanecarboxylate C22H31FNO7P 详情 详情
(IX) 55742 ethyl 1-{4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]-2,5-dihydro-1H-pyrrol-3-yl}cyclopropanecarboxylate C18H20FNO3 详情 详情
(X) 44225 ethyl 1-[(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl]cyclopropanecarboxylate C18H22FNO3 详情 详情
(XI) 55743 1-{(3S,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropanecarboxylic acid C16H18FNO3 详情 详情
(XII) 55744 tert-butyl 1-{(3R,4S)-4-fluoro-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropylcarbamate C20H27FN2O3 详情 详情
(XIII) 55745 tert-butyl 1-{(3R,4S)-4-fluoro-1-[(1S)-1-phenylethyl]pyrrolidinyl}cyclopropylcarbamate C20H29FN2O2 详情 详情
(XIV) 44231 tert-butyl 1-[(3R,4S)-4-fluoropyrrolidinyl]cyclopropylcarbamate C12H21FN2O2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(A)

The cyclization of (S)-(+)-phenylethylenediamine (I) with CS2 in alkaline water gives (S)-(+)-4-phenyl-2-mercaptoimidazolidine (II), which is then cyclized again with 1,2-dibromoethane (A) in alkaline isopropanol-water.

参考文献 中间体
合成目标
【1】 Castañer, J.; Hopkins, S.J.; Blancafort, P.; Serradell, M.N.; Levamisole hydrochloride. Drugs Fut 1979, 4, 6, 420.
【2】 Raeymaekers, A.H.M.; et al.; Absolute configurations of the optical isomers of the broad spectrum anthelmintic tetramisole. Tetrahedron Lett 1967, 16, 1467-70.
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) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(I) 39497 (1S)-1-phenyl-1,2-ethanediamine; (1S)-2-amino-1-phenylethylamine C8H12N2 详情 详情
(II) 39498 (4S)-4-phenyl-4,5-dihydro-1H-imidazole-2-thiol; (4S)-4-phenyl-4,5-dihydro-1H-imidazol-2-ylhydrosulfide C9H10N2S 详情 详情

合成路线19

该中间体在本合成路线中的序号：

In a related procedure, iodination of acetophenone (XI) gave (XII). Subsequent alkylation of (XII) with dibromoethane afforded bromoethyl ether (XIII), which was converted to sulfide (XIV) by condensation with 4-chlorothiophenol (IX). Mannich reaction of (XIV) with paraformaldehyde and dimethylamine hydrochloride produced tertiary amine (XV), which was quaternized to (XVI) with MeI. Elimination in the resulting ammonium salt (XVI) produced vinyl ketone (XVII). Diketone (XIX) was then obtained by condensation with trimethoxybenzaldehyde (XVIII) in the presence of thiazolium salt (IV). Reduction of both ketone groups of (XIX) using NaBH4 yielded diol (XX), which was further cyclized with orthophosphoric acid in refluxing benzene to furnish a diastereomeric mixture of cis and trans diaryltetrahydrofurans (XXI). Iodine displacement in (XXI) with CuCN produced the corresponding diastereomeric mixture of cyanides, from which the target trans isomer was isolated by column chromatography.

参考文献 中间体
合成目标
【1】 Ram, B.; et al.; (±)-Trans-2-[3-methoxy-4-(4-chlorophenyl thioethoxy)-5-cyanophenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, a potent PAF-receptor antagonist. Tetrahedron 1999, 55, 33, 10163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(IV) 27942 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride 4568-71-2 C13H16ClNOS 详情 详情
(IX) 27947 4-chlorobenzenethiol 106-54-7 C6H5ClS 详情 详情
(XI) 22604 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone 498-02-2 C9H10O3 详情 详情
(XII) 27949 1-(4-hydroxy-3-iodo-5-methoxyphenyl)-1-ethanone C9H9IO3 详情 详情
(XIII) 27950 1-[4-(2-bromoethoxy)-3-iodo-5-methoxyphenyl]-1-ethanone C11H12BrIO3 详情 详情
(XIV) 27951 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-1-ethanone C17H16ClIO3S 详情 详情
(XV) 27952 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-3-(dimethylamino)-1-propanone C20H23ClINO3S 详情 详情
(XVI) 27953 3-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-N,N,N-trimethyl-3-oxo-1-propanaminium iodide C21H26ClI2NO3S 详情 详情
(XVII) 27954 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-2-propen-1-one C18H16ClIO3S 详情 详情
(XVIII) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(XIX) 27955 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione C28H28ClIO7S 详情 详情
(XX) 27956 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol C28H32ClIO7S 详情 详情
(XXI) 27957 2-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran C28H30ClIO6S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

Treatment of acetonitrile derivative (I) with dibromoethane (II) in toluene in the presence of NaNH2 affords bromo compound (III), which is then condensed with imidazole derivative (IV) by means of Et3N in DMF to provide compound (V). Hydrolysis of the cyano group of (V) with aqueous H2SO4 yields amide derivative (VI), which is finally subjected to alkyl quaternization by reaction with bromobenzyl bromide (VI) in acetone to furnish the desired product.

参考文献 中间体
合成目标
【1】 Miyachi, H.; Kiyota, H.; Segawa, M.; Design, synthesis and antimuscarinic activity of some imidazolium derivatives. Bioorg Med Chem Lett 1999, 9, 20, 3003.
【2】 Miyachi, H.; Okazaki, K.; Kiyota, H.; Segawa, M. (Kyorin Pharmaceutical Co., Ltd.); Novel imidazole deriv. and process for producing the same. EP 0733621; US 5932607; US 6103747; WO 9515951 .
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) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 26217 4-Bromo-2,2-diphenylbutyronitrile; 4-Bromo-2,2-diphenylbutanenitrile 39186-58-8 C16H14BrN 详情 详情
(IV) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(V) 26218 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanenitrile C20H19N3 详情 详情
(VI) 47152 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide 170105-16-5 C20H21N3O 详情 详情
(VII) 16109 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide 589-15-1 C7H6Br2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

The sodium salt of triethyl methanetricarboxylate (I) was alkylated with 1,2-dibromoethane (II) to afford bromide (III). Subsequent condensation of 6-(methylamino)-2-chloropurine (IV) with bromide (III) in the presence of K2CO3 gave adduct (V). Mono-decarbethoxylation of tricarboxylate (V) upon treatment with NaOMe produced malonate (VI), which was further reduced to diol (VII) by means of NaBH4 in CH2Cl2-MeOH. Treatment of (VII) with tetrabenzyl pyrophosphate in the presence of LDA gave rise to the bis-phosphate ester (VIII). The benzyl groups of (VIII) were then cleaved employing boron trichloride, and the resulting phosphoric acid was purified through an ion-exchange resin in the presence of ammonium bicarbonate to furnish the title tetraammonium salt.

参考文献 中间体
合成目标
【1】 Boyer, J.L.; Nandanan, E.; Kim, Y.-C.; Adams, M.; Harden, T.K.; Jang, S.-Y.; Jacobson, K.A.; Gallo-Rodriguez, C.; Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y1 receptor antagonists. J Med Chem 2000, 43, 4, 746.
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) 47051 triethyl methanetricarboxylate 6279-86-3 C10H16O6 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 11646 triethyl 3-bromo-1,1,1-propanetricarboxylate C12H19BrO6 详情 详情
(IV) 47052 2-chloro-N-methyl-9H-purin-6-amine; N-(2-chloro-9H-purin-6-yl)-N-methylamine C6H6ClN5 详情 详情
(V) 47053 triethyl 3-[2-chloro-6-(methylamino)-9H-purin-9-yl]-1,1,1-propanetricarboxylate C18H24ClN5O6 详情 详情
(VI) 47054 diethyl 2-[2-[2-chloro-6-(methylamino)-9H-purin-9-yl]ethyl]malonate C15H20ClN5O4 详情 详情
(VII) 47055 2-[2-[2-chloro-6-(methylamino)-9H-purin-9-yl]ethyl]-1,3-propanediol C11H16ClN5O2 详情 详情
(VIII) 47056 dibenzyl 2-([[bis(benzyloxy)phosphoryl]oxy]methyl)-4-[2-chloro-6-(methylamino)-9H-purin-9-yl]butyl phosphate C39H42ClN5O8P2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(A)

The starting phenylethylamine (I) is prepared by condensation of N-formyl-5-bromo-3,4-methylenedioxyphenylethylamine (VIII) with N-carbobenzoxy-3-methoxy-4-hydroxyphenylethylamine (IX) through an Ullman condensation catalysed by CuO, followed by elimination of the formyl group with HCl in methanol. Compound (VIII) is prepared as follows: 3,4-dihydroxy-5-bromobenzaldehyde (X) is methylenated with methylene bromide (A) and CuO in DMF giving 3,4-methylenedioxy-5-bromobenzaldehyde (XI), which is condensed with nitromethane (B) in acetic acid containing ammonium acetate affording 3,4-methylenedioxy-5-bromo-beta-nitrostyrene (XII). The reduction of (XII) under Clemensen conditions yields 3,4-methylenedioxy-5-bromophenylethylamine (XIII), which is finally formylated with formic acid in decalin. Compound (IX) is prepared as follows: 3-methoxy-4-hydroxy-beta-nitrostyrene (XIV) is treated with ethyl chloroformate (C) in pyridine yielding the corresponding ethoxycarbonyl derivative (XV), which is reduced under Clemensen conditions to 3-methoxy-4-ethoxycarbonyloxyphenylethylamine (XVI). Finally, this compound is treated first with benzyloxycarbonyl chloride and then with aqueous NaHCO3.

参考文献 中间体
合成目标
【1】 Tomita, M.; et al.; Synthesis of di-cepharanthine. Tetrahedron Lett 1967, 1201-06.
【2】 Serradell, M.N.; Blancafort, P.; Mealy, N.; Castañer, J.; Cepharanthine. Drugs Fut 1979, 4, 7, 481.
【3】 Kondo, H.; et al.; US 2206407 .
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) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(B) 39563 nitromethane 75-52-5 CH3NO2 详情 详情
(I) 39554 benzyl 4-[[6-(2-aminoethyl)-1,3-benzodioxol-4-yl]oxy]-3-methoxyphenethylcarbamate C26H28N2O6 详情 详情
(VIII) 39566 2-(7-bromo-1,3-benzodioxol-5-yl)ethylformamide C10H10BrNO3 详情 详情
(IX) 39570 benzyl 3-hydroxy-4-methoxyphenethylcarbamate C17H19NO4 详情 详情
(X) 39561 3-bromo-4,5-dihydroxybenzaldehyde 16414-34-9 C7H5BrO3 详情 详情
(XI) 39562 7-bromo-1,3-benzodioxole-5-carbaldehyde C8H5BrO3 详情 详情
(XII) 39564 4-bromo-6-[(E)-2-nitroethenyl]-1,3-benzodioxole C9H6BrNO4 详情 详情
(XIII) 39565 2-(7-bromo-1,3-benzodioxol-5-yl)ethylamine; 2-(7-bromo-1,3-benzodioxol-5-yl)-1-ethanamine C9H10BrNO2 详情 详情
(XIV) 39567 2-methoxy-5-[(E)-2-nitroethenyl]phenol C9H9NO4 详情 详情
(XV) 39568 ethyl 2-methoxy-5-[(E)-2-nitroethenyl]phenyl carbonate C12H13NO6 详情 详情
(XVI) 39569 5-(2-aminoethyl)-2-methoxyphenyl ethyl carbonate C12H17NO4 详情 详情
(C) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情

合成路线23

该中间体在本合成路线中的序号：(II)

Alkylation of cyclopentane carboxylic acid ethyl ester (I) by treatment with dibromoethane (II) in the presence of BuLi in THF affords derivative (III), which is then converted into azide (IV) by first hydrolysis of ethyl ester with NaOH in dioxane, followed by reaction with NaN3 in DMF. Coupling of (IV) with protected cysteines (V) and (VI) by means of HBTU yields compound (VII), which is then subjected to simultaneous Trt removal and oxidation by means of iodine in CHCl3/MeOH to provide cystine derivative (VIII). Acid deprotection of (VIII), followed by coupling to protected tyrosine (IX) and final deprotection of the resulting compound, furnishes the desired cyclic cystine compound. Alternatively, (VII) can be first subjected to acid deprotection to allow next coupling with protected tyrosine (IX), furnishing derivative (X), which is finally oxidized with iodine in CHCl3/MeOH and further deprotected to afford the target cyclic cystine derivative.

参考文献 中间体
合成目标
【1】 Cook, C.; Kaplan, G.; Fry, D.; Tilley, J.W.; Wolitzky, B.; Hanglow, A.; Joshi, P.; Rowan, K.; Schwinge, V.; Fotouhi, N.; The design and synthesis of potent cyclic peptide VCAM-VLA-4 antagonists incorporating an achiral Asp-Pro mimetic. Bioorg Med Chem Lett 2000, 10, 11, 1171.
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) 46208 ethyl cyclopentanecarboxylate C8H14O2 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 46209 ethyl 1-(2-bromoethyl)cyclopentanecarboxylate C10H17BrO2 详情 详情
(IV) 46210 1-(2-azidoethyl)cyclopentanecarboxylic acid C8H13N3O2 详情 详情
(V) 38971 (5R)-5-benzyl-2-pyrrolidinone C11H13NO 详情 详情
(VI) 46211 tert-butyl (2R)-2-amino-3-(tritylsulfanyl)propanoate C26H29NO2S 详情 详情
(VII) 46212 tert-butyl (2R)-2-([[1-(2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propanoyl]amino]ethyl)cyclopentyl]carbonyl]amino)-3-(tritylsulfanyl)propanoate C61H69N3O6S2 详情 详情
(VIII) 46213 tert-butyl (8R,13R)-13-[(tert-butoxycarbonyl)amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylate C23H39N3O6S2 详情 详情
(IX) 25395 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid 3978-80-1 C14H19NO5 详情 详情
(X) 46214 tert-butyl (2R)-2-[[(1-[(5R,8S)-8-(4-hydroxybenzyl)-12,12-dimethyl-4,7,10-trioxo-5-[(tritylsulfanyl)methyl]-11-oxa-3,6,9-triazatridec-1-yl]cyclopentyl)carbonyl]amino]-3-(tritylsulfanyl)propanoate C70H78N4O8S2 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VII)

The protection of the OH group of 4-hydroxy-3,5-dimethoxybenzaldehyde (I) with benzyl bromide and K2CO3 DMF gives the benzyl ether (II), which is condensed with ethyl 2-azidoacetate (III) by means of NaOMe in methanol to yield the 2-azido acrylic acid derivative (IV). The cyclization of (IV) in refluxing xylene affords the indole carboxylate (V), which is deprotected by hydrogenation with H2 over PtO2 in THF/methanol to provide 6-hydroxy-5,7-dimethoxy-1H-indole-2-carboxylic acid methyl ester (I). The condensation of (VI) with 1,2-dibromoethane (VII) by means of K2CO3 in DMF gives the 2-bromoethoxy derivative (VIII), which is treated with sodium azide in DMF to yield the 2-azidoethoxy compound (IX). The hydrolysis of the ester group of (IX) with NaOH in THF/water affords the carboxylic acid (X), which is esterified with 4-nitrophenol (XI) by means of DCC and DMAP in dichloromethane to provide the activated ester (XII). The condensation of (XII) with the tetracyclic compound (XIII) by means of NaH in DMF gives the adduct (XIV), which is finally reduced at the azido group with H2 over Pd/C in THF/HOAc to yield the target compound.

参考文献 中间体
合成目标
【1】 Suzawa, T.; et al.; Synthesis of a novel duocarmycin derivative DU-257 and its application to immunoconjugate using poly(ethylene glycol-dipeptidyl linker capable of tumor specific activation. Bioorg Med Chem 2000, 8, 8, 2175.
【2】 Saito, H.; Nagamura, S.; Suzawa, T.; Yamasaki, M.; Ohta, S.; Hanai, N. (Kyowa Hakko Kogyo Co., Ltd.); Toxin conjugates. US 6103236; WO 9635451 .
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) 49243 3,5-Dimethoxy-4-hydroxybenzaldehyde; 4-Hydroxy-3,5-dimethoxybenzaldehyde; Syringaldehyde 134-96-3 C9H10O4 详情 详情
(II) 49244 4-Benzyloxy-3,5-dimethoxybenzaldehyde C16H16O4 详情 详情
(III) 49245 alpha-azido acetic acid methyl ester C3H5N3O2 详情 详情
(IV) 49246 methyl (Z)-2-azido-3-[4-(benzyloxy)-3,5-dimethoxyphenyl]-2-propenoate C19H19N3O5 详情 详情
(V) 49247 methyl 6-(benzyloxy)-5,7-dimethoxy-1H-indole-2-carboxylate C19H19NO5 详情 详情
(VI) 49248 methyl 6-hydroxy-5,7-dimethoxy-1H-indole-2-carboxylate C12H13NO5 详情 详情
(VII) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(VIII) 49249 methyl 6-(2-bromoethoxy)-5,7-dimethoxy-1H-indole-2-carboxylate C14H16BrNO5 详情 详情
(IX) 49250 methyl 6-(2-azidoethoxy)-5,7-dimethoxy-1H-indole-2-carboxylate C14H16N4O5 详情 详情
(X) 49251 6-(2-azidoethoxy)-5,7-dimethoxy-1H-indole-2-carboxylic acid C13H14N4O5 详情 详情
(XI) 11236 4-Nitrophenol; p-Nitrophenol 100-02-7 C6H5NO3 详情 详情
(XII) 49252 4-nitrophenyl 6-(2-azidoethoxy)-5,7-dimethoxy-1H-indole-2-carboxylate C19H17N5O7 详情 详情
(XIII) 38365 methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate C14H14N2O3 详情 详情
(XIV) 49253 methyl (3bR,4aS)-6-[[6-(2-azidoethoxy)-5,7-dimethoxy-1H-indol-2-yl]carbonyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate C27H26N6O7 详情 详情

合成路线25

该中间体在本合成路线中的序号：(II)

Alkylation of 7-ethyl-10-hydroxycamptothecin (I) with 1,2-dibromoethane (II) under Williamson's ether synthesis conditions furnished the bromoethyl ether (III). Subsequent regioselective nitration of (III) provided the desired 9-nitro compound (IV), which was further reduced to the corresponding amine (V) by using SnCl2 in concentrated HCl. Finally, cyclization of the bromo amine (V) to give the title hexacyclic compound was carried out either in the presence of KI and K2CO3 in refluxing acetone or on standing in a DMSO solution at room temperature.

参考文献 中间体
合成目标
【1】 Kim, D.-K.; et al.; Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues. J Med Chem 2001, 44, 10, 1594.
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) 10819 (4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin C22H20N2O5 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 50975 (4S)-9-(2-bromoethoxy)-4,11-diethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C24H23BrN2O5 详情 详情
(IV) 50976 (4S)-9-(2-bromoethoxy)-4,11-diethyl-4-hydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C24H22BrN3O7 详情 详情
(V) 50977 (4S)-10-amino-9-(2-bromoethoxy)-4,11-diethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C24H24BrN3O5 详情 详情

合成路线26

该中间体在本合成路线中的序号：(II)

4-Iodophenol (I) is alkylated with 1,2-dibromoethane (II) to afford 1-(2-bromoethoxy)-4-iodobenzene (III). Subsequent palladium-catalyzed coupling of aryl iodide (III) with 3-butyn-1-ol (IV) furnishes the phenylbutynol adduct (V), which is further hydrogenated in the presence of Pd/C to the saturated alcohol (VI). Condensation of the alkyl bromide (VI) with (R)-p-chlorobenzhydrylpiperazine (VII) produces the dialkylated piperazine (VIII). Then, Mitsunobu coupling of arylbutanol (VIII) with phenoxycarbonylaminophenoxyformate (IX) leads to the protected hydroxamic acid (X). This is finally treated with methanolic ammonia to provide the title N-hydroxyurea derivative.

参考文献 中间体
合成目标
【1】 Chatelain, P.; Differding, E.; Cai, X.; Hussoin, S.; Grewal, G.; Young, M.; Lewis, T.; Toy-Palmer, A.; Scannel, R.; Ellis, J.; Lassoie, M.-A. (UCB SA); Cpds. and methods for treatment of asthma, allergy and inflammatory disorders. JP 2002540198; US 6451801; WO 0058295 .
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) 22242 4-iodophenol 540-38-5 C6H5IO 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 64422 1-(2-bromoethoxy)-4-iodobenzene; 2-bromoethyl 4-iodophenyl ether C8H8BrIO 详情 详情
(IV) 32507 3-butyn-1-ol 927-74-2 C4H6O 详情 详情
(V) 64423 4-[4-(2-bromoethoxy)phenyl]-3-butyn-1-ol C12H13BrO2 详情 详情
(VI) 64424 4-[4-(2-bromoethoxy)phenyl]-1-butanol C12H17BrO2 详情 详情
(VII) 30404 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine C17H19ClN2 详情 详情
(VIII) 64425 4-[4-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethoxy)phenyl]-1-butanol C29H35ClN2O2 详情 详情
(IX) 19646 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene C14H11NO5 详情 详情
(X) 64426 1-[(R)-(4-chlorophenyl)(phenyl)methyl]-4-{2-[4-(4-{(phenoxycarbonyl)[(phenoxycarbonyl)oxy]amino}butyl)phenoxy]ethyl}piperazine C43H44ClN3O6 详情 详情

合成路线27

该中间体在本合成路线中的序号：(XII)

Reductive alkylation of (S)-(4-fluorophenyl)glycine (VI) with benzaldehyde and NaBH4 generated the N-benzyl amino acid (XI). This was cyclized with 1,2-dibromoethane (XII) to yield the morpholinone (XIII). Reduction of the lactone function of (XIII) with L-Selectride at -70 C, followed by acylation of the intermediate lactol (XIV) with 3,5-bis(trifluoromethyl)benzoyl chloride (XV), furnished the aroyloxy morpholine (XVI) as the main isomer. Ester (XVI) was converted to the enol ether (XVII) upon treatment with dimethyltitanocene, generated from titanocene dichloride and methyllithium. Catalytic hydrogenation of the enol ether double bond of (XVII) with simultaneous benzyl group hydrogenolysis generated the desired morpholine (XVIII) along with its diastereoisomer (XIX); these were separated by flash chromatography.

参考文献 中间体
合成目标
【1】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 43098 (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid 7292-73-1 C8H8FNO2 详情 详情
(XI) 44190 (2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid C15H14FNO2 详情 详情
(XII) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(XIII) 18288 (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone C17H16FNO2 详情 详情
(XIV) 18289 (2S,3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinol C17H18FNO2 详情 详情
(XV) 18290 3,5-Bis(trifluoromethyl)benzoyl chloride 785-56-8 C9H3ClF6O 详情 详情
(XVI) 18291 (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate C26H20F7NO3 详情 详情
(XVII) 18292 (2R,3S)-4-benzyl-2-([1-[3,5-bis(trifluoromethyl)phenyl]vinyl]oxy)-3-(4-fluorophenyl)morpholine; (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 1-[3,5-bis(trifluoromethyl)phenyl]vinyl ether C27H22F7NO2 详情 详情
(XVIII) 18293 (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine 171482-05-6 C20H18F7NO2 详情 详情
(XIX) 53292 (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine n/a C20H18F7NO2 详情 详情

合成路线28

该中间体在本合成路线中的序号：(II)

Guaiacol (I) was alkylated by means of boiling dibromoethane (II) to produce the bromoethyl ether (III). From this, the intermediate amine (VI) was prepared by Gabriel synthesis, via condensation with potassium phthalimide (IV) in hot DMF, followed by hydrazinolysis of the resultant N-substituted phthalimide (V).

参考文献 中间体
合成目标
【1】 Lin, T.-H.; Chen, I.-J.; Guaiacoxypropanolamines with alpha/beta-adrenergic blocking activity. EP 1108710; WO 0005209 .
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) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 51402 2-(2-Bromoethoxy)methoxybenzene; 1-Bromo-2-(2-methoxyphenoxy)ethane 4463-59-6 C9H11BrO2 详情 详情
(IV) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(V) 59617 2-[2-(2-methoxyphenoxy)ethyl]-1H-isoindole-1,3(2H)-dione C17H15NO4 详情 详情
(VI) 31105 2-(2-methoxyphenoxy)ethylamine; 2-(2-methoxyphenoxy)-1-ethanamine 1836-62-0 C9H13NO2 详情 详情

合成路线29

该中间体在本合成路线中的序号：(A)

Esterification of 5-iodosalicylic acid (I) with methanol and H2SO4 provides the methyl ester (II). Subsequent palladium-catalyzed coupling of (II) with 3-butyn-1-ol (III) yields adduct (IV). Alkylation of the phenolic hydroxyl group of (IV) with 1,2-dibromoethane affords the bromoethyl ether (V). The bromide group of (V) is then displaced with (R)-p-chlorobenzhydryl piperazine (VI) to produce the disubstituted piperazine (VII). Mitsunobu coupling of alcohol (VII) with phenoxycarbonylamino phenoxyformate (VIII) furnishes the protected N-hydroxy carbamate (IX). Finally, ammonolysis of the ester groups of (IX) gives rise to a mixture of the title N-hydroxyurea derivative, along with the analogous methyl ester (X), which can be separated by means of flash chromatography

参考文献 中间体
合成目标
【1】 Chatelain, P.; Differding, E.; Cai, X.; Hussoin, S.; Grewal, G.; Young, M.; Lewis, T.; Toy-Palmer, A.; Scannel, R.; Ellis, J.; Lassoie, M.-A. (UCB SA); Cpds. and methods for treatment of asthma, allergy and inflammatory disorders. JP 2002540198; US 6451801; WO 0058295 .
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) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(I) 60359 2-hydroxy-5-iodobenzoic acid C7H5IO3 详情 详情
(II) 37875 methyl 2-hydroxy-5-iodobenzoate C8H7IO3 详情 详情
(III) 32507 3-butyn-1-ol 927-74-2 C4H6O 详情 详情
(IV) 60360 methyl 2-hydroxy-5-(4-hydroxy-1-butynyl)benzoate C12H12O4 详情 详情
(V) 60361 methyl 2-[(2-bromoethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate C14H15BrO4 详情 详情
(VI) 30404 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine C17H19ClN2 详情 详情
(VII) 60362 methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate C31H33ClN2O4 详情 详情
(VIII) 19646 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene C14H11NO5 详情 详情
(IX) 60363 methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-[4-([(phenyloxy)carbonyl]{[(phenyloxy)carbonyl]oxy}amino)-1-butynyl]benzoate C45H42ClN3O8 详情 详情
(X) 60364 methyl 5-{4-[(aminocarbonyl)(hydroxy)amino]-1-butynyl}-2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]benzoate C32H35ClN4O5 详情 详情
Extended Information