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【结 构 式】

【分子编号】11847

【品名】2-Chloroacetic acid; Chloroacetic Acid

【CA登记号】79-11-8

【 分 子 式 】C2H3ClO2

【 分 子 量 】94.49732

【元素组成】C 25.42% H 3.2% Cl 37.52% O 33.86%
与该中间体有关的原料药合成路线共 15 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1

该中间体在本合成路线中的序号：(II)

The condensation of 3-(tert butoxycarbonyl amino)-1-hydroxy-4-methylazetidin-2-one (I) with chloroacetic acid (II) by means of K2CO3 gives 2-(3-(tert butoxycarbonylamino)-4-methyl-2-oxoazetidin-1-yloxy]acetic acid (III), which is deprotected with trifluoroacetic acid yielding 2-(3-amino 4-methyl-2-oxoazetidin-1-yloxy)acetic acid (IV). Finally, this compound is condensed with 2-(2-amino-thiazol-4-yl)-2-(methoxyimino)acetyl chloride (V) by means of Na2CO3.

参考文献 中间体
合成目标
【1】 Breuer, H.; et al.; [(2-Oxo-1-azetidinyl)oxy]acetic acids: A new class of synthetic monobactams. J Antibiot 1985, 38, 6, 813.
【2】 Miller, M.J.; Woulfe, S.R.; Synthesis and biological activity of substituted [(3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy]acetic acids. A new class of heteroatom-activated beta-lactam antibiotics. J Med Chem 1985, 28, 10, 1447.
【3】 Breuer, H.; Straub, H.; Treuner, U.D. (Von Heyden); beta-Lactam derivs.. DE 3328047; GB 2125794 .
【4】 Castaner, J.; Prous, J.; Oximonam sodium. Drugs Fut 1986, 11, 9, 759.
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) 24312 butyl (2S,3S)-1-hydroxy-2-methyl-4-oxoazetidinylcarbamate C9H16N2O4 详情 详情
(II) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(III) 24314 2-([(2S,3S)-3-[(butoxycarbonyl)amino]-2-methyl-4-oxoazetidinyl]oxy)acetic acid C11H18N2O6 详情 详情
(IV) 24315 2-[[(2S,3S)-3-amino-2-methyl-4-oxoazetidinyl]oxy]acetic acid C6H10N2O4 详情 详情
(V) 24316 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl chloride C6H6ClN3O2S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XXII)

The reaction of 4-phenyl-1-butene (XX) with hypophosphorous acid gives 4-phenylbutylphosphinic acid (XXI), which is condensed with chloroacetic acid (XXII) yielding 2-[hydroxy(4-phenylbutyl)phosphoryl]acetic acid (XXIII). The esterifica-tion of (XXII) with benzyl alcohol affords the benzyl acetate (XXIV), which is esterified at the OH group of the phosphinic acid with 2-methyl-1-(propionyloxy)propyl chloride (XXV) giving the completely esterified derivative (XXVI). The debenzylation of (XXVI) with H2 over Pd/C yields the acetic acid derivative (XXVII), which is submitted to optical resolution affording the desired (S)-isomer (XXVIII). Finally, this compound is condensed with the desired intermediate trans-4-cyclohexyl-L-proline (XI) by means of CDI and NaOH.

参考文献 中间体
合成目标
【1】 Anderson, N.G.; et al.; Generation and fate of regioisomeric side-chain impurities in the preparation of fosinopril sodium. Org Process Res Dev 1997, 1, 4, 315.
【2】 Anderson, N.G.; et al.; Process development for the preparation of a monopril intermediate by a trimethylsilyl-modified arbuzov reaction. Org Process Res Dev 1997, 1, 3, 211.
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) 38567 (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid C11H19NO2 详情 详情
(XX) 20933 1-(3-butenyl)benzene 768-56-9 C10H12 详情 详情
(XXI) 20932 4-phenylbutylphosphinic acid C10H15O2P 详情 详情
(XXII) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(XXIII) 38575 2-[hydroxy(4-phenylbutyl)phosphoryl]acetic acid C12H17O4P 详情 详情
(XXIV) 38576 2-(benzyloxy)-2-oxoethyl(4-phenylbutyl)phosphinic acid C19H23O4P 详情 详情
(XXV) 38577 1-chloro-2-methylpropyl propionate C7H13ClO2 详情 详情
(XXVI) 38578 1-[[[2-(benzyloxy)-2-oxoethyl](4-phenylbutyl)phosphoryl]oxy]-2-methylpropyl propionate C26H35O6P 详情 详情
(XXVII) 38579 2-[[2-methyl-1-(propionyloxy)propoxy](4-phenylbutyl)phosphoryl]acetic acid C19H29O6P 详情 详情
(XXVIII) 38580 2-[[[(1S)-2-methyl-1-(propionyloxy)propyl]oxy](4-phenylbutyl)phosphoryl]acetic acid C19H29O6P 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 two enantiomers of amlodipine have been obtained as follows: The reaction of 2-azidoethanol (I) with chloroacetic acid (II) by means of NaH in THF gives 2-(2-azidoethoxy)acetic acid (III), which is condensed with Meldrum's acid (IV) and 3-hydroxypropionitrile (V) in dichloromethane to yield the 2-cyanoethyl acetoacetate (VI). The cyclization of (VI) with 2-chlorobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing ethanol affords the dihydropyridine (IX), which is selectively hydrolyzed at the 2-cyanoethylester with NaOH to give the dihydropyridine monocarboxylic acid (X). The esterification of (X) with (S)-2-methoxy-2-phenylethanol (XI) by means of CDI in dichloromethane provides the ester (XII) as a diastereomeric mixture, which is separated by chromatography to furnish diastereomers (XXI A) and (XII B). The selective ethanolysis of (XII A) and (XII B) with sodium ethoxide in refluxing ethanol/diglyme gives enantiomers (+)-(XIII) and (-)-(XIII), which are finally reduced with H2 over Pd/CaCO3 in ethanol to afford the (-)- and (+)-isomers, respectively, of the target compound.

参考文献 中间体
合成目标
【1】 Arrowsmith, J.E.; et al.; Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents. J Med Chem 1986, 29, 9, 1696.
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) 24111 2-azido-1-ethanol C2H5N3O 详情 详情
(II) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(III) 48263 2-(2-azidoethoxy)acetic acid C4H7N3O3 详情 详情
(IV) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(V) 14029 Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile 109-78-4 C3H5NO 详情 详情
(VI) 48264 2-cyanoethyl 4-(2-azidoethoxy)-3-oxobutanoate C9H12N4O4 详情 详情
(VII) 24114 2-chlorobenzaldehyde 89-98-5 C7H5ClO 详情 详情
(VIII) 11372 Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate C5H9NO2 详情 详情
(IX) 48265 3-(2-cyanoethyl) 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate C21H22ClN5O5 详情 详情
(X) 48266 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-3-pyridinecarboxylic acid C18H19ClN4O5 详情 详情
(XI) 48267 (2S)-2-methoxy-2-phenyl-1-ethanol 66051-01-2 C9H12O2 详情 详情
(XII) 48268 3-[(2S)-2-methoxy-2-phenylethyl] 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate C27H29ClN4O6 详情 详情
(XIII) 24115 3-ethyl 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate C20H23ClN4O5 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

Aceclofenac was prepared by selective hydrolysis of other labile ester precursors. Alkylation of diclofenac sodium (I) with tetrahydropyranyl chloroacetate (IX), prepared by protection of chloroacetic acid (VIII) with dihydropyran, furnished the tetrahydropyranyl ester of aceclofenac (X), which was then deprotected by treatment with HCl. Similarly, the preparation of aceclofenac was reported by acidic hydrolysis of the analogous tetrahydrofuranyl ester (XI).

参考文献 中间体
合成目标
【1】 Flores Ramos, R. (Almirall Prodesfarma, SA); Process for obtaining 2-[(2,6-dichlorophenyl)amino]phenylacetoxy acetic acid. ES 2046141 .
【2】 Zirngibl, L.; Gnehm, R. (Siegfried AG); Process for the preparation of a phenylacetic acid deriv.. CH 682747 .
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) 56535 sodium 2-[2-(2,6-dichloroanilino)phenyl]acetate C14H10Cl2NNaO2 详情 详情
(VIII) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(IX) 56539 tetrahydro-2H-pyran-2-yl 2-chloroacetate C7H11ClO3 详情 详情
(X) 56540 2-oxo-2-(tetrahydro-2H-pyran-2-yloxy)ethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate C21H21Cl2NO5 详情 详情
(XI) 56541 2-oxo-2-(tetrahydro-2-furanyloxy)ethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate C20H19Cl2NO5 详情 详情

合成路线5

该中间体在本合成路线中的序号：(A)

This compound can be prepared in several different ways: 1) The reaction of benzhydryl bromide (I) with thiourea (II) in refluxing water gives diphenyl - methanethiol (III), which is condensed with chloroacetic acid (A) by means of NaOH in hot water yielding (benzhydrylthio)acetic acid (IV). The esterification of (IV) with ethanol and H2SO4 affords the corresponding ethyl ester (V), which is treated with hydroxylamine hydrochloride and KOH in methanol to give benzhydrylthioacetohydroxamic acid (VI). Finally, this compound is oxidized with H2O2 in acetic acid. 2) Compound (III) can also be obtained by reaction of benzhydrol (VII) with thiourea and aqueous 48% HBr at 100 C. 3) Compound (IV) can be oxidized with H2O2 in water to give benzhydrylsulfinylacetic acid (VIII), which is methylated with dimethyl sulfate and NaHCO3 in water to the corresponding methyl ester (IX). Finally, this compound is treated with hydroxylamine and NaOH in water

参考文献 中间体
合成目标
【1】 Lafon, L. (Laboratoires L. Lafon); New benzhydrysulphinyl derivatives. DE 2642511; FR 2326181; GB 1520812; JP 52046058; US 4066686 .
【2】 Mignonac, S.; Guy, A.; De Lamer, V. (Sanofi-Synthelabo); Preparation of polyamine(s), substd. on terminal nitrogen atoms. FR 2714052 .
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) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(I) 12079 Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide 776-74-9 C13H11Br 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 32695 diphenylmethanethiol; benzhydrylhydrosulfide C13H12S 详情 详情
(IV) 11848 2-(Benzhydrylsulfanyl)acetic acid C15H14O2S 详情 详情
(V) 32696 ethyl 2-(benzhydrylsulfanyl)acetate C17H18O2S 详情 详情
(VI) 32697 2-(benzhydrylsulfanyl)-N-hydroxyacetamide 63547-44-4 C15H15NO2S 详情 详情
(VII) 11845 Diphenylmethanol; Benzhydrol 91-01-0 C13H12O 详情 详情
(VIII) 11851 2-(Benzhydrylsulfinyl)acetic acid C15H14O3S 详情 详情
(IX) 11852 methyl 2-(benzhydrylsulfinyl)acetate C16H16O3S 详情 详情

合成路线6

该中间体在本合成路线中的序号：(A)

(rac)-1,2-Diaminopropane is resolved using (-)-L-tartaric acid. The bitartrate salt is treated with HCl to give the dihydrochloride salt, (-)-S-1,2-diaminopropane dihydrochloride (I). (I) in water is added to a solution of chloroacetic acid and sodium hydroxide below 20 C, and allowed to stand at room temperature for 7 days. After concentration and filtration, the product is isolated by passing the filtrate down an ion exchange column and eluting with water. The portion of the eluate containing the bulk of the optical activity is concentrated by heating. Crystals of (+)-(S)-1,2-propylene dinitrilotetraacetic acid (II) are obtained by filtration. (II) is heated under nitrogen for 20 h at 165 C to give (+)-(S)-1,2-di(piperazine-2,6-dione)propane.

参考文献 中间体
合成目标
【1】 NS-2330 enters phase IIb in Alzheimer's disease. J Pharm Sci 1976, 65, 238-242.
【2】 Eastland, G.; ICRF-187. Drugs Fut 1987, 12, 11, 1017.
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) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(I) 27996 (1S)-2-amino-1-methylethylamine C3H10N2 详情 详情
(II) 27997 2-[[(1S)-2-[bis(carboxymethyl)amino]-1-methylethyl](carboxymethyl)amino]acetic acid C11H18N2O8 详情 详情

合成路线7

该中间体在本合成路线中的序号：(III)

This compound can be obtained by two related ways: 1) The condensation of benzhydrol (I) with chloroacetic acid (II) by means of thiourea (III) in concentrated hydrobromic acid at 95 C gives 2-(diphenylmethylthio)acetic acid (IV), which by reaction with SOCl2 in refluxing benzene is converted into the acid chloride (V). The reaction of (V) with ammonium hydroxide in water - methylene chloride affords 2-(diphenylmethylthio)acetamide (VI), which is finally oxidized with hydrogen peroxide. 2) Acid (IV) can also be oxidized with hydrogen peroxide to give 2-(diphenylmethylsulfinyl)acetic acid (VII), which is methylated with dimethylsulfate and NaHCO3 to the corresponding methyl ester (VIII). Finally, this compound is treated with ammonia in anhydrous methanol.

参考文献 中间体
合成目标
【1】 Lafon, L. (Laboratoires L. Lafon); Acetamide derivs. DE 2809625; FR 2385693; US 4177290 .
【2】 Prous, J.; Castaner, J.; MODAFINIL. Drugs Fut 1990, 15, 2, 130.
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) 11845 Diphenylmethanol; Benzhydrol 91-01-0 C13H12O 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(IV) 11848 2-(Benzhydrylsulfanyl)acetic acid C15H14O2S 详情 详情
(V) 11849 2-(Benzhydrylsulfanyl)acetyl chloride C15H13ClOS 详情 详情
(VI) 11850 2-(Benzhydrylsulfanyl)acetamide C15H15NOS 详情 详情
(VII) 11851 2-(Benzhydrylsulfinyl)acetic acid C15H14O3S 详情 详情
(VIII) 11852 methyl 2-(benzhydrylsulfinyl)acetate C16H16O3S 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IV)

The chiral diamine (II) was obtained by resolution of racemic 1,2-diaminopropane (I) with D-tartaric acid. Condensation of diamine (II) with formaldehyde and NaCN produced the tetranitrile (III). Acidic hydrolysis of tetranitrile (III) produced tetraamide (VI). The cyclization of (VI) upon heating in phenol furnished the title bis-piperazinedione. The cyclization of tetraamide (VI) has also been reported using polyphosphoric acid or sodium (methylsulfinyl)methyde. Alternatively, the synthesis of Dexrazoxane can be performed by by alkylation of diamine (II) with chloroacetic acid (IV) by means of NaOH in water to afford tetraacid (V), which is then subjected to cyclization in hot formamide.

参考文献 中间体
合成目标
【1】 Miller, W.D.; Process for preparing (S)(+)-4,4'-(1-methyl-1,2-ethanediyl)-bis(2,6-piperazinedione). EP 0284594 .
【2】 Tu, C.-Y.J.; Clark, G.W.; Borsotti, G.; Process for preparing bis(3,5-dioxopiperazinyl)alkanes or alkenes. EP 0330381 .
【3】 Creighton, A.M. (National Research Development Corp.); (3,5,3',5'-Tetraoxo)-1,2-dipiperazinoalkane cpds. and process for their preparation. DE 1910283; DE 1967027 .
【4】 Holthuis, J.J.M.; MacDonald, P.L.; Stradi, R.; Rossetto, P. (EuroCetus BV); Process for preparing (S)(+)-4,4'-(1-methyl-1,2-ethanediyl)-bis(2,6-piperazinedione). WO 9308172 .
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) 30691 1,2-propanediamine; 2-amino-1-methylethylamine 78-90-0 C3H10N2 详情 详情
(II) 27996 (1S)-2-amino-1-methylethylamine C3H10N2 详情 详情
(III) 55629 2-[{(1S)-2-[bis(cyanomethyl)amino]-1-methylethyl}(cyanomethyl)amino]acetonitrile C11H14N6 详情 详情
(IV) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(V) 27997 2-[[(1S)-2-[bis(carboxymethyl)amino]-1-methylethyl](carboxymethyl)amino]acetic acid C11H18N2O8 详情 详情
(VI) 55630 2-((2-amino-2-oxoethyl){(1S)-2-[bis(2-amino-2-oxoethyl)amino]-1-methylethyl}amino)acetamide C11H22N6O4 详情 详情

合成路线9

该中间体在本合成路线中的序号：

Proxodolol (V) was obtained as shown in Scheme 21696501a: Monoalkylation of pyrocatechol with chloroacetic acid gives 2-hydroxyphenoxyacetic acid (I), which is cyclized on heating into 1,4-benzodioxan-2-one (II). Condensation of (II) with acetamidoxime, giving 2-methyl-5-(2-hydroxyphenoxymethyl)-1,2,4-oxadiazole (III), followed by alkylation with epichlorohydrin yields the corresponding diether (IV), which smoothly reacts with tert-BuNH2, and the amine (V) is converted into its hydrochloride by reaction with HCl.

参考文献 中间体
合成目标
【1】 Mashkovski, M.D.; Sokolov, S.D.; Vinogradova, S.M.; Yuzhakov, S.D.; Yermakova, V.N.; Proxodolol. Drugs Fut 1997, 22, 5, 499.
【2】 Sokolov, S.D.; Vinogradova, S.M.; Azarevich, O.G.; Berg, M.V.; Mashkovski, M.D.; Yuzhakov, S.D.; Morozov, A.V. (Center for Chemistry of Drugs); The hydrochlorides of derivs. of 5-phenoxymethyl-1,2, 4-oxadiaxole, possessing beta- and alpha-adrenoblocking activities. SU 1132505 .
【3】 Sokolov, S.D.; Vinogradova, S.M.; Azarevich, O.G. (Center for Chemistry of Drugs); The method for producing of 5-(2-hydroxyphenoxymethyl)-1,2,4-oxadiazoles. SU 1139129 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
11599 o-Dihydroxybenzene; Catechol; Pyrocatechol 120-80-9 C6H6O2 详情 详情
11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
64134 N'-hydroxyethanimidamide C2H6N2O 详情 详情
(I) 16894 2-Hydroxyphenoxyacetic acid; o-Hydroxyphenoxyacetic acid; 2-(2-hydroxyphenoxy)acetic acid 6324-11-4 C8H8O4 详情 详情
(II) 16895 1,4-BENZODIOXAN-2-ONE; 1,4-benzodioxin-2(3H)-one 4385-48-2 C8H6O3 详情 详情
(III) 16896 2-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]phenol C10H10N2O3 详情 详情
(IV) 16897 2-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]phenyl 2-oxiranylmethyl ether; 3-methyl-5-[[2-(2-oxiranylmethoxy)phenoxy]methyl]-1,2,4-oxadiazole C13H14N2O4 详情 详情
(V) 16898 1-(tert-butylamino)-3-[2-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]phenoxy]-2-propanol hydrochloride C17H26ClN3O4 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XXII)

Reaction of chloroacetic acid (XXII) with sodium ethoxide (XXIII) in ethanol gives 2-ethoxyacetic acid ethyl ester (XXIV), which is condensed with 4-methoxybenz-aldehyde (XXV) by means of t-BuOK in THF to yield 2-ethoxy-3-(4-methoxyphenyl)-2-propenoic acid ethyl ester (XXVI). Hydrolysis of ester (XXVI) with NaOH in hot ethanol/water affords the propenoic acid derivative (XXVII), which is reduced with H2 over Pd/C in ethanol to provide racemic 2-ethoxy-3-(4-methoxyphenyl)propionic acid (XXVIII). Optical resolution of mixture (XXVIII) is performed by salt formation with 1(S)-(1-naphthyl)ethylamine (XXIX) followed by crystallization to give the diastereomeric salt (XXX), which is treated with NaOH, followed by acidification with HCl to yield 2(S)-ethoxy-3-(4-methoxyphenyl)propionic acid (XXXI). Demethylation of compound (XXXI) by reaction with NaOH and octanethiol in NMP affords 2(S)-ethoxy-3-(4-hydroxyphenyl)propionic acid (XXXII), which is esterified with ethanol/HCl to provide the corresponding ethyl ester (XXXIII). Condensation of ester (XXXIII) with the bismesylate (II) by means of either K2CO3 in 2-butanone or Na2CO3 in acetone provides 2(S)-ethoxy-3-[4-[2-[4-(methanesulfonyloxy)-phenyl]ethoxy]phenyl]propionic acid ethyl ester (XXI), which is finally hydrolyzed with NaOH or LiOH in acetone/water.

参考文献 中间体
合成目标
【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tesaglitazar. Drugs Fut 2003, 28, 10, 959.
【2】 Ioannidis, P.; Ehrl, R.; MacKintosh, W. (AstraZeneca AB); Process for the preparation 3-aryl-2-hydroxypropionic acid deriv.. WO 0296865 .
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) 50403 4-[2-[(methylsulfonyl)oxy]ethyl]phenyl methanesulfonate C10H14O6S2 详情 详情
(XX) 50418 ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate C13H18O4 详情 详情
(XXI) 50419 ethyl (2S)-2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]propanoate C22H28O7S 详情 详情
(XXII) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(XXIII) 63048 sodium 1-ethanolate C2H5NaO 详情 详情
(XXIV) 63049 ethyl 2-ethoxyacetate C6H12O3 详情 详情
(XXV) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(XXVI) 63050 ethyl (E)-2-ethoxy-3-(4-methoxyphenyl)-2-propenoate C14H18O4 详情 详情
(XXVII) 63051 (E)-2-ethoxy-3-(4-methoxyphenyl)-2-propenoic acid C12H14O4 详情 详情
(XXVIII) 63052 2-ethoxy-3-(4-methoxyphenyl)propanoic acid C12H16O4 详情 详情
(XXIX) 17443 (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine 3886-70-2 C12H13N 详情 详情
(XXX) 63053 (1S)-1-(1-naphthyl)-1-ethanaminium (2S)-2-ethoxy-3-(4-methoxyphenyl)propanoate C24H29NO4 详情 详情
(XXXI) 63054 (2S)-2-ethoxy-3-(4-methoxyphenyl)propanoic acid C12H16O4 详情 详情
(XXXII) 63055 (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid C11H14O4 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XXXV)

Finally, etoricoxib is obtained by several related ways: Cyclization of ketosulfone (XXIV) with 2-chloromalondialdehyde (XXIX) or the aniline derivative (XXX) and ammonium acetate in hot propionic acid. Cyclization of ketosulfone (XXIV) with aminoacrolein (XXXI) in the absence of ammonium acetate. Aminoacrolein (XXXI) is prepared by treatment of chloromalondialdehyde (XXIX) with isopropanol, yielding the ether (XXXII) and followed by reaction with ammoniun hydroxide. Cyclization of the lithium enolate of ketosulfone (XXIV) with 2,3-dichloroacrolein (XXXIII) -- obtained by treatment of chloromalondialdehyde (XXIX) with oxalyl chloride and DMF in toluene -- followed by reaction with ammonium acetate or anhydrous ammonia. Reaction of ketosulfone (XXIV) with 2-chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) in the presence of an equimolar amount of t-BuOK followed by treatment with HOAc/TFA and then heating at reflux with an excess of ammonium hydroxide. 2-Chloro-1,3-bis(dimethylamino)trimethinium hexaflourophosphate salt (XXXIV) is obtained by reaction of chloroacetic acid (XXXV) with hot dimethylformamide (XXXVI) and POCl3, and then the reaction mixture is treated with 5N NaOH and hexafluorophosphoric acid in water.

参考文献 中间体
合成目标
【1】 Davies, I.W.; Marcoux, J.-F.; Wu, J.; et al.; An efficient preparation of vinamidinium hexafluorophosphate salts. J Org Chem 2000, 65, 15, 4571.
【2】 Castañer, R.M.; Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; Etoricoxib. Drugs Fut 2001, 26, 4, 346.
【3】 Davies, I.W.; Marcoux, J.-F.; Corley, E.G.; et al.; A practical synthesis of a COX-2-specific inhibitor. J Org Chem 2000, 65, 25, 8415.
【4】 Rossen, K.; Robbins, M.A.; Corley, E.G.; Wu, J.; Davies, I.W.; Marcoux, J.-F.; Reider, P.J.; Pye, P.; Larsen, R.D.; Annulation of ketones with vinamidinium hexafluorophosphate salts: An efficient preparation of trisubstituted pyridines. Org Lett 2000, 2, 15, 2339.
【5】 Corley, E.G.; Davies, I.W.; Larsen, R.D.; Rossen, K.; Pye, P.J. (Merck & Co., Inc.); Process for synthesizing COX-2 inhibitors. US 6040319; WO 9955830 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIV) 45711 1-(6-methyl-3-pyridinyl)-2-[4-(methylsulfonyl)phenyl]-1-ethanone C15H15NO3S 详情 详情
(XXIX) 45712 (E)-2-chloro-3-hydroxy-2-propenal C3H3ClO2 详情 详情
(XXX) 45714 (E)-3-anilino-2-chloro-2-propenal C9H8ClNO 详情 详情
(XXXI) 45716 (E)-3-amino-2-chloro-2-propenal C3H4ClNO 详情 详情
(XXXII) 45715 (E)-2-chloro-3-isopropoxy-2-propenal C6H9ClO2 详情 详情
(XXXIII) 45713 (E)-2,3-dichloro-2-propenal C3H2Cl2O 详情 详情
(XXXIV) 45717 　 C7H14ClF6N2P 详情 详情
(XXXV) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(XXXVI) 33491 Dimethylformamide 68-12-2 C3H7NO 详情 详情
(XXXVII) 45718 N-[(E)-2-chloro-3-(dimethylamino)-2-propenylidene]-N-methylmethanaminium chloride C7H14Cl2N2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(V)

The cyclization of methyl acetoacetate (I), 2-methoxybenzaldehyde (II) and thiourea (III) by means of HCl in refluxing ethanol gives the tetrahydropyrimidine (IV), which is finally cyclized with chloroacetic acid (V) and benzaldehyde (VI) by means of sodium acetate in a refluxing mixture of acetic acid and acetic anhydride.

参考文献 中间体
合成目标
【1】 Kelicen, P.; Ertan, M.; Demirdamar, R.; Krebs, B.; Tozkoparan, B.; Lage, M.; Condensed heterocyclic compounds: Synthesis and antiinflammatory activity of novel thiazolo[3,2-a]pyrimidines. Arch Pharm 1998, 331, 6, 201.
【2】 Assandri, A.; et al.; Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog. Arzneim-Forsch Drug Res 1985, 35, 2, 508.
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) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(II) 12568 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde 135-02-4 C8H8O2 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 27432 methyl 4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H16N2O3S 详情 详情
(V) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情

合成路线13

该中间体在本合成路线中的序号：(I)

Thiazolidinedione (III) was prepared by condensation of chloroacetic acid (I) with thiourea (II). Alkylation of the potassium salt of (III) with 4-methoxyphenacyl bromide (IV) furnished the 3-phenacyl thiazolidinedione (V). Finally, aldol condensation of (V) with flavone-6-carboxaldehyde (VI) in the presence of NaOAc in HOAc provided the title compound.

参考文献 中间体
合成目标
【1】 Altanlar, N.; Ayhan-Killergil, G.; Synthesis of 3-substituted phenacyl-5-[2-phenyl-4H-4-oxo-1-benzopyran-6-yl(methylenyl]thiazolidine-2,4-diones and evaluation of their antimicrobial activity. Arzneim-Forsch Drug Res 2000, 50, 2, 154.
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) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(IV) 21991 2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone 2632-13-5 C9H9BrO2 详情 详情
(V) 50131 3-[2-(4-methoxyphenyl)-2-oxoethyl]-1,3-thiazolidine-2,4-dione C12H11NO4S 详情 详情
(VI) 50132 4-oxo-2-phenyl-4H-chromene-6-carbaldehyde C16H10O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(B)

Compound can be prepared in two related ways: 1) The acylation of 2,6-dimethylaniline (I) with chloroacetyl chloride (II) in acetic acid gives omega-chloro-2,6-dimethylacetanilide (III), which is then condensed with disodium salt of iminodiacetic acid (IV) in refluxing ethanol-water. 2) The reaction of (III) with ammonia in ethanol gives omega-amino-2,6-dimethylacetanilide (V), which is finally treated with chloroacetic acid (A) and NaOH in refluxing 95% ethanol.

参考文献 中间体
合成目标
【1】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Paton, D.M.; Lidofenin. Drugs Fut 1979, 4, 5, 342.
【2】 Callery, P.S.; et al.; Tissue distribution of technetium-99m and carbon-14 labeled N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid. J Med Chem 1976, 19, 7, 962-964.
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) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(I) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情
(IV) 39492 2-[(carboxymethyl)amino]acetic acid 142-73-4 C4H7NO4 详情 详情
(V) 39493 2-amino-N-(2,6-dimethylphenyl)acetamide C10H14N2O 详情 详情

合成路线15

该中间体在本合成路线中的序号：(III)

The reaction of 2'-O-(triethylsilyl)paclitaxel (I) with dimethyl sulfide (DMS) and Bz2O2 in acetonitrile gives the 7-O-(methylsulfanylmethyl) derivative (II), which is condensed with chloroacetic acid (III) by means of N-iodosuccinimide (NIS) and Ag-OTf in THF to yield the 7-O-(chloroacetoxymethyl) derivative (IV). The desilylation of (IV) by means of HCl in acetonitrile affords the intermediate (V), which is finally condensed with the secondary amine (VI) by means of NaI in acetone to provide the target hybrid molecule.

参考文献 中间体
合成目标
【1】 Long, B.H.; Vyas, D.M.; Fairchild, C.; Kadow, J.F.; Rose, W.C.; Johnston, K.; Wittman, M.D.; Lee, F.L.; Synthesis and antitumor activity of novel paclitaxel-chlorambucil hybrids. Bioorg Med Chem Lett 2001, 11, 6, 811.
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) 49369 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C53H65NO14Si 详情 详情
(II) 49370 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-9-[(methylsulfanyl)methoxy]-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C55H69NO14SSi 详情 详情
(III) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(IV) 49371 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-9-[[(2-chloroacetyl)oxy]methoxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C56H68ClNO16Si 详情 详情
(V) 49372 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-9-[[(2-chloroacetyl)oxy]methoxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C50H54ClNO16 详情 详情
(VI) 49373 2-([2-[(4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyl)oxy]ethyl]amino)ethyl 4-[4-[bis(2-chloroethyl)amino]phenyl]butanoate C32H45Cl4N3O4 详情 详情
Extended Information