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【结 构 式】

【分子编号】12309

【品名】methyl 2-bromoacetate; methyl bromoacetate

【CA登记号】96-32-2

【 分 子 式 】C3H5BrO2

【 分 子 量 】152.9755

【元素组成】C 23.55% H 3.29% Br 52.23% O 20.92%
与该中间体有关的原料药合成路线共 20 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1

该中间体在本合成路线中的序号：(V)

The oxidation of 2-methyl-1-cyclopentene-1-carbaldehyde (I) with O3 and Ag2O gives 2,6-dioxoheptanoic acid (II), which is esterified with cephalotaxine (III) by means of (COCl)2, yielding the ester (IV). Reformatsky reaction of (IV) with methyl bromoacetate (V) and Zn affords the adduct (VI), which is treated with an excess of methylmagnesium iodide to provide the target homoharringtonine (as a single diastereomer), along with some starting cephalotaxine that is separated by chromatography.

参考文献 中间体
合成目标
【1】 Hiranuma, S.; Hudlicky, T.; Synthesis of homoharringtonine and its derivative by partial esterification of cephalotaxine. Tetrahedron Lett 1982, 23, 34, 3431.
【2】 Hiranuma, S.; et al.; Studies in Cephalotaxus alkaloids. Stereospecific total synthesis of homoharringtonine. J Org Chem 1983, 48, 26, 5321.
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) 52795 2-methyl-1-cyclopentene-1-carbaldehyde C7H10O 详情 详情
(II) 52796 2,6-dioxoheptanoic acid C7H10O4 详情 详情
(III) 52797 (3aS,14bS)-2-ethyl-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-ol C19H23NO3 详情 详情
(IV) 52798 (3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl 2,6-dioxoheptanoate C25H29NO7 详情 详情
(V) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(VI) 52799 1-[(1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl] 4-methyl 2-hydroxy-2-(4-oxopentyl)succinate C28H35NO9 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The title compound has also been obtained by solid phase synthesis. Bromoacetic acid (I) is coupled to hydroxymethyl polystyrene resin by means of DIC/DMAP to produce the bromoacetyl resin (II). Bromide displacement with tert-butyl carbazate (III) leads to the N-Boc hydrazino ester (IV), which is further deprotected to (V) employing trifluoroacetic acid. The hydrazinoacetic acid-bound resin (V) is then condensed with 5-(p-nitrophenyl)furfural (VI) to furnish hydrazone (VII). Acylation of resin (VII) with p-nitrophenyl chloroformate (VIII) produces the p-nitrophenyl carbamate (IX), which upon treatment with ammonia gives rise to the semicarbazone (X). Finally, concomitant intramolecular ring closure and resin cleavage of (X) produces the target aminohydantoin derivative (XI) (4, 5).

参考文献 中间体
合成目标
【1】 Wilson, L.J.; Li, M.; Portlock, D.E.; Solid phase synthesis of 1-aminohydantoin libraries. Tetrahedron Lett 1998, 39, 29, 5135.
【2】 Portlock, D.E.; Li, M.; Wilson, L.J. (The Procter & Gamble Co.); Solid phase synthesis of 1-aminohydantoins. WO 9942450 .
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) 23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 12091 1-Methylhydrazine; Monomethyl hydrazine 60-34-4 CH6N2 详情 详情
(IV) 63589 2-[2-(tert-butoxycarbonyl)hydrazino]acetic acid C7H14N2O4 详情 详情
(V) 63590 2-hydrazinoacetic acid C2H6N2O2 详情 详情
(VI) 63583 5-(4-nitrophenyl)-2-furaldehyde C11H7NO4 详情 详情
(VII) 63591 2-(2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C13H11N3O5 详情 详情
(VIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(IX) 63592 2-(1-[(4-nitrophenoxy)carbonyl]-2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C20H14N4O9 详情 详情
(X) 63593 2-(1-(aminocarbonyl)-2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid C14H12N4O6 详情 详情
(XI) 63586 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione C14H10N4O5 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The cyclization of 2-amino-6-isoproylphenol (I) with 2-bromo-3-methylbutyryl chloride (II) by means of NaHCO3 in ethyl acetate - water gives 2,8-diisopropyl-2H-1,4-benzoxazin-3(4H)-one (III), which is condensed with methyl bromoacetate (IV) by means of NaH in DMF yielding 2,8-diisopropyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-acetic acid methyl ester (V). The reaction of (V) with P2S5 in refluxing toluene affords the corresponding thioxo derivative (VI), which is finally hydrolyzed with NaOH in dioxane - methanol.

参考文献 中间体
合成目标
【1】 Meguro, K.; Ikeda, H.; Yamamoto, Y. (Senju Pharmaceuticals Co., Ltd.; Takeda Chemical Industries, Ltd.); Thiolactam-N-acetic acid derivs., their production and use. EP 0243018; JP 1988107970; US 4771050 .
【2】 Prous, J.; Castaner, J.; AD-5467. Drugs Fut 1991, 16, 1, 13.
【3】 Ikeda, H.; Meguro, K.; Yamamoto, Y.; Tawada, Sugiyama, Y.; Studies on antidiabetic agents. IX. A new aldose reductase inhibitor, AD-5467, and related 1,4-benzoxazine and 1,4-benzothiazine derivatives: Synthesis and biological activity. Chem Pharm Bull 1990, 38, 5, 1238-45.
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) 12306 2-Amino-6-isopropylphenol C9H13NO 详情 详情
(II) 12307 alpha-Bromoisovaleryl chloride; 2-Bromo-3-methylbutanoyl chloride 52574-82-0 C5H8BrClO 详情 详情
(III) 12308 2,8-diisopropyl-2H-1,4-benzoxazin-3(4H)-one C14H19NO2 详情 详情
(IV) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(V) 12310 methyl 2-(2,8-diisopropyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate C17H23NO4 详情 详情
(VI) 12311 methyl 2-(2,8-diisopropyl-3-thioxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate C17H23NO3S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(IX)

The reaction of the prostaglandin E1 derivative (I) with N,S-dimethylphenylsulfonimide (II) by means of methylmagnesium chloride in THF gives intermediate (III), which is treated with aluminum amalgam in HOAc/water to yield the methylene derivative (IV). Hydroboration of (IV) with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF affords the hydroxymethyl derivative (V), which is treated with methanesulfonyl chloride and TEA in dichloromethane to provide mesylate (VI). Desilylation of compound (VI) with TBAF in THF gives the phenol derivative (VII), which is cyclized by means of NaH in THF yielding the tricyclic prostaglandin derivative (VIII). Alkylation of compound (VIII) with methyl bromoacetate (IX) by means of NaH in glyme affords the 2-hydroxyacetate derivative (X), which is treated first with HOAc/water in order to eliminate the THP protecting groups, and then with KOH in methanol/water to hydrolyze the methyl ester group providing the prostaglandin F1 derivative (XI). Finally, this compound is hydrogenated over Pd/C in ethyl acetate.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; UT-15. Drugs Fut 2001, 26, 4, 364.
【2】 Aristoff, P.A.; Kelly, R.C.; Nelson, N.A. (Pharmacia Corp.); Carbacyclin analogues. CH 648017; CH 655308; FR 2484413; GB 2070596; JP 1990167248; JP 1994145085 .
【3】 Aristoff, P.A. (Pharmacia Corp.); Methano carbacyclin analogs. US 4349689 .
【4】 Agoh, Y.; Agoh, M.; Tamura, T.; Kuriyama, H.; Soga, M.; Mori, T. (Maruishi Pharmaceutical Co., Ltd.); 1,2-Disubstd. 1,4-dihydro-4-oxoquinoline cpds.. EP 1081138; JP 2001064259; JP 2001064261; JP 2001089455; JP 2001089476 .
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) 46549 (2R,3R,4R)-2-(3-[[tert-butyl(dimethyl)silyl]oxy]benzyl)-4-(tetrahydro-2H-pyran-2-yloxy)-3-[(E,3S)-3-(tetrahydro-2H-pyran-2-yloxy)-1-octenyl]cyclopentanone C36H58O6Si 详情 详情
(II) 46550 methyl(methylimino)oxo(phenyl)-lambda(6)-sulfane C8H11NOS 详情 详情
(III) 46551 tert-butyl(dimethyl)[3-([(1R,2R,3R)-5-[[methyl(phenyl)sulfonimidoyl]methyl]-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3S)-3-(tetrahydro-2H-pyran-2-yloxy)-1-octenyl]cyclopentyl]methyl)phenoxy]silane C44H69NO6SSi 详情 详情
(IV) 46552 tert-butyl(dimethyl)silyl 3-([(1R,2R,3R)-5-methylene-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3S)-3-(tetrahydro-2H-pyran-2-yloxy)-1-octenyl]cyclopentyl]methyl)phenyl ether; tert-butyl(dimethyl)[3-([(1R,2R,3R)-5-methylene-3-(tetrahydro-2H-pyran-2-yloxy)-2-[(E,3S)-3-(tetrahydro-2H-pyran-2-yloxy)-1-octenyl]cyclopentyl]methyl)phenoxy]silane C37H60O5Si 详情 详情
(V) 46553 [(1S,2S,3S,4R)-2-(3-[[tert-butyl(dimethyl)silyl]oxy]benzyl)-4-(tetrahydro-2H-pyran-2-yloxy)-3-[(E,3S)-3-(tetrahydro-2H-pyran-2-yloxy)-1-octenyl]cyclopentyl]methanol C37H62O6Si 详情 详情
(VI) 46554 [(1S,2S,3S,4R)-2-(3-[[tert-butyl(dimethyl)silyl]oxy]benzyl)-4-(tetrahydro-2H-pyran-2-yloxy)-3-[(E,3S)-3-(tetrahydro-2H-pyran-2-yloxy)-1-octenyl]cyclopentyl]methyl methanesulfonate C38H64O8SSi 详情 详情
(VII) 46555 [(1S,2S,3S,4R)-2-(3-hydroxybenzyl)-4-(tetrahydro-2H-pyran-2-yloxy)-3-[(E,3S)-3-(tetrahydro-2H-pyran-2-yloxy)-1-octenyl]cyclopentyl]methyl methanesulfonate C32H50O8S 详情 详情
(VIII) 46556 (1S,2R,3aS,9aS)-2-(tetrahydro-2H-pyran-2-yloxy)-1-[(E,3S)-3-(tetrahydro-2H-pyran-2-yloxy)-1-octenyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-ol C31H46O5 详情 详情
(IX) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(X) 46507 3-bromo-6-phenyl-2-pyrazinecarbonitrile C11H6BrN3 详情 详情
(XI) 46508 1-[(E)-2-phenylethenyl]pyrrolidine C12H15N 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XV)

The alkylation of the protected hydroxyproline (I) with 4-iodo-1-butene (II) by means of LDA in THF gives the 2-alkylproline (III), which is reduced with DIBAL in toluene to yield the carbinol (IV). The oxidation of (IV) by means of TPAP and NMO in dichloromethane affords the carbaldehyde (V), which is oxidated at its terminal vinyl group by means of PdCl2, CuCl2 and O2 in aqueous DMF to provide the methyl ketone (VI). The cyclization of (VI) by means of KOH in ethanol furnishes the cyclic aldol (VII), which is treated with Ms-Cl and TEA to give the mesylate (VIII). The elimination reaction of (VIII) over chromatographic silicagel yields enone (IX), which is hydrogenated with H2 over Pd/C in benzene to afford the spiranic ketone (X). The reaction of (X) with ethyleneglycol and Ts-OH in refluxing benzene provides the ethylene ketal (XI), which is desilylated by means of TBAF in THF to gives the alcohol (XII). The reaction of (XII) with DPPA, DEAD and PPh3 in THF yields the azide (XIII), which is subjected to removal of the Boc protecting group by means of TFA affording unprotected spiro pyrrolidine derivative (XIV). Alkylation of (XIV) with ethyl bromoacetate (XV) by means of K2CO3 in acetonitrile provides the ester (XVI), which is reduced at the azido group by means of H2 over Pd/C in methanol to give the aminoester (XVII). The hydrolysis of the ester group of (XVII) with LiOH in water yields the spiranic aminoacid (XVIII), which is cyclized by means of DPPA and TEA in DMF to afford the tetracyclic amide (XIX). Finally this compound is methylated by means of methyl iodide and NaH in THF to provide the target tetracyclic intermediate (XX) (see scheme no.18599903a, intermediate (XV)).

参考文献 中间体
合成目标
【1】 Nagumo, S.; et al.; Synthesis of (-)-TAN1251A using 4-hydroxy-L-proline as a chiral source. Tetrahedron 2002, 58, 49, 9871.
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) 60484 1-(tert-butyl) 2-methyl (2S,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-1,2-pyrrolidinedicarboxylate C27H37NO5Si 详情 详情
(II) 60485 4-iodo-1-butene C4H7I 详情 详情
(III) 60486 1-(tert-butyl) 2-methyl (4R)-2-(3-butenyl)-4-{[tert-butyl(diphenyl)silyl]oxy}-1,2-pyrrolidinedicarboxylate C31H43NO5Si 详情 详情
(IV) 60487 tert-butyl (4R)-2-(3-butenyl)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-(hydroxymethyl)-1-pyrrolidinecarboxylate C30H43NO4Si 详情 详情
(V) 60488 tert-butyl (4R)-2-(3-butenyl)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-formyl-1-pyrrolidinecarboxylate C30H41NO4Si 详情 详情
(VI) 60489 tert-butyl (4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-formyl-2-(3-oxobutyl)-1-pyrrolidinecarboxylate C30H41NO5Si 详情 详情
(VII) 60490 tert-butyl (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-6-hydroxy-8-oxo-1-azaspiro[4.5]decane-1-carboxylate C30H41NO5Si 详情 详情
(VIII) 60491 tert-butyl (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-6-[(methylsulfonyl)oxy]-8-oxo-1-azaspiro[4.5]decane-1-carboxylate C31H43NO7SSi 详情 详情
(IX) 60492 tert-butyl (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-8-oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylate C30H39NO4Si 详情 详情
(X) 60493 tert-butyl (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-8-oxo-1-azaspiro[4.5]decane-1-carboxylate C30H41NO4Si 详情 详情
(XI) 60494 tert-butyl (11R)-11-{[tert-butyl(diphenyl)silyl]oxy}-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane-9-carboxylate C32H45NO5Si 详情 详情
(XII) 60495 tert-butyl (11R)-11-hydroxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane-9-carboxylate C16H27NO5 详情 详情
(XIII) 60496 tert-butyl (11S)-11-azido-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane-9-carboxylate C16H26N4O4 详情 详情
(XIV) 60497 (11S)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl azide; (11S)-11-azido-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane C11H18N4O2 详情 详情
(XV) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(XVI) 60498 　 C14H22N4O4 详情 详情
(XVII) 60499 　 C14H24N2O4 详情 详情
(XVIII) 60648 2-[(11S)-11-amino-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetic acid C13H22N2O4 详情 详情
(XIX) 60649 　 C13H20N2O3 详情 详情
(XX) 48806 　 C14H22N2O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(III)

The esterification of indole-2-carboxylic acid (I) with benzyl alcohol and CDI gives the corresponding benzyl ester (II), which is alkylated with methyl bromoacetate (III) by means of NaH in DMF yielding 1-(methoxycarbonylmethyl)-1H-indole-2-carboxylic acid benzyl ester (IV). The debenzylation of (IV) with H2 over Pd/C in ethanol/DMF affords the free acid (V), which is condensed with 4-(2-chlorophenyl)thiazol-2-amine (VI) by means of benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) in DMF to give the carboxamide (VII). Finally, the ester group of (VII) is hydrolyzed with NaOH or KOH in methanol/water.

参考文献 中间体
合成目标
【1】 Bras, J.-P.; Frehel, D.; Gully, D.; Valette, G. (Sanofi-Synthélabo ); Heterocyclic derivs. of acylaminothiazole, their preparation and pharmaceutical compsns. containing them. EP 0432040; FR 2655344; FR 2661677; JP 1991279374; JP 1998130147; US 5189049 .
【2】 Radisson, J. (Sanofi-Synthelabo ); Method for preparing lintitript potassium salt. FR 2781227; WO 0005233 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情
(I) 25226 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid 1477-50-5 C9H7NO2 详情 详情
(II) 34572 benzyl 1H-indole-2-carboxylate C16H13NO2 详情 详情
(III) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(IV) 34573 benzyl 1-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate C19H17NO4 详情 详情
(V) 34574 1-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylic acid C12H11NO4 详情 详情
(VI) 34575 4-(2-chlorophenyl)-1,3-thiazol-2-ylamine; 4-(2-chlorophenyl)-1,3-thiazol-2-amine C9H7ClN2S 详情 详情
(VII) 34576 methyl 2-[2-([[4-(2-chlorophenyl)-1,3-thiazol-2-yl]amino]carbonyl)-1H-indol-1-yl]acetate C21H16ClN3O3S 详情 详情
(VIII) 34577 2-bromo-1-(2-chlorophenyl)-1-ethanone C8H6BrClO 详情 详情
(IX) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线7

该中间体在本合成路线中的序号：(XIII)

Reformatskii condensation of the organozinc reagent derived from methyl bromoacetate (XIII) with n-heptyl cyanide (XII) gave rise to the keto ester adduct (XIV). Catalytic hydrogenation of (XIV) in the presence of the chiral catalyst generated from dichloro(cycloocta-1,5-diene)ruthenium and (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl furnished the (R)-hydroxyester (XV) in high enantiomeric excess. Ester group reduction in (XV) by means of LiAlH4 afforded diol (XVI), which was further converted to the primary tosylate (XVII) with p-toluenesulfonyl chloride in pyridine. Then, alkylation of the intermediate alcohol (XI) with tosylate (XVII) under Williamson's ether synthesis conditions provided the common precursor (XVIII).

参考文献 中间体
合成目标
【1】 Christ, W.J.; Kawata, T.; Hawkins, L.D.; Kobayashi, S.; Asano, O.; Rossignol, D.P. (Eisai Co., Ltd.); Anti-endotoxin cpds.. EP 0536969; JP 1993194470; US 5530113 .
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) 59080 (4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol C15H29N3O5Si 详情 详情
(XII) 59081 octanenitrile 124-12-9 C8H15N 详情 详情
(XIII) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(XIV) 59082 methyl 3-oxodecanoate C11H20O3 详情 详情
(XV) 59083 methyl (3R)-3-hydroxydecanoate C11H22O3 详情 详情
(XVI) 59084 (3R)-1,3-decanediol C10H22O2 详情 详情
(XVII) 49121 (3R)-3-hydroxydecyl 4-methylbenzenesulfonate C17H28O4S 详情 详情
(XVIII) 59085 (3R)-1-[((4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)oxy]-3-decanol C25H49N3O6Si 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

The intermediate mixed anhydride (V) has been obtained as follows: the condensation of 2-nitroimidazole (I) with methyl 2-bromoacetate (II) by means of NaOMe in methanol gives 2-(2-nitro-1H-imidazol-1-yl)acetic acid methyl ester (III), which is hydrolyzed with NaOH to yield the corresponding acid (IV). Finally, this compound is condensed with isobutyl chloroformate by means of NMM in THF to afford the desired mixed anhydride intermediate (V). The condensation of 2,2,2-trifluoroacetaldehyde ethyl hemiacetal (VI) with nitromethane (VII) by means of K2CO3 gives 1,1,1-trifluoro-3-nitro-2-propanol (VIII), which is reduced with H2 over RaNi in ethanol to yield 3-amino-1,1,1-trifluoro-2-propanol (IX). Finally, this compound is condensed with the mixed anhydride intermediate (V) by means of NMM in THF to afford the target amide.

参考文献 中间体
合成目标
【1】 Tracy, M.; Kelson, A.B.; Workman, P.; Lewis, A.D.; Aboagye, E.O. (Cancer Research UK; SRI International); Fluorinated 2-nitroimidazole analogs for detecting hypoxic tumor cells. EP 0775117; JP 1998506104; US 5721265; WO 9604249 .
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) 10145 2-Nitro-1H-imidazole; 2-Nitroimidazole 527-73-1 C3H3N3O2 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 10258 methyl 2-(2-nitro-1H-imidazol-1-yl)acetate; Methyl 2-nitro-1-imidazoleacetate 22813-31-6 C6H7N3O4 详情 详情
(IV) 56733 2-(2-nitro-1H-imidazol-1-yl)acetic acid C5H5N3O4 详情 详情
(V) 56734 　 C10H13N3O6 详情 详情
(VI) 26582 1-ethoxy-2,2,2-trifluoro-1-ethanol 433-27-2 C4H7F3O2 详情 详情
(VII) 39563 nitromethane 75-52-5 CH3NO2 详情 详情
(VIII) 56735 1,1,1-trifluoro-3-nitro-2-propanol C3H4F3NO3 详情 详情
(IX) 56736 3-amino-1,1,1-trifluoro-2-propanol 431-38-9 C3H6F3NO 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 tert-butyl (5-hydroxy-2-naphthyl)propionate (I) with methyl bromoacetate (II) in the presence of K2CO3 provided ether (III). Subsequent deprotection of the tert-butyl ester of (III) using trifluoroacetic acid in CH2Cl2 gave carboxylic acid (IV). This was coupled to benzhydrylamine in the presence of EDC and DMAP to afford amide (VI). Finally, ester hydrolysis of (IV) with NaOH yielded the target compound.

参考文献 中间体
合成目标
【1】 Nagao, Y.; Torisu, K.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); Naphthyloxyacetic acid derivs. and their use as PGE2 agonists and antagonists. EP 0719760; JP 1996239356 .
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) 26497 tert-butyl 3-(5-hydroxy-1-naphthyl)propanoate C17H20O3 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 26498 tert-butyl 3-[5-(2-methoxy-2-oxoethoxy)-1-naphthyl]propanoate C20H24O5 详情 详情
(IV) 26499 3-[5-(2-methoxy-2-oxoethoxy)-1-naphthyl]propionic acid C16H16O5 详情 详情
(V) 15149 alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine 91-00-9 C13H13N 详情 详情
(VI) 26500 methyl 2-([5-[3-(benzhydrylamino)-3-oxopropyl]-1-naphthyl]oxy)acetate C29H27NO4 详情 详情

合成路线10

该中间体在本合成路线中的序号：

A further route to benzyl ester (X) is shown in the next scheme: Protection of 2,4,6-trimethylaniline (XI) with Boc2O gave carbamate (XII). Condensation of (XII) with diethyl oxalate in the presence of sec-butyllithium produced the intermediate ketoester (XIII), which was deprotected and cyclized under acidic conditions to yield indole (V). Hydrolysis, followed by alkylation with benzyl bromide as above provided the corresponding benzyl ester (X). An alternative and more direct procedure consisted in the condensation of protected aniline (XII) with dibenzyl oxalate, and then cyclization upon treatment with trifluoroacetic acid. The intermediate indole (X) was N-alkylated with tert-butyl bromoacetate and NaH to give the indole diester (XIV). Subsequent deprotection of the benzyl ester group by hydrogenation over Pd/C gave rise to diacid mono tert-butyl ester (XV). Optionally, the analogous methyl ester (XVII) was prepared by alkylation of indole (X) with methyl bromoacetate, followed by benzyl group hydrogenolysis.

参考文献 中间体
合成目标
【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
40591 benzyl 2-(benzyloxy)-2-oxoacetate C16H14O4 详情 详情
(V) 32914 ethyl 5,7-dimethyl-1H-indole-2-carboxylate C13H15NO2 详情 详情
(X) 32919 benzyl 5,7-dimethyl-1H-indole-2-carboxylate C18H17NO2 详情 详情
(XI) 28804 2,4,6-trimethylaniline 88-05-1 C9H13N 详情 详情
(XII) 32920 tert-butyl mesitylcarbamate C14H21NO2 详情 详情
(XIII) 32921 ethyl 3-[2-[(tert-butoxycarbonyl)amino]-3,5-dimethylphenyl]-2-oxopropanoate C18H25NO5 详情 详情
(XIV) 32922 benzyl 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylate C24H27NO4 详情 详情
(XV) 32923 1-[2-(tert-butoxy)-2-oxoethyl]-5,7-dimethyl-1H-indole-2-carboxylic acid C17H21NO4 详情 详情
(XVI) 32924 benzyl 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylate C21H21NO4 详情 详情
(XVII) 32925 1-(2-methoxy-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid C14H15NO4 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

The alkylation of 5-cyanoindole (I) with methyl bromoacetate (II) in the presence of NaH in DMF provided the indolylacetate ester (III), which was hydrolyzed to the corresponding carboxylic acid (IV) with methanolic KOH. Coupling of (IV) with 4-benzylpiperidine (V) employing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) afforded amide (VI). Pinner reaction of (VI) with methanolic HCl produced imidate (VII), which was finally treated with ammonium carbonate in MeOH to yield the target amidine

参考文献 中间体
合成目标
【1】 Duffy, D.E.; Dominguez, C.; Han, Q.; et al.; Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors. Bioorg Med Chem Lett 1999, 9, 7, 925.
【2】 Dominguez, C.; Han, Q.; Duffy, D.E.; Park, J.M.; Quan, M.L.; Rossi, K.A.; Wexler, R.R. (DuPont Pharmaceuticals Co.); Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of factor Xa and of thrombin. EP 0960102; WO 9801428 .
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) 31341 5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile 15861-24-2 C9H6N2 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 31342 methyl 2-(5-cyano-1H-indol-1-yl)acetate C12H10N2O2 详情 详情
(IV) 31343 2-(5-cyano-1H-indol-1-yl)acetic acid C11H8N2O2 详情 详情
(V) 26225 4-benzylpiperidine 31252-42-3 C12H17N 详情 详情
(VI) 31344 1-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-1H-indole-5-carbonitrile C23H23N3O 详情 详情
(VII) 31345 methyl 1-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-1H-indole-5-carboximidoate C24H27N3O2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

Alkylation of 3-nitrophenol (I) with methyl bromoacetate (II) in the presence of K2CO3 provided phenoxyacetate (III). Then, reduction of the nitro group of (III) by hydrogenation on Pd/C gave amine (IV), which was subsequently condensed with N-tert-butoxycarbonyl glycine (V) on treatment with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) to afford amide (VI). Alkylation with bromoacetamide (VII) in the presence of NaH in THF provided (VIII), and removal of the Boc protecting group with trifluoroacetic acid gave amine (IX). This amine was condensed with 3-tolyl isocyanate (X) to give urea (XI). Then, alkaline hydrolysis of the ester group afforded acid (XII), which was finally condensed with N-methylaniline (XIII) to yield the target compound.

参考文献 中间体
合成目标
【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 .
【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 .
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) 18076 Metanitrophenol; 3-nitrophenol 554-84-7 C6H5NO3 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 18077 methyl 2-(3-nitrophenoxy)acetate C9H9NO5 详情 详情
(IV) 18078 methyl 2-(3-aminophenoxy)acetate C9H11NO3 详情 详情
(V) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(V) 18068 2-bromo-N-methyl-N-phenylacetamide C9H10BrNO 详情 详情
(VI) 18079 methyl 2-[3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)phenoxy]acetate C16H22N2O6 详情 详情
(VIII) 18080 methyl 2-(3-[[2-[(tert-butoxycarbonyl)amino]acetyl][2-(methylanilino)-2-oxoethyl]amino]phenoxy)acetate C25H31N3O7 详情 详情
(IX) 18081 methyl 2-(3-[(2-aminoacetyl)[2-(methylanilino)-2-oxoethyl]amino]phenoxy)acetate C20H23N3O5 详情 详情
(X) 18071 m-Tolyl Isocyanate; 1-isocyanato-3-methylbenzene; 3-methylphenyl isocyanate 621-29-4 C8H7NO 详情 详情
(XI) 18082 methyl 2-[3-([2-(methylanilino)-2-oxoethyl][2-[(3-toluidinocarbonyl)amino]acetyl]amino)phenoxy]acetate C28H30N4O6 详情 详情
(XII) 18083 2-[3-([2-(methylanilino)-2-oxoethyl][2-[(3-toluidinocarbonyl)amino]acetyl]amino)phenoxy]acetic acid C27H28N4O6 详情 详情
(XIII) 10409 N-Methyl-N-phenylamine; N-methylaniline; Monomethylaniline 100-61-8 C7H9N 详情 详情

合成路线13

该中间体在本合成路线中的序号：

A new, more efficient synthesis has been reported for the intermediate (XVIII). The saccharin derivative (IV) was prepared by two alternative routes. Thus, 2-sulfobenzoic acid cyclic anhydride (XII) was treated with two equivalents of 2-(trifluoromethyl)aniline (II) to give the anilinium salt (XIII), which was cyclized with POCl3 to produce (IV). Also, starting from benzenesulfonyl chloride (XIV), the corresponding sulfonamide (II) was obtained by reaction with aniline (II). Ortho lithiation with n-butyllithium at low temperature, followed by CO2 quenching, afforded carboxylic acid (XVI), which upon treatment with Ac2O and methanesulfonic acid cyclized to the saccharin (IV). Then, the saccharin ring was opened by treatment with NaOMe, and subsequent treatment with methyl bromoacetate furnished diester (XVII). Finally, Claisen cyclization promoted by TiCl4 formed the key intermediate (XVIII).

参考文献 中间体
合成目标
【1】 Lee, C.; et al.; Synthetic studies toward a series of endothelin receptor antagonists. 1,1-Dioxo-2,4-diphenyl-2H-1,2-benzothiazine. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 058.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(II) 25812 2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline 88-17-5 C7H6F3N 详情 详情
(III) 25813 methyl 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoate C15H12F3NO4S 详情 详情
(IV) 25814 2-[2-(trifluoromethyl)phenyl]-1H-1,2-benzisothiazole-1,1,3(2H)-trione C14H8F3NO3S 详情 详情
(XII) 25821 2-Sulfobenzoic acid anhydride; 2,1lambda(6)-benzoxathiole-1,1,3-trione 81-08-3 C7H4O4S 详情 详情
(XIII) 25822 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoic acid C14H10F3NO4S 详情 详情
(XIV) 14713 benzenesulfonyl chloride 98-09-9 C6H5ClO2S 详情 详情
(XV) 25823 N-[2-(trifluoromethyl)phenyl]benzenesulfonamide C13H10F3NO2S 详情 详情
(XVI) 25822 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoic acid C14H10F3NO4S 详情 详情
(XVII) 25824 methyl 2-[[(2-methoxy-2-oxoethyl)-2-(trifluoromethyl)anilino]sulfonyl]benzoate C18H16F3NO6S 详情 详情
(XVIII) 25825 methyl 4-hydroxy-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C17H12F3NO5S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

The reaction of 3-formylbenzonitrile (I) with methyl 2-bromoacetate (II) by means of activated Zn in hot THF gives 3-(3-cyanophenyl)-3-hydroxypropionic acid methyl ester (III), which is oxidized with activated MnO2 in hot dichloromethane yielding the oxoester (IV). The bromination of (IV) with NBS in CCl4 affords the alpha bromo derivative (V), which is cyclized with thioacetamide (VI) in hot THF affording 4-(3-cyanophenyl)-2-methylthiazole-5-carboxylic acid methyl ester (VII). The condensation of (VII) with 4'-amino-N-tert-butylbiphenyl-2-sulfonamide (VIII) by means of trimethylaluminum in toluene/dichloromethane gives the corresponding amide (IX), which is treated with hot TFA to eliminate the ter-butyl protecting group yielding intermediate (X). Finally, the cyano group of (X) is treated first with anhydrous HCl in methanol, and finally with ammonium carbonate in the same solvent to obtain the target amidine.

参考文献 中间体
合成目标
【1】 Quan, M.L.; Pinto, D.J.P.; Fevig, J.M.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Oxygen or sulfur containing heteroaromatics as fac. WO 9828282 .
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) 13245 3-Formylbenzonitrile; 3-Cyanobenzaldehyde 24964-64-5 C8H5NO 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 28346 methyl 3-(3-cyanophenyl)-3-hydroxypropanoate C11H11NO3 详情 详情
(IV) 28347 methyl 3-(3-cyanophenyl)-3-oxopropanoate C11H9NO3 详情 详情
(V) 28348 methyl 2-bromo-3-(3-cyanophenyl)-3-oxopropanoate C11H8BrNO3 详情 详情
(VI) 19170 ethanethioamide 62-55-5 C2H5NS 详情 详情
(VII) 28349 methyl 4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxylate C13H10N2O2S 详情 详情
(VIII) 23363 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide C16H20N2O2S 详情 详情
(IX) 28350 N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxamide C28H26N4O3S2 详情 详情
(X) 28351 N-[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]-4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxamide C24H18N4O3S2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

Alkylation of 3-phenylpropylamine (I) with methyl bromoacetate (II) provided secondary amine (III), which was coupled with N-Boc-(2-chlorophenyl)alanine (IV) using diisopropyl carbodiimide (DIC) and 7-hydroxy azabenzotriazole (HOAt). After deprotection of the Boc group from the resulting amide (V) with trifluoroacetic acid, cyclization in the presence of Et3N in refluxing MeOH funished piperazinedione (VI). The amide N of (VI) was alkylated with tert-butyl bromoacetate, and the tert-butyl group was then removed using trifluoroacetic acid to provide piperazineacetic acid (VII). This was then coupled to protected amino acid (VIII) by means of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and HOAt to give (IX). Finally, the 2,2,5,7,8-pentamethylchroman-6-sulfonyl protecting group of (IX) was removed with trifluoroacetic acid to furnish the target compound.

参考文献 中间体
合成目标
【1】 Cody, W.L.; et al.; The discovery of potent and selective peptidomimetic inhibitors of thrombin. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 077.
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) 18791 3-phenylpropylamine; 3-phenyl-1-propanamine 2038-57-5 C9H13N 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 25282 methyl 2-[(3-phenylpropyl)amino]acetate C12H17NO2 详情 详情
(IV) 25283 (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-chlorophenyl)propionic acid C14H18ClNO4 详情 详情
(V) 25284 methyl 2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-chlorophenyl)propanoyl](3-phenylpropyl)amino]acetate C26H33ClN2O5 详情 详情
(VI) 25285 (3R)-3-(2-chlorobenzyl)-1-(3-phenylpropyl)-2,5-piperazinedione C20H21ClN2O2 详情 详情
(VII) 25286 2-[(2R)-2-(2-chlorobenzyl)-3,6-dioxo-4-(3-phenylpropyl)piperazinyl]acetic acid C22H23ClN2O4 详情 详情
(VIII) 25287 N-[[3-[(2S)-2-amino-3-oxo-3-(1,3-thiazol-2-yl)propyl]-1-piperidinyl](imino)methyl]-2,2,5,7,8-pentamethyl-6-chromanesulfonamide C26H37N5O4S2 详情 详情
(IX) 25288 2-[(2R)-2-(2-chlorobenzyl)-3,6-dioxo-4-(3-phenylpropyl)piperazinyl]-N-[(1S)-1-[[1-(imino[[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-chromen-6-yl)sulfonyl]amino]methyl)-3-piperidinyl]methyl]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]acetamide C48H58ClN7O7S2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The alkylation of (R)-alpha-methylbenzylamine (I) with methyl bromoacetate (II) gave aminoacetate (III). This was coupled with protected histidine (IV) by means of HATU as the coupling agent, yielding the protected dipeptide (V). Subsequent saponification of (V) using LiOH gave acid (VI). beta,beta-Dimethyl-phenethylamine (IX) was prepared by alkylation of phenylacetonitrile (VII) with iodomethane and NaH, followed by hydrogenation of the resulting dimethylated compound (VIII) in the presence of Raney Nickel. Coupling of amine (IX) with dipeptide (VI) provided the corresponding amide (X). The trityl protecting group of (X) was finally removed by treatment with trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Doherty, A.M.; Quin, J. III; Kaltenbronn, J.S.; Leonard, D.M.; McNamara, D.J. (Pfizer Inc.); Functionalized alkyl and alkenyl side chain derivs. of glycinamides as farnesyl transferase inhibitors. WO 9955725 .
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) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(II) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(III) 34626 methyl 2-[[(1R)-1-phenylethyl]amino]acetate C11H15NO2 详情 详情
(IV) 34627 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1-trityl-1H-imidazol-4-yl)propionic acid C33H29N3O4 详情 详情
(V) 34628 methyl 2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1-trityl-1H-imidazol-4-yl)propanoyl][(1R)-1-phenylethyl]amino]acetate C44H42N4O5 详情 详情
(VI) 34629 2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1-trityl-1H-imidazol-4-yl)propanoyl][(1R)-1-phenylethyl]amino]acetic acid C43H40N4O5 详情 详情
(VII) 17046 Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide 140-29-4 C8H7N 详情 详情
(VIII) 34630 2-methyl-2-phenylpropanenitrile C10H11N 详情 详情
(IX) 34631 2-methyl-2-phenylpropylamine; 2-methyl-2-phenyl-1-propanamine C10H15N 详情 详情
(X) 34632 benzyl (1S)-2-[[2-[(2-methyl-2-phenylpropyl)amino]-2-oxoethyl][(1R)-1-phenylethyl]amino]-2-oxo-1-[(1-trityl-1H-imidazol-4-yl)methyl]ethylcarbamate C53H53N5O4 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VIII)

Alkylation of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione (VII) with methyl bromoacetate (VIII) in the presence of cesium carbonate gave rise to the aryloxy acetate (IX). Subsequent cleavage of the N-trityl protecting group of (IX) was achieved by treatment with HOAc in aqueous dioxan at 80 C. The resulting ester (X) was finally condensed with phenylenediamine (VI) to produce the target benzimidazole.

参考文献 中间体
合成目标
【2】 Fujita, T.; Fujiwara, T.; Izumi, T. (Sankyo Co., Ltd.); Hydrochloride of fused-heterocycle cpd.. EP 1180519; JP 2001039976; US 2002111373; WO 0071540 .
【1】 Fujita, T.; Wada, K.; Oguchi, M.; Yanagisawa, H.; Fujimoto, K.; Fujiwara, T.; Horikoshi, H.; Yoshioka, T. (Sankyo Co., Ltd.); Benzimidazole derivs., their preparation and their therapeutic use. CA 2177858; EP 0745600; JP 1997295970; JP 2000001487; US 5886014 .
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) 46877 N-(2-amino-5-methoxyphenyl)-N-methylamine; 4-methoxy-N(2)-methyl-1,2-benzenediamine C8H12N2O 详情 详情
(VII) 18803 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione C29H23NO3S 详情 详情
(VIII) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(IX) 46878 methyl 2-[4-[(2,4-dioxo-3-trityl-1,3-thiazolidin-5-yl)methyl]phenoxy]acetate C32H27NO5S 详情 详情
(X) 46879 methyl 2-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]acetate C13H13NO5S 详情 详情

合成路线18

该中间体在本合成路线中的序号：(X)

Solution synthesis: In this case the target product is obtained by alkylation of 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (VII) with 1-(chloromethyl)naphthalene (VIII) by means of K2CO3 and NaI in refluxing 2-butanone, followed by acylation with methyl bromoacetate (X) in DMF by means of NaH.

参考文献 中间体
合成目标
【1】 Watson, B.; Thomsen, C.; Hohlweg, R. (Novo Nordisk A/S); Novel 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes. EP 1080091; WO 9959997 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 18116 1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1021-25-6 C13H17N3O 详情 详情
(VIII) 27408 1-(Chloromethyl)naphthalene 86-52-2 C11H9Cl 详情 详情
(IX) 47326 8-(1-naphthylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one C24H25N3O 详情 详情
(X) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(IV)

Metalation of the biarylmethane derivative (I) by means of butyllithium, followed by iodination with N-iodosuccinimide, leads to aryl iodide (II). After desilylation of (II) using tetrabutylammonium fluoride, the resultant phenolic compound (III) is alkylated with methyl bromoacetate (IV) to produce ether (V). Palladium-catalyzed coupling between aryl iodide (V) and the phenylethynyl boronate reagent (VI) furnishes the diaryl acetylene (VII). The amino group of (VII) is oxidized to the corresponding nitro derivative employing m-chloroperbenzoic acid, and the methoxymethyl protecting group is then removed by acidic hydrolysis to afford (VIII). Finally, methyl ester hydrolysis in (VIII) in the presence of LiOH gives the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Nguyen, N.-H.; et al.; Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment. J Med Chem 2002, 45, 15, 3310.
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) 58467 (4-{2,6-dimethyl-4-[(triisopropylsilyl)oxy]benzyl}-2-isopropylphenoxy)methyl methyl ether; triisopropyl{4-[3-isopropyl-4-(methoxymethoxy)benzyl]-3,5-dimethylphenoxy}silane C29H46O3Si 详情 详情
(II) 58468 (4-{2,6-dimethyl-4-[(triisopropylsilyl)oxy]benzyl}-2-iodo-6-isopropylphenoxy)methyl methyl ether; {4-[3-iodo-5-isopropyl-4-(methoxymethoxy)benzyl]-3,5-dimethylphenoxy}(triisopropyl)silane C29H45IO3Si 详情 详情
(III) 58469 4-[3-iodo-5-isopropyl-4-(methoxymethoxy)benzyl]-3,5-dimethylphenol C20H25IO3 详情 详情
(IV) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(V) 58470 methyl 2-{4-[3-iodo-5-isopropyl-4-(methoxymethoxy)benzyl]-3,5-dimethylphenoxy}acetate C23H29IO5 详情 详情
(VI) 58471 　 C17H23BKNO 详情 详情
(VII) 58472 methyl 2-{4-[3-[2-(4-aminophenyl)ethynyl]-5-isopropyl-4-(methoxymethoxy)benzyl]-3,5-dimethylphenoxy}acetate C31H35NO5 详情 详情
(VIII) 58473 methyl 2-(4-{4-hydroxy-3-isopropyl-5-[2-(4-nitrophenyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetate C29H29NO6 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XVII)

The precursors N-(benzyloxycarbonyl)-N-[1-(benzyloxycarbonyl)-3(R)-pyrrolidinyl]glycine (XII) and its dicyclohexylamine salt (XIII) are prepared as follows. Alkylation of 3(R)-amino-1-(benzyloxycarbonyl)pyrrolidine or its hydrochloride (XVI) with methyl 2-bromoacetate (XVII) by means of K2CO3 in MTBE/H2O yields the amino ester (XVIII), which, without isolation, is further protected with benzyloxycarbonyl chloride to provide the diprotected compound (XIX). Hydrolysis of the methyl ester (XIX) with NaOH in refluxing MTBE/H2O followed by in situ treatment of the obtained sodium salt with HCl leads to the carboxylic acid (XII) , which by treatment with dicyclohexylamine in THF provides the corresponding dicyclohexylammonium salt (XIII) .

参考文献 中间体
合成目标
【1】 Wu, Z.P., Campbell, D.A., Cherrington, J.M. (Phenomix Corp.). Solid citrate and tartrate salts of DPP-IV inhibitors. EP 2061474, JP 2010502610, WO 2008027273.
【4】 Campbell, D.A., Winn, D.T. (Phenomix Corp.). Methods of preparing heterocyclic boronic acids and derivatives thereof. EP 1919485, JP 2009503077, US 2008300413, WO2007016356.
【6】 Campbell, D.A., Leitao, E.P.T., Wu, Z.-P., Wang, P. (Phenomix Corp.). Methods and intermediates for synthesis of selective DPP-IV inhibitors. EP 2173709, WO 2008109681.
【7】 Wang, P. (Phenomix Corp.). A crystalline synthetic intermediate for pyrrolidin-3-yl-glycylaminoalkylboronates. WO 2009094462.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 63162 2-[(E)-2-phenyldiazenyl]malononitrile 6017-21-6 C9H6N4 详情 详情
(XIII) 63163 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine 428854-23-3 C23H18FN9 详情 详情
(XVI) 65989 (3R)-1-Cbz-3-Aminopyrrolidine hydrochloride 870621-17-3 C12H16N2O2.HCl 详情 详情
(XVII) 12309 methyl 2-bromoacetate; methyl bromoacetate 96-32-2 C3H5BrO2 详情 详情
(XVIII) 65990 　 　 C15H20N2O4 详情 详情
(XIX) 65991 　 　 C23H26N2O6 详情 详情
Extended Information