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【结 构 式】

【分子编号】10456

【品名】Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate

【CA登记号】13831-31-7

【 分 子 式 】C4H5ClO3

【 分 子 量 】136.5346

【元素组成】C 35.19% H 3.69% Cl 25.97% O 35.15%

与该中间体有关的原料药合成路线共 13 条

合成路线1

该中间体在本合成路线中的序号:(II)

A new partial synthesis for taxol has been reported: The cyclization of N-(4-methoxyphenyl)benzylideneimine (I) with acetoxyacetyl chloride (II) by means of triethylamine in dichloromethane gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (III), which is treated with ceric ammonium nitrate in acetonitrile to afford cis-3-acetoxy-4-phenylazetidin-2-one (IV). Hydrolysis of (IV) with KOH in THF-water yields cis-3-hydroxy-4-phenylazetidin-2-one (V), which is submitted to optical resolution giving the (3R,4S)-isomer (VI). The reaction of (VI) with ethyl vinyl ether (VII) by means of methanesulfonic acid in THF affords (3R,4S)-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (VIII), which is benzoylated with benzoyl chloride (IX) and butyllithium in hexane to give (X). Opening of the azetidine ring of (X) with KOH in THF-water gives (2R,3S)-3-(benzamido)-2-(1-ethoxyethoxy)propanoic acid (XI), which is cyclized with potassium tert-butoxide and methanesulfonyl chloride to (4S,5R)-5-(1-ethoxyethoxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-6-one (XII). Finally, this compound is condensed with 7-O-(triethylsilyl)baccatin III (XIV) [prepared from 10-deacetylbaccatin III (XIII) by successive reaction with triethylsilyl chloride and acetyl chloride] by means of dimethylaminopyridine (DMAP) in pyridine.

1 Holton, R.A. (University of Florida); Method for preparation of taxol using an oxazinone. US 5015744 .
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) 10455 N-(4-Methoxyphenyl)-N-[(Z)-benzylidene]amine; 4-Methoxy-N-[(Z)-benzylidene]aniline 783-08-4 C14H13NO 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(III) 10457 (3R,4S)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetanyl acetate C18H17NO4 详情 详情
(IV) 10458 (3R,4S)-2-oxo-4-phenylazetanyl acetate C11H11NO3 详情 详情
(V) 63030 cis-3-Hydroxy-4-phenyl-2-azetanone; (3R*,4S*)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(VI) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(VII) 18762 1-Ethoxyethylene; Ethyl vinyl ether;Ethoxyethene 109-92-2 C4H8O 详情 详情
(VIII) 10462 (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone C13H17NO3 详情 详情
(IX) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(X) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(XI) 10465 (2R,3S)-3-(Benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropionic acid C20H23NO5 详情 详情
(XII) 10466 (4S,5R)-5-(1-Ethoxyethoxy)-2,4-diphenyl-4,5-dihydro-6H-1,3-oxazin-6-one C20H21NO4 详情 详情
(XIII) 10467 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12,15-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 32981-86-5 C29H36O10 详情 详情
(XIV) 10468 (1S,2S,3R,4S,7R,9R,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IX)

The synthesis of tritium-labeled taxol [3''-3H]-taxol has been described: The reaction of baccatin III (I) with chlorotriethylsilane in pyridine gives the protected compound (II), which is condensed with cis-1-benzoyl-4-(3-bromophenyl)-3-(triethylsilyloxy)azetidin-2-one (III) by means of butyllithium in THF, yielding 3''-bromo-2',7-bis-O-(triethylsilyl)taxol (IV). The deprotection of (IV) with pyridine and 48% HF in THF affords 3''-bromotaxol (V), which is finally debrominated with tritium by means of Pd/C and triethylamine in THF. The starting azetidinone (III) is obtained as follows: The condensation of 3-bromobenzaldehyde (VI) with 4-methoxyaniline (VII) in refluxing benzene gives the enamine (VIII), which is cyclized with acetoxyacetyl chloride (IX) by means of triethylamine in dichloromethane, yielding cis-3-acetoxy-4-(3-bromophenyl)-1-(4-methoxyphenyl)azetidin-2-one (X). The reaction of (X) with ceric ammonium nitrate (CAN) in acetonitrile affords cis-3-acetoxy-4-(3-bromophenyl)azetidin-2-one (XI), which is deacetylated with KOH in THF-water giving cis-4-(3-bromophenyl)-3-hydroxyazetidin-2-one (XII). The silylation of (XII) with chlorotriethylsilane in pyridine yields cis-4-(3-bromophenyl)-3-(triethylsilyloxy)azetidin-2-one (XIII), which is finally benzoylated with benzoyl chloride (XIV) and butyllithium in THF to afford the desired azetidinone (III).

1 Taylor, G.F.; Thornton, S.S.; Tallent, C.R.; Kepler, J.A.; Synthesis of [3''-3H]taxol and [13-3H]taxol. J Label Compd Radiopharm 1993, 33, 6, 501.
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) 10447 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C31H38O11 详情 详情
(II) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(III) 10474 (3R,4S)-1-Benzoyl-4-(3-bromophenyl)-3-[(triethylsilyl)oxy]-2-azetidinone C22H26BrNO3Si 详情 详情
(IV) 10475 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-(3-bromophenyl)-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C59H78BrNO14Si2 详情 详情
(V) 10476 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-3-(3-bromophenyl)-2-hydroxypropanoyl]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 C47H50BrNO14 详情 详情
(VI) 10477 3-Bromobenzaldehyde; m-Bromobenzaldehyde 3132-99-8 C7H5BrO 详情 详情
(VII) 10478 p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine 104-94-9 C7H9NO 详情 详情
(VIII) 10479 N-[(Z)-(3-Bromophenyl)methylidene]-N-(4-methoxyphenyl)amine; N-[(Z)-(3-Bromophenyl)methylidene]-4-methoxyaniline C14H12BrNO 详情 详情
(IX) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(X) 10481 (2S,3R)-2-(3-bromophenyl)-1-(4-methoxyphenyl)-4-oxoazetanyl acetate C18H16BrNO4 详情 详情
(XI) 10482 (2S,3R)-2-(3-bromophenyl)-4-oxoazetanyl acetate C11H10BrNO3 详情 详情
(XII) 10483 (3R,4S)-4-(3-Bromophenyl)-3-hydroxy-2-azetanone C9H8BrNO2 详情 详情
(XIII) 10484 (3R,4S)-4-(3-Bromophenyl)-3-[(triethylsilyl)oxy]-2-azetanone C15H22BrNO2Si 详情 详情
(XIV) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情

合成路线3

该中间体在本合成路线中的序号:(II)

A new synthesis of paclitaxel has been reported: The cyclization of the 4-methoxyphenylimine of benzaldehyde (I) with acetoxyacetyl chloride (II) by means of triethylamine gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (III), which is treated with ceric ammonium nitrate to afford cis-3-acetoxy-4-phenylazetidin-2-one (IV). The hydrolysis of (IV) with KOH in THF/water affords the corresponding hydroxy compound (V), which is submitted to optical resolution by crystallization of the 2-methoxy-2-[2-(trifluoromethyl)phenyl]acetic esters. The (3R,4S)-regioisomer (VI) is protected with ethyl vinyl ether, giving the 1-ethoxyethyl derivative (VII), which is benzoylated with benzoyl chloride and butyllithium to afford (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (VIII). The condensation of (VIII) with baccatin III (IX) by means of dimethylaminopyridine (DMAP) in pyridine yields the protected paclitaxel derivative (X), which is finally deprotected with HCl in ethanol/water.

1 Holton, R.A. (University of Florida); Method for preparation of taxol. EP 0400971; US 5336785 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(I) 10455 N-(4-Methoxyphenyl)-N-[(Z)-benzylidene]amine; 4-Methoxy-N-[(Z)-benzylidene]aniline 783-08-4 C14H13NO 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(III) 10457 (3R,4S)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetanyl acetate C18H17NO4 详情 详情
(IV) 10458 (3R,4S)-2-oxo-4-phenylazetanyl acetate C11H11NO3 详情 详情
(V) 63030 cis-3-Hydroxy-4-phenyl-2-azetanone; (3R*,4S*)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(VI) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(VII) 10462 (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone C13H17NO3 详情 详情
(VIII) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(IX) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(X) 10505 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C57H73NO15Si 详情 详情

合成路线4

该中间体在本合成路线中的序号:(V)

A new synthesis of [14C]-labeled paclitaxel has been published: The protection of L-threonine methyl ester (I) with tert-butoxydiphenylchlorosilane (BPS-Cl) gives the compound (II), which is condensed with [14C]-labeled benzaldehyde (III), yielding the imine (IV). The cyclization of (IV) with acetoxyacetyl chloride (V) by means of triethylamine affords the azetidinone (VI), which is deprotected with tetrabutylammonium fluoride to the hydroxy ester (VII). The dehydration of (VII) with p-toluenesulfonyl chloride and triethylamine affords the unsaturated ester (VIII), which by ozonolysis is converted to the oxalimide (IX). Elimination of the oxalyl group with hydrazine gives the labeled azetidinone (X), which is deacetylated to the hydroxyazetidinone (XI) and protected with triethylchlorosilane (TES-Cl) to (XII). The benzoylation of (XII) with benzoyl chloride (XIII) and dimethylaminopyridine (DMAP) yields the corresponding benzoylated compound (XIV), which is then condensed with triethylsilyl-baccatin III (XV) by means of butyllithium to afford silylated labeled paclitaxel (XVI). Finally, this compound is deprotected with HCl. The intermediate silylated baccatin III (XV) is obtained from paclitaxel (XVII) by hydrogenolysis with NaBH4 to baccatin III (XVIII) and silylation with triethylsilyl chloride to (XV).

1 Walker, D.G.; Swigor, J.E.; Standridge, R.T.; Synthesis of paclitaxel-C3'-C-14. J Label Compd Radiopharm 1995, 36, 5, 479.
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) 10674 (2S,3R)-3-Hydroxy-1-methoxy-1-oxo-2-butanaminium chloride C5H12ClNO3 详情 详情
(II) 10675 methyl (2S,3R)-2-amino-3-methoxybutanoate C21H29NO4Si 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 44663 benzaldehyde C7H6O 详情 详情
(IV) 10677 methyl (2S,3R)-3-methoxy-2-[[(E)-benzylidene]amino]butanoate C28H33NO4Si 详情 详情
(IV) 44664 methyl (2S,3R)-3-methoxy-2-[[(E)-benzylidene]amino]butanoate C13H17NO3 详情 详情
(V) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(VI) 10679 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate C32H37NO7Si 详情 详情
(VI) 44665 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate C17H21NO6 详情 详情
(VII) 10680 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate C16H19NO6 详情 详情
(VII) 44666 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate C16H19NO6 详情 详情
(VIII) 10681 methyl (Z)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate C16H17NO5 详情 详情
(VIII) 44667 methyl (Z)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate C16H17NO5 详情 详情
(IX) 10682 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(IX) 44668 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(X) 10683 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(X) 44669 (3R,4S)-2-oxo-4-phenylazetidinyl acetate C11H11NO3 详情 详情
(XI) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(XI) 44670 (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone C9H9NO2 详情 详情
(XII) 10685 (3R,4S)-4-Phenyl-3-[(triethylsilyl)oxy]-2-azetidinone C15H23NO2Si 详情 详情
(XII) 44673 (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone C9H9NO2 详情 详情
(XIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XIV) 10687 (3R,4S)-1-Benzoyl-3-hydroxy-4-phenyl-2-azetidinone C16H13NO3 详情 详情
(XIV) 44671 (3R,4S)-1-benzoyl-3-hydroxy-4-phenyl-2-azetidinone C16H13NO3 详情 详情
(XV) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(XVI) 10689 (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-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate n/a AB 详情 详情
(XVI) 44672 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]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 C47H51NO14 详情 详情
(XVII) 10595 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]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 33069-62-4 C47H51NO14 详情 详情
(XVIII) 10447 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C31H38O11 详情 详情

合成路线5

该中间体在本合成路线中的序号:(VI)

Chlorination of 5-amino-2,4,6-triiodoisophthalic acid (I) with SOCl2 in EtOAc or toluene affords acid chloride (II). Yields have been improved with the addition of benzyltriethylammonium chloride as a catalyst. Acid chloride (II) is then condensed with 3-amino-1,2-propanediol (III) to produce diamide (IV). Compound (IV) is converted to the tetraacetate ester (V) employing acetic anhydride in pyridine. Subsequent acylation of the amino group of (V) with acetoxyacetyl chloride (VI) gives amide (VII). After saponification of the ester groups of (VII), the resultant hydroxy acetamide (VIII) is alkylated by 2-chloroethanol (IX) to furnish the title compound. Alternatively, amide (VIII) is alkylated by bromoethyl acetate (X), producing (XI). Hexa-ester (XI) is finally hydrolyzed with aqueous sulfuric acid. An improved procedure for this final hydrolysis step uses 1,1,2-trichloroethane as co-solvent.

1 Lin, Y. (Mallinckrodt Medical Inc.); Cpds. suitable for X-ray visualisation methods. EP 0083964; US 4396598 .
2 Dunn, T.J.; White, D.H.; Kneller, M.T.; Jones, M.M.; Doran, N.O. III; Bailey, A.R. (Mallinckrodt Medical Inc.); Process for producing ioversol. WO 9727172 .
3 Kneller, M.T.; Bailey, A.R.; Sathe, S.S.; Spears, A.T.; Wisneski, R.C. (Mallinckrodt Medical Inc.); Improved synthesis of ioversol. WO 9323365 .
4 Villa, M.; Castaldi, G.; Pozzoli, C.; Russo, L. (Zambon Group SpA); Process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride by chlorination with thionyl chloride in the presence of a catalyst. WO 9636590 .
5 Lin, Y.; Dean, R.T.; Kneller, M.; Wallace, R.A.; McCarthy, W.Z.; White, D.H. (Mallinckrodt Medical Inc.); Process for production of ioversol. WO 9111431 .
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) 22006 5-amino-2,4,6-triiodoisophthalic acid 35453-19-1 C8H4I3NO4 详情 详情
(II) 31194 5-amino-2,4,6-triiodoisophthaloyl dichloride 37441-29-5 C8H2Cl2I3NO2 详情 详情
(III) 12979 3-Amino-1,2-propanediol;3-aminopropane-1,2-diol 616-30-8 C3H9NO2 详情 详情
(IV) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(V) 59322 2-(acetyloxy)-1-({[3-amino-5-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodobenzoyl]amino}methyl)ethyl acetate C22H26I3N3O10 详情 详情
(VI) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(VII) 59323 2-(acetyloxy)-1-({[3-{[2-(acetyloxy)acetyl]amino}-5-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodobenzoyl]amino}methyl)ethyl acetate C26H30I3N3O13 详情 详情
(VIII) 59324 N~1~,N~3~-bis(2,3-dihydroxypropyl)-5-(glycoloylamino)-2,4,6-triiodoisophthalamide C16H20I3N3O8 详情 详情
(IX) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(X) 10384 2-Chloro-1-ethanol; Ethylene chlorohydrin 107-07-3 C2H5ClO 详情 详情
(XI) 59325 2-[[2-(acetyloxy)acetyl]-3,5-bis({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodoanilino]ethyl acetate C30H36I3N3O15 详情 详情

合成路线6

该中间体在本合成路线中的序号:(II)

A further synthetic variation for the title compound is based on the acylation of intermediate (I) with acetoxyacetyl chloride (II) to afford (III). Amide alkylation with bromoethyl acetate (IV) furnishes (V). The ester groups of (V) are finally hydrolyzed in aqueous sulfuric acid.

1 Lin, Y.; Wallace, R.A.; McCarthy, W.Z.; Kneller, M.T.; White, D.H. (Mallinckrodt Medical Inc.); Synthesis of ioversol using a minimal excessof acetoxyacetylchloride. US 5371278 .
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) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(III) 59331 2-[(3-{[2-(acetyloxy)acetyl]amino}-5-{[(2,3-bis{[2-(acetyloxy)acetyl]oxy}propyl)amino]carbonyl}-2,4,6-triiodobenzoyl)amino]-1-({[2-(acetyloxy)acetyl]oxy}methyl)ethyl 2-(acetyloxy)acetate C34H38I3N3O21 详情 详情
(IV) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(V) 59332 2-[(3-{[2-(acetyloxy)acetyl][2-(acetyloxy)ethyl]amino}-5-{[(2,3-bis{[2-(acetyloxy)acetyl]oxy}propyl)amino]carbonyl}-2,4,6-triiodobenzoyl)amino]-1-({[2-(acetyloxy)acetyl]oxy}methyl)ethyl 2-(acetyloxy)acetate C38H44I3N3O23 详情 详情

合成路线7

该中间体在本合成路线中的序号:(II)

TB-2285 was synthesized by acylation of 3,5-diamino-4-chlorobenzonitrile (I) with 2-acetoxyacetyl chloride (II) in pyridine.

1 Rabasseda, X.; Mealy, N.; Castaner, J.; TYB-2285. Drugs Fut 1995, 20, 7, 686.
2 Taguchi, H.; Katsushima, T.; Ban, M.; Watanabe, A. (Toyobo Co., Ltd.); Novel amide cpds. EP 0315112; JP 1989121256 .
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) 13525 3,5-Diamino-4-chlorobenzonitrile C7H6ClN3 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情

合成路线8

该中间体在本合成路线中的序号:(III)

Hydrogenolysis of PNU-100542 (I) removed the benzyloxycarbonyl group and afforded secondary amine (II), which was acylated with (acetoxy)acetyl chloride (III) in the presence of triethylamine to provide amide PNU-142581 (IV). Then, acetate and phthaloyl protecting groups were both removed on treatment with an hydroalcoholic solution of methylamine, and the resulting aminoalcohol PNU-141718 (V) was N-acylated with dichloroacetyl chloride (VI) to yield the desired amide PNU-109230.

1 Ulanowicz, D.A.; et al.; Synthesis and biological activity of N-acetyl modified analogs of oxazolidinone anticancer agents linezolid and eperezolid. 37th Intersci Conf Antimicrob Agents Chemother (Sept 28-Oct 1, Toronto) 1997, Abst F-21.
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) 17824 benzyl 4-(4-[(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C30H27FN4O6 详情 详情
(II) 17825 2-([(5S)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)-1H-isoindole-1,3(2H)-dione C22H21FN4O4 详情 详情
(III) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(IV) 17827 2-[4-(4-[(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinyl]-2-oxoethyl acetate C26H25FN4O7 详情 详情
(V) 17828 (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-glycoloyl-1-piperazinyl)phenyl]-1,3-oxazolidin-2-one C16H21FN4O4 详情 详情
(VI) 17829 2,2-dichloroacetyl chloride; dichloroacetyl chloride 79-36-7 C2HCl3O 详情 详情

合成路线9

该中间体在本合成路线中的序号:(XII)

The asymmetric 1,3-dipolar cycloaddition of the nitrile oxide resulting from 4-bromo-N-hydroxybenzenecarboximidoyl chloride (I) to allyl alcohol (II) in the presence of (R,R)-diisopropyl tartrate and diethylzinc afforded the (R)-5-(hydroxymethyl)isoxazoline (III). After conversion of (III) to the mesylate (IV), treatment with ammonium hydroxide in a sealed vessel provided primary amine (V), which was then acetylated with Ac2O and pyridine to give amide (VI). Further treatment of (VI) with hexamethylditin and dichlorobis(triphenylphosphine) palladium yielded the trimethylstannyl derivative (VII). Reaction of N-Boc-4-piperidone (VIII) with lithium diisopropylamide and N-phenyl-trifluoromethanesulfonimide at low temperature furnished the corresponding vinyl triflate (IX). Subsequent coupling of (IX) with stannyl derivative (VII) in the presence of tris(dibenzylideneacetone)dipalladium and triphenylarsine gave rise to the N-Boc-tetrahydropyridylphenylisoxazole (X). The Boc group of (X) was then deprotected using trifluoroacetic acid, and the deprotected tetrahydropyridine (XI) was condensed with acetoxyacetyl chloride (XII), yielding the acetoxyacetamide (XIII). The acetate ester of (XIII) was finally hydrolyzed by means of K2CO3 in MeOH.

1 Ukaji, Y.; et al.; Enantioselective synthesis of 2-isoxazolines via asymmetric 1,3-dipolar cycloaddition of nitrile oxides to achiral allyl alcohols. Chem Lett 1993, 11, 1847.
2 Barbachyn, M.R.; Thomas, R.C.; Cleek, G.J. (Pharmacia & Upjohn AB); Isoxazoline derivs. useful as antimicrobials. EP 0920421; US 5990136; WO 9807708 .
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) 32966 4-bromo-N-hydroxybenzenecarboximidoyl chloride C7H5BrClNO 详情 详情
(II) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(III) 32967 [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methanol C10H10BrNO2 详情 详情
(IV) 32968 [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methyl methanesulfonate C11H12BrNO4S 详情 详情
(V) 32969 [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methylamine; [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methanamine C10H11BrN2O 详情 详情
(VI) 32970 N-[[(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methyl]acetamide C12H13BrN2O2 详情 详情
(VII) 32971 N-([(5R)-3-[4-(trimethylstannyl)phenyl]-4,5-dihydro-5-isoxazolyl]methyl)acetamide C15H22N2O2Sn 详情 详情
(VIII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(IX) 32972 tert-butyl 4-[[(trifluoromethyl)sulfonyl]oxy]-3,6-dihydro-1(2H)-pyridinecarboxylate C11H16F3NO5S 详情 详情
(X) 32973 tert-butyl 4-(4-[(5R)-5-[(acetamido)methyl]-4,5-dihydro-3-isoxazolyl]phenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate C22H29N3O4 详情 详情
(XI) 32974 N-([(5R)-3-[4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-4,5-dihydro-5-isoxazolyl]methyl)acetamide C17H21N3O2 详情 详情
(XII) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(XIII) 32975 2-[4-(4-[(5R)-5-[(acetamido)methyl]-4,5-dihydro-3-isoxazolyl]phenyl)-3,6-dihydro-1(2H)-pyridinyl]-2-oxoethyl acetate C21H25N3O5 详情 详情

合成路线10

该中间体在本合成路线中的序号:(XI)

2-Methylindole (I) was nitrated employing NaNO3 in H2SO4 and the resultant 5-nitroindole (II) was further reduced to the corresponding indoline (III) by means of NaBH3CN in the presence of HOAc. Catalytic hydrogenation of the nitro group of (III) over Pd/C furnished diamine (IV), which was converted to the bis-carbamate (V) by treatment with benzyl chloroformate. Oxazolidinone (VII) was then obtained by condensation of carbamate (V) with (R)-glycidyl butyrate (VI) in the presence of BuLi at -78 C. After conversion of alcohol (VII) to the corresponding nosylate (VIII), displacement of its sulfonate group with ammonium hydroxide gave rise to the primary amine (IX). Acetylation of amine (IX), followed by hydrogenolysis of the remaining N-benzyloxycarbonyl group, yielded acetamide (X). The indoline N of (X) was then acylated by acetoxyacetyl chloride (XI) to produce amide (XII). The title compound was then obtained by smooth hydrolysis of the acetoxy group of (XII) with K2CO3, followed by separation of the resultant mixture of diastereoisomers by chiral HPLC.

1 Genin, M.J.; Barbachyn, M.R.; Grega, K.C.; et al.; The potentiating effect of remote chirality on the antibacterial activity of a series of 2-substituted indolinyl phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1042.
2 Hester, J.B. Jr.; Barbachyn, M.R.; Johnson, P.D.; Genin, M.J. (Pharmacia Corp.); Bicyclic oxazolidinones as antibacterial agent. EP 1181288; US 6387896; WO 0073301 .
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) 28747 2-methyl-1H-indole 95-20-5 C9H9N 详情 详情
(II) 55948 2-methyl-5-nitro-1H-indole; 2-Methyl-5-nitroindole 7570-47-0 C9H8N2O2 详情 详情
(III) 55949 2-methyl-5-nitroindoline C9H10N2O2 详情 详情
(IV) 55950 2-methyl-2,3-dihydro-1H-indol-5-ylamine; 2-methyl-5-indolinamine C9H12N2 详情 详情
(V) 55951 benzyl 5-{[(benzyloxy)carbonyl]amino}-2-methyl-1-indolinecarboxylate C25H24N2O4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 55952 benzyl 5-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-methyl-1-indolinecarboxylate C21H22N2O5 详情 详情
(VIII) 55953 benzyl 2-methyl-5-[(5R)-5-({[(3-nitrophenyl)sulfonyl]oxy}methyl)-2-oxo-1,3-oxazolidin-3-yl]-1-indolinecarboxylate C27H25N3O9S 详情 详情
(IX) 55954 benzyl 5-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-methyl-1-indolinecarboxylate C21H23N3O4 详情 详情
(X) 55955 N-{[(5S)-3-(2-methyl-2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C15H19N3O3 详情 详情
(XI) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(XII) 55956 2-(5-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate C19H23N3O6 详情 详情

合成路线11

该中间体在本合成路线中的序号:(II)

In a related synthetic strategy, acylation of 2-bromoaniline (I) with acetoxyacetyl chloride (II) affords the acetoxy acetanilide (III). Alkylation of amide (III) with iodomethane and NaH leads to the N-methyl amide (IV). Then, Stille coupling of aryl bromide (IV) with tributyl (1-ethoxyvinyl)tin (V) gives rise to the enol ether (VI). Bromination of (VI) with N-bromosuccinimide in moist THF, followed by displacement of the resultant bromo ketone (VII) with NaN3 provides azido ketone (VIII). The key oxazole (X) is then obtained by condensation of azido ketone (VIII) with isothiocyanate (IX) in the presence of PPh3. Alkaline hydrolysis of the acetate ester (X) yields alcohol (XI), which is converted to mesylate (XII) by means of methanesulfonyl chloride and triethylamine. The mesylate group is finally displaced with morpholine (XIII) to furnish the title compound.

1 Dhar, T.G.M.; Guo, J.; Shen, Z.; et al.; A modified approach to 2-(N-aryl)-1,3-oxazoles: application to the synthesis of the IMPDH inhibitor BMS-337197 and analogues. Org Lett 2002, 4, 12, 2091.
2 Dhar, T.G.M.; et al.; Discovery of N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]-amino]-5-oxazolyl]phenyl]-N-methyl-4-morpholineacetamide as a novel and potent inhibitor of inosine monophosphate dehydrogenase with excellent in vivo activity. J Med Chem 2002, 45, 11, 2127.
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) 27739 2-bromoaniline 615-36-1 C6H6BrN 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(III) 61853 2-(2-bromoanilino)-2-oxoethyl acetate C10H10BrNO3 详情 详情
(IV) 61854 2-[2-bromo(methyl)anilino]-2-oxoethyl acetate C11H12BrNO3 详情 详情
(V) 19760 ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane 97674-02-7 C16H34OSn 详情 详情
(VI) 61855 2-[2-(1-ethoxyvinyl)(methyl)anilino]-2-oxoethyl acetate C15H19NO4 详情 详情
(VII) 61856 2-[2-(2-bromoacetyl)(methyl)anilino]-2-oxoethyl acetate C13H14BrNO4 详情 详情
(VIII) 61857 2-[2-(2-azidoacetyl)(methyl)anilino]-2-oxoethyl acetate C13H14N4O4 详情 详情
(IX) 61697 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole C11H8N2O2S 详情 详情
(X) 61858 2-[2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}(methyl)anilino]-2-oxoethyl acetate C24H22N4O6 详情 详情
(XI) 61859 2-hydroxy-N-(2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}phenyl)-N-methylacetamide C22H20N4O5 详情 详情
(XII) 61860 2-[2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}(methyl)anilino]-2-oxoethyl methanesulfonate C23H22N4O7S 详情 详情
(XIII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线12

该中间体在本合成路线中的序号:(II)

The title trans beta-lactam is obtained by condensation of imine (I) with acetyloxyacetyl chloride (II) in the presence of Et3N in cold CH2Cl2 under Staudinger reaction conditions. (1,2)

1 Banik, N.K.; Becker, F.F.; Unprecedented stereoselectivity in the Staudinger reaction with polycyclic aromatic imines. Tetrahedron Lett 2000, 41, 34, 6551.
2 Banik, I.; Becker, F.F.; Banik, B.K.; Stereoselective synthesis of beta-lactams with polyaromatic imines: Entry to new and novel anticancer agents. J Med Chem 2003, 46, 1, 12.
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) 64398 N-(6-chrysenyl)-N-[(E)-phenylmethylidene]amine; N-[(E)-phenylmethylidene]-6-chrysenamine C25H17N 详情 详情
(II) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情

合成路线13

该中间体在本合成路线中的序号:(VII)

3,4,5-Trifluorobenzaldehyde (I) is converted into oxime (II) upon treatment with hydroxylamine in aqueous EtOH. Subsequent oxidation of oxime (II) with N-chlorosuccimide produces the hydroximinoyl chloride (III). In situ conversion of (III) to the corresponding nitrile oxide, followed by cycloaddition with N-allyl acetamide (IV) generates the racemic isoxazoline (V). After resolution of (V) by means of chiral HPLC, displacement of the para-fluoride group with piperazine in hot DMSO furnishes (VI). Acylation of piperazine (VI) by means of acetoxyacetyl chloride (VII) gives rise to amide (VIII). Finally, methanolysis of the acetoxy group of (VIII) in the presence of K2CO3 leads to the target hydroxyacetylpiperazine derivative. (1,2)

1 Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogens. J Med Chem 2003, 46, 2, 284.
2 Thomas, R.C.; Barbachyn, M.R.; Morris, J.; Wishka, D.G.; Cleek, G.J. (Pfizer Inc.); Substd. aminophenyl isoxazoline derivs. useful as antimicrobials. JP 2002503655; US 6069141; WO 9941244 .
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) 64391 3,4,5-trifluorobenzaldehyde C7H3F3O 详情 详情
(II) 64392 3,4,5-trifluorobenzaldehyde oxime C7H4F3NO 详情 详情
(III) 64393 3,4,5-trifluoro-N-hydroxybenzenecarboximidoyl chloride C7H3ClF3NO 详情 详情
(IV) 64394 N-(2-propenyl)acetamide C5H9NO 详情 详情
(V) 64395 N-{[3-(3,4,5-trifluorophenyl)-4,5-dihydro-5-isoxazolyl]methyl}acetamide C12H11F3N2O2 详情 详情
(VI) 64396 N-({3-[3,5-difluoro-4-(1-piperazinyl)phenyl]-4,5-dihydro-5-isoxazolyl}methyl)acetamide C16H20F2N4O2 详情 详情
(VII) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(VIII) 64397 2-[4-(4-{5-[(acetylamino)methyl]-4,5-dihydro-3-isoxazolyl}-2,6-difluorophenyl)-1-piperazinyl]-2-oxoethyl acetate C20H24F2N4O5 详情 详情
Extended Information