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【结 构 式】

【分子编号】10464

【品名】(3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone

【CA登记号】

【 分 子 式 】C20H21NO4

【 分 子 量 】339.39108

【元素组成】C 70.78% H 6.24% N 4.13% O 18.86%

与该中间体有关的原料药合成路线共 6 条

合成路线1

该中间体在本合成路线中的序号:(X)

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:(XII)

A new partial synthesis of taxol has been described: The esterification of (1S,2R)-2-phenylcyclohexanol (I) with benzyloxyacetyl chloride (II) gives the corresponding chiral ester (III), which is deprotected by hydrogenolysis to the hydroxy ester (IV). Silylation of (IV) with triisopropylsilyl chloride affords the silylated ester (V), which is cyclized with trimethylsilylbenzaldimine (VI) [obtained from benzaldehyde (VII) and hexamethyldisilazane (HMSA)] by means of butyllithium in THF giving (3R,4S)-3-(triisopropylsilyloxy)-4-phenylazetidin-2-one (VIII). The deprotection of (VIII) with tetrabutylammonium fluoride affords (3R,4S)-3-hydroxy-4-phenylazetidin-2-one (IX), which is treated with ethyl vinyl ether to give the 1-ethoxyethyl ether (X). The benzoylation of (X) with benzoyl chloride (XI) by means of dimethylaminopyridine and triethylamine yields (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (XII), which is condensed with 7-O-(triethylsilyl)baccatin III (XIII) by means of NaH in THF, affording 2'-O-(1-ethoxyethyl)-7-O-(triethylsilyl)taxol (XIV). Finally, this compound is deprotected with HCl in ethanol.

1 Habus, I.; Zhao, M.; Brigaud, T.; Zucco, M.; Ojima, I.; Sun, C.M.; Park, Y.H.; New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of beta-lactam synthon method. Tetrahedron 1992, 48, 34, 6985.
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) 10492 (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol 2362-61-0 C12H16O 详情 详情
(II) 10493 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride 19810-31-2 C9H9ClO2 详情 详情
(III) 10494 (1S,2R)-2-phenylcyclohexyl 2-(benzyloxy)acetate C21H24O3 详情 详情
(IV) 10495 (1S,2R)-2-phenylcyclohexyl 2-hydroxyacetate C14H18O3 详情 详情
(V) 10496 (1S,2R)-2-phenylcyclohexyl 2-(triisopropylsilyl)acetate C23H38O2Si 详情 详情
(VI) 10507 Trimethyl-N-[(E)-benzylidene]silanamine; N-[(E)-Benzylidene]-N-(trimethylsilyl)amine 17599-61-0 C10H15NSi 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 10499 (3R,4S)-4-Phenyl-3-[(triisopropylsilyl)oxy]-2-azetanone C18H29NO2Si 详情 详情
(IX) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(X) 10462 (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone C13H17NO3 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(XIII) 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
(XIV) 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3

该中间体在本合成路线中的序号:(I)

2) The condensation of (3R,4S)-1-benzoyl-3-(1-ethoxyethyl)-4-phenyloxazolidin-2-one (I) with monosilylated baccatin III (II) by means of DMAP in pyridine (or NaH) gives the protected paclitaxel precursor (III), which is easily deprotected by treatment with HCl in ethanol/water. (Holton, R.A. EP 400971).

1 Guy, R.K.; Nicolaou, K.C.; Dai, W.M.; Chemistry and biology of taxol. Angew Chem. Int Ed Engl 1994, 33, 1, 15.
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) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 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) 10540 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1,9-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 C57H73NO15Si 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VIII)

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5

该中间体在本合成路线中的序号:(XI)

The reaction of 10-O-deacetyl-baccatin III (I) with triethylsilyl chloride and pyridine gives the 7-O-silyl derivative (II), which is acylated with Ac2O and pyridine to yield 7-O-(triethylsilyl)baccatin III (III). The desilylation of (III) by means of HCl in ethanol yields baccatin III (VIII), which is condensed with DMSO by means of Ac2O and HOAc to afford the ketonic derivative (IX). The reduction of (IX) by means of NaBH4 in ethanol affords 7-O-(methylsulfanylmethyl)baccatin III (X), which is condensed with the chiral azetidinone (XI) by means of LiHMDS in THF to provide 2'-O-(1-ethoxyethyl)-7-O-(methylsulfanylmethyl)taxol (XII). Finally, this compound is deprotected by means of HCl in ethanol to give the target 7-O-(methylsulfanylmethyl)taxol.

1 Bourzat, J.-D.; Commercon, A.; Ojima, I.; Bouchard, H. (Aventis Pharma SA; State University of New York, Albany); Methods for preparing new taxoids and pharmaceutical compsns. containing them. WO 0270498 .
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) 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
(II) 10537 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-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 C35H50O10Si 详情 详情
(III) 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
(VIII) 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
(IX) 57906 (1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetyloxy)-1-hydroxy-10,14,17,17-tetramethyl-9-[(methylsulfanyl)methoxy]-11,15-dioxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate C33H40O11S 详情 详情
(X) 57907 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-1,15-dihydroxy-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 C33H42O11S 详情 详情
(XI) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(XII) 57908 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-{[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]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 C53H63NO15S 详情 详情

合成路线6

该中间体在本合成路线中的序号:(XI)

The reaction of 10-O-deacetyl-baccatin III (I) with triethylsilyl chloride and pyridine gives the 7-O-silyl derivative (II), which is acylated with Ac2O and pyridine to yield 7-O-(triethylsilyl)baccatin III (III). The condensation of (III) with the chiral azetidine (XI) by means of LiHMDS In THF affords 2'-O-(1-ethoxyethyl)-7-O-(triethylsilyl)taxol (XIII), which is treated with HF and pyridine to provide the desilylated taxol derivative (XIV). The reaction of (XIV) with DMSO, Ac2O and HOAc gives the 2'-O-protected 7-O-(methylsulfanylmethyl) derivative (XII), which is finally deprotected by means of HCl in ethanol to yield the target 7-O-(methylsulfanylmethyl)taxol.

1 Bourzat, J.-D.; Commercon, A.; Ojima, I.; Bouchard, H. (Aventis Pharma SA; State University of New York, Albany); Methods for preparing new taxoids and pharmaceutical compsns. containing them. WO 0270498 .
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) 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
(II) 10537 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-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 C35H50O10Si 详情 详情
(III) 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
(XI) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(XII) 57908 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-{[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]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 C53H63NO15S 详情 详情
(XIII) 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
(XIV) 10540 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1,9-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 C57H73NO15Si 详情 详情
Extended Information