(4S,5R)-2,4-Diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】10597

【品名】(4S,5R)-2,4-Diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylic acid

【CA登记号】

【分子式】C₁₆H₁₃NO₃

【分子量】267.28416

【元素组成】C 71.9% H 4.9% N 5.24% O 17.96%

与该中间体有关的原料药合成路线共 5 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1

该中间体在本合成路线中的序号：(II)

A new synthesis of paclitaxel starting from baccatin (III) has been described: The esterification of 7-O-(triethylsilyl)baccatin III (I) with (4S,5R)-2,4-diphenyl-2-oxazoline-5-carboxylic acid (II) by means of dicyclohexylcarbodiimide (DCC) and 4-(4-pyrrolidinyl)pyridine (PPyr) in dry toluene gives the intermediate ester (III), which is then hydrolyzed with diluted HCl.

参考文献中间体

合成目标

【1】 Chaudhary, A.G.; Kingston, D.G.I.; Middleton, M.; Gunatilaka, A.K.L.; Synthesis of taxol from baccatin III via an oxazoline intermediate. Tetrahedron Lett 1994, 35, 26, 4483.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	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
(II)	10597	(4S,5R)-2,4-Diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylic acid	C₁₆H₁₃NO₃	详情	详情
(III)	10598	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-2-(benzoyloxy)-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-15-yl (4S,5R)-2,4-diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylate	C₅₃H₆₃NO₁₃Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

1) The selective protection of baccatin III (I) with 2,2,2-trichloroethoxycarbonyl chloride and Li-HMDS in DMF gives 7-O-(2,2,2-trichloroethoxycarbonyl)baccatin III (II), which is condensed with the chiral oxazolidine (III) by means of DCC and DMAP in toluene affording the 13-O-oxazolidinyl derivative (III). Finally, this compound is submitted to deprotection with Zn/acetic acid and to cleavage of the oxazolidine ring with trifluoroacetic acid/acetic acid.

参考文献中间体

合成目标

【1】 Gibson, F.S. (Bristol-Myers Squibb Co.); Synthesis of paclitaxel baccatin III by protecting the 7-hydroxyl using a strong base and an electrophile. WO 9945001 .

中间体序号	中间体编号	品名	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)	10448	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate	C₃₄H₃₉Cl₃O₁₃	详情	详情
(III)	10597	(4S,5R)-2,4-Diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylic acid	C₁₆H₁₃NO₃	详情	详情
(IV)	32008	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (4S,5R)-2,4-diphenyl-4,5-dihydro-1,3-oxaz	C₅₀H₅₀Cl₃NO₁₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

2) The selective protection of baccatin III (I) with benzyloxycarbonyl anhydride and Li-HMDS in DMF gives 7-O-(benzyloxycarbonyl)baccatin III (V), which is condensed with the chiral oxazolidine (III) by means of DCC and DMAP in toluene affording the 13-O-oxazolidinyl derivative (VI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in ethanol, and treated with trifluoroacetic acid/acetic acid as before.

参考文献中间体

合成目标

【1】 Gibson, F.S. (Bristol-Myers Squibb Co.); Synthesis of paclitaxel baccatin III by protecting the 7-hydroxyl using a strong base and an electrophile. WO 9945001 .

中间体序号	中间体编号	品名	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
(III)	10597	(4S,5R)-2,4-Diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylic acid	C₁₆H₁₃NO₃	详情	详情
(V)	32009	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-9-[[(benzyloxy)carbonyl]oxy]-1,15-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	C₃₉H₄₄O₁₃	详情	详情
(VI)	32010	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-2-(benzoyloxy)-9-[[(benzyloxy)carbonyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (4S,5R)-2,4-diphenyl-4,5-dihydro-1,3-oxazole-5-carbox	C₅₅H₅₅NO₁₅	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

3) The selective protection of baccatin III (I) with tert-butoxycarbonyl anhydride and Li-HMDS in DMF gives 7-O-(tert-butoxycarbonyl)baccatin III (VII), which is condensed with the chiral oxazolidine (III) by means of DCC and DMAP in toluene affording the 13-O-oxazolidinyl derivative (VIII). Finally, this compound is deprotected with formic or acetic acids, and the oxazolidine ring is cleaved with trifluoroacetic acid/acetic acid.

参考文献中间体

合成目标

【1】 Gibson, F.S. (Bristol-Myers Squibb Co.); Synthesis of paclitaxel baccatin III by protecting the 7-hydroxyl using a strong base and an electrophile. WO 9945001 .

中间体序号	中间体编号	品名	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
(III)	10597	(4S,5R)-2,4-Diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylic acid	C₁₆H₁₃NO₃	详情	详情
(VII)	32011	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-9-[(tert-butoxycarbonyl)oxy]-1,15-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	C₃₆H₄₆O₁₃	详情	详情
(VIII)	32012	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-2-(benzoyloxy)-9-[(tert-butoxycarbonyl)oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (4S,5R)-2,4-diphenyl-4,5-dihydro-1,3-oxazole-5-carbox	C₅₂H₅₇NO₁₅	详情	详情

合成路线5

该中间体在本合成路线中的序号：(V)

A novel semisynthetic method for the production of paclitaxel from 10-deacetylbaccantin-III using dialkyldichlorosilanes has been reported: The protection of the 7-OH of 10-deacetylbaccatin-III (I) by reaction first with dichlorodiethylsilane (II) and imidazole and then with methanol gives 7-O-[diethyl(methoxy)silyl]baccatin-III (III), which is regioselectively acetylated at the 10-OH with acetylimidazole and LiHMDS to yield the acetate (IV). The esterification of (IV) with the chiral oxazolinecarboxylic acid (V) by means of LiHMDS affords the corresponding ester (VI), which is treated with TFA in HOAc/water in order to perform desilylation and open the oxazoline ring to furnish paclitaxel. Other silylating agents, such as dimethyldichlorosilane, dipropyldichlorosilane, diisopropyldichlorosilane, dibutyldichlorosilane and diphenyldichlorosilane, and other alcohols, such as EtOH, PrOH, i-PrOH, t-BuOH, 3,3,3-trifluoroethanol and others, can also be used in the silylation step.

参考文献中间体

合成目标

【1】 Dillon, J.L. Jr.; Vemishetti, P.; Gibson, F.S. (Bristol-Myers Squibb Co.); Semi-synthesis of paclitaxel using dialkyldichlorosilanes. WO 0073293 .

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)	43822	dichloro(diethyl)silane	1719-53-5	C₄H₁₀Cl₂Si	详情	详情
(III)	43823	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-9-[[diethyl(methoxy)silyl]oxy]-1,12,15-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		C₃₄H₄₈O₁₁Si	详情	详情
(IV)	43824	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-9-[[diethyl(methoxy)silyl]oxy]-1,15-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		C₃₆H₅₀O₁₂Si	详情	详情
(V)	10597	(4S,5R)-2,4-Diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylic acid		C₁₆H₁₃NO₃	详情	详情
(VI)	43825	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-2-(benzoyloxy)-9-[[diethyl(methoxy)silyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (4S,5R)-2,4-diphenyl-4,5-dihydro-1,3-oxazole-5-carb		C₅₂H₆₁NO₁₄Si	详情	详情

Extended Information