(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate -Drug Synthesis Database

【结构式】

【分子编号】23892

【品名】(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate

【CA登记号】

【分子式】C₃₅H₃₈Cl₆O₁₄

【分子量】895.39452

【元素组成】C 46.95% H 4.28% Cl 23.76% O 25.02%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

A new synthesis of docetaxel has been developed: The stereoselective dihydroxylation of methyl cinnamate (I) by the Sharpless AD process gives the enantiopure diol (II), which was treated first with tosyl chloride/triethylamine and then with K2CO3 in DMF yielding epoxide (III). Hydrolysis of the ester group of (III) with LiOH in methanol/water affords the epoxy-acid (IV), which is coupled with 7,10-bis(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatin III (V) by means of dicyclohexylcarbodiimide (CDD) and dimethylaminopyridine in hot toluene to give the ester (VI). Regioselective cleavage of the epoxide ring of (VI) with NaN3 in aqueous methanol yielded the azide derivative (VII), which was treated with triphenylphosphine in the presence of tert-butoxycarbonyl anhydride and K2CO3 in dichloromethane affording the tert-butoxycarbonylamino derivative (VIII). Finally, (VIII) was submitted to a reductive deprotection with zinc powder in acetic acid.

参考文献中间体

合成目标

【1】 Harada, N.; Yamaguchi, T.; Hashiyama, T.; Ozaki, K.; Synthesis of taxoids 3. A novel and efficient method for preparation of taxoids employing cis-glycidic acid. Tetrahedron Lett 1998, 39, 5575.

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)	23888	methyl (E)-3-phenyl-2-propenoate	103-26-4	C₁₀H₁₀O₂	详情	详情
(II)	23889	methyl (2S,3R)-2,3-dihydroxy-3-phenylpropanoate		C₁₀H₁₂O₄	详情	详情
(III)	23890	methyl (2R,3R)-3-phenyl-2-oxiranecarboxylate	99528-65-1	C₁₀H₁₀O₃	详情	详情
(IV)	23891	(2R,3R)-3-phenyl-2-oxiranecarboxylic acid		C₉H₈O₃	详情	详情
(V)	23892	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₃₅H₃₈Cl₆O₁₄	详情	详情
(VI)	23893	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (2R,3R)-3-phenyl-2-oxiranecarboxylate		C₄₄H₄₄Cl₆O₁₆	详情	详情
(VII)	23894	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-azido-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl ben		C₄₄H₄₅Cl₆N₃O₁₆	详情	详情
(VIII)	23895	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]		C₄₉H₅₅Cl₆NO₁₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

Taxane intermediates (XIII) and (XIV) were prepared by two related ways. Wittig condensation of cyclopropanecarboxaldehyde (I) with methoxycarbonylmethylenetriphenyl phosphorane (II) gave methyl trans-cyclopropylacrylate (III). This was oxidized with potassium ferricyanide in the presence of OsO4 and the chiral catalyst 1,4-bis(9-O-dihydroquinidyl)phthalazine to furnish (2S,3R)-diol (IV). After conversion of (IV) to tosylate (V), its cyclization by means of K2CO3 produced epoxide (VI). Subsequent epoxide opening with NaN3 gave azide (VII), which was hydrogenated in the presence of Pd/C and di tert-butyl dicarbonate to furnish carbamate (VIII). Treatment of (VIII) with isopropenyl methyl ether (IX) and pyridinium tosylate, followed by ester hydrolysis, produced oxazolidine (X). This was coupled to protected taxane (XI) by means of DCC and DMAP to provide ester (XII). Oxazolidine hydrolysis in (XII) with formic acid, followed by reprotection of the amine with Boc2O, furnished intermediate (XIII). Optionally, the trichloroethoxycarbonyl groups of (XIII) were removed upon treatment with Zn and AcOH to produce intermediate (XIV).

参考文献中间体

合成目标

【1】 Tsujihari, K.; Hashiyama, T.; Ohashi, M.; Nakanishi, N. (Tanabe Seiyaku Co., Ltd.); Baccatin derivs. and processes for preparing the same. CA 2162759; EP 0712854; JP 1997151181; US 5589502 .

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)	26463	cyclopropanecarbaldehyde	1489-69-6	C₄H₆O	详情	详情
(II)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(III)	26464	methyl (E)-3-cyclopropyl-2-propenoate		C₇H₁₀O₂	详情	详情
(IV)	26465	methyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropanoate		C₇H₁₂O₄	详情	详情
(V)	26466	methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-[[(4-methylphenyl)sulfonyl]oxy]propanoate		C₁₄H₁₈O₆S	详情	详情
(VI)	26467	methyl (2R,3R)-3-cyclopropyl-2-oxiranecarboxylate		C₇H₁₀O₃	详情	详情
(VII)	26468	methyl (2R,3S)-3-azido-3-cyclopropyl-2-hydroxypropanoate		C₇H₁₁N₃O₃	详情	详情
(VIII)	26469	methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoate		C₁₂H₂₁NO₅	详情	详情
(IX)	26470	3-methoxy-1-butene		C₅H₁₀O	详情	详情
(X)	26471	(4S,5R)-3-(tert-butoxycarbonyl)-4-cyclopropyl-2,2-dimethyl-1,3-oxazolidine-5-carboxylic acid		C₁₄H₂₃NO₅	详情	详情
(XI)	23892	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₃₅H₃₈Cl₆O₁₄	详情	详情
(XII)	26472	methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate		C₄₉H₅₉Cl₆NO₁₈	详情	详情
(XIII)	26473	methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate		C₄₆H₅₅Cl₆NO₁₈	详情	详情
(XIV)	26474	methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate		C₄₀H₅₃NO₁₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

In a related procedure, epoxy carboxylic acid (XVII) was either obtained by basic hydrolysis of ethyl ester (XV) or by hydrogenolysis of benzyl ester (XVI). Alternatively, acid (XVII) was isolated as the dimethylaminopyridinium salt. Coupling of (XVII) with protected taxane (XI) provided ester (XVIII). Then, epoxide opening in (XVIII) with either NaN3 or Bu3SnN3 and ZnI2 gave azide (XIX). Subsequent hydrogenation of (XIX) produced amine (XX), which was treated with Boc2O to yield intermediate (XIII).

参考文献中间体

合成目标

【1】 Tsujihari, K.; Hashiyama, T.; Ohashi, M.; Nakanishi, N. (Tanabe Seiyaku Co., Ltd.); Baccatin derivs. and processes for preparing the same. CA 2162759; EP 0712854; JP 1997151181; US 5589502 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	23892	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate	C₃₅H₃₈Cl₆O₁₄	详情	详情
(XIII)	26472	methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate	C₄₉H₅₉Cl₆NO₁₈	详情	详情
(XV)	26467	methyl (2R,3R)-3-cyclopropyl-2-oxiranecarboxylate	C₇H₁₀O₃	详情	详情
(XVI)	26475	benzyl (2R,3R)-3-cyclopropyl-2-oxiranecarboxylate	C₁₃H₁₄O₃	详情	详情
(XVII)	26476	(2R,3R)-3-cyclopropyl-2-oxiranecarboxylic acid	C₆H₈O₃	详情	详情
(XVIII)	26477	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (2R,3R)-3-cyclopropyl-2-oxiranecarboxylate	C₄₁H₄₄Cl₆O₁₆	详情	详情
(XIX)	26478	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-azido-3-cyclopropyl-2-hydroxypropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate	C₄₁H₄₅Cl₆N₃O₁₆	详情	详情
(XX)	26479	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-amino-3-cyclopropyl-2-hydroxypropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate	C₄₁H₄₇Cl₆NO₁₆	详情	详情

Extended Information