T-3782, -Drug Synthesis Database

【结构式】

【药物名称】T-3782

【化学名称】[2aR-[2aalpha,4beta,4abeta,6beta,9alpha(2R,3S),11beta,12alpha,12aalpha,12balpha]]-12b-Acetoxy-9-[2(R)-[2-[3(S)-amino-3-carbamoylpropionyloxy)acetoxy]-3(S)-(tert-butoxycarbonylamino)-3-cyclopropylpropionyloxy]-12-(benzoyloxy)-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxet-5-one tosylate

【CA登记号】178247-98-8 (free base), 178247-99-9 (monomesylate salt)

【分子式】C₅₃H₆₉N₃O₂₁S

【分子量】1116.21238

【开发单位】Tanabe Seiyaku (Originator)

【药理作用】Antimitotic Drugs, Microtubule-Stabilizing Agents, Taxanes

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

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

【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2

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

【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

合成路线3

Coupling of taxane intermediate (XIII) with benzyloxyacetic acid (XXI) in the presence of DCC and DMAP provided ester (XXII). After hydrogenolytic deprotection of the benzyl group of (XXII), the resulting hydroxyacetate ester (XXIII) was further condensed with N-carbobenzoxy-L-aspartic acid 1-amide (XXIV) to yield (XXV). Deprotection of the trichloroethoxycarbonyl groups of (XXV) with Zn and AcOH gave (XXVI). Finally, hydrogenolytic cleavage of the N-carbobenzoxy group of (XXVI) in the presence of p-toluenesulfonic acid furnished the title compound.

参考文献中间体

【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
(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
(XXI)	24966	2-ethoxyacetic acid	627-03-2	C₄H₈O₃	详情	详情
(XXII)	26480	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-2-[[2-(benzyloxy)acetyl]oxy]-3-[(tert-butoxycarbonyl)amino]-3-cyclopropylpropanoyl]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		C₅₅H₆₃Cl₆NO₂₀	详情	详情
(XXIII)	26481	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-(glycoloyloxy)propanoyl]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		C₄₈H₅₇Cl₆NO₂₀	详情	详情
(XXIV)	26482	(3S)-4-amino-3-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid		C₁₂H₁₄N₂O₅	详情	详情
(XXV)	26483	(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 (5S,12R)-5-(aminocarbonyl)-12-[(S)-[(tert-butoxycarbonyl)amino](cyclopropyl)methyl]-3,7,10-trioxo-1-phenyl-2,8,11-trioxa-4-azatridecan-13-oate		C₆₀H₆₉Cl₆N₃O₂₄	详情	详情
(XXVI)	26484	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1,9,12-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (5S,12R)-5-(aminocarbonyl)-12-[(S)-[(tert-butoxycarbonyl)amino](cyclopropyl)methyl]-3,7,10-trioxo-1-phenyl-2,8,11-trioxa-4-azatridecan-13-oate		C₅₄H₆₇N₃O₂₀	详情	详情

合成路线4

In a further procedure, hydroxy amino ester (VIII) was treated with anisaldehyde dimethyl acetal (XXVII) to provide oxazolidine (XXVIII) as a diastereomeric mixture. Ester hydrolysis of (XXVIII) with LiOH gave acid (XXIX), which was then coupled with taxane (XXX) to furnish ester (XXXI). Acidic treatment of (XXXI) cleaved the oxazolidine and deprotected the silyl ether group to produce (XXXII). Subsequent coupling of (XXXII) with acid (XXVII), followed by reductive deprotection of the trichloroethylcarbonyl group, provided intermediate (XXVI), which was finally converted into the title compound by hydrogenolysis in the presence of p-TsOH as above.

参考文献中间体

【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
(VIII)	26469	methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoate		C₁₂H₂₁NO₅	详情	详情
(XXVI)	26484	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1,9,12-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (5S,12R)-5-(aminocarbonyl)-12-[(S)-[(tert-butoxycarbonyl)amino](cyclopropyl)methyl]-3,7,10-trioxo-1-phenyl-2,8,11-trioxa-4-azatridecan-13-oate		C₅₄H₆₇N₃O₂₀	详情	详情
(XXVII)	26485	1-(dimethoxymethyl)-4-methoxybenzene	2186-92-7	C₁₀H₁₄O₃	详情	详情
(XXVIII)	26486	3-(tert-butyl) 5-methyl (4S,5R)-4-cyclopropyl-2-(4-methoxyphenyl)-1,3-oxazolidine-3,5-dicarboxylate		C₂₀H₂₇NO₆	详情	详情
(XXIX)	26487	(4S,5R)-3-(tert-butoxycarbonyl)-4-cyclopropyl-2-(4-methoxyphenyl)-1,3-oxazolidine-5-carboxylic acid		C₁₉H₂₅NO₆	详情	详情
(XXX)	26488	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-12-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₃₈H₅₁Cl₃O₁₂Si	详情	详情
(XXXI)	26489	5-[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-12-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl] 3-(tert-butyl) (4S,5R)-4-cyclopropyl-2-(4-methoxyphenyl)-1,3-oxazolidine-3,5-dicarboxylate		C₅₇H₇₄Cl₃NO₁₇Si	详情	详情
(XXXII)	26490	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoyl]oxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-12-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₄₃H₅₄Cl₃NO₁₆	详情	详情
(XXXIII)	26491	2-[((3S)-4-amino-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoyl)oxy]acetic acid		C₁₄H₁₆N₂O₇	详情	详情

合成路线5

In an alternative procedure, acid (XXVII) was activated as the mixed anhydride (XXXV) with isopropyl chloroformate (XXXIV), and then condensed with taxane intermediate (XIV) to give ester (XXVI). Hydrogenolytic deprotection of the N-carbobenzoy group of (XXVI) yielded the title compound.

参考文献中间体

【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
(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
(XXVI)	26484	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1,9,12-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (5S,12R)-5-(aminocarbonyl)-12-[(S)-[(tert-butoxycarbonyl)amino](cyclopropyl)methyl]-3,7,10-trioxo-1-phenyl-2,8,11-trioxa-4-azatridecan-13-oate		C₅₄H₆₇N₃O₂₀	详情	详情
(XXVII)	26485	1-(dimethoxymethyl)-4-methoxybenzene	2186-92-7	C₁₀H₁₄O₃	详情	详情
(XXXIV)	26492	2-[(chlorocarbonyl)oxy]propane	108-23-6	C₄H₇ClO₂	详情	详情
(XXXV)	26493	4-Amino-3(S)-(benzyloxycarbonylamino)-4-oxobutyric acid 2-(isopropoxycarbonyloxy)-2-oxoethyl ester		C₁₈H₂₂N₂O₉	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)