SB-T-12130301, -Drug Synthesis Database

【结构式】

【药物名称】SB-T-12130301

【化学名称】3-Methoxybenzoic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-9-[3(S)-(tert-butoxycarboxamido)-2(R)-hydroxy-5-methyl-4-hexenoyloxy]-4,11-dihydroxy-6-[2-(4-methoxyphenyl)acetoxy]-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl ester

【CA登记号】

【分子式】C₅₁H₆₅NO₁₇

【分子量】964.0832

【开发单位】Roswell Park Cancer Institute (Originator), State University of New York,Stony Brook (Originator)

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

合成路线1 合成路线2

合成路线1

Ring opening of cyclohexene oxide (I) with phenylmagnesium bromide in the presence of CuI, followed by acetylation of the resulting alcohol (II) gave the racemic trans-2-phenylcyclohexyl acetate (III). Enzymatic resolution of (III) using porcine liver acetone powder yielded the desired (-)-alcohol (II) along with unreacted (+)-acetate (III). Condensation of the sodium alkoxide of benzyl alcohol with bromoacetic acid (IV) afforded benzyloxyacetic acid (V), which was then coupled with the chiral alcohol (-)-(II) to give ester (VI). Hydrogenolysis of the O-benzyl group of (VI), followed by silylation of the resulting hydroxyacetate ester (VII) with triisopropylsilyl chloride, furnished (VIII). Imine (XI) was prepared by condensation of 3-methyl-2-butenal (IX) with p-anisidine (X). The asymmetric cyclocondensation reaction of the lithium enolate derived from ester (VIII) with imine (XI) yielded the chiral beta-lactam (XII). Oxidative removal of the p-methoxyphenyl protecting group of (XII) and then reprotection of the lactam N atom with Boc2O furnished the intermediate N-Boc lactam (XIII).

参考文献中间体

【1】 Strum, M.; Tynebor, R.; Pera, P.; Bernacki, R.J.; Ojima, I.; Synthesis and SAR of advanced second generation taxoids. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 132.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(rac)-(III)	51206	(1R,2S)-2-phenylcyclohexyl acetate		C₁₄H₁₈O₂	详情	详情
(rac)-(II)	51208	(1R,2S)-2-phenylcyclohexanol		C₁₂H₁₆O	详情	详情
(-)-(II)	51209	(-)-(1R,2S)-2-phenylcyclohexanol		C₁₂H₁₆O	详情	详情
(+)-(III)	51210	(1S,2R)-2-phenylcyclohexyl acetate		C₁₄H₁₈O₂	详情	详情
(I)	17986	7-oxabicyclo[4.1.0]heptane; cyclohexene oxide	286-20-4	C₆H₁₀O	详情	详情
(IV)	23660	2-Bromoacetic acid	79-08-3	C₂H₃BrO₂	详情	详情
(V)	51207	2-(benzyloxy)acetic acid		C₉H₁₀O₃	详情	详情
(VI)	51211	(1R,2S)-2-phenylcyclohexyl 2-(benzyloxy)acetate		C₂₁H₂₄O₃	详情	详情
(VII)	51212	(1R,2S)-2-phenylcyclohexyl 2-hydroxyacetate		C₁₄H₁₈O₃	详情	详情
(VIII)	19151	(1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate		C₂₃H₃₈O₃Si	详情	详情
(IX)	19152	3-methyl-2-butenal	107-86-8	C₅H₈O	详情	详情
(X)	10478	p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine	104-94-9	C₇H₉NO	详情	详情
(XI)	19154	4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine		C₁₂H₁₅NO	详情	详情
(XII)	19155	(3R,4S)-1-(4-methoxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone		C₂₃H₃₇NO₃Si	详情	详情
(XIII)	19157	tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate		C₂₁H₃₉NO₄Si	详情	详情

合成路线2

10-Deacetylbaccatin III (XIV) was protected by treatment with triethylsilyl chloride and imidazole, and the resulting trisilylated compound (XV) was debenzoylated to diol (XVI) by using Red-Al(R). Selective coupling of (XVI) with m-anisic acid (XVII) yielded the m-methoxybenzoate ester (XVIII). Complete desilylation of (XVIII) with HF-pyridine, followed by selective resilylation at C-7, furnished (XIX). The 10-hydroxyl group was then selectively acylated with p-methoxyphenylacetyl chloride (XX) to afford ester (XXI). Finally, coupling of the modified baccatin (XXI) with the intermediate lactam (XIII) in the presence of lithium hexamethyldisilazide, and then deprotection with HF-pyridine, gave rise to the desired taxoid.

参考文献中间体

【1】 Strum, M.; Tynebor, R.; Pera, P.; Bernacki, R.J.; Ojima, I.; Synthesis and SAR of advanced second generation taxoids. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 132.

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)	19157	tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate		C₂₁H₃₉NO₄Si	详情	详情
(XIV)	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
(XV)	51201	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₄₇H₇₈O₁₀Si₃	详情	详情
(XVI)	51202	(1S,2S,3R,7R,9S,10S,12R,15S)-1,2-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-4-yl acetate		C₄₀H₇₄O₉Si₃	详情	详情
(XVII)	28559	m-Anisic acid; 3-Methoxybenzoic acid	586-38-9	C₈H₈O₃	详情	详情
(XVIII)	51203	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 3-methoxybenzoate		C₄₈H₈₀O₁₁Si₃	详情	详情
(XIX)	51204	(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 3-methoxybenzoate		C₃₆H₅₂O₁₁Si	详情	详情
(XX)	26758	2-(4-methoxyphenyl)acetyl chloride	4693-91-8	C₉H₉ClO₂	详情	详情
(XXI)	51213	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-12-[[2-(4-methoxyphenyl)acetyl]oxy]-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 3-methoxybenzoate		C₄₅H₆₀O₁₃Si	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)