(5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one; Podophyllotoxin -Drug Synthesis Database

【结构式】

【分子编号】14608

【品名】(5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one; Podophyllotoxin

【CA登记号】518-28-5

【分子式】C₂₂H₂₂O₈

【分子量】414.41188

【元素组成】C 63.76% H 5.35% O 30.89%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(I)

The partial demethylation of (±)-podophyllotoxin (I) with HBr in ether - dichloromethane, followed by alkaline hydrolysis with BaCO3 in aqueous acetone, gives (±)-4'-O-demethyl-1-epipodophyllotoxin (II), which is partially esterified with chloroacetyl chloride and pyridine, yielding (±)-4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (III). The glycosidation of (III) with 2-(benzyloxocarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (IV) by means of BF3 ethearate in dichloromethane affords (±)-1-O-[2-(benzyloxycarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl]-4'-O-(chloroacetyl)-4'-O-demethyl-1-epipodophyllotoxin (±)-(V) which, after separation of the diastereomers and elimination of the protecting groups with zinc acetate in refluxing methanol and H2 over Pd/C in ethyl acetate - ethanol, gives 1-O-(2-amino-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (VI). Finally, this compound is methylated with formaldehyde and sodium cyanoborohydride in methanol. The sugar moiety has been obtained as follows: The reaction of 2-(benzyloxycarbonylamino)-2-deoxy-beta-D-glucopyranose (VII) with acetaldehyde and concentrated H2SO4 gives 2-(benzyloxycarbonylamino)-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (VIII), which is then esterified with chloroacetyl chloride to (IV).

参考文献中间体

合成目标

【1】 Umezawa, H.; Takeuchi, T.; Kondo, S.; Tanaka, W.; Takita, T.; Nishimura, Y.; Yoshikawa, H. (Microbial Chemistry Research Foundation); 4'-Demethyl-4-epipodophyllotoxin derivs., a process for their preparation and their use as medicaments. EP 0196618; ES 8706713; JP 1986227590; US 4716221 .
【2】 Prous, J.; Castaner, J.; NK-611. Drugs Fut 1991, 16, 2, 113.
【3】 Saito, H.; Nishimura, Y.; Kondo, S.; Umezawa, H.; Syntheses of all four possible diastereomers of etoposide and its aminoglycosidic analogues via optical resolution of (±)-podophyllotoxin by glucosidation with D- and L-sugars. Chem Lett 1987, 5, 5, 799-802.
【4】 Saito, H.; Yoshikawa, H.; Nishimura, Y.; Kondo, S.; Takeuchi, T.; Umezawa, H.; Studies on lignan lactone antitumor agents. II. Synthesis of N-alkylamino- and 2,6-dideoxy-2-aminoglycosidic lignan variants related to podophyllotoxin. Chem Pharm Bull 1986, 34, 9, 3741-46.

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)	14608	(5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one; Podophyllotoxin	518-28-5	C₂₂H₂₂O₈	详情	详情
(II)	13053	(5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one	6559-91-7	C₂₁H₂₀O₈	详情	详情
(III)	31239	4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl 2-chloroacetate		C₂₃H₂₁ClO₉	详情	详情
(IV)	31240	(2R,4aR,7R,8R,8aR)-7-[[(benzyloxy)carbonyl]amino]-6-hydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl 2-chloroacetate		C₁₈H₂₂ClNO₈	详情	详情
(V)	31241	4-[(5R,5aR,8aR,9S)-9-([(2R,4aR,6R,7R,8R,8aR)-7-[[(benzyloxy)carbonyl]amino]-8-[(2-chloroacetyl)oxy]-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl 2		C₄₁H₄₁Cl₂NO₁₆	详情	详情
(VI)	31242	(5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7-amino-8-hydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one		C₂₉H₃₃NO₁₂	详情	详情
(VII)	31243	benzyl (3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-ylcarbamate	16684-31-4	C₁₄H₁₉NO₇	详情	详情
(VIII)	31244	benzyl (2R,4aR,7R,8R,8aS)-6,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate		C₁₆H₂₁NO₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Podophyllotoxin (I), isolated from the roots of Podophyllum emodi Wall var. chinensis sprague by extraction with ethanol and purified through repeated recrystallization from ethanol-benzene, is demethylated and brominated in a single step. (I) is suspended in a cold mixture of ethylene dichloride and ether. Anhydrous hydrogen bromide is passed until the calculated weight increase is reached. After standing at 0-2 C for 20 hours, the solvent is removed under reduced pressure. 4-Bromo-4-deoxy-4'-demethylepipodophyllotoxin (II) is recrystallized from acetone. A solution of (II) and 4-amino-2,2,6,6-tetramethylpiperidin-1-oxyl (III) with a trace of anhydrous pyridine in THF is refluxed under nitrogen atmosphere for 4 hours. The insoluble solid is removed by filtration and the solvent is distilled off under reduced pressure. The crude product is chromatographed twice through silica gel, using methylene chloride-acetone-diethylamine (40:1:1, by volume) as eluent. GP-7 is recrystallized from acetone-hexane.

参考文献中间体

合成目标

【1】 Zhang, C.; Chen, Y.; Tian, X.; Spin-labeled antitumor derivatives of podophyllotoxin. Scientia Sin 1987, 30-B, 1070-9.
【2】 Zhang, P.; Tian, X.; Li, J.; Wang, Y.; Chen, Y.; Jia, Z.; Anticancer drugs II. Synthesis and biological evaluation of spin labeled derivatives of podophyllotoxin. Life Sci 1989, 45, 26, 2569-75.
【3】 Ruyun, J.; GP-7. Drugs Fut 1992, 17, 3, 191.

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)	14608	(5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one; Podophyllotoxin	518-28-5	C₂₂H₂₂O₈	详情	详情
(II)	14609	(5R,5aR,8aR,9S)-9-bromo-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one		C₂₁H₁₉BrO₇	详情	详情
(III)	14610	4-Amino-TEMPO; 4-amino-2,2,6,6-tetramethyltetrahydro-1(2H)-pyridinol	14691-88-4	C₉H₁₉N₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Reaction of propionic acid hydrazide (I) with CS-2 and KOH gave dithiocarbamate (II), which was cyclized to aminotriazole (III) upon treatment with hydrazine. Demethylation of podophyllotoxin (IV) with HBr, followed by treatment with BaCO3 afforded 4'-demethyl epipodophyllotoxin (V). Finally, condensation of (V) with triazole (III) in the presence of trifluoroacetic acid furnished the title compound.

参考文献中间体

合成目标

【1】 Chen, Y.Z.; Lu, K.K.; Synthesis and antitumor activities of 4beta-S-(5''-alkyl-4''-amino-1'',2'',4''-triazole-3''-yl)-4-deoxy-4'-O-demethyl-epipodophyllotoxin derivatives. Acta Pharm Sin 1999, 34, 1, 63.

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)	25213	propanohydrazide		C₃H₈N₂O	详情	详情
(II)	25214	2-propionyl-1-hydrazinecarbodithioate		C₄H₇N₂OS₂	详情	详情
(III)	25215	4-amino-5-ethyl-4H-1,2,4-triazol-3-ylhydrosulfide; 4-amino-5-ethyl-4H-1,2,4-triazole-3-thiol		C₄H₈N₄S	详情	详情
(IV)	14608	(5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one; Podophyllotoxin	518-28-5	C₂₂H₂₂O₈	详情	详情
(V)	13053	(5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one	6559-91-7	C₂₁H₂₀O₈	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

Reaction of butyric acid hydrazide (I) with CS-2 and KOH gave dithiocarbamate (II), which was cyclized to aminotriazole (III) upon treatment with hydrazine. Demethylation of podophyllotoxin (IV) with HBr, followed by treatment with BaCO3 afforded 4'-demethyl epipodophyllotoxin (V). Finally, condensation of (V) with triazole (III) in the presence of trifluoroacetic acid furnished the title compound.

参考文献中间体

合成目标

【1】 Chen, Y.Z.; Lu, K.K.; Synthesis and antitumor activities of 4beta-S-(5''-alkyl-4''-amino-1'',2'',4''-triazole-3''-yl)-4-deoxy-4'-O-demethyl-epipodophyllotoxin derivatives. Acta Pharm Sin 1999, 34, 1, 63.

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)	25210	butanohydrazide	3538-65-6	C₄H₁₀N₂O	详情	详情
(II)	25211	2-butyryl-1-hydrazinecarbodithioate		C₅H₉N₂OS₂	详情	详情
(III)	25212	1-amino-5-propyl-1H-pyrrol-2-ylhydrosulfide		C₇H₁₂N₂S	详情	详情
(IV)	14608	(5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one; Podophyllotoxin	518-28-5	C₂₂H₂₂O₈	详情	详情
(V)	13053	(5R,5aR,8aR,9S)-9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one	6559-91-7	C₂₁H₂₀O₈	详情	详情

Extended Information