2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate -Drug Synthesis Database

【结构式】

【分子编号】18906

【品名】2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate

【CA登记号】

【分子式】C₄₃H₅₆Cl₄N₂O₁₀

【分子量】902.73592

【元素组成】C 57.21% H 6.25% Cl 15.71% N 3.1% O 17.72%

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：(IX)

Title compound can be prepared either by bacterial fermentation or by chemical synthesis. Thus, the compund was isolated from cultures of Nostoc sp. GSV 224, growing in the presence of 2,2-dimethyl-b-alanine. After lyophilization and extraction with CH3CN-CH2Cl2, the extract was subjected to several chromatographic purifications to provide the pure compound. Alternatively, 2,2-dimethyl-b-alanine tert-butyl ester (I) was deprotected with trifluoroacetic acid, and the resulting carboxylic acid (II) was treated with di tert-butyl oxalate (III) in the presence of NaOH to afford carbamate (IV). Subsequent coupling with allyl (S)-2-hydroxy-4-methylpentanoate (V) using DCC and DMAP gave ester (VI). The allyl ester was then cleaved by treatment with Pd(Ph3P)4 and morpholine in THF at r.t., and the resulting acid (VII) was coupled with compound (VIII) in the presence of DCC and DMAP to afford (IX). After deprotection of the trichloroethyl ester group by treatment with Zn in AcOH and subsequent cleavage of the N-Boc group with trifluoroacetic acid, the resulting amino acid compound (XI) was cyclized using pentafluorophenyl diphenyl phosphinate (FDPP) to furnish (XII). Finally, epoxidation with meta-chloroperbenzoic acid provided a mixture of diastereomeric epoxides that were separated by reverse phase HPLC.

参考文献中间体

合成目标

【1】 Shih, C.; Gossett, L.S.; Gruber, J.M.; Grossman, C.S.; Andis, S.L.; Schultz, R.M.; Worzalla, J.F.; Corbett, T.H.; Metz, J.T.; Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region. Bioorg Med Chem Lett 1999, 9, 1, 69.
【2】 Moore, R.E.; Patel, V.F.; Ray, J.E.; Toth, J.E. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0850057; JP 2000501067; WO 9707798; WO 9708334 .
【3】 Shih, C. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0869786; JP 2000502351; WO 9723211 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	18898	tert-butyl 3-amino-2,2-dimethylpropanoate	C₉H₁₉NO₂	详情	详情
(II)	18899	2,2-dimethyl-beta-alanine	C₅H₁₁NO₂	详情	详情
(III)	18900	tert-butyl 2-(tert-butoxy)-2-oxoacetate	C₁₀H₁₈O₄	详情	详情
(IV)	18901	N-(tert-butoxycarbonyl)-2,2-dimethyl-beta-alanine	C₁₀H₁₉NO₄	详情	详情
(V)	18902	allyl (2S)-2-hydroxy-4-methylpentanoate	C₉H₁₆O₃	详情	详情
(VI)	18903	allyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate	C₁₉H₃₃NO₆	详情	详情
(VII)	18904	(2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid	C₁₆H₂₉NO₆	详情	详情
(VIII)	18905	2,2,2-trichloroethyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-[[(2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenyl-2,7-octadienoyl]amino]propanoate	C₂₇H₂₉Cl₄NO₅	详情	详情
(IX)	18906	2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate	C₄₃H₅₆Cl₄N₂O₁₀	详情	详情
(X)	18907	(10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oic acid	C₄₁H₅₅ClN₂O₁₀	详情	详情
(XI)	18908	(2R)-2-[[(2E,5S,6R,7E)-5-([(2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoyl]oxy)-6-methyl-8-phenyl-2,7-octadienoyl]amino]-3-(3-chloro-4-methoxyphenyl)propionic acid	C₃₆H₄₇ClN₂O₈	详情	详情
(XII)	18909	(3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone	C₃₆H₄₅ClN₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXV)

Synthesis of 261501: The optical resolution of trans-3-penten-2-ol (IX) with porcine pancreatic lipase (PPL) and trifluoroethyl laurate in ethyl ether gives the (S)-trans-isomer (X), which is condensed with propargyl alcohol (XI) by means of tetrabutylammonium hyrogensulfate and NaOH in water, yielding the corresponding ether (XII). Rearrangement of (XII) by means of BuLi in THF affords (3R,4R,5E)-4-methylhept-5-en-1-yn-3-ol (XIII), which is silylated with Tbdms-Cl and imidazole to afford the corresponding silyl ether (XIV). The reaction of (XIV) with BH3 in THF provides the aldehyde (XV), which is condensed with phosphonate (XVI) by means of tetramethylguanidine (TMG) in THF to give the nonadienoic ester (XVII). Ozonolysis of (XVII), followed by reaction with Zn/HOAc yields the aldehyde (XVIII), which is condensed with benzyltriphenylphosphonium chloride (XIX) by means of BuLi in THF to afford the 8-phenyloctadienoic ester (XX). The hydrolysis of (XX) with LiOH in acetone/water furnishes the corresponding free acid (XXI), which is condensed with 3-chloro-4-methoxy-L-phenylalanine trichloroethyl ester (XXII) by means of pentafluorodiphenylphosphinate (FDPP) and DIEA in DMF to give the corresponding amide (XXIII). The desilylation of (XXIII) with aqueous HF in acetonitrile affords the hydroxyamide (XXIV), which is esterified with the intermediate 2(S)-[3-(tert-butoxycarbonylamino)-2,2-dimethylpropionyloxy]-4-methylpentanoic acid (VIII) by means of DCC and DMAP in dichloromethane gives the corresponding ester (XXV).

参考文献中间体

合成目标

【1】 WO 9640184 .

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)	18904	(2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid		C₁₆H₂₉NO₆	详情	详情
(IX)	42786	(E)-3-penten-2-ol		C₅H₁₀O	详情	详情
(X)	42787	(2S,3E)-3-penten-2-ol		C₅H₁₀O	详情	详情
(XI)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(XII)	42788	(1S,2E)-1-methyl-2-butenyl 2-propynyl ether; (E,4S)-4-(2-propynyloxy)-2-pentene		C₈H₁₂O	详情	详情
(XIII)	42789	(3R,4R,5E)-4-methyl-5-hepten-1-yn-3-ol		C₈H₁₂O	详情	详情
(XIV)	42790	tert-butyl(dimethyl)silyl (1R,2R,3E)-1-ethynyl-2-methyl-3-pentenyl ether; tert-butyl[[(1R,2R,3E)-1-ethynyl-2-methyl-3-pentenyl]oxy]dimethylsilane		C₁₄H₂₆OSi	详情	详情
(XV)	42791	(3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-heptenal		C₁₄H₂₈O₂Si	详情	详情
(XVI)	27698	methyl 2-(diethoxyphosphoryl)acetate	1067-74-9	C₇H₁₅O₅P	详情	详情
(XVII)	42792	methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2,7-nonadienoate		C₁₇H₃₂O₃Si	详情	详情
(XVIII)	42793	methyl (E,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-oxo-2-heptenoate		C₁₅H₂₈O₄Si	详情	详情
(XIX)	42794	Benzyl(triphenyl)phosphonium chloride	1449-46-3	C₂₅H₂₂ClP	详情	详情
(XX)	34373	methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate		C₂₂H₃₄O₃Si	详情	详情
(XXI)	34374	(2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid		C₂₁H₃₂O₃Si	详情	详情
(XXII)	42795	2,2,2-trichloroethyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate		C₁₂H₁₃Cl₄NO₃	详情	详情
(XXIII)	42796	2,2,2-trichloroethyl (2R)-2-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)amino]-3-(3-chloro-4-methoxyphenyl)propanoate		C₃₃H₄₃Cl₄NO₅Si	详情	详情
(XXIV)	18905	2,2,2-trichloroethyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-[[(2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenyl-2,7-octadienoyl]amino]propanoate		C₂₇H₂₉Cl₄NO₅	详情	详情
(XXV)	18906	2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate		C₄₃H₅₆Cl₄N₂O₁₀	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXV)

Elimination of the trichloroethyl group of (XXV) with Zn in acetic acid gives the carboxyl free intermediate (XXVI), which is treated with TFA to yield intermediate (XXVII) with free amino and carboxy groups. The cyclization of (XXVII) with pentafluorodiphenylphosphinate (FDPP) and DIEA in DMF affords the corresponding cyclic amide (XXVIII), which is finally epoxidated with MCPBA in dichloromethane, furnishing a diastereomeric mixture of epoxides that are separated by reverse phase chromatography.

参考文献中间体

合成目标

【1】 WO 9640184 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXV)	18906	2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate	C₄₃H₅₆Cl₄N₂O₁₀	详情	详情
(XXVI)	18907	(10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oic acid	C₄₁H₅₅ClN₂O₁₀	详情	详情
(XXVII)	18908	(2R)-2-[[(2E,5S,6R,7E)-5-([(2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoyl]oxy)-6-methyl-8-phenyl-2,7-octadienoyl]amino]-3-(3-chloro-4-methoxyphenyl)propionic acid	C₃₆H₄₇ClN₂O₈	详情	详情
(XXVIII)	18909	(3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone	C₃₆H₄₅ClN₂O₇	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

The previously reported open-chain styrene intermediate (I) is submitted to a Sharpless asymmetric epoxidation to give, after chromatographic purification, the diol (II), which is cyclized by means of TFA and 2-hydroxypyridine yielding the macrocycle (III). The reaction of (III) with trimethyl orthoformate and pyridinium p-toluenesulfonate (PPTS) in dichloromethane affords the cyclic orthoester (IV), which is treated with trimethylsilyl iodide to provide the iodo formate (V). Finally, this compound is converted into the target macrocyclic epoxide by treatment with K2CO3 in methanol/THF. Alternatively, the intermediate cyclic orthoester (IV) can be treated with acetyl bromide to give the bromo formate (VI), which is converted into the target epoxide by reaction with K2CO3 as before.

参考文献中间体

合成目标

【1】 WO 9640184 .
【2】 Liang, J.; et al.; Synthesis of cryptophycin 52 using the Sharpless asymetric dihydroxylation: Diol to epoxide transformation optimized for a base-sensitive substrate. J Org Chem 2000, 65, 10, 3143.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	18906	2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate	C₄₃H₅₆Cl₄N₂O₁₀	详情	详情
(II)	42797	2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-13-[(1R,2R,3R)-2,3-dihydroxy-1-methyl-3-phenylpropyl]-10-isobutyl-2,2,7,7-tetramethyl-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate	C₄₃H₅₈Cl₄N₂O₁₂	详情	详情
(III)	42798	(3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-16-[(1R,2R,3R)-2,3-dihydroxy-1-methyl-3-phenylpropyl]-3-isobutyl-6,6-dimethyl-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone	C₃₆H₄₇ClN₂O₉	详情	详情
(IV)	42799	(3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-16-[(1R)-1-[(4R,5R)-2-methoxy-5-phenyl-1,3-dioxolan-4-yl]ethyl]-6,6-dimethyl-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone	C₃₈H₄₉ClN₂O₁₀	详情	详情
(V)	42800	(1R,2R)-2-[(3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diaza-13-cyclohexadecen-16-yl]-1-[(S)-iodo(phenyl)methyl]propyl formate	C₃₇H₄₆ClIN₂O₉	详情	详情
(VI)	42801	(1R,2R)-1-[(S)-bromo(phenyl)methyl]-2-[(3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diaza-13-cyclohexadecen-16-yl]propyl formate	C₃₇H₄₆BrClN₂O₉	详情	详情

Extended Information