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【结 构 式】 
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【分子编号】27698 【品名】methyl 2-(diethoxyphosphoryl)acetate 【CA登记号】1067-74-9 |
【 分 子 式 】C7H15O5P 【 分 子 量 】210.166862 【元素组成】C 40% H 7.19% O 38.06% P 14.74% |
合成路线1
该中间体在本合成路线中的序号：2) The esterification of 2-hydroxy-3-methoxybenzaldehyde (XXIV) with methanesulfonyl chloride and triethylamine gives the corresponding mesylate (XXV), which is nitrated with fuming HNO3 to 2-(methanesulfonyloxy)-3-methoxy-6-nitrobenzaldehyde (XXVI). The condensation of (XXVI) or 2-(benzenesulfonyloxy)-3-methoxy-6-nitrobenzaldehyde (XXVIII) with 2-(diethoxyphosphoryl)acetic acid methyl ester by means of NaH in THF yields 3-(2-hydroxy-3-methoxy-6-nitrophenyl)acrylic acid methyl ester (XXVII), which is benzylated with benzyl bromide and K2CO3 to the benzyl derivative (XXIX). The cyclization of (XXIX) with refluxing triethyl phosphite affords 4-benzyloxy-5-methoxy-1H-indole-2-carboxylic acid methyl ester (XXX), which is reduced to the corresponding carbaldehyde (XXXI) according to Tetrahedron Lett 1994, 50: 7657. The methylation of (XXXI) with NaH and methyl iodide in DMF yields the N-methyl derivative (XXXII), which is condensed with 2-(diethoxyphosphoryl)acetic acid methyl ester by means of NaH in THF to afford 3-(4-benzyloxy-5-methoxy-1-methylindol-2-yl)acrylic acid methyl ester (XXXIII). The formylation of (XXXIII) with POCl3 and DMF gives the 4-formyl derivative (XXXIV), which is debenzylated with trimethylsilyl iodide in acetonitrile to the 4-hydroxy compound (XXXV). The oxidation of (XXXV) with Fremy's salt as before yields 3-(3-formyl-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-2-yl) acrylic acid methyl ester (XXXVI), which is treated successively with Na2S2O4, DIBAL, and finally with FeCl3, as before, to afford the dihydroxy quinone (XXII), already obtained.
| 【1】 Cotterill, A.S.; Moody, C.J.; Roffey, J.R.; An improved synthesis of the indolequinone anticancer agent EO9. Tetrahedron 1995, 51, 26, 7223-30. |
| 【2】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 | |
| (XXII) | 12618 | 3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione | C14H15NO5 | 详情 | 详情 | |
| (XXIII) | 10151 | Ethyleneimine; Aziridine; Azirane | 151-56-4 | C2H5N | 详情 | 详情 |
| (XXIV) | 12620 | o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde | 148-53-8 | C8H8O3 | 详情 | 详情 |
| (XXV) | 12621 | 2-formyl-6-methoxyphenyl methanesulfonate | C9H10O5S | 详情 | 详情 | |
| (XXVI) | 12622 | 2-formyl-6-methoxy-3-nitrophenyl methanesulfonate | C9H9NO7S | 详情 | 详情 | |
| (XXVII) | 12623 | methyl (E)-3-(2-hydroxy-3-methoxy-6-nitrophenyl)-2-propenoate | C11H11NO6 | 详情 | 详情 | |
| (XXVIII) | 12624 | 2-formyl-6-methoxy-3-nitrophenyl benzenesulfonate | C14H11NO7S | 详情 | 详情 | |
| (XXIX) | 12625 | methyl (E)-3-[2-(benzyloxy)-3-methoxy-6-nitrophenyl]-2-propenoate | C18H17NO6 | 详情 | 详情 | |
| (XXX) | 12626 | methyl 4-(benzyloxy)-5-methoxy-1H-indole-2-carboxylate | C18H17NO4 | 详情 | 详情 | |
| (XXXI) | 12627 | 4-(Benzyloxy)-5-methoxy-1H-indole-2-carbaldehyde | C17H15NO3 | 详情 | 详情 | |
| (XXXII) | 12628 | 4-(Benzyloxy)-5-methoxy-1-methyl-1H-indole-2-carbaldehyde | C18H17NO3 | 详情 | 详情 | |
| (XXXIII) | 12629 | ethyl (E)-3-[4-(benzyloxy)-5-methoxy-1-methyl-1H-indol-2-yl]-2-propenoate | C22H23NO4 | 详情 | 详情 | |
| (XXXIV) | 12630 | ethyl (E)-3-[4-(benzyloxy)-3-formyl-5-methoxy-1-methyl-1H-indol-2-yl]-2-propenoate | C23H23NO5 | 详情 | 详情 | |
| (XXXV) | 12631 | ethyl (E)-3-(3-formyl-4-hydroxy-5-methoxy-1-methyl-1H-indol-2-yl)-2-propenoate | C16H17NO5 | 详情 | 详情 | |
| (XXXVI) | 12632 | ethyl (E)-3-(3-formyl-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indol-2-yl)-2-propenoate | C16H15NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LI)The reaction of (XXXVIII) with Li-TMP and LiBr in THF gives the lithium enolate (XLII), which is condensed with the chiral octadienoic aldehyde intermediate (XXV) in THF to yield the aldol adduct (XLIII). The reduction of the phenyl ester group of (XLIII) by means of LiAlH4 in THF affords the diol (XLIV), which is submitted to a regioselective esterification with mesitylenesulfonyl chloride (XLV) to provide the sulfonate (XLVI). The deoxygenation of (XLVI) by means of LiAlH4 gives the desired alcohol (XLVII), which is protected with Tbdms-OTf and TEA to yield the fully protected compound (XLVIII). The selective deprotection of (XLVIII) by means of DDQ in dichloromethane affords the diol (XLIX), which is selectively oxidated at the primary OH group with TEMPO and PhI(OAc)2 to provide the aldehyde (L). The condensation of (L) with phosphonate (LI) by means of K2CO3 and 18-C-6 in toluene furnishes the chiral octadecatetraenoic ester (LII).
| 【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 详情 | 详情 | |
| (XXXVIII) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 | |
| (XLII) | 62849 | C34H51LiO5Si | 详情 | 详情 | ||
| (XLIII) | 42641 | 2,6-dimethylphenyl (2S,3S,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienoate | C52H76O8Si | 详情 | 详情 | |
| (XLIV) | 42642 | (2R,3R,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadiene-1,3-diol | C44H70O7Si | 详情 | 详情 | |
| (XLV) | 41158 | 2,4,6-trimethylbenzenesulfonyl chloride | 773-64-8 | C9H11ClO2S | 详情 | 详情 |
| (XLVI) | 62850 | (2R,3R,4S,5S,6S,7Z)-2-{(Z,4S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl}-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienyl 2,4,6-trimethylbenzenesulfonate | C53H80O9SSi | 详情 | 详情 | |
| (XLVII) | 42643 | (3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-14-[[tert-butyl(dimethyl)silyl]oxy]-6,16-bis[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-ol | C44H70O6Si | 详情 | 详情 | |
| (XLVIII) | 42644 | (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl 4-methoxybenzyl ether | n/a | C50H84O6Si2 | 详情 | 详情 |
| (XLIX) | 42645 | (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol | n/a | C34H68O4Si2 | 详情 | 详情 |
| (L) | 42646 | (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal | n/a | C34H66O4Si2 | 详情 | 详情 |
| (LI) | 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 |
| (LII) | 42647 | methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate | n/a | C37H70O5Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVI)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).
| 【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4
该中间体在本合成路线中的序号：(IX)By deprotection of tripeptide (V) (hydrogenolysis of the benzyl group with H2 over Pd/C) followed by condensation with amino acid ester (XI) by means of diethyl cyanophosphonate (DECP) in DMF. The intermediates (V) and (XI) have been obtained as follows: 1.- The condensation of N-(tert-butoxycarbonyl)-L-valine (I) with L-leucine benzyl ester (II) by means of DCC, NMM and NHS gives the dipeptide (III), which is condensed with L-phenylalanine benzyl ester (IV) by first debenzylation and condensation as before yielding the desired tripeptide (V). 2.- The cyclization of N-(tert-butoxycarbonyl)-L-glutamine (VI) by means of DCC and NHS gives the glutarimide (VII), which is partially reduced with NaBH4 to the cyclic Boc-glutaminal (VIII). The condensation of (VIII) with the phosphonate (IX) by means of NaH in THF affords the unsaturated protected aminoester (X), which is finally deprotected with trifluoroacetic acid in dichloromethane providing the desired amino acid ester (XI).
| 【1】 Shepherd, T.A.; Furness, K.; Venkatraman, S.; Wang, Q.M.; Aubé, J.; Nimkar, S.; Kong, J.; Hanzlik, R.P.; Synthesis and evaluation of peptidyl Michael acceptors that inactivate human rhinovirus 3C protease and inhibit virus replication. J Med Chem 1998, 41, 14, 2579. |
| 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) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (II) | 27691 | benzyl (2S)-2-amino-5-methylhexanoate | C14H21NO2 | 详情 | 详情 | |
| (III) | 27692 | benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-5-methylhexanoate | C24H38N2O5 | 详情 | 详情 | |
| (IV) | 27693 | benzyl (2S)-2-amino-3-phenylpropanoate；L-phenylalanine benzyl ester | C16H17NO2 | 详情 | 详情 | |
| (V) | 27694 | benzyl (6S,9S,12S)-12-benzyl-9-isopentyl-6-isopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate | C33H47N3O6 | 详情 | 详情 | |
| (VI) | 27695 | (2S)-6-amino-2-[(tert-butoxycarbonyl)amino]-6-oxohexanoic acid | C11H20N2O5 | 详情 | 详情 | |
| (VII) | 27696 | tert-butyl (3S)-2,6-dioxopiperidinylcarbamate | C10H16N2O4 | 详情 | 详情 | |
| (VIII) | 27697 | tert-butyl (3S)-2-hydroxy-6-oxopiperidinylcarbamate | C10H18N2O4 | 详情 | 详情 | |
| (IX) | 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 |
| (X) | 27699 | methyl (E,4S)-8-amino-4-[(tert-butoxycarbonyl)amino]-8-oxo-2-octenoate | C14H24N2O5 | 详情 | 详情 | |
| (XI) | 27700 | methyl (E,4S)-4,8-diamino-8-oxo-2-octenoate | C9H16N2O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Horner-Emmons condensation of 1,4-dibenzyl-2-piperazinecarboxaldehyde (I) with phosphonate (II) gave piperazineacrylate (III). Subsequent double bond hydrogenation and hydrogenolysis of the benzyl groups of (III) produced the spontaneous cyclization of the resulting amino ester to furnish the diazabicyclononanone (IV). Finally, condensation of amine (IV) with p-fluorobenzenesulfonyl chloride (V) yielded the title sulfonamide.
| 【1】 Manetti, D.; et al.; Design, synthesis, and preliminary pharmacological evaluation of 1,4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents. J Med Chem 2000, 43, 10, 1969. |
| 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) | 42117 | 1,4-dibenzyl-2-piperazinecarbaldehyde | C19H22N2O | 详情 | 详情 | |
| (II) | 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 |
| (III) | 42118 | methyl (E)-3-(1,4-dibenzyl-2-piperazinyl)-2-propenoate | C22H26N2O2 | 详情 | 详情 | |
| (IV) | 42119 | hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one | C7H12N2O | 详情 | 详情 | |
| (V) | 12292 | 4-Fluorobenzenesulfonyl chloride | 349-88-2 | C6H4ClFO2S | 详情 | 详情 |