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【结 构 式】 
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【分子编号】13272 【品名】Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate 【CA登记号】5927-18-4 |
【 分 子 式 】C5H11O5P 【 分 子 量 】182.113102 【元素组成】C 32.98% H 6.09% O 43.93% P 17.01% |
合成路线1
该中间体在本合成路线中的序号：(II)The Horner-Wadsworth-Emmons condensation of (E,E)-muconaldehyde (I) with triethyl phosphonoacetate (II) by means of Ba(OH)2 in THF/water gives (E,E,E,E)-decatetraenedioic acid diethyl ester (III), which is hydrolyzed with LiOH to provide the target intermediate; the (E,E,E,E)-decatetraenedioic acid (IV).
| 【1】 Vosburg, D.A.; et al.; Concise stereocontrolled routes to fumagillol, fumagillin, and TNP-470. Chirality 2003, 15, 2, 156. |
| 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) | 61443 | E,E-2,4-Hexadienedial; E,Z-2,4-Hexadienedial; transtrans-Muconaldehyde | C6H6O2 | 详情 | 详情 | |
| (II) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (III) | 61444 | diethyl (2E,4E,6E,8E)-2,4,6,8-decatetraenedioate | C14H18O4 | 详情 | 详情 | |
| (IV) | 61445 | (2E,4E,6E,8E)-2,4,6,8-decatetraenedioic acid | C10H10O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carboxaldehyde (I) with trimethylphosphonoacetic acid methyl ester (II) by means of NaH in hot toluene gives 3(E)-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid methyl ester (III), which is hydrolyzed with NaOH in methanol - water yielding the corresponding free acid (IV). The reaction of (IV) with SOCl2 in DMF affords the acyl chloride (V), which is finally condensed with 2(R)-(2-hydroxyethyl)piperidine (VI) by means of bis(trimethylsilyl)acetamide and triethylamine in dichloromethane.
| 【1】 Shiokawa, Y.; Akahane, A.; Katayama, H.; Mitsunaga, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpds. and their production method. JP 91141222 . |
| 【2】 Shiokawa, Y.; Akahane, A.; Katayama, H.; Mitsunaga, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpds. and processes for preparation thereof. AU 8817602; EP 0299209; JP 1989045385; US 4925849; US 4994453; US 5087629; US 5102878; US 5179103; US 5296490 . |
| 【3】 Castaner, J.; Prous, J.; FK-453. Drugs Fut 1992, 17, 11, 991. |
| 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) | 13271 | 2-Phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde | C14H10N2O | 详情 | 详情 | |
| (II) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (III) | 13273 | methyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C17H14N2O2 | 详情 | 详情 | |
| (IV) | 13274 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid | C16H12N2O2 | 详情 | 详情 | |
| (V) | 13275 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride | C16H11ClN2O | 详情 | 详情 | |
| (VI) | 13276 | 2-[(2R)Piperidinyl]-1-ethanol | C7H15NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)The synthesis of [1S-(1alpha,2alpha,3alpha,4alpha)]-2-[2-[2-(methoxycarbonyl)ethyl]benzyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid (VI), a key intermediate in the synthesis of 203961 [see scheme 20396101a] has been presented: This compound has been obtained by two similar ways: 1) The condensation of L-valinol (XII) with anhydride (XXII) catalyzed by oxalic acid gives imide (XIII), which is treated with ethylmagnesium chloride, the Grignard reagent (XIV) and NaBH4 yielding intermediate (XV). This intermediate, without isolation, is treated with HCl in THF to afford the substituted benzaldehyde (XVI), which is condensed with trimethyl phosphonoacetate (XVII) and DBU in acetonitrile giving the propenoic ester (XVIII). Finally, this compound is submitted to a simultaneous reduction and hydrogenolysis with H2 over a Pearlman catalyst in methanol to provide the target of [1S-(1alpha,2alpha,3alpha,4alpha)]-2-[2-[2-(methoxycarbonyl)ethyl]benzyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid (VI). 2) The preceding reaction sequence can also be performed using (S)-2-phenylglycinol (XIX) instead of the L-valinol (XII) yielding the previously reported benzaldehyde (XVI) through the imide (XX) and the nonisolated intermediate (XXI).
| 【1】 Mueller, R.H.; et al.; Diastereoselective reaction of a grignard reagent with chiral imides: A practical preparation of a key intermediate in the synthesis of ifetroban sodium. Org Process Res Dev 1997, 1, 1, 14. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 14870 | (1R,2S,3R,4S)-3-[2-(3-methoxy-3-oxopropyl)benzyl]-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid | C18H22O5 | 详情 | 详情 | |
| (XII) | 36480 | (2S)-2-amino-3-methyl-1-butanol; (S)-(+)-Valinol; L-Valinol | 2026-48-4 | C5H13NO | 详情 | 详情 |
| (XIII) | 36473 | (1R,2R,6S,7S)-4-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-10-oxa-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C13H19NO4 | 详情 | 详情 | |
| (XIV) | 36475 | bromo[2-(1,3-dioxolan-2-yl)phenyl]magnesium | C9H9BrMgO2 | 详情 | 详情 | |
| (XV) | 36476 | (1S,2S,5R,6R,7R)-4-[(1S)-1,2-dimethylpropyl]-5-[2-(1,3-dioxolan-2-yl)phenyl]-5-hydroxy-10-oxa-4-azatricyclo[5.2.1.0(2,6)]decan-3-one | C22H29NO5 | 详情 | 详情 | |
| (XVI) | 36478 | 2-[(1R,2R,3S,6S,7S)-5-oxo-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-3-yl]benzaldehyde | C15H14O4 | 详情 | 详情 | |
| (XVII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (XVIII) | 36479 | methyl (E)-3-[2-[(1R,2R,3S,6S,7S)-5-oxo-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-3-yl]phenyl]-2-propenoate | C18H18O5 | 详情 | 详情 | |
| (XIX) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (XX) | 36474 | (1R,2R,6S,7S)-4-[(1R)-2-hydroxy-1-phenylethyl]-10-oxa-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C16H17NO4 | 详情 | 详情 | |
| (XXI) | 36477 | (1S,2S,5R,6R,7R)-5-[2-(1,3-dioxolan-2-yl)phenyl]-5-hydroxy-4-[(1S)-1-phenylethyl]-10-oxa-4-azatricyclo[5.2.1.0(2,6)]decan-3-one | C25H27NO5 | 详情 | 详情 | |
| (XXII) | 36472 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The intermediate epoxyamide (XVIII) has been obtained as follows: The cyclization of 2-methylacetoacetic acid ethyl ester (I) by means of potassium tert-butoxide gives 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (I), which is enantiomerically reduced with Mortierella isabellina ATCC 42613 yielding (S,S)-4-hydroxy-3-methyltetrahydropyran-2-one (III). The silylation of (III) by means of TBDMS-Cl, imidazole and DMAP affords the silyl ether (IV), which is reduced with DIBAL to the corresponding lactol and condensed with benzyldiphenylphosphine oxide (V) to give (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenyl-5-hexen-1-ol (VI). The oxidation of (VI) with oxalyl chloride in dichloromethane/DMSO yields the corresponding aldehyde (VII), which is submitted to a Wittig condensation with trimethyl phosphonoacetate (VIII) by means of 1,1,3,3-tetramethylguanidine (TMG) to afford the octadienoic ester (IX). The hydrolysis of (IX) with KOH in dioxane gives the corresponding acid (X), which is esterified with N-hydroxysuccinimide (XI) and EDC to give the activated ester (XII). The epoxidation of (XII) with oxone or MCPBA, followed by HPLC chromatography separation of the resulting mixture of epoxides, gives the (2E,5S,6S,7R,8R)-5-(tert-butyldimethylsilyloxy)-7,8-epoxy-6-methyl-8-phenyl-2-octenoic acid N-succinimidinyl ester (XIII). The condensa-tion of activated ester (XIII) with amino acid (XIV) yields the corresponding amide (XV), which is desilylated with TBAF in DMF to afford the hydroxyacid (XVI). Finally, compound (XVI) is treated with DMSO and NaHCO3 and tert-butyl bromide to provide the desired intermediate the epoxyamide.
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 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) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (II) | 36494 | 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one | C6H8O3 | 详情 | 详情 | |
| (III) | 36495 | (3S,4S)-4-hydroxy-3-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (IV) | 36496 | (3S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyltetrahydro-2H-pyran-2-one | C12H24O3Si | 详情 | 详情 | |
| (V) | 36497 | benzyl(diphenyl)phosphine oxide; benzyl(oxo)diphenylphosphorane | 2959-74-2 | C19H17OP | 详情 | 详情 |
| (VI) | 36498 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexen-1-ol | C19H32O2Si | 详情 | 详情 | |
| (VII) | 36499 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexenal | C19H30O2Si | 详情 | 详情 | |
| (VIII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (X) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XII) | 36500 | 1-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)oxy]-2,5-pyrrolidinedione | C25H35NO5Si | 详情 | 详情 | |
| (XIII) | 36501 | 1-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]oxy)-2,5-pyrrolidinedione | C25H35NO6Si | 详情 | 详情 | |
| (XIV) | 36502 | (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid | C10H12ClNO3 | 详情 | 详情 | |
| (XV) | 36503 | (2R)-2-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C31H42ClNO6Si | 详情 | 详情 | |
| (XVI) | 36504 | N,N,N-tributyl-1-butanaminium (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C41H63ClN2O6 | 详情 | 详情 | |
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)The intermediate epoxyamide (XVII) has been obtained as follows: The cyclization of 2-methylacetoacetic acid ethyl ester (I) by means of potassium tert-butoxide gives 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (I), which is enantiomerically reduced with Mortierella isabellina ATCC 42613 yielding (S,S)-4-hydroxy-3-methyltetrahydropyran-2-one (III). The silylation of (III) by means of TBDMS-Cl, imidazole and DMAP affords the silyl ether (IV), which is reduced with DIBAL to the corresponding lactol and condensed with benzyldiphenylphosphine oxide (V) to give (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenyl-5-hexen-1-ol (VI). The oxidation of (VI) with oxalyl chloride in dichloromethane/DMSO yields the corresponding aldehyde (VII), which is submitted to a Wittig condensation with trimethyl phosphonoacetate (VIII) by means of 1,1,3,3-tetramethylguanidine (TMG) to afford the octadienoic ester (IX). The hydrolysis of (IX) with KOH in dioxane gives the corresponding acid (X), which is esterified with N-hydroxysuccinimide (XI) and EDC to give the activated ester (XII). The epoxidation of (XII) with oxone or MCPBA, followed by HPLC chromatography separation of the resulting mixture of epoxides, gives the (2E,5S,6S,7R,8R)-5-(tert-butyldimethylsilyloxy)-7,8-epoxy-6-methyl-8-phenyl-2-octenoic acid N-succinimidinyl ester (XIII). The condensation of activated ester (XIII) with amino acid (XIV) yields the corresponding amide (XV), which is desilylated with TBAF in DMF to afford the hydroxyacid (XVI). Finally, compound (XVI) is treated with DMSO and NaHCO3 and tert-butyl bromide to provide the desired intermediate the epoxyamide (XVII).
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 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) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (II) | 36494 | 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one | C6H8O3 | 详情 | 详情 | |
| (III) | 36495 | (3S,4S)-4-hydroxy-3-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (IV) | 36496 | (3S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyltetrahydro-2H-pyran-2-one | C12H24O3Si | 详情 | 详情 | |
| (V) | 36497 | benzyl(diphenyl)phosphine oxide; benzyl(oxo)diphenylphosphorane | 2959-74-2 | C19H17OP | 详情 | 详情 |
| (VI) | 36498 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexen-1-ol | C19H32O2Si | 详情 | 详情 | |
| (VII) | 36499 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexenal | C19H30O2Si | 详情 | 详情 | |
| (VIII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (X) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XII) | 36500 | 1-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)oxy]-2,5-pyrrolidinedione | C25H35NO5Si | 详情 | 详情 | |
| (XIII) | 36501 | 1-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]oxy)-2,5-pyrrolidinedione | C25H35NO6Si | 详情 | 详情 | |
| (XIV) | 36502 | (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid | C10H12ClNO3 | 详情 | 详情 | |
| (XV) | 36503 | (2R)-2-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C31H42ClNO6Si | 详情 | 详情 | |
| (XVI) | 36504 | N,N,N-tributyl-1-butanaminium (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C41H63ClN2O6 | 详情 | 详情 | |
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(X)The reaction of benzaldehyde (I) with the sulfoxide (II) by means of benzyltrimethylammonium hydroxide in methanol gives the styrene derivative (III), which is hydrolyzed with HCl in methanol to the phenylacetate (IV). The condensation of (IV) with dimethyl oxalate by means of NaH in THF yields the succinate (V), which by reaction with formaldehyde and K2CO3 is converted into the acrylate (VI). The condensation of (VI) with ethyl 3-(methylamino)propionate gives intermediate (VII), which is cyclized by means of NaH in refluxing toluene yielding the piperidinone (IX). The condensation of (IX) with trimethyl phosphonoacetate (X) by means of NaH in THF affords the expected piperidinyleneacetate (XI), which is reduced with H2 over Pd/C in methanol giving the piperidinylacetate (XII). The cyclization of (XII) by means of polyphosphoric acid (PPA) in refluxing toluene yields the benzoisoquinoline (XIII), which is finally selectively demethylated with BBr3 in methylene chloride to the target compound.
| 【1】 Stadler, H.; Bos, M.; Wichmann, J. (F. Hoffmann-La Roche AG); Tricyclic benzo[e]isoindoles and benzo[h]isoquinolines . EP 0958285; JP 2000507965; WO 9830546 . |
| 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) | 20754 | 4-ethyl-3,5-dimethoxybenzaldehyde | C11H14O3 | 详情 | 详情 | |
| (II) | 20766 | methyl (methylsulfanyl)methyl sulfoxide; methyl[(methylsulfanyl)methyl]oxo-lambda(4)-sulfane | 33577-16-1 | C3H8OS2 | 详情 | 详情 |
| (III) | 20767 | methyl (Z)-2-(4-ethyl-3,5-dimethoxyphenyl)-1-(methylsulfanyl)-1-ethenesulfenate | C14H20O3S2 | 详情 | 详情 | |
| (IV) | 20768 | methyl 2-(4-ethyl-3,5-dimethoxyphenyl)acetate | C13H18O4 | 详情 | 详情 | |
| (V) | 20769 | dimethyl 2-(4-ethyl-3,5-dimethoxyphenyl)-3-oxosuccinate | C16H20O7 | 详情 | 详情 | |
| (VI) | 20770 | methyl 2-(4-ethyl-3,5-dimethoxyphenyl)acrylate | C14H18O4 | 详情 | 详情 | |
| (VII) | 20771 | ethyl 3-(methylamino)propanoate | C6H13NO2 | 详情 | 详情 | |
| (VIII) | 20772 | methyl 3-[(3-ethoxy-3-oxopropyl)(methyl)amino]-2-(4-ethyl-3,5-dimethoxyphenyl)propanoate | C20H31NO6 | 详情 | 详情 | |
| (IX) | 20773 | 3-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-4-piperidinone | C16H23NO3 | 详情 | 详情 | |
| (X) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (XI) | 20775 | methyl 2-[3-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-4-piperidinylidene]acetate | C19H27NO4 | 详情 | 详情 | |
| (XII) | 20776 | methyl 2-[3-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-4-piperidinyl]acetate | C19H29NO4 | 详情 | 详情 | |
| (XIII) | 20777 | (4aR,10bS)-8-ethyl-7,9-dimethoxy-2-methyl-1,3,4,4a,5,10b-hexahydrobenzo[h]isoquinolin-6(2H)-one | C18H25NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)Indanone derivative (II) was obtained as the major product from the ozonolysis of vitamin D3 (I). Horner-Emmons condensation of ketone (II) with trimethyl phosphonoacetate (III) provided the unsaturated ester (IV). This was finally hydrolyzed to the corresponding carboxylic acid by treatment with LiOH.
| 【1】 Yamada, Y.; Takahashi, M.; Sugimoto, Y.; Dodo, K.; Hashimoto, Y.; Shirai, R.; Synthesis of a novel class of cdc25A inhibitors from vitamin D3. Bioorg Med Chem Lett 2000, 10, 7, 615. |
| 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) | 46339 | (1S)-3-((Z)-2-[(1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene]ethylidene)-4-methylenecyclohexanol | C27H44O | 详情 | 详情 | |
| (II) | 46340 | (1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-one | C18H32O | 详情 | 详情 | |
| (III) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IV) | 46341 | methyl 2-[(1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-ylidene]acetate | C21H36O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The synthesis of the intermediate (S,S)-3-(Fmoc-amino)-2-methyl-5-phenyl-4-pentenoic acid (XI) has been performed as follows: The Horner-Wadsworth-Emmons condensation of cinnamaldehyde (I) with phosphonate (II) by means of NaH in THF gives (E,E)-5-phenyl-2,4-pentadienoic acid ethyl ester (III), which is condensed with (S)-N-benzyl-N-(alpha-methylbenzyl)amine (IV) by means of BuLi in THF to yield the chiral adduct (V). The reaction of (V) with LDA affords the corresponding lithium enolate, which is methylated with methyl iodide in THF to afford the enantioselectively methylated compound (VI). The hydrogenation of (VI) with H2 over Pd(OH)2 in methanol/water/HOAc provides (S,S)-3-amino-2-methyl-5-phenylpentanoic acid methyl ester (VII), which is treated with Boc2O and NaHCO3 in dioxane/water to give the N-protected ester (VIII). The reaction of (VIII) with NBS in CCl4, followed by treatment with DBU at 60 C, yields the pentenoic ester derivative (IX), which is treated first with LiOH and then with TFA to provide (S,S)-3-amino-2-methyl-5-phenyl-4-pentanoic acid (X). Finally, this compound is N-protected by reaction with Fmoc-Cl and K2CO3 in dioxane/water to furnish the target pentenoic acid intermediate (XI).
| 【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696. |
| 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) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
| (II) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (III) | 52431 | methyl 5-phenyl-2,4-pentadienoate | C12H12O2 | 详情 | 详情 | |
| (IV) | 38470 | (1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine | 38235-77-7 | C15H17N | 详情 | 详情 |
| (V) | 52432 | methyl 5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate | C27H29NO2 | 详情 | 详情 | |
| (VI) | 52433 | methyl 2-methyl-5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate | C28H31NO2 | 详情 | 详情 | |
| (VII) | 52434 | methyl 3-amino-2-methyl-5-phenylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 52435 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenylpentanoate | C18H27NO4 | 详情 | 详情 | |
| (IX) | 52436 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoate | C18H25NO4 | 详情 | 详情 | |
| (X) | 52437 | 3-amino-2-methyl-5-phenyl-4-pentenoic acid | C12H15NO2 | 详情 | 详情 | |
| (XI) | 52438 | 3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid | C27H25NO4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VII)The cyclization of 5,6-diamino-1,3-dipropylpyrimidine-2,4(1H,3H)-dione (I) with bicyclo[2,2,2]octane-1,4-dicarboxylic acid monoethyl ester (II) by means of HATU and TEA in acetonitrile gives the dipropylxanthine derivative (III), which is esterified with MeOH and sulfuric acid, yielding the methyl ester (IV). The reduction of the ester group of (IV) by means of LiBH4 in refluxing THF affords the hydroxymethyl derivative (V), which is oxidized with DMP in dichloromethane to provide the carbaldehyde (VI). The condensation of aldehyde (VI) with phosphonate (VII) by means of KHMDS in toluene leads to the acrylic acid methyl ester (VIII), which is hydrolyzed with LiOH in methanol/water to give the free acid (IX). Finally the double bond of the acrylic moiety is hydrogenated with H2 over Pd/C in methanol to yield the target xanthine derivative.
| 【1】 Ensinger, C.L.; Kumaravel, G.; Petter, R.C.; Dowling, J.E.; Kiesman, W.F.; Chang, H.X.; Lin, K.C. (Biogen, Inc.); Polycycloalkylpurines as adenosine receptor antagonists. EP 1230243; JP 2003513982; WO 0134610 . |
| 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) | 14628 | 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione | C10H18N4O2 | 详情 | 详情 | |
| (II) | 60200 | 4-[(propyloxy)carbonyl]bicyclo[2.2.2]octane-1-carboxylic acid | C13H20O4 | 详情 | 详情 | |
| (III) | 60201 | 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]octane-1-carboxylic acid | C20H28N4O4 | 详情 | 详情 | |
| (IV) | 60202 | methyl 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]octane-1-carboxylate | C21H30N4O4 | 详情 | 详情 | |
| (V) | 60203 | 8-[4-(hydroxymethyl)bicyclo[2.2.2]oct-1-yl]-1,3-dipropyl-3,9-dihydro-1H-purine-2,6-dione | C20H30N4O3 | 详情 | 详情 | |
| (VI) | 60204 | 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]octane-1-carbaldehyde | C20H28N4O3 | 详情 | 详情 | |
| (VII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (VIII) | 60205 | methyl 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]oct-1-yl]-2-propenoate | C23H32N4O4 | 详情 | 详情 | |
| (IX) | 60206 | 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)bicyclo[2.2.2]oct-1-yl]-2-propenoic acid | C22H30N4O4 | 详情 | 详情 |