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【结 构 式】 
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【分子编号】48591 【品名】Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester 【CA登记号】924-44-7 |
【 分 子 式 】C4H6O3 【 分 子 量 】102.08984 【元素组成】C 47.06% H 5.92% O 47.02% |
合成路线1
该中间体在本合成路线中的序号：(I)The intermediate (S)-3-(2-mesyloxyethoxy)-4-(triphenylmethoxy)-1-butanol mesylate (VIII) has been obtained as follows: The hetero Diels Alder cyclization of ethyl glyoxylate (I) with butadiene (II) in toluene at 160-70 C gives racemic 3,6-dihydro-2H pyran-2-carboxylic acid ethyl ester (III), which is submitted to enzymatic resolution by means of B.lentus protease, yielding a mixture of the hydrolyzed (R)-acid and unchanged (S)-ester (IV), that is easily separated. The reduction of the (S)-ester (IV) by means of LiAlH4 in THF affords the hydroxymethyl derivative (V), which is treated with Tr-Cl and DMAP in pyridine to provide the trityl ether (VI). Ozonolysis of the dihydropyran ring of (VI) by means of ozone and NaBH4 in dichloromethane/methanol gives (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (VII). Finally this compound is treated with Ms-Cl and TEA in dichloromethane to yield the target intermediate (S)-3-(2-mesyloxyethoxy)-4-(triphenylmethoxy)-1-butanol mesylate (VIII). (see scheme no. 25239601a, intermediate no. (X).
| 【1】 Caille, J.C.; Hetero diels-alder-biocatalysis approach for the synthesis of (S)-3-[2-{(methylsulfonyl)oxy}ethoxy]-4- (triphenylmethoxy)-1-butanol sulfonate, a key intermediate for the synthesis of the PKC inhibitor LY333531. Org Process Res Dev 2002, 6, 4, 471. |
| 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) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
| (II) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (III) | 56904 | ethyl 3,6-dihydro-2H-pyran-2-carboxylate | C8H12O3 | 详情 | 详情 | |
| (IV) | 56905 | ethyl (2S)-3,6-dihydro-2H-pyran-2-carboxylate | C8H12O3 | 详情 | 详情 | |
| (V) | 56906 | (2S)-3,6-dihydro-2H-pyran-2-ylmethanol | C6H10O2 | 详情 | 详情 | |
| (VI) | 56907 | (2S)-2-[(trityloxy)methyl]-3,6-dihydro-2H-pyran; (2S)-3,6-dihydro-2H-pyran-2-ylmethyl trityl ether | C25H24O2 | 详情 | 详情 | |
| (VII) | 41010 | (3S)-3-(2-hydroxyethoxy)-4-(trityloxy)-1-butanol | C25H28O4 | 详情 | 详情 | |
| (VIII) | 41011 | (3S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(trityloxy)butyl methanesulfonate | C27H32O8S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Protection of 4-piperidone (I) with trityl chloride and TEA gives 1-tritylpiperidin-4-one (II), which is condensed with ethyl 2-oxoacetate (III) by means of pyrrolidine in refluxing benzene to yield 3-(ethoxycarbonylmethylene)-1-tritylpiperidin-4-one (IV). The deprotection and simultaneous reduction of compound (IV) with NaBH4 in methanol affords the 4-hydroxypiperidine derivative (V), which is condensed with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone (VI) by means of K2CO3 in DMF to provide the adduct (VII). Reaction of the OH group of (VII) with CBr4 and PPh3 in dichloromethane gives the 4-bromopiperidine derivative (VIII), which by reaction with potassium thioacetate (IX) in ethanol provides the 4-(acetylthio)piperidine derivative (X). Selective hydrolysis of compound (X) with HCl in ethanol yields the 4-sulfanylpiperidine derivative (XI), which is finally submitted to a new hydrolysis with HCl in acetic acid.
| 【1】 Castaner, J.; Mealy, N.E.; Doggrell, S.A.; CS-747 and R-99224. Drugs Fut 2001, 21, 9, 835. |
| 【2】 Asai, F.; Sugidachi, A.; Ikeda, T.; Koike, H.; Inoue, T.; Takata, K.; Iwamura, R.; Kita, J.; Yoneda, K. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Cyclic amine derivs.. EP 0934928; JP 1998120649; US 6087379; WO 9808811 . |
| 【3】 Shibakawa, N.; Iwabuchi, H.; Sugidachi, A.; Ikeda, T.; Iwamura, R.; Kuroki, Y.; Inoue, T.; Asai, F. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Cyclic amino cpds.. EP 1063230; WO 9943648 . |
| 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) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (II) | 48590 | 1-trityl-4-piperidinone | C24H23NO | 详情 | 详情 | |
| (III) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
| (IV) | 48592 | ethyl 2-(4-oxo-1-trityl-3-piperidinylidene)acetate | C28H27NO3 | 详情 | 详情 | |
| (V) | 48593 | ethyl 2-(4-hydroxy-3-piperidinylidene)acetate | C9H15NO3 | 详情 | 详情 | |
| (VI) | 48584 | 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone | 204205-33-4 | C11H10BrFO | 详情 | 详情 |
| (VII) | 48594 | ethyl 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-hydroxy-3-piperidinylidene]acetate | C20H24FNO4 | 详情 | 详情 | |
| (VIII) | 48595 | ethyl 2-[4-bromo-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-piperidinylidene]acetate | C20H23BrFNO3 | 详情 | 详情 | |
| (IX) | 17190 | potassium ethanethioate | 10387-40-3 | C2H3KOS | 详情 | 详情 |
| (X) | 48596 | ethyl 2-[4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-piperidinylidene]acetate | C22H26FNO4S | 详情 | 详情 | |
| (XI) | 48597 | ethyl 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanyl-3-piperidinylidene]acetate | C20H24FNO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Condensation between (S)-alpha-methylbenzylamine (I) and ethyl glyoxylate (II) afforded imine (III), which was subjected to hetero-Diels-Alder cycloaddition with 2-(trimethylsilyloxy)-1,3-butadiene (IV) producing piperidinecarboxylate (V) as the major diastereoisomer. Ketalization of (V) with triethyl orthoformate gave the corresponding the diethyl acetal (VI). The ester group of (VI) was then reduced to alcohol (VII) employing LiAlH4. Mitsunobu condensation of alcohol (VII) with phthalimide (VIII) gave (IX) which, followed by acidic ketal hydrolysis, furnished (X). Condensation of piperidinone (X) with t-butyl cyanoacetate (XI) in the presence of sulfur and morpholine gave rise to two regioisomeric thienopyridine derivatives (XII) and (XIII), which were separated by column chromatography.
| 【1】 Lau, J.; Andersen, H.S.; Newman, M.J.; Hansen, T.K.; Olsen, O.H.; Bakir, F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H.; Shapira, B.Z. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). WO 0204459 . |
| 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) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (II) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
| (III) | 58785 | ethyl 2-{[(1S)-1-phenylethyl]imino}acetate | C12H15NO2 | 详情 | 详情 | |
| (IV) | 18557 | 1-methylene-2-propenyl trimethylsilyl ether; trimethyl[(1-methylene-2-propenyl)oxy]silane | 38053-91-7 | C7H14OSi | 详情 | 详情 |
| (V) | 58786 | ethyl (2R)-4-oxo-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (VI) | 58787 | ethyl (2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate | C20H31NO4 | 详情 | 详情 | |
| (VII) | 58788 | {(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methanol | C18H29NO3 | 详情 | 详情 | |
| (VIII) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (IX) | 58789 | 2-({(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione | C26H32N2O4 | 详情 | 详情 | |
| (X) | 58790 | 2-({(2R)-4-oxo-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione | C22H22N2O3 | 详情 | 详情 | |
| (XI) | 14330 | tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate | 1116-98-9 | C7H11NO2 | 详情 | 详情 |
| (XII) | 58791 | tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C29H31N3O4S | 详情 | 详情 | |
| (XIII) | 58792 | tert-butyl (5R)-2-amino-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C29H31N3O4S | 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 cyclization of 2-oxoacetic acid ethyl ester (I), 1-phenylethylamine (II) and cyclopentadiene (III) by means of BF3 and TFA in dichloromethane gives the 2-azabicyclo[2.2.1]heptene (IV), which is debenzylated with H2 over Pd/C in ethanol to yield 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylic acid ethyl ester (V) The acylation of (V) with 5-chloro-2-nitrobenzoyl chloride (VI) and TEA in dichloromethane affords the bicyclic amide (VII), which is submitted to a reductive cyclization with Fe in refluxing acetic acid to afford the polycyclic benzodiazepinedione (VIII). The reduction of the carbonyl groups of (VIII) by means of LiAlH4 in THF provides the benzodiazepine (IX), which is acylated with 4-nitrobenzoyl chloride (X) and TEA in dichloromethane to give the polycyclic amide (XI). The reduction of the nitro group of (XI) with Zn and NH4Cl in refluxing methanol yields the corresponding amino derivative (XII), which is finally acylated with 4'-methylbiphenyl-2-carbonyl chloride (XIII) and TEA in dichloromethane to furnish the target polycyclic benzodiazepine.
| 【1】 Dyatkin, A.B.; Demarest, K.; Look, R.; Maryanoff, B.E.; Hoekstra, W.J.; Gunnet, J.; Andrade-Gordon, P.; DeGaravilla, L.; Hlasta, D.J.; Structurally novel V2-selective and dual V1A/V2 vasopressin receptor antagonists. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 35. |
| 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) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
| (II) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (III) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (IV) | 54051 | ethyl 2-(1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate | n/a | C17H21NO2 | 详情 | 详情 |
| (V) | 54052 | ethyl 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate | n/a | C9H13NO2 | 详情 | 详情 |
| (VI) | 44133 | 5-chloro-2-nitrobenzoyl chloride | C7H3Cl2NO3 | 详情 | 详情 | |
| (VII) | 54053 | ethyl 2-(5-chloro-2-nitrobenzoyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate | n/a | C16H15ClN2O5 | 详情 | 详情 |
| (VIII) | 54054 | 6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraene-3,11-dione | n/a | C14H11ClN2O2 | 详情 | 详情 |
| (IX) | 54055 | 6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraene | n/a | C14H15ClN2 | 详情 | 详情 |
| (X) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (XI) | 54056 | (6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraen-10-yl)(4-nitrophenyl)methanone | n/a | C21H18ClN3O3 | 详情 | 详情 |
| (XII) | 54057 | (4-aminophenyl)(6-chloro-2,10-diazatetracyclo[11.2.1.0~2,12~.0~4,9~]hexadeca-4,6,8,14-tetraen-10-yl)methanone | n/a | C21H20ClN3O | 详情 | 详情 |
| (XIII) | 54058 | 4'-methyl[1,1'-biphenyl]-2-carbonyl chloride | n/a | C14H11ClO | 详情 | 详情 |