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【结 构 式】

【分子编号】11183

【品名】1,3-Cyclopentadiene

【CA登记号】

【 分 子 式 】C5H6

【 分 子 量 】66.10264

【元素组成】C 90.85% H 9.15%
与该中间体有关的原料药合成路线共 17 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5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17

合成路线1

该中间体在本合成路线中的序号：(VI)

The reaction of 3(R)-(tert-butyldimethylsilyloxy)-4(R)-methoxy-4(R)-methyl-1-(tributylstannyl)-1(E)-octene (II) with butyllithium, cuprous iodide and tributylphosphine gives an intermediate copper derivative which is condensed first with 4(R)-(tert-butyldimethylsilyloxy)-2-cyclopentenone (I) and then with methyl 6-formylhexanoate (III) to give the 7-hydroxy PGE1 derivative (IV). The dehydration of (IV) with mesyl chloride yields the unsaturated PGE compound (V), which is reduced with tributystannyl hydride and finally deprotected with acetic acid in THF. The starting products (I) and (II) are obtained as follows: 1) The oxidation of cyclopentadiene (VI) gives 2-cyclopentene-1,4-diol (VII), which is acetylated to the diacetate (VIII). Selective hydrolysis of (VIII) yields (1S, 4R)-4-hydroxy-2-cyclopentenyl acetate (IX), which is protected with tert-butyldimethylsilyl chloride to the protected acetate (X). Partial hydrolysis of (X) affords the semiprotected alcohol (XI), which is finally oxidized to the cyclopentenone (I).

参考文献 中间体
合成目标
【1】 Kolb, M.; Van Hijfte, L.; Ireland, R.E.; A highly convergent synthesis of mexiprostil: 16(R) 16-methoxy 16-methyl PGE1 methyl ester. Tetrahedron Lett 1988, 29, 51, 6769.
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) 13805 (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one C11H20O2Si 详情 详情
(II) 21528 (1R,2R,3E)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(tributylstannyl)-3-butenyl methyl ether C28H60O2SiSn 详情 详情
(III) 21529 methyl 7-oxoheptanoate 35376-00-2 C8H14O3 详情 详情
(IV) 21530 methyl 7-[(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyl-1-octenyl)-5-oxocyclopentyl]-7-hydroxyheptanoate C35H68O7Si2 详情 详情
(V) 21531 methyl 7-[(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyl-1-octenyl)-5-oxocyclopentylidene]heptanoate C35H66O6Si2 详情 详情
(VI) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(VII) 21533 4-cyclopentene-1,3-diol C5H8O2 详情 详情
(VIII) 21534 4-(acetoxy)-2-cyclopenten-1-yl acetate C9H12O4 详情 详情
(IX) 21535 (1R,4R)-4-hydroxy-2-cyclopenten-1-yl acetate C7H10O3 详情 详情
(X) 21536 (1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl acetate C13H24O3Si 详情 详情
(XI) 21537 (1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol C11H22O2Si 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

This compound can be obtained in two different ways: 1) By reaction of 4-oxa-5-hydroxytricyclo[5.2.1.0(2,6)]dec-8-en-3-one (I) with methyl isocyanate (II) in refluxing THF. 2) By a Diels-Alder reaction of cyclopentadiene (III) with 2-(N-methylcarbamoyloxy)-2,5-dihydrofuran-5 one (IV) in THF at 120 C in a pressure vessel.

参考文献 中间体
合成目标
【1】 Wiersdorff, W.W.; Wilsmann, K.; DE 2510714 .
【2】 Ammann, A.; et al. (BASF AG); Carbamates and their use as pharmaceuticals. US 3965119 .
【3】 Blancafort, P.; Neuman, M.; Serradell, M.N.; Castaner, J.; LU-253. Drugs Fut 1981, 6, 2, 89.
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) 37407 5-hydroxy-4-oxatricyclo[5.2.1.0(2,6)]dec-8-en-3-one C9H10O3 详情 详情
(II) 11019 (Methylimino)(oxo)methane; methyl isocyanate C2H3NO 详情 详情
(III) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(IV) 37408 5-oxo-2,5-dihydro-2-furanyl methylcarbamate C6H7NO4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The synthesis of SM-3997 labeled in the carbonyl groups or the pyrimidine ring has been reported: The Diels-Alder condensation of cyclopentadiene (II) with [14C]-labeled maleic anhydride (I) gives bicyclo[2.2.1]hept-5-ene-2,3-endo-di[14C]-carboxylic anhydride (III), which by treatment with ammonia in THF is converted to the corresponding imide (IV endo). Heating of (IV endo) at 190 C in diphenylether affords the corresponding exo isomer (IV exo), which is hydrogenated with H2 over Pd/C in ethanol - THF to give the saturated exo-imide (V). The condensation of (V) with 1,4-dibromobutane (VI) by means of K2CO3 in refluxing acetone yields the N-(4-bromobutyl)imide (VII), which is finally condensed with 1-(2-pyrimidinyl)piperazine (VIII) by means of K2CO3 and KI in hot DMF to afford SM-399 [14C]-labeled at the carbonyl groups.

参考文献 中间体
合成目标
【1】 Kanamaru, H.; Nishioka, K.; 14C-labeling of a novel anxiolytic agent tandospirone. J Label Compd Radiopharm 1992, 31, 6, 427.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV endo) 11185 (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H9NO2 详情 详情
(IV exo) 11186 (1R,2R,6S,7S)-4-Azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H9NO2 详情 详情
(IV endo) 45052 (1R,2R,6S,7S)-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H9NO2 详情 详情
(IV exo) 45053 (1R,2S,6R,7S)-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H9NO2 详情 详情
(I) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情
(I) 45050 2,5-furandione C4H2O3 详情 详情
(II) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(III) 11184 (1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H8O3 详情 详情
(III) 45051 (1R,2R,6S,7S)-4-oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H8O3 详情 详情
(V) 11173 (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C9H11NO2 详情 详情
(V) 45054 (1R,2R,6S,7S)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C9H11NO2 详情 详情
(VII) 11174 (1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C13H18BrNO2 详情 详情
(VII) 45055 (1R,2R,6S,7S)-4-(4-bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C13H18BrNO2 详情 详情
(VIII) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 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 photooxidation of cyclopentadiene (I) gives cis-4-cyclopentene-1,3-diol (II), which is acylated with Ac2O to yield the diacetate (II). Enzymatic selective hydrolysis of (II) using porcine pancreas lipase (PPL) affords the chiral monoacetate (IV), which is protected with dihydropyran (DHP) and Ts-OH to provide the tetrahydropyranyl ether (V). The hydrolysis of the acetate group of (V) with KOH in methanol gives the alcohol (VI), which is silylated with TbdmsCl and imidazole to yield the silyl ether (VII). Elimination of the THP-protecting group of (VII) with Me2AlCl in dichloromethane affords the cyclopentenol (VIII), which is oxidized with PCC to the cyclopentenone (IX). The condensation of (IX) with chloroiodomethane and BuLi in THF gives the chiral chloromethyl derivative (X), which is treated with potassium methoxide in THF to obtain the chiral epoxide (XI). Stereocontrolled opening of the epoxide ring of (XI) by means of DIBAL in hexane provides the cyclopentenyl-methanol derivative (XII), which is desilylated with TBAF in THF to give the chiral diol (XIII). The esterification of the diol (XIII) with methyl chloroformate and pyridine yields the bis-carbonate (XIV), which is condensed with 2-amino-6-chloropurine (XV) by means of Pd(PPh3)4 in DMF to afford the carbocyclic purine derivative (XVI). Finally, this compound is hydrolyzed with NaOH in refluxing water to provide the target carbocyclic guanine.

参考文献 中间体
合成目标
【1】 Nokami, J.; et al.; Palladium-catalyzed chemoselective reaction of allylic carbonate with nucleoside bases and its application for the synthesis of carbocyclic nucleosides. (-)-and (+)-carbovirs. Chem Lett 1994, 1071.
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) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 33168 (1R,3S)-4-cyclopentene-1,3-diol C5H8O2 详情 详情
(III) 45374 (1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate C9H12O4 详情 详情
(IV) 45407 (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol 60410-16-4 C7H10O3 详情 详情
(V) 45339 　 C8H11N 详情 详情
(VI) 45400 (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-ol C11H18O3 详情 详情
(VII) 45401 tert-butyl(dimethyl)([(1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl]oxy)silane; tert-butyl(dimethyl)silyl (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl ether C17H32O3Si 详情 详情
(VIII) 33174 (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol C11H22O2Si 详情 详情
(IX) 13805 (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one C11H20O2Si 详情 详情
(X) 45402 (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-(chloromethyl)-2-cyclopenten-1-ol C12H23ClO2Si 详情 详情
(XI) 45403 tert-butyl(dimethyl)silyl (3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yl ether; tert-butyl(dimethyl)[(3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yloxy]silane C12H22O2Si 详情 详情
(XII) 45404 ((1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl)methanol C12H24O2Si 详情 详情
(XIII) 45405 (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(XIV) 45406 [(1S,4R)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XV) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XVI) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(I)

The reaction of cyclopentadiene (I) with tosyl cyanide in acidic water gives the racemic bicyclic lactam (II), which is opened by means of TsCl and NaH to yield cis-3-(tosylamino)-4-cyclopentene-1-carboxylic acid (III). The reduction of (III) with NaBH4 affords the corresponding carbinol (IV), which is acylated with Ac2O and pyridine to provide the acetate (V). The reaction of (V) with Ts-Cl and NaH yields the ditosylamino derivative (VI), which is condensed with 2-amino-6-chloropurine (VII) by means of a Pd catalyst, affording the carbocyclic purine (VIII). Finally, this compound is hydrolyzed with hot aqueous NaOH to give the target carbocyclic guanine.

参考文献 中间体
合成目标
【1】 Jung, M.E.; Rhee, H.; pi-Allylpalladium formation from allylic amines via N,N-ditosylimides and N-tosylamides: Efficient synthesis of the antiviral agent carbovir. J Org Chem 1994, 59, 17, 4719.
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) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 33410 cis-2-azabicyclo[2.2.1]hept-5-en-3-one C6H7NO 详情 详情
(III) 45408 (1S,4R)-4-[[(4-methylphenyl)sulfonyl]amino]-2-cyclopentene-1-carboxylic acid C13H15NO4S 详情 详情
(IV) 45409 N-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]-4-methylbenzenesulfonamide C13H17NO3S 详情 详情
(V) 45410 ((1S,4R)-4-[[(4-methylphenyl)sulfonyl]amino]-2-cyclopenten-1-yl)methyl acetate C15H19NO4S 详情 详情
(VI) 45411 ((1S,4R)-4-[bis[(4-methylphenyl)sulfonyl]amino]-2-cyclopenten-1-yl)methyl acetate C22H25NO6S2 详情 详情
(VII) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(VIII) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

The addition of HCl to cyclopentadiene (I) gives 3-chlorocyclopentene (II), which is converted to racemic 2-cyclopentene-1-carboxylic acid (III). Optical resolution of (II) by crystallization of its (-)-1-phenylethylamine yields the desired enantiomer (IV), which is reduced with LiAlH4 in ethyl ether affording the chiral carbinol (V) (ee 98%). The reaction of (V) successively with BuLi, CO2 and I2 provides the iodinated cyclic carbonate (VI), which is treated with DBU in hot toluene to give the unsaturated cyclic carbonate (VII). The condensation of (VII) with 2-amino-6-chloropurine (VIII) by means of a Pd catalyst yields the carbocyclic purine (IX), which is finally hydrolyzed with aqueous NaOH to afford the target carbocyclic guanine. Alternatively, carbinol (V) can also be obtained by the vitamin B12/Zn/NH4Cl-catalyzed isomerization of 1,2-epoxycyclopentane (X) to the chiral cyclopentenol (XI), which by a [2,3]-sigmatropic Wittig rearrangement with KH, ICH2-SnBu4 and BuLi yields the target carbinol (V). However, the enantiomeric excess obtained is only ee 54%.

参考文献 中间体
合成目标
【1】 Hildbrand, S.; et al.; A short synthesis of (-)-carbovir. Helv Chim Acta 1994, 77, 5, 1236.
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) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 19541 3-chloro-1-cyclopentene C5H7Cl 详情 详情
(III) 45419 2-cyclopentene-1-carboxylic acid C6H8O2 详情 详情
(IV) 45420 (1S)-2-cyclopentene-1-carboxylic acid C6H8O2 详情 详情
(V) 45421 (1S)-2-cyclopenten-1-ylmethanol C6H10O 详情 详情
(VI) 45422 (4aR,7S,7aS)-7-iodohexahydrocyclopenta[d][1,3]dioxin-2-one C7H9IO3 详情 详情
(VII) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(VIII) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(IX) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情
(X) 38011 6-oxabicyclo[3.1.0]hexane 285-67-6 C5H8O 详情 详情
(XI) 45423 (1R)-2-cyclopenten-1-ol C5H8O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The cyclization of glyoxylic acid (I) with cyclopentadiene (II) gives the racemic hydroxylactone (III), which is acylated with Ac2O to yield acetoxy compound (rac)-(IV). The enzymatic optical resolution of (rac)-(IV) by means of Pseudomonas fluorescens affords the chiral hydroxylactone (-)-(V), which is reduced with LiAlH4 in refluxing THF to provide the lactol (VI). The oxidation of (VI) with NaIO4 in ethyl ether/water gives the chiral carbaldehyde (VII), which is reduced with NaBH4 in ethanol to afford the diol (VIII). The reaction of (VIII) with triphosgene by means of TEA in dichloromethane affords the cyclic carbonate (IX), which is condensed with chloropurine (X) by means of Pd(PPh3)4 in DMSO/THF to provide the adduct (XI). Finally, this compound is hydrolyzed with NaOH to afford the target (-)-carbovir.

参考文献 中间体
合成目标
【1】 Yu, J.; Olivo, H.F.; Practical enantiodivergent syntheses of both enantiomers of carbovir, 1592U89 and six-membered ring analogues. J Chem Soc - Perkins Trans I 1998, 3, 3, 391-2.
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) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(II) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(III) 55545 (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one C7H8O3 详情 详情
(IV) 17679 (3S,3aR,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate C9H10O4 详情 详情
(V) 17678 (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one C7H8O3 详情 详情
(VI) 55544 (3S,3aR,6aR)-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2,3-diol C7H10O3 详情 详情
(VII) 17682 (1S,2R)-2-hydroxy-3-cyclopentene-1-carbaldehyde C6H8O2 详情 详情
(VIII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(IX) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(X) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XI) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XXXVI)

The condensation of propane-1,3-diol (XXV) with benzaldehyde by means of p-toluenesulfonic acid gives the corresponding cyclic acetal (XXVI), which is reduced with diisobutylaluminum hydride in toluene yielding 3-benzoyloxy-1-propanol (XXVII). The oxidation of (XXVII) with oxalyl chloride as before affords the corresponding aldehyde (XXVIII), which is submitted to a Wittig condensation with 2-(triphenylphosphoranylidene)acetic acid methyl ester (XXIX) giving (E)-5-benzyloxy-2-pentenoic acid methyl ester (XXX). The hydrolysis of (XXX) with NaOH in THF-water yields the corresponding acid (XXXI), which is condensed with pivaloyl chloride (XXXII) to afford the mixed anhydride (XXXIII). The condensation of (XXXIII) with 4(S)-benzyloxazolidin-2-one (XXXIV) by means of BuLi in THF gives 4(S)-benzyl-3-[5-benzyloxy-2(E)-pentenoyl]oxazolidin-2-one (XXXV), which is submitted to a Diels-Alder cycloaddition with cyclopentadiene (XXXVI) to yield 4-benzyl-3-[(3R,4R,5S,6S)-5-(2-benzyloxyethyl)bicyclo[2.2.1]hept-2-en-4-ylcarbonyl]oxazolidin-2-one (XXXVII). Hydrogenation of (XXXVII) with H2 over Pt in ethylacetate, followed by hydrolysis with H2O2 and LiOH affords (1R,2R,3S,4S)-3-(2-benzyloxyethyl)bicyclo[2.2.1]heptane-2-carboxylic acid (XXXVIII). The formation of the corresponding azide with ethyl chloroformate and sodium azide followed by degradation in refluxing toluene gives the amine (XXXIX), which is acylated with benzenesulfonyl chloride as before yielding the sulfonamide (XL). The deprotection of (XL) by hydrogenolysis with H2 over Pd/C in ethanol affords the substituted ethanol (XLI). Oxidation of (XLI) with oxalyl chloride as before gives the aldehyde (XLII), which is finally submitted to a Wittig condensation with 4-carboxybutyl triphenylphosphonium bromide and t-BuOK to yield acid (XIV) enantiomerically pure, already obtained.

参考文献 中间体
合成目标
【1】 Wong and F.F. Sun (Eds.), Raven Press, Ltd., New York 1989, 19, 659-62.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 14674 (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid C20H27NO4S 详情 详情
(XXV) 14685 1,3-propanediol; Trimethylene Glycol 504-63-2 C3H8O2 详情 详情
(XXVI) 14686 2-phenyl-1,3-dioxane C10H12O2 详情 详情
(XXVII) 14687 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol 4799-68-2 C10H14O2 详情 详情
(XXVIII) 14688 3-(benzyloxy)propanal C10H12O2 详情 详情
(XXIX) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XXX) 14690 Methyl (E)-5-(benzyloxy)-2-pentenoate C13H16O3 详情 详情
(XXXI) 14691 (E)-5-(Benzyloxy)-2-pentenoic acid C12H14O3 详情 详情
(XXXII) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XXXIII) 14693 (E)-4-(Benzyloxy)-2-pentenoic 1,1-Dimethylpropionic anhydride C17H22O4 详情 详情
(XXXIV) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XXXV) 14695 (4S)-4-benzyl-3-[(E)-5-(benzyloxy)-2-pentenoyl]-1,3-oxazolan-2-one C22H23NO4 详情 详情
(XXXVI) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(XXXVII) 14697 (4S)-4-benzyl-3-([(1R,2S,3S,4S)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-5-en-2-yl]carbonyl)-1,3-oxazolan-2-one C27H29NO4 详情 详情
(XXXVIII) 14698 (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptane-2-carboxylic acid C17H22O3 详情 详情
(XXXIX) 14699 (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptan-2-amine; (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-ylamine C16H23NO 详情 详情
(XL) 14700 N-[(1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C22H27NO3S 详情 详情
(XLI) 14701 N-[(1S,2S,3S,4R)-3-(2-hydroxyethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C15H21NO3S 详情 详情
(XLII) 14673 N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C15H19NO3S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XXXVI)

5) The water promoted condensation of glyoxylic acid (XXXV) with cyclopentadiene (XXXVI) gives the racemic cis-hydroxylactone (XXXVII), which is acetylated with acetic anhydride to the acetate (XXXVIII). The selective enzymatic hydrolysis of (XXXVIII) with Pseudomonas fluorescens lipase yields the pre (-)-enantiomer (XXXIX), which is reduced with LiAlH4 in refluxing THF, affording triol (XL). The oxidation of the vicinal glycol of (XL) with NaIO4 in ethyl ether/water yields the hydroxyaldehyde (XLI), which is reduced with NaBH4 in ethanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). This compound, by reaction with triphosgene and triethylamine in dichloromethane, results in the cyclic carbonate intermediate (XXXII), already reported.

参考文献 中间体
合成目标
【1】 Yu, J.; Olivo, H.F.; Practical enantiodivergent syntheses of both enantiomers of carbovir, 1592U89 and six-membered ring analogues. J Chem Soc - Perkins Trans I 1998, 3, 3, 391-2.
【2】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXX) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(XXXII) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(XXXV) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(XXXVI) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(XXXVII) 63844 (rac)-(3R*,3aS*,6aS*)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one C7H8O3 详情 详情
(XXXVIII) 17679 (3S,3aR,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate C9H10O4 详情 详情
(XXXIX) 17678 (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one C7H8O3 详情 详情
(XL) 17681 (1S)-1-[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]-1,2-ethanediol C7H12O3 详情 详情
(XLI) 17682 (1S,2R)-2-hydroxy-3-cyclopentene-1-carbaldehyde C6H8O2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

The regioselective reaction of cyclopentadiene (I) and sodium or commercial sodium cyclopentadienide (II) with benzyl chloromethyl ether (III) by means of the chiral catalyst (-)-diisopinocampheylborane in THF, followed by hydroxylation with H2O2/NaOH, gives (1S-trans)-2-(benzyloxymethyl)-3-cyclopenten-1-ol (IV), which is regioselectively epoxidized with tert-butyl hydroperoxide and vanadyl acetylacetonate in 2,2,4-trimethylpentane, yielding [1S-(1alpha,2alpha,3beta,5alpha)-2-(benzyloxymethyl)-6-oxabicyclo[3.1.0]hexan-3-ol (V). The protection of (V) with benzyl bromide and NaH affords the corresponding ether (VI), which is condensed with 6-O-benzylguanine (VII) by means of LiH in DMF to give the guanine derivative (VIII). The protection of the amino group of (VIII) with 4-methoxyphenyl(diphenyl)chloromethane (IX), TEA and DMAP in dichloromethane gives intermediate (X), which is oxidized at the free hydroxyl group with methylphosphonic acid, DCC and oxalic acid in DMSO or Dess Martin periodinane in dichloromethane, yielding the cyclopentanone derivative (XI). The reaction of (XI) with (i) Zn/TiCl4/CH2Br2 complex in THF/CH2Cl2, (ii) activated Zn/PbCl2/CH2I2/TiCl4 in THF/CH2Cl2 (2), (iii) Nysted reagent/TiCl4 in THF/CH2Cl2 or (iv) Tebbe reagent in toluene affords the corresponding methylene derivative (XII), which is partially deprotected with 3N HCl in hot THF, providing the dibenzylated compound (XI). Finally, this compound is treated with BCl3 in dichloromethane. (Scheme 18263401a)

参考文献 中间体
合成目标
【1】 Bisacchi, G.S.; Chao, S.T.; Bachard, C.; et al.; BMS-200475. A novel carbocyclic 2'-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro. Bioorg Med Chem Lett 1997, 7, 2, 127.
【2】 Castaner, J.; Graul, A.; BMS-200475. Drugs Fut 1999, 24, 111, 1173.
【3】 Zahler, R.; Slusarchyk, W.A. (Bristol-Myers Squibb Co.); Hydroxymethyl(methylenecyclopentyl)purines and pyrimidines. EP 0481754; JP 1992282373; US 5206244 .
【4】 Bisacchi, G.S.; Sundeen, J.E. (Bristol-Myers Squibb Co.); Improved process for preparing the antiviral agent [1S-(1alpha, 3alpha, 4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one. WO 9809964 .
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) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 29887 Sodium cyclopentadienide 4984-82-1 C5H5Na 详情 详情
(III) 14560 Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene 3587-60-8 C8H9ClO 详情 详情
(IV) 29888 (1S,2R)-2-[(benzyloxy)methyl]-3-cyclopenten-1-ol C13H16O2 详情 详情
(V) 29889 (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexan-3-ol C13H16O3 详情 详情
(VI) 29890 (1S,2R,3S,5R)-3-(benzyloxy)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexane; benzyl (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hex-3-yl ether C20H22O3 详情 详情
(VII) 14383 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine 19916-73-5 C12H11N5O 详情 详情
(VIII) 29891 (1S,2S,3S,5S)-5-[2-amino-6-(benzyloxy)-9H-purin-9-yl]-3-(benzyloxy)-2-[(benzyloxy)methyl]cyclopentanol C32H33N5O4 详情 详情
(IX) 12700 4-[Chloro(diphenyl)methyl]phenyl methyl ether; 1-[Chloro(diphenyl)methyl]-4-methoxybenzene; p-Anisylchlorodiphenylmethane 14470-28-1 C20H17ClO 详情 详情
(X) 29892 (1S,2S,3S,5S)-3-(benzyloxy)-5-(6-(benzyloxy)-2-[[(4-methoxyphenyl)(diphenyl)methyl]amino]-9H-purin-9-yl)-2-[(benzyloxy)methyl]cyclopentanol C52H49N5O5 详情 详情
(XI) 29893 (2R,3S,5S)-3-(benzyloxy)-5-(6-(benzyloxy)-2-[[(4-methoxyphenyl)(diphenyl)methyl]amino]-9H-purin-9-yl)-2-[(benzyloxy)methyl]cyclopentanone C52H47N5O5 详情 详情
(XII) 29894 6-(benzyloxy)-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-N-[(4-methoxyphenyl)(diphenyl)methyl]-9H-purin-2-amine; N-(6-(benzyloxy)-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-9H-purin-2-yl)-N-[(4-methoxyphenyl)(diphenyl)methyl]amine 142217-80-9 C53H49N5O4 详情 详情
(XIII) 29895 2-amino-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one 142217-81-0 C26H27N5O3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

The Diels-Alder condensation of the fumaric acid (S)-methyl lactate ester (I) with cyclopentadiene (II) gives the norbornene derivative (III), which is submitted to saponification with LiOH and iodolactonization with KI and I2 yielding the iodolactone (IV). The reaction of (IV) with SOCl2 and then with ammonia affords the amide (V). The Hofmann-type rearrangement of (V) by means of hydroxytosyloxy iodobenzene (HTIB) gives the primary amine (VI), which is treated with TsCl and pyridine to yield the sulfonamide (VII). The iodolactone ring is then cleaved with Zn/AcOH affording the norbornene-carboxylic acid (VIII), which is submitted to ozonolysis with O3 to give the dialdehyde (IX). The reduction of (IX) with NaBH4 provides the diol (X), which is cyclized in acidic medium to lactone (XI). The reaction of (XI) with ammonia affords the amide (XII), which is reduced with BH3 to the primary amine (XIII). The protection of (XIII) with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Boc-ON) gives the carbamate (XIV), which is treated with Ts-Cl to yield the ditosylate (XV). The cyclization of (XV) by means of TFA affords the azanoradamantane sulfonamide (XVI), which is treated with calcium in liquid ammonia to obtain thee corresponding primary amine (XVII). Finally, this compound is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XVIII) by means of carbonyldiimidazole (CDI) in DMF.

参考文献 中间体
合成目标
【1】 Becker, D.P.; et al.; Enantioselective synthesis of dual 5-HT4/5-HT3 serotonergic azanoradamantane SC-52491. Tetrahedron 1999, 55, 40, 11787.
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) 32307 bis[(1S)-2-ethoxy-1-methyl-2-oxoethyl] (E)-2-butenedioate C14H20O8 详情 详情
(II) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(III) 32308 bis[(1S)-2-ethoxy-1-methyl-2-oxoethyl] (2R,3R)bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate C19H26O8 详情 详情
(IV) 32309 (2S,3S,6R,9S)-2-iodo-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]nonane-9-carboxylic acid C9H9IO4 详情 详情
(V) 32310 (2S,3S,6R,9S)-2-iodo-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]nonane-9-carboxamide C9H10INO3 详情 详情
(VI) 32311 (2S,3S,6R,9S)-9-amino-2-iodo-4-oxatricyclo[4.2.1.0(3,7)]nonan-5-one C8H10INO2 详情 详情
(VII) 32312 N-[(2S,3S,6R,9S)-2-iodo-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]non-9-yl]-4-methylbenzenesulfonamide C15H16INO4S 详情 详情
(VIII) 32313 (2R,3R)-3-[[(4-methylphenyl)sulfonyl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxylic acid C15H17NO4S 详情 详情
(IX) 32314 (1R,2R,3S,5R)-3,5-diformyl-2-[[(4-methylphenyl)sulfonyl]amino]cyclopentanecarboxylic acid C15H17NO6S 详情 详情
(X) 32315 (1R,2R,3S,5R)-3,5-bis(hydroxymethyl)-2-[[(4-methylphenyl)sulfonyl]amino]cyclopentanecarboxylic acid C15H21NO6S 详情 详情
(XI) 32316 N-[(3aR,4R,5S,6aR)-5-(hydroxymethyl)-3-oxohexahydro-2H-cyclopenta[b]furan-4-yl]-4-methylbenzenesulfonamide C15H19NO5S 详情 详情
(XII) 32317 (1R,2R,3S,5R)-3,5-bis(hydroxymethyl)-2-[[(4-methylphenyl)sulfonyl]amino]cyclopentanecarboxamide C15H22N2O5S 详情 详情
(XIII) 32318 N-[(1S,2S,3R,5S)-2-(aminomethyl)-3,5-bis(hydroxymethyl)cyclopentyl]-4-methylbenzenesulfonamide C15H24N2O4S 详情 详情
(XIV) 32319 tert-butyl ((1S,2S,3S,5R)-3,5-bis(hydroxymethyl)-2-[[(4-methylphenyl)sulfonyl]amino]cyclopentyl)methylcarbamate C20H32N2O6S 详情 详情
(XV) 32320 [(1S,2S,3S,4R)-3-[[(tert-butoxycarbonyl)amino]methyl]-2-[[(4-methylphenyl)sulfonyl]amino]-4-([[(4-methylphenyl)sulfonyl]oxy]methyl)cyclopentyl]methyl 4-methylbenzenesulfonate C34H44N2O10S3 详情 详情
(XVI) 32321 N-[(3S,4S,5R,7R)-1-azatricyclo[3.3.1.0(3,7)]non-4-yl]-4-methylbenzenesulfonamide C15H20N2O2S 详情 详情
(XVII) 32322 (3S,4S,5R,7R)-1-azatricyclo[3.3.1.0(3,7)]nonan-4-amine; (3S,4S,5R,7R)-1-azatricyclo[3.3.1.0(3,7)]non-4-ylamine C8H14N2 详情 详情
(XVIII) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

The reaction of cyclopentadiene (I) with Br2 gives 1,4-dibromo-2-cyclopentene (II), which is treated with potassium acetate in tert-butanol yielding 1,4-diacetoxy-2-cyclopentene (III). The hydrolysis of (III) with KHCO3 in methanol affords 2-cyclopentene-1,4-diol (IV) as a mixture of the cis and trans isomers. The treatment of (cis/trans) (IV) or (cis) (IV) with pancreatin, vinyl acetate (V) and triethylamine gives (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is hydrogenated with H2 over RaNi in ethanol to yield the corresponding saturated (1S,3R)-3-acetoxycyclopentanol (VII). The reaction of (VII) with methanesulfonyl chloride and TEA in dichloromethane affords the corresponding mesylate (VIII), which is condensed with adenine (IX) by means of NaH in hot DMF providing the final intermediate (X). Finally, this compound is deacetylated with HCl in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615.
【2】 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(cis/trans)(IV) 21533 4-cyclopentene-1,3-diol C5H8O2 详情 详情
(cis)(IV) 33168 (1R,3S)-4-cyclopentene-1,3-diol C5H8O2 详情 详情
(I) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 33167 3,5-dibromo-1-cyclopentene C5H6Br2 详情 详情
(III) 21534 4-(acetoxy)-2-cyclopenten-1-yl acetate C9H12O4 详情 详情
(V) 24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(VI) 33169 (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate C7H10O3 详情 详情
(VII) 33170 (1R,3S)-3-hydroxycyclopentyl acetate C7H12O3 详情 详情
(VIII) 33171 (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate C8H14O5S 详情 详情
(IX) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(X) 33172 (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate C12H15N5O2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(III)

The oxidation of 4,8-dimethoxynaphthalene-1,5-diol (I) with FeCl3 in CH3CN/MeOH gives the naphthoquinone (II), which is submitted to a Diels Alder condensation with cyclopentadiene (III) yielding the methanoanthraquinone (IV). The reduction of (IV) with NaBH4 in THF/methanol affords the triol (V), which is condensed with 1-iodo-8-methoxynaphthalene (VI) by means of Cu2O in refluxing pyridine providing the diaryl ether (VII). The demethylation of (VII) by means of lithium diphenylphosphine in THF gives the tetrahydroxy compound (VIII), which is cyclized by means of PhI(OAc)2 in hexafluoroisopropanol yielding the spiro-13-dioxane derivative (IX). The selective silylation of (IX) with TBDMS-OTf and lutidine in dichloromethane affords the silyl ether (X), which is oxidized with pyridinium dichromate (PDC) in DMF to provide the diketonic compound (XI). The epoxidation of (XI) with H2O2 and K2CO3 in THF/water gives the diepoxy compound (XII), which is submitted to a retro Diels Alder reaction in refluxing diphenyl ether yielding the silylated precursor (XIII). Finally this compound is desilylated with HF in acetonitrile/water.

参考文献 中间体
合成目标
【1】 Wipf, P.; Jung, J.-K.; Formal total synthesis of (+)-diepoxin sigma. J Org Chem 2000, 65, 20, 6319.
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) 41874 4,8-dimethoxy-1,5-naphthalenediol C12H12O4 详情 详情
(II) 41875 5-hydroxy-8-methoxynaphthoquinone C11H8O4 详情 详情
(III) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(IV) 41876 (1R,2R,11S,12S)-5-hydroxy-8-methoxytetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,10-dione C16H14O4 详情 详情
(V) 41877 (1R,2R,3R,10S,11S,12S)-8-methoxytetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,5,10-triol C16H18O4 详情 详情
(VI) 41878 8-iodo-1-naphthyl methyl ether; 1-iodo-8-methoxynaphthalene C11H9IO 详情 详情
(VII) 41879 (1S,2S,3S,10R,11R,12R)-5-methoxy-8-[(8-methoxy-1-naphthyl)oxy]tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,10-diol C27H26O5 详情 详情
(VIII) 41880 (1S,2S,3S,10R,11R,12R)-8-[(8-hydroxy-1-naphthyl)oxy]tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,5,10-triol C25H22O5 详情 详情
(IX) 41881 　 C25H20O5 详情 详情
(X) 41882 　 C31H34O5Si 详情 详情
(XI) 41883 　 C31H32O5Si 详情 详情
(XII) 41884 　 C31H32O7Si 详情 详情
(XIII) 41885 　 C26H26O7Si 详情 详情

合成路线14

该中间体在本合成路线中的序号：(IV)

1) The Diels-Alder cyclization of butadiene (I) with 2-methylbenzophenone (II) by means of acetic acid in refluxing toluene followed by oxidation with ceric ammonium nitrate gives 2-methyl-1,4-naphthoquinone (III), which by a new Diels-Alder cyclization with cyclopentadiene (IV) yields 4aalpha-methyl-1,4,4a,5,8,9a-hexahydro-1alpha,4alpha-methanoanthraquinone (V). The alkylation of (V) with 3,7,11,15-tetramethyl-2(E),6(E),10(E),14-hexadecatetraeanyl bromide (VI) by means of potassium tert-butoxide in THF affords the alkylated anthraquinone (VII), which is submitted to a retro Diels-Alder reaction in refluxing toluene containing dichlorodicyanobenzoquinone (DDQ) in order to obtain a simultaneous dehydrogenation. 2) The Diels-Alder cyclization of 1,4-naphthoquinone (VIII) with cyclopentadiene as before gives 1,4,4a,9a-tetrahydro-1,4-methanoanthraquinone (IX), which is alkylated with the alkyl bromide (VI) as before to yield the alkylated anthraquinone (X). The methylation of (X) with methyl iodide and potassium tert-butoxide affords the 9a-methylated anthraquinone (XI), which is finally submitted to a retro Diels-Alder reaction in refluxing toluene.

参考文献 中间体
合成目标
【1】 Graul, A.; Castañer, J.; Menatetrenone. Drugs Fut 1996, 21, 6, 615.
【2】 Hamamura, K.; Iwama, T.; Seki, C.; Konishi, M. (Eisai Co., Ltd.); Preparation process of quinone deriv. and intermediate for the preparation thereof. EP 0613877 .
【3】 Hamamura, K.; Seki, C.; Konishi, M. (Eisai Co., Ltd.); Preparation process of naphthoquinone derivs. and intermediates for the preparation thereof. EP 0636598 .
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) 11579 1,3-Butadiene; Butadiene 106-99-0 C4H6 详情 详情
(II) 16555 2-methyl-2,5-cyclohexadiene-1,4-dione; 2-methylbenzo-1,4-quinone 553-97-9 C7H6O2 详情 详情
(III) 16556 2-methyl-5,8-dihydro-1,4-naphthalenedione C11H10O2 详情 详情
(IV) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(V) 16558 (2R)-2-methyltetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4(9),6,13-triene-3,10-dione C16H16O2 详情 详情
(VI) 16559 (2E,6E,10E)-1-bromo-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene C20H33Br 详情 详情
(VII) 16560 (2R,11S)-2-methyl-11-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4(9),6,13-triene-3,10-dione C36H48O2 详情 详情
(VIII) 16561 naphthoquinone; 1,4-Naphthoquinone 130-15-4 C10H6O2 详情 详情
(IX) 16562 tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,10-dione C15H12O2 详情 详情
(X) 16563 (2S)-2-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,10-dione C35H44O2 详情 详情
(XI) 16564 (2R,11S)-2-methyl-11-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]tetracyclo[10.2.1.0(2,11).0(4,9)]pentadeca-4,6,8,13-tetraene-3,10-dione C36H46O2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The asymmetric Diels-Alder cycloaddition of cyclopentadiene (II) with the acrylic ester (I) of the chiral auxiliary D-pantolactone catalyzed by TiCl4 gives the chiral norbornene (III), which is treated with LiOH or NaOH to eliminate the auxiliary to yield the carboxylic acid (IV). The reaction of (IV) with oxalyl chloride affords the acyl chloride (V), which is condensed with 5,6-diamino-1,3-dipropyluracil (VI) by means of DMAP in pyridine to provide the amide (VII). The cyclization of (VII) by means of NaOH in dioxane gives the 1,3-dipropylxanthine derivative (VIII), which is finally epoxidated by means of magnesium monoperphthalate (MMPP) in aq. isopropanol to furnish the target xanthine derivative.

参考文献 中间体
合成目标
【1】 Pfister, J.R.; et al.; Synthesis and biological evaluation of the enantiomers of the potent and selective A1-adenosine antagonist 1, 3-dipropyl-8-[2-(5,6-epoxynorbonyl)]xanthine. J Med Chem 1997, 40, 12, 1773.
【2】 Belardinelli, L.; Olsson, R.; Baker, S.; Scammells, P.J.; Milner, P.G.; Pfister, J.R.; Schreiner, G.F. (University of Florida); Novel A1 adenosine receptor agonists and antagonists. EP 0725782; JP 1997507052; US 5446046; WO 9511904 .
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) 54720 (3R)-2,2-dimethyl-4-oxotetrahydro-3-furanyl acrylate C9H12O4 详情 详情
(II) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(III) 54721 (3R)-2,2-dimethyl-4-oxotetrahydro-3-furanyl (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carboxylate C14H18O4 详情 详情
(IV) 54722 (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid C8H10O2 详情 详情
(V) 54723 (1S,2S,4S)bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride C8H9ClO 详情 详情
(VI) 14628 5,6-diamino-1,3-dipropyl-2,4(1H,3H)-pyrimidinedione C10H18N4O2 详情 详情
(VII) 54724 (1S,2S,4S)-N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-5-pyrimidinyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide C18H26N4O3 详情 详情
(VIII) 54725 8-[(1S,2S,4S)bicyclo[2.2.1]hept-5-en-2-yl]-1,3-dipropyl-3,9-dihydro-1H-purine-2,6-dione C18H24N4O2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

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.

参考文献 中间体
合成目标
【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

合成路线17

该中间体在本合成路线中的序号：(II)

In an alternative procedure, Diels-Alder condensation between methyl (E)-3-nitroacrylate (I) and cyclopentadiene (II) produces a mixture of bicyclic adducts (III) and (IV) in a 6:1 ratio. After chromatographic isolation of the major isomer (III), catalytic hydrogenation of its olefin double bond in the presence of PtO2 yields nitro ester (V). Subsequent nitro group reduction in (V) by transfer hydrogenation with ammonium formate and Pd/C produces the racemic amino ester (VI). Coupling of racemic (VI) with carboxylic acid (VII) leads to a mixture of diastereoisomeric amides (VIII) and (IX). Finally, after alkaline hydrolysis of its methyl ester function, the target carboxylic acid isomer is isolated by flash chromatography.

参考文献 中间体
合成目标
【1】 Chang, L.L.; Truong, Q.; Doss, G.; et al.; Orally active, conformationally constrained small molecule VLA-4 antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 325.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(V) 60443 methyl (1S,2R,3R,4R)-3-nitrobicyclo[2.2.1]heptane-2-carboxylate C9H13NO4 详情 详情
rac-(VI) 60444 methyl (1S,2R,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate C9H15NO2 详情 详情
(I) 60440 methyl (E)-3-nitro-2-propenoate C4H5NO4 详情 详情
(II) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(III) 60441 methyl (1R,2R,3R,4S)-3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate C9H11NO4 详情 详情
(IV) 60442 methyl (1R,2S,3S,4S)-3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate C9H11NO4 详情 详情
(VII) 60435 (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid C11H11Cl2NO4S 详情 详情
(VIII) 60445 methyl (1S,2R,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate C20H24Cl2N2O5S 详情 详情
(IX) 60446 methyl (1R,2S,3S,4S)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate C20H24Cl2N2O5S 详情 详情
Extended Information