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【结 构 式】 
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【分子编号】17668 【品名】acrylaldehyde; Acrolein 【CA登记号】107-02-8 |
【 分 子 式 】C3H4O 【 分 子 量 】56.06416 【元素组成】C 64.27% H 7.19% O 28.54% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of the chiral diene (I) with acrolein (II) by means of BF3/Et2O in dichloromethane gives the chiral cyclohexene (III), which is dihydroxylated under Upjohn conditions (OsO4) yielding the dihydroxy compound (IV). The reaction of (IV) with acetone (V) and TsOH affords the isopropylidene derivative (VI), which is treated with NaOH in THF/water to eliminate the chiral auxiliary to yield the cyclohexene carbaldehyde (VII). The regio- and diastereoselective condensation of (VII) with bromide (VIII) by means of t-BuLi and BF3/Et2O affords the adduct (IX), which is treated with N-cyclohexyl-hydroxylamine (X) to provide the nitrone (XI). The reaction of (XI) with acetyl chloride gives the alpha-acetoxy-N-cyclohexylimine (XIII), through the intermediate (XII). The hydrolysis of (XIII) with AcOH and NaOAc yields the carbaldehyde (XIV), which is reduced with LiAlH4 in ethanol to afford the hydroxymethyl derivative (XV). The hydrolysis of the acetoxy and isopropylidene groups of (XV) by means of HCl in THF provides the tetrahydroxy derivative (XVI), which is converted into the epoxide (XVII) by a treatment with MsCl, TEA, DMAP and NaOH in dichloromethane. A new epoxidation of (XVII) by means of VO(acac)2 and t-BuOOH in benzene gives the bis-epoxide compound (XVIII), which is finally monomethylated by means of t-BuONa and MeI in THF to yield the target intermediate fumagillol (XIX).
| 【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) | 61435 | (4S)-3-[(1E)-1,3-butadienyl]-4-phenyl-1,3-oxazolidin-2-one | C13H13NO2 | 详情 | 详情 | |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 61436 | (1R,2S)-2-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-3-cyclohexene-1-carbaldehyde | C16H17NO3 | 详情 | 详情 | |
| (IV) | 61437 | (1R,2S,3S,4R)-3,4-dihydroxy-2-[(3R,4S)-2-oxo-4-phenyltetrahydro-3-furanyl]cyclohexanecarbaldehyde | C17H20O5 | 详情 | 详情 | |
| (V) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (VI) | 61438 | (3aS,4S,5R,7aR)-2,2-dimethyl-4-[(3R,4S)-2-oxo-4-phenyltetrahydro-3-furanyl]hexahydro-1,3-benzodioxole-5-carbaldehyde | C20H24O5 | 详情 | 详情 | |
| (VII) | 52852 | (3aS,7aR)-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carbaldehyde | C10H14O3 | 详情 | 详情 | |
| (VIII) | 52853 | (2E)-2-bromo-6-methyl-2,5-heptadiene | C8H13Br | 详情 | 详情 | |
| (IX) | 52855 | (3aS,4S,5S,7aR)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-2,2-dimethylhexahydro-1,3-benzodioxole-5-carbaldehyde | C18H28O3 | 详情 | 详情 | |
| (X) | 52856 | N-Cyclohexylhydroxylamine | C6H13NO | 详情 | 详情 | |
| (XI) | 61439 | ((Z)-{(3aS,4S,5S,7aR)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-2,2-dimethylhexahydro-1,3-benzodioxol-5-yl}methylidene)(cyclohexyl)ammoniumolate | C24H39NO3 | 详情 | 详情 | |
| (XII) | 52858 | (3aS,4R,7aR)-5-{(E)-[(acetyloxy)(cyclohexyl)amino]methylidene}-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-2,2-dimethylhexahydro-1,3-benzodioxole | C26H41NO4 | 详情 | 详情 | |
| (XIII) | 61440 | (3aS,4S,5R,7aR)-5-[(cyclohexylimino)methyl]-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-2,2-dimethylhexahydro-1,3-benzodioxol-5-yl acetate | C26H41NO4 | 详情 | 详情 | |
| (XIV) | 61441 | (3aS,4S,5R,7aR)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-5-formyl-2,2-dimethylhexahydro-1,3-benzodioxol-5-yl acetate | C20H30O5 | 详情 | 详情 | |
| (XV) | 61442 | (3aS,4S,5R,7aR)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-5-(hydroxymethyl)-2,2-dimethylhexahydro-1,3-benzodioxol-5-yl acetate | C20H32O5 | 详情 | 详情 | |
| (XVI) | 52861 | (1R,2S,3S,4R)-3-[(1E)-1,5-dimethyl-1,4-hexadienyl]-4-(hydroxymethyl)-1,2,4-cyclohexanetriol | C15H26O4 | 详情 | 详情 | |
| (XVII) | 52863 | (3R,4S,5S,6R)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-1-oxaspiro[2.5]octane-5,6-diol | C15H24O3 | 详情 | 详情 | |
| (XVIII) | 52864 | (3R,4S,5S,6R)-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octane-5,6-diol | C15H24O4 | 详情 | 详情 | |
| (XIX) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The condensation of propenal (VII) with tert-butylacetylene (VIII) by means of butyllithium gives 6,6-dimethylhept-1-en-4-yn-3-ol (IX), which is rearranged with HBr to the allyl isomer 6,6-dimethylhept-2-en-4-yn-1-yl bromide (X). Finally, this compound is condensed with amine (IV) by means of Na2CO3 in DMF.
| 【1】 Stutz, A.; SF-86327 and related compounds: Synthetic methods. Int Con Chemother 1983, 116, 5-8. |
| 【2】 Stutz, A. (Novartis AG); Propenylamines, pharmaceutical compositions containing them and their use as pharmaceuticals. EP 0024587; JP 56032440; JP 63313753; Us 4755534 . |
| 【3】 Serradell, M.N.; Castaner, J.; SF-86327. Drugs Fut 1984, 9, 6, 425. |
| 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) | 10108 | N-Methyl(1-naphthyl)methanamine; N-Methyl-N-(1-naphthylmethyl)amine; 1-Methyl-1-naphthalenemethylamine | 65473-13-4 | C12H13N | 详情 | 详情 |
| (VII) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (VIII) | 30538 | 4,4-dimethyl-2-pentyne | 999-78-0 | C7H12 | 详情 | 详情 |
| (IX) | 30539 | 6,6-dimethyl-1-hepten-4-yn-3-ol | C9H14O | 详情 | 详情 | |
| (X) | 30540 | (E)-1-bromo-5,5-dimethyl-1-hexen-3-yne | C8H11Br | 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 Org-6370 is carried out in eight steps as follows: The 5,9-methanobenzocyclooctene system is prepared from tetralonepyrrolidine enamine (I) and acrolein (II), giving a mixture of the epimeric 8-alcohols (III), which are dehydroxylated via the intermediate p-toluenesulfonate esters. The unsaturated 11-ketone (IV) is converted by a reductive amination process using methylamine and sodium borohydride to an epimeric mixture of 11-methylamines. At this stage the epimeric amines are separated by crystallization and the required (11S*)-compound (V) is further methylated and converted to the hydrochloride.
| 【1】 Timmer, C.J.; van der Waart, M.; Sam A.P.; Sitsen, J.M.A.; de Graaf, J.S.; Redpath, J.; ORG-6370. London: Libbey (B.S. Meldrum and R.J. Porter (Eds.) 1986. |
| 【2】 Pento, J.T.; ORG-6370. Drugs Fut 1989, 14, 2, 130. |
| 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) | 20382 | 1-(3,4-dihydro-2-naphthalenyl)pyrrolidine | 21403-95-2 | C14H17N | 详情 | 详情 |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 20384 | 10-hydroxytricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-13-one | C13H14O2 | 详情 | 详情 | |
| (IV) | 20385 | tricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-13-one | C13H14O | 详情 | 详情 | |
| (V) | 20386 | N-methyl-N-[(13S)tricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraen-13-yl]amine; (13S)-N-methyltricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraen-13-amine | C14H17N | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The condensation of the chiral oxazolidinone (I) with the pentenoic anhydride (II) by means of n-BuLi in THF gives the N-pentenoyloxazolidinone (III), which is condensed with acrolein (IV) catalyzed by TiCl4 and (-)-spartein in dichloromethane, yielding the chiral adduct (V). The ring-closing metathesis of (V) by means of a Ru catalyst in dichloromethane affords the chiral cyclopentenol derivative (VI), which is reduced to the (R,R)-5-(hydroxymethyl)-2-cyclopenten-1-ol (VII) by means of LiBH4 in THF. The reaction of diol (VII) with Ac2O; with methyl chloroformate, TEA and DMAP; or with ethyl chloroformate and pyridine gives the diacetate (VIII), the cyclic carbonate (IX) or the dicarbonate (X), respectively. The condensation of (VIII), (IX) or (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Finally, these compounds are hydrolyzed with aqueous NaOH to the target carbocyclic guanine.
| 【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499. |
| 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) | 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 |
| (II) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (III) | 17667 | (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C15H17NO3 | 详情 | 详情 | |
| (IV) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (V) | 17669 | (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H21NO4 | 详情 | 详情 | |
| (VI) | 17670 | (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one | C16H17NO4 | 详情 | 详情 | |
| (VII) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 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) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XI) | 11664 | 4-Chloro-3-nitroquinoline | C9H5ClN2O2 | 详情 | 详情 | |
| (XII) | 45424 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate | C13H14ClN5O2 | 详情 | 详情 | |
| (XIII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XIV) | 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：(III)The protection of 5-amino-1-pentanol (I) gives the fully protected compound (II), which is condensed with propenal (III) yielding the 3-aminopropanal derivative (IV). The condensation of aldehyde (IV) with phosphorane (V) yielded the protected 5-amino-2-bromopentenoic ester derivative (VI), which is deprotected with trimethylsilyl triflate to afford the ester (VII) with an unprotected secondary amino group.
| 【1】 Martin, S.F.; et al.; Enantioselective total synthesis of ircinal A and related manzamine alkaloids. J Am Chem Soc 1999, 121, 4, 866. |
| 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) | 22846 | 5-amino-1-pentanol | 2508-29-4 | C5H13NO | 详情 | 详情 |
| (II) | 24910 | tert-butyl 5-[[tert-butyl(diphenyl)silyl]oxy]pentylcarbamate | C26H39NO3Si | 详情 | 详情 | |
| (III) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (IV) | 24912 | tert-butyl 5-[[tert-butyl(diphenyl)silyl]oxy]pentyl(3-oxopropyl)carbamate | C29H43NO4Si | 详情 | 详情 | |
| (V) | 24913 | methyl 2-bromo-2-(triphenylphosphoranylidene)acetate | C21H18BrO2P | 详情 | 详情 | |
| (VI) | 24914 | methyl (Z)-2-bromo-5-[(tert-butoxycarbonyl)(5-[[tert-butyl(diphenyl)silyl]oxy]pentyl)amino]-2-pentenoate | C32H46BrNO5Si | 详情 | 详情 | |
| (VII) | 24915 | methyl (Z)-2-bromo-5-[(5-[[tert-butyl(diphenyl)silyl]oxy]pentyl)amino]-2-pentenoate | C27H38BrNO3Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXVII)4) The acylation of 4(S)-benzyloxazolidin-2-one (XXIV) with 4-pentenoyl pivaloyl anhydride (XXV) by means of NaH in THF gives 4(S)-benzyl-3-(4-pentenoyl)oxazolidin-2-one (XXVI), which is submitted to a diastereoselective syn aldol condensation with acrolein (XXVII), using dibutylboron triflate as catalyst, affording the aldol (XXVIII). The cyclization of (XXVIII) by means of the Grubbs catalyst in dichloromethane yields the cyclopentenol (XXIX), which is reduced with LiBH4 in THF/methanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). The reaction of (XXX) with methyl chloroformate/pyridine/DMAP or methyl chloroformate/triethylamine/DMAP or acetic anhydride gives the diols (XXXI), (XXXII) and (XXXIII), respectively, each of which coupled with 2-amino-6-chloropurine (XXXIV) in the presence of NaH and palladium tetrakis(triphenylphosphine) in THF/DMSO, affords the purine intermediate (IX) already reported.
| 【1】 King, B.W.; Crimmins, M.T.; An efficient asymmetric approach to carbocyclic nucleosides: Asymmetric synthesis of 1592U89, a potent inhibitor of HIV reverse transcriptase. J Org Chem 1996, 61, 13, 4192-3. |
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XXIV) | 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 |
| (XXV) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (XXVI) | 17667 | (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C15H17NO3 | 详情 | 详情 | |
| (XXVII) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (XXVIII) | 17669 | (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H21NO4 | 详情 | 详情 | |
| (XXIX) | 17670 | (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one | C16H17NO4 | 详情 | 详情 | |
| (XXX) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XXXI) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XXXII) | 17673 | (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one | C7H8O3 | 详情 | 详情 | |
| (XXXIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 详情 | 详情 | |
| (XXXIV) | 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 |
合成路线7
该中间体在本合成路线中的序号：(II)A new solid phase synthesis of abacavir has been reported: Condensation of the chiral 4(R)-benzyl-3-(4-pentenoyl)oxazolidin-2-thione (I) with acrolein (II) by means of TiCl4 and DIEA gives the adduct (III), which was transformed into the chiral cyclopentene (IV) by catalytic ring-closing metathesis. The reductive removal of the chiral auxiliary with LiBH4 affords the chiral diol (V), which is selectively silylated with TBDMSCl providing the primary silyl ether (VI). Acylation of the secondary alcohol of (VI) with benzoic anhydride gives the benzoate (VII), which is desilylated with HF in acetonitrile yielding the allylic benzoate (VIII). Benzoate (VIII) is condensed with a p-nitrophenyl Wang carbonate resin (IX) by means of DIEA and DMAP affording the solid phase resin (X) which is condensed with 2-amino-6-chloropurine (XI) by means of a Pd catalyst furnishing the adduct (XII). Thermal condensation of (XII) with cyclopropylamine (XIII) yields the diaminopurine resin (XIV) which, after cleavage from the resin by a treatment with TFA in dichloromethane, gives directly abacavir.
| 【1】 Zuercher, W.J.; Crimmins, M.T.; Solid-phase synthesis of carbocyclic nucleosides. Org Lett 2000, 2, 8, 1065. |
| 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) | 41704 | 1-[(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-4-penten-1-one | C15H17NO2S | 详情 | 详情 | |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 41705 | (2S,3R)-2-allyl-1-[(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-3-hydroxy-4-penten-1-one | C18H21NO3S | 详情 | 详情 | |
| (IV) | 41706 | [(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl][(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]methanone | C16H17NO3S | 详情 | 详情 | |
| (V) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VI) | 41707 | (1R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-ol | C12H24O2Si | 详情 | 详情 | |
| (VII) | 41708 | (1R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-yl benzoate | C19H28O3Si | 详情 | 详情 | |
| (VIII) | 41709 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-yl benzoate | C13H14O3 | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)An efficient asymmetric synthesis of abacavir has been reported: Acylation of the chiral oxazolidinone (I) with the mixed anhydride (II) by means of BuLi in THF gives the N-pentenoyloxazolidinone (III), which by condensation with acrolein (IV) catalyzed by TiCl4 and ()-spartein in dichloromethane yields the chiral adduct (V). The ring-closing metathesis of adduct (V) by means of the ruthenium catalyst (Cy3P)Cl2Ru=CHPh in dichloromethane affords the chiral cyclopentenol (VI), which is reduced to 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (VII) by means of LiBH4 in THF. Reaction of diol (VII) with a) Ac2O, TEA and DMAP, b) methyl chloroformate, TEA and DMAP or c) methyl chloroformate, pyridine and DMAP gives a) the diacetate (VIII), b) the cyclic carbonate (IX) or c) the dicarbonate (X), respectively. The condensation of diacetate (VIII), cyclic carbonate (IX) or dicarbonate (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Treatment of these chloro-purines (XII), (XIII) and (XIV) with cyclopropylamine (XV) in hot DMSO provides the corresponding cyclopropylaminopurine carbonate (XVI), abacavir or cyclopropylaminopurine acetate (XVII), respectively. Finally, the protecting groups of purines (XVI) and (XVII) are hydrolyzed with aqueous NaOH.
| 【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499. |
| 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) | 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 |
| (II) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (III) | 17667 | (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C15H17NO3 | 详情 | 详情 | |
| (IV) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (V) | 17669 | (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H21NO4 | 详情 | 详情 | |
| (VI) | 17670 | (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one | C16H17NO4 | 详情 | 详情 | |
| (VII) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 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) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 45424 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate | C13H14ClN5O2 | 详情 | 详情 | |
| (XIII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XIV) | 45398 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate | C13H14ClN5O3 | 详情 | 详情 | |
| (XV) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XVI) | 49433 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate | C16H20N6O2 | 详情 | 详情 | |
| (XVII) | 49434 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl methyl carbonate | C16H20N6O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Boron-catalyzed condensation of propionyl oxazolidinone (I) with acrolein (II) stereoselectively provided the aldol product (III), and further methanolysis afforded beta-hydroxy ester (IV). A second aldol condensation of (IV) with methacrolein (V) furnished a difficultly separable mixture of diols (VI). Conversion of (VI) to the corresponding acetonides by treatment with 2-methoxypropene (VII) allowed chromatographical separation of the required major isomer (VIII). Hydrolysis of the acetonide, followed by ring-closing metathesis of diene (XI) in the presence of Grubbs catalyst gave rise to cyclopentene (XII). Selective silylation of the less hindered allylic hydroxyl of (XII) with tert-butyldimethylsilyl chloride yielding (XIII) and subsequent oxidation of the remaining alcohol group with MnO2 then provided ketone (XIV). Conjugate addition of lithium di-n-butylcuprate to the unsaturated ketone, followed by phenylselenylation of the intermediate enolate with PhSeBr yielded alpha-selenyl ketone (XV). Oxidative elimination of the phenylselenyl group gave a (1:1) mixture of the required unsaturated ketone (XVII) and its exomethylene isomer (XVI). Isomerization of (XVI) to the desired endo isomer (XVII) was carried out by treatment with RhCl3.
| 【1】 Sunazuka, T.; et al.; Total synthesis of (+)-madindoline A and (-)-madindoline B, potent, selective inhibitors of interleukin 6. Determination of the relative and absolute configurations. J Am Chem Soc 2000, 122, 9, 2122. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 36695 | methyl (2R,3R)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (VIb) | 36696 | methyl (2S,3R)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (VIc),(XI) | 36697 | methyl (2S,3S)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (I) | 11535 | (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one | 77877-19-1 | C9H15NO3 | 详情 | 详情 |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 36693 | (4S)-3-[(2S,3R)-3-hydroxy-2-methyl-4-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C12H19NO4 | 详情 | 详情 | |
| (IV) | 36694 | methyl (2S,3R)-3-hydroxy-2-methyl-4-pentenoate | C7H12O3 | 详情 | 详情 | |
| (V) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (VII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VIII) | 36698 | methyl (4S,5R,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (IX) | 36699 | methyl (4R,5R,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (X) | 36700 | methyl (4R,5S,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (XII) | 36701 | methyl (1S,2S,5R)-2,5-dihydroxy-1,3-dimethyl-3-cyclopentene-1-carboxylate | C9H14O4 | 详情 | 详情 | |
| (XIII) | 36702 | methyl (1R,2S,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-1,3-dimethyl-3-cyclopentene-1-carboxylate | C15H28O4Si | 详情 | 详情 | |
| (XIV) | 36703 | methyl (1S,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethyl-2-oxo-3-cyclopentene-1-carboxylate | C15H26O4Si | 详情 | 详情 | |
| (XV) | 36704 | methyl (1S,5R)-4-butyl-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethyl-2-oxo-3-(phenylselanyl)cyclopentanecarboxylate | C25H40O4SeSi | 详情 | 详情 | |
| (XVI) | 36705 | methyl (1S,2R)-3-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-methylene-5-oxocyclopentanecarboxylate | C19H34O4Si | 详情 | 详情 | |
| (XVII) | 36706 | methyl (1S,2R)-3-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1,4-dimethyl-5-oxo-3-cyclopentene-1-carboxylate | C19H34O4Si | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XX)The silylation of the acetonide (XVIII) with Tms-Cl and LDA in THF gives dienolate (XIX), which is enantioselectively condensed with acrolein (XX) by means of Carreira's Ti catalyst in ethyl ether to yield the chiral allyl alcohol (XXI). The reaction of (XXI), N,O-dimethylhydroxylamine (XXII) and Me2AlCl affords the amide (XXIII), which is selectively reduced with Me4NBH(OAc)3 in HOAc/acetonitrile to provide the dihydroxyamide (XXIV). The silylation of the OH groups of (XXIV) with Tbdms-Cl and imidazole gives the disilylated compound (XXV), which is submitted to a Grignard reaction with vinylmagnesium bromide (XXVI) in THF to yield the vinyl ketone (XXVII). The Michael addition reaction with Ph2P(O)-Li and simultaneous triflation with (XXVIII) in THF affords the enol triflate (XXIX), which is cyclized by means of Pd(OAc)2, PPh3 and TEA in THF to provide the phosphorane (XXXa-b) as an inseparable mixture of the (Z)- and (E)-isomers. Finally, this mixture is submitted to photochemical isomerization with a medium-pressure UV mercury lamp in the presence of 9-fluorenone, furnishing the target intermediate, the (Z)-isomer (X) with a 95 % yield.
| 【1】 Anné, S.; et al.; Enantioselective syntheses of key A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Synlett 1999, 9, 1435. |
| 【2】 Hiyamizu, H.; et al.; A concise enantioselective synthesis of a key A-ring synthon for 1alpha-hydroxyvitamin D3 compounds. Org Lett 2001, 3, 3, 473. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXa),(X) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (XXXb) | 53658 | (E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide; (E)-[2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane | n/a | C33H51O3PSi2 | 详情 | 详情 |
| (XVIII) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (XIX) | 53651 | [(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether | n/a | C10H18O3Si | 详情 | 详情 |
| (XX) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (XXI) | 53652 | 6-[(2S)-2-hydroxy-3-butenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one | n/a | C10H14O4 | 详情 | 详情 |
| (XXII) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XXIII) | 53653 | (5S)-5-hydroxy-N-methoxy-N-methyl-3-oxo-6-heptenamide | n/a | C9H15NO4 | 详情 | 详情 |
| (XXIV) | 53654 | (3S,5S)-3,5-dihydroxy-N-methoxy-N-methyl-6-heptenamide | n/a | C9H17NO4 | 详情 | 详情 |
| (XXV) | 53655 | (3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methyl-6-heptenamide | n/a | C21H45NO4Si2 | 详情 | 详情 |
| (XXVI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XXVII) | 53626 | (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone | n/a | C19H27N3O3 | 详情 | 详情 |
| (XXVIII) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (XXIX) | 53657 | (3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(E)-2-(diphenylphosphoryl)ethylidene]-6-heptenyl trifluoromethanesulfonate | n/a | C34H52F3O6PSSi2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Condensation of 1-formyl-2-isopropylhydrazine (I) with acrolein (II) in cold Et2O produced the tetrahydropyrazole (III). Subsequent quaternization of (III) with iodomethane provided the title ammonium salt.
| 【1】 Zelenin, K.N.; et al.; Anti-inflammatory activity of 2-acyl-5(3)-hydroxytetrahydro-1H-pyrazole derivatives. Arzneim-Forsch Drug Res 1999, 49, 2, 843. |
合成路线12
该中间体在本合成路线中的序号：(II)The title compound was prepared by several synthetic routes: The condensation between N-benzylglycine t-butyl ester (I) and acrolein (II) furnished pyrrolidine (III) as a mixture of epimers at C-4. The mixture of aldehydes was further equilibrated to an 8:1 ratio by stirring the crude product with Et3N in EtOAc. Aldehyde reduction employing NaBH4 produced the corresponding mixture of alcohols, from which the desired isomer (IV) was isolated by column chromatography. After protection of the alcohol function as the acetate ester (V), dihydroxylation of the vinyl group of (V) with N-methylmorpholine N-oxide in the presence of OsO4 provided diol (VI). The N-benzyl group of (VI) was then removed by transfer hydrogenolysis with ammonium formate and Pd/C to give the secondary amine (VII), which was further converted to the N-Boc derivative (VIII). Selective silylation of the primary hydroxyl group of (VIII) employing triisopropylsilyl chloride and imidazole afforded the silyl ether (IX). The secondary hydroxyl group was then oxidized under Swern conditions to ketone (X). Reductive amination of (X) with ammonium acetate in the presence of NaBH3CN led to a mixture of epimeric amines (XI).
| 【1】 Inhibitors of neuraminidases. WO 0128996 . |
| 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) | 55134 | tert-butyl 2-(benzylamino)acetate | C13H19NO2 | 详情 | 详情 | |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 55135 | tert-butyl (2R,5S)-1-benzyl-4-formyl-5-vinyl-2-pyrrolidinecarboxylate | C19H25NO3 | 详情 | 详情 | |
| (IV) | 55136 | tert-butyl (2R,4R,5S)-1-benzyl-4-(hydroxymethyl)-5-vinyl-2-pyrrolidinecarboxylate | C19H27NO3 | 详情 | 详情 | |
| (V) | 55137 | tert-butyl (2R,4R,5S)-4-[(acetyloxy)methyl]-1-benzyl-5-vinyl-2-pyrrolidinecarboxylate | C21H29NO4 | 详情 | 详情 | |
| (VI) | 55138 | tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-1-benzyl-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate | C21H31NO6 | 详情 | 详情 | |
| (VII) | 55139 | tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate | C14H25NO6 | 详情 | 详情 | |
| (VIII) | 55140 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-1,2-pyrrolidinedicarboxylate | C19H33NO8 | 详情 | 详情 | |
| (IX) | 55141 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-hydroxy-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H53NO8Si | 详情 | 详情 | |
| (X) | 55142 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{2-[(triisopropylsilyl)oxy]acetyl}-1,2-pyrrolidinedicarboxylate | C28H51NO8Si | 详情 | 详情 | |
| (XI) | 55143 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(II)The condensation between N-benzylglycine t-butyl ester (I) and acrolein (II) furnished pyrrolidine (III) as a mixture of epimers at C-4. The mixture of aldehydes was further equilibrated to an 8:1 ratio by stirring the crude product with Et3N in EtOAc. Aldehyde (III) reduction employing NaBH4 produced the corresponding mixture of alcohols, from which the desired isomer (IV) was isolated by column chromatography. After protection of the alcohol function of (IV) as the acetate ester (V), dihydroxylation of the vinyl group of (V) with N-methylmorpholine N-oxide in the presence of OsO4 provided diol (VI). The N-benzyl group of (VI) was then removed by transfer hydrogenolysis with ammonium formate and Pd/C to give the secondary amine (VII), which was further converted to the N-Boc derivative (VIII). Selective silylation of the primary hydroxyl group of (VIII) employing triisopropylsilyl chloride and imidazole afforded the silyl ether (IX). The secondary hydroxyl group of (IX) was then oxidized under Swern conditions to ketone (X). Reductive amination of (X) with ammonium acetate in the presence of NaBH3CN led to a mixture of epimeric amines (XI).
| 【1】 Inhibitors of neuraminidases. WO 0128996 . |
| 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) | 55134 | tert-butyl 2-(benzylamino)acetate | C13H19NO2 | 详情 | 详情 | |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 55135 | tert-butyl (2R,5S)-1-benzyl-4-formyl-5-vinyl-2-pyrrolidinecarboxylate | C19H25NO3 | 详情 | 详情 | |
| (IV) | 55136 | tert-butyl (2R,4R,5S)-1-benzyl-4-(hydroxymethyl)-5-vinyl-2-pyrrolidinecarboxylate | C19H27NO3 | 详情 | 详情 | |
| (V) | 55137 | tert-butyl (2R,4R,5S)-4-[(acetyloxy)methyl]-1-benzyl-5-vinyl-2-pyrrolidinecarboxylate | C21H29NO4 | 详情 | 详情 | |
| (VI) | 55138 | tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-1-benzyl-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate | C21H31NO6 | 详情 | 详情 | |
| (VII) | 55139 | tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate | C14H25NO6 | 详情 | 详情 | |
| (VIII) | 55140 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-1,2-pyrrolidinedicarboxylate | C19H33NO8 | 详情 | 详情 | |
| (IX) | 55141 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-hydroxy-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H53NO8Si | 详情 | 详情 | |
| (X) | 55142 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{2-[(triisopropylsilyl)oxy]acetyl}-1,2-pyrrolidinedicarboxylate | C28H51NO8Si | 详情 | 详情 | |
| (XI) | 55143 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(II)The condensation between N-benzylglycine t-butyl ester (I) and acrolein (II) furnished pyrrolidine (III) as a mixture of epimers at C-4. The mixture of aldehydes (III) was further equilibrated to an 8:1 ratio by stirring the crude product with Et3N in EtOAc. Aldehyde (III) reduction employing NaBH4 produced the corresponding mixture of alcohols, from which the desired isomer (IV) was isolated by column chromatography. After protection of the alcohol function of (IV) as the acetate ester (V), dihydroxylation of the vinyl group of (V) with N-methylmorpholine N-oxide in the presence of OsO4 provided diol (VI). The N-benzyl group of (VI) was then removed by transfer hydrogenolysis with ammonium formate and Pd/C to give the secondary amine (VII), which was further converted to the N-Boc derivative (VIII). Selective silylation of the primary hydroxyl group of (VIII) employing triisopropylsilyl chloride and imidazole afforded the silyl ether (IX). The secondary hydroxyl group of (IX) was then oxidized under Swern conditions to ketone (X). Reductive amination of (X) with ammonium acetate in the presence of NaBH3CN led to a mixture of epimeric amines (XI).
| 【1】 Inhibitors of neuraminidases. WO 0128996 . |
| 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) | 55134 | tert-butyl 2-(benzylamino)acetate | C13H19NO2 | 详情 | 详情 | |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 55135 | tert-butyl (2R,5S)-1-benzyl-4-formyl-5-vinyl-2-pyrrolidinecarboxylate | C19H25NO3 | 详情 | 详情 | |
| (IV) | 55136 | tert-butyl (2R,4R,5S)-1-benzyl-4-(hydroxymethyl)-5-vinyl-2-pyrrolidinecarboxylate | C19H27NO3 | 详情 | 详情 | |
| (V) | 55137 | tert-butyl (2R,4R,5S)-4-[(acetyloxy)methyl]-1-benzyl-5-vinyl-2-pyrrolidinecarboxylate | C21H29NO4 | 详情 | 详情 | |
| (VI) | 55138 | tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-1-benzyl-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate | C21H31NO6 | 详情 | 详情 | |
| (VII) | 55139 | tert-butyl (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-2-pyrrolidinecarboxylate | C14H25NO6 | 详情 | 详情 | |
| (VIII) | 55140 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-(1,2-dihydroxyethyl)-1,2-pyrrolidinedicarboxylate | C19H33NO8 | 详情 | 详情 | |
| (IX) | 55141 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-hydroxy-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H53NO8Si | 详情 | 详情 | |
| (X) | 55142 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{2-[(triisopropylsilyl)oxy]acetyl}-1,2-pyrrolidinedicarboxylate | C28H51NO8Si | 详情 | 详情 | |
| (XI) | 55143 | di(tert-butyl) (2R,4R,5R)-4-[(acetyloxy)methyl]-5-{1-amino-2-[(triisopropylsilyl)oxy]ethyl}-1,2-pyrrolidinedicarboxylate | C28H54N2O7Si | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(LVIII)Conjugate addition of acrolein (LVIII) to nitromethane in the presence of KOH in MeOH followed by treatment with Na2S2O5 in H2O gives the nitrodisulfonate (LIX), which is hydrolyzed with glyoxylic acid by means of NaHCO3 to yield 4-nitroheptanedial (LX). Compound (LX) is cyclized in the presence of pyrrolidine and PhCOOH in CH2Cl2, providing 5-nitro-1-cyclohexenecarbaldehyde (LXI). Wittig reaction of aldehyde (LXI) with (methoxycarbonylmethylene)triphenylphosphorane (LXII) leads to conjugated ester (LXIII), which is finally saponified with NaOH .
Acid (XXXVII) can be alternatively prepared by Knoevenagel condensation of aldehyde (LXI) with malonic acid (LXIV) .
Hydrolysis of ethylene ketal (XVI) with aqueous p-toluenesulfonic acid gives ketone (LXV), which, without isolation, is converted to oxime (LXVI) by addition of hydroxylamine hydrochloride. Subsequent oxidation of oxime (LXVI) using sodium molybdate and H2O2 leads to compound (XXXVII) .
| 【1】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415. |
| 【2】 Thiruvengadam, T.K., Wang, T., Chiu, J.S., Liao, J. (Schering Corp.). Synthesis of 3-(5-nitrocyclohex-1-enyl)acrylic acid and esters thereof. EP 2035364, JP 2009542675, US 2008009651, WO 2008005344. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 68716 | (E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid | C11H14O4 | 详情 | 详情 | |
| (XXXVII) | 68733 | (E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid;3-(5-nitro-1-cyclohexenyl)-2-propenoic acid | C9H11NO4 | 详情 | 详情 | |
| (LVIII) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (LIX) | 68754 | sodium 1,7-dihydroxy-4-nitroheptane-1,7-disulfonate | C7H13NNa2O10S2 | 详情 | 详情 | |
| (LX) | 68755 | 4-nitroheptanedial | C7H11NO4 | 详情 | 详情 | |
| (LXI) | 68756 | 5-nitro-1-cyclohexenecarbaldehyde | C7H9NO3 | 详情 | 详情 | |
| (LXII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (LXIII) | 68757 | (E)-methyl 3-(5-nitrocyclohex-1-en-1-yl)acrylate | C10H13NO4 | 详情 | 详情 | |
| (LXIV) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (LXV) | 68758 | (E)-3-(5-oxocyclohex-1-en-1-yl)acrylic acid | C9H10O3 | 详情 | 详情 | |
| (LXVI) | 68759 | (E)-3-((E)-5-(hydroxyimino)cyclohex-1-en-1-yl)acrylic acid | C9H11NO3 | 详情 | 详情 |