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【结 构 式】 
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【分子编号】16659 【品名】ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate 【CA登记号】687-47-8 |
【 分 子 式 】C5H10O3 【 分 子 量 】118.1326 【元素组成】C 50.84% H 8.53% O 40.63% |
合成路线1
该中间体在本合成路线中的序号：(XXX)Protection of ethyl lactate (XXX) with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole provides derivative (XXXI), which is then converted into dipeptide (XXXII) by first hydrolysis with LiOH in THF/H2O followed by coupling with L-proline methyl ester (X) by means of DCC, HOBt and NMM. Next, hydrolysis of the methyl ester of (XXXII) with LiOH in THF/H2O yields carboxylic acid (XXXIII). Esterification of Z-D-N-Me-Leu (XXXIV) with 2-(trimethylsilyl)ethanol (XXXV) by means of EDCI, DMAP and Et3N in DMF furnishes leucine derivative (XXXVI), whose Z protecting group is removed by hydrogenation over Pd/C in MeOH/AcOEt to afford secondary amine (XXXVII). Coupling of carboxylic acid (XXXIII) with amine (XXXVII) is then performed by means of BOPCl, Et3N. Treatment with tetrabutylammonium fluoride in DMF allows protecting group removal to provide carboxylic acid derivative (XXXVIII), which is then attached to macrocycle (XXIX) by means of BOP and NMM in CH2Cl2 to furnish the target didemnin.
| 【1】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 29552 | methyl (2S)-2-pyrrolidinecarboxylate | 2133-40-6 | C6H11NO2 | 详情 | 详情 |
| (XXIX) | 50769 | ethyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate | C11H24O3Si | 详情 | 详情 | |
| (XXX) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (XXXI) | 50769 | ethyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate | C11H24O3Si | 详情 | 详情 | |
| (XXXII) | 50770 | methyl (2S)-1-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (XXXIII) | 50771 | (2S)-1-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylic acid | C14H27NO4Si | 详情 | 详情 | |
| (XXXIV) | 50772 | (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid | C15H21NO4 | 详情 | 详情 | |
| (XXXV) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (XXXVI) | 50773 | 2-(trimethylsilyl)ethyl (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoate | C20H33NO4Si | 详情 | 详情 | |
| (XXXVII) | 50774 | 2-(trimethylsilyl)ethyl (2R)-4-methyl-2-(methylamino)pentanoate | C12H27NO2Si | 详情 | 详情 | |
| (XXXVIII) | 37840 | (2R)-2-[([(2S)-1-[(2S)-2-hydroxypropanoyl]pyrrolidinyl]carbonyl)(methyl)amino]-4-methylpentanoic acid | C15H26N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXII)Treatment of ethyl lactate (XXXII) with benzyl bromide and silver oxide in DMF gives Bzl-Lac-OH (XXXIII), which is then coupled with H-Pro-OMe (XXXIV) by means of DEPC and then saponified with NaOH in MeOH to yield derivative (XXXV). Finally, didemnin B is obtained by coupling of intermediate (XXXI) with (XXXV) by means of BOPCl and Et3N, followed by debenzylation with HCO2H and Pd in MeOH.
| 【1】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837. |
| 【2】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669. |
| 【3】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXI) | 50796 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C49H78N6O12 | 详情 | 详情 | |
| (XXXII) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (XXXIII) | 50797 | (2S)-2-(benzyloxy)propionic acid | C10H12O3 | 详情 | 详情 | |
| (XXXIV) | 29552 | methyl (2S)-2-pyrrolidinecarboxylate | 2133-40-6 | C6H11NO2 | 详情 | 详情 |
| (XXXV) | 50798 | (2S)-1-[(2S)-2-(benzyloxy)propanoyl]-2-pyrrolidinecarboxylic acid | C15H19NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)2) The condensation of 4-fluorophenol (I) with ethyl (S)-lactate (II) by means of diethyl azodicarboxylate and triphenylphosphine in THF gives ethyl 2(R)-(4-fluorophenoxy)propionate (III), which is reduced with LiAlH4 in THF yielding 2(R)-(4-fluorophenoxy)propanol (IV). The reaction of (IV) with Br2 and triphenylphosphine in DMF affords 1-bromo-2(R)-(4-fluorophenoxy)propane (V), which is condensed with N-benzoyl-2-hydroxyglycine (VI) by means of methanesulfonic acid to give (RS)-N-benzoyl-2-[2-(1-bromo-2(R)propoxy)-5-fluorophenyl]glycine (VII). The cyclization of (VII) by means of acetic anhydride and K2CO3 in acetone yields 6-fluoro-2(R)-methyl-2'-phenylspiro[2,3-dihydro-4H-1-benzopyran-4(RS),4'-oxazolidin]-5'-one (VIII), which is hydrolyzed with refluxing formic acid-HCl affording 4(RS)-amino-6-fluoro-2(R)-methyl-2,3-dihydro-4H-1-benzopyran-4-carboxylic acid (IX). The esterification of (IX) with Cl2SO and methanol gives the corresponding methyl ester (X), which is submitted to optical resolution with alpha-chymotrypsine to yield methyl 4(S)-amino-6-fluoro-2(R)-methyl-2,3-dihydro-4H-1-benzopyran-4-carboxylate (XI). Finally, this compound is cyclized with sodium cyanate in acetic acid.
| 【1】 Prous, J.; Castaner, J.; METHOSORBINIL. Drugs Fut 1989, 14, 4, 325. |
| 【2】 Moore, B.S.; Urban, F.J.; Dirlam, N.L.; Novel synthesis of the aldose reductase inhibitor sorbinil via amidoalkylation, intramolecular oxazolidin-5-one alkylation, and chymotrypsin resolution. J Org Chem 1987, 52, 16, 3587. |
| 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) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
| (II) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (III) | 20603 | ethyl (2R)-2-(4-fluorophenoxy)propanoate | C11H13FO3 | 详情 | 详情 | |
| (IV) | 20604 | (2R)-2-(4-fluorophenoxy)-1-propanol | C9H11FO2 | 详情 | 详情 | |
| (V) | 20605 | 1-[[(1R)-2-bromo-1-methylethyl]oxy]-4-fluorobenzene; (1R)-2-bromo-1-methylethyl 4-fluorophenyl ether | C9H10BrFO | 详情 | 详情 | |
| (VI) | 20606 | 2-(benzoylamino)-2-hydroxyacetic acid | 16555-77-4 | C9H9NO4 | 详情 | 详情 |
| (VII) | 20607 | 2-(benzoylamino)-2-(2-[[(1R)-2-bromo-1-methylethyl]oxy]-5-fluorophenyl)acetic acid | C18H17BrFNO4 | 详情 | 详情 | |
| (VIII) | 20608 | 6-Fluoro-2(R)-methyl-2'-phenyl-3,4,4',5'-tetrahydro-2H-spiro[1-benzopyran-4,4'-oxazol]-5'-one | C18H14FNO3 | 详情 | 详情 | |
| (IX) | 20609 | (2R)-4-amino-6-fluoro-2-methyl-3,4-dihydro-2H-chromene-4-carboxylic acid | C11H12FNO3 | 详情 | 详情 | |
| (X) | 20610 | methyl (2R)-4-amino-6-fluoro-2-methyl-3,4-dihydro-2H-chromene-4-carboxylate | C12H14FNO3 | 详情 | 详情 | |
| (XI) | 20611 | (2R,4S)-4-amino-6-fluoro-2-methyl-3,4-dihydro-2H-chromene-4-carboxylic acid | C11H12FNO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVIII)3) The tosylation of (S)-lactic acid ethyl ester (XVIII) with tosyl chloride and triethylamine gives the corresponding tosylate (XIX), which is reduced with NaBH4, diisobutylaluminum hydride (DIBAL) or borane.THF complex yielding 2(S)-(tosyloxy)-1-propanol (XX). The epoxidation of (XX) with KOH in water or NaH in DMSO/THF affords (R)-propylene oxide (XXI), which is condensed with 1-(benzyloxy)-2-propynyl (XXII) [obtained by benzylation of propargyl alcohol (XXIII) with benzyl chloride and NaOH] by means of butyllithium in THF or lithium amide in DMSO to give 6-benzyloxy-4-hexyn-2(R)-ol (XXIV). The acetylation of (XXIV) with acetic anhydride yields the corresponding acetate (XXV), which is reduced with H2 over Raney Nickel in ethanol to afford the expected 2(R),6-hexanediol derivative (XXVI). The debenzylation of (XXVI) by hydrogenation with H2 over Pd/C in acetic acid gives 5(R)-acetoxy-1-hexanol (XXVII), which is treated with SOCl2 to yield the corresponding hexyl chloride (XXVIII). The condensation of (XXVIII) with 3,7-dimethylxanthine (X) by means of sodium methoxide in DMSO affords the 5'-O-acetyllisofylline (XXIX), which is finally deacetylated by treatment with HCl in methanol/water. 4) The 5(R)-acetoxy-1-hexanol (XXVII) can also be obtained as follows: The addition of chiral epoxide (XXI) to acetaldehyde ethyl propargyl acetal (XXX) by means of lithium amide in DMSO gives 6-(1-ethoxyethoxy)-4-hexyn-2(R)-ol (XXXI), which is acetylated with acetic anhydride as before to the acetate (XXXII). The hydrogenation of (XXXII) with H2 over Raney Nickel in ethanol yields the corresponding saturated acetate (XXXIII), which is finally deprotected with aqueous HCl to the expected 5(R)-acetoxy-1-hexanol (XXVII) already reported.
| 【1】 Graul, J.; Casas, A.; Castañer, J.; Lisofylline. Drugs Fut 1997, 22, 5, 492. |
| 【2】 Klein, J.P.; Leigh, A.J.; Michnick, J.; Kumar, A.M.; Underiner, G.E. (Cell Therapeutics, Inc.); Asymetric synthesis of chiral secondary alcohols. WO 9531450 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 16651 | theobromine; 3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione | 83-67-0 | C7H8N4O2 | 详情 | 详情 |
| (XVIII) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (XIX) | 16660 | ethyl (2S)-2-[[(4-methylphenyl)sulfonyl]oxy]propanoate | 57057-80-4 | C12H16O5S | 详情 | 详情 |
| (XX) | 16661 | (1S)-2-hydroxy-1-methylethyl 4-methylbenzenesulfonate | C10H14O4S | 详情 | 详情 | |
| (XXI) | 16662 | (2R)-2-Methyloxirane; (R)-(+)-Propylene oxide | 15448-47-2 | C3H6O | 详情 | 详情 |
| (XXII) | 16663 | benzyl 2-propynyl ether; 1-[(2-propynyloxy)methyl]benzene | C10H10O | 详情 | 详情 | |
| (XXIII) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (XXIV) | 16665 | (2R)-6-(benzyloxy)-4-hexyn-2-ol | C13H16O2 | 详情 | 详情 | |
| (XXV) | 16666 | (1R)-5-(benzyloxy)-1-methyl-3-pentynyl acetate | C15H18O3 | 详情 | 详情 | |
| (XXVI) | 16667 | (1R)-5-(benzyloxy)-1-methylpentyl acetate | C15H22O3 | 详情 | 详情 | |
| (XXVII) | 16668 | (1R)-5-hydroxy-1-methylpentyl acetate | C8H16O3 | 详情 | 详情 | |
| (XXVIII) | 16669 | (1R)-5-chloro-1-methylpentyl acetate | C8H15ClO2 | 详情 | 详情 | |
| (XXIX) | 16670 | (1R)-5-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-1-methylpentyl acetate | C15H22N4O4 | 详情 | 详情 | |
| (XXX) | 16671 | 1-ethoxyethyl 2-propynyl ether; Acetaldehyde ethyl propargyl acetal; 3-(1-ethoxyethoxy)-1-propyne | 18669-04-0 | C7H12O2 | 详情 | 详情 |
| (XXXI) | 16672 | (2R)-6-(1-ethoxyethoxy)-4-hexyn-2-ol | C10H18O3 | 详情 | 详情 | |
| (XXXII) | 16673 | (1R)-5-(1-ethoxyethoxy)-1-methyl-3-pentynyl acetate | C12H20O4 | 详情 | 详情 | |
| (XXXIII) | 16674 | (1R)-5-(1-ethoxyethoxy)-1-methylpentyl acetate | C12H24O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)A new synthesis of Sch-56592 has been described: The reaction of (S)-ethyl lactate (I) with pyrrolidine (II) gives 1-[(S)-lactoyl]pyrrolidine (III), which is benzylated as usual with benzyl chloride yielding the benzyl ether (IV). The reaction of (IV) with ethylmagnesium bromide in THF affords 2(S)-benzyloxy-3-pentanone (V), which is reduced with LiBH4 in dimethoxyethane giving 2(S)-benzyloxy-3(RS)-pentanol (VI). The reaction of (VI) with 4-chlorobenzenesulfonyl chloride (VII) yields the corresponding sulfonate (VIII), which is treated with hydrazine in ethanol to afford a diastereomeric mixture of hydrazines that is resolved with L-dibenzoyltartaric acid giving the (S,S)-enantiomer (IX). The formylation of (IX) with refluxing ethyl formate yields the chiral formyl hydrazide (X), which is cyclized with N-[4-[4-[4-(trimethylsilyloxy)phenyl]piperazin-1-yl]phenyl]carbamic acid phenyl ester (XI) affording the triazolone (XII). Finally, this compound is condensed with the chiral tetrahydrofuran derivative (XIII) by means of NaOH in DMSO, and debenzylated by hydrogenation with H2 over Pd/C in formic acid
| 【1】 Andrews, D.R.; Gala, D.; Gosteli, J.; Guenter, F.; Leong, W.; Mergelsberg, I.; Sudhakar, A. (Schering Corp.); Process for the preparation of triazolones. WO 9633178 . |
| 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) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 17099 | (2S)-2-hydroxy-1-(1-pyrrolidinyl)-1-propanone | C7H13NO2 | 详情 | 详情 | |
| (IV) | 17100 | (2S)-2-(benzyloxy)-1-(1-pyrrolidinyl)-1-propanone | 122151-32-0 | C14H19NO2 | 详情 | 详情 |
| (V) | 17101 | (2S)-2-(benzyloxy)-3-pentanone | C12H16O2 | 详情 | 详情 | |
| (VI) | 17102 | (2S)-2-(benzyloxy)-3-pentanol | C12H18O2 | 详情 | 详情 | |
| (VII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (VIII) | 17104 | (2S)-2-(benzyloxy)-1-ethylpropyl 4-chlorobenzenesulfonate | C18H21ClO4S | 详情 | 详情 | |
| (IX) | 17105 | 1-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]hydrazine; benzyl (1S,2S)-2-hydrazino-1-methylbutyl ether | C12H20N2O | 详情 | 详情 | |
| (X) | 17106 | N'-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]formic hydrazide | C13H20N2O2 | 详情 | 详情 | |
| (XI) | 17107 | phenyl 4-(4-[4-[(trimethylsilyl)methyl]phenyl]-1-piperazinyl)phenylcarbamate | C27H33N3O2Si | 详情 | 详情 | |
| (XII) | 17108 | 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C30H35N5O3 | 详情 | 详情 | |
| (XIII) | 17109 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-chlorobenzenesulfonate | C20H18ClF2N3O4S | 详情 | 详情 | |
| (XIV) | 17110 | 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine | 74853-08-0 | C16H19N3O | 详情 | 详情 |
| (XV) | 17111 | phenyl N-[4-[4-(4-hydroxyphenyl)piperazino]phenyl]carbamate | C23H23N3O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The Horner-Emmons reaction of 1-azabicyclo[2.2.1]heptan-3-one (I) with triethyl phosphonoacetate (II) gave conjugated ester (III). Subsequent Michael addition of the oxyanion of ethyl (S)-lactate (IV), generated in the presence of NaH in DMF, with concomitant Dieckmann cyclization, produced ketoester (V). Then, hydrolysis and decarboxylation in boiling 1 N HCl, followed by separation of the syn and anti isomers, yielded the title compound.
| 【1】 Wu, E.S.C.; Kover, A.; Semus, S.F.; Synthesis and modeling studies of a potent conformationally rigid muscarinic agonist: 1-Azabicyclo[2.2.1]heptanespirofuranone. J Med Chem 1998, 41, 22, 4181. |
| 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) | 20473 | 1-azabicyclo[2.2.1]heptan-3-one | C6H9NO | 详情 | 详情 | |
| (II) | 20474 | ethyl 2-[(diethoxyphosphino)oxy]acetate | C8H17O5P | 详情 | 详情 | |
| (III) | 20475 | ethyl 2-(1-azabicyclo[2.2.1]hept-3-ylidene)acetate | C10H15NO2 | 详情 | 详情 | |
| (IV) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (V) | 20477 | 5'-Methyl-4'-oxospiro[1-azabicyclo[2,2,1]octane-3(S),2'-tetrahydrofuran]-3'-ylcarboxylic acid ethyl ester | C13H19NO4 | 详情 | 详情 |