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【结 构 式】 
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【分子编号】14687 【品名】3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol 【CA登记号】4799-68-2 |
【 分 子 式 】C10H14O2 【 分 子 量 】166.21996 【元素组成】C 72.26% H 8.49% O 19.25% |
合成路线1
该中间体在本合成路线中的序号：(I)A new and stereoselective synthesis of (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), a key intermediate in the synthesis of PS-5 has been developed: The oxidation of 3-benzyloxy-1-propanol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which is condensed with the phosphonate (III) by means of NaH yielding a mixture of the (Z)- and (E)-isomers of 5-benzyloxy-2-ethyl-2-pentenoic acid ethyl ester (IV) and (V). The undesired (Z)-isomer (IV) is isomerized by treating the mixture with diphenyldisulfide in refluxing THF. The hydrolysis of (V) with LiOH in THF/methanol/water gives the expected free acid (VI), which is treated with SOCl2 in refluxing benzene to afford the acid chloride (VII). The condensation of (VII) with the chiral oxazolidinone (VIII) by means of butyllithium in THF gives the acylated compound (IX), which is treated with benzenethiol and butyllithium in THF to give the addition compound (X) that is purified by medium pressure column chromatography to eliminate the undesired diastereomer. The elimination of the oxazolidinone group of (X) by reaction with trimethylaluminum, benzylthiol and butyllithium in THF yields the thioester (XI), which is treated with silver trfluoroacetate and water to afford the corresponding free acid (XII). The reaction of (XII) with methoxyamine and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDPC) in water affords the methoxyamide (XIII), which is methylated by means of methyl iodide and silver perchlorate to give the sulfonium salt (XIV). The cyclization of (XIV) by means of K2CO3 yields the azetidinone (XV), which is debenzylated by means of calcium in liquid ammonia affording (3R-trans)-3-ethyl-4-(2-hydrxyethyl)azetidin-2-one (XVI). Finally, this compound is silylated with tert-butyldimethylsilyl (TBDMS) trifluoromethanesulfonate affording (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), the desired target key intermediate in the synthesis of PS-5.
| 【1】 Fujiwara,Y.; Ninomiya, I.; Miyata, O.; Naito, T.; Efficient stereoselective route to beta-lactams and their application to the stereoselective synthesis of a key intermediate for carbapenem antibiotic (+)-PS-5. J Chem Soc - Perkins Trans I 1998, 14, 14, 2167. |
| 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) | 14687 | 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol | 4799-68-2 | C10H14O2 | 详情 | 详情 |
| (II) | 14688 | 3-(benzyloxy)propanal | C10H12O2 | 详情 | 详情 | |
| (IV) | 20274 | ethyl 2-(diethoxyphosphoryl)butanoate | 17145-91-4 | C10H21O5P | 详情 | 详情 |
| (V) | 20275 | ethyl (Z)-5-(benzyloxy)-2-ethyl-2-pentenoate | C16H22O3 | 详情 | 详情 | |
| (VI) | 20277 | (E)-5-(benzyloxy)-2-ethyl-2-pentenoic acid | C14H18O3 | 详情 | 详情 | |
| (VII) | 20278 | (E)-5-(benzyloxy)-2-ethyl-2-pentenoyl chloride | C14H17ClO2 | 详情 | 详情 | |
| (VIII) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (IX) | 20280 | (4S)-3-[(E)-5-(benzyloxy)-2-ethyl-2-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C20H27NO4 | 详情 | 详情 | |
| (X) | 20281 | (4S)-3-[(2S,3S)-5-(benzyloxy)-2-ethyl-3-(phenylsulfanyl)pentanoyl]-4-isopropyl-1,3-oxazolidin-2-one | C26H33NO4S | 详情 | 详情 | |
| (XI) | 20282 | S-benzyl (2R,3S)-5-(benzyloxy)-2-ethyl-3-(phenylsulfanyl)pentanethioate | C27H30O2S2 | 详情 | 详情 | |
| (XII) | 20283 | (2S,3S)-5-(benzyloxy)-2-ethyl-3-(phenylsulfanyl)pentanoic acid | C20H24O3S | 详情 | 详情 | |
| (XIII) | 20284 | (2S,3S)-5-(benzyloxy)-2-ethyl-N-methoxy-3-(phenylsulfanyl)pentanamide | C21H27NO3S | 详情 | 详情 | |
| (XIV) | 20285 | [(1S,2S)-1-[2-(benzyloxy)ethyl]-2-[(methoxyamino)carbonyl]butyl](methyl)phenylsulfonium iodide | C22H30INO3S | 详情 | 详情 | |
| (XV) | 20286 | (3R,4R)-4-[2-(benzyloxy)ethyl]-3-ethyl-1-methoxy-2-azetidinone | C15H21NO3 | 详情 | 详情 | |
| (XVI) | 20287 | (3R,4R)-3-ethyl-4-(2-hydroxyethyl)-2-azetidinone | C7H13NO2 | 详情 | 详情 | |
| (XVII) | 20051 | (3R,4R)-1-[tert-butyl(dimethyl)silyl]-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-ethyl-2-azetidinone | C19H41NO2Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)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.
| 【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3
该中间体在本合成路线中的序号：(IV)Orcinol (I) is first derivatized to (III) by reaction with sulfonyl chloride (II) in a mixture of aqueous NaHCO3 (sat) and Et2O. Monosulfonate (III) undergoes Mitsunobu reaction with monobenzylated diol (IV) in the presence of PPh3 and DEAD in dichloromethane to yield derivative (V), which is then debenzylated by hydrogenolysis over Pd/C in MeOH, or in THF/HCl/dioxane, to afford (VI). Alcohol (VI) is oxidized with SO3·pyr complex in DMSO/dichloromethane in the presence of DIEA to provide aldehyde (VIII), which finally reacts with aminoguanidine nitrate in EtOH in the presence of HCl/dioxane.
| 【1】 Soll, R.M.; Lu, T.; Tomczuk, B.; et al.; Amidinohydrazones as guanidine bioisosteres: Application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors. Bioorg Med Chem Lett 2000, 10, 1, 1. |
| 【2】 Soll, R.M.; Lu, T.; Fedde, C.L.; Tomczuk, B.E.; Illig, C. (3-Dimensional Pharmaceuticals, Inc.); Amidinohydrazones as protease inhibitors. EP 0906091; JP 2000507588; US 5891909; WO 9736580 . |
| 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) | 27257 | 5-Methyl-1,3-benzenediol; Orcinol | 505-15-4 | C7H8O2 | 详情 | 详情 |
| (II) | 30817 | 2-chlorobenzenesulfonyl chloride | 2905-23-9 | C6H4Cl2O2S | 详情 | 详情 |
| (III) | 30818 | 3-hydroxy-5-methylphenyl 2-chlorobenzenesulfonate | C13H11ClO4S | 详情 | 详情 | |
| (IV) | 14687 | 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol | 4799-68-2 | C10H14O2 | 详情 | 详情 |
| (V) | 30819 | 3-[3-(benzyloxy)propoxy]-5-methylphenyl 2-chlorobenzenesulfonate | C23H23ClO5S | 详情 | 详情 | |
| (VI) | 30820 | 3-(3-hydroxypropoxy)-5-methylphenyl 2-chlorobenzenesulfonate | C16H17ClO5S | 详情 | 详情 | |
| (VII) | 30821 | 3-methyl-5-(3-oxopropoxy)phenyl 2-chlorobenzenesulfonate | C16H15ClO5S | 详情 | 详情 | |
| (VIII) | 10015 | 1-Hydrazinecarboximidamide; Hydrazinecarboximidamide | 79-17-4 | CH6N4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Iodophenylpentadecanoic acid (I) was reduced to the corresponding alcohol (II) with borane in THF and then converted to the tosylate (III). Treatment of 3-(benzyloxy)propanol (IV) with CBr4 and PPh3 afforded bromide (V). This was treated with Mg in THF and the resulting Grignard reagent was coupled with tosylate (III) in the presence of Li2CuCl4 to provide octadecyl benzyl ether (VI), which was cleaved to the aryl octadecanol (VII) using AlCl3 and anisole. Reaction of alcohol (VII) with phospholane (VIII), followed by condensation with trimethylamine then furnished the title compound.
| 【1】 Weichert, J.P.; Rampy, M.A.; Counsell, R.E.; Longino, M.A.; Pinchuk, A.N. (University of Michigan); Radioiodinated phospholipid ether analogs and methods of using the same. WO 9824480 . |
| 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) | 28077 | 15-(4-iodophenyl)pentadecanoic acid | C21H33IO2 | 详情 | 详情 | |
| (II) | 28078 | 15-(4-iodophenyl)-1-pentadecanol | C21H35IO | 详情 | 详情 | |
| (III) | 28079 | 15-(4-iodophenyl)pentadecyl 4-methylbenzenesulfonate | C28H41IO3S | 详情 | 详情 | |
| (IV) | 14687 | 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol | 4799-68-2 | C10H14O2 | 详情 | 详情 |
| (V) | 28080 | 1-[(3-bromopropoxy)methyl]benzene | C10H13BrO | 详情 | 详情 | |
| (VI) | 28081 | benzyl 18-(4-iodophenyl)octadecyl ether | C31H47IO | 详情 | 详情 | |
| (VII) | 28081 | benzyl 18-(4-iodophenyl)octadecyl ether | C31H47IO | 详情 | 详情 | |
| (VIII) | 28082 | 18-(4-iodophenyl)-1-octadecanol | C24H41IO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)2-Chlorobenzenesulfonyl chloride (I) was coupled to orcinol (II) to give sulfonate (III). Subsequent condensation of (III) with 3-benzyloxypropanol (IV) under Mitsunobu conditions afforded ether (V). After hydrogenolytic deprotection of the benzyl group, Swern oxidation of the resulting alcohol (VI) with DMSO and SO3-pyridine complex provided aldehyde (VII). The title amidinohydrazone was then obtained by treatment of (VII) with aminoguanidine nitrate (VIII).
| 【1】 Soll, R.M.; Lu, T.; Fedde, C.L.; Tomczuk, B.E.; Illig, C. (3-Dimensional Pharmaceuticals, Inc.); Amidinohydrazones as protease inhibitors. EP 0906091; JP 2000507588; US 5891909; WO 9736580 . |
| 【2】 Tomczuk, B.E.; Stagnaro, T.P.; Fedde, C.L.; Lu, T.; Markotan, T.P.; Illig, C.R.; Soll, R.M. (3-Dimensional Pharmaceuticals, Inc.); Aminoguanidines and alkoxyguanidines as protease inhibitors. EP 0944590; WO 9823565 . |
| 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) | 30817 | 2-chlorobenzenesulfonyl chloride | 2905-23-9 | C6H4Cl2O2S | 详情 | 详情 |
| (II) | 27257 | 5-Methyl-1,3-benzenediol; Orcinol | 505-15-4 | C7H8O2 | 详情 | 详情 |
| (III) | 30818 | 3-hydroxy-5-methylphenyl 2-chlorobenzenesulfonate | C13H11ClO4S | 详情 | 详情 | |
| (IV) | 14687 | 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol | 4799-68-2 | C10H14O2 | 详情 | 详情 |
| (V) | 30819 | 3-[3-(benzyloxy)propoxy]-5-methylphenyl 2-chlorobenzenesulfonate | C23H23ClO5S | 详情 | 详情 | |
| (VI) | 30820 | 3-(3-hydroxypropoxy)-5-methylphenyl 2-chlorobenzenesulfonate | C16H17ClO5S | 详情 | 详情 | |
| (VII) | 30821 | 3-methyl-5-(3-oxopropoxy)phenyl 2-chlorobenzenesulfonate | C16H15ClO5S | 详情 | 详情 | |
| (VIII) | 10015 | 1-Hydrazinecarboximidamide; Hydrazinecarboximidamide | 79-17-4 | CH6N4 | 详情 | 详情 |