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【结 构 式】 
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【分子编号】14685 【品名】1,3-propanediol; Trimethylene Glycol 【CA登记号】504-63-2 |
【 分 子 式 】C3H8O2 【 分 子 量 】76.09532 【元素组成】C 47.35% H 10.6% O 42.05% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of trimethylene glycol (I) with PCl3 gives 2-chloro-1,3,2-dioxaphosphorinane (II), which is condensed with propargyl alcohol (III) by means of triethylamine in acetonitrile to give a mixture of 2-allenyl- and 2-propargyl-2-oxo-1,3,2-dioxaphosphorinane (IV and V). The reaction of this mixture with isobutylamine in acetonitrile affords 2-(2-isobutylamino-1-propenyl)-2-oxo-1,3,2-dioxaphosphorinane (VI). The hydrolysis of the enamine (VI) with malonic acid gives 2-acetonyl-2-oxo-1,3,2-dioxaphosphorinane (VII), which is condensed with isobutyl-(2-nitrobenzylidene)amine (VIII) to yield 2-[1-(2-nitrobenzylidene)-2-oxopropyl]-2-oxo-1,3,2-dioxaphosphorinane (IX). Finally, this compound is cyclized with methyl 3-aminocrotonate (X) in refluxing acetonitrile.
| 【1】 Morita, I.; Tsuda, M.; Kise, M.; Sugiyama, M.; Improved synthesis of methyl 2, 6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3, 2-dioxaphosphorinan-2-yl)-1, 4-dihydropyridine-3-carboxylate (DHP-218). Chem Pharm Bull 1988, 36, 3, 1139-42. |
| 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) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (II) | 20567 | 2-chloro-1,3,2-dioxaphosphinane | C3H6ClO2P | 详情 | 详情 | |
| (III) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (IV) | 20569 | 2-(1,2-propadienyl)-1,3,2lambda(5)-dioxaphosphinan-2-one | C6H9O3P | 详情 | 详情 | |
| (V) | 20570 | 2-(1-propynyl)-1,3,2lambda(5)-dioxaphosphinan-2-one | C6H9O3P | 详情 | 详情 | |
| (VI) | 20571 | 2-[(E)-2-(isobutylamino)-1-propenyl]-1,3,2lambda(5)-dioxaphosphinan-2-one | C10H20NO3P | 详情 | 详情 | |
| (VII) | 20572 | 2-(2-oxopropyl)-1,3,2lambda(5)-dioxaphosphinan-2-one | C6H11O4P | 详情 | 详情 | |
| (VIII) | 20573 | 2-methyl-N-[(Z)-(2-nitrophenyl)methylidene]-1-propanamine; N-isobutyl-N-[(Z)-(2-nitrophenyl)methylidene]amine | C11H14N2O2 | 详情 | 详情 | |
| (IX) | 20574 | 2-[(Z)-1-acetyl-2-(2-nitrophenyl)ethenyl]-1,3,2lambda(5)-dioxaphosphinan-2-one | C13H14NO6P | 详情 | 详情 | |
| (X) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (XI) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The synthesis of the title compound has been reported starting from the known Diels-Alder adduct (I) of a cholestadiene derivative with 4-phenyl-1,2,4-triazolidinedione. Epoxide ring opening in (I) with 1,3-propanediol (II) in the presence of p-toluenesulfonic acid gave the 1,3-dihydroxy-2-(hydroxypropoxy) derivative (III). Subsequent retro-Diels-Alder reaction in (III) under reductive conditions furnished the cholestadiene compound (IV) (1). In a related sequence, initial retro-cycloaddition reaction in hot dimethylimidazolidinone, followed by ring opening of the resultant epoxide (V) with diol (II) provided an alternative access to diene (IV) (2). Conversion of diene (IV) to the title vitamin D3 analogue was effected by irradiation using a high pressure mercury lamp, followed by thermal isomerization in boiling THF
| 【1】 Miyamoto, K.; Kubodera, N.; Ochi, K.; Matsunaga, I.; Murayama, E. (Chugai Pharmaceutical Co. Ltd.); Vitamin D3 derivs. having a substituent at 2-position. EP 0184206; JP 1986267549; US 4666634 . |
| 【2】 Miyamoto, K.; et al.; Synthetic studies of vitamin D analogues. XIV. Synthesis and calcium regulating activity of vitamin D3 analogues bearing a hydroxyalkoxy group at the 2beta-position. Chem Pharm Bull 1993, 41, 6, 1111. |
| 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) | 59850 | (1S,2R,5R,6R,10R,11S,13S,14R,16S)-14-hydroxy-5-[(1R)-5-hydroxy-1,5-dimethylhexyl]-6,10-dimethyl-19-phenyl-12-oxa-17,19,21-triazaheptacyclo[14.5.2.0~1,9~.0~2,6~.0~10,16~.0~11,13~.0~17,21~]tricos-22-ene-18,20-dione | C35H47N3O5 | 详情 | 详情 | |
| (II) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (III) | 59851 | (1S,2R,5R,6R,10R,11R,12R,13R,15S)-11,13-dihydroxy-5-[(1R)-5-hydroxy-1,5-dimethylhexyl]-12-(3-hydroxypropoxy)-6,10-dimethyl-18-phenyl-16,18,20-triazahexacyclo[13.5.2.0~1,9~.0~2,6~.0~10,15~.0~16,20~]docos-21-ene-17,19-dione | C38H55N3O7 | 详情 | 详情 | |
| (IV) | 59852 | (1R,2R,3R,10R,13R,14R,17R)-17-[(1R)-5-hydroxy-1,5-dimethylhexyl]-2-(3-hydroxypropoxy)-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C30H50O5 | 详情 | 详情 | |
| (V) | 59853 | (2R,2aS,3aS,3bR,5aR,6R,8aR)-6-[(1R)-5-hydroxy-1,5-dimethylhexyl]-3b,5a-dimethyl-2,2a,3a,3b,3c,4,5,5a,6,7,8,8a-dodecahydro-1H-cyclopenta[7,8]phenanthro[3,4-b]oxiren-2-ol | C27H42O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Preparation of the allyl alcohol precursor (XXX) was further reported by an alternative method described in the two following schemes: The symmetrical epoxide (XXXV) was cleaved by 1,3-propanediol (II) in the presence of potassium tert-butoxide to give the diol (XXXVI). After protection of the primary alcohol of (XXXVI) as the pivalate ester (XXXVII), the benzyl ether groups of (XXXVII) were removed by hydrogenation in the presence of palladium hydroxide to provide (XXXVIII). Protection of the vicinal diol moiety of (XXXVII) as the corresponding acetonide (XXXIX) was achieved by treatment with 2,2-dimethoxypropane and p-TsOH. Subsequent Swern oxidation of the primary alcohol function of (XXXIX) gave aldehyde (XL). Addition of vinylmagnesium bromide to aldehyde (XL) afforded the allylic alcohol (XLI) as a diastereomeric mixture. Esterification of (XLI) with pivaloyl chloride provided dipivalate ester (XLII). Epoxide (XLIII) was then prepared by acidic acetonide (XLII) hydrolysis, followed by cyclization of the resultant vicinal diol under Mitsunobu conditions to afford epoxide (XLIII). Addition of the O-protected lithium acetylide (XLIV) to epoxide (XLIII) furnished the acetylene adduct (XLV)
| 【1】 Hatakeyama, S.; Ikeda, T.; Maeyama, J.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Convergent synthesis of 1alpha, 25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71). Bioorg Med Chem Lett 1997, 7, 22, 2871. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (XXXV) | 25266 | benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XXXVI) | 46308 | (2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol | C21H28O5 | 详情 | 详情 | |
| (XXXVII) | 46309 | 3-([(1S,2R)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate | C26H36O6 | 详情 | 详情 | |
| (XXXVIII) | 59880 | 3-{[(1S,2R)-2,3-dihydroxy-1-(hydroxymethyl)propyl]oxy}propyl pivalate | C12H24O6 | 详情 | 详情 | |
| (XXXIX) | 46310 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl]oxy)propyl pivalate | C15H28O6 | 详情 | 详情 | |
| (XL) | 46311 | 3-([(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethyl]oxy)propyl pivalate | C15H26O6 | 详情 | 详情 | |
| (XLI) | 46312 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-3-butenyl]oxy)propyl pivalate | C17H30O6 | 详情 | 详情 | |
| (XLII) | 59883 | 3-({(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(2,2-dimethylpropanoyl)oxy]-3-butenyl}oxy)propyl pivalate | C22H38O7 | 详情 | 详情 | |
| (XLIII) | 46314 | 3-([(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(2R)oxiranyl]-3-butenyl]oxy)propyl pivalate | C19H32O6 | 详情 | 详情 | |
| (XLIV) | 59881 | {3-[(4-methoxybenzyl)oxy]-1-propynyl}lithium | C11H11LiO2 | 详情 | 详情 | |
| (XLV) | 59882 | 3-({(1R,2R)-1-{1-[(2,2-dimethylpropanoyl)oxy]-2-propenyl}-2-hydroxy-6-[(4-methoxybenzyl)oxy]-4-hexynyl}oxy)propyl pivalate | C30H44O8 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXV)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5
该中间体在本合成路线中的序号：2-Chloro-4-propionylpyridine (I) was protected as the cyclic ketal (II) with 1,3-propanediol and p-toluenesulfonic acid in refluxing toluene with azeotropical removal of water. Subsequent halogen displacement in (II) with sodium methoxide in boiling acetonitrile gave methoxypyridine (III). Lithiation of (III) with mesityllithium, followed by condensation with dimethylformamide provided formylpyridine (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. The hydroxyl group of (V) was protected as the benzyl ether (VI), and the ketal group was then hydrolyzed to ketone (VII) with aqueous trifluoroacetic acid. Reformatskii reaction of (VII) with tert-butyl bromoacetate and zinc afforded the beta-hydroxyester (VIII). Further hydrogenolysis of benzyl ether of (VIII) over Pd/C gave alcohol (IX). Then, treatment of (IX) with trifluoroacetic acid produced lactone (X), and hydrolysis of the methoxy group of (X) with aqueous HCl furnished pyridone (XI). Condensation of 3,4-difluoroacetanilide (XII) with Vilsmeier reagent yielded quinolinecarboxaldehyde (XIII), which was reduced to alcohol (XIV) with NaBH4. This was then coupled with pyridone (XI) under Mitsunobu conditions to give (XV). Finally, Heck reaction of (XV) with palladium acetate and triphenyl phosphine generated the target pentacyclic compound.
| 【1】 Lavergne, O.; Lesuer-Ginot, L.; Pla Rodas, F.; Kasprzyk, P.G.; Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D.C.; Homocamptothecins: Synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem 1998, 41, 27, 5410. |
| 【2】 Bigg, D.; Lavergne, O.; Pla Rodas, F.; Pommier, J.; Ulibarri, G. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Novel camptothecin analogues, preparation methods therefor, use thereof as drugs, and pharmaceutical compsns. containing said analogues. EP 0835258; JP 1999508249; US 5981542; WO 9700876 . |
| 【3】 Lanco, C.; Rolland, A.; Bigg, D.; Lavergne, O.; Harnett, J.; Liberatore, A.-M. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Pro-drugs and counterparts of camptothecin, their application as medicines . EP 0946566; WO 9828304 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 | |
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 25461 | 1-(2-chloro-4-pyridinyl)-1-propanone | C8H8ClNO | 详情 | 详情 | |
| (II) | 25462 | 2-chloro-4-(2-ethyl-1,3-dioxan-2-yl)pyridine | C11H14ClNO2 | 详情 | 详情 | |
| (III) | 25463 | 4-(2-ethyl-1,3-dioxan-2-yl)-2-pyridinyl methyl ether; 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine | C12H17NO3 | 详情 | 详情 | |
| (IV) | 25464 | 4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxynicotinaldehyde | C13H17NO4 | 详情 | 详情 | |
| (V) | 25465 | [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methanol | C13H19NO4 | 详情 | 详情 | |
| (VI) | 25466 | 3-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxypyridine; benzyl [4-(2-ethyl-1,3-dioxan-2-yl)-2-methoxy-3-pyridinyl]methyl ether | C20H25NO4 | 详情 | 详情 | |
| (VII) | 25467 | 1-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-1-propanone | C17H19NO3 | 详情 | 详情 | |
| (VIII) | 25468 | tert-butyl 3-[3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl]-3-hydroxypentanoate | C23H31NO5 | 详情 | 详情 | |
| (IX) | 25469 | tert-butyl 3-hydroxy-3-[3-(hydroxymethyl)-2-methoxy-4-pyridinyl]pentanoate | C16H25NO5 | 详情 | 详情 | |
| (X) | 25470 | 5-ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H15NO4 | 详情 | 详情 | |
| (XI) | 25471 | 5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H13NO4 | 详情 | 详情 | |
| (XII) | 25472 | N-(3,4-difluorophenyl)acetamide | 458-11-7 | C8H7F2NO | 详情 | 详情 |
| (XIII) | 25473 | 2-chloro-6,7-difluoro-3-quinolinecarbaldehyde | C10H4ClF2NO | 详情 | 详情 | |
| (XIV) | 25474 | (2-chloro-6,7-difluoro-3-quinolinyl)methanol | C10H6ClF2NO | 详情 | 详情 | |
| (XV) | 25475 | 8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C21H17ClF2N2O4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIV)The A ring fragment (XXV) was synthesized as follows. Ring opening of epoxide (XIII) with 1,3-propanediol (XIV) in the presence of potassium tert-butoxide afforded the hydroxy ether (XV). The primary alcohol group of (XV) was then esterified with pivaloyl chloride (XVI) in the presence of pyridine to give (XVII). After hydrogenolysis of the benzyl ethers of (XVII), the 1,2-diol moiety was protected as the corresponding acetonide (XVIII) by means of 2,2-dimethoxypropane. Swern oxidation of the free alcohol group of (XVIII) generated aldehyde (XIX), and subsequent addition of vinylmagnesium bromide to (XIX) provided the allylic alcohol (XX) as a diastereomeric mixture. After protection of the hydroxyl group of (XX) as the pivalate ester, acid hydrolysis of the acetonide furnished diol (XXI). This was then converted to epoxide (XXII) under Mitsunobu conditions. Addition of lithium trimethylsilylacetylide (XXIII) to the epoxide (XXII) and then hydrolysis of the pivalate esters yielded (XXIV). This compound was protected as the tris(tert-butyldimethylsilyl) ether, and the diastereomeric mixture was separated by flash chromatography to provide intermediate (XXV).
| 【1】 Hatakeyama, S.; et al.; Synthesis and biological characterization of 1alpha,24,25-trihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (24-hydroxylated ED-71). Steroids 2001, 66, 3-5, 267. |
| 【2】 Watanabe, H.; Hatakeyama, S.; Kawase, A. (Chugai Pharmaceutical Co. Ltd.); 24-Hydroxyvitamin D derivs.. EP 1061070; WO 9943645 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 46307 | benzyl [(2R,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2R,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XIV) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (XV) | 46308 | (2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol | C21H28O5 | 详情 | 详情 | |
| (XVI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XVII) | 46309 | 3-([(1S,2R)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate | C26H36O6 | 详情 | 详情 | |
| (XVIII) | 46310 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl]oxy)propyl pivalate | C15H28O6 | 详情 | 详情 | |
| (XIX) | 46311 | 3-([(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethyl]oxy)propyl pivalate | C15H26O6 | 详情 | 详情 | |
| (XX) | 46312 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-3-butenyl]oxy)propyl pivalate | C17H30O6 | 详情 | 详情 | |
| (XXI) | 46313 | 3-([(1R)-1-[(1R)-1,2-dihydroxyethyl]-2-[(2,2-dimethylpropanoyl)oxy]-3-butenyl]oxy)propyl pivalate | C19H34O7 | 详情 | 详情 | |
| (XXII) | 46314 | 3-([(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(2R)oxiranyl]-3-butenyl]oxy)propyl pivalate | C19H32O6 | 详情 | 详情 | |
| (XXIII) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (XXIV) | 46315 | (4R,5R)-4-(3-hydroxypropoxy)-1-octen-7-yne-3,5-diol | C11H18O4 | 详情 | 详情 | |
| (XXV) | 46316 | (5R,6R)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-butynyl)-2,2,3,3,12,12,13,13-octamethyl-5-vinyl-4,7,11-trioxa-3,12-disilatetradecane; tert-butyl(dimethyl)silyl 3-[[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propenyl)-4-pentynyl]oxy]propyl ether | C29H60O4Si3 | 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 furazanyloxypropanol derivative (III) was obtained by condensation of 3,4-bis(benzenesulfonyl)furoxan (I) with 1,3-propanediol (II) in the presence of NaOH. Subsequent acylation of alcohol (III) with ibuprofen acid chloride (IV) provided the corresponding ibuprofen ester.
| 【1】 Lolli, M.L.; et al.; A new class of ibuprofen derivatives with reduced gastrotoxicity. J Med Chem 2001, 44, 21, 3463. |
| 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) | 52494 | 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazol-2-ium-2-olate | C14H10N2O6S2 | 详情 | 详情 | |
| (II) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (III) | 52495 | 4-[(3-hydroxypropyl)oxy]-3-(phenylsulfonyl)-1,2,5-oxadiazol-2-ium-2-olate | C11H12N2O6S | 详情 | 详情 | |
| (IV) | 22117 | 2-(4-isobutylphenyl)propanoyl chloride | C13H17ClO | 详情 | 详情 |