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【结 构 式】 
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【分子编号】11091 【品名】Octanoic acid 【CA登记号】124-07-2 |
【 分 子 式 】C8H16O2 【 分 子 量 】144.21384 【元素组成】C 66.63% H 11.18% O 22.19% |
合成路线1
该中间体在本合成路线中的序号：(XXXIV)The oxetanone (XXIII) can also be obtained as follows: The condensation of 3(R)-benzyloxytetradecanal (XI) with octanoic acid (XXXIV) by means of lithium diisopropylamide gives 5(R)-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid (XXXV), which is deprotected by hydrogenation with H2 over Pd/C yielding the dihydroxy acid (XXXVI). The lactonization of (XXXVI) with p-toluenesulfonic acid affords the hydroxy lactone (XXXVII), which is oxidized with CrO3 H2SO4 to 3-hexyl-6(R)-undecyltetrahydropyran-2,4-dione (XXXVIII). Hydrogenation of (XXXVIII) with H2 over PtO2/C in ethylacetate gives (3S,4S,6R)-3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one (XXXIX), which is benzylated with benzyl trichloroacetimidate to the 4-benzyloxy derivative (XL). Ring opening of (XL) with KOH in dioxane-water yields the hydroxy acid (XLI), which is esterified with benzyl bromide to the benzyl ester (XLII). The reaction of (XLII) with dihydropyran (DHP) by means of p-toluenesulfonic acid in dichloromethane affords (2S,3S,5R)-3-benzyloxy-2-hexyl-5-(tetrahydropyran-2-yloxy)hexadecanoic acid benzyl ester (XLIII), which is debenzylated by hydrogenation with H2 over Pd/C in THF to the hydroxy acid (XLIV). The cyclization of (XLIV) with p-toluenesulfonyl chloride in pyridine gives (3S,4S)-3-hexyl-4-[2(R)-(tetrahydropyran-2-yloxy)tridecyl]oxetan-2-one (XLV), which is finally deprotected with pyridinium p-toluenesulfonate in ethanol to afford the oxetanone (XXIII), already obtained in scheme 11082301a.
| 【1】 Barbier, P.; Schneider, F.; Synthesis of tetrahydrolipstatin and tetrahydroesterastin, compounds with beta-lactone moiety. Stereoselective hydrogenation of a beta-keto delta-lactone and conversion of the delta-lactone into a beta-lactone. J Org Chem 1988, 53, 6, 1218-21. |
| 【2】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIV) | 11091 | Octanoic acid | 124-07-2 | C8H16O2 | 详情 | 详情 |
| (XXXV) | 11092 | (5R)-5-(Benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid | C29H50O4 | 详情 | 详情 | |
| (XXXVI) | 11093 | (5R)-2-Hexyl-3,5-dihydroxyhexadecanoic acid | C22H44O4 | 详情 | 详情 | |
| (XXXVII) | 11094 | (6R)-3-Hexyl-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one | C22H42O3 | 详情 | 详情 | |
| (XXXVIII) | 11095 | (6R)-3-Hexyl-6-undecyldihydro-2H-pyran-2,4(3H)-dione | C22H40O3 | 详情 | 详情 | |
| (XXXIX) | 11096 | (3S,4S,6R)-3-Hexyl-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one | C22H42O3 | 详情 | 详情 | |
| (XL) | 11097 | (3S,4S,6R)-4-(Benzyloxy)-3-hexyl-6-undecyltetrahydro-2H-pyran-2-one | C29H48O3 | 详情 | 详情 | |
| (XLI) | 11098 | (2S,3S,5R)-3-(Benzyloxy)-2-hexyl-5-hydroxyhexadecanoic acid | C29H50O4 | 详情 | 详情 | |
| (XLII) | 11099 | benzyl (2S,3S,5R)-3-(benzyloxy)-2-hexyl-5-hydroxyhexadecanoate | C36H56O4 | 详情 | 详情 | |
| (XLIII) | 11100 | benzyl (2S,3S,5R)-3-(benzyloxy)-2-hexyl-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate | C41H64O5 | 详情 | 详情 | |
| (XLIV) | 11101 | (2S,3S,5R)-2-Hexyl-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoic acid | C27H52O5 | 详情 | 详情 | |
| (XLV) | 11102 | (3S,4S)-3-Hexyl-4-[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)tridecyl]-2-oxetanone | C27H50O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXIV)A new synthesis of orlistat has been described: The ozonolysis of 3(R)-(tetrahydropyranyloxy)-6-heptenoic acid ethyl ester (LV) with O3 gives the corresponding terminal aldehyde (LVI), which is submitted to a Wittig condensation with octyl triphenylphosphonium bromide (LVII) and butyllithium in ether-THF yielding 3(R)-(tetrahydropyranyloxy)-6(Z)-tetradecenoic acid ethyl ester (LVIII). The reduction of (LVIII) with DIBAL in toluene-dichloromethane affords the corresponding aldehyde (LIX), which is condensed with octanoic acid (XXXIV) by means of butyllithium and diisopropylamine in THF to give 2-hexyl-3-hydroxy-5(R)-(tetrahydropyranyloxy)-8(Z)-hexadecenoic acid (LX), which is lactonized with benzenesulfonyl chloride in pyridine to the protected oxetanone (LXI). The deprotection of (LXI) with pyridinium p-toluenesulfonate in hot ethanol affords 3-hexyl-4-[2(R)-hydroxy-5(Z)-tridecenyl]oxetan-2-one (LXII) as a mixture of diastereomers, which are separated by column chromatography yielding the (3S,4S,2'R)-isomer (LXIII). The condensation of (LXIII) with N-formyl-L-leucine (XXIV) as before gives dihydrolipstatin (LXIV), which is finally hydrogenated with H2 over Pd/C in THF.
| 【1】 Barbier, P.; Schneider, F.; Syntheses of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin. Helv Chim Acta 1987, 70, 196-202. |
| 【2】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 11081 | N-Formyl-L-leucine; (2S)-2-(Formylamino)-4-methylpentanoic acid | 6113-61-7 | C7H13NO3 | 详情 | 详情 |
| (XXXIV) | 11091 | Octanoic acid | 124-07-2 | C8H16O2 | 详情 | 详情 |
| (LV) | 11112 | ethyl (3R)-3-(tetrahydro-2H-pyran-2-yloxy)-6-heptenoate | C14H24O4 | 详情 | 详情 | |
| (LVI) | 11113 | ethyl (3R)-6-oxo-3-(tetrahydro-2H-pyran-2-yloxy)hexanoate | C13H22O5 | 详情 | 详情 | |
| (LVII) | 11114 | Octyl(triphenyl)phosphonium bromide | 42036-78-2 | C26H32BrP | 详情 | 详情 |
| (LVIII) | 11115 | ethyl (3R,6Z)-3-(tetrahydro-2H-pyran-2-yloxy)-6-tetradecenoate | C21H38O4 | 详情 | 详情 | |
| (LIX) | 11116 | (3R,6Z)-3-(Tetrahydro-2H-pyran-2-yloxy)-6-tetradecenal | C19H34O3 | 详情 | 详情 | |
| (LX) | 11117 | (5R,8Z)-2-Hexyl-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)-8-hexadecenoic acid | C27H50O5 | 详情 | 详情 | |
| (LXI) | 11118 | 3-Hexyl-4-[(2R,5Z)-2-(tetrahydro-2H-pyran-2-yloxy)-5-tridecenyl]-2-oxetanone | C27H48O4 | 详情 | 详情 | |
| (LXII) | 11119 | 3-Hexyl-4-[(2R,5Z)-2-hydroxy-5-tridecenyl]-2-oxetanone | C22H40O3 | 详情 | 详情 | |
| (LXIII) | 11120 | (3S,4S)-3-Hexyl-4-[(2R,5Z)-2-hydroxy-5-tridecenyl]-2-oxetanone | C22H40O3 | 详情 | 详情 | |
| (LXIV) | 11121 | (1S,4Z)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]-4-dodecenyl (2S)-2-(formylamino)-4-methylpentanoate | C29H51NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)A new asymmetric synthesis of orlistat has been described: Reaction of the chiral aminoindanol (I) with octanoyl chloride (II) in pyridine gives the chiral ester (III), which is condensed with cinnamaldehyde (IV) by means of TiCl4, DIEA and Bu2BOTf in dichloromethane yielding, after chromatographic purification, the anti-aldol adduct (V). Hydrolysis of the chiral auxiliary of (V) with lithium hydroperoxide affords the beta-hydroxy acid (VI), which is protected as the 1,3-dioxan-4-one (VIII) by reaction with pivalaldehyde (VII), TMS-OTf and isopropoxytrimethylsilane (TMS-O-i-Pr). Ozonolysis of (VIII) with O3 in dichloromethane yields the aldehyde (IX), which is condensed with 1-nitrododecane (X) by means of TBAF in DMF to provide the nitroaldol (XI). The dehydration of (XI) with DCC and CuCl in hot acetonitrile gives the nitroalkene (XII), which is reduced with Zn/HOAc to oxime (XIII). Oxidative hydrolysis of (XIII) with ceric ammonium nitrate (CAN) and HNO3 yields diketone (XIV), which is hydrolyzed with HCl in THF providing the beta-hydroxy acid (XV). Esterification of (XV) with benzyl iodide and CsCO3 gives the benzyl ester (XVI), which is estereoselectively reduced with Me4NB(OAc)3H in HOAc/acetonitrile yielding the chiral anti-1,3-diol (XVII). The selective protection of (XVII) with TIPS-OTf and 2,6-lutidine affords the monosilylated ester (XVIII), which is treated with H2 over Pd(OH)2 in ethyl acetate/methanol to furnish the free beta-hydroxy acid (XIX). Cyclization of acid (XIX) by means of PhSO2Cl in pyridine affords the beta-lactone (XX), which is desilylated with TBAF and HOAc in THF giving lactone (XXI). Finally, lactone (XXI) is esterified under Mitsunobu conditions with N-formyl-L-leucine (XXII) by means of DIAD and PPh3 in THF.
| 【1】 Ghosh, A.K.; Fidanze, S.; Asymmetric synthesis of (-)-tetrahydrolipstatin: An anti-aldol-based strategy. Org Lett 2000, 2, 16, 2405. |
| 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) | 41710 | N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-4-methylbenzenesulfonamide | C16H17NO3S | 详情 | 详情 | |
| (II) | 11091 | Octanoic acid | 124-07-2 | C8H16O2 | 详情 | 详情 |
| (III) | 41711 | (1S,2R)-1-[[(4-methylphenyl)sulfonyl]amino]-2,3-dihydro-1H-inden-2-yl octanoate | C24H31NO4S | 详情 | 详情 | |
| (IV) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
| (V) | 41713 | (1S,2R)-1-[[(4-methylphenyl)sulfonyl]amino]-2,3-dihydro-1H-inden-2-yl (2S,3S,4E)-2-hexyl-3-hydroxy-5-phenyl-4-pentenoate | C33H39NO5S | 详情 | 详情 | |
| (VI) | 41714 | (2S,3S,4E)-2-hexyl-3-hydroxy-5-phenyl-4-pentenoic acid | C17H24O3 | 详情 | 详情 | |
| (VII) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VIII) | 41715 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-one | C22H32O3 | 详情 | 详情 | |
| (IX) | 41716 | (2S,4R,5S)-2-(tert-butyl)-5-hexyl-6-oxo-1,3-dioxane-4-carbaldehyde | C15H26O4 | 详情 | 详情 | |
| (X) | 41717 | 1-nitroundecane | C11H23NO2 | 详情 | 详情 | |
| (XI) | 41718 | (2S,5S,6R)-2-(tert-butyl)-5-hexyl-6-(1-hydroxy-2-nitrododecyl)-1,3-dioxan-4-one | C26H49NO6 | 详情 | 详情 | |
| (XII) | 41719 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[(E)-2-nitro-1-dodecenyl]-1,3-dioxan-4-one | C26H47NO5 | 详情 | 详情 | |
| (XIII) | 41720 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[2-(hydroxyimino)dodecyl]-1,3-dioxan-4-one | C26H49NO4 | 详情 | 详情 | |
| (XIV) | 41721 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-(2-oxododecyl)-1,3-dioxan-4-one | C26H48O4 | 详情 | 详情 | |
| (XV) | 41722 | (2S,3S)-2-hexyl-3-hydroxy-5-oxopentadecanoic acid | C21H40O4 | 详情 | 详情 | |
| (XVI) | 41723 | benzyl (2S,3S)-2-hexyl-3-hydroxy-5-oxopentadecanoate | C28H46O4 | 详情 | 详情 | |
| (XVII) | 41724 | benzyl (2S,3S,5R)-2-hexyl-3,5-dihydroxypentadecanoate | C28H48O4 | 详情 | 详情 | |
| (XVIII) | 41725 | benzyl (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(triisopropylsilyl)oxy]pentadecanoate | C37H68O4Si | 详情 | 详情 | |
| (XIX) | 41726 | (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(triisopropylsilyl)oxy]pentadecanoic acid | C30H62O4Si | 详情 | 详情 | |
| (XX) | 41727 | (3S,4S)-3-hexyl-4-[(2R)-2-[(triisopropylsilyl)oxy]dodecyl]-2-oxetanone | C30H60O3Si | 详情 | 详情 | |
| (XXI) | 41728 | (3S,4S)-3-hexyl-4-[(2R)-2-hydroxydodecyl]-2-oxetanone | C21H40O3 | 详情 | 详情 | |
| (XXII) | 11081 | N-Formyl-L-leucine; (2S)-2-(Formylamino)-4-methylpentanoic acid | 6113-61-7 | C7H13NO3 | 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 dilithium anion of octanoic acid (I) was alkylated with iodomethane in the presence of HMPA to afford 2-methyloctanoic acid (II). After conversion of (II) to the corresponding acid chloride (III), condensation with (-)-epigallocatechin (IV) using trifluoroacetic acid as the catalyst furnished the title 3-O-acyl epigallocatechin.
| 【1】 Uesato, S.; et al.; Antitumor promoting activities of 3-O-acyl-(-)-epigallocatechins. Bioorg Med Chem Lett 2000, 10, 15, 1673. |
合成路线5
该中间体在本合成路线中的序号：(II)The chiral amino alcohol (I) is acylated with octanoic acid (II), using EDC and HOBt, to afford amide (III). The lithium alkoxide of (III) is then phosphorylated by dibenzyl phosphorochloridate, yielding phosphate ester (IV). Benzyl groups cleavage in (IV) is effected by catalytic hydrogenation of (IV) over Pd/C to produce acid (V), which is finally converted to the title disodium salt by treatment with NaOH in EtOH.
| 【1】 Matsui, T.; Ohmawari, N. (Ono Pharmaceutical Co., Ltd.); Drugs containing phosphoric acid derivs. as the active ingredient. EP 1156054; US 6495533; WO 0050429 . |
| 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) | 57795 | (1R,2S)-1-amino-1-(3-methoxyphenyl)-2-propanol | C10H15NO2 | 详情 | 详情 | |
| (II) | 11091 | Octanoic acid | 124-07-2 | C8H16O2 | 详情 | 详情 |
| (III) | 57796 | N-[(1R,2S)-2-hydroxy-1-(3-methoxyphenyl)propyl]octanamide | C18H29NO3 | 详情 | 详情 | |
| (IV) | 57797 | dibenzyl (1S,2R)-2-(3-methoxyphenyl)-1-methyl-2-(octanoylamino)ethyl phosphate | C32H42NO6P | 详情 | 详情 | |
| (V) | 57798 | (1S,2R)-2-(3-methoxyphenyl)-1-methyl-2-(octanoylamino)ethyl dihydrogen phosphate | C18H30NO6P | 详情 | 详情 |