【结 构 式】 |
【分子编号】11081 【品名】N-Formyl-L-leucine; (2S)-2-(Formylamino)-4-methylpentanoic acid 【CA登记号】6113-61-7 |
【 分 子 式 】C7H13NO3 【 分 子 量 】159.18516 【元素组成】C 52.82% H 8.23% N 8.8% O 30.15% |
合成路线1
该中间体在本合成路线中的序号:(XXIV)1) The condensation of (S)-L-malic acid (I) and cyclohexanone (II) by means of boron trifluoride etherate gives the cyclic lactone (III), which is reduced by borane and treated with tert-butyldiphenylchlorosilane yielding the silyl ether (IV). The transesterification of (IV) with sodium methoxide in methanol affords 4-(tert-butyldiphenylsilyloxy)-2(S)-hydroxybutyric acid methyl ester (V), which is reduced with borane as before and esterified with naphthalenesufonyl chloride to give the sulfonate (VI). The treatment of (VI) with sodium methoxide affords the epoxide (VII), which is alkylated with decyllithium yielding 1-(tert-butyldiphenylsilyloxy)tetradecan-3(R)-ol (VIII). The benzylation of (VIII) with benzyl trichloroacetimidate (BTA) gives the benzyl ether (IX), which is desilylated with HF in acetonitrile yielding 3(R)-benzyloxytetradecan-1-ol (X). The oxidation of (X) with PDC gives 3(R)-benzyloxytetradecanal (XI), which is condensed with 1-(trimethylsilyl)-2(E)-nonene (XII) by means of a titanium dichloride complex yielding the diastereoisomeric mixture of alcohols (3R,4S,6R)- (XIII) and (3S,4S,6R)- (XIV), which are separated by column chromatography. The silylation of both isomers with tert-butyldimethylsilyl chloride affords both isomers (XV) and (XVI), which are ozonolyzed with O3 and oxidized with NaClO2 to yield the corresponding acids (XVII) and (XVIII). The desilylation of (XVII) and (XVIII) with HF in acetonitrile gives the hydroxy acids (XIX) and (XX), which are cyclized by means of benzenesulfonyl chloride and pyridine to the isomeric oxetanones (XXI) and (XXII). The unwanted isomer (XXII) can be isomerized by means of lithium diisopropylamide in THF to the correct isomer (XXI). The debenzylation of (XXI) by hydrogenation with H2 over Pd/C affords (3S,4S)-3-hexyl-4-[2(R)-hydroxytridecyl]oxetan-2-one (XXIII), which is finally condensed with N-formyl-L-leucine (XXIV) by means of diethyl azodicarboxylate (DEAD) in THF.
【1】 Barbier, P.; Schneider, F.; Widmer, U. (F. Hoffmann-La Roche AG); Process for the preparation of oxetanones. EP 0189577 . |
【2】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
【3】 Tehim, A.; Chen, P.; Hanessian, S.; Total synthesis of (-)-tetrahydrolipstatin. J Org Chem 1993, 58, 27, 7768-81. |
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) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
(II) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
(III) | 11060 | 2-[(2S)-3-Oxo-1,4-dioxaspiro[4.5]dec-2-yl]acetic acid | C10H14O5 | 详情 | 详情 | |
(IV) | 11061 | (3S)-3-(2-[[tert-Butyl(diphenyl)silyl]oxy]ethyl)-1,4-dioxaspiro[4.5]decan-2-one | C26H34O4Si | 详情 | 详情 | |
(V) | 11062 | methyl (2S)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-hydroxybutanoate | C21H28O4Si | 详情 | 详情 | |
(VI) | 11063 | (1R)-3-[[tert-butyl(diphenyl)silyl]oxy]-1-hydroxypropyl 2-naphthalenesulfonate | C29H32O5SSi | 详情 | 详情 | |
(VII) | 11064 | tert-Butyl(diphenyl)silyl 2-[(2S)oxiranyl]ethyl ether; tert-Butyl[2-[(2S)oxiranyl]ethoxy]diphenylsilane | C20H26O2Si | 详情 | 详情 | |
(VIII) | 11065 | (3R)-1-[[tert-Butyl(diphenyl)silyl]oxy]-3-tetradecanol | C30H48O2Si | 详情 | 详情 | |
(IX) | 11066 | Benzyl (1R)-1-(2-[[tert-butyl(diphenyl)silyl]oxy]ethyl)dodecyl ether; [[(3R)-3-(Benzyloxy)tetradecyl]oxy](tert-butyl)diphenylsilane | C37H54O2Si | 详情 | 详情 | |
(X) | 11067 | (3R)-3-(Benzyloxy)-1-tetradecanol | C21H36O2 | 详情 | 详情 | |
(XI) | 11068 | (3R)-3-(Benzyloxy)tetradecanal | C21H34O2 | 详情 | 详情 | |
(XII) | 11069 | Trimethyl[(E)-2-nonenyl]silane | C12H26Si | 详情 | 详情 | |
(XIII) | 11070 | (3R,4S,6R)-6-(Benzyloxy)-3-hexyl-1-heptadecen-4-ol | C30H52O2 | 详情 | 详情 | |
(XIV) | 11071 | (3S,4S,6R)-6-(Benzyloxy)-3-hexyl-1-heptadecen-4-ol | C30H52O2 | 详情 | 详情 | |
(XV) | 11072 | ([(1S,2R)-1-[(2R)-2-(Benzyloxy)tridecyl]-2-hexyl-3-butenyl]oxy)(tert-butyl)dimethylsilane; benzyl (1R,3S,4R)-3-[[tert-Butyl(dimethyl)silyl]oxy]-4-hexyl-1-undecyl-5-hexenyl ether | C36H66O2Si | 详情 | 详情 | |
(XVI) | 11073 | ([(1S,2S)-1-[(2R)-2-(Benzyloxy)tridecyl]-2-hexyl-3-butenyl]oxy)(tert-butyl)dimethylsilane; benzyl (1R,3S,4S)-3-[[tert-Butyl(dimethyl)silyl]oxy]-4-hexyl-1-undecyl-5-hexenyl ether | C36H66O2Si | 详情 | 详情 | |
(XVII) | 11074 | (2S,3S,5R)-5-(Benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-hexylhexadecanoic acid | C35H64O4Si | 详情 | 详情 | |
(XVIII) | 11075 | (2R,3S,5R)-5-(Benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-hexylhexadecanoic acid | C35H64O4Si | 详情 | 详情 | |
(XIX) | 11076 | (2S,3S,5R)-5-(Benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid | C29H50O4 | 详情 | 详情 | |
(XX) | 11077 | (2R,3S,5R)-5-(Benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid | C29H50O4 | 详情 | 详情 | |
(XXI) | 11078 | (3S,4S)-4-[(2R)-2-(Benzyloxy)tridecyl]-3-hexyl-2-oxetanone | C29H48O3 | 详情 | 详情 | |
(XXII) | 11079 | (3R,4S)-4-[(2R)-2-(Benzyloxy)tridecyl]-3-hexyl-2-oxetanone | C29H48O3 | 详情 | 详情 | |
(XXIII) | 11080 | (3S,4S)-3-Hexyl-4-[(2R)-2-hydroxytridecyl]-2-oxetanone | C22H42O3 | 详情 | 详情 | |
(XXIV) | 11081 | N-Formyl-L-leucine; (2S)-2-(Formylamino)-4-methylpentanoic acid | 6113-61-7 | C7H13NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XXIV)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:(XXII)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 |