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【结 构 式】

【分子编号】13226

【品名】2-Methylpropanal; Isobutyraldehyde

【CA登记号】78-84-2

【 分 子 式 】C4H8O

【 分 子 量 】72.10692

【元素组成】C 66.63% H 11.18% O 22.19%
与该中间体有关的原料药合成路线共 17 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17

合成路线1

该中间体在本合成路线中的序号：(II)

The condensation of 2-pyridylacetonitrile (I) with isobutyraldehyde (II) in refluxing benzene gives 4-methyl-2-(2-pyridyl)-2-pentenenitrile (III), which is hydrogenated over Pd/C yielding 4-methyl-2-(2-pyridyl)pentanenitrile (IV). The alkylation of (IV) with 2-(diisopropylamino)ethyl chloride (A) in DMF affords 2-[2-(diisopropylamino)ethyl]-4-methyl-2-(2-pyridyl)pentanenitrile (V), which is then hydrolyzed in concentrated sulfuric acid.

参考文献 中间体
合成目标
【1】 EP 0027412 .
【2】 Gagnol, J.P.; Gautier, P.; Bernhart, C.A.; Serre, M.; Condamine, C.; Demarne, H.; Roncucci, R.; Synthesis and antiarrhythmic activity of new (dialkylamino)alkylpyridylacetamides. J Med Chem 1983, 26, 3, 451.
【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; CM-7857. Drugs Fut 1983, 8, 12, 1016.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 36182 N-(2-chloroethyl)-N-isopropyl-2-propanamine; N-(2-chloroethyl)-N,N-diisopropylamine C8H18ClN 详情 详情
(I) 36179 2-(2-pyridinyl)acetonitrile C7H6N2 详情 详情
(II) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(III) 36180 (E)-4-methyl-2-(2-pyridinyl)-2-pentenenitrile C11H12N2 详情 详情
(IV) 36181 4-methyl-2-(2-pyridinyl)pentanenitrile C11H14N2 详情 详情
(V) 36183 2-[2-(diisopropylamino)ethyl]-4-methyl-2-(2-pyridinyl)pentanenitrile C19H31N3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

1) The reaction of N-methyl-N-benzylamine (I) with isobutyraldehyde (II) and formaldehyde (III) in refluxing isopropanol, followed by hydrogenation with NaBH4 gives 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (IV), which is condensed with diketene (V) in refluxing benzene to yield 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (VI). Finally, this compound is submitted to cyclization with 2-fluoro-5-nitrobenzeldehyde (VII) (prepared by oxidation of 2-fluoro-5-nitrotoluene (VIII) with CrO3 in acetic ahydride-H2SO4) and methyl 3-aminocrotonate (IX) in refluxing isopropanol.

参考文献 中间体
合成目标
【1】 Yamaguchi, H.; Odamiya, Y.; Kanno, H.; Sunakawa, K. (Teijin Ltd.); 1,4-Dihydropyridine derivs., process for production thereof and pharmaceutical use thereof. EP 0128010; JP 1984222474; JP 1984227859; JP 1985104065; US 4578395 .
【2】 Prous, J.; Castaner, J.; TC-81. Drugs Fut 1989, 14, 3, 239.
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) 11969 N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine 103-67-3 C8H11N 详情 详情
(II) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(IV) 12110 3-[Benzyl(methyl)amino]-2,2-dimethyl-1-propanol C13H21NO 详情 详情
(V) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(VI) 12112 3-[benzyl(methyl)amino]-2,2-dimethylpropyl 3-oxobutanoate C17H25NO3 详情 详情
(VII) 12108 2-Fluoro-5-nitrobenzaldehyde 27996-87-8 C7H4FNO3 详情 详情
(VIII) 20560 1-fluoro-2-methyl-4-nitrobenzene 455-88-9 C7H6FNO2 详情 详情
(IX) 11372 Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate C5H9NO2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

Iganidipine can be obtained by two similar ways: 1) The condensation of 1-(tert-butoxycarbonyl)piperazine (I) with isobutyraldehyde (II) and formaldehyde in acetic acid gives 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2,2-dimethylpropionaldehyde (III), which is reduced with NaBH4 in isopropanol to the corresponding alcohol (IV). The condensation of (IV) with diketene (V) by mens of dimethylaminopyridine (DMAP) in dichloromethane affords the acetoacetic ester (VI), which is cyclized with 3-nitrobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing isopropanol to give the protected dihydropyridine (IX). The elimination of the tert-butoxycarbonyl group of (IX) with HCl in ethanol yields dihydropyridine (X), which is finally alkylated with allyl chloride (XI) and triethylamine in hot THF. 2) The condensation of 3-(4-allylpiperazin-1-yl)-2,2-dimethylpropanol (XII) with diketene (V) in dichloromethane gives the corresponding acetoacetic ester (XIII), which is treated with dry NH3 in methanol to yield the 3-aminocrotonic ester (XIV). Finally, this compound is cyclized with 2-(3-nitrobenzylidene)acetoacetic acid methyl ester (XV) in hot isopropanol.

参考文献 中间体
合成目标
【1】 Robinson, C.P.; Robinson, K.A.; Castaner, J.; Iganidipine Hydrochloride. Drugs Fut 1997, 22, 1, 23.
【2】 Matsui, H.; Fukata, F.M.; Mori, T.; Kakeya, N.; Kitao, K. (Kyoto Pharmaceutical Industries, Ltd.); 1,4-Dihydropyridine derivs. and pharmaceutical compsn. Thereof. AU 8812519; EP 0289746; JP 1988225355; US 4937242 .
【3】 Kakeya, N.; Fukada, F.; Nishizawa, S. (Kyoto Pharmaceutical Industries, Ltd.); 3-Aminocrotonic acid ester. JP 1991099064 .
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) 13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情
(II) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(III) 13227 tert-butyl 4-(2,2-dimethyl-3-oxopropyl)-1-piperazinecarboxylate C14H26N2O3 详情 详情
(IV) 13228 tert-butyl 4-(3-hydroxy-2,2-dimethylpropyl)-1-piperazinecarboxylate C14H28N2O3 详情 详情
(V) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(VI) 13230 tert-butyl 4-[3-(acetoacetoxy)-2,2-dimethylpropyl]-1-piperazinecarboxylate C18H32N2O5 详情 详情
(VII) 12646 3-Nitrobenzaldehyde 99-61-6 C7H5NO3 详情 详情
(VIII) 11372 Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate C5H9NO2 详情 详情
(IX) 13233 3-[3-[4-(tert-butoxycarbonyl)-1-piperazinyl]-2,2-dimethylpropyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate C30H42N4O8 详情 详情
(X) 13234 3-[2,2-dimethyl-3-(1-piperazinyl)propyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate C25H34N4O6 详情 详情
(XI) 13235 Allyl chloride; 3-Chloro-1-propene 107-05-1 C3H5Cl 详情 详情
(XII) 13236 3-(4-Allyl-1-piperazinyl)-2,2-dimethyl-1-propanol C12H24N2O 详情 详情
(XIII) 13237 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl 3-oxobutanoate C16H28N2O3 详情 详情
(XIV) 13238 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl (E)-3-amino-2-butenoate C16H29N3O2 详情 详情
(XV) 11375 Methyl-2-(2-nitrobenzylidene)acetoacetate; methyl (Z)-2-acetyl-3-(2-nitrophenyl)-2-propenoate 39562-27-1 C12H11NO5 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

An asymmetric synthesis of pregabalin has been reported: Condensation of isobutyraldehyde (I) with acrylonitrile (II) by means of DBU and 2,6-di-tert-butyl-4- methylphenol (DBP) gives 3-hydroxy-4-methyl-2-methylenepentanenitrile (III), which is acylated with AcCl or Ac2O and pyridine to yield the acetate (IV). The carboxylation of (IV) by means of Pd(OAc)2, PPh3, CO and EtOH affords 3-cyano-4-methyl-3-hexenoic acid ethyl ester (Va-b), which is hydrolyzed with KOH in THF/water to provide the corresponding carboxylic acid potassium salt (VIa-b). Acidification of (VIa-b) with HCl, followed by reaction with tert-butylamine gives the corresponding salt (VIIa-b), which is reduced with H2 over a chiral (R,R)-rhodium catalyst [(R,R)-Rh] in THF/water to yield (S)-3-cyano-5-methylhexanoic acid butylammonium salt (VIII). Finally, the CN group of (VIII) is reduced with H2 over a sponge-Ni catalyst in basic (KOH) ethanol. Alternatively, intermediate (VIa-b) can be reduced with H2 over a chiral (R,R)-rhodium catalyst [(R,R)-Rh] in THF/water to yield (S)-3-cyano-5-methylhexanoic acid potassium salt (IX). Finally, the CN group of (IX) is reduced with H2 over a sponge-Ni catalyst in basic (KOH) ethanol.

参考文献 中间体
合成目标
【1】 Mich, T.F.; Goel, O.P.; Mulhern, T.A.; Burk, M.J.; Hoekstra, M.S.; Ramsden, J.A. (Pfizer Inc.); Asymmetric synthesis of pregabalin. WO 0155090 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Va) 52664 ethyl 3-cyano-5-methyl-3-hexenoate C10H15NO2 详情 详情
(Vb) 52665 ethyl 3-cyano-5-methyl-3-hexenoate C10H15NO2 详情 详情
(VIa) 52666 potassium 3-cyano-5-methyl-3-hexenoate C8H10KNO2 详情 详情
(VIb) 52667 potassium 3-cyano-5-methyl-3-hexenoate C8H10KNO2 详情 详情
(VIIa) 52668 2-methyl-2-propanaminium 3-cyano-5-methyl-3-hexenoate C12H22N2O2 详情 详情
(VIIb) 52669 2-methyl-2-propanaminium 3-cyano-5-methyl-3-hexenoate C12H22N2O2 详情 详情
(I) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(III) 52660 2-(1-hydroxy-2-methylpropyl)-2-propenenitrile C7H11NO 详情 详情
(IV) 52661 2-cyano-1-(1-methylethyl)-2-propenyl acetate C9H13NO2 详情 详情
(VIII) 52662 2-methyl-2-propanaminium 3-cyano-5-methylhexanoate C12H24N2O2 详情 详情
(IX) 52663 potassium 3-cyano-5-methylhexanoate C8H12KNO2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(V)

The reaction of N,N-dibenzyl-L-alaninal (I) with nitromethane, catalyzed by the chiral ammonium salt (II) and KF in THF gives the chiral nitroalcohol (III), which is reduced with NiCl2 and NaBH4 to yield the aminoalcohol (IV). The condensation of (IV) with isobutyraldehyde (V) affords the Schiff base (VI), which is reduced with NaBH4 to provide the secondary amine (VII). The reaction of (VII) with 4-nitrobenzenesulfonyl chloride (VIII) and TEA in dichloromethane furnishes the sulfonamide (IX), which is deprotected by hydrogenation with H2 over Pd/C in methanol, giving the diamino compound (X). Finally, this compound is condensed with 3(S)-tetrahydrofuryl (N-oxysuccinimidyl) carbonate (XI) by means of TEA in dichloromethane to afford the target carbamate.

参考文献 中间体
合成目标
【1】 Corey, E.J.; Zhang, F.-Y.; Re- and si-face-selective nitroaldol reactions catalyzed by a rigid chiral quaternary ammonium salt: A highly stereoselective synthesis of the HIV protease inhibitor amprenavir (Vertex 478). Angew Chem. Int Ed Engl 1999, 38, 13-14, 1931.
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) 37936 (2S)-2-(dibenzylamino)-3-phenylpropanal C23H23NO 详情 详情
(II) 45528 1-(9-anthrylmethyl)-2-[(benzyloxy)(4-quinolinyl)methyl]-5-vinyl-1-azoniabicyclo[2.2.2]octane fluoride C41H39FN2O 详情 详情
(III) 45529 (2R,3S)-3-(dibenzylamino)-1-nitro-4-phenyl-2-butanol C24H26N2O3 详情 详情
(IV) 45530 (2R,3S)-1-amino-3-(dibenzylamino)-4-phenyl-2-butanol C24H28N2O 详情 详情
(V) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(VI) 45531 (2R,3S)-3-(dibenzylamino)-1-[[(E)-2-methylpropylidene]amino]-4-phenyl-2-butanol C28H34N2O 详情 详情
(VII) 37940 (2R,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol C28H36N2O 详情 详情
(VIII) 15809 4-nitrobenzenesulfonyl chloride 98-74-8 C6H4ClNO4S 详情 详情
(IX) 45532 N-[(2R,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-nitrobenzenesulfonamide C34H39N3O5S 详情 详情
(X) 45533 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide C20H29N3O3S 详情 详情
(XI) 39664 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione C9H11NO6 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

A new synthesis of ML-3000 has been published: The reaction of 3-phenyl-2-propynyl chloride (I) with isobutyraldehyde (II) by means of tetrabutylammonium iodide/NaI/NaOH in toluene/water gives 2,2-dimethyl-5-phenyl-4-pentynal (III), which is condensed with glycine methyl ester by means of NaBH(OAc)3 and triethylamine in dichloromethane yielding the N-alkyl-glycine (V). The cyclization of (V) by means of pivalic acid at 150 C affords the bicyclic ketone (VI), which is condensed with diethyl oxalate (VII) by means of sodium ethoxide in ethanol giving the ethoxalyl derivative (VIII). The esterification of (VIII) with the triflic amide (IX) yields the triflate (X), which is condensed with 4-chlorophenylboronic acid (XI) by means of palladium tetrakis(triphenylphosphine) as catalyst in refluxing THF affording the compound (XII). The reduction of the oxoacetic group with tosyl hydrazide (XIII) in refluxing ethanol gives the expected acetate derivative (XIV), which is finally hydrolyzed with NaOH in hot ethanol/water.

参考文献 中间体
合成目标
【1】 Cossy, J.; Belotti, D.; Synthesis of ML-3000, an inhibitor of cyclooxygenase and 5-lipoxygenase. J Org Chem 1997, 62, 23, 7900.
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) 17565 1-(3-chloro-1-propynyl)benzene C9H7Cl 详情 详情
(II) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(III) 17567 2,2-dimethyl-5-phenyl-4-pentynal C13H14O 详情 详情
(IV) 17568 methyl 2-aminoacetate C3H7NO2 详情 详情
(V) 17569 methyl 2-[(2,2-dimethyl-5-phenyl-4-pentynyl)amino]acetate C16H21NO2 详情 详情
(VI) 17570 2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-6(5H)-one C15H17NO 详情 详情
(VII) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(VIII) 17572 ethyl 2-(6-hydroxy-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate C19H21NO4 详情 详情
(IX) 17573 N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide 37595-74-7 C8H5F6NO4S2 详情 详情
(X) 17574 ethyl 2-(2,2-dimethyl-7-phenyl-6-[[(trifluoromethyl)sulfonyl]oxy]-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate C20H20F3NO6S 详情 详情
(XI) 17575 4-chlorophenylboronic acid 1679-18-1 C6H6BClO2 详情 详情
(XII) 17576 ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetate C25H24ClNO3 详情 详情
(XIII) 17577 p-Toluenesulfonyl Hydrazide; 4-methylbenzenesulfonohydrazide 1576-35-8 C7H10N2O2S 详情 详情
(XIV) 16723 ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate C25H26ClNO2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

Treatment of cis-oxazolidine derivative (I) with isobutyraldehyde (II), LDA and LiBr in THF yields aldol product (III), which is then converted into (IV) by first aminal cleavage by means of MeOH and TfOH, followed by silylation with Tbdms-Cl and imidazole in DMF. Reaction of (IV) with formaldehyde and TsOH in benzene gives oxazolidine system (V), which is then first reduced with LiBH4 in THF/MeOH and then oxidized by means of DMSO, oxalyl chloride and Et3N in CH2Cl2 to provide aldehyde (VI). Mukaiyama aldol coupling of (VI) and (VII) in CH2Cl2 with MgI2 as catalyst, followed by treatment with K2CO3 in MeOH, yields aldol product (VIII), which is then converted into hydroxy lactam (IX) by the sequence: i) N-benzyl cleavage by hydrogenolysis over Pd/C in EtOH in the presence of DIEA; ii) ring closure by heating in MeOH; and iii) desilylation by treatment with HF in acetonitrile. Conversion of alcohol (IX) into dihydroxy acid (X) is achieved by a first oxidation with DMSO, oxalyl chloride and Et3N in CH2Cl2, followed by reaction with NaClO2, NaH2PO4 in t-BuOH and 2-Me-butene and final N/O methylene bridge removal with 1,3-propanedithiol (A) catalyzed by HCl and TFA. Compound (X) undergoes beta-lactonization to omuralide (XI) by means of BOPCl and Et3N in CH2Cl2 and finally (XI) is coupled to N-acetyl-L-cysteine (XII) in CH2Cl2 in the presence of Et3N.

参考文献 中间体
合成目标
【1】 Corey, E.J.; Li, W.-D.Z.; Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem Pharm Bull 1999, 47, 1, 1.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 29729 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide 109-80-8 C3H8S2 详情 详情
(I) 43582 methyl (2R,4S)-3-benzyl-2-(tert-butyl)-1,3-oxazolidine-4-carboxylate C16H23NO3 详情 详情
(II) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(III) 43583 methyl (2R,4R)-3-benzyl-2-(tert-butyl)-4-(1-hydroxy-2-methylpropyl)-1,3-oxazolidine-4-carboxylate C20H31NO4 详情 详情
(IV) 43584 methyl (2R,3S)-2-(benzylamino)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-hydroxy-4-methylpentanoate C21H37NO4Si 详情 详情
(V) 43585 methyl (4R,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidine-4-carboxylate C22H37NO4Si 详情 详情
(VI) 43586 (4R,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidine-4-carbaldehyde C21H35NO3Si 详情 详情
(VII) 43587 (E)-1-methoxy-1-propenyl trimethylsilyl ether; [[(E)-1-methoxy-1-propenyl]oxy](trimethyl)silane 34880-70-1 C7H16O2Si 详情 详情
(VIII) 43588 methyl (2R,3S)-3-[(4S,5S)-3-benzyl-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-isopropyl-1,3-oxazolidin-4-yl]-3-hydroxy-2-methylpropanoate C25H43NO5Si 详情 详情
(IX) 43589 (1S,6R,7S,7aS)-7-hydroxy-7a-(hydroxymethyl)-1-isopropyl-6-methyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C11H19NO4 详情 详情
(X) 43590 (2R,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid C10H17NO5 详情 详情
(XI) 43591 (1R,4R,5S)-1-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione C10H15NO4 详情 详情
(XII) 43592 (2R)-2-(acetamido)-3-sulfanylpropionic acid C5H9NO3S 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

Methylation of bicyclic oxazolidine (XXIX) by means of LDA and MeI, followed by selenenylation with PhSeBr/LDA in THF and ozonolysis in CH2Cl2, affords unsaturated derivative (XXX). Treatment of (XXX) with Tbdms-OTf and 2,6-lutidine in CH2Cl2 yields silyloxypyrrole (XXXI), which is converted into (XXXII) by an aldol reaction with (II) in the presence of SnCl4 in Et2O. Acetylation of (XXXII) by means of Ac2O, pyridine followed by dihydroxylation with OsO4 and N-methylmorpholine N-oxide allows formation of diol (XXXIII), whose tertiary hydroxyl group is removed by means of N,N'-thiocarbonyldiimidazole, followed by reduction with Bu3SnH and catalytic AIBN in toluene to provide derivative (XXXIV). Treatment of (XXXIV) with NaOH in MeOH followed by hydrogenolysis over Pd/C in HCl yields derivative (XXXV), which is converted into (XXXVI) by protection of primary alcohol by means of Et3SiCl and acetylation of secondary alcohol by treatment with Ac2O in pyridine. Regeneration of primary alcohol by treatment of (XXXVI) with HF in CH3CN furnishes (XXXVII), which is then oxidized by means of Jones reagent to yield (XXXVIII). Finally, saponification of diacetate acid (XXXVIII) with NaOH gives lactam (X).

参考文献 中间体
合成目标
【1】 Uno, H.; et al.; Stereocontrolled Mukaiyama-type aldol reaction of siloxypyrroles derived from (S)-glutamic acid. Synlett 1997, 390.
【2】 Uno, H.; et al.; Total synthesis of (+)-lactacystin from (R)-glutamate. J Am Chem Soc 1994, 116, 5, 2139.
【3】 Corey, E.J.; Li, W.-D.Z.; Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem Pharm Bull 1999, 47, 1, 1.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIVa) 43614 (1S)-1-[(3S,6S,7S)-7-hydroxy-6-methyl-5-oxo-3-phenyldihydro-1H-pyrrolo[1,2-c][1,3]oxazol-7(5H)-yl]-2-methylpropyl acetate C19H25NO5 详情 详情
(XXXIVb) 43615 (1S)-1-[(3S,6R,7S)-7-hydroxy-6-methyl-5-oxo-3-phenyldihydro-1H-pyrrolo[1,2-c][1,3]oxazol-7(5H)-yl]-2-methylpropyl acetate C19H25NO5 详情 详情
(II) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(X) 43590 (2R,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid C10H17NO5 详情 详情
(XXIX) 43653 (3S,7aR)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C12H13NO2 详情 详情
(XXX) 43610 (3S,7aR)-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C13H13NO2 详情 详情
(XXXI) 43611 (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-3-phenyl-1H-pyrrolo[1,2-c][1,3]oxazole; tert-butyl(dimethyl)silyl (3S)-6-methyl-3-phenyl-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl ether C19H27NO2Si 详情 详情
(XXXII) 43612 (3S,7aR)-7a-[(1S)-1-hydroxy-2-methylpropyl]-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C17H21NO3 详情 详情
(XXXIII) 43613 (1S)-1-[(3S,6R,7R)-6,7-dihydroxy-6-methyl-5-oxo-3-phenyldihydro-1H-pyrrolo[1,2-c][1,3]oxazol-7(5H)-yl]-2-methylpropyl acetate C19H25NO6 详情 详情
(XXXV) 43616 (1S)-1-[(2S,3S,4R)-3-hydroxy-2-(hydroxymethyl)-4-methyl-5-oxopyrrolidinyl]-2-methylpropyl acetate C12H21NO5 详情 详情
(XXXVI) 43617 (1S)-1-((2R,3S,4R)-3-(acetoxy)-4-methyl-5-oxo-2-[[(triethylsilyl)oxy]methyl]pyrrolidinyl)-2-methylpropyl acetate C20H37NO6Si 详情 详情
(XXXVII) 43618 (1S)-1-[(2R,3S,4R)-3-(acetoxy)-2-(hydroxymethyl)-4-methyl-5-oxopyrrolidinyl]-2-methylpropyl acetate C14H23NO6 详情 详情
(XXXVIII) 43619 (2R,3S,4R)-3-(acetoxy)-2-[(1S)-1-(acetoxy)-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid C14H21NO7 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

The condensation of isobutyraldehyde (I) with triethyl phosphonoacetate (II) by means of NaH in THF gives 4-methyl-2-pentenoic acid ethyl ester (III), which is reduced with DIBAL in THF to yield the allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) by means of Ti(O-iPr)4, (+)-diethyl tartrate ((+)-DET) and tBu-OOH in toluene affords the epoxy alcohol (V), which is treated with trichloroacetonitrile and DBU to provide the acetimidate (VI). The cyclization of (VI) by means of triethyl aluminum chloride in dichloromethane gives the oxazoline (VII), which is silylated with Tbdms-OTf and TEA in dichloromethane to afford the silyl ether (VIII). The cleavage of the oxazoline ring of (VIII) by means of HCl in THF yields the chiral amino alcohol (IX), which is protected with Tbdms-OTf as before to afford the silylated amine (X). The monoalkylation of (X) with 1,3-dibromo-2-methylpropene (XI) and Cs-OH in DMF provides the secondary amine (XII). The cyclization of (XII) by means of KHMDS in toluene/ethyl ether gives the non isolated intermediate (XIII) that rearranges to the pyrroline (XIV). The reaction of (XIV) with TPAP and NMO in acetonitrile yields the cyclic imine (XV), which is oxidized with NaClO2 to the 1-chloropyrrolin-2-one (XVI). The dechlorination of (XVI) by means of NaBH4 affords the pyrrolinone (XVII), which is selectively monodesilylated with TBAF in THF to provide the primary alcohol (XVIII). The cyclization of (XVIII) with benzaldehyde dimethylacetal and Ts-OH in refluxing toluene gives the bicyclic pyrrolo oxazole (XIX), which is finally deprotected by means of TBAF in THF to yield the target bicyclic intermediate (XX) (see scheme no. 23327701c intermediate (XXXII)).

参考文献 中间体
合成目标
【1】 Green, M.P.; et al.; An enantioselective formal synthesis of the proteasome inhibitor (+)-lactacystin. Tetrahedron Lett 2002, 43, 37, 6609.
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(III) 57196 ethyl (E)-4-methyl-2-pentenoate C8H14O2 详情 详情
(IV) 43593 (E)-4-methyl-2-penten-1-ol C6H12O 详情 详情
(V) 57181 [(2S,3S)-3-isopropyloxiranyl]methanol C6H12O2 详情 详情
(VI) 57182 [(2S,3S)-3-isopropyloxiranyl]methyl 2,2,2-trichloroethanimidoate C8H12Cl3NO2 详情 详情
(VII) 57183 (1S)-2-methyl-1-[(4R)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]-1-propanol C8H12Cl3NO2 详情 详情
(VIII) 57184 (4R)-4-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazole; tert-butyl(dimethyl)silyl (1S)-2-methyl-1-[(4R)-2-(trichloromethyl)-4,5-dihydro-1,3-oxazol-4-yl]propyl ether C14H26Cl3NO2Si 详情 详情
(IX) 57185 (2R,3S)-2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-1-pentanol C12H29NO2Si 详情 详情
(X) 57186 (5S,6R)-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; (1R,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutylamine C18H43NO2Si2 详情 详情
(XI) 57187 (E)-1,3-dibromo-2-methyl-1-propene C4H6Br2 详情 详情
(XII) 57188 N-[(E)-3-bromo-2-methyl-2-propenyl]-N-[(1R,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amine; (5S,6R)-N-[(E)-3-bromo-2-methyl-2-propenyl]-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine C22H48BrNO2Si2 详情 详情
(XIII) 57189 (5S,6S)-N-[(Z)-3-bromo-2-methyl-2-propenyl]-5-isopropyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine; N-[(Z)-3-bromo-2-methyl-2-propenyl]-N-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-methylbutyl]amine C22H48BrNO2Si2 详情 详情
(XIV) 57190 (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-4-methyl-2,5-dihydro-1H-pyrrole; tert-butyl(dimethyl)silyl (1S)-1-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methyl-2,5-dihydro-1H-pyrrol-2-yl]-2-methylpropyl ether C22H47NO2Si2 详情 详情
(XV) 57191 tert-butyl(dimethyl)silyl (1S)-1-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methyl-2H-pyrrol-2-yl]-2-methylpropyl ether; (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-4-methyl-2H-pyrrole C22H45NO2Si2 详情 详情
(XVI) 57192 (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-1-chloro-3-methyl-1,5-dihydro-2H-pyrrol-2-one C22H44ClNO3Si2 详情 详情
(XVII) 57193 (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one C22H45NO3Si2 详情 详情
(XVIII) 57194 (5R)-5-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-5-(hydroxymethyl)-3-methyl-1,5-dihydro-2H-pyrrol-2-one C16H31NO3Si 详情 详情
(XIX) 57195 (3S,7aS)-7a-((1S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C23H35NO3Si 详情 详情
(XX) 43612 (3S,7aR)-7a-[(1S)-1-hydroxy-2-methylpropyl]-6-methyl-3-phenyl-1,7a-dihydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C17H21NO3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(X)

On the other hand, Wittig condensation of isobutyraldehyde (X) with methyl (triphenylphosphoranylidene)acetate (XI) afforded (E)-4-methylpent-2-enoic acid methyl ester (XII). Sharpless catalytic asymmetric dihydroxylation of (XII) gave diol (XIII). Condensation of diol (XIII) with trimethyl orthobenzoate in the presence of BF3.Et2O, followed by treatment of the crude cyclic orthoester with acetyl bromide produced bromo ester (XIV). The required alpha-amino group was then introduced by nucleophilic displacement of the bromide of (XIV) with NaN3 in DMSO, followed by catalytic hydrogenation of the resulting azide (XV). The intermediate amino ester (XVI) was then rearranged to hydroxy amide (XVII) upon refluxing in EtOAc. Cyclization of (XVII) to the required trans oxazoline (XVIII) was then achieved by treatment with p-toluenesulfonic acid in boiling toluene.

参考文献 中间体
合成目标
【1】 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967.
【2】 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 .
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(XI) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XII) 37799 methyl (E)-4-methyl-2-pentenoate C7H12O2 详情 详情
(XIII) 37800 methyl (2S,3R)-2,3-dihydroxy-4-methylpentanoate C7H14O4 详情 详情
(XIV) 37801 (1S,2S)-2-bromo-1-isopropyl-3-methoxy-3-oxopropyl benzoate C14H17BrO4 详情 详情
(XV) 37802 (1S,2R)-2-azido-1-isopropyl-3-methoxy-3-oxopropyl benzoate C14H17N3O4 详情 详情
(XVI) 37803 (1S,2R)-2-amino-1-isopropyl-3-methoxy-3-oxopropyl benzoate C14H19NO4 详情 详情
(XVII) 37804 methyl (2R,3S)-2-(benzoylamino)-3-hydroxy-4-methylpentanoate C14H19NO4 详情 详情
(XVIII) 37805 methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate C14H17NO3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

The title dihydropyridine was prepared by Hantzsch synthesis by condensation of aminocrotonate ester (I), isobutyraldehyde (II) and keto ester (III) in boiling isopropanol.

参考文献 中间体
合成目标
【1】 Tasaka, S.; Tanabe, H.; Omori, H.; Kiue, A. (Nikken Chemicals Co., Ltd.); 1,4-Dihydropyridine derivs.. EP 0943615; JP 1998204061; WO 9823607 .
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) 41326 3-(3-pyridinyl)propyl (E)-3-amino-2-butenoate C12H16N2O2 详情 详情
(II) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(III) 41327 ethyl 3-[4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]-3-oxopropanoate C18H17N3O3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

Tetrahydrofuranone (XIII): The Grignard condensation of isobutyraldehyde (I) with vinylmagnesium bromide (II) in THF gives the magnesium alcoholate (III), which is condensed with ethyl malonyl chloride (IV) in the same solvent, yielding the mixed ester (V). Treatment of (V) with Ti(OEt)4 at 190 C affords 6-methyl-4(E)-heptenoic acid methyl ester (VI), which by reaction with (R,R)-(-)-pseudoephedrine (VII), oxalyl chloride and DMF in benzene gives the amide (VIII). The regiocontrolled addition of 4-fluorobenzyl chloride (IX) to the chiral amide (VIII) by means of BuLi and LiCl in THF yields the 2(S)-(4-fluorobenzyl)heptanamide (X), which by reaction with NBS in THF/water/acetic acid at 0 C, followed by reflux for 45 min, affords 5(S)-[1(R)-bromo-2-methylpropyl]-3(R)-(4-fluorobenzyl)tetrahydrofuran-2-one (XI). The reaction of (XI) with NaN3 in DMF gives the corresponding azide (XII), which is reduced with H2 over Pd/C, and the resulting amine is protected with tert-butoxycarbonyl anhydride to obtain the desired tetrahydrofuranone (XIII).

参考文献 中间体
合成目标
【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.
【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9.
【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 .
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 32096 4-Methyl-1-penten-3-ol bromomagnesium salt C6H11BrMgO 详情 详情
(IV) 13188 ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride 36239-09-5 C5H7ClO3 详情 详情
(V) 32097 1-ethyl 3-(1-isopropyl-2-propenyl) malonate C11H18O4 详情 详情
(VI) 32098 methyl (E)-6-methyl-4-heptenoate C9H16O2 详情 详情
(VII) 32104 (1R,2R)-2-amino-1-phenyl-1-propanol C9H13NO 详情 详情
(VIII) 32099 (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide C17H25NO2 详情 详情
(IX) 24611 1-(bromomethyl)-4-fluorobenzene 459-46-1 C7H6BrF 详情 详情
(X) 32100 (2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-6-methyl-4-heptenamide C24H30FNO2 详情 详情
(XI) 32101 (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone C15H18BrFO2 详情 详情
(XII) 32102 (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone C15H18FN3O2 详情 详情
(XIII) 32103 tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate C20H28FNO4 详情 详情

合成路线13

该中间体在本合成路线中的序号：(I)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III). Condensation of (III) with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with benzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献 中间体
合成目标
【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 24605 4-methyl-1-penten-3-ol C6H12O 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 24607 diethyl 2-[(E)-4-methyl-2-pentenyl]malonate C13H22O4 详情 详情
(VI) 24608 (E)-6-methyl-4-heptenoic acid C8H14O2 详情 详情
(VII) 24609 (1R,2R)-2-(methylamino)-1-phenyl-1-propanol C10H15NO 详情 详情
(VIII) 24610 (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C18H27NO2 详情 详情
(IX) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(X) 24634 (2S,4E)-2-benzyl-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C25H33NO2 详情 详情
(XI) 24635 (3R,5S)-3-benzyl-5-[(1R)-1-bromo-2-methylpropyl]dihydro-2(3H)-furanone C15H19BrO2 详情 详情
(XII) 24636 (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-benzyldihydro-2(3H)-furanone C15H19N3O2 详情 详情
(XIII) 24637 tert-butyl (1S)-1-[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate C20H29NO4 详情 详情
(XIV) 24638 (2R,4S,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-6-methylheptanoic acid C20H31NO5 详情 详情
(XV) 24639 (2R,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-6-methyl-4-oxoheptanoic acid C20H29NO5 详情 详情

合成路线14

该中间体在本合成路线中的序号：(I)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-methylbenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献 中间体
合成目标
【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 24605 4-methyl-1-penten-3-ol C6H12O 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(VI) 24608 (E)-6-methyl-4-heptenoic acid C8H14O2 详情 详情
(VII) 24609 (1R,2R)-2-(methylamino)-1-phenyl-1-propanol C10H15NO 详情 详情
(VIII) 24610 (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C18H27NO2 详情 详情
(IX) 24623 1-(bromomethyl)-4-methylbenzene 104-81-4 C8H9Br 详情 详情
(X) 24624 (2S,4E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-2-(4-methylbenzyl)-4-heptenamide C26H35NO2 详情 详情
(XI) 24625 (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-methylbenzyl)dihydro-2(3H)-furanone C16H21BrO2 详情 详情
(XII) 24626 (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-methylbenzyl)dihydro-2(3H)-furanone C16H21N3O2 详情 详情
(XIII) 24627 tert-butyl (1S)-2-methyl-1-[(2S,4R)-4-(4-methylbenzyl)-5-oxotetrahydro-2-furanyl]propylcarbamate C21H31NO4 详情 详情
(XIV) 24628 (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-6-methyl-2-(4-methylbenzyl)heptanoic acid C21H33NO5 详情 详情
(XV) 24629 (2R,5S)-5-[(tert-butoxycarbonyl)amino]-6-methyl-2-(4-methylbenzyl)-4-oxoheptanoic acid C21H31NO5 详情 详情

合成路线15

该中间体在本合成路线中的序号：(I)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-flourobenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献 中间体
合成目标
【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.
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) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 24605 4-methyl-1-penten-3-ol C6H12O 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 24607 diethyl 2-[(E)-4-methyl-2-pentenyl]malonate C13H22O4 详情 详情
(VI) 24608 (E)-6-methyl-4-heptenoic acid C8H14O2 详情 详情
(VII) 24609 (1R,2R)-2-(methylamino)-1-phenyl-1-propanol C10H15NO 详情 详情
(VIII) 24610 (E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C18H27NO2 详情 详情
(IX) 24611 1-(bromomethyl)-4-fluorobenzene 459-46-1 C7H6BrF 详情 详情
(X) 24612 (2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide C25H32FNO2 详情 详情
(XI) 24613 (3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone C15H18BrFO2 详情 详情
(XII) 24614 (3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone C15H18FN3O2 详情 详情
(XIII) 24615 tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate C20H28FNO4 详情 详情
(XIV) 24616 (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-4-hydroxy-6-methylheptanoic acid C20H30FNO5 详情 详情
(XV) 24617 (2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoic acid C20H28FNO5 详情 详情

合成路线16

该中间体在本合成路线中的序号：(A)

Treatment of the alcohol (I) with MsCl in the presence of TEA, followed by treatment with NaN3 in presence of HMPA yields the azide derivative (II). This species reacts with isobutyraldehide under reductive conditions (H2, Pd/C) leading to the substituted amine (III) which will be further substituted by reaction with the bromine derivative (IV) in basic conditions to yield derivative (V). Derivative (V) can also be obtained by following this pathway: Reduction of azide (II) with PPh3 in THF followed by reaction with refluxing water yields amine derivative (VI). This derivative is reductocondensed with the aldehyde (VII) and NaBH4 providing the substituted amine (VIII). This amine is further substituted by reductocondensation with isobutyraldehyde and NaCNBH3. Reduction of the substituted amine (V) with LiBH4 or LiAlH4 affords the alcohol (IX), which is converted into the corresponding azide (X) as already reported for (II). Reduction of azide (X) by means of SnCl2·2H2O/NaOH in water yields amine (XI), which is condensed with acid (XII) in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrocloride (WSC) and HOBt. Elimination of the protecting group Boc with HCl provides derivative (XIII), which is finally condensed with the aromatic acid (XIV) in the same conditions described for the coupling of (XI) with (XII).

参考文献 中间体
合成目标
【1】 Nishi, K.; Seno, K.; Okuno, T.; et al.; Pyrrolidine inhibitors of human cytosolic phospholipase A2. J Med Chem 2000, 43, 6, 1041.
【2】 Seno, K.; Ohtani, M.; Watanabe, F. (Shionogi & Co. Ltd.); Pyrrolidine derivs. having phospholipase A2 inhibitory activity. EP 0976748; WO 9833797 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(I) 15783 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate C11H19NO5 详情 详情
(II) 15785 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate C11H18N4O4 详情 详情
(III) 40992 1-(tert-butyl) 2-methyl (2S,4R)-4-(isobutylamino)-1,2-pyrrolidinedicarboxylate C15H28N2O4 详情 详情
(IV) 40993 2-(bromomethyl)-1,1'-biphenyl C13H11Br 详情 详情
(V) 40994 1-(tert-butyl) 2-methyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1,2-pyrrolidinedicarboxylate C28H38N2O4 详情 详情
(VI) 15786 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate C11H20N2O4 详情 详情
(VII) 40996 [1,1'-biphenyl]-2-carbaldehyde C13H10O 详情 详情
(VIII) 40995 1-(tert-butyl) 2-methyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)amino]-1,2-pyrrolidinedicarboxylate C24H30N2O4 详情 详情
(IX) 40997 tert-butyl (2R,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-2-hydroxy-1-pyrrolidinecarboxylate C26H36N2O3 详情 详情
(X) 40998 tert-butyl (2S,4R)-2-(azidomethyl)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1-pyrrolidinecarboxylate C27H37N5O2 详情 详情
(XI) 40999 tert-butyl (2S,4R)-2-(aminomethyl)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-1-pyrrolidinecarboxylate C27H39N3O2 详情 详情
(XII) 41000 (E)-3-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl]-2-propenoic acid C13H9NO4S 详情 详情
(XIII) 41001 tert-butyl (2S,4R)-4-[([1,1'-biphenyl]-2-ylmethyl)(isobutyl)amino]-2-[[((E)-3-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl]-2-propenoyl)amino]methyl]-1-pyrrolidinecarboxylate C40H46N4O5S 详情 详情
(XIV) 41002 2-(2,4-difluorobenzoyl)benzoic acid C14H8F2O3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XVI)

Synthesis of intermediate (I):
N-Protection of 2-piperidone (VIII) with PMB-Cl using KOH and TBAB in toluene gives N-PMB-2-piperidone (IX), which is then hydrolyzed with NaOH to afford 5-(4-methoxybenzylamino)pentanoic acid (X). Condensation of amine (X) with 5-bromo-2-fluorobenzaldehyde (XI) by means of Na2CO3 in DMSO/H2O then provides the tertiary amine (XII). Methylation of carboxylic acid (XII) with MeI in the presence of K2CO3 leads to the corresponding methyl ester (XIII), which then undergoes intramolecular cyclization by means of NaOMe and CO(OMe)2 to yield the N-PMB-1-benzazocine derivative (XIV). Debenzylation of compound (XIV) by means of TFA in toluene affords N-unsubstituted benzazocine (XV), which is then reductocondensed with isobutyraldehyde (XVI) by means of NaBH(OAc)3 in CH2Cl2, affording the 1-isobutyl derivative (XVII). Suzuki coupling of the 8-bromo-1-benzazocine derivative (XVII) with 4-(2-butoxyethoxy)phenylboronic acid (XVIII) by means of Pd(PPh3)4 provides adduct (XIX). Finally, hydrolysis of methyl ester (XIX) with NaOH in THF/MeOH gives the target carboxylic acid (I) (3). Scheme 2.

参考文献 中间体
合成目标
【3】 Seto, M., Aikawa, K., Miyamoto, N. et al. Highly potent and orally active CCR5 antagonists as Anti-HIV-1 agents: Synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety. J Med Chem 2006, 49(6): 2037-48.
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) 66037 　 　 C28H37NO4 详情 详情
(VIII) 43366 2-piperidinone 675-20-7 C5H9NO 详情 详情
(IX) 66044 1-(p-Methoxybenzyl)-2-piperidinone 128773-73-9 C13H17NO2 详情 详情
(X) 66045 5-[N-(4-methoxybenzyl)amino]pentanoic acid 　 C13H19NO3 详情 详情
(XI) 66046 5-bromo-2-fluorobenzaldehyde 93777-26-5 C7H4BrFO 详情 详情
(XII) 66047 　 　 C20H22BrNO4 详情 详情
(XIII) 66048 　 　 C21H24BrNO4 详情 详情
(XIV) 66049 　 　 C21H22BrNO3 详情 详情
(XV) 66050 　 　 C13H14BrNO2 详情 详情
(XVI) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(XVII) 66051 　 　 C17H22BrNO2 详情 详情
(XVIII) 66052 　 　 C12H19BO4 详情 详情
(XIX) 66053 　 　 C29H39NO4 详情 详情
Extended Information