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【结 构 式】 
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【分子编号】12641 【品名】Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 【CA登记号】126-30-7 |
【 分 子 式 】C5H12O2 【 分 子 量 】104.14908 【元素组成】C 57.66% H 11.61% O 30.72% |
合成路线1
该中间体在本合成路线中的序号：(A)18-Methyl-4-oestrene-3,17-dione (I) is hydroxylated by fermentation with Penicillium raistrickii giving the 15alpha-hydroxy compound (II), which is ketalized with 2,2-dimethylpropanediol (A), triethyl orthoformate and p-toluenesulfonic acid in CH2Cl2 giving a mixture of the DELTA(5-6) and DELTA(5-10)-ketals (IIIa-b). These ketals are mesylated witn methanesulfonyl chloride in pyridine yielding the mesyl ester (IVa-b), which is treated with sodium acetate in DMF to afford the oestradiene ketal (Va-b). Finally, this compound is treated with ethynylmagnesium bromide (B) and refluxed with oxalic acid (C) in methanol.
| 【1】 Hofmeister, H.; Wiechert, R.; Annen, K.; Laurent, H.; Steinbeck, H.; Steroids and pharmaceutical compositions thereof. BE 0847090; FR 2326927; GB 1569135; JP 52046060; US 4081537 . |
| 【2】 Castaner, J.; Blancafort, P.; Gestodene. Drugs Fut 1977, 2, 12, 805. |
| 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) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (B) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
| (IIIa) | 33952 | C24H36O4 | 详情 | 详情 | ||
| (IIIb) | 33953 | C24H36O4 | 详情 | 详情 | ||
| (IVa) | 33954 | C27H42O4S | 详情 | 详情 | ||
| (IVb) | 33955 | C27H42O4S | 详情 | 详情 | ||
| (Va) | 33956 | C24H34O3 | 详情 | 详情 | ||
| (Vb) | 33957 | C24H34O3 | 详情 | 详情 | ||
| (I) | 33950 | (8R,9S,10R,13S,14S)-13-ethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H26O2 | 详情 | 详情 | |
| (II) | 33951 | (8R,9S,10R,13S,14S,15S)-13-ethyl-15-hydroxy-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H26O3 | 详情 | 详情 | |
| (C) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A new synthesis of efonidipine has been described: The cyclization of 2,2-dimethylbutane-1,4-diol (I) with triethyl phosphite (II) by heating at 100 C gives 2-methoxy-5,5-dimethyl-1,3,2-dioxaphosphorinan (III), which, by treatment with iodoacetone (IV) in refluxing ether, yields 2-acetonyl-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) by means of piperidine in acetic acid affords 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-buten-2-one (VII), which is finally cyclized with 3-amino-2-propenoic acid 2-(N-benzyl-N-phenylamino)ethyl ester (VIII) in refluxing toluene.
| 【1】 Sakoda, R.; Kamikawaji, Y.; Seto, K.; Synthesis of 1,4-dihydropyridine-5-phosphonates and their calcium antagonistic and antihypertensive activities: Novel calcium-antagonist NZ-105 and its crystal structure. Chem Pharm Bull 1992, 40, 9, 2362. |
| 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) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (II) | 12642 | Trimethyl phosphite | 121-45-9 | C3H9O3P | 详情 | 详情 |
| (III) | 12643 | 2-Methoxy-5,5-dimethyl-1,3,2lambda(5)-dioxaphosphinan-2-one | C6H13O4P | 详情 | 详情 | |
| (IV) | 12644 | 1-Iodoacetone | C3H5IO | 详情 | 详情 | |
| (V) | 12645 | 5,5-Dimethyl-2-(2-oxopropyl)-1,3,2lambda(5)-dioxaphosphinan-2-one | C8H15O4P | 详情 | 详情 | |
| (VI) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (VII) | 12647 | 2-[(Z)-1-Acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-1,3,2lambda(5)-dioxaphosphinan-2-one | C15H18NO6P | 详情 | 详情 | |
| (VIII) | 12648 | 2-(benzylanilino)ethyl (E)-3-amino-2-butenoate | C19H22N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIX)C17-C27 Fragment: The monotosylation of 2,2-dimethylpropane-1,3-diol (XXIX) with TsCl and pyridine in CH2Cl2 gives the monotosylate (XXX), which is condensed with thiophenol by means of NaH in hot DMF yielding the phenylsulfanyl derivative (XXXI). The oxidation of (XXXI) with MCPBA in dichloromethane affords the corresponding sulfone (XXXII), which is oxidized with oxalyl chloride in DMSO to give the aldehyde (XXXIII). The Grignard reaction of (XXXIII) with 4-pentenylmagnesium bromide (XXXIV) in ethyl ether/CH2Cl2 yields the secondary alcohol (XXXV), which is oxidized with oxalyl chloride in DMSO to the ketone (XXXVI). The dihydroxylation of the double bond of (XXXVI) with K2OsO4 in t-BuOH/H2O followed by oxidation with NaIO4 in t-BuOH/H2O/THF affords the keto aldehyde (XXXVII), which is condensed with the chiral butanone (XXXVIII) by means of (-)-diisopinocampheyl chloride ((-)-DIP-Cl) and Et3N in dichloromethane to give aldol (XXXIX). The SmI2 catalyzed Tishchenko reduction of (XXXIX) in the presence of 4-nitrobenzaldehyde yields the diastereomerically pure 4-nitrobenzoate (XL), which is silylated with TBDMS-OTf to afford the protected ketone (XLI). The hydrolysis of the 4-nitrobenzoate group of (XLI) with LiOH in THF/MeOH/H2O gives the alcohol (XLII), which is cyclized by means of camphorsulfonic acid (CSA) in refluxing benzene yielding the dihydropyran (XLIII), the desired C17-C27 fragment. The intermediate, the chiral butanone (XXXVIII) has been obtained as follows: The optical resolution of 3-methyl-4-phenyl-3-buten-2-ol (XLIV) with (+)-DIPT gives the (R)-isomer (XLV), which is protected with p-methoxybenzyl bromide and NaH yielding the benzyl ether (XLVI). Finally, (XLVI) is ozonolyzed with O3 in MeOH / CH2Cl2 dichloromethane to afford the desired intermediate (XXXVIII).
| 【1】 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIX) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (XXX) | 39420 | 3-hydroxy-2,2-dimethylpropyl 4-methylbenzenesulfonate | C12H18O4S | 详情 | 详情 | |
| (XXXI) | 39421 | 2,2-dimethyl-3-(phenylsulfanyl)-1-propanol | C11H16OS | 详情 | 详情 | |
| (XXXII) | 39422 | 2,2-dimethyl-3-(phenylsulfonyl)-1-propanol | C11H16O3S | 详情 | 详情 | |
| (XXXIII) | 39423 | 2,2-dimethyl-3-(phenylsulfonyl)propanal | C11H14O3S | 详情 | 详情 | |
| (XXXIV) | 39424 | bromo(4-pentenyl)magnesium | C5H9BrMg | 详情 | 详情 | |
| (XXXV) | 39425 | 2,2-dimethyl-1-(phenylsulfonyl)-7-octen-3-ol | C16H24O3S | 详情 | 详情 | |
| (XXXVI) | 39426 | 2,2-dimethyl-1-(phenylsulfonyl)-7-octen-3-one | C16H22O3S | 详情 | 详情 | |
| (XXXVII) | 39427 | 6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptanal | C15H20O4S | 详情 | 详情 | |
| (XXXVIII) | 39428 | (3R)-3-[(4-methoxybenzyl)oxy]-2-butanone | C12H16O3 | 详情 | 详情 | |
| (XXXIX) | 39429 | (7S,10R)-7-hydroxy-10-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1-(phenylsulfonyl)-3,9-undecanedione | C27H36O7S | 详情 | 详情 | |
| (XL) | 39430 | (1S)-1-[(2R,3R)-2-hydroxy-3-[(4-methoxybenzyl)oxy]butyl]-6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptyl 4-nitrobenzoate | C34H41NO10S | 详情 | 详情 | |
| (XLI) | 39431 | (1S)-1-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptyl 4-nitrobenzoate | C40H55NO10SSi | 详情 | 详情 | |
| (XLII) | 39432 | (7S,9R,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-10-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1-(phenylsulfonyl)-3-undecanone | C33H52O7SSi | 详情 | 详情 | |
| (XLIII) | 39433 | tert-butyl([(1R,2R)-1-([(2S)-6-[1,1-dimethyl-2-(phenylsulfonyl)ethyl]-3,4-dihydro-2H-pyran-2-yl]methyl)-2-[(4-methoxybenzyl)oxy]propyl]oxy)dimethylsilane; 2-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-2-methylpropyl phenyl sulfone | C33H50O6SSi | 详情 | 详情 | |
| (XLIV) | 39434 | (E)-3-methyl-4-phenyl-3-buten-2-ol | C11H14O | 详情 | 详情 | |
| (XLV) | 39435 | (2R,3E)-3-methyl-4-phenyl-3-buten-2-ol | C11H14O | 详情 | 详情 | |
| (XLVI) | 39436 | (1R,2E)-1,2-dimethyl-3-phenyl-2-propenyl 4-methoxybenzyl ether; 1-([[(1R,2E)-1,2-dimethyl-3-phenyl-2-propenyl]oxy]methyl)-4-methoxybenzene | C19H22O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXI)3) The condensation of 2-bromobenzoic acid (XII) with 4-nitroaniline (XIII) by means of SOCl2 in DMF gives the corresponding amide (XIV), which is cyclized with sodium azide and SOCl2 in acetonitrile - DMF, yielding 5-(2-bromophenyl)-1-(4-nitrophenyl)tetrazole (XV). The condensation of (XV) with the boronic acid (VI, Scheme 1) by means of Na2CO3 and tetrakis(triphenylphosphine)palladium in methanol - water - toluene affords 5-(4'-methylbiphenyl-2-yl)-1-(4-nitrophenyl)tetrazole (XVI), which is brominated with NBS and AIBN to the corresponding bromomethyl derivative (XVII). The condensation of (XVII) with quinolone (III, Scheme 1) by means of K2CO3 in hot N-methylpyrrolidone gives 2-ethyl-4-[2'-[1-(4-nitrophenyl)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (XVIII), which is finally deprotected with NaH and propanethiol in N-methylpyrrolidone. 4) The dehydration of the boronic acid (VI), followed by bromination with bromine and AIBN, gives 4-(bromomethyl)boronic anhydride (XIX), which is condensed with quinolone (III) by means of K2CO3 in N-methylpyrrolidone, yielding 4-(2-ethylquinolin-4-yloxymethyl)phenylboronic acid (XX). The condensation of (XX) with the bromophenyl-tetrazole (XV) by means of K2CO3 and tetrakis(triphenylphosphine)palladium in water - methanol - toluene yields compound (XVIII), already obtained (5). Scheme 2. 5) The reaction of the boronic acid (VI) with 2,2-dimethylpropane-1,3-diol (XXI) in refluxing cyclohexane gives the cyclic boronic ester (XXII), which is brominated with BBS as before to the bromomethyl derivative (XXIII). The condensation of (XXIII) with quinolone (III) affords 2-[4-(2-ethylquinolin-4-yloxymethyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane (XXIV), which is condensed with (XV) as before to give (XVIII), already obtained.
| 【1】 Roberts, D.A.; Russell, S.T.; Pearce, R.J. (AstraZeneca plc); Quinoline derivs., process for their preparation and their use as medicaments. AU 9160955; EP 0412848; GB 2234748; JP 1991169863; US 5444071 . |
| 【2】 Prous, J.; Castaner, J.; Graul, A.; ICI-D8731. Drugs Fut 1993, 18, 5, 428. |
| 【3】 Bradbury, R.H.; Allott, C.P.; Dennis, M.; et al.; New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives. J Med Chem 1992, 35, 22, 4027. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (XII) | 15546 | 2-bromobenzoic acid; o-bromobenzoic acid | 88-65-3 | C7H5BrO2 | 详情 | 详情 |
| (XIII) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (XIV) | 15548 | 2-bromo-N-(4-nitrophenyl)benzamide | C13H9BrN2O3 | 详情 | 详情 | |
| (XV) | 11451 | 5-(2-Bromophenyl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C13H8BrN5O2 | 详情 | 详情 | |
| (XVI) | 15550 | 5-(4'-methyl[1,1'-biphenyl]-2-yl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C20H15N5O2 | 详情 | 详情 | |
| (XVII) | 15551 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C20H14BrN5O2 | 详情 | 详情 | |
| (XVIII) | 15552 | 2-ethyl-4-quinolinyl [2'-[1-(4-nitrophenyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl ether; 2-ethyl-4-([2'-[1-(4-nitrophenyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methoxy)quinoline | C20H14BrN5O2 | 详情 | 详情 | |
| (XIX) | 15553 | 1,3-bis[4-(bromomethyl)phenyl]-3-hydroxy-1-diboroxanol | C14H14B2Br2O3 | 详情 | 详情 | |
| (XX) | 15554 | 4-[[(2-ethyl-4-quinolinyl)oxy]methyl]phenylboronic acid | C18H18BNO3 | 详情 | 详情 | |
| (XXI) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (XXII) | 15556 | 5,5-dimethyl-2-(4-methylphenyl)-1,3,2-dioxaborinane | C12H17BO2 | 详情 | 详情 | |
| (XXIII) | 15557 | 2-[4-(bromomethyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane | C12H16BBrO2 | 详情 | 详情 | |
| (XXIV) | 15558 | 4-[[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl]oxy]-2-ethylquinoline; 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl 2-ethyl-4-quinolinyl ether | C23H26BNO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, TsOH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and TsOH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 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) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (II) | 44529 | 3-(benzyloxy)-2,2-dimethyl-1-propanol | C12H18O2 | 详情 | 详情 | |
| (III) | 44504 | 3-(benzyloxy)-2,2-dimethylpropanal | C12H16O2 | 详情 | 详情 | |
| (IV) | 33891 | Methyl ethyl ketone; 2-Butanone | 78-93-3 | C4H8O | 详情 | 详情 |
| (V) | 44505 | (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one | C16H22O2 | 详情 | 详情 | |
| (VI) | 44506 | 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone | C16H22O3 | 详情 | 详情 | |
| (VII) | 44507 | 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime | C17H25NO3 | 详情 | 详情 | |
| (VIII) | 44508 | (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime | C18H29NO3 | 详情 | 详情 | |
| (IX) | 44509 | (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone | C17H26O3 | 详情 | 详情 | |
| (X) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XI) | 44510 | (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one | C20H30O3 | 详情 | 详情 | |
| (XII) | 44511 | (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol | C20H32O3 | 详情 | 详情 | |
| (XIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XIV) | 44512 | benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane | C23H36O3 | 详情 | 详情 | |
| (XV) | 44513 | 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol | C16H30O3 | 详情 | 详情 | |
| (XVI) | 44514 | 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal | C16H28O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 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) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (II) | 44529 | 3-(benzyloxy)-2,2-dimethyl-1-propanol | C12H18O2 | 详情 | 详情 | |
| (III) | 44504 | 3-(benzyloxy)-2,2-dimethylpropanal | C12H16O2 | 详情 | 详情 | |
| (IV) | 33891 | Methyl ethyl ketone; 2-Butanone | 78-93-3 | C4H8O | 详情 | 详情 |
| (V) | 44505 | (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one | C16H22O2 | 详情 | 详情 | |
| (VI) | 44506 | 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone | C16H22O3 | 详情 | 详情 | |
| (VII) | 44507 | 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime | C17H25NO3 | 详情 | 详情 | |
| (VIII) | 44508 | (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime | C18H29NO3 | 详情 | 详情 | |
| (IX) | 44509 | (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone | C17H26O3 | 详情 | 详情 | |
| (X) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XI) | 44510 | (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one | C20H30O3 | 详情 | 详情 | |
| (XII) | 44511 | (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol | C20H32O3 | 详情 | 详情 | |
| (XIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XIV) | 44512 | benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane | C23H36O3 | 详情 | 详情 | |
| (XV) | 44513 | 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol | C16H30O3 | 详情 | 详情 | |
| (XVI) | 44514 | 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal | C16H28O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 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) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (II) | 44529 | 3-(benzyloxy)-2,2-dimethyl-1-propanol | C12H18O2 | 详情 | 详情 | |
| (III) | 44504 | 3-(benzyloxy)-2,2-dimethylpropanal | C12H16O2 | 详情 | 详情 | |
| (IV) | 33891 | Methyl ethyl ketone; 2-Butanone | 78-93-3 | C4H8O | 详情 | 详情 |
| (V) | 44505 | (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one | C16H22O2 | 详情 | 详情 | |
| (VI) | 44506 | 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone | C16H22O3 | 详情 | 详情 | |
| (VII) | 44507 | 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime | C17H25NO3 | 详情 | 详情 | |
| (VIII) | 44508 | (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime | C18H29NO3 | 详情 | 详情 | |
| (IX) | 44509 | (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone | C17H26O3 | 详情 | 详情 | |
| (X) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XI) | 44510 | (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one | C20H30O3 | 详情 | 详情 | |
| (XII) | 44511 | (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol | C20H32O3 | 详情 | 详情 | |
| (XIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XIV) | 44512 | benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane | C23H36O3 | 详情 | 详情 | |
| (XV) | 44513 | 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol | C16H30O3 | 详情 | 详情 | |
| (XVI) | 44514 | 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal | C16H28O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)3-Bromo-4-hydroxybenzaldehyde (I) was protected as the corresponding cyclic ketal (III) by treatment with neopentyl glycol (II) and pyridinium p-toluenesulfonate. Lithiation of (III) with n-butyllithium, followed by addition to methyl 4-methoxybenzoate (IV), furnished the triaryl carbinol (V). Deketalization of (V) with concomitant reduction of the tertiary alcohol to yield (VI) was accomplished upon heating in formic acid. Subsequent cleavage of the methoxy groups of (VI) by means of boron tribromide afforded the trihydroxy derivative (VII). Finally, dialdehyde (VII) was condensed with 1-amino-5-methyltetrazole (VIII) to generate the title bis-imine.
| 【1】 Pevear, D.C.; Nitz, T.J. (ViroPharma, Inc.); Cpds., compsns. and methods for treating or preventing pneumovirus infection and associated diseases. WO 9938508 . |
| 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) | 44081 | 3-bromo-4-methoxybenzaldehyde | 34841-06-0 | C8H7BrO2 | 详情 | 详情 |
| (II) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (III) | 44082 | 2-(3-bromo-4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane; 2-bromo-4-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl methyl ether | C13H17BrO3 | 详情 | 详情 | |
| (IV) | 44083 | methyl p-anisate; methyl 4-methoxybenzoate | 121-98-2 | C9H10O3 | 详情 | 详情 |
| (V) | 44084 | bis[5-(5,5-dimethyl-1,3-dioxan-2-yl)-2-methoxyphenyl](4-methoxyphenyl)methanol | C34H42O8 | 详情 | 详情 | |
| (VI) | 44085 | 3-[(5-formyl-2-methoxyphenyl)(4-methoxyphenyl)methyl]-4-methoxybenzaldehyde | C24H22O5 | 详情 | 详情 | |
| (VII) | 44086 | 3-[(5-formyl-2-hydroxyphenyl)(4-hydroxyphenyl)methyl]-4-hydroxybenzaldehyde | C21H16O5 | 详情 | 详情 | |
| (VIII) | 44087 | 5-methyl-1H-1,2,3,4-tetraazol-1-ylamine; 5-methyl-1H-1,2,3,4-tetraazol-1-amine | C2H5N5 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and RaNi in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).
| 【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521. |
| 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) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (II) | 44529 | 3-(benzyloxy)-2,2-dimethyl-1-propanol | C12H18O2 | 详情 | 详情 | |
| (III) | 44504 | 3-(benzyloxy)-2,2-dimethylpropanal | C12H16O2 | 详情 | 详情 | |
| (IV) | 33891 | Methyl ethyl ketone; 2-Butanone | 78-93-3 | C4H8O | 详情 | 详情 |
| (V) | 44505 | (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one | C16H22O2 | 详情 | 详情 | |
| (VI) | 44506 | 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone | C16H22O3 | 详情 | 详情 | |
| (VII) | 44507 | 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime | C17H25NO3 | 详情 | 详情 | |
| (VIII) | 44508 | (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime | C18H29NO3 | 详情 | 详情 | |
| (IX) | 44509 | (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone | C17H26O3 | 详情 | 详情 | |
| (X) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XI) | 44510 | (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one | C20H30O3 | 详情 | 详情 | |
| (XII) | 44511 | (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol | C20H32O3 | 详情 | 详情 | |
| (XIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XIV) | 44512 | benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane | C23H36O3 | 详情 | 详情 | |
| (XV) | 44513 | 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol | C16H30O3 | 详情 | 详情 | |
| (XVI) | 44514 | 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal | C16H28O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Indolizinone (I) was converted to the cyclic ketal (III) upon treatment with 2,2-dimethyl-1,3-propanediol (II) in the presence of p-toluenesulfonic acid. Carbethoxylation of (III) with diethyl carbonate and NaH afforded ester (IV), which was halogenated with either bromine or N-chlorosuccinimide to produce the corresponding alpha-bromo (V) or alpha-chloro (VI) ester, respectively. Sulfonylation of (R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (VII) with 4-biphenylylsulfonyl chloride (VIII) provided the chiral auxiliary (IX). This was then condensed with halo ester (V) or (VI) in the presence of K2CO3 to furnish adduct (X). Diastereoselective alkylation of the sodium enolate of (X) with ethyl iodide produced (XI) as the major isomer. The cyano group of (XI) was then converted to acetamide (XII) by catalytic hydrogenation over Raney nickel in the presence of Ac2O and HOAc. Subsequent nitrosation of amide (XII) with NaNO2 in Ac2O/HOAc gave acetate ester (XIII).
| 【1】 Nomura, S.; Tsujihara, K.; Kawaguchi, T. (Tanabe Seiyaku Co., Ltd.); S type 2-substd. hydroxy-2-indolidinylbutyric ester cpds. and process for preparation thereof. US 6277992 . |
| 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) | 15640 | 7-methyl-1,5-dioxo-1,2,3,5-tetrahydro-6-indolizinecarbonitrile | C10H8N2O2 | 详情 | 详情 | |
| (II) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (III) | 49934 | C15H18N2O3 | 详情 | 详情 | ||
| (IV) | 49935 | C18H22N2O5 | 详情 | 详情 | ||
| (V) | 49936 | C18H21BrN2O5 | 详情 | 详情 | ||
| (VI) | 49937 | C18H21ClN2O5 | 详情 | 详情 | ||
| (VII) | 49944 | D-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid | 41220-48-8 | C10H11NO2 | 详情 | 详情 |
| (VIII) | 49939 | 4-Biphenylsulfonyl chloride | 1623-93-4 | C12H9ClO2S | 详情 | 详情 |
| (IX) | 49938 | (3R)-2-([1,1'-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid | C22H19NO4S | 详情 | 详情 | |
| (X) | 49940 | C40H39N3O9S | 详情 | 详情 | ||
| (XI) | 49941 | C42H43N3O9S | 详情 | 详情 | ||
| (XII) | 49942 | C44H49N3O10S | 详情 | 详情 | ||
| (XIII) | 49943 | C44H48N2O11S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(III)Alkylation of ethyl 1-benzyloxycarbonyl-3-oxopyrrolidine-4-carboxylate (I) with iodomethane and K2CO3 produced the 4-methylpyrrolidine (II). The keto group of (III) was then protected as the corresponding ketal (IV) with 2,2-dimethyl-1,3-propanodiol (III). Replacement of the benzyloxycarbonyl protecting group of (IV) with a benzyl group (V) was accomplished by catalytic hydrogenolysis, followed by alkylation of the resulting pyrrolidine with benzyl chloride. The ester group of (V) was then reduced to the primary alcohol (VI) using LiAlH4. After conversion of alcohol (VI) to the corresponding mesylate, displacement with NaN3 provided the alkyl azide (VII). This was reduced to the primary amine (VIII) by catalytic hydrogenation over Raney-Ni. Resolution of the racemic amine (VIII) was carried out via acylation with N-tosyl-L-proline (IX), followed by chromatographic separation of the diastereomeric amides. Base-promoted hydrolysis of the chiral auxiliary from the desired diastereoisomer (X) provided the (R)-amine, which was further protected as the N-Boc derivative (XI). The N-benzyl group of (XI) was then removed by catalytic hydrogenolysis over Pd/C to yield the target pyrrrolidine (XII).
| 【1】 Yoon, S.J.; Chung, Y.H.; Lee, C.W.; Choi, D.R.; Lee, J.S.; Yang, W.Y.; Kim, N.D.; Jin, Y.H.; Song, W.J.; Kim, I.H.; Shin, J.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Optically active quinoline carboxylic acid derivs. having 7-pyrrolidine substitutes causing optical activity and a process for preparing thereof. WO 0071541 . |
| 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) | 53053 | 1-benzyl 3-ethyl 4-oxo-1,3-pyrrolidinedicarboxylate | n/a | C15H17NO5 | 详情 | 详情 |
| (II) | 53054 | 1-benzyl 3-ethyl 3-methyl-4-oxo-1,3-pyrrolidinedicarboxylate | n/a | C16H19NO5 | 详情 | 详情 |
| (III) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (IV) | 53055 | 2-benzyl 4-ethyl 4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2,4-dicarboxylate | n/a | C21H29NO6 | 详情 | 详情 |
| (V) | 53056 | ethyl 2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-4-carboxylate | n/a | C20H29NO4 | 详情 | 详情 |
| (VI) | 53057 | (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methanol | n/a | C18H27NO3 | 详情 | 详情 |
| (VII) | 50358 | (5S,6R)-6-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyltetrahydro-2H-pyran-2-one | C14H28O3Si | 详情 | 详情 | |
| (VIII) | 53059 | (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methanamine; (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methylamine | n/a | C18H28N2O2 | 详情 | 详情 |
| (IX) | 53060 | (2S)-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarboxylic acid | n/a | C12H15NO4S | 详情 | 详情 |
| (X) | 53061 | (2S)-N-{[(4R)-2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methyl}-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarboxamide | n/a | C30H41N3O5S | 详情 | 详情 |
| (XI) | 53062 | tert-butyl [(4R)-2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate | n/a | C23H36N2O4 | 详情 | 详情 |
| (XII) | 53063 | tert-butyl [(4S)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate | n/a | C16H30N2O4 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(IV)In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,N-diisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib (1, 2).
Intermediate (V) can also be prepared by reaction of 1-(4-ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitro derivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).
In an alternative strategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishes N-(4-ethoxybenzylidene)-4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α-amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib (3). Scheme 1.
| 【1】 Kojima, S., Ooyama, J. (Daiichi Sankyo Co., Ltd.). Process for production of brominated acetophenone. WO 2008020617. |
| 【2】 Fujimoto, K., Takebayashi, T., Noguchi, Y., Saitou, T. (Daiichi Sankyo Co., Ltd.). Production of 4-methyl-1,2-diarylpyrrole and intermediate for synthesizing the same. JP 2000080078. |
| 【3】 Kimura, T., Noguchi, Y., Nakao, A., Suzuki, K., Ushiyama, S., Kawara, A., Miyamoto, M. (Daiichi Sankyo Co., Ltd.). 1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses. CA 2201812, EP 0799823, JP 1997823971, US 5908858. |
| 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) | 66028 | 4'-Ethoxyacetophenone; 1-(4-Ethoxyphenyl)ethan-1-one | 1676-63-7 | C10H12O2 | 详情 | 详情 |
| (II) | 66029 | 2-Bromo-1-(4-Ethoxyphenyl)Ethanone; Zinc02649911 | 51012-63-6 | C10H11BrO2 | 详情 | 详情 |
| (III) | 66030 | 2-methyl-N-(2-methylpropyl)-N-prop-1-enylpropan-1-amine | 100334-82-5 | C11H23N | 详情 | 详情 |
| (IV) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (V) | 66031 | C18H26O4 | 详情 | 详情 | ||
| (VI) | 54719 | 4-Aminobenzenesulfonamide; p-Aminobenzene sulfonyl amide; p-Aminobenzenesulfonamide; p-Anilinesulfonamide; Sulfanilamide | 63-74-1 | C6H8N2O2S | 详情 | 详情 |
| (VII) | 66032 | C12H14O2 | 详情 | 详情 | ||
| (VIII) | 66033 | C13H17NO4 | 详情 | 详情 | ||
| (IX) | 66034 | 4-Ethoxybenzaldehyde; p-Ethoxybenzaldehyde | 10031-82-0 | C9H10O2 | 详情 | 详情 |
| (X) | 66035 | C15H16N2O3S | 详情 | 详情 | ||
| (XI) | 61447 | Trimethylsilyl cyanide; Cyanotrimethylsilane; TMSCN; Trimethylsilyl carbonitrile; Trimethylsilylnitrile; Cyantrimethylsilan; Trimethylsilylnitrile; Cyanotrimethylsilane; TRIMETHYLSILYLCYANIDE; Cyanotrimethylsilane; (CYANOTRIMETHYLSILANE) | 7677-24-9 | C4H9NSi | 详情 | 详情 |
| (XII) | 66036 | C16H17N2O3S | 详情 | 详情 | ||
| (XIII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |