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【结 构 式】

【分子编号】11295

【品名】Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol

【CA登记号】107-21-1

【 分 子 式 】C2H6O2

【 分 子 量 】62.06844

【元素组成】C 38.7% H 9.74% O 51.55%
与该中间体有关的原料药合成路线共 53 条
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合成路线1

该中间体在本合成路线中的序号：(AI)

The ketalization of 2beta-ethoxy-3alpha-hydroxy-5alpha-pregnane-11,20-dione (I) with ethylene glycol (A) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding 20,20-ethylenedioxy derivative (II), which is treated with hydroxylamine hydrochloride and NaOH refluxing ethanol to yield 20,20-ethylenedioxy-2beta-ethoxy-3alpha-hydroxy-5alpha-pregnan-11-one 11-oxime (III). The reduction of (III) with Na in refluxing propanol (B) affords 11alpha-amino-20,20-ethylenedioxy-2beta-ethoxy-3alpha-hydroxy-5alpha-pregnan (IV), which is finally methylated with methyl iodide and K2CO3 or with formaldehyde and formic acid, and hydrolyzed with HCl or H2SO4.

参考文献 中间体
合成目标
【1】 Philips, G.H.; Ewan, G.; DE 2715078 .
【2】 Hillier, K.; Castaner, J.; Blancafort, P.; Serradell, M.N.; Minaxolone. Drugs Fut 1980, 5, 12, 614.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(AI) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(B) 29338 1-propanol 71-23-8 C3H8O 详情 详情
(I) 39209 (2S,3S,5S,8S,9S,10S,13S,14S,17S)-17-acetyl-2-ethoxy-3-hydroxy-10,13-dimethylhexadecahydro-11H-cyclopenta[a]phenanthren-11-one C23H36O4 详情 详情
(II) 39210 (2S,3S,5S,8S,9S,10S,13S,14S,17S)-2-ethoxy-3-hydroxy-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydro-11H-cyclopenta[a]phenanthren-11-one C25H40O5 详情 详情
(III) 39211 (2S,3S,5S,8S,9S,10S,13S,14S,17S)-2-ethoxy-3-hydroxy-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydro-11H-cyclopenta[a]phenanthren-11-one oxime C25H41NO5 详情 详情
(IV) 39212 (2S,3S,5S,8S,9S,10S,11R,13S,14S,17S)-11-amino-2-ethoxy-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol C25H43NO4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The reaction of gamma-chlorobutyrophenone (I) with ethylene glycol (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene ketal (III), which is condensed with cis-2,6-dimethylpiperidine (IV) by means of Na and heat, and hydrolyzed with concentrated HCl yielding gamma-(cis-2,6-dimethyl-1-piperidyl)butyrophenone (V). Finally, this compound is condensed with 2-bromopyridine (VI) by means of butyllithium in THF.

参考文献 中间体
合成目标
【1】 Fleming, R.W. (Pfizer Inc.); Antiarrhythmic (+,-)-cis- alpha [3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2-pyridinemethanols. US 4112103 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Hillier, K.; Pirmenol hydrochloride. Drugs Fut 1981, 6, 4, 234.
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) 32227 gamma-Chlorobutyrophenone; 4-Chloro-1-phenyl-1-butanone 939-52-6 C10H11ClO 详情 详情
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(III) 32228 2-(3-chloropropyl)-2-phenyl-1,3-dioxolane C12H15ClO2 详情 详情
(IV) 32229 (2R,6S)-2,6-dimethylpiperidine; cis-2,6-dimethylpiperidine C7H15N 详情 详情
(V) 32230 gamma-(cis-2,6-dimethyl-1-piperidyl)butyrophenone; 4-[(2R,6S)-2,6-dimethylpiperidinyl]-1-phenyl-1-butanone; gamma-(cis-2,6-dimethyl-1-piperidyl)butyrophenone C17H25NO 详情 详情
(VI) 29052 2-Bromopyridine；α-bromopyridine;α-bromoazine 109-04-6 C5H4BrN 详情 详情

合成路线3

该中间体在本合成路线中的序号：(A)

The ketalization of 11alpha-hydroxy-18-methyl-DELTA4-estrene-3,17-dione (I) with ethylene glycol (A) by means of ethyl orthoformate and p-toluene sulfonic acid gives the diketal (II), which is oxidized with CrO3 in acetone yielding the ketone (III). The Wittig reaction of (III) with triphenylmethyl-phosphonium bromide (B) by means of NaH in benzene-DMSO affords 11-methylene-18-methyl-DELTA4-estren-3,17-dione diethyleneketal (IV), which is hydrolyzed with HCl in acetone to the diketone (V). The reaction of (V) with pyrrolidine (C) in methanol gives the N-pyrrolidinyl derivative (VI), which is condensed with potassium acetylide (D) in THF yielding 17alpha-ethynyl derivative (VII). Finally, this compound is hydrolyzed with acetic acid in methanol - water.

参考文献 中间体
合成目标
【1】 Van den Broek, A.J.; Novel 11,11-alkylidene steroids. DE 2361120; ES 421253; FR 2209577; GB 1455270; JP 50029548; US 3927046 .
【2】 Hillier, K.; Castaner, J.; ORG-3236. Drugs Fut 1978, 3, 9, 664.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(B) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(D) 33587 Potassium acetylide C2HK 详情 详情
(I) 33580 (8S,9S,10R,11R,13S,14S)-13-ethyl-11-hydroxy-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione; 11alpha-Hydroxy-18-methyl-delta4-estrene-3,17-dione C19H26O3 详情 详情
(II) 33581 11alpha-Hydroxy-18-methylestr-4-ene-3,17-dione bis(ethyleneketal) C23H34O5 详情 详情
(III) 33582 18-Methylestr-4-ene-3,11,17-trione 3,17-bis(ethyleneketal) C23H32O5 详情 详情
(IV) 33583 11-Methylene-18-methyl-delta4-estren-3,17-dione diethyleneketal; 18-Methyl-11,11-methyleneestr-4-ene-3,17-dione bis(ethyleneketal) C24H34O4 详情 详情
(V) 33584 (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione C20H26O2 详情 详情
(VI) 33585 (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C24H33NO 详情 详情
(VII) 33586 (8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-11-methylene-3-(1-pyrrolidinyl)-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-ol C26H35NO 详情 详情
(C) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情

合成路线4

该中间体在本合成路线中的序号：(A)

The starting product being 21-acetoxy-11alpha,17alpha-dihydroxy-pregn-4-ene-3,20-dione (I). The first step is the ketalization of (I) giving the ethylenedioxy derivative (II), which is epoxidized with monoperphthalic acid (B) to the epoxide (III), then the epoxide ring is opened with HF giving the fluoro derivative (IV); its bromination in dioxane affords (V), which by reaction with methanesulfonyl chloride gives the mesyl ester (VI). This compound is acetylated with acetic anhydride to the triacetoxy derivative (VII), which by treatment first with sodium acetate and then with bromine gives the mono unsaturated dibromo compound (VIII). This product by treatment with lithium carbonate and lithium bromide is converted into the triene derivative (IX); this product by treatment with 1,3-dibromo-5,5-dimethylhydantoine (C) adds BrOH giving (X), which is epoxidized by treatment with potassium carbonate yielding (Xl). This epoxide ring is finally opened with HF.

参考文献 中间体
合成目标
【1】 Riva, M.; Toscano, L.; 2-Bromo-6beta-fluoropregna-1,4-3,20-diones. BE 0826030; DE 2533377; ES 455934; FR 2261776; GB 1499822 .
【2】 Castaner, J.; de Angelis, L.; Halopredone diacetate. Drugs Fut 1976, 1, 11, 526.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(B) 34077 2-carboperoxybenzoic acid C8H6O5 详情 详情
(I) 34075 2-[(8S,10R,11R,14S,17R)-11,17-dihydroxy-10-methyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate C22H30O6 详情 详情
(II) 34076 　 C25H36O7 详情 详情
(III) 34078 (5α,6α,11α)-21-(acetyloxy)-5,6-epoxy-11,17-dihydroxypregnane-3,20-dione cyclic 3-(1,2-ethanediyl acetal) 57781-08-5 C25H36O8 详情 详情
(IV) 34079 2-[(5R,6R,8S,10R,11R,13S,14S,17R)-6-fluoro-5,11,17-trihydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate 913-49-5 C23H33FO7 详情 详情
(V) 34080 2-[(2R,5R,6R,8S,10R,11R,13S,14S,17R)-2-bromo-6-fluoro-5,11,17-trihydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate 57781-10-9 C23H32BrFO7 详情 详情
(VI) 34081 2-((2R,5R,6R,8S,10R,11R,13S,14S,17R)-2-bromo-6-fluoro-5,17-dihydroxy-10,13-dimethyl-11-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate C26H38BrFO7S 详情 详情
(VII) 34082 (2R,5R,6R,8S,10R,11R,13S,14S,17R)-5-(acetoxy)-17-[2-(acetoxy)acetyl]-2-bromo-6-fluoro-10,13-dimethyl-11-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate C30H42BrFO9S 详情 详情
(VIII) 34083 (6R,8S,10R,11R,13S,14S,17R)-17-[2-(acetoxy)acetyl]-2,2-dibromo-6-fluoro-10,13-dimethyl-11-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate C28H37Br2FO7S 详情 详情
(IX) 34084 (6R,8S,10R,13S,14S,17R)-17-[2-(acetoxy)acetyl]-2-bromo-6-fluoro-10,13-dimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl acetate 57808-78-3 C25H28BrFO6 详情 详情
(X) 34085 (6R,8S,9R,10S,11S,13S,14S,17R)-17-[2-(acetoxy)acetyl]-2,9-dibromo-6-fluoro-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl acetate 57781-13-2 C25H29Br2FO7 详情 详情
(XI) 34086 (4aS,4bS,5aS,6aS,7R,9aS,9bS,11R)-7-[2-(acetoxy)acetyl]-3-bromo-11-fluoro-4a,6a-dimethyl-2-oxo-2,4a,5a,6,6a,7,8,9,9a,9b,10,11-dodecahydrocyclopenta[7,8]phenanthro[4b,5-b]oxiren-7-yl acetate C25H28BrFO7 详情 详情
(C) 31277 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione 77-48-5 C5H6Br2N2O2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(A)

The ketalization of cis-bicyclo[3.3.0]octane-3,7-dione (I) with ethylene glycol (A) and p-toluenesulfonic acid gives the diethyleneketal (II), which by controlled hydrolysis with acetic acid-THF-water is converted into the monoketal (III). Carboxylation of (III) with diethyl carbonate by means of NaH yields the ketoester (IV), which is reduced with sodium borohydride in ethanol to afford the hydroxyester (V). Protection of (V) with dimethyl-tert-butylsilyl chloride gives the silylether (VI), which is reduced with diisobutylaluminum hydride to the alcohol (VII). Oxidation of (VII) with pyridinium chlorochromate affords the aIdehyde (VIII), which by a Wittig reaction with the sodium salt of dimethyl 2-oxoheptylphosphonate (IX) is converted into the enone (X). The reduction of (X) with zinc borohydride yields the protected alcohol (XI), which is deprotected to the corresponding dihydroxyketone (XII) by treatment with acetic acid-THF-water. Finally, this compound is submitted to a Wittig reaction with the sodium salt of 4-carboxybutyltriphenylphosphorane (XIII) in DMS.

参考文献 中间体
合成目标
【1】 Shibasaki, M.; Ikegami, S.; Ueda, J.; New synthetic routes to 9(O)-methanopostacyclin. A highly stable and biologically potent analog of prostacyclin. Tetrahedron Lett 1979, 5, 433-436.
【2】 Magolda, R.L.; Barnette, W.E.; Nicolaou, K.C.; Seitz, S.; Sipio, W.J.; Total synthesis of carboprostacyclin, a stable and biologically active analog of prostacyclin (PGI2). J Chem Soc Chem Commun 1978, 23, 1067-68.
【3】 Castaner, J.; Hillier, K.; Carbacyclin. Drugs Fut 1981, 6, 12, 753.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 37496 tetrahydro-2,5(1H,3H)-pentalenedione C8H10O2 详情 详情
(II) 37497 　 C12H18O4 详情 详情
(III) 11311 Perhydropentalene-2,5-dione mono ethyleneketal C10H14O3 详情 详情
(IV) 37498 　 C13H18O5 详情 详情
(V) 37499 　 C13H20O5 详情 详情
(VI) 37500 　 C19H34O5Si 详情 详情
(VII) 37501 　 C17H32O4Si 详情 详情
(VIII) 11315 (3'aS,4'R,5'R,6'aR)-5'-(tert-Butyldimethylsilyloxy)perhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarbaldehyde C17H30O4Si 详情 详情
(IX) 13738 dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate 36969-89-8 C9H19O4P 详情 详情
(X) 37502 　 C24H42O4Si 详情 详情
(XI) 37503 　 C24H44O4Si 详情 详情
(XII) 37504 (3aS,4S,5R,6aR)-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]hexahydro-2(1H)-pentalenone C16H26O3 详情 详情
(XIII) 37505 5-(triphenylphosphoranylidene)pentanoic acid C23H23O2P 详情 详情

合成路线6

该中间体在本合成路线中的序号：(A)

The decarboxylative hydrolysis of 2,4-dimethoxycarbonyl-3-(3-phenylpropyl)cyclopentanone (XIV) with HCl in acetic acid gives 4-carboxy-3-(3-phenylpropyl)cyclopentanone (XV), which by reaction with oxalyl chloride (B) is converted into the corresponding acyl chloride (XVI). The Arndt-Eistert carbon homologation in (XVI) with diazomethane and silver benzoate (C) in methanol affords 4-(methoxycarbonylmethyl)-4-(3-phenylpropyl)cyclopentanone (XVIIa), which is dehydrogenated by the sequence of reactions: N-bromosuccinimide and sodium selenofenolate (D) [to obtain intermediates (XVIIb) and (XVIIc), respectively], followed by reaction with hydrogen peroxide to give 4-(methoxycarbonylmethyl)-3-(3-phenylallyl)cyclopentanone (XVIIIa). Oxidation of (XVIIIa) first with osmium tetroxide and then with Jones reagent (CrO3) [to obtain intermediates (XVIIIb) and (XVIIIc), respectively], followed by methylation of (XVIIIc) with CH2N2 affords 3,4-di(methoxycarbonylmethyl)cyclopentanone (XIX), which is ketalized in the usual way to the ketal (XX). Finally, this compound is submitted to a Dieckmann condensation with sodium methoxide in DMS to yield the protected ketoester (IVa), the methyl ester analogue of the compound (IV) obtained in scheme 09083302a. This compound can then be used instead of (IV) in scheme 09083302a.

参考文献 中间体
合成目标
【1】 Sakai, K.; Kojima, K.; Synthetic studies of prostanoids. XVII. Total synthesis of 9(O)-methanoprostacyclin and its isomers. Tetrahedron Lett 1978, 39, 3743-46.
【2】 Castaner, J.; Hillier, K.; Carbacyclin. Drugs Fut 1981, 6, 12, 753.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IVa) 11312 (3'aS,4'R,6'aS)-5'-Oxoperhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarboxylic acid methyl ester C12H16O5 详情 详情
(XVIIa) 24518 methyl 2-[(1S,2S)-4-oxo-2-(3-phenylpropyl)cyclopentyl]acetate C17H22O3 详情 详情
(XVIIIa) 24519 methyl 2-[(1S,2S)-4-oxo-2-[(E)-3-phenyl-2-propenyl]cyclopentyl]acetate C17H20O3 详情 详情
(B) 29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(XVIIb) 37510 methyl 2-[(1S,2S)-2-(3-bromo-3-phenylpropyl)-4-oxocyclopentyl]acetate C17H21BrO3 详情 详情
(D) 37511 sodium benzeneselenolate C6H5NaSe 详情 详情
(XVIIc) 37512 methyl 2-[(1S,2S)-4-oxo-2-[3-phenyl-3-(phenylselanyl)propyl]cyclopentyl]acetate C23H26O3Se 详情 详情
(XVIIIb) 37513 methyl 2-[(1S,2S)-4-oxo-2-(2-oxoethyl)cyclopentyl]acetate C10H14O4 详情 详情
(XVIIIc) 37514 2-[(1R,2S)-2-(2-methoxy-2-oxoethyl)-4-oxocyclopentyl]acetic acid C10H14O5 详情 详情
(XIV) 37506 dimethyl (1R,2R,3S)-4-oxo-2-(3-phenylpropyl)-1,3-cyclopentanedicarboxylate C18H22O5 详情 详情
(XV) 37507 (1R,2S)-4-oxo-2-(3-phenylpropyl)cyclopentanecarboxylic acid C15H18O3 详情 详情
(XVI) 37508 (1R,2S)-4-oxo-2-(3-phenylpropyl)cyclopentanecarbonyl chloride C15H17ClO2 详情 详情
(XIX) 24520 methyl 2-[(1R,2S)-2-(2-methoxy-2-oxoethyl)-4-oxocyclopentyl]acetate C11H16O5 详情 详情
(XX) 24521 methyl 2-[(7R,8S)-8-(2-methoxy-2-oxoethyl)-1,4-dioxaspiro[4.4]non-7-yl]acetate C13H20O6 详情 详情
(C) 37509 silver(1+) benzoate 532-31-0 C7H5AgO2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(A)

Compound can be prepared in two different ways: 1) By dehydration of 13beta-ethyl-11beta,17beta-dihydroxy-17alpha-ethynyl-gona-4,9-diene-3-one (IV) with 60% formic acid at 100 C or with perchloric acid in methylene chloride containing acetonitrile. 2) The ketalization of 13beta-ethyl-gona-4,9,11-triene-3,17-dione (I) by means of glycol (A) and oxalic acid in dichloroethane affords 3-ethylenedioxy-13beta-ethyl-gona-4,9,11-trien-17-one (II), which is then treated with methylmagnesium bromide (B) and acetylene (C) in THF to yield 3-ethylenedioxy-13beta-ethyl-17beta-hydroxy-17alpha-ethynyl-gona-4,9,11-triene (III). Finally, this compound is hydrolyzed in an acidic medium.

参考文献 中间体
合成目标
【1】 Bertin, D.; Pierdet, A.; 19-Nor-delta(4,9,11)-gonatriene-3-ones. DE 1618810; FR 1503984; GB 1128787; US 3484462 .
【2】 Bertin, D.; Pierdet, A; Process for the preparation of unsaturated 19-nor steroids. DE 1618815; FR 1479352; GB 1128788; US 3478067 .
【3】 Nomine, G.; et al.; New Steroid compounds, compositions incorporating them and processes for their preparation. GB 1069709 .
【4】 Nomine, G.; et al.; Novel 13beta-alkyl-4,9,11-gonatriene-3-ones. DE 1291337; DE 1593307; FR 1426077; FR 1453214; FR 1492782; NL 6607609; US 3248294; US 3257278 .
【5】 Castaner, J.; Thorpe, P.; R-2323. Drugs Fut 1977, 2, 2, 131.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(B) 33623 bromo(methyl)magnesium 75-16-1 CH3BrMg 详情 详情
(I) 33619 (8S,13R,14S)-13-ethyl-7,8,13,14,15,16-hexahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione C19H22O2 详情 详情
(II) 33620 　 C21H26O3 详情 详情
(III) 33621 　 C23H28O3 详情 详情
(IV) 33622 (8S,11S,13S,14S,17R)-13-ethyl-17-ethynyl-11,17-dihydroxy-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one C21H26O3 详情 详情
(C) 23634 acetylene 74-86-2 C2H2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

By reaction of theophylline-7-acetaldehyde (I) with ethylene glycol (II) by means of p-toluenesulfonic acid in refluxing benzene.

参考文献 中间体
合成目标
【1】 De Martiis, F.; Toffoli, F.; Avico, U.; Diossolani ed 1,3-diossani. Farm Sci Ed 1962, 17, 73-80.
【2】 Franzone, J.S.; Di Carlo, R.; Fonzo, D.; Reboani, C.; Pharmacoligical researches on 2-(7'-theophyllinemethyl)-1,3-dioxolane. Farm Sci Ed 1981, 36, 201-219.
【3】 Franzone, J.S.; Tamietto, T. (Istituto Biologico Chemioterapico "ABC" SpA); Pharmaceutical composition with anti-bronchospasmodic and anti-tussive activity. BE 0868556; DE 2827497; FR 2421614; GB 1582510; JP 1123066C; JP 54138127; JP 57015088B; NL 7807152; US 4187308 .
【4】 Dowle, M.D.; Wu, W.-Y.; Jin, B.; Mason, A.M.; McConnell, D.; MacDonald, S.J.F.; Shanahan, S.E.; Nguyen, V.T.T. (Biota Scientific Management Pty Ltd.); Dimeric cpds. and their use as anti-viral agents. WO 0340135 .
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) 31948 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)acetaldehyde; theophylline-7-acetaldehyde 5614-53-9 C9H10N4O3 详情 详情
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情

合成路线9

该中间体在本合成路线中的序号：

The condensation of chiral tetraline (I) with phthalic anhydride (II) by means of AlCl3 at 180 C gives the naphthacenedione (III), which is ketalized at the acetyl group with ethylene glycol and p-toluenesulfonic acid yielding the dioxolane (IV). The hydroxylation of (IV) with Br2 and AIBN in CCl4/CHCl3 affords the 4-demethoxy-7-epidaunomycinone (V), which is isomerized with TFA yielding 4-demethoxydaunomycinone (VI) . The condensation of (VI) with the acylated hexopyranosyl chloride (VII) by means of CF3SO3Ag of Br2Hg affords the trifluoroacetylated 4-demethoxydaunomycin (VIII), which is finally treated with NaOH in order to eliminate the trifluoroacetyl groups

参考文献 中间体
合成目标
【1】 Arcamone, F.; et al.; Synthesis and antitumour activity of new daunorubicin and adriamycin analogues. Experientia 1978, 34, 1255.
【2】 Bernardi, L.; Arcamone, F.; Patelli, B.; Di Marco, A. (Pharmacia Corp.); Daunomycin analogues, their preparation and use. DE 2525633; US 4046878 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 34606 1-[(2R)-2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-1-ethanone C14H18O4 详情 详情
(II) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(III) 34607 (8R)-8-acetyl-6,8,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione C20H16O6 详情 详情
(IV) 34608 (8R)-6,8,11-trihydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-7,8,9,10-tetrahydro-5,12-naphthacenedione C22H20O7 详情 详情
(V) 34609 (2S,4R)-2-acetyl-2,4,5,12-tetrahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione C20H14O8 详情 详情
(VI) 34610 (2S,4S)-2-acetyl-2,4,5,12-tetrahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione C20H14O8 详情 详情
(VII) 34611 (2S,3S,4S,6S)-6-chloro-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl 2,2,2-trifluoroacetate C10H10ClF6NO4 详情 详情
(VIII) 34612 (3S,4S,6R)-6-[[(1S,3S)-3-acetyl-3,5,12-trihydroxy-4,6,11-trioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy]-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl 2,2,2-trifluoroacetate C30H23F6NO12 详情 详情

合成路线10

该中间体在本合成路线中的序号：

The reaction of daunomycinone (IX) with AlCl3 in dichloromethane gives 4-demethyldaunomycinone (X), which is ketalized with ethylene glycol as before yielding the dioxolane (XI). The selective sulfonation of (XI) with TsCl, DIEA and DMAP in pyridine affords the 4-tosyloxy derivative (XII), which is treated with 4-methoxybenzylamine (XIII) in pyridine providing the secondary benzylamine (XIV). Elimination of the benzyl protecting group of (XIV) with TFA gives 4-amino-4-demethoxydaunomycinone ethylene ketal (XV), which is deaminated by reaction with TFA, NaNO2 and H3PO2 to give 4-demethoxydaunomycinone (XVI). Finally, this compound is submitted to fermentation with Streptomyces peucetius corneus, S. Peucetius caesius, S. Caeruleus, S. Peucetius, S. Coeruleorubidus, and other chemical or radio-induced mutants thereof.

参考文献 中间体
合成目标
【1】 Francalanci, F.; Martinengo, T.; de Bernardinis, S.; Cabri, W. (Pharmacia Corp.); Process for the preparation of 4-demethoxydaunomycinone, the aglycone of 4-demethoxy-daunorubicin. EP 0328399 .
【2】 Mitscher, L.A.; Lednicer, D. (Pharmacia Corp.); Biosynthesis of simplified anthracyclines. US 4471052 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IX) 34613 (2S,4S)-2-acetyl-2,4,5,12-tetrahydroxy-7-methoxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione C21H16O9 详情 详情
(X) 34614 (2S,4S)-2-acetyl-2,4,5,7,12-pentahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione C20H14O9 详情 详情
(XI) 34615 (2R,4S)-2,4,5,7,12-pentahydroxy-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione C22H18O10 详情 详情
(XII) 34616 (8R,10S)-6,8,10,11-tetrahydroxy-8-(2-methyl-1,3-dioxolan-2-yl)-5,7,12-trioxo-5,7,8,9,10,12-hexahydro-1-naphthacenyl 4-methylbenzenesulfonate C29H24O12S 详情 详情
(XIII) 15098 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine 2393-23-9 C8H11NO 详情 详情
(XIV) 34617 (2R,4S)-2,4,5,12-tetrahydroxy-7-[(4-methoxybenzyl)amino]-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione C30H27NO10 详情 详情
(XV) 34618 (2R,4S)-7-amino-2,4,5,12-tetrahydroxy-2-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-1,6,11(2H)-naphthacenetrione C22H19NO9 详情 详情
(XVI) 34610 (2S,4S)-2-acetyl-2,4,5,12-tetrahydroxy-3,4-dihydro-1,6,11(2H)-naphthacenetrione C20H14O8 详情 详情

合成路线11

该中间体在本合成路线中的序号：

The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethyleneketal (II), which is condensed with 4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 1-(4-fluorophenyl)-4-(4-hydroxypiperidin-1-yl)-1-butanone ethyleneketal (IV). The Oppenauer oxidation of (IV) with 9-fluorenone and potassium tert-butoxide in hot benzene affords the piperidinone (V), which is condensed with 4-bromo-N-(trimethylsilyl)aniline (VI) by means of BuLi in hot hexane to give 4-[4-(4-aminophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone (VII). Finally, this compound is treated with CuBr2 and NO in THF.

参考文献 中间体
合成目标
【1】 Vincent, S.H.; et al.; Synthesis of [82Br]bromperidol and preliminary tissue distribution studies in the rat. J Med Chem 1980, 23, 1, 75.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 35864 4-chloro-1-(4-fluorophenyl)-1-butanone 3874-54-2 C10H10ClFO 详情 详情
(II) 28203 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane 3308-94-9 C12H14ClFO2 详情 详情
(III) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(IV) 35865 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol C17H24FNO3 详情 详情
(V) 35866 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinone C17H22FNO3 详情 详情
(VI) 35867 N-(4-bromophenyl)(trimethyl)silanamine; N-(4-bromophenyl)-N-(trimethylsilyl)amine C9H14BrNSi 详情 详情
(VII) 35868 4-[4-(4-aminophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone C21H25FN2O2 详情 详情
(VIII) 22531 4-Bromoaniline; 4-Bromophenylamine 106-40-1 C6H6BrN 详情 详情
(IX) 35869 　 C6H5Br2MgN 详情 详情

合成路线12

该中间体在本合成路线中的序号：

The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethyleneketal (II), which is condensed with 4-(chlorophenyl)-4-hydroxypiperidine (VIII) by means of K2CO3 in hot DMF yielding 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone ethyleneketal (IX). The reaction of (IX) with HCl in methanol yields the corresponding free butanone (X), which is treated with trimethylstannyl sodium in glyme to afford the expected stannyl derivative (XI). Finally, this compound is treated with Br2 in chloroform.

参考文献 中间体
合成目标
【1】 Moerlein, S.M.; Stocklin, G.L.; Synthesis of high specific activity [75Br]- and [77Br]-bromperidol and tissue distribution studies in the rat. J Med Chem 1985, 28, 9, 1319.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 35864 4-chloro-1-(4-fluorophenyl)-1-butanone 3874-54-2 C10H10ClFO 详情 详情
(II) 28203 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane 3308-94-9 C12H14ClFO2 详情 详情
(III) 35870 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine 39512-49-7 C11H14ClNO 详情 详情
(IX) 35871 4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol C23H27ClFNO3 详情 详情
(X) 35872 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone 52-86-8 C21H23ClFNO2 详情 详情
(XI) 35873 1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone C24H32FNO2Sn 详情 详情

合成路线13

该中间体在本合成路线中的序号：

The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene-ketal (II), which is condensed with 4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 1-(4-fluorophenyl)-4-(4-hydroxypiperidin-1-yl)-1-butanone ethyle-neketal (IV). The Oppenauer oxidation of (IV) with 9-fluorenone and potassium tert-butoxide in hot benzene affords the piperidinone (V), which is condensed with 4-bromo-N-(trimethylsilyl)aniline (VI) by means of BuLi in hot hexane to give 4-[4-(4-aminophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone (VII). Finally, this compound is treated with Cu82Br2 and NO in THF.

参考文献 中间体
合成目标
【1】 Vincent, S.H.; et al.; Synthesis of [82Br]bromperidol and preliminary tissue distribution studies in the rat. J Med Chem 1980, 23, 1, 75.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 35864 4-chloro-1-(4-fluorophenyl)-1-butanone 3874-54-2 C10H10ClFO 详情 详情
(II) 28203 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane 3308-94-9 C12H14ClFO2 详情 详情
(III) 12076 4-Piperidinol; 4-Hydroxypiperidine 5382-16-1 C5H11NO 详情 详情
(IV) 35865 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol C17H24FNO3 详情 详情
(V) 35866 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinone C17H22FNO3 详情 详情
(VI) 35867 N-(4-bromophenyl)(trimethyl)silanamine; N-(4-bromophenyl)-N-(trimethylsilyl)amine C9H14BrNSi 详情 详情
(VII) 35868 4-[4-(4-aminophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone C21H25FN2O2 详情 详情
(VIII) 22531 4-Bromoaniline; 4-Bromophenylamine 106-40-1 C6H6BrN 详情 详情
(IX) 35869 　 C6H5Br2MgN 详情 详情

合成路线14

该中间体在本合成路线中的序号：

The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene-ketal (II), which is condensed with 4-(chlorophenyl)-4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone ethyleneketal (IV). The reaction of (IV) with HCl in methanol yields the corresponding free butanone (V), which is treated with trimethylstannyl sodium in glyme to afford the expected stannyl derivative (VI). Finally, this compound is treated with 75Br2 or 77Br2 and dichloramin T in methanol or H2O2 in acetic acid.

参考文献 中间体
合成目标
【1】 Moerlein, S.M.; Stocklin, G.L.; Synthesis of high specific activity [75Br]- and [77Br]-bromperidol and tissue distribution studies in the rat. J Med Chem 1985, 28, 9, 1319.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 35864 4-chloro-1-(4-fluorophenyl)-1-butanone 3874-54-2 C10H10ClFO 详情 详情
(II) 28203 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane 3308-94-9 C12H14ClFO2 详情 详情
(III) 35870 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine 39512-49-7 C11H14ClNO 详情 详情
(IV) 35871 4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol C23H27ClFNO3 详情 详情
(V) 35872 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone 52-86-8 C21H23ClFNO2 详情 详情
(VI) 35873 1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone C24H32FNO2Sn 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The reaction of benzonitrile (I) with refluxing ethylene glycol (II) gives ethylene glycol monobenzoate (III), which is chloromethylated with formaldehyde and dry HCl in CH2Cl2 affording 1-benzoyloxy-2-chloromethoxyethane (IV). The condensation of (IV) with 2,6-dichloropurine (V) by means of triethylamine in DMF yields 2,6-dichloro-9-(2-benzoyloxyethoxymethyl)purine (VI), which is aminated and debenzoylated by treatment with NH3 in methanol at 95 C in a pressure vessel giving 2-chloro-9-(2-hydroxyethoxymethyl)adenine (VII). The Sandmeyer reaction of (VII) with NaNO2 in acetic acid affords 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (VIII), which is finally amonolyzed with ammonia in methanol at 125 C in a pressure vessel.

参考文献 中间体
合成目标
【1】 Schaeffer, H.J.; et al.; 9-(2-Hydroxyethoxy)guanine activity aganist viruses of the herpes group. Nature 1978, 272, 583-585.
【2】 Castaner, J.; Hillier, K.; Acycloguanosine. Drugs Fut 1978, 3, 11, 788.
【3】 Schaeffer, H.J. (Glaxo Wellcome plc); Purine derivs.. US 4294831 .
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) 25904 benzonitrile 100-47-0 C7H5N 详情 详情
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(III) 39965 2-hydroxyethyl benzoate C9H10O3 详情 详情
(IV) 39966 2-(chloromethoxy)ethyl benzoate C10H11ClO3 详情 详情
(V) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(VI) 39967 2-[(2,6-dichloro-9H-purin-9-yl)methoxy]ethyl benzoate C15H12Cl2N4O3 详情 详情
(VII) 39968 2-[(6-amino-2-chloro-9H-purin-9-yl)methoxy]-1-ethanol C8H10ClN5O2 详情 详情
(VIII) 39969 2-chloro-9-[(2-hydroxyethoxy)methyl]-9H-purin-6-ol C8H9ClN4O3 详情 详情

合成路线16

该中间体在本合成路线中的序号：(A)

The condensation of diethyl 2-acetylglutarate (I) with 5-(1,1-dimethylheptyl)resorcinol (II) by means of POCl3 gives ethyl 7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-propionate (III), which is cyclized by means of NaH in DMSO yielding 3-(1,1-dimethylheptyl)-7,10-dihydro-1-hydroxy-6H-dibenzo[b,d]pyran-6,9-(8H)-dione (IV). The ketalization of (IV) with ethylene glycol (A) and p-toluenesulfonic acid affords the ketal (V), which by a Grignard reaction with methylmagnesium iodide in refluxing ether is converted into dl-3-(1,1-dimethylheptyl)-6,6a,7,8-tetrahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (VI). Finally, this compound is reduced with Li in liquid ammonia.

参考文献 中间体
合成目标
【1】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as analgesic drugs. US 3944673 .
【2】 Archer, R.A.; Dihydroxyhexahydrodibenzo[b,d]pyrans. DE 2451934; ES 431674; FR 2249664; GB 1487637; JP 50071678; US 3968125 .
【3】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as an anti-anxiety drug. DE 2451932; ES 431675; FR 2249663; GB 1487636; JP 50082073; NL 7414437; US 3928598 .
【4】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as psychotropic, particularly anti-depressant drugs. US 3953603 .
【5】 Castaner, J.; Weetman, D.F.; Nabilone. Drugs Fut 1978, 3, 3, 207.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 15865 Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate 1501-06-0 C11H18O5 详情 详情
(II) 20233 5-(1,1-dimethylheptyl)-1,3-benzenediol C15H24O2 详情 详情
(III) 33507 ethyl 3-[7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl]propanoate C24H34O5 详情 详情
(IV) 33508 3-(1,1-dimethylheptyl)-1-hydroxy-7,10-dihydro-6H-benzo[c]chromene-6,9(8H)-dione C22H28O4 详情 详情
(V) 33509 3-(1,1-Dimethylheptyl)-9,9-(ethylenedioxy)-1-hydroxy-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one C24H32O5 详情 详情
(VI) 33510 3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6,6a,7,8-tetrahydro-9H-benzo[c]chromen-9-one C24H34O3 详情 详情
(VII) 20225 iodo(methyl)magnesium 917-64-6 CH3IMg 详情 详情

合成路线17

该中间体在本合成路线中的序号：

2) The silylation of the hydroxyketal (XXXI) with TBDMS-Tf in dichloromethane gives the corresponding silyl ether (XXXII), which is treated sequentially with borane in THF, with H2O2 and tetrapropylammonium perruthenate catalyst to afford ketone (XXXIII). The reaction of (XXXIII) with KHMDS and TFNP in anhydrous THF yields the enol triflate (XXXIV), which by addition of CO catalyzed by triphenylphosphine and Pd(OAc)2 in methanol is converted to the methyl ester (XXXV). The reduction of (XXXV) with DIBAL in hexane gives the alcohol derivative (XXXVI), which by OsO4 oxidation in acetone/water gives the triol (XXXVII). The dehydration of (XXXVII) by previous silylation with TMS-Cl and reaction with trifluoromethanesulfonic anhydride in dichloromethane affords the oxetane derivative (XXXVIII), which is submitted to deketalization with CLTS to yield the ketone (XXXIX). The dehydrogenation of (XXXIX) by reaction with lithium diisopropylamide TMS-Cl and Pd(OAc)2 in THF gives the enone (XL), which is silylated with TBDMS-Cl in DMF to the fully silylated enone (XLI). The enolization of (XLI) with butyllithium and TMS-Cl followed by ozonolysis with O3 in dichloromethane yields the dialdehyde (XLII), which is submitted to a selective ketalization of the less hindered aldehyde group, affording the monoketal (XLIII). The addition of the lithium dithiane derivative (XLIV) to (XLIII) followed by a Swern oxidation of the intermediate alcohol gives the ketone (XLV), which is deketalized in acidic medium to yield the keto aldehyde (XLVI). The addition of the vinyllithium compound (XLVII) to (XLVI) gives the Diels-Alder precursor (XLVIII), which is submitted to cyclization by heating to afford the polycyclic compound (II) with the basic skeleton of paclitaxel.

参考文献 中间体
合成目标
【1】 Danishefsky, S.J.; Bornmann, W.G.; Queneau, Y.; Magee, T.V.; Krol, W.J. (Sloan-Kettering Institute); Total synthesis of taxol. US 5416225 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IL) 10666 (2aR,4S,11S,12aR,12bS)-11-(Methoxymethyl)-4a,8,13,13-tetramethyl-4,12b-bis(tert-butyldimethylsilyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxete-5,6,12-trione 6,6-propyleneditihoketal C37H64O7S2Si2 详情 详情
(XXXI) 10648 4'a-Methyl-3',4',4'a,5',6',7'-hexahydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalen]-5'-ol C13H20O3 详情 详情
(XXXII) 10649 tert-Butyl-dimethyl-(4'a-methyl-3',4',4'a,5',6',7'-hexahydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalen]-5'-yloxy)-silane C19H34O3Si 详情 详情
(XXXIII) 10650 5'-(tert-Butyl-dimethyl-silanyloxy)-4'a-methyl-octahydro-spiro[[1,3]dioxolane-2,2'-naphthalen]-8'-one C19H34O4Si 详情 详情
(XXXIV) 10651 Trifluoro-methanesulfonic acid 5'-(tert-butyl-dimethyl-silanyloxy)-4'a-methyl-3',4',4'a,5',6',8'a-hexahydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalen]-8'-yl ester C20H33F3O6SSi 详情 详情
(XXXV) 10652 5'-(tert-Butyl-dimethyl-silanyloxy)-4'a-methyl-3',4',4'a,5',6',8'a-hexahydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalene]-8'-carboxylic acid methyl ester C21H36O5Si 详情 详情
(XXXVI) 10653 (4aS,8aS)-8-(Hydroxymethyl)-4a-methyl-5-(tert-butyldimethylsilyloxy)-1,2,3,4,4a,5,6,8a-octahydronaphthalen-2-one ethyleneketal C20H36O4Si 详情 详情
(XXXVII) 10654 5'-(tert-Butyl-dimethyl-silanyloxy)-8'-hydroxymethyl-4'a-methyl-octahydro-spiro[[1,3]dioxolane-2,2'-naphthalene]-7',8'-diol C20H38O6Si 详情 详情
(XXXVIII) 10655 (2'aR,4'S,4'aS,8'aS)-4'a-Methyl-4'-(tert-butyldimethylsilyloxy)perhydrospiro[1,3-dioxolane-2,7'-naphtho[1,2-b]oxet]-8'b-ol C20H36O5Si 详情 详情
(XXXIX) 10656 (2aR,4S,4aS,8aS,8bS)-4-[[tert-butyl(dimethyl)silyl]oxy]-8b-hydroxy-4a-methyldecahydro-7H-naphtho[2,1-b]oxet-7-one C18H32O4Si 详情 详情
(XL) 10657 (2aR,4S,4aS,8aS,8bS)-4-[[tert-Butyl(dimethyl)silyl]oxy]-8b-hydroxy-4a-methyl-1,2a,3,4,4a,8,8a,8b-octahydro-7H-naphtho[2,1-b]oxet-7-one C18H30O4Si 详情 详情
(XLI) 10658 (2aR,4S,4aS,8aS,8bS)-4,8b-bis[[tert-Butyl(dimethyl)silyl]oxy]-4a-methyl-1,2a,3,4,4a,8,8a,8b-octahydro-7H-naphtho[2,1-b]oxet-7-one C24H44O4Si2 详情 详情
(XLII) 10659 (1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-7-oxabicyclo[4.2.0]octane-2,3-dicarbaldehyde C22H42O5Si2 详情 详情
(XLIII) 10660 (1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-(1,3-dioxolan-2-yl)-3-methyl-7-oxabicyclo[4.2.0]octane-3-carbaldehyde C24H46O6Si2 详情 详情
(XLIV) 10661 [2-(1-Isopropenyl-2-methyl-1-propenyl)-1,3-dithian-2-yl]lithium C11H17LiS2 详情 详情
(XLV) 10662 [(1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-(1,3-dioxolan-2-yl)-3-methyl-7-oxabicyclo[4.2.0]oct-3-yl][2-(1-isopropenyl-2-methyl-1-propenyl)-1,3-dithian-2-yl]methanone C35H62O6S2Si2 详情 详情
(XLVI) 10663 (1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[[2-(1-isopropenyl-2-methyl-1-propenyl)-1,3-dithian-2-yl]carbonyl]-3-methyl-7-oxabicyclo[4.2.0]octane-2-carbaldehyde C33H58O5S2Si2 详情 详情
(XLVII) 10664 [1-(Methoxymethoxy)vinyl]lithium C4H7LiO2 详情 详情
(XLVIII) 10665 1-((1S,2S,3S,4S,6R)-1,4-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[[2-(1-isopropenyl-2-methyl-1-propenyl)-1,3-dithian-2-yl]carbonyl]-3-methyl-7-oxabicyclo[4.2.0]oct-2-yl)-2-(methoxymethoxy)-2-propen-1-one C37H64O7S2Si2 详情 详情

合成路线18

该中间体在本合成路线中的序号：

A new asymmetric synthesis of irinotecan has been reported: The reaction of 2,6-dihydroxypyridine-4-carboxylic acid (I) with hot POCl3 and trimethylammonium chloride gives 2,6-dichloropyridine-4-carboxylic acid (II), which by a Grignard condensation with ethylmagnesium bromide in THF is converted into the propanone (III). The ketalization of (III) with ethylene glycol and trimethylsilyl chloride (TMS-Cl) affords the dioxolane (IV), which by reaction with sodium methoxide in refluxing methanol gives the monomethoxy-pyridine derivative (V). The carbonylation of (V) with butyllithium and DMF affords the pyridine-carbaldehyde (VI), which is reduced to the methanol (VII) with NaBH4. The protection of the hydroxy group of (VII) with benzyl bromide and potassium tert-butoxide in THF affords the benzyl ether (VIII), which is treated with CO, K2CO3, palladium acetate and 1,3-bis(diphenylphosphino)propane (DPPP) in propanol/DMF giving the propyl ester (IX). The treatment of (IX) with trifluoroacetic acid yields the propanone (X), which is treated with methyltriphenylphosphonium bromide and potassium bis(trimethylsilyl)amide (KHMDS) in DMF to afford the expected methylene derivative (XI). The oxidation of (XI) with OsO4 in tert-butanol gives the racemic diol (XII), which is submitted to optical resolution with PS-30 catalyst (Pseudomonas cepaica lipase over Celite 521) to give the corresponding (S)-enantiomer (XIII). The oxidation of (XIII) with NaOCl affords the 2(S)-hydroxybutyraldehyde (XIV), which is submitted to cyclization by debenzylation with H2 over Pd/C in methanol giving the cyclized diol (XV). The oxidation of (XV) with NaOCl in dichloromethane affords the hydroxylactone (XVI), which is treated with trimethylsilyl chloride and NaI to give the pyridone (XVII). A new cyclization of (XVII) with tert-butyl acrylate (XVIII) by means of Cs2CO3 in DMSO yield the tricyclic tert-butyl ester (XIX), which is decarboxylated with trifluoroacetic acid in refluxing toluene to afford the tricyclic trione (XX). The cyclization of (XX) with 2-amino-5-hydroxypropiophenone (XXI) by means of p-toluenesulfonic acid in hot toluene/acetic acid gives the camptothecin derivative (XXII), which is finally acylated with 4-(1-piperidyl)piperidine-1-carbonyl chloride (XXIII) in pyridine.

参考文献 中间体
合成目标
【1】 Ashford, S.W.; Sih, J.C.; Gu, R.L.; Henegar, K.E.; Baughman, T.A.; Practical asymmetric synthesis of (S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione, a key intermediate for the synthesis of irinotecan and other camptothecin analogs. J Org Chem 1997, 62, 19, 6588.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 10822 2,6-Dihydroxyisonicotinic acid; Citrazinic acid 99-11-6 C6H5NO4 详情 详情
(II) 10823 2,6-Dichloroisonicotinic acid 5398-44-7 C6H3Cl2NO2 详情 详情
(III) 10824 1-(2,6-Dichloro-4-pyridinyl)-1-propanone C8H7Cl2NO 详情 详情
(IV) 10825 2,6-Dichloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridine C10H11Cl2NO2 详情 详情
(V) 10826 2-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-6-methoxypyridine; 6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-pyridinyl methyl ether C11H14ClNO3 详情 详情
(VI) 10827 6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxynicotinaldehyde C12H14ClNO4 详情 详情
(VII) 10828 [6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methanol C12H16ClNO4 详情 详情
(VIII) 10829 3-[(Benzyloxy)methyl]-6-chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine; Benzyl [6-chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methyl ether C19H22ClNO4 详情 详情
(IX) 10830 propyl 5-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxolan-2-yl)-6-methoxy-2-pyridinecarboxylate C23H29NO6 详情 详情
(X) 10831 propyl 5-[(benzyloxy)methyl]-6-methoxy-4-propionyl-2-pyridinecarboxylate C21H25NO5 详情 详情
(XI) 10832 propyl 5-[(benzyloxy)methyl]-4-(1-ethylvinyl)-6-methoxy-2-pyridinecarboxylate C22H27NO4 详情 详情
(XII) 10833 propyl 5-[(benzyloxy)methyl]-4-[1-hydroxy-1-(hydroxymethyl)propyl]-6-methoxy-2-pyridinecarboxylate C22H29NO6 详情 详情
(XIII) 10834 propyl 5-[(benzyloxy)methyl]-4-[(1S)-1-hydroxy-1-(hydroxymethyl)propyl]-6-methoxy-2-pyridinecarboxylate C22H29NO6 详情 详情
(XIV) 10835 propyl 5-[(benzyloxy)methyl]-4-[(1S)-1-formyl-1-hydroxypropyl]-6-methoxy-2-pyridinecarboxylate C22H27NO6 详情 详情
(XV) 10836 propyl (4S)-4-ethyl-3,4-dihydroxy-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-carboxylate C15H21NO6 详情 详情
(XVI) 10837 propyl (4S)-4-ethyl-4-hydroxy-8-methoxy-3-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-carboxylate C15H19NO6 详情 详情
(XVII) 10838 propyl (4S)-4-ethyl-4-hydroxy-3,8-dioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-6-carboxylate C14H17NO6 详情 详情
(XVIII) 12760 tert-butyl acrylate 1663-39-4 C7H12O2 详情 详情
(XIX) 10840 tert-butyl (4S)-4-ethyl-4,6-dihydroxy-3,10-dioxo-3,4,8,10-tetrahydro-1H-pyrano[3,4-f]indolizine-7-carboxylate C18H21NO7 详情 详情
(XX) 10841 (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione C13H13NO5 详情 详情
(XXI) 10842 1-(2-Amino-5-hydroxyphenyl)-1-propanone C9H11NO2 详情 详情
(XXII) 10819 (4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin C22H20N2O5 详情 详情
(XXIII) 63047 　 C11H19ClN2O 详情 详情

合成路线19

该中间体在本合成路线中的序号：(A)

Compound can be prepared in two different ways both starting from 14-hydroxydihydronormorphinone (I): 1) By reaction of (I) with cyclopropylmethyl bromide (C) in DMF at 70 C. 2) Product (I) is ketalized with ethylene glycol (A) by means of p-toluenesulfonic acid giving the cyclic ketal (II), m.p. 311-3 C; this in turn, is treated with cyclopropyl carbonyl chloride (B) in a mixture of methylene chloride and triethylamine yielding the N,O-dicyclopropylcarbonyl derivative (III), mp 219-20 C. Compound (III) is reduced with LiAlH4, in refluxing THF yielding the ethylene ketal of naltrexone (IV), m.p. 221-2 C, which is finally hydrolyzed with aqueous HCl at 100 C.

参考文献 中间体
合成目标
【1】 Blumberg, H.; et al.; 14-Hydroxydihydronormorphinone derivatives. US 3332950 .
【2】 Blumberg, H.; et al.; Verfahren zur Herstellung von N-substituierten 14-Hydroxydidronormorphinen. CH 493522; DE 1670616; DE 1795707; GB 1119270 .
【3】 Derives de 14-hydroxydihydronormorphinones. FR 6358M .
【4】 Castaner, J.; Roberts, P.J.; Naltrexone. Drugs Fut 1977, 2, 1, 45.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(B) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(I) 33610 (1S,5R,13R,17R)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one C16H17NO4 详情 详情
(II) 33611 　 C18H21NO5 详情 详情
(III) 33612 　 C26H29NO7 详情 详情
(IV) 33613 　 C22H27NO5 详情 详情
(C) 22277 Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane 7051-34-5 C4H7Br 详情 详情

合成路线20

该中间体在本合成路线中的序号：(I)

This compound can be prepared by two similar ways: 1) The monoacylation of ethylene glycol (I) with chloroacetyl chloride (II) and triethylamine gives 2-hydroxyethyl chloroacetate (III), which is condensed with saccharine (IV) by means of NaOH in ethylene glycol yielding 2-hydroxyethyl 3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide (V). Isomerization of (V) by means of potassium tert-butoxide in DMSO affords2-hydroxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (VI), which is methylated with NaOH and methyl iodide in aqueous ethanol giving the corresponding N-methyl derivative (VII). Hydrolysis of (VII) with NaOH in ethanol - water yields the corresponding free acid (VIII), which is acylated with cinnamoyl chloride (IX) by means of triethylamine in dichloromethane to afford the biscinnamoyl derivative (X). Finally, this compound is treated with 2-aminopyridine (XI) in dichloromethane. 2) The preceding sequence can also be carried out with cyclohexanol (XII) instead of ethylene glycol (I), then producing compounds (XIII), (XIV), (XV) and (XVI), which by hydrolysis affords the free acid (VIII).

参考文献 中间体
合成目标
【1】 Bruzzese, T.; Dell'Acqua, E.; Ottonni, F.; Van den Heuvel, H.H. (SPA (Societa Prodotti Antibiotici)); Process for preparing benzothiazine compds. EP 0146102 .
【2】 Prous, J.; Castaner, J.; CINNOXICAM. Drugs Fut 1990, 15, 2, 119.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 11297 2-hydroxyethyl 2-chloroacetate C4H7ClO3 详情 详情
(IV) 11298 1H-1,2-Benzisothiazole-1,1,3(2H)-trione; Saccharin 81-07-2 C7H5NO3S 详情 详情
(V) 11299 2-hydroxyethyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate C11H11NO6S 详情 详情
(VI) 11300 2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C11H11NO6S 详情 详情
(VII) 11301 2-hydroxyethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C12H13NO6S 详情 详情
(VIII) 11302 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid C10H9NO5S 详情 详情
(IX) 11303 (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride 102-92-1 C9H7ClO 详情 详情
(X) 11304 2-Methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic (E)-2-phenyl-2-propenoic anhydride C28H21NO7S 详情 详情
(XI) 11305 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine 504-29-0 C5H6N2 详情 详情
(XII) 11306 Cyclohexanol 108-93-0 C6H12O 详情 详情
(XIII) 11307 cyclohexyl 2-chloroacetate C8H13ClO2 详情 详情
(XIV) 11308 cyclohexyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate C15H17NO5S 详情 详情
(XV) 11309 cyclohexyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C15H17NO5S 详情 详情
(XVI) 11310 cyclohexyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C16H19NO5S 详情 详情

合成路线21

该中间体在本合成路线中的序号：(A)

Reaction of the lactone (I) with lithium ethyl acetate followed by acid catalyzed dehydration and hydrolysis of the ester group with K2CO3 in methanol affords the hydroxy compound (II), which gives after Collins oxidation, treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and reduction with NaBH4, the ketoester (III). Dealkoxy carbonylation with DABCO in toluene, benzoylation and removal of the silyl group with acetic acid in THF-water yield the ketone (IV). Ketalization of the ketone (IV) with ethylene glycol, Collins oxidation and condensation of the resulting aldehyde with the sodium salt of the phosphonate (V) afford the enone (VI). Reduction of (VI) with NaBH4 in methanol, cleavage of the ketal function with acetic acid-H2O and subsequent tetrahydropyranylation lead to the ketone (VII). Wittig condensation of the ketone (VII) with (VIII) and NaH in DMSO affords after chromatographic separation the acid (IX), which is finally deprotected to (X) (ZK-36374) by treatment with acetic acid in THF-water mixture.

参考文献 中间体
合成目标
【1】 Skuballa, W.; Raduechel, B.; Vorbrueggen, H.; Mannesmann, G.; Losert, W.; Casals, J. (Schering AG); Novel prostacyclin derivatives and a process for the preparation thereof.. DE 2845770; ES 485199; US 4692464 .
【2】 Vorbruggen, H.; Schillinger, E.; Ciloprost. Drugs Fut 1981, 6, 11, 676.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IIIa) 32254 ethyl (1R,3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-2-oxooctahydro-1-pentalenecarboxylate C18H32O5Si 详情 详情
(IIIb) 32255 (3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-1-methylhexahydro-2(1H)-pentalenone C18H32O5Si 详情 详情
(VIa) 32257 Benzoic acid (1S,2R,3aR,6aS)-5,5-(ethylenedioxy)-1-(4(S)-methyl-3-oxo-1(E)-octen-6-yn-1-yl)octahydropentalen-2-yl ester C26H30O5 详情 详情
(VIb) 32258 Benzoic acid (1S,2R,3aR,6aS)-5,5-(ethylenedioxy)-1-(4(R)-methyl-3-oxo-1(E)-octen-6-yn-1-yl)octahydropentalen-2-yl ester C26H30O5 详情 详情
(VIIa) 32259 (3aS,4S,5R,6aR)-4-[(E,3S,4S)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone C29H44O5 详情 详情
(VIIb) 32260 (3aS,4S,5R,6aR)-4-[(E,3S,4R)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone C29H44O5 详情 详情
(IXa) 32261 5-[(3aS,4S,5R,6aR)-4-[(E,3S,4S)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid C34H52O6 详情 详情
(IXb) 32262 5-[(3aS,4S,5R,6aR)-4-[(E,3S,4R)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid C34H52O6 详情 详情
(I) 32252 (3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C21H30O5Si 详情 详情
(II) 32253 ethyl 2-[(3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-ylidene]acetate C18H32O5Si 详情 详情
(IV) 32256 (1S,2R,3aR,6aS)-1-(hydroxymethyl)-5-oxooctahydro-2-pentalenyl benzoate C16H18O4 详情 详情
(V) 24482 dimethyl 3-methyl-2-oxo-5-heptynylphosphonate C10H17O4P 详情 详情
(VIII) 29762 sodium 5-(triphenylphosphoranylidene)pentanoate C23H22NaO2P 详情 详情

合成路线22

该中间体在本合成路线中的序号：(IV)

The reaction of lovastatin (I) with benzoyl chloride (II) and pyridine gives the expected benzoate (III), which is treated with ethyleneglycol (IV), triethyl orthoformate and H2SO4 to yield the cyclic orthoformate (V). The methylation of (V) by means of MeI and BuLi in pyrrolidine affords the 2,2-dimethylbutyrate ester (VI), which is finally deprotected with HCl in THF to provide the target simvastatin.

参考文献 中间体
合成目标
【1】 Dabak, K.; Adiyaman, M.; A new method for the synthesis of antihypercholesterolemic agent simvastatin. Helv Chim Acta 2003, 86, 3, 673.
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) 64415 (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate C24H36O5 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 64416 (2R,4R)-2-[2-((1S,2S,6R,8S,8aR)-2,6-dimethyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydro-1-naphthalenyl)ethyl]-6-oxotetrahydro-2H-pyran-4-yl benzoate C31H40O6 详情 详情
(IV) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(V) 64417 (7R,9R)-7-[2-((1S,2S,6R,8S,8aR)-2,6-dimethyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydro-1-naphthalenyl)ethyl]-1,4,6-trioxaspiro[4.5]dec-9-yl benzoate C33H44O7 详情 详情
(VI) 64418 (1S,3R,7S,8S,8aR)-8-{2-[(7R,9R)-9-hydroxy-1,4,6-trioxaspiro[4.5]dec-7-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl 2,2-dimethylbutanoate C27H42O6 详情 详情

合成路线23

该中间体在本合成路线中的序号：(II)

A new synthesis of AS-101 has been reported: By reaction of tellurium tetrachloride (I) with ethylene glycol (II) and ammonium chloride (III) at 80 C. A mechanism for the unusual synthesis in refluxing acetonitrile, reported previously in the original monograph, is also suggested.

参考文献 中间体
合成目标
【1】 Tamari, T.; Sredni, B.; Albeck, M.; Synthesis and properties of ammonium trichloro(dioxyethylene-O,O')tellurate (AS-101). A new immunomodulating compound. Synthesis 1989, 8, 8, 635.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情

合成路线24

该中间体在本合成路线中的序号：(XIV)

The reaction of L-tyrosine methyl ester (I) with ethyl chloroformate and K2CO3 in water gives the carbamate (II), which is protected with Bn-Br and K2CO3 in DMF, yielding the benzyl ether (III). The reduction of (III) by means of LiAlH4 in refluxing THF affords the chiral 2-methylaminopropanol (IV), which is protected as its Boc derivative (V) by means of Boc2O. The oxidation of (V) by means of DMP provides the carbaldehyde (VI), which is reductocondensed with glycine methyl ester (VII) by means of NaBH3CN in methanol to give the adduct (VIII). Elimination of the Boc protecting group of (VIII) by means of TFA yields the diamine (IX), which is cyclized by means of NH4OH in ethanol to afford the piperazinone (X). Elimination of the benzyl protecting group of (X) by hydrogenation with H2 over Pd/C provides the phenol (XIa)-(XIb), which is cyclized by means of bis(acetoxy)iodobenzene in hexafluoroisopropanol to give the spiranic cyclohexadienone (XII). The hydrogenation of (XII) by means of Tes-H and CuI in dichloromethane yields the spiranic cyclohexanone (XIII), which is finally ketalized by means of ethyleneglycol (XIV) and PPTS in refluxing benzene to provide the target ethyleneketal intermediate (XV) (See scheme no. 18599903a, intermediate (XV)).

参考文献 中间体
合成目标
【1】 Mizutani, H.; et al.; Facile synthesis of enantiopure (-)-TAN1251A. Tetrahedron Lett 2002, 43, 13, 2411.
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) 21431 methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate 1080-06-4 C10H13NO3 详情 详情
(II) 57099 methyl (2S)-2-[(ethoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate C13H17NO5 详情 详情
(III) 57100 methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[(ethoxycarbonyl)amino]propanoate C20H23NO5 详情 详情
(IV) 57101 (2S)-3-[4-(benzyloxy)phenyl]-2-(methylamino)-1-propanol C17H21NO2 详情 详情
(V) 57102 tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-hydroxyethyl(methyl)carbamate C22H29NO4 详情 详情
(VI) 57103 tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-oxoethyl(methyl)carbamate C22H27NO4 详情 详情
(VII) 17568 methyl 2-aminoacetate C3H7NO2 详情 详情
(VIII) 57104 methyl 2-({(2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)(methyl)amino]propyl}amino)acetate C25H34N2O5 详情 详情
(IX) 57105 methyl 2-{[(2S)-3-[4-(benzyloxy)phenyl]-2-(methylamino)propyl]amino}acetate C20H26N2O3 详情 详情
(X) 57106 (6S)-6-[4-(benzyloxy)benzyl]-1-methyl-2-piperazinone C19H22N2O2 详情 详情
(XI) 57107 (6S)-6-(4-hydroxybenzyl)-1-methyl-2-piperazinone C12H16N2O2 详情 详情
(XII) 57108 　 C12H14N2O2 详情 详情
(XIII) 57109 　 C12H18N2O2 详情 详情
(XIV) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XV) 48806 　 C14H22N2O3 详情 详情

合成路线25

该中间体在本合成路线中的序号：

Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with 3-hydroxypropionitrile (XXV) by means of LDA in THF provides 17a-(1-cyano-2- hydroxyethyl)-17b-hydroxyandrosta-4,9(11)-dien-3-one (XXVI), which is selectively monoacetylated by means of Ac2O in pyridine to yield monoacetate (XXVII). Dehydration of (XXVII) by means of SOCl2 in pyridine gives 20-cyano-21-acetoxypregna-4,9(11),17(20)-trien-3-one (XXVIII), which is treated with ethylene glycol, trimethyl orthoformate and TsOH in dichloromethane to afford the ethylene ketal (XXIX). Finally, compound (XXIX) is oxidized with KMnO4 in acetone/ethylene glycol and treated with NaHSO3 and HCOOH.

参考文献 中间体
合成目标
【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039.
【2】 Walker, J.A. (Pharmacia Corp.); Corticosteroids from 17-keto steroids via 20-cyano-DELTA17(20)-pregnanes. US 4600538 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XI) 18040 (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one C20H26O2 详情 详情
(XXV) 14029 Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile 109-78-4 C3H5NO 详情 详情
(XXVI) 56615 3-hydroxy-2-[(8S,10R,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]propanenitrile C22H29NO3 详情 详情
(XXVII) 56616 2-cyano-2-[(8S,10R,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethyl acetate C24H31NO4 详情 详情
(XXVIII) 56617 2-cyano-2-[(8S,10R,13S,14S)-10,13-dimethyl-3-oxo-1,2,3,6,7,8,10,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-ylidene]ethyl acetate C24H29NO3 详情 详情
(XXIX) 56618 　 C26H33NO4 详情 详情

合成路线26

该中间体在本合成路线中的序号：(VIII)

The condensation of diethyl (2-methoxyphenoxy)malonate (I) with pyrimidine-2-carboxamidine (II) by means of NaOMe (Na in MeOH), followed by treatment with NaOH, provides the dihydroxy pyrimidine derivative (III), which is converted into the dichloro derivative (IV) by treatment with refluxing PCl5 and DIEA. Compound (IV) can also be obtained from the pyrimidinedione (V) by reaction with phosphorus oxychloride at 90 C. Reaction of compound (IV) with 4-tert-butylbenzenesulfonamide (VI), performed either directly in DMSO or by means of benzyltriethylammonium chloride (BTEAC) or tetrabutylammonium bromide (TBAB) and K2CO3 in refluxing toluene, gives compound (VII). Finally, this compound is converted into bosentan by reaction with sodium and ethylene glycol (VIII).

参考文献 中间体
合成目标
【1】 Mealy, N.E.; del Fresno, M.; Bayes, M.; Bosentan. Drugs Fut 2001, 26, 12, 1149.
【2】 Burri, K.; Clozel, M.; Fischli, W.; Hirth, G.; Loffler, B.-M.; Ramuz, H.; Neidhart, W. (F. Hoffmann-La Roche AG); Sulfonamide, preparation and use thereof as medicine and intermediate. EP 0526708; JP 1993222003; US 4292740 .
【3】 Dehoff, B.S.; Harrington, P.J.; Khatri, H.N. (Roche Colorado Corp.); Preparation of sulfonamides. US 6136971 .
【4】 Harrington, P.J.; Dehoff, B.S.; Khatri, H.N. (F. Hoffmann-La Roche AG); Preparation of sulfonamides. WO 0155120 .
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) 50138 diethyl 2-(2-methoxyphenoxy)malonate C14H18O6 详情 详情
(II) 50368 2-pyrimidinecarboximidamide C5H6N4 详情 详情
(III) 50369 　 C15H12N4O4 详情 详情
(IV) 41585 　 C15H10Cl2N4O2 详情 详情
(V) 50370 5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4,6(1H,5H)-pyrimidinedione C15H12N4O4 详情 详情
(VI) 50371 4-(tert-Butyl)benzenesulphonamide C10H15NO2S 详情 详情
(VII) 50372 　 C25H24ClN5O4S 详情 详情
(VIII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IX) 50373 2-tert-Butoxyethanol; Ethylene glycol mono-tert-butyl ester 7580-85-0 C6H14O2 详情 详情
(X) 50374 　 C31H37N5O6S 详情 详情
(XI) 50375 　 C28H29N5O7S 详情 详情

合成路线27

该中间体在本合成路线中的序号：(IX)

The title compound has been obtained by several related ways: The reaction of 2-chloro-3-nitropyridine (I) with methylboronic acid by means of Pd(PPh3)4 and K2CO3 in hot dioxane gives 2-methyl-3-nitropyridine (III), which is condensed with dimethylformamide dimethylacetal (IV) to yield 2-[2-(dimethylamino)vinyl]-3-nitropyridine (V). The oxidation of (V) by means of NaIO4 affords 3-nitropyridine-2-carbaldehyde (VI), which is condensed with semicarbazide (VII) to provide the corresponding semicarbazone (VIII). Finally, the nitro group of (VIII) is reduced with SnCl2 or Na2S to furnish the target 3-aminopyridine-2-carbaldehyde semicarbazone. 2-Methyl-3-nitropyridine (III) can also be obtained by condensation of 2-chloro-3-nitropyridine (I) with diethyl malonate (II) by means of Na, followed by decarboxylative hydrolysis with H2SO4 at 125 C. The direct oxidation of 2-methyl-3-nitropyridine (III) with SeO2 in dioxane gives carbaldehyde (VI), which is treated with ethyleneglycol (IX) and Ts-OH to yield the cyclic acetal (X). The reduction of (X) with H2 over Pd/C in ethanol affords 3-aminopyridine-2-carbaldehyde ethylene ketal (XI), which is treated with semicarbazide (VI) and HCl to afford the target 3-aminopyridine-2-carbaldehyde semicarbazone. The condensation of 2-chloro-3-nitropyridine (I) with tributyl vinyl tin (XII) Pd(PPh3)4 and PPH3 in refluxing toluene gives 3-nitro-2-vinylpyridine (XIII), which is oxidized with O3 and Me2S in methanol to yield 3-nitropyridine-2-carbaldehyde (VI). This compound is condensed with semicarbazide (VII) and reduced to the target compound as already described.

参考文献 中间体
合成目标
【1】 Li, J.; et al.; Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-Amino-4-methylpyridine-2-carboxaldehyde-thiosemicarbazone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs. Curr Med Chem 2001, 8, 2, 121.
【2】 Niu, C.; et al.; Synthesis of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). Tetrahedron 1998, 54, 23, 6311.
【3】 Liu, M-C.; et al.; Synthesis and antitumor activity of amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone. J Med Chem 1992, 35, 20, 3672.
【4】 Sartorelli, A.C.; Lin, T.-S. (Yale University); 2-Formylpyridine thiosemicarbazone derivs., their preparation and their use as antitumor agents. EP 0570294; JP 1994128230; US 5281715; US 5721259 .
【5】 Doyle, T.W.; Li, J.; Chen, S.-H.; Li, X.; Niu, C.-S. (Vion Pharmaceuticals, Inc.); Process for the synthesis of ribonucleotide reductase inhibitors 3-AP and 3-AMP. US 5869676; WO 9851670 .
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) 10321 2-Chloro-3-nitropyridine 5470-18-8 C5H3ClN2O2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 54410 2-methyl-3-nitropyridine 18699-87-1 C6H6N2O2 详情 详情
(IV) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(V) 54411 (E)-N,N-dimethyl-2-(3-nitro-2-pyridinyl)-1-ethenamine; N,N-dimethyl-N-[(E)-2-(3-nitro-2-pyridinyl)ethenyl]amine C9H11N3O2 详情 详情
(VI) 54414 3-nitro-2-pyridinecarbaldehyde 10261-94-6 C6H4N2O3 详情 详情
(VII) 12954 1-Hydrazinecarbothioamide; Thiosemicarbazide 79-19-6 CH5N3S 详情 详情
(VIII) 54415 2-[(E)-(3-nitro-2-pyridinyl)methylidene]-1-hydrazinecarbothioamide C7H7N5O2S 详情 详情
(IX) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(X) 54413 2-(1,3-dioxolan-2-yl)-3-nitropyridine C8H8N2O4 详情 详情
(XI) 54412 2-(1,3-dioxolan-2-yl)-3-pyridinylamine; 2-(1,3-dioxolan-2-yl)-3-pyridinamine C8H10N2O2 详情 详情
(XII) 54417 3,3-dibutyl-1-heptene C15H30 详情 详情
(XIII) 54416 3-nitro-2-vinylpyridine C7H6N2O2 详情 详情

合成路线28

该中间体在本合成路线中的序号：(XII)

The cyclization of 2-hydroxyacetophenone (I) with pyruvic aldehyde dimethylacetal (II) by means of pyridine in refluxing toluene gives 2-(dimethoxymethyl)-2-methyl-3,4-dihydro-2H-1-benzopyran-4-one (III), which is nitrated with ammonium nitrate and TFA yielding the 6-nitro derivative (IV). The reduction of (IV) with NaBH4 in methanol affords the benzopyranol (V), which is treated with MsCl and DIEA to provide the mesylate (VI). The reaction of (VI) with DBU in refluxing toluene gives 2-(dimethoxymethyl)-2-methyl-6-nitro-2H-1-benzopyran (VII), which is treated with NBS in DMSO to yield the bromohydrin (VIII). Epoxidation of (VIII) with NaOH in dioxane/water affords the epoxide (IX), which is treated with 2-pyrrolidinone (X) and potassium tert-butoxide in tert-butanol to furnish 1-[2-(dimethoxymethyl)-3-hydroxy-2-methyl-3,4-dihydro-2H-1-benzpyran-4-yl]pyrrolidin-2-one (XI). The trans-acetalization of (XI) with ethylene glycol (XII) and TsOH in refluxing toluene gives the 1,3-dioxolanyl derivative (XIII), which is finally dehydrated to the target compound with NaOH in refluxing dioxane.

参考文献 中间体
合成目标
【1】 Yoo, S.-E.; Yi, K.Y.; Jeong, N.C.; Suh, J.H.; Kim, S.-J.; Shin, H.-S.; Lee, B.H.; Jung, K.S. (Korea Research Institute of Chemical Technology); Spiro-benzopyran derivs. and useful for treating asthma and hypertension. EP 0514935; US 5300511; US 5493029 .
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) 29654 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone 118-93-4 C8H8O2 详情 详情
(II) 25433 1,1-dimethoxyacetone 6342-56-9 C5H10O3 详情 详情
(III) 38906 2-(dimethoxymethyl)-2-methyl-2,3-dihydro-4H-chromen-4-one C13H16O4 详情 详情
(IV) 38907 2-(dimethoxymethyl)-2-methyl-6-nitro-2,3-dihydro-4H-chromen-4-one C13H15NO6 详情 详情
(V) 38908 2-(dimethoxymethyl)-2-methyl-6-nitro-4-chromanol C13H17NO6 详情 详情
(VI) 38909 2-(dimethoxymethyl)-2-methyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-nitrochromane; methoxy(2-methyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-nitro-3,4-dihydro-2H-chromen-2-yl)methyl methyl ether C16H23NO6S 详情 详情
(VII) 38910 methoxy(2-methyl-6-nitro-2H-chromen-2-yl)methyl methyl ether; 2-(dimethoxymethyl)-2-methyl-6-nitro-2H-chromene C13H15NO5 详情 详情
(VIII) 38911 3-bromo-2-(dimethoxymethyl)-2-methyl-6-nitro-4-chromanol C13H16BrNO6 详情 详情
(IX) 38912 methoxy(2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-2-yl)methyl methyl ether; 2-(dimethoxymethyl)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromene C13H15NO6 详情 详情
(X) 27397 2-Pyrrolidinone 616-45-5 C4H7NO 详情 详情
(XI) 38913 1-[2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]-2-pyrrolidinone C17H22N2O7 详情 详情
(XII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XIII) 38914 1-[2-(1,3-dioxolan-2-yl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]-2-pyrrolidinone C17H20N2O7 详情 详情

合成路线29

该中间体在本合成路线中的序号：(III)

This compound can be obtained in two different ways: 1) By direct nitration of camptothecin (I) with nitric acid in sulfuric acid. 2) By direct nitration of camptothecin (I) with different inorganic nitrates (or mixtures of inorganic nitrates) in sulfuric acid. 3) The reaction of 2,6-dinitrobenzaldehyde (II) with ethylene glycol (III) and p-toluenesulfonic acid in refluxing toluene gives the corresponding ethylene ketal (IV), which is reduced with sodium sulfide in refluxing ehanol/water yielding 2-amino-6-nitrobenzaldehyde ethylene ketal (V). The hydrolysis of (V) with aqueous sulfuric acid affords 2-amino-6-nitrobenzaldehyde (VI), which is finally cyclized with the tricyclic ketone (VII) in refluxing acetic acid (the same cyclization can be performed with the ketal (V) and the ketone (VII).

参考文献 中间体
合成目标
【1】 Cao, Z.S.; et al.; Nitration of campothecin with various inorganic nitrate salts in concentrated sulfuric acid: A new preparation of anticancer drug 9-nitrocamptothecin. Synthesis 1998, 12, 1724.
【2】 Sawada, S.; Matsuoka, S.-I.; Nokata, K.-I.; Nagata, H.; Furuta, T.; Yokokura, T.; Miyasaka, T.; Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins. Chem Pharm Bull 1991, 39, 12, 3183.
【3】 Wani, M.C.; Nicholas, A.W.; Wall, M.E.; Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues. J Med Chem 1986, 29, 11, 2358.
【4】 Leitner, P.; Tele, C.; Truesdale, A.; Nicholas, A.W.; Moore, L.; Besterman, J.M.; Manikumar, G.; Wani, M.C.; Wall, M.E.; Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs. J Med Chem 1993, 36, 18, 2689.
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) 10816 Camptothecin; (4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-et-4-hydroxy-1,12-dihydro-4h-2-oxa-6,12a-diaza-dibenzo(b,h)fluorene-3,13-dione 7689-03-4 C20H16N2O4 详情 详情
(II) 39891 2,6-dinitrobenzaldehyde 606-31-5 C7H4N2O5 详情 详情
(III) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IV) 39892 2-(2,6-dinitrophenyl)-1,3-dioxolane C9H8N2O6 详情 详情
(V) 39893 2-(1,3-dioxolan-2-yl)-3-nitrophenylamine; 2-(1,3-dioxolan-2-yl)-3-nitroaniline C9H10N2O4 详情 详情
(VI) 15649 2-amino-6-nitrobenzaldehyde C7H6N2O3 详情 详情
(VII) 10841 (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione C13H13NO5 详情 详情

合成路线30

该中间体在本合成路线中的序号：(XXXIII)

Synthesis of the cholestane aglycon (XXXVI): The protection of the OH group of dehydroisoandrosterone (XXVI) with Tbdms-Cl and imidazole gives the silyl ether (XXVII), which is condensed with ethyl triphenylphosphonium bromide (XXVIII) and potassium tert-butoxide in refluxing THF to yield the ethylidene compound (XXIX). The hydroxylation of (XXIX) with SeO2 and TBHP affords the 16alpha-hydroxy compound (XXX), which by a Swern oxidation is converted into the ketone (XXXI). The condensation of (XXXI) with the intermediate cuprate (XXV) provides the adduct (XXXII), which is treated with ethyleneglycol (XXXIII) and PPTS to give the spiroketal (XXXIV). The oxidative cleavage of the enol acetate of (XXXIV) with tBu-OK and Davis reagent yields the alpha-hydroxyketone (XXXV), which is finally reduced with LiAlH4 to afford the desired cholestane aglycon (XXXVI).

参考文献 中间体
合成目标
【1】 Jin, Z.; Yu, W.; A new strategy for the stereoselective introduction of steroid side chain via alpha-alkoxy vinyl cuprates: Total synthesis of a highly potent antitumor natural product OSW-1. J Am Chem Soc 2001, 123, 14, 3369.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXV) 48957 　 C54H99CuNO4 详情 详情
(XXVI) 11713 Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one 53-43-0 C19H28O2 详情 详情
(XXVII) 16818 (3S,8R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one C25H42O2Si 详情 详情
(XXVIII) 11717 Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide 1530-32-1 C20H20BrP 详情 详情
(XXIX) 48958 tert-butyl(dimethyl)silyl (3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl ether; tert-butyl([(3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl]oxy)dimethylsilane C27H46OSi 详情 详情
(XXX) 48959 (3S,10R,13S,16R)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-ol C27H46O2Si 详情 详情
(XXXI) 48960 (3S,10R,13S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one C27H44O2Si 详情 详情
(XXXII) 48961 (3S,10R,13S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate C41H68O4Si 详情 详情
(XXXIII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XXXIV) 48962 (3S,10R,13S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate C37H62O5Si 详情 详情
(XXXV) 48963 (3S,10R,13S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one C35H60O5Si 详情 详情
(XXXVI) 48964 (3S,10R,13S,16S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol C35H62O5Si 详情 详情

合成路线31

该中间体在本合成路线中的序号：(XXVII)

Synthesis of the cholestane aglycone (XXXII): The condensation of the commercial dehydroisoandrosterone (XVIII) with ethyl triphenylphosphonium bromide (XIX) and potassium tert-butoxide in refluxing THF gives the ethylidene derivative (XX), which is silylated at the 3-OH group with Tbdps-Cl and imidazole to yield the silyl ether (XXI). The reaction of (XXI) with paraformaldehyde in the presence of catalytic BF3/Et2O affords the desired homoallylic alcohol (XXII) stereoselectively. Oxidation of alcohol (XXII) with DMP in dichloromethane provides the corresponding aldehyde (XXIII), which when treated with the Grignard reagent (XXIV) of the 1-bromo-3-methyl butane in ether furnishes the adduct (XXV). The oxidation of the secondary alcohol of (XXV) with PDC in DMF/dichloromethane gives the expected ketone (XXVI), which is protected as the spiroketal (XXVIII) by reaction with ethyleneglycol (XXVII), TsOH and triethyl orthoformate. The Tbdps protecting group of (XXVIII) was now converted into the Tbdms group by desilylation with TBAF and resilylation with Tbdms-Cl and imidazole to give (XXIX). The oxidation of (XXIX) with OsO4 and pyridine in ether yields the 16alpha,17alpha-diol (XXX), which is oxidized with oxalyl chloride to afford the ketone (XXXI). The reduction of (XXXI) with NaBH4 and CeCl3 in THF provides the target 16beta,17alpha-diol (XXXII).

参考文献 中间体
合成目标
【1】 Deng, S.; et al.; First total synthesis of an exceptionally potent antitumor saponin, OSW-1. J Org Chem 1999, 64, 1, 202.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 11713 Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one 53-43-0 C19H28O2 详情 详情
(XIX) 11717 Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide 1530-32-1 C20H20BrP 详情 详情
(XX) 48980 (3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-ol C21H32O 详情 详情
(XXI) 48981 tert-butyl([(3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl]oxy)diphenylsilane; tert-butyl(diphenyl)silyl (3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl ether C37H50OSi 详情 详情
(XXII) 48982 (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-propanol C38H52O2Si 详情 详情
(XXIII) 48983 (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)propanal C38H50O2Si 详情 详情
(XXIV) 13532 Bromo(isopentyl)magnesium C5H11BrMg 详情 详情
(XXV) 48984 (2S,3S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-6-methyl-3-heptanol C43H62O2Si 详情 详情
(XXVI) 48985 (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-6-methyl-3-heptanone C43H60O2Si 详情 详情
(XXVII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XXVIII) 48986 tert-butyl([(3S,10R,13S)-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy)diphenylsilane; tert-butyl(diphenyl)silyl (3S,10R,13S)-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether C45H64O3Si 详情 详情
(XXIX) 48987 tert-butyl([(3S,10R,13S)-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (3S,10R,13S)-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether C35H60O3Si 详情 详情
(XXX) 48988 (3S,10R,13S,16R,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol C35H62O5Si 详情 详情
(XXXI) 48963 (3S,10R,13S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one C35H60O5Si 详情 详情
(XXXII) 48964 (3S,10R,13S,16S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol C35H62O5Si 详情 详情

合成路线32

该中间体在本合成路线中的序号：(A)

Synthesis of the target cholestane glycoside. The reaction of 3-beta-hydroxy-5-androsten-17-one (XXV) with Tbdms-Cl gives the silyl ether (XXVI), which is condensed with phosphorane (XXVII), yielding the ethylidene derivative (XXVIII). The oxidation of (XXVIII) by means of SeO2 and tert-butyl hydroperoxide affords the alcohol (XXIX), which is submitted to a Swern oxidation to provide the enone (XXX). The condensation of (XXX) with the intermediate vinyl bromide (XXIV) by means of CuCN, LiCl and Tms-Cl gives the non isolated intermediate (XXXI), which is treated with acetyl chloride to yield the enol acetate (XXXII). The reaction of (XXXII) with ethyleneglycol and PPTS in dichloromethane affords the ethylene ketal (XXXIII), which is submitted to a stereoselective oxidation with Davis reagent and t-BuOK to provide the hydroxy ketone (XXXIV). The stereoselective reduction of (XXXIV) by means of LiAlH4 in dichloromethane leads to the dihydroxy compound (XXXV).

参考文献 中间体
合成目标
【1】 Yu, W.; Jin, Z.; Total synthesis of the anticancer natural product OSW-1. J Am Chem Soc 2002, 124, 23, 6576.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XXIV) 48956 (E)-1-bromo-4-methyl-1-pentenyl cyclohexyl ether; 1-[[(E)-1-bromo-4-methyl-1-pentenyl]oxy]cyclohexane C12H21BrO 详情 详情
(XXV) 11713 Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one 53-43-0 C19H28O2 详情 详情
(XXVI) 16818 (3S,8R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one C25H42O2Si 详情 详情
(XXVII) 60152 ethylidene(triphenyl)phosphorane C20H19P 详情 详情
(XXVIII) 60153 tert-butyl(dimethyl)silyl (3S,8S,9S,10R,13S,14S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl ether; tert-butyl({(3S,8S,9S,10R,13S,14S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl}oxy)dimethylsilane C27H46OSi 详情 详情
(XXIX) 60154 (3S,8R,9S,10R,13S,14S,16R)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-ol C27H46O2Si 详情 详情
(XXX) 60155 (3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(E)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one C27H44O2Si 详情 详情
(XXXI) 60156 tert-butyl(dimethyl)silyl (3S,8R,9S,10R,13S,14S)-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-16-[(trimethylsilyl)oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether; tert-butyl({(3S,8R,9S,10R,13S,14S)-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-16-[(trimethylsilyl)oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl}oxy)dimethylsilane C42H74O3Si2 详情 详情
(XXXII) 60157 (3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate C41H68O4Si 详情 详情
(XXXIII) 60158 (3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate C37H62O5Si 详情 详情
(XXXIV) 60159 (3S,8R,9S,10R,13S,14S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-hydroxy-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one C35H60O5Si 详情 详情
(XXXV) 60160 (3S,8R,9S,10R,13S,14S,16S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol C35H62O5Si 详情 详情

合成路线33

该中间体在本合成路线中的序号：(VII)

The condensation of allylmalonic acid diethyl ester (I) with 2-methoxyethyl bromide (II) by means of NaOEt in ethanol gives 2-allyl-2-(2-methoxyethyl)malonic acid diethyl ester (III), which is monodecarboxylated with LiCl in DMSO/DMF at 170 C to yield the pentenoic ester (IV). The reduction of the ester group of (IV) with LiAlH4 in dry ether affords the alcohol (V), which is oxidized to the corresponding aldehyde (VI) with (COCl)2 in dichloromethane. The protection of the aldehyde group of (VI) with ethyleneglycol (VII) and Ts-OH affords the cyclic ketal (VIII), which is treated with BH3/Me2S in dichloromethane to provide the primary alcohol (IX). The oxidation of (IX) with (COCl)2 as before gives the corresponding aldehyde (X), which is condensed with the indoloazepine (XI) in refluxing toluene, yielding the pyrrolocarbazole derivative (XII). The reductive ring opening of (XII) with NaBH4 in hot acetic acid affords the tricyclic intermediate (XIII), which is debenzylated with H2 over Pd/C in acetic acid to provide the secondary amine (XIV). The deprotection of the cyclic ketal group of (XIV) with HCl and HOAc, followed by treatment with NaOH, induces cyclization to the tetracyclic compound (XV), which is finally cyclized to the target compound in refluxing toluene.

参考文献 中间体
合成目标
【1】 Bandarage, U.K.; et al.; Total syntheses of racemic albifloranine and its anti-addictive congeners, including 18-methoxycoronaridine. Tetrahedron 1999, 55, 31, 9405.
【2】 Glick, S.D.; Kuehne, M.E. (Albany Medical College; University of Vermont); Ibogamine congeners. US 6211360; WO 9705869 .
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) 51458 Allylmalonic acid diethyl ester; Allyl malonic acid; Diethyl allylmalonate 2049-80-1 C10H16O4 详情 详情
(II) 51459 2-Methoxyethyl bromide; 2-Bromoethyl methyl ether; 1-Bromo-2-methoxyethane; Methyl 2-bromoethyl ether 6482-24-2 C3H7BrO 详情 详情
(III) 51460 diethyl 2-allyl-2-(2-methoxyethyl)malonate C13H22O5 详情 详情
(IV) 51461 ethyl 2-(2-methoxyethyl)-4-pentenoate C10H18O3 详情 详情
(V) 51462 2-(2-methoxyethyl)-4-penten-1-ol C8H16O2 详情 详情
(VI) 51463 2-(2-methoxyethyl)-4-pentenal C8H14O2 详情 详情
(VII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(VIII) 51464 2-[1-(2-methoxyethyl)-3-butenyl]-1,3-dioxolane; 3-(1,3-dioxolan-2-yl)-5-hexenyl methyl ether C10H18O3 详情 详情
(IX) 51465 4-(1,3-dioxolan-2-yl)-6-methoxy-1-hexanol C10H20O4 详情 详情
(X) 48474 4-(1,3-dioxolan-2-yl)-6-methoxyhexanal C10H18O4 详情 详情
(XI) 51466 methyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate C21H22N2O2 详情 详情
(XII) 51468 methyl (3aS,4R,11bR)-3-benzyl-4-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate C31H38N2O5 详情 详情
(XIII) 51467 methyl (5R)-3-benzyl-5-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate C31H40N2O5 详情 详情
(XIV) 51469 methyl (5R)-5-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate C24H34N2O5 详情 详情
(XV) 48482 methyl (13R,15S)-17-(2-methoxyethyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9,17-pentaene-13-carboxylate C22H28N2O3 详情 详情

合成路线34

该中间体在本合成路线中的序号：(XXI)

Assembly of the target compound: The reaction of methyl 3-bromopropionate (XVII) with ethylmagnesium bromide (XVIII) and Ti(iPrO)4 gives 1-(2-bromoethyl)cyclopropan-1-ol (XIX), which is brominated by NBS in CCl4 to yield 1,5-dibromo-3-pentanone (XX). The reaction of (XX) with ethylene glycol (XXI), HC(OEt)3 and PPTS affords the cyclic ketal (XXII), which is cyclized with the indolinone intermediate (VII) by means of NaH in DMF to provide the spiro compound (XXIII). The deprotection of (XXIII) with PPTS in acetone/water gives the spiranic diketone (XXIV), which is selectively reduced with NaBH4 in methanol to yield the spiro cyclohexanol (XXV). The condensation of (XXV) with 4-(2-chloroethyl)morpholine (XXVI) by means of NaH in hot toluene affords the corresponding ether (XXVII), which is debenzylated by means of Li/NH3 to provide intermediate (XXVIII) with a free NH group. Finally, the sulfonation of (XXVIII) with intermediate chlorosulfonyl benzamide (XVI) by means of potassium tert-butoxide gives the target sulfonyl benzamide compound.

参考文献 中间体
合成目标
【1】 Venkatesan, H.; et al.; Total synthesis of SR 121463 A, a highly potent and selective vasopressin V2 receptor antagonist. J Org Chem 2001, 66, 11, 3653.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 50276 1-benzyl-5-ethoxy-1,3-dihydro-2H-indol-2-one C17H17NO2 详情 详情
(XVI) 50284 4-[(tert-butylamino)carbonyl]-2-methoxybenzenesulfonyl chloride C12H16ClNO4S 详情 详情
(XVII) 50285 3-Bromopropionic acid methyl ester; Methyl 3-bromopropionate 3395-91-3 C4H7BrO2 详情 详情
(XVIII) 24239 bromo(ethyl)magnesium；ethylmagnesium bromide 925-90-6 C2H5BrMg 详情 详情
(XIX) 50286 1-(2-bromoethyl)cyclopropanol C5H9BrO 详情 详情
(XX) 50287 1,5-dibromo-3-pentanone C5H8Br2O 详情 详情
(XXI) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XXII) 50288 2,2-bis(2-bromoethyl)-1,3-dioxolane C7H12Br2O2 详情 详情
(XXIII) 50289 　 C24H27NO4 详情 详情
(XXIV) 50290 　 C22H23NO3 详情 详情
(XXV) 50291 　 C22H25NO3 详情 详情
(XXVI) 27355 4-(2-chloroethyl)morpholine 3647-69-6 C6H12ClNO 详情 详情
(XXVII) 50292 　 C28H36N2O4 详情 详情
(XXVIII) 50293 　 C21H30N2O4 详情 详情

合成路线35

该中间体在本合成路线中的序号：(X)

Protection of 3,4,5-trimethoxybenzaldehyde (IX) with ethylene glycol (X) affords acetal (XI). After lithiation of (XI) by means of butyllithium, addition to veratraldehyde (XII) furnishes carbinol (XIII). Finally, cyclization of hydroxy acetal (XIII) with alkyne (VIII) under acidic conditions provides the title naphthol derivative.

参考文献 中间体
合成目标
【1】 Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T. (Shionogi & Co. Ltd.); Lignan analog, production thereof, and hypolipidemic drug. EP 0597107; EP 0701991; JP 1993310634; US 5731455; WO 9308155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 57432 methyl 6-ethyl-4-oxo-2-octynoate C11H16O3 详情 详情
(IX) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(X) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XI) 57434 2-(3,4,5-trimethoxyphenyl)-1,3-dioxolane; 4-(1,3-dioxolan-2-yl)-2,6-dimethoxyphenyl methyl ether C12H16O5 详情 详情
(XII) 18304 3,4-Dimethoxybenzaldehyde; Veratraldehyde 120-14-9 C9H10O3 详情 详情
(XIII) 57435 (3,4-dimethoxyphenyl)[6-(1,3-dioxolan-2-yl)-2,3,4-trimethoxyphenyl]methanol C21H26O8 详情 详情

合成路线36

该中间体在本合成路线中的序号：(III)

A different method starts with the chloromethylation of trimethyl psoralen (I) to afford (II). Subsequent condensation of chloride (II) with ethylene glycol (III) yields the hydroxyethoxy derivative (IV). This is converted to mesylate (V) upon treatment with methanesulfonyl chloride and triethylamine. Mesylate displacement by NaN3 leads to azide (VI). Finally, azide reduction to the target amine is accomplished by treatment with triphenylphosphine in moist THF.

参考文献 中间体
合成目标
【1】 Wollowitz, S.; Isaacs, S.T.; Rapoport, H.; Spielmann, H.P. (Steritech, Inc.); Cpds. for the photodecontamination of pathogens in blood. US 5399719; WO 9500141 .
【2】 Wollowitz, S.; Isaacs, S.T.; Rapoport, H.; Spielman, H.P.; Niero, A. (Steritech, Inc.); Cpds. for the photodecontamination of pathogens in blood. WO 9614739 .
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) 58856 2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one C14H12O3 详情 详情
(II) 58857 3-(chloromethyl)-2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one C15H13ClO3 详情 详情
(III) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IV) 58858 3-[(2-hydroxyethoxy)methyl]-2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one C17H18O5 详情 详情
(V) 58859 2-[(2,5,9-trimethyl-7-oxo-7H-furo[3,2-g]chromen-3-yl)methoxy]ethyl methanesulfonate C18H20O7S 详情 详情
(VI) 58860 3-[(2-azidoethoxy)methyl]-2,5,9-trimethyl-7H-furo[3,2-g]chromen-7-one C17H17N3O4 详情 详情

合成路线37

该中间体在本合成路线中的序号：

Ketalization of 17alpha-methyltestosterone (I) by means of ethylene glycol and p-toluenesulfonic acid provided the DELTA5(6)-ketal (II), and subsequent allylic oxidation of (II) with CrO3-3,5-dimethylpyrazole complex gave enone (III). Hydrogenation of the olefinic double bond of (III) afforded the saturated ketone (IV), which was reduced employing NaBH4 and CeCl3 to furnish an unseparable mixture of epimeric alcohols (Va-b). After removal of the ethylene ketal of (Va-b) with p-toluenesulfonic acid/acetone, the major 7beta-alcohol (VI) was isolated by flash chromatography. The 7beta-tosylate (VII) was then prepared by reaction of (VI) with p-tosyl chloride in pyridine. Finally, exchange of the tosylate group of (VII) with tetrabutylammonium fluoride yielded the desired 7alpha-fluoride.

参考文献 中间体
合成目标
【1】 Labaree, D.C.; et al.; 7alpha-Iodo and 7alpha-fluoro steroids as androgen receptor-mediated imaging agents. J Med Chem 1999, 42, 11, 2021.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(Va) 34387 　 C22H36O4 详情 详情
(Vb) 34388 　 C22H36O4 详情 详情
(I) 34383 (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13,17-trimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one 58-18-4 C20H30O2 详情 详情
(II) 34384 　 C22H34O3 详情 详情
(III) 34385 　 C22H32O4 详情 详情
(IV) 34386 　 C22H34O4 详情 详情
(VI) 34389 (5S,7S,8R,9S,10S,13S,14S,17S)-7,17-dihydroxy-10,13,17-trimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one C20H32O3 详情 详情
(VII) 34390 (5S,7S,8R,9S,10S,13S,14S,17S)-17-hydroxy-10,13,17-trimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-7-yl 4-methylbenzenesulfonate C27H38O5S 详情 详情

合成路线38

该中间体在本合成路线中的序号：(A)

This compound has been obtained by several related ways: 1.- The Sam and Thompson cyclization of 3-(2-thienyl)acrylic acid (I) gives the thienocyclopentanone (II), which is condensed with oxoacetic acid (III) yielding 2-(4-oxo-5,6-dihydro-4H-cyclopenteno[b]furan-5-ylidene)acetic acid (IV). The reduction of (IV) with Zn and acetic acid affords the corresponding saturated compound (V), which is condensed with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (VI) by means of DCC and HOBt in dichloromethane to give the corresponding piperidide (VII). The protection of the ketonic group of (VII) with ethylene glycol and TsOH yields the ethylene ketal (VIII), which is reduced at the piperidide group with LiAlH4 in ethyl ether yielding the final intermediate (IX). Finally, this compound is treated with HCl to eliminate the ethylene ketal protecting group. 2.- The condensation of the thienocyclopentanone (II) with ethyl bromoacetate (X) by means of LDA gives the acetate (XI), which is hydrolyzed with KOH in ethanol affording the previously reported saturated acetic acid derivative (V). 3.- The condensation of acetate (XI) with piperidine (VI) by means of Me3Al gives also the previously reported piperidide (VII).

参考文献 中间体
合成目标
【1】 Negreira, J.; Cid, J.; Raviña, E.; et al.; Conformationally constrained butyrophenones with mixed dopaminergic (D(2)) and serotoninergic (5-HT(2A), 5-HT(2C)) affinities: Synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo- and -thienocycloalkanones as putative atypical an. J Med Chem 1999, 42, 15, 2774.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 31893 (Z)-3-(2-thienyl)-2-propenoic acid 15690-25-2 C7H6O2S 详情 详情
(II) 31894 5,6-dihydro-4H-cyclopenta[b]thiophen-4-one C7H6OS 详情 详情
(III) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(IV) 31895 2-(4-oxo-4,6-dihydro-5H-cyclopenta[b]thiophen-5-ylidene)acetic acid C9H6O3S 详情 详情
(V) 31896 2-(4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)acetic acid C9H8O3S 详情 详情
(VI) 17910 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole C12H13FN2O 详情 详情
(VII) 31897 5-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-oxoethyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-4-one C21H19FN2O3S 详情 详情
(VIII) 31898 3-[4,4-(Ethylenedioxy)-5,6-dihydro-4H-cyclopeta[b]thiophen-5-yl]-1-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-propanone C23H23FN2O4S 详情 详情
(IX) 31899 1-[2-[4,4-(Ethylenedioxy)-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl]ethyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine C23H25FN2O3S 详情 详情
(X) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XI) 31900 ethyl 2-(4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)acetate C11H12O3S 详情 详情

合成路线39

该中间体在本合成路线中的序号：(III)

Treatment of 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (I) with acetic anhydride and pyridine provided the cyclic anhydride (II). Ethylene glycol octyl ether (V) was prepared by Williamson's synthesis from the sodium alkoxide of ethylene glycol (III) and n-octyl bromide (IV). Finally, the title diester was obtained by heating anhydride (II) with the octyl ether of ethyleneglycol (V).

参考文献 中间体
合成目标
【1】 Kozak, A.; Shapiro, I. (D-Pharm Ltd.); Lipophilic diesters of chelating agents. JP 2001518458; WO 9916741 .
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) 52462 　 C22H24N2O10 详情 详情
(II) 52463 4-{2-[(2-{[2-(2,6-dioxo-4-morpholinyl)phenyl]oxy}ethyl)oxy]phenyl}-2,6-morpholinedione C22H20N2O8 详情 详情
(III) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IV) 52464 Octyl bromide; 1-Octyl bromide; 1-Bromooctane; Capryl bromide; n-Octyl bromide 111-83-1 C8H17Br 详情 详情
(V) 52465 Ethylene glycol monooctyl ether; n-Octyl-monooxyethylene; Octylglycol 10020-43-6 C10H22O2 详情 详情

合成路线40

该中间体在本合成路线中的序号：(IX)

Reaction of 4-cyano-pyridine (I) with Na in methanol followed by treatment with ammonium chloride provides 4-amidino-pyridine hydrochloride (II), which is then converted into 5-(2-methoxyphenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (IV) by condensation with diethyl malonate derivative (III) by means of Na in MeOH. By heating compound (IV) with phosphorus oxychloride (POCl3), 4,6-dichloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl)pyrimidine (V) is obtained, which in turn is oxidized with peracetic acid in refluxing acetonitrile to afford N-oxide derivative (VI). Condensation of (VI) with 5-isopropylpyridine-2-sulfonamide potassium (VII) furnishes 5-isopropylpyridine-2-sulfonic acid 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide (VIII), which is then dissolved in dimethoxyethane and subjected to reaction with Na in hot ethylene glycol (IX) to provide N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-5-isopropylpyridine-2-sulfonamide (X). Refluxing of (X) with trimethylsilylcyanide and Et3N in acetonitrile yields cyano derivative (XI), which is then converted into the tetrazole derivative (XII) by reaction with sodium azide and NH4Cl in DMF at 70 C. Finally, the disodium salt of tezosentan is obtained by treatment of (XII) with Na/MeOH in THF.

参考文献 中间体
合成目标
【1】 Chilman-Blair, K.; Castaner, J.; Leeson, P.A.; Bayes, M.; Tezosentan Disodium. Drugs Fut 2003, 28, 8, 754.
【2】 Breu, V.; Burri, K.; Cassal, J.-M.; Clozel, M.; Hirth, G.; Loffler, B.-M.; Muller, M.; Neidhart, W.; Ramuz, H. (F. Hoffmann-La Roche AG); Novel sulfonamides. EP 0799209; JP 1998509182; WO 9619459 .
【3】 Spurr, P. (F. Hoffmann-La Roche AG); Process for the preparation of 2,5-disubstd. pyridines. EP 0897914 .
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) 50136 4-Cyanopyridine; Pyridine-4-carbonitrile; Isonicotinic acid nitrile; Isonicotinonitrile; iso-Nicotinonitrile 100-48-1 C6H4N2 详情 详情
(II) 50137 4-pyridinecarboximidamide C6H7N3 详情 详情
(III) 50138 diethyl 2-(2-methoxyphenoxy)malonate C14H18O6 详情 详情
(IV) 50139 5-(2-methoxyphenoxy)-2-(4-pyridinyl)-4,6-pyrimidinediol C16H13N3O4 详情 详情
(V) 50140 4,6-dichloro-2-(4-pyridinyl)-5-pyrimidinyl 2-methoxyphenyl ether; 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridinyl)pyrimidine C16H11Cl2N3O2 详情 详情
(VI) 50141 4-[4,6-dichloro-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate C16H11Cl2N3O3 详情 详情
(VII) 50142 　 C8H11KN2O2S 详情 详情
(VIII) 50143 4-[4-chloro-6-[[(5-isopropyl-2-pyridinyl)sulfonyl]amino]-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate C24H22ClN5O5S 详情 详情
(IX) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(X) 50144 4-[4-(2-hydroxyethoxy)-6-[[(5-isopropyl-2-pyridinyl)sulfonyl]amino]-5-(2-methoxyphenoxy)-2-pyrimidinyl]-1-pyridiniumolate C26H27N5O7S 详情 详情
(XI) 50145 N-[2-(2-cyano-4-pyridinyl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-5-isopropyl-2-pyridinesulfonamide C27H26N6O6S 详情 详情
(XII) 50146 N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-1,2,3,4-tetraazol-5-yl)-4-pyridinyl]-4-pyrimidinyl]-5-isopropyl-2-pyridinesulfonamide C27H27N9O6S 详情 详情

合成路线41

该中间体在本合成路线中的序号：

3-Acetylbenzonitrile (I) was protected as the ethylene ketal (II) employing ethylene glycol and boron trifluoride etherate. Reduction of the cyano group of (II) with LiAlH4 gave amine (III), and further ketal hydrolysis provided 3-acetylbenzylamine (IV). This was acetylated using acetyl chloride and Et3N to yield the intermediate amide (V). Alternatively, intermediate (V) was obtained by addition of methylmagnesium bromide to N-(3-cyanobenzyl)acetamide (VI). Bromination of (V) in dioxan furnished the bromoacetophenone (VII). This was cyclized to the aminothiazole (IX) by treatment with thiourea (VIII) in refluxing ethanol. Condensation of (IX) with benzoyl isothiocyanate (X) provided the benzoyl thiourea (XI). After selective hydrolysis of the benzoyl group of (XI) with NaOH in MeOH-H2O at 60 C, the resulting thiourea (XII) was methylated with iodomethane yielding S-methylisothiourea (XIII). Finally, displacement of the methylthio group with 2-methoxyetylamine (XIV) furnished the title guanidinothiazole.

参考文献 中间体
合成目标
【1】 Katsura, Y.; Tomishi, T.; Inoue, Y.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Guanidino thiazoles and their use as H2-receptor antagonist. EP 0545376; JP 1994321921; US 5532258 .
【2】 Inoue, Y.; Morinaga, C.; Ishikawa, H.; Takasugi, H.; Tomishi, T.; Matsumoto, Y.; Katsura, Y.; Sakane, K.; Anti-Helicobacter pylori agents.4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives. J Med Chem 2000, 43, 17, 3315.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
33623 bromo(methyl)magnesium 75-16-1 CH3BrMg 详情 详情
(I) 17992 m-Cyanoacetophenone; 3-acetylbenzonitrile 6136-68-1 C9H7NO 详情 详情
(II) 34665 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile C11H11NO2 详情 详情
(III) 34673 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine; [3-(2-methyl-1,3-dioxolan-2-yl)phenyl]methanamine C11H15NO2 详情 详情
(IV) 34666 1-[3-(aminomethyl)phenyl]-1-ethanone C9H11NO 详情 详情
(V) 34674 N-(3-acetylbenzyl)acetamide C11H13NO2 详情 详情
(VI) 34667 N-(3-cyanobenzyl)acetamide C10H10N2O 详情 详情
(VII) 34668 N-[3-(2-bromoacetyl)benzyl]acetamide C11H12BrNO2 详情 详情
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IX) 34669 N-[3-(2-amino-1,3-thiazol-4-yl)benzyl]acetamide C12H13N3OS 详情 详情
(X) 23530 benzoyl isothiocyanate 532-55-8 C8H5NOS 详情 详情
(XI) 34670 N-[3-(2-[[(benzoylamino)carbothioyl]amino]-1,3-thiazol-4-yl)benzyl]acetamide C20H18N4O2S2 详情 详情
(XII) 34671 N-(3-[2-[(aminocarbothioyl)amino]-1,3-thiazol-4-yl]benzyl)acetamide C13H14N4OS2 详情 详情
(XIII) 34672 4-[3-[(acetamido)methyl]phenyl]-2-[[(E)-amino(methylsulfanyl)methylidene]amino]-1,3-thiazole C14H16N4OS2 详情 详情
(XIV) 34675 2-methoxyethylamine; 2-methoxy-1-ethanamine 109-85-3 C3H9NO 详情 详情

合成路线42

该中间体在本合成路线中的序号：(VIII)

The ethanolysis of 1-benzylpyrrolidin-2-one (I) with HCl in ethanol gives 4-(benzylamino)butyric acid ethyl ester (II), which is alkylated with ethyl bromoacetate (III), yielding the tertiary amine (IV). The cyclization of (IV) by means of sodium ethoxide affords 1-benzyl-3-hydroxy-1,2,5,6-tetrahydropyridine-4-carboxylic acid ethyl ester (V), which by hydrogenolytic debenzylation, followed by reaction with methyl chloroformate (VI), affords the 1,4-dicarboxylate (VII). The reaction of (VII) with ethyleneglycol (VIII) and TsOH gives the cyclic ketal (IX), which is treated with hydroxylamine and NaOMe to yield the carbohydroxamic acid (X). The cyclization of (X) by means of H2SO4 affords 3-hydroxy-4,5,6,7-tetrahydropyrido[4,3-d]oxazole-6-carboxylic acid methyl ester (XI), which is finally decarboxylated by means of HBr and TEA.

参考文献 中间体
合成目标
【1】 Krogsgaard-Larsen, P.; Muscimol analogues. II. Synthesis of some bicylic 3-isoxazol zwitterions. Acta Chem Scand 1977, B31, 584-588.
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Paton, D.M.; THIP. Drugs Fut 1980, 5, 5, 257.
【3】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597.
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) 43664 1-benzyl-2-pyrrolidinone 5291-77-0 C11H13NO 详情 详情
(II) 43665 ethyl 4-(benzylamino)butanoate C13H19NO2 详情 详情
(III) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IV) 43666 ethyl 4-[benzyl(2-ethoxy-2-oxoethyl)amino]butanoate C17H25NO4 详情 详情
(V) 43667 ethyl 1-benzyl-5-hydroxy-1,2,3,6-tetrahydro-4-pyridinecarboxylate C15H19NO3 详情 详情
(VI) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(VII) 43668 4-ethyl 1-methyl 5-hydroxy-3,6-dihydro-1,4(2H)-pyridinedicarboxylate C10H15NO5 详情 详情
(VIII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IX) 43675 10-ethyl 7-methyl 1,4-dioxa-7-azaspiro[4.5]decane-7,10-dicarboxylate C12H19NO6 详情 详情
(X) 43676 methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate C10H16N2O6 详情 详情
(XI) 43677 methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate C8H10N2O4 详情 详情

合成路线43

该中间体在本合成路线中的序号：(V)

The deprotection of 1-benzyl-2-oxopiperidine-3-carboxylic acid ethyl ester (I) by hydrogenation with H2 over Pd/C in aq. ethanol gives 2-oxopiperidine-3-carboxylic acid ethyl ester (II), which is condensed with methyl chloroformate (III) and K2CO3 in water to yield 1-(methoxycarbonyl)-2-oxopiperidine-3-carboxylic acid ethyl ester (IV). The reaction of (IV) with ethyleneglycol (V) and Ts-OH in refluxing benzene affords the ethylene ketal (VI), which is treated with hydroxylamine and KOH in methanol to provide the carbohydroxamic acid (VII). The cyclization of (VII) by means of hot conc. HCl or HClO4 gives 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylic acid methyl ester (VIII), which is finally treated with HBr in refluxing acetic acid and neutralized with TEA to yield the target isoxazolo-pyridine derivative.

参考文献 中间体
合成目标
【1】 Krogsgaard-Larsen, P. (H. Lundbeck A/S); Heterocyclic cpds.. EP 0000167; EP 0000338; EP 0027279; EP 0028017; US 4278676; US 4301287 .
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) 57371 ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate C15H19NO3 详情 详情
(II) 57372 ethyl 3-oxo-4-piperidinecarboxylate C8H13NO3 详情 详情
(III) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(IV) 57373 4-ethyl 1-methyl 3-oxo-1,4-piperidinedicarboxylate C10H15NO5 详情 详情
(V) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(VI) 43675 10-ethyl 7-methyl 1,4-dioxa-7-azaspiro[4.5]decane-7,10-dicarboxylate C12H19NO6 详情 详情
(VII) 43676 methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate C10H16N2O6 详情 详情
(VIII) 43677 methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate C8H10N2O4 详情 详情

合成路线44

该中间体在本合成路线中的序号：

Protection of cyanohydrin ketal (I) with bromomethyldimethylsilyl chloride (A) in presence of DMAP and Et3N affords derivative (II), which is converted into (III) by means of LDA in cyclohexane and aqueous HBr. Treatment of (III) with KOAc in acetone yields acetoxy derivative (IV), which is then hydrolyzed to provide (V) by means of KHCO3 in refluxing MeOH. Protection of (V) as its acetal form by treatment with ethylene glycol in p-TsOH affords (VI), which is converted into methyl ether (VII) by treatment with Me3O+BF4- in presence of 1,8-bis(dimethylamino)-naphthalene. Oxidation of (VII) by means of H2O2, Na2HPO4 and (CF3)2CO in CH2Cl2 yields epoxide (VIII), which is converted into (X) by a Grignard reaction with (IX) in THF followed by treatment with CuCl. Diketal (X) is then deprotected by means of TFA in THF to provide derivative (XI), which is finally acetylated with (CF3CO)2O in a mixture of HOAc, p-TsOH and CH2Cl2.

参考文献 中间体
合成目标
【1】 Kim, H.K.; Blye, R.P.; Rao, P.N.; Cessac, J.W.; Acosta, C.K. (US Department of Health & Human Services); 21-Substd. progesterone derivs. as new antiprogestational agents. JP 2000509396; WO 9741145 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(A) 41668 (bromomethyl)(chloro)dimethylsilane 16532-02-8 C3H8BrClSi 详情 详情
(I) 40864 　 C21H27NO3 详情 详情
(II) 41669 　 C24H34BrNO3Si 详情 详情
(III) 41670 (13S,17R)-17-(2-bromoacetyl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one C20H25BrO3 详情 详情
(IV) 41671 2-[(13S,17R)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate C22H28O5 详情 详情
(V) 41672 (13S,17R)-17-glycoloyl-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one C20H26O4 详情 详情
(VI) 41673 　 C24H34O6 详情 详情
(VII) 41674 　 C25H36O6 详情 详情
(VIII) 41675 　 C25H36O7 详情 详情
(IX) 10863 Bromo[4-(dimethylamino)phenyl]magnesium 7353-91-5 C8H10BrMgN 详情 详情
(X) 41676 　 C33H47NO7 详情 详情
(XI) 41677 (11R,13S,17R)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(2-methoxyacetyl)-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one C29H37NO4 详情 详情

合成路线45

该中间体在本合成路线中的序号：(X)

N-protection of the NH group of (I) with Boc2O and NaOH in Et2O yields derivative (II), which is then condensed with compound (III) by means of NaH in DMF to provide (IV). N-deprotection of (IV) by treatment with TFA in CH2Cl2 followed by reductocondensation with N-Boc-4-piperidone (V) in CH2Cl2 in the presence of Na(OAc)3BH affords compound (VI), which is oxidized with NaBO3.4H2O to provide (VII). Boc removal of (VII) by treatment with TFA in CH2Cl2, followed by reaction of the resulting secondary amine with sulfonyl chloride (VIII) in CH2Cl2 in the presence of Et3N, affords propylsulfonamide derivative (IX). Finally, treatment of (IX) with ethyleneglycol (X) in toluene in the presence of HC(OEt)3 and p-TsOH furnishes the target compound.

参考文献 中间体
合成目标
【1】 Boyle, C.D.; Chackalamannil, S.; Chen, L.-Y.; et al.; Benzylidine ketal derivatives as M2 muscarinic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 24, 2727.
【2】 Chackalamannil, S.; Chen, L.-Y.; Boyle, C.D.; et al.; Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 114.
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) 21497 (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine 56346-57-7 C12H14FNO 详情 详情
(II) 45867 tert-butyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate C17H22FNO3 详情 详情
(III) 28620 1,3-benzodioxole-5-thiol C7H6O2S 详情 详情
(IV) 45868 tert-butyl 4-[4-(1,3-benzodioxol-5-ylsulfanyl)benzoyl]-1-piperidinecarboxylate C24H27NO5S 详情 详情
(V) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VI) 45869 　 C29H36N2O5S 详情 详情
(VII) 45870 　 C29H36N2O7S 详情 详情
(VIII) 45871 1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride; 10147-36-1 C3H7ClO2S 详情 详情
(IX) 45872 　 C27H34N2O7S2 详情 详情
(X) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情

合成路线46

该中间体在本合成路线中的序号：(VIII)

Treatment of naltrexone hydrochloride (I) with 2-nitrophenylhydrazine (II) under Fischer conditions in HCl:HOAc provides nitroindole derivative (III), which is reduced by means of hydrazine and Ni Raney in EtOH to afford amine (IV). Separately, 3,4-dimethylbenzoic acid (V) is brominated with NBS and benzoyl peroxide in refluxing CCl4 to furnish tetrabromo derivative (VI), which is then hydrolyzed with Na2CO3 in H2O to yield 3,4-diformylbenzoic acid (VII). Bis acetalization of (VII) with ethylene glycol (VIII) in benzene in the presence of p-TsOH affords carboxylic acid (IX), which is then coupled with intermediate (IV) by means of DCC and HOBt in DMF to give the corresponding amido ester derivative (X). Selective saponification of (X) with K2CO3 in MeOH affords amide (XI), which is finally converted into the target compound by hydrolysis with HCl in acetone.

参考文献 中间体
合成目标
【1】 Portoghese, P.S.; et al.; delta Opioid antagonist activity and binding studies of regioisomeric isothiocyanate derivatives of naltrindole: Evidence for delta receptor subtypes. J Med Chem 1992, 35, 22, 4086.
【3】 Le Bourdonnec, B.; et al.; Reporter affinity labels: An o-phthalaldehyde derivative of beta-naltrexamide as a fluorogenic ligand for opioid receptors. J Med Chem 2000, 43, 13, 2489.
【2】 Poda, G.; Loh, H.H.; Le Bourdonnec, B.; Law, P.Y.; WEl Kouhen, R.; Portoghese, P.S.; Ferguson, D.M.; Covalently induced activation of the delta opioid receptor by a fluorogenic affinity label, 7'-(phthalaldehyde-carboxamido)naltrindole (PNTI). J Med Chem 2001, 44, 7, 1017.
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) 37822 (1S,5R,13R,17R)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one C20H23NO4 详情 详情
(II) 50196 1-(2-nitrophenyl)hydrazine C6H7N3O2 详情 详情
(III) 50197 (1S,2R,13R,21R)-22-(cyclopropylmethyl)-9-nitro-14-oxa-11,22-diazaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaene-2,16-diol C26H25N3O5 详情 详情
(IV) 50198 (1S,2R,13R,21R)-9-amino-22-(cyclopropylmethyl)-14-oxa-11,22-diazaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaene-2,16-diol C26H27N3O3 详情 详情
(V) 50199 3,4-Dimethylbenzoic acid; o-Xylene-4-carboxylic acid 619-04-5 C9H10O2 详情 详情
(VI) 50200 3,4-bis(dibromomethyl)benzoic acid C9H6Br4O2 详情 详情
(VII) 50201 3,4-bis(2-oxoethyl)benzoic acid C11H10O4 详情 详情
(VIII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IX) 50202 3,4-di(1,3-dioxolan-2-yl)benzoic acid C13H14O6 详情 详情
(X) 50203 (1S,2R,13R,21R)-22-(cyclopropylmethyl)-9-[[3,4-di(1,3-dioxolan-2-yl)benzoyl]amino]-2-hydroxy-14-oxa-11,22-diazaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-16-yl 3,4-di(1,3-dioxolan-2-yl)benzoate C52H51N3O13 详情 详情
(XI) 50204 N-[(1S,2R,13R,21R)-22-(cyclopropylmethyl)-2,16-dihydroxy-14-oxa-11,22-diazaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-9-yl]-3,4-di(1,3-dioxolan-2-yl)benzamide C39H39N3O8 详情 详情

合成路线47

该中间体在本合成路线中的序号：(II)

Formation of ketal (III) is achieved by treatment of 5-hydroxy-8-methoxy-1-tetralone (I) with ethylene glycol (II) and pyridinium p-toluenesulfonate (PPTS) in benzene. Coupling of hydroxy derivative (III) with 8-iodo-1-methoxynaphthalene (IV) by means of Cu2O and K2CO3 in refluxing pyridine provides naphthyl ether (V), which is then hydrolyzed to ketone (VI) by means of TsOH in acetone/H2O. Demethylation of derivative (VI) is then performed by treatment with BBr3 in dichloromethane to yield hydroxy derivative (VII), which is reduced by means of LiAlH4 in Et2O to give triol (VIII). Oxidative cyclization of (VIII) using PhI(OAc)2 in trifluoroethanol affords naphthalene spiroketal (IX), which is converted into palmarumycin CP1 (X) by a two-step protocol consisting in a first oxidation with Dess-Martin periodane (and subsequent purification) followed by aromatization with MnO2 in dichloromethane. Finally, the target product is obtained by a Mitsunobu reaction of derivative (X) with alcohol (XI) using polystyrene-bound triphenylphosphine and DEAD in dichloromethane.

参考文献 中间体
合成目标
【1】 Wipf, P.; et al.; Synthesis and biological evaluation of deoxypreussomerin A and palmarumycin CP1 and related naphthoquinone spiroketals. Tetrahedron 2001, 57, 2, 283.
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) 46802 5-hydroxy-8-methoxy-3,4-dihydro-1(2H)-naphthalenone C11H12O3 详情 详情
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(III) 46803 　 C13H16O4 详情 详情
(IV) 41878 8-iodo-1-naphthyl methyl ether; 1-iodo-8-methoxynaphthalene C11H9IO 详情 详情
(V) 46804 　 C24H24O5 详情 详情
(VI) 46805 8-methoxy-5-[(8-methoxy-1-naphthyl)oxy]-3,4-dihydro-1(2H)-naphthalenone C22H20O4 详情 详情
(VII) 46806 8-hydroxy-5-[(8-hydroxy-1-naphthyl)oxy]-3,4-dihydro-1(2H)-naphthalenone C20H16O4 详情 详情
(VIII) 46807 5-[(8-hydroxy-1-naphthyl)oxy]-1,2,3,4-tetrahydro-1,8-naphthalenediol C20H18O4 详情 详情
(IX) 46808 　 C20H16O4 详情 详情
(X) 46809 　 C20H12O4 详情 详情
(XI) 13848 2-Furylmethanol; Furfuryl Alcohol 98-00-0 C5H6O2 详情 详情

合成路线48

该中间体在本合成路线中的序号：(I)

The condensation of ArgoGel-OH resin (I) with N-(Fmoc)-glycine (II) by means of DIC and DMAP gives the resin-bound Fmoc-glycine (III), which is deprotected with piperidine to yield the resin-bound glycine (IV). The reaction of (IV) with 2-nitrophenylsulfonyl chloride (V) affords the sulfonamide (VI), which is alkylated with 2-cyclopentylethanol (VII) by means of DIAD and PPh3 to provide the N-alkylated sulfonamide (VIII). The reaction of (VIII) with Ph-SH, DBU and pyridine gives the N-alkylated resin-bound glycine (IX), which is condensed with 1-(chlorocarbonyl)-L-proline tert-butyl ester (X) to yield the resin-bound dipeptide tert-butyl ester (XI). Hydrolysis of the ester group of (XI) with TFA affords the free resin-bound dipeptide (XII), which is condensed with 4,5-dimethylthiazole-2-amine (XIII) by means of PyBOP and DMAP to provide the corresponding prolinamide (XIV). Finally, this compound is treated with hydroxylamine in order to cleave the title compound from the resin by formation of the desired hydroxamic acid.

参考文献 中间体
合成目标
【1】 Lewis, J.G.; Wu, C.; Jacobs, J.; et al.; Iterative parallel synthesis-derived N-alkyl urea hydroxamic acids: A new class of peptide deformylase inhibitors. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-358.
【2】 Patel, D.V.; Jacobs, J.W.; Lewis, J.; Ni, Z.-J. (Versicor, Inc.); Novel urea cpds., compsns. and methods of use and preparation. WO 0144178 .
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(II) 42131 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid 29022-11-5 C17H15NO4 详情 详情
(III) 54030 2-hydroxyethyl 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetate C19H19NO5 详情 详情
(IV) 54031 2-hydroxyethyl 2-aminoacetate C4H9NO3 详情 详情
(V) 32624 2-Nitrobenzenesulfonyl chloride 1694-92-4 C6H4ClNO4S 详情 详情
(VI) 54032 2-hydroxyethyl 2-{[(2-nitrophenyl)sulfonyl]amino}acetate C10H12N2O7S 详情 详情
(VII) 54033 2-Cyclopentylethanol; 2-Hydroxyethylcyclopentane; alpha-Methylcyclopentanemethanol; Cyclopentylmethylcarbinol 766-00-7 C7H14O 详情 详情
(VIII) 54034 2-hydroxyethyl 2-{(2-cyclopentylethyl)[(2-nitrophenyl)sulfonyl]amino}acetate C17H24N2O7S 详情 详情
(IX) 54035 2-hydroxyethyl 2-[(2-cyclopentylethyl)amino]acetate C11H21NO3 详情 详情
(X) 54036 tert-butyl (2S)-1-(chlorocarbonyl)-2-pyrrolidinecarboxylate C10H16ClNO3 详情 详情
(XI) 54037 tert-butyl (2S)-1-({(2-cyclopentylethyl)[2-(2-hydroxyethoxy)-2-oxoethyl]amino}carbonyl)-2-pyrrolidinecarboxylate C21H36N2O6 详情 详情
(XII) 54038 (2S)-1-({(2-cyclopentylethyl)[2-(2-hydroxyethoxy)-2-oxoethyl]amino}carbonyl)-2-pyrrolidinecarboxylic acid C17H28N2O6 详情 详情
(XIII) 54039 4,5-dimethyl-1,3-thiazol-2-ylamine; 4,5-dimethyl-1,3-thiazol-2-amine C5H8N2S 详情 详情
(XIV) 54040 2-hydroxyethyl 2-{(2-cyclopentylethyl)[((2S)-2-{[(4,5-dimethyl-1,3-thiazol-2-yl)amino]carbonyl}pyrrolidinyl)carbonyl]amino}acetate C22H34N4O5S 详情 详情

合成路线49

该中间体在本合成路线中的序号：(IV)

Treatment of bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (I) with acetic anhydride in hot pyridine produced the cyclic anhydride (II). Ethyleneglycol mono-ether (V) was prepared by Williamson's synthesis from the sodium alkoxide of ethylene glycol (IV) and octadecyl bromide (III). Then, heating the bis-anhydride (II) with ethyleneglycol monoether (V) produced the title diester

参考文献 中间体
合成目标
【1】 Kozak, A.; Shapiro, I. (D-Pharm Ltd.); Lipophilic diesters of chelating agents. JP 2001518458; WO 9916741 .
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) 52462 　 C22H24N2O10 详情 详情
(II) 52463 4-{2-[(2-{[2-(2,6-dioxo-4-morpholinyl)phenyl]oxy}ethyl)oxy]phenyl}-2,6-morpholinedione C22H20N2O8 详情 详情
(III) 28797 1-bromooctadecane 112-89-0 C18H37Br 详情 详情
(IV) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(V) 53031 2-(octadecyloxy)-1-ethanol n/a C20H42O2 详情 详情

合成路线50

该中间体在本合成路线中的序号： (XXII)

Aldol condensation of 6-chloro-5-fluoroisatin (XIX) with acetone (XX) by means of Et2NH and K2CO3 gives the hydroxyl-ketone (XXI),which is protected with ethylene glycol (XXII) in the presence of HC(OEt)3 and p-TsOH in CH2Cl2 to yield the corresponding ketal (XXIII). Reduction of compound (XXIII) with Red-Al in THF, followed by treatment with aqueous HCl leads to 1-(6-chloro-5-fluoroindol-3-yl)acetone (XXIV). Alternatively, reduction of nitropropenyl intermediate (XVI) with H2 over Raney-Ni in MeOH/H2O or sequential reduction to oxime with H2 over Pt/C in EtOAc and then hydrolysis using NaHSO3 in EtOH furnishes ketone (XXIV). Enzymatic transamination of intermediate (XXIV) with isopropylamine hydrochloride (XXV) in the presence of transaminase SEQ ID 134 and pyridoxal-5’-phosphate (PLP) in H2O/PEG200 produces the corresponding (S)-amine, which is isolated as the camphorsulfonate salt (XXVI) by treatment with CSA in i-PrOAc. Condensation of tryptamine derivative (XXVI) with 5-chloroisatin (XII) in the presence of Et3N in refluxing i-PrOH and subsequent Pictet-Spengler cyclization in the presence of CSA provides cipargamin camphorsulfonate (XXVII), which is finally treated with Na2CO3 in EtOH/H2O .

参考文献 中间体
合成目标
【1】 Crowe, M., Foulkes, M., Francese, G., et al. (Novartis AG). Chemical process for preparing spiroindolones and intermediates thereof. KR 2014137374; CN 104185634; US 2015045562; EP 2828256; WO 2013139987.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XII) 14099 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin 17630-76-1 C8H4ClNO2 详情 详情
(XVI) 67562 (Z)-6-chloro-5-fluoro-3-(2-nitroprop-1-en-1-yl)-1H-indole 　 C11H8ClFN2O2 详情 详情
(XIX) 67565 6-chloro-5-fluoroisatin;6-Chloro-5-fluoro-1H-indole-2,3-dione;1H-Indole-2,3-dione,6-chloro-5-fluoro- 96202-57-2 C8H3ClFNO2 详情 详情
(XX) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(XXI) 67566 1-(6-chloro-5-fluoro-3-hydroxyindolin-3-yl)propan-2-one 　 C11H11ClFNO2 详情 详情
(XXIII) 67567 6-chloro-5-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)indolin-3-ol 　 C13H15ClFNO3 详情 详情
(XXIV) 67568 1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-one 　 C11H9ClFNO 详情 详情
(XXV) 67569 propan-2-amine hydrochloride 　 C3H9N.HCl 详情 详情
(XXVI) 67570 (R)-1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate 　 C11H12ClFN2.C10H16O4S 详情 详情
(XXVII) 67571 (1'S,3'R)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate 　 C19H14Cl2FN3O.C10H16O4S 详情 详情

合成路线51

该中间体在本合成路线中的序号：(II)

Protection of prasterone (I) with ethylene glycol (II) in the presence of p-TsOH in refluxing benzene gives the corresponding ketal (III), which is further protected as the 3-O-silyl ether (IV) by treatment with TBDMSCl and imidazole in DMF. Allylic oxidation of compound (IV) by means of CrO3 and 3,5-dimethylpyrazole in CH2Cl2 or using RuCl3 and t-BuOOH in cyclohexane/water affords enone (V), which by chemoselective 1,2-reduction with NaBH4 and CeCl3 in THF/MeOH provides (R)-alcohol (VI). Subsequent esterification of alcohol (VI) with Ac2O and DMAP in pyridine produces acetate (VII), which is subjected to double bond hydroboration with BH3·THF in THF and oxidative hydrolysis using H2O2 and NaOH to yield diol (VIII). Protection of diol (VIII) with Ac2O and DMAP in pyridine gives diacetate (IX), which is selectively deprotected at C-3 by treatment with TBAF in THF resulting in the 3-hydroxysteroid (X). Hydrolysis of diacetate (X) using NaOMe in MeOH affords compound (XI), which by deketalization by means of AcOH provides ketone (XII). Protection of the 6,7-diol (XII) with 2,2-dimethoxypropane (XIII) in the presence of CSA then gives acetonide (XIV), which is submitted to a Wittig reaction with CH3PPh3Br in the presence of t-BuOK in refluxing THF to give alkene (XV) .

参考文献 中间体
合成目标
【1】 Burgoyne, D.L., Shen, Y., Langlands, J.M., Rogers, C., Chau, J.H.-L., Piers, E., Salari, H. (Biolipox AB). 6,7-Oxygenated steroids and uses related thereto. EP 1304333; US 6046185; WO 1998002450; JP 2001503732.
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) 67588 (3R,6S,7S,8S,9R,10S,13R,14R)-3-hydroxy-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane]-6,7-diyl diacetate 　 C25H38O7 详情 详情
(I) 11713 Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one 53-43-0 C19H28O2 详情 详情
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(III) 67581 (3R,8S,9R,10S,13R,14R)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-3-ol 　 C21H32O3 详情 详情
(IV) 67582 tert-butyl(((3R,8S,9R,10S,13R,14R)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-3-yl)oxy)dimethylsilane 　 C27H46O3Si 详情 详情
(V) 67583 (3R,8S,9R,10S,13R,14R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyl-1,3,4,8,9,10,11,12,13,14,15,16-dodecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-7(2H)-one 　 C27H44O4Si 详情 详情
(VI) 67584 　 　 C27H46O4Si 详情 详情
(VII) 67585 (3R,7S,8S,9R,10S,13R,14R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-7-yl acetate 　 C29H48O5Si 详情 详情
(VIII) 67586 (3R,6S,7S,8S,9R,10S,13R,14R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane]-6,7-diol 　 C27H48O5Si 详情 详情
(IX) 67587 (3R,6S,7S,8S,9R,10S,13R,14R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane]-6,7-diyl diacetate 　 C31H52O7Si 详情 详情
(XI) 67589 (3R,6S,7S,8S,9R,10S,13R,14R)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane]-3,6,7-triol 　 C21H34O5 详情 详情
(XII) 67590 (3R,6S,7S,8S,9R,10S,13R,14R)-3,6,7-trihydroxy-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-17(2H)-one 　 C19H30O4 详情 详情
(XIII) 67580 2,2-dimethoxypropane 　 C4H12O2 详情 详情
(XIV) 67591 (2R,4aS,4bR,6aR,9aR,9bS,9cS,12aS)-2-hydroxy-4a,6a,11,11-tetramethyltetradecahydro-1H-cyclopenta[1,2]phenanthro[9,10-d][1,3]dioxol-7(8H)-one 　 C22H34O4 详情 详情

合成路线52

该中间体在本合成路线中的序号：(II)

Protection of 2-bromo-5-hydroxybenzaldehyde (I) as the corresponding ethylene ketal (III) by means of ethylene glycol (II) and p-TsOH in refluxing toluene, followed by coupling with 4-fluorobenzonitrile (IV) in the presence of K2CO3 in DMF and subsequent acetal hydrolysis with HCl in refluxing H2O/THF provides 4-(4-bromo-3-formylphenoxy) benzonitrile (V). Reduction of aldehyde (V) with NaBH4 in MeOH affords the benzylic alcohol (VI), which is then protected with DHP in the presence of CSA in CH2Cl2 to give the tetrahydropyranyl ether (VII). Finally, aryl bromide (VII) is submitted to halogen-metal exchange by treatment with BuLi, followed by borylation with (i-PrO)3B in THF and then treatment with HCl in refluxing H2O/THF .

参考文献 中间体
合成目标
【1】 Akama, T., Baker, S.J., Zhang, Y.K. et al. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 2009, 19(8): 2129-32.
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) 67826 2-bromo-5-hydroxybenzaldehyde 　 C7H5BrO2 详情 详情
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(III) 67827 4-bromo-3-(1,3-dioxolan-2-yl)phenol 　 C9H9BrO3 详情 详情
(IV) 14144 4-Fluorobenzonitrile 1194-02-1 C7H4FN 详情 详情
(V) 67828 4-(4-bromo-3-formylphenoxy)benzonitrile 　 C14H8BrNO2 详情 详情
(VI) 67829 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile 　 C14H10BrNO2 详情 详情
(VII) 67830 4-(4-bromo-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenoxy)benzonitrile 　 C19H18BrNO3 详情 详情

合成路线53

该中间体在本合成路线中的序号：(I)

　

参考文献 中间体
合成目标
【1】 Artus Surroca JJ,Janet Bonet M,Rafecas Jane L.Intermediate compounds for obtaining main active anti-hypertensive agents together with corresponding procedures:ES,Patent 2,211,317,2004.
【2】 Yiu SH,Knaus EE.Synthesis,calcium channel antagonist activity,and anticonvulsant activity of 3-ehtyl 5-methyl 1,4-dihydro-2-[(2-hydroxyethoxy)methyl]-6-methyl-4-(2,3-dichloro-phenyl)-3,5-pyridinedicarboxylate coupled to a 1-methyl-1,4-dihydropyridyl-3-carbonyl chemical delivery system. Arch Pharma,1999,332:363.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(II) 13684 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran 110-87-2 C5H8O 详情 详情
(III) 69576 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol C7H14O3 详情 详情
(IV) 23541 ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate 638-07-3 C6H9ClO3 详情 详情
(V) 69577 ethyl 3-oxo-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)butanoate C13H22O6 详情 详情
(VI) 69578 ethyl 4-(2-hydroxyethoxy)-3-oxobutanoate C8H14O5 详情 详情
(VII) 44034 methyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate C12H11ClO3 详情 详情
(VIII) 69579 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-hydroxyethoxy)methyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate C20H24ClNO6 详情 详情
(IX) 69580 3-ethyl 5-methyl 4-(2-chlorophenyl)-6-methyl-2-((2-((methylsulfonyl)oxy)ethoxy)methyl)-1,4-dihydropyridine-3,5-dicarboxylate C21H26ClNO8S 详情 详情
(X) 69570 Benzenesulfonic acid;Phenylsulfonic acid;Benzenemonosulfonic acid;Benzensulfonic acid;Benzenesulphonic acid; 98-11-3 C6H6O3S 详情 详情
Extended Information