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【结 构 式】

【分子编号】23897

【品名】ethynyl(trimethyl)silane；trimethylsilyl acetylene

【CA登记号】1066-54-2

【 分 子 式 】C5H10Si

【 分 子 量 】98.2199

【元素组成】C 61.14% H 10.26% Si 28.59%
与该中间体有关的原料药合成路线共 26 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26

合成路线1

该中间体在本合成路线中的序号：(IV)

1) The reaction of benzhydryl 2alpha-methyl-2beta-(chloromethyl)penam-3alpha-carboxylate (I) with sodium azide in DMF gives the corresponding azidomethyl derivative (II), which is oxidized with KMnO4 in aqueous acetic acid to the dioxide (III). The cyclization of (III) with trimethylsilylacetylene (IV) at 95 C yields benzhydryl 2a-methyl-2B-(4 trimethylsilyl-1,2,3-triazol-1 ylmethyl)penam 3a-carboxylate-1,1-dioxide (V), which is desilylated with KF and 18-crown-6 in hot DMF affording the benzhydryl ester of YTR-830 (VI). Then this compound is submitted to hydrogenolysis with H2 over Pd/C in ethyl / acetate / water.

参考文献 中间体
合成目标
【1】 Micetich, R.G.; et al. (Taiho Pharmaceutical Co., Ltd.); Penicillin derivatives and process for preparation of the same. EP 0097446; ES 523701; ES 538020 .
【2】 Cai, S.X.; Drewe, J.A. (Cytovia, Inc.); Substd. nicotinamides and analogs as activators of caspases and inducers of apoptosis and the use thereof. WO 0155115 .
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) 24533 benzhydryl (2S,3R)-3-(chloromethyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C21H20ClNO3S 详情 详情
(II) 24534 benzhydryl (2S,3S)-3-(azidomethyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C21H20N4O3S 详情 详情
(III) 24535 benzhydryl (2S,3S)-3-(azidomethyl)-3-methyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C21H20N4O5S 详情 详情
(IV) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(V) 24538 benzhydryl (2S,3S)-3-methyl-4,4,7-trioxo-3-[[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]methyl]-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C26H30N4O5SSi 详情 详情
(VI) 24539 benzhydryl (2S,3S)-3-methyl-4,4,7-trioxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C23H22N4O5S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

This compound has been obtained by two similar ways: 1. The reaction of 5-iodouracil (I) with trimethylsilylacetylene (II) by means of PdCl2(PPh3)2 and CuI2 in TEA/DMF gives 5-(trimethylsilylethynyl)uracil (III), which is then desilylated with sodium methoxide or NaOH in methanol. 2. The reaction of 5-iodouracil (I) with POCl3 at 120 C catalyzed by N,N-diethylaniline gives 2,4-dichloro-5-iodopyrimidine (IV), which by reaction with NaOMe in methanol is converted into 2,4-dimethoxy-5-iodopyrimidine (V). The condensation of (V) with trimethylsilylacetylene by means of PdCl2(PPh3)2 and CuI2 in TEA/DMF yields 2,4-dimethoxy-5-(trimethylsilylethynyl)pyrimidine (VI), which is treated with NaI and Tms-Cl in refluxing acetonitrile to afford 5-(trimethylsilylethynyl)uracil (III).

参考文献 中间体
合成目标
【1】 Cooke, J.W.B.; et al.; Process research and development of a dihydropyrimidine dehydrogenase inactivator: Large-scale preparation of eniluracil using a Sonogashira coupling. Org Process Res Dev 2001, 5, 4, 383.
【2】 Spector, T.; Porter, D.J.T.; Rahim, S.G. (Glaxo Wellcome plc); Uracil reductase inactivators. EP 0550580; JP 1994504263; JP 1998045623; WO 9204901 .
【3】 Spector, T.; Porter, D.J.T.; Rahim, S.G. (Glaxo Wellcome plc); Enzyme inactivators. EP 0539442; EP 0711555; JP 1994502619; JP 2000297076; WO 9201452 .
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) 11867 5-Iodo-2,4(1H,3H)-pyrimidinedione 696-07-1 C4H3IN2O2 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 47911 5-[2-(trimethylsilyl)ethynyl]-2,4(1H,3H)-pyrimidinedione C9H12N2O2Si 详情 详情
(IV) 11868 2,4-Dichloro-5-iodopyrimidine C4HCl2IN2 详情 详情
(V) 11869 5-Iodo-2-methoxy-4-pyrimidinyl methyl ether; 5-Iodo-2,4-dimethoxypyrimidine 52522-99-3 C6H7IN2O2 详情 详情
(VI) 47912 2,4-dimethoxy-5-[2-(trimethylsilyl)ethynyl]pyrimidine; 2-methoxy-5-[2-(trimethylsilyl)ethynyl]-4-pyrimidinyl methyl ether C11H16N2O2Si 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The condensation of the 2-chloroquinoline-3-methanol (I) with trimethylsilyl acetylene (II) by means of PdCl2(PPh3)2 and CuI in DMF gives 2-(trimethylsilylethynyl)quinoline-3-methanol (III), which is treated with PPh3, CBr4 and sodium azide to yield the azidomethyl derivative (IV). The reduction of (IV) with PPh3 in THF/water affords the aminomethyl compound (V), which is condensed with fumaric acid monoethyl ester (VI) by means of BOP in acetonitrile to provide the amide (VII). The cyclization of (VII) by means of Tms-Cl, DIEA and ZnCl2 in toluene at 180 C in a sealed tube gives the tetracyclic ester (VIII), which is treated with HBr in ethyl acetate to yield the intermediate ethyl ester (IX). The transesterification of (IX) catalyzed by H2SO4 in refluxing methanol affords the methyl ester (X), which is methylated with diazomethane to provide 2-methyl-1-oxo-1,11-dihydroindolizino[1,2-b]quinoline-3-carboxylic acid methyl ester (XI). The reduction of (XI) with LiBH4 in hot bis(2-methoxyethyl)ether gives the tetracyclic carbinol (XII), which is oxidized with DMSO in hot Ac2O to yield the carbaldehyde (XIII). Finally, this compound is treated with diazoethane in ethyl ether to afford the target propionyl derivative.

参考文献 中间体
合成目标
【1】 Kametani, T.; et al.; Studies on the syntheses of heterocyclic compounds. Part DCXXII. Total synthesis of (±)-mappicine [7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one]. J Chem Soc - Perkins Trans I 1975, 1825.
【2】 Toyota, M.; et al.; A concise formal total synthesis of mappicine and nothapodytine B via and intramolecular hetero Diels-Alder reaction. J Org Chem 2000, 65, 21, 7110.
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) 49526 (2-chloro-3-quinolinyl)methanol C10H8ClNO 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 49527 [2-[2-(trimethylsilyl)ethynyl]-3-quinolinyl]methanol C15H17NOSi 详情 详情
(IV) 49528 3-(azidomethyl)-2-[2-(trimethylsilyl)ethynyl]quinoline; [2-[2-(trimethylsilyl)ethynyl]-3-quinolinyl]methyl azide C15H16N4Si 详情 详情
(V) 49529 [2-[2-(trimethylsilyl)ethynyl]-3-quinolinyl]methylamine; [2-[2-(trimethylsilyl)ethynyl]-3-quinolinyl]methanamine C15H18N2Si 详情 详情
(VI) 49530 Fumaric acid monoethyl ester; Ethyl hydrogen fumarate; Ethyl Fumarate Monoester; Monoethyl fumarate 2459-05-4 C6H8O4 详情 详情
(VII) 49531 ethyl (E)-4-oxo-4-[([2-[2-(trimethylsilyl)ethynyl]-3-quinolinyl]methyl)amino]-2-butenoate C21H24N2O3Si 详情 详情
(VIII) 49532 ethyl 9-oxo-6-(trimethylsilyl)-7,8,9,11-tetrahydroindolizino[1,2-b]quinoline-7-carboxylate C21H24N2O3Si 详情 详情
(IX) 49533 ethyl 9-oxo-9,11-dihydroindolizino[1,2-b]quinoline-7-carboxylate C18H14N2O3 详情 详情
(X) 49534 methyl 9-oxo-9,11-dihydroindolizino[1,2-b]quinoline-7-carboxylate C17H12N2O3 详情 详情
(XII) 49535 methyl 8-methyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinoline-7-carboxylate C18H14N2O3 详情 详情
(XIII) 49536 7-(hydroxymethyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one C17H14N2O2 详情 详情
(XIV) 49537 8-methyl-9-oxo-9,11-dihydroindolizino[1,2-b]quinoline-7-carbaldehyde C17H12N2O2 详情 详情
(XV) 49538 　 C2H4N2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XXXIV)

4) Lactone form: The condensation of 2(S)-(chloromethyl)oxirane (XXXIII) with trimethylsilylacetylene (XXXIV) by means of butyllithium and BF3 ethearate in THF gives 5-chloro-4(S)-hydroxy-1-(trimethylsilyl)-1-pentyne (XXXV), which is cyclized with KOH in THF to the chiral epoxide (XXXVI). The condensation of (XXXVI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII, see Scheme 5) by means of butyllithium in THF affords the silylated heptynol (XXXVIII), which is desilylated with K2CO3 in methanol to the terminal acetylene (XXXIX). The carboxylation of (XXXIX) with CO by means of PdCl2/CuCl2 in methanol yields the heptynoic acid ester (XL), which is selectively reduced with H2 over the Lindlar catalyst in methanol to the cis-heptenoic ester (XLI). The cyclization of (XLI) with PPTS in refluxing toluene affords the (S)-unsaturated lactone (XLII), which is oxidized with m-chloroperbenzoic acid to the corresponding sulfinyl derivative (XLIII).

参考文献 中间体
合成目标
【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859.
【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IL) 17460 1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-[(2R)oxiranyl]ethyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[2-[(2R)oxiranyl]-1-(phenylsulfanyl)ethyl]quinoline C28H24FNOS 详情 详情
(XXXIII) 13917 (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin 67843-74-7 C3H5ClO 详情 详情
(XXXIV) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XXXV) 17449 (2S)-1-chloro-5-(trimethylsilyl)-4-pentyn-2-ol C8H15ClOSi 详情 详情
(XXXVI) 17450 trimethyl[3-[(2S)oxiranyl]-1-propynyl]silane C8H14OSi 详情 详情
(XXXVII) 17451 [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline C25H20FNS 详情 详情
(XXXVIII) 17452 (3S)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-1-(phenylsulfanyl)-6-(trimethylsilyl)-5-hexyn-3-ol C33H34FNOSSi 详情 详情
(XXXIX) 17453 (3S)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-1-(phenylsulfanyl)-5-hexyn-3-ol C30H26FNOS 详情 详情
(XL) 17454 methyl (5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-7-(phenylsulfanyl)-2-heptynoate C32H28FNO3S 详情 详情
(XLI) 17455 methyl (Z,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-7-(phenylsulfanyl)-2-heptenoate C32H30FNO3S 详情 详情
(XLII) 17456 (6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfanyl)ethyl]-5,6-dihydro-2H-pyran-2-one C31H26FNO2S 详情 详情
(XLIII) 17457 (6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfinyl)ethyl]-5,6-dihydro-2H-pyran-2-one C31H26FNO3S 详情 详情
(XLVII) 38067 (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin 51594-55-9 C3H5ClO 详情 详情
(XLVIII) 17459 (2R)-1-chloro-4-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-4-(phenylsulfanyl)-2-butanol C28H25ClFNOS 详情 详情
(L) 17461 ethynyllithium C2HLi 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XII)

The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 2) The treatment of (trimethylsilyl)acetylene (XII) with butyllithium and NMM in methyl tert-butyl ether (MTBE), followed by hydrolysis with aqueous HCl, gives 3-(trimethylsilyl)-2-propynal (XIII). Treatment of (XIII) with lithium bis(trimethylsilyl)amide (LiHMDS) and trimethylsilyl chloride at -20 C gives the imine (XIV), which is reacted in situ with lithium tert-butyl acetate followed by hydrolysis with aqueous NH4Cl to afford racemic tert-butyl ester (XV). Treatment of (XV) with refluxing ethanol in the presence of p-toluenesulfonic acid gives the corresponding ethyl ester (VII) (already obtained in the preceding scheme). Desilylation of (VII) with NaOEt/EtOH affords racemic 3-amino-4-pentynoic acid ethyl ester in situ, which is then resolved using R-(-)-mandelic acid in ethyl acetate/MTBE to give mandelic acid salt (XVI). Recrystallization of (XVI) from acetonitrile/MTBE and treatment with gaseous HCl in MTBE affords ethyl ester (III) as the hydrochloride.

参考文献 中间体
合成目标
【1】 Graul, A.; Martel, A.M.; Castaner, J.; Xemilofiban. Drugs Fut 1997, 22, 5, 508.
【2】 Process for the preparation of ethyl 3S-[4[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate. US 5536869 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
33800 4-morpholinecarbaldehyde 4394-85-8 C5H9NO2 详情 详情
(III) 16297 ethyl (3S)-3-amino-4-pentynoate C7H11NO2 详情 详情
(VII) 16301 3-amino-5-(trimethylsilyl)-4-pentynoic acid C8H15NO2Si 详情 详情
(XII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XIII) 20043 3-(trimethylsilyl)-2-propynal C6H10OSi 详情 详情
(XIV) 16307 trimethyl-N-[(E)-3-(trimethylsilyl)-2-propynylidene]silanamine; N-(trimethylsilyl)-N-[(E)-3-(trimethylsilyl)-2-propynylidene]amine C9H19NSi2 详情 详情
(XV) 16308 tert-butyl 3-amino-5-(trimethylsilyl)-4-pentynoate C12H23NO2Si 详情 详情
(XVI) 16309 2(R)-Hydroxy-2-phenylacetic salt with acid 3(S)-amino-4-pentynoic acid ethyl ester C15H19NO5 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

A short and efficient synthesis of xemilofiban has been achieved as follows: The reaction of ethyl chloroformate (I) with trimethylsilylacetylene (II) by means of butyllithium gives ethyl 3-(trimethylsilyl)propyonate (III), which is condensed with the lithium salt of ethyl acetate (IV) yielding ethyl 5-(trimethylsilyl)-3-oxo-4-pentynoate (V). The selective reduction of (V) with lyophilized baker's yeast (Saccharomyces cerevisiae, Sigma type II) affords ethyl 3(R)-hydroxy-5-(trimethylsilyl)-4-pentynoate (VI), which by reaction with ammonia (VII), diethyl azodicarboxylate (VIII) and triphenylphosphine, followed by hydrolysis with water gives 3(S)-amino-5-(trimethylsilyl)-4-pentynoate (IX). Finally, this compound is condensed with N-(4-amidinophenyl)succinamic acid (XI) by means of isobutyl chloroformate and N-methylmorpholine (NMM). The intermediate succinamic acid (XI) has been obtained by condensation of 4-aminobenzamidine (XII) with succinic anhydride (XIII) in DMF.

参考文献 中间体
合成目标
【1】 Cossy, J.; Schmitt, A.; Cinquin, C.; Buisson, D.; Belotti, D.; A very short, efficient and inexpensive synthesis of the prodrug form of SC-54701A a platelet aggregation inhibitor. Bioorg Med Chem Lett 1997, 7, 13, 1699.
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 23898 ethyl 3-(trimethylsilyl)-2-propynoate 29394-58-9 C8H14O2Si 详情 详情
(IV) 23899 lithium 1-ethoxy-1-ethylenolate C4H7LiO2 详情 详情
(V) 23900 ethyl 3-oxo-5-(trimethylsilyl)-4-pentynoate C10H16O3Si 详情 详情
(VI) 23901 ethyl (3R)-3-hydroxy-5-(trimethylsilyl)-4-pentynoate C10H18O3Si 详情 详情
(VIII) 20989 Diethylazadicarboxylate; Diethyl Azodiformate; Azodiformic Acid Diethyl Ester; Diethyl Azodicarboxylate; Azodicarboxylic Acid Diethyl Ester; Diethyl 1,2-diazenedicarboxylate 1972-28-7 C6H10N2O4 详情 详情
(IX) 23904 ethyl (3S)-3-amino-5-(trimethylsilyl)-4-pentynoate C10H19NO2Si 详情 详情
(X) 16297 ethyl (3S)-3-amino-4-pentynoate C7H11NO2 详情 详情
(XI) 16296 4-[4-[amino(imino)methyl]anilino]-4-oxobutyric acid C11H13N3O3 详情 详情
(XII) 16295 4-aminobenzenecarboximidamide hydrochloride; 4-aminobenzamidine 3858-83-1 C7H9N3 详情 详情
(XIII) 11291 Dihydro-2,5-furandione; Succinic anhydride 108-30-5 C4H4O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

Palladium-catalyzed coupling of methyl 5-iodosalycilate (I) with trimethylsilyl acetylene (II) produced the ethynyl salycilate (III). The trimethylsilyl protecting group of (III) was then cleaved by treatment with KF in DMF to give (IV). On the other hand, sulfonamide (VII) was obtained by condensation of 4-iodobenzenesulfonyl chloride (V) with 2-amino-3-methylpyridine (VI). A further Suzuki coupling between acetylene (IV) and iodosulfonamide (VII) furnished diaryl acetylene (VIII). The methyl ester group of (VIII) was finally saponified with NaOH to provide the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Agback, H.; Ahrgren, L.; Berglindh, T.; Haraldsson, M.; Smedegard, G.; Olsson, L.-I. (Pharmacia & Upjohn AB); Substd. salicylic acids. JP 1995501330; US 5403930; WO 9310094 .
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) 37875 methyl 2-hydroxy-5-iodobenzoate C8H7IO3 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 37876 methyl 2-hydroxy-5-[2-(trimethylsilyl)ethynyl]benzoate C13H16O3Si 详情 详情
(IV) 37877 methyl 5-ethynyl-2-hydroxybenzoate C10H8O3 详情 详情
(V) 27811 4-iodobenzenesulfonyl chloride 98-61-3 C6H4ClIO2S 详情 详情
(VI) 13016 3-Methyl-2-pyridinylamine; 3-Methyl-2-pyridinamine; 2-Amino-3-picoline; 2-Amino-3-methylpyridine 1603-40-3 C6H8N2 详情 详情
(VII) 37878 4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide C12H11IN2O2S 详情 详情
(VIII) 37879 methyl 2-hydroxy-5-[2-(4-[[(3-methyl-2-pyridinyl)amino]sulfonyl]phenyl)ethynyl]benzoate C22H18N2O5S 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XVII)

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
【2】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情
(XVI) 19241 (2S)oxiranylmethanol 60456-23-7 C3H6O2 详情 详情
(XVII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XVIII) 40293 tert-butyl(dimethyl)silyl (1R)-1-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-(trimethylsilyl)-3-butynyl ether; (5R)-2,2,3,3,8,8,9,9-octamethyl-5-[3-(trimethylsilyl)-2-propynyl]-4,7-dioxa-3,8-disiladecane C20H44O2Si3 详情 详情
(XIX) 40294 tert-butyl(dimethyl)silyl (2R,4E)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-pentenyl ether; (5R)-5-[(E)-3-iodo-2-propenyl]-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane C17H37IO2Si2 详情 详情
(XX) 40295 (E,7R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-4-octen-3-one C46H78O6Si2 详情 详情
(XXI) 40296 　 C15H23AlCl2O 详情 详情
(XXII) 40297 　 C46H78O6Si2 详情 详情
(XXIII) 40298 　 C34H50O6 详情 详情
(XXIV) 35692 　 C33H46O5 详情 详情
(XXV) 35693 [2-[(E)-3-pentenyl]-1,3-dithian-2-yl]lithium C9H15LiS2 详情 详情
(XXVI) 35694 　 C42H62O5S2 详情 详情
(XXVII) 35695 　 C48H76O5S2Si 详情 详情
(XXVIII) 35696 　 C49H75F3O7S3Si 详情 详情

合成路线9

该中间体在本合成路线中的序号：(IV)

The selective protection of 1,2-O-isopropylidene-D-xylofuranose (I) with Tbdms-Cl and pyridine gives the silyl ether (II), which is oxidized with CrO3, pyridine and Ac2O in dichloromethane to yield the ketone (III). Stereoselective addition of trimethylsilylacetylene (IV) to the ketone (III) by means of BuLi in THF affords the beta-adduct (V), which is desilylated by means of TBAF in THF to provide 3-C-ethynyl-2,3-o-isopropylidene-alpha-D-ribofuranose (VI). The selective monobenzoylation of (VI) with benzoyl chloride and pyridine gives the monobenzoate (VII), which is treated with HCl in methanol to cleave the isopropylidene protecting group and yield (VIII). The exhaustive benzoylation of (VIII) with benzoyl chloride and DMAP in pyridine at 100 C affords the tribenzoate (IX), which is treated with H2SO4 and Ac2O to provide the monoacetate (X). The condensation of (X) with cytosine (XI) by means of SnCl4 in acetonitrile gives the cytidine derivative (XII), which is finally debenzoylated by means of NH3 in methanol to yield the target ethynyl-cytidine derivative.

参考文献 中间体
合成目标
【1】 Nomura, M.; Sato, T.; Masato, W.; Tanaka, M.; Asao, T.; Shuto, S.; Matsuda, A.; Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbruggen glycosylation . Tetrahedron 2002, 58, 7, 1279.
【3】 Hattori, H.; et al.; Nucleosides and nucleotides. 158. 1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil, and their nucleobase analogues as new potential multifunctional antitumor nucleosides with a broad spectrum of activity. J Med Chem 1996, 39, 25, 5005.
【2】 Nozawa, E.; Hattori, H.; Shuto, S.; Tanaka, M.; Sasaki, T.; Matsuda, A.; Synthesis and antitumor activity of 1-(3-C-ethynyl-beta-D-ribo-pentfuranosyl)cytosine, -uracil and their sugar modified derivatives. Nucleic Acids Symp Ser 1996, 35, 31.
【4】 Matsuda, A.; Sasaki, T. (Taiho Pharmaceutical Co., Ltd.); 3'-Substd. nucleoside derivs.. EP 0747389; WO 9618636 .
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) 41907 (3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol 20031-21-4 C8H14O5 详情 详情
(II) 54394 (3aR,5R,6S,6aR)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol C14H28O5Si 详情 详情
(III) 54395 (3aR,5R,6aS)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(5H)-one C14H26O5Si 详情 详情
(IV) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(V) 54396 (3aR,5R,6R,6aR)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]tetrahydrofuro[2,3-d][1,3]dioxol-6-ol C19H36O5Si2 详情 详情
(VI) 54397 (3aR,5R,6R,6aR)-6-ethynyl-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol C10H14O5 详情 详情
(VII) 54398 [(3aR,5R,6R,6aR)-6-ethynyl-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate C17H18O6 详情 详情
(VIII) 54399 [(2R,3S,4R,5S)-3-ethynyl-3,4-dihydroxy-5-methoxytetrahydro-2-furanyl]methyl benzoate C15H16O6 详情 详情
(IX) 54400 [(2R,3R,4R,5S)-3,4-bis(benzoyloxy)-3-ethynyl-5-methoxytetrahydro-2-furanyl]methyl benzoate C29H24O8 详情 详情
(X) 54401 [(2R,3R,4R,5R)-5-(acetyloxy)-3,4-bis(benzoyloxy)-3-ethynyltetrahydro-2-furanyl]methyl benzoate C30H24O9 详情 详情
(XI) 12706 Cytosine; 4-Amino-2(1H)-pyrimidinone 71-30-7 C4H5N3O 详情 详情
(XII) 54402 [(2R,3R,4R,5R)-5-[4-amino-2-oxo-1(2H)-pyrimidinyl]-3,4-bis(benzoyloxy)-3-ethynyltetrahydro-2-furanyl]methyl benzoate C32H25N3O8 详情 详情

合成路线10

该中间体在本合成路线中的序号：(VIII)

The reaction of cytidine (I) with benzoyl anhydride in dioxane gives N-benzoylcytidine (II), which is selectively monoprotected at the primary OH group by means of 4-methoxytrityl chloride and pyridine to yield N-benzoyl-5'O-(monomethoxytrityl)cytidine (III). The monosilylation of (III) by means of Tbdms-Cl and AgNO3 in pyridine/THF affords a mixture of the 3'-O-silyl (IV) and the desired 2'-O-silyl (V) derivative which is easily separated by flash chromatography. (The yield of the desired 2'-O-silyl isomer (V) can be improved by isomerization of the 3'-O-silyl isomer (IV) by means of pyridine in methanol at 70 C). The oxidation of (V) by means of CrO3 and Ac2O provides the 3'-oxonucleoside (VI), which is selectively deprotected by means of TsOH in chloroform/methanol to give compound (VII). The reaction of (VII) with trimethylsilylacetylene (VIII) by means of BuLi and CeCl3 in THF yields the protected ethynyl nucleoside (IX), which is debenzoylated by means of NH3 in methanol to afford the silylated nucleoside (X). Finally, this compound is treated with TBAF in THF to obtain the target ethynyl cytidine.

参考文献 中间体
合成目标
【1】 Ludwig, P.S.; Schwender, R.A.; Schott, H.; A new laboratory scale synthesis for the anticancer drug 3'-C.ethynylcytidine. Synthesis (Stuttgart) 2002, 16, 2387.
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) 27920 Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone 65-46-3 C9H13N3O5 详情 详情
(II) 61580 N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide 13089-48-0 C16H17N3O6 详情 详情
(III) 61581 N-[1-((2R,3R,4S,5R)-3,4-dihydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide C38H37N3O9 详情 详情
(IV) 61582 N-[1-((2R,3R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide C44H51N3O9Si 详情 详情
(V) 61583 N-[1-((2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide C44H51N3O9Si 详情 详情
(VI) 61584 N-[1-((2R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-5-{[tris(4-methoxyphenyl)methoxy]methyl}tetrahydro-2-furanyl)-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide C44H49N3O9Si 详情 详情
(VII) 61585 N-{1-[(2R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(hydroxymethyl)-4-oxotetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide C22H29N3O6Si 详情 详情
(VIII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(IX) 61586 N-(1-{(2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-(hydroxymethyl)-4-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl}-2-oxo-1,2-dihydro-4-pyrimidinyl)benzamide C27H39N3O6Si2 详情 详情
(X) 61587 4-amino-1-{(2R,3R,4R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-(hydroxymethyl)-4-[2-(trimethylsilyl)ethynyl]tetrahydro-2-furanyl}-2(1H)-pyrimidinone C20H35N3O5Si2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VIII)

Treatment of 5-bromo-3-pyridinecarboxylic acid (I) with thionyl chloride in 1,2-dichloroethane (DCE) gives acid chloride hydrochloride (II), which is converted to ester (III) on treatment with ethanol in DCE. Claisen condensation of ester (III) with N-vinylpyrrolidinone (IV) in the presence of littium bis(trimethylsilyl)amide followed by refluxing in aqueous hydrochloric acid gives the pyrroline (V). The reduction of pyrroline (V) with sodium borohydride in the presence of the chiral auxiliary N-carbobenzyloxy-L-proline yields the enantiomerically enriched (S)-pyrrolidine (VI) with an e.e. of 30%. This compound is reductively methylated in a mixture of aqueous formaldehyde and formic acid, and the resulting N-methylpyrrolidine (VII) is converted to the di-p-toluoyl-D-tartaric acid salt, and recrystallized from ethanol-ethyl acetate to increase the e.e. to 90%. The free amine (VII) is coupled with trimethylsilyl acetylene (VIII), in the presence of bis(triphenylphosphine)palladium dichloride, cuprous iodide, and triethylamine in THF. The resulting compound (IX) is treated with cesium carbonate in refluxing methanol to remove the trimethylsilyl group, and finally converted to the maleate salt on treatment with maleic acid in methanol.

参考文献 中间体
合成目标
【1】 McCallum, J.S.; Cosford, N.D.P.; McDonald, I.A.; Herbaut, A.; Bleicher, L.S.; A practical and efficient synthesis of the selective neuronal acetylcholine-gated ion channel agonist (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate (SIB-1508Y). J Org Chem 1998, 63, 4, 1109.
【2】 Cosford, N.D.P.; et al.; (S)-(-)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate (SIB-1508Y): A novel anti-parkinsonian agent with selectivity for neuronal nicotinic acetylcholine receptors. J Med Chem 1996, 39, 17, 3225.
【3】 McDonald, I.A.; Whitten, J.P.; Cosford, N.D. (SIBIA Neurosciences, Inc.); Pyridine modulators of acetylcholine receptors. EP 0739342; JP 1997508648; US 5594011; WO 9615123 .
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) 17913 5-Bromonicotinic acid 20826-04-4 C6H4BrNO2 详情 详情
(II) 14130 5-Bromonicotinoyl chloride 39620-02-5 C6H3BrClNO 详情 详情
(III) 17915 Ethyl 5-bromonicotinate 20986-40-7 C8H8BrNO2 详情 详情
(IV) 17916 N-Vinyl-2-Pyrrolidinone; 1-vinyl-2-pyrrolidinone 88-12-0 C6H9NO 详情 详情
(V) 17917 3-bromo-5-(3,4-dihydro-2H-pyrrol-5-yl)pyridine C9H9BrN2 详情 详情
(VI) 17918 3-bromo-5-[(2R)pyrrolidinyl]pyridine C9H11BrN2 详情 详情
(VII) 17919 3-bromo-5-[(2R)-1-methylpyrrolidinyl]pyridine C10H13BrN2 详情 详情
(VIII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(IX) 17921 3-[(2R)-1-methylpyrrolidinyl]-5-[2-(trimethylsilyl)ethynyl]pyridine C15H22N2Si 详情 详情
(X) 17922 2-methyl-3-butyn-2-ol; 3-Methyl butynol 115-19-5 C5H8O 详情 详情
(XI) 17923 2-methyl-4-[5-[(2R)-1-methylpyrrolidinyl]-3-pyridinyl]-3-butyn-2-ol C15H20N2O 详情 详情

合成路线12

该中间体在本合成路线中的序号：(III)

Bromination of tetralone (I) in the presence of AlCl3 provided (II), which was coupled with (trimethylsilyl)acetylene (III) using PdCl2(PPh3)2 and CuI as the catalysts yielding (IV). Removal of the protecting trimethylsilyl group from (IV) with K2CO3 in MeOH gave the arylacetylene (V), which was subjected to a second Pd-catalyzed coupling reaction with ethyl 4-iodobenzoate (VI) to furnish diarylacetylene (VII). Ketone group of (VII) was then reduced with NaBH4 to provide racemic alcohol (VIII), which was separated into the enantiomers employing chiral HPLC. Alternatively, enantioselective reduction using several chiral reducing agents furnished the enantiomerically enriched alcohols. The desired (R)-alcohol was condensed with dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid to yield a diastereomeric mixture of tetrahydropyranyl ethers (IX). After isolation by means of normal phase-HPLC, the (R,R)-isomer was finally hydrolyzed with LiOH to the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Kochar, D.M.; Chandraratna, R.A.S.; Standeven, A.M.; Lin, Y.; Vuligonda, V.; Thacher, S.M.; A new class of RAR subtype selective retinoids: Co. Bioorg Med Chem 1999, 7, 2, 263.
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) 23791 4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone 2979-69-3 C12H14O 详情 详情
(II) 23792 7-bromo-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone C12H13BrO 详情 详情
(III) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(IV) 23794 4,4-dimethyl-7-[2-(trimethylsilyl)ethynyl]-3,4-dihydro-1(2H)-naphthalenone C17H22OSi 详情 详情
(V) 23795 7-ethynyl-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone C14H14O 详情 详情
(VI) 23796 ethyl 4-iodobenzoate 51934-41-9 C9H9IO2 详情 详情
(VII) 23797 ethyl 4-[2-(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl)ethynyl]benzoate C23H22O3 详情 详情
(VIII) 23798 ethyl 4-[2-(8-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethynyl]benzoate C23H24O3 详情 详情
(IX) 23799 ethyl 4-[2-[(8R)-5,5-dimethyl-8-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-2-naphthalenyl]ethynyl]benzoate C28H32O4 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XIII)

Erlotinib can be obtained by three related ways: 1) Alkylation of 3,4-dihydroxybenzoic acid ethyl ester (I) with 2-bromoethyl methyl ether (II) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in refluxing acetone gives 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (III), which is nitrated with HNO3 in acetic acid to yield 4,5-bis(2-methoxyethoxy)-2-nitrobenzoic acid ethyl ester (IV). Reduction of ester (IV) with H2 over PtO2 in ethanol/HCl affords the corresponding aniline derivative (V), which is cyclized with ammonium formate (VI) in formamide at 165 C to provide 6,7-bis(2-methoxyethoxy)-quinazolin-4(3H)-one (VII). Reaction of quinazoline (VII) with oxalyl chloride in refluxing chloroform gives the expected 4-chloroquinazoline derivative (VIII), which is finally condensed with 3-ethynylaniline (IX) in refluxing isopropanol containing pyridine. 2) Reaction of the 4-chloroquinazoline derivative (VIII) with 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol (X) in refluxing acetonitrile gives the secondary amine (XI), which is finally treated with anhydrous solid NaOH in refluxing either 1-butanol, 2-butanol, isopropanol or 2-methoxyethanol. 3) Reaction of 3-bromonitrobenzene (XII) with trimethylsilylacetylene (XIII) by means of a Pd catalyst and Cu2I in hot TEA gives 3-(trimethylsilylethynyl)nitrobenzene (XIV), which is reduced with H2 over Pt/Al2O3 in isopropanol to provide 3-(trimethylsilylethynyl)aniline (XV). Condensation of the aniline (XV) with the quinazoline derivative (VIII) in refluxing isopropanol affords the silylated quinazoline derivative (XVI), which is finally deprotected with TBAF in THF.

参考文献 中间体
合成目标
【1】 Bayes, M.; Castaner, J.; Sorbera, L.A.; Silvestre, J.S.; Erlotinib Hydrochloride. Drugs Fut 2002, 27, 10, 923.
【2】 Schnur, R.C.; Arnold, L.D. (Pfizer Inc.); Alkynyl and azido-substd. 4-anilinoquinazolines. US 5747498 .
【3】 Schnur, R.C.; Arnold, L.D. (Pfizer Inc.); Quinazoline derivs.. EP 0817775; EP 1110953; JP 1998506633; WO 9630347 .
【4】 Santafianos, D.P.; Norris, T.; Lehner, R.S. (Pfizer Inc.); Processes and intermediates for preparing anti-cancer cpds.. EP 1044969; JP 2000290262; US 6476040 .
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) 56439 3,4-Dihydrohybenzoic acid ethyl ester; Ethyl 3,4-dihydroxybenzoate; Ethyl Protocatechuate; Protocatechuic acid ethyl ester 3943-89-3 C9H10O4 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) 56440 ethyl 3,4-bis(2-methoxyethoxy)benzoate 183322-16-9 C15H22O6 详情 详情
(IV) 56441 ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate 179688-26-7 C15H21NO8 详情 详情
(V) 56442 ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate 179688-27-8 C15H23NO6 详情 详情
(VII) 56443 6,7-bis(2-methoxyethoxy)-4(3H)-quinazolinone 179688-29-0 C14H18N2O5 详情 详情
(VIII) 56444 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline; 4-chloro-6-(2-methoxyethoxy)-7-quinazolinyl 2-methoxyethyl ether 183322-18-1 C14H17ClN2O4 详情 详情
(IX) 56445 3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene 54060-30-9 C8H7N 详情 详情
(X) 56446 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol C11H13NO 详情 详情
(XI) 56447 4-(3-{[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amino}phenyl)-2-methyl-3-butyn-2-ol C25H29N3O5 详情 详情
(XII) 56448 1-Bromo-3-nitrobenzene; 3-Bromonitrobenzene; 3-Nitrobromobenzene; m-Bromonitrobenzene; m-Nitrobromobenzene 585-79-5 C6H4BrNO2 详情 详情
(XIII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XIV) 56449 trimethyl[2-(3-nitrophenyl)ethynyl]silane C11H13NO2Si 详情 详情
(XV) 56450 3-[2-(trimethylsilyl)ethynyl]aniline; 3-[2-(trimethylsilyl)ethynyl]phenylamine C11H15NSi 详情 详情
(XVI) 56451 N-[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]-N-{3-[2-(trimethylsilyl)ethynyl]phenyl}amine; 6,7-bis(2-methoxyethoxy)-N-{3-[2-(trimethylsilyl)ethynyl]phenyl}-4-quinazolinamine C25H31N3O4Si 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XVII)

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829.
【2】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情
(XVI) 19241 (2S)oxiranylmethanol 60456-23-7 C3H6O2 详情 详情
(XVII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XVIII) 40293 tert-butyl(dimethyl)silyl (1R)-1-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-(trimethylsilyl)-3-butynyl ether; (5R)-2,2,3,3,8,8,9,9-octamethyl-5-[3-(trimethylsilyl)-2-propynyl]-4,7-dioxa-3,8-disiladecane C20H44O2Si3 详情 详情
(XIX) 40294 tert-butyl(dimethyl)silyl (2R,4E)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-pentenyl ether; (5R)-5-[(E)-3-iodo-2-propenyl]-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane C17H37IO2Si2 详情 详情
(XX) 40295 (E,7R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-4-octen-3-one C46H78O6Si2 详情 详情
(XXI) 40296 　 C15H23AlCl2O 详情 详情
(XXII) 40297 　 C46H78O6Si2 详情 详情
(XXIII) 40298 　 C34H50O6 详情 详情
(XXIV) 35692 　 C33H46O5 详情 详情
(XXV) 35693 [2-[(E)-3-pentenyl]-1,3-dithian-2-yl]lithium C9H15LiS2 详情 详情
(XXVI) 35694 　 C42H62O5S2 详情 详情
(XXVII) 35695 　 C48H76O5S2Si 详情 详情
(XXVIII) 35696 　 C49H75F3O7S3Si 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 cyclization of ribofuranoside (I) with trimethylsilyl acetylene (II) by means of NBS in DMF gives the trimethylsilylisoxazole (III), which is desilylated with NaOH in methanol yielding the isoxazole (IV). Elimination of the isopropylidene protecting group of (IV) by passing through a Dowex 50 H+ column affords the dihydroxy compound (V), which is benzoylated with benzoyl chloridde and DMAP in pyridine giving the dibenzoyl derivative (VI). The condensation of (VI) with 2,6-dichloro-9H-purine (VII) in refluxing hexamethyldisilazane (HMDA) provides the purine derivative (VIII), which is treated with 0-methylhydroxylamine and triethylamine in refluxing dioxane yielding the adenosine derivative (IX). Finally, this compound is debenzoylated with ammonia in methanol.

参考文献 中间体
合成目标
【1】 Knutsen, L.; Olsen, U.B.; Roberts, S.M.; Varley, D.R.; Bowler, A.N. (Novo Nordisk A/S); Novel N-alkoxyadenine derivs. acting as cytokine inhibitors. WO 9801459 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
15455 (aminooxy)methane; O-methylhydroxylamine 67-62-9 CH5NO 详情 详情
(I) 25249 (3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde O-methyloxime C10H17NO5 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 25250 3-[(3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-5-(trimethylsilyl)isoxazole; (3aS,4R,6R,6aR)-2,2-dimethyl-6-[5-(trimethylsilyl)-3-isoxazolyl]tetrahydrofuro[3,4-d][1,3]dioxol-4-yl methyl ether C14H23NO5Si 详情 详情
(IV) 25251 3-[(3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]isoxazole; (3aS,4R,6R,6aR)-6-(3-isoxazolyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl methyl ether C11H15NO5 详情 详情
(V) 25252 (2R,3S,4S,5R)-2-(3-isoxazolyl)-5-methoxytetrahydro-3,4-furandiol C8H11NO5 详情 详情
(VI) 25253 (2R,3R,4R,5R)-4-(benzoyloxy)-2-(3-isoxazolyl)-5-methoxytetrahydro-3-furanyl benzoate C22H19NO7 详情 详情
(VII) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(VIII) 25255 (2R,3R,4S,5R)-4-(benzoyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-(3-isoxazolyl)tetrahydro-3-furanyl benzoate C26H17Cl2N5O6 详情 详情
(IX) 25256 (2R,3R,4S,5R)-4-(benzoyloxy)-2-[2-chloro-6-(methoxyamino)-9H-purin-9-yl]-5-(3-isoxazolyl)tetrahydro-3-furanyl benzoate C27H21ClN6O7 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The reaction of the protected carbohydrate (I) with trimethylsilylacetylene (II) gives adduct (III) with no stereoselectivity at the reaction point. The oxidation of the OH group of (III) with DMP gives the corresponding oxo compound (IV), which is stereoselectively reduced with N-Selectride to yield the (R)-diastereomer (V) in a 33:1 ratio. The desilylation of (V) with TBAF in THF affords the free compound (VI), which is benzoylated with Bz2O, TEA and DMAP in acetonitrile to provide the tribenzoate (VII). The reaction of (VII) with Ac2O, H2SO4 and AcOH gives the 1-acetoxy compound (VIII), which is condensed with N6-benzoyladenine (IX) by means of Tms-OTf and TEA in acetonitrile, yielding the adenosine derivative (X). Finally, this compound is debenzoylated with ammonia in methanol.

参考文献 中间体
合成目标
【1】 Umino, T.; et al.; Nucleosides and nucleotides. Part 201: Alternative method to synthesize 9-(6,7-dideoxy-beta-D-allo-hept-5-ynofuranosyl)adenine, a selective and potent ligand for P-3 purinoceptor-like protein: A stereoselective reduction based on sugar puckering of the fu. Tetrahedron Lett 2000, 41, 33, 6419.
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) 42083 (2S,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methoxytetrahydro-2-furancarbaldehyde C18H38O5Si2 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 42084 (1R)-1-((2R,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methoxytetrahydro-2-furanyl)-3-(trimethylsilyl)-2-propyn-1-ol C23H48O5Si3 详情 详情
(IV) 42085 1-((2S,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methoxytetrahydro-2-furanyl)-3-(trimethylsilyl)-2-propyn-1-one C23H46O5Si3 详情 详情
(V) 42086 1-((2R,3R,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methoxytetrahydro-2-furanyl)-3-(trimethylsilyl)-2-propyn-1-ol C23H48O5Si3 详情 详情
(VI) 42087 (2R,3S,4R,5R)-2-(1-hydroxy-2-propynyl)-5-methoxytetrahydro-3,4-furandiol C8H12O5 详情 详情
(VII) 42088 (2R,3R,4R,5R)-4-(benzoyloxy)-2-[1-(benzoyloxy)-2-propynyl]-5-methoxytetrahydro-3-furanyl benzoate C29H24O8 详情 详情
(VIII) 42089 (3R,4R,5R)-2-(acetoxy)-4-(benzoyloxy)-5-[1-(benzoyloxy)-2-propynyl]tetrahydro-3-furanyl benzoate C30H24O9 详情 详情
(IX) 10035 N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine 4005-49-6 C12H9N5O 详情 详情
(X) 42090 1-[(2R,3R,4R,5R)-5-[6-(benzoylamino)-9H-purin-9-yl]-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]-2-propynyl benzoate C40H29N5O8 详情 详情

合成路线17

该中间体在本合成路线中的序号：(III)

4-Iodophenol (I) was protected as the trimethylsilyl ether (II) with Me3SiCl and then coupled with (trimethylsilyl)acetylene (III) using palladium catalyst and CuI to afford the O-desilylated ethynylphenol (IV). This was condensed under Mitsunobu conditions with N-Boc-imidazolylpropanol (VI), prepared from imidazolylpropanol (V) and Boc2O, to afford ether (VII). Deprotection of the Boc group of (VII) with methanolic hydrazine at r.t. yielded a mixture of (VIII) and the fully desilylated analogue (IX), which was isolated by column chromatography and finally crystallized as the maleate salt from EtOH-Et2O.

参考文献 中间体
合成目标
【1】 Krause, M.; Ligneau, X.; Stark, H.; Garbarg, M.; Schwartz, J.C.; Schunack, W.; 4-Alkynylphenyl imidazolylpropyl ethers as selective histamine H3-receptor antagonists with high oral central nervous system activity. J Med Chem 1998, 41, 21, 4171.
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) 22242 4-iodophenol 540-38-5 C6H5IO 详情 详情
(II) 22243 (4-iodophenoxy)(trimethyl)silane; 4-iodophenyl trimethylsilyl ether C9H13IOSi 详情 详情
(III) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(IV) 22245 4-[2-(trimethylsilyl)ethynyl]phenol C11H14OSi 详情 详情
(V) 21245 3-(1H-imidazol-4-yl)-1-propanol C6H10N2O 详情 详情
(VI) 22247 tert-butyl 4-(3-hydroxypropyl)-1H-imidazole-1-carboxylate C11H18N2O3 详情 详情
(VII) 22248 tert-butyl 4-(3-[4-[2-(trimethylsilyl)ethynyl]phenoxy]propyl)-1H-imidazole-1-carboxylate C22H30N2O3Si 详情 详情
(VIII) 22249 4-(3-[4-[2-(trimethylsilyl)ethynyl]phenoxy]propyl)-1H-imidazole; 3-(1H-imidazol-4-yl)propyl 4-[2-(trimethylsilyl)ethynyl]phenyl ether C17H22N2OSi 详情 详情
(IX) 22250 4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether; 4-[3-(4-ethynylphenoxy)propyl]-1H-imidazole C14H14N2O 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XXII)

2) The reduction of (XIV) with DIBAL followed by protection with methoxymethyl chloride (MOM-Cl) yields the methoxymethyl ether (XV), which by regioselective dihydroxylation with AD-mix-beta, followed by mesylation with mesyl chloride affords the dimesylate (XVI). A new regioselective dihydroxylation of (XVI) with AD-mix-beta gives the diol (XVII), which is cyclized by treatment first with p-toluenesulfonic acid and then by heating at 140 C in pyridine yielding the bis(tetrahydrofuran) derivative (XVIII). The deprotection of (XVIII) with boron trilfuoride.ethearate, followed by tosylation with tosyl chloride in pyridine affords the tosylate (XIX), which is cyclized to the epoxide (XX) by reaction with K2CO3 in methanol. The acetylation of the secondary alcohol of (XIX) with acetic anhydride in pyridine affords the acetate (XXI), which is condensed with trimethylsilylacetylene (XXII) by means of n-BuLi in THF giving the acetylenic alcohol (XXIII).

参考文献 中间体
合成目标
【1】 Yazbak, A.; et al.; Total synthesis of uvaricin. J Org Chem 1998, 63, 17, 5863.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 20188 ethyl (2E,6E)-9-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2,6-nonadienoate C26H46O4 详情 详情
(XV) 20190 (2E,6E)-9-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-2,6-nonadienyl methoxymethyl ether; (4S,5R)-4-decyl-5-[(3E,7E)-9-(methoxymethoxy)-3,7-nonadienyl]-2,2-dimethyl-1,3-dioxolane C26H48O4 详情 详情
(XVI) 20191 (4S,5R)-4-decyl-5-((3S,4S,7E)-9-(methoxymethoxy)-3,4-bis[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-7-nonenyl)-2,2-dimethyl-1,3-dioxolane; (E,6S,7S)-9-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]-6,7-bis[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2-nonenyl methoxymethyl ether C32H62O6S2 详情 详情
(XVII) 20192 (4S,5S,8R,9R)-4-[2-[(4R,5S)-5-decyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-2-methyl-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2-methylene-3,11,13-trioxa-2lambda(6)-thia-1-tetradecene-8,9-diol C32H64O8S2 详情 详情
(XVIII) 20193 1(S)-[5(R)-[5(R)-[1(R)-Hydroxy-2-(methoxymethoxy)ethyl]tetrahydrofuran-2(R)-yl]tetrahydrofuran-2(R)-yl]undecan-1-ol C23H44O6 详情 详情
(XIX) 20194 1(S)-[5(R)-[5(R)-[1(R)-Hydroxy-2-(p-toluenesulfonyloxy)ethyl]tetrahydrofuran-2(R)-yl]tetrahydrofuran-2(R)-yl]undecan-1-ol C28H46O7S 详情 详情
(XX) 20195 1(S)-[5(R)-[5(R)-(1(R),2-Epoxyethyl)tetrahydrofuran-2(R)-yl]tetrahydrofuran-2(R)-yl]undecan-1-ol C21H38O4 详情 详情
(XXI) 20196 Acetic acid 1(S)-[5(R)-[5(R)-(1(R),2-Epoxyethyl)tetrahydrofuran-2(R)-yl]tetrahydrofuran-2(R)-yl]undecyl ester C23H40O5 详情 详情
(XXII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XXIII) 20198 Acetic acid 1(S)-[5(R)-[5(R)-(1(R)-hydoxy-3-butynyl)tetrahydrofuran-2(R)-yl]tetrahydrofuran-2(R)-yl]undecyl ester C25H42O5 详情 详情
(XXIV) 20205 (5S)-3-[(E)-9-iodo-8-nonenyl]-5-methyl-3-(phenylsulfanyl)dihydro-2(3H)-furanone C20H27IO2S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(VIII)

Addition of 3-methyl-2-butenoic acid (II) to 4-methoxythiophenol (I) in the presence of piperidine at 105 C afforded adduct (III). After conversion of (III) to the corresponding acid chloride (IV) with oxalyl chloride, Friedel-Crafts cyclization using SnCl4 produced thiochromanone (V). Cleavage of the methyl ether of (V) by means of BBr3 gave phenol (VI), which was converted to triflate (VII) with trifluoromethanesulfonic anhydride in pyridine. Coupling of (VII) with trimethylsilyl acetylene (VIII) using a palladium catalyst provided (IX). Subsequent desilylation of (IX) with K2CO3 in MeOH, followed by palladium-catalyzed coupling of the resulting alkyne with ethyl 4-iodobenzoate (X) afforded the diaryl acetylene (XI). Introduction of the 4-aryl group in (XI) was achieved by conversion of (XI) to vinyl triflate (XIII) upon treatment of the sodium enolate with the bis-triflimide reagent (XII), and further condensation with 4-ethyl-phenylzinc chloride (XIV) yielding (XV). Finally, basic hydrolysis of the ethyl ester (XV) furnished the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Standeven, A.M.; Escobar, M.; Wang, L.; Johnson, A.T.; Chandraratna, R.A.S.; Synthesis and biological activity of high-affinity retinoic acid receptor antagonists. Bioorg Med Chem 1999, 7, 1321.
【2】 Klein, E.S.; Chandraratna, R.A.; Teng, M.; Duong, T.T.; Gillett, S.J.; Beard, R.L.; Vuligonda, V.; Johnson, A.T.; Standeven, A.M.; Nagpal, S. (Allergan, Inc.); Benzopyran and benzothiopyran derivs. having retinoid antagonist-like activity. WO 9933821 .
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) 25639 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol 34320-82-6 C7H8OS 详情 详情
(II) 34677 3-methyl-2-butenoic acid 541-47-9 C5H8O2 详情 详情
(III) 34678 3-[(4-methoxyphenyl)sulfanyl]-3-methylbutyric acid C12H16O3S 详情 详情
(IV) 34679 3-[(4-methoxyphenyl)sulfanyl]-3-methylbutanoyl chloride C12H15ClO2S 详情 详情
(V) 34680 6-methoxy-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one C12H14O2S 详情 详情
(VI) 34681 6-hydroxy-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one C11H12O2S 详情 详情
(VII) 34682 2,2-dimethyl-4-oxo-3,4-dihydro-2H-thiochromen-6-yl trifluoromethanesulfonate C12H11F3O4S2 详情 详情
(VIII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(IX) 34683 2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-4H-thiochromen-4-one C16H20OSSi 详情 详情
(X) 23796 ethyl 4-iodobenzoate 51934-41-9 C9H9IO2 详情 详情
(XI) 34684 ethyl 4-[2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-thiochromen-6-yl)ethynyl]benzoate C22H20O3S 详情 详情
(XII) 34685 N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide 145100-51-2 C7H3ClF6N2O4S2 详情 详情
(XIII) 34686 ethyl 4-[2-(2,2-dimethyl-4-[[(trifluoromethyl)sulfonyl]oxy]-2H-thiochromen-6-yl)ethynyl]benzoate C23H19F3O5S2 详情 详情
(XIV) 34687 chloro(4-ethylphenyl)zinc C8H9ClZn 详情 详情
(XV) 34688 ethyl 4-[2-[4-(4-ethylphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]ethynyl]benzoate C30H28O2S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(VII)

Iodination of 3-methylcyclohexenone (I) using iodine and azidotrimethylsilane produced the iodo ketone (II) (1). Palladium-catalyzed coupling of iodide (II) with 2-(tributylstannyl)ethenyltrimethylsilane (III), prepared from (trimethylsilyl)acetylene and tributyltin hydride, furnished the silylethenyl cyclohexenone (IV), which was further treated with iodine to yield vinyl iodide (V) (1,2). Ethyl 4-ethynylbenzoate (VIII) was prepared by reaction of ethyl 4-iodobenzoate (VI) with (trimethylsilyl)acetylene (VII) in the presence of palladium catalyst (1). Heck reaction between acetylene (VIII) and vinyl iodide (V) provided adduct (IX). Conjugate addition of the in situ generated lithium dimethylcuprate to the unsaturated ketone (IX) gave the 3,3-dimethyl cyclohexanone (X). Treatment of (X) with triflic anhydride and a hindered base produced the desired vinyl triflate (XI) along with its vinyl regioisomer, which were separated by preparative chromatography. Reaction of triflate (XI) with 4-tolylzinc bromide (XIII), prepared from 4-iodotoluene (XII), yielded the phenylcyclohexene derivative (XIV). The ethyl ester group of (XIV) was finally hydrolyzed to the corresponding carboxylic acid using NaOH.

参考文献 中间体
合成目标
【1】 Standeven, A.M.; Escobar, M.; Beard, R.L.; Klein, E.S.; Chandraratna, R.A.S.; Phenylcyclohexene and phenylcyclohexadiene substituted compounds having retinoid antagonist activity. Bioorg Med Chem Lett 2001, 11, 6, 765.
【2】 Beard, R.L.; Johnson, A.T.; Teng, M.; Vuligonda, V.; Chandraratna, R.A. (Allergan, Inc.); Aryl- and heteroarylcyclohexenyl substd. alkenes having retinoid agonist, antagonist or inverse agonist type biological activity. EP 0970036; JP 2001513113; US 5760276; WO 9839284 .
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) 51163 3-Methyl-2-cyclohexen-1-one; 3-Methyl-2-cyclohexenone 1193-18-6 C7H10O 详情 详情
(II) 51164 2-iodo-3-methyl-2-cyclohexen-1-one C7H9IO 详情 详情
(III) 51165 trimethyl[(E)-2-(tributylstannyl)ethenyl]silane C17H38SiSn 详情 详情
(IV) 51166 3-methyl-2-[(E)-2-(trimethylsilyl)ethenyl]-2-cyclohexen-1-one C12H20OSi 详情 详情
(V) 51167 2-[(E)-2-iodoethenyl]-3-methyl-2-cyclohexen-1-one C9H11IO 详情 详情
(VI) 23796 ethyl 4-iodobenzoate 51934-41-9 C9H9IO2 详情 详情
(VII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(VIII) 51168 ethyl 4-ethynylbenzoate C11H10O2 详情 详情
(IX) 51169 ethyl 4-[(E)-4-(2-methyl-6-oxo-1-cyclohexen-1-yl)-3-buten-1-ynyl]benzoate C20H20O3 详情 详情
(X) 51170 ethyl 4-[(E)-4-(2,2-dimethyl-6-oxocyclohexyl)-3-buten-1-ynyl]benzoate C21H24O3 详情 详情
(XI) 51171 ethyl 4-[(E)-4-(6,6-dimethyl-2-[[(trifluoromethyl)sulfonyl]oxy]-1-cyclohexen-1-yl)-3-buten-1-ynyl]benzoate C22H23F3O5S 详情 详情
(XII) 46620 1-iodo-4-methylbenzene C7H7I 详情 详情
(XIII) 51172 bromo(4-methylphenyl)zinc C7H7BrZn 详情 详情
(XIV) 51173 ethyl 4-[(E)-4-[6,6-dimethyl-2-(4-methylphenyl)-1-cyclohexen-1-yl]-3-buten-1-ynyl]benzoate C28H30O2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(VI)

2-Pivaloylamino-pyrrolo[2,3-d]pyrimidine-4-one (I) is chlorinated to (II) in refluxing POCl3. Subsequent, Stille coupling of (II) with tributyl vinyltin gives the vinyl pyrrolopyrimidine (III), which is further reduced to the corresponding ethyl derivative (IV) by catalytic hydrogenation over Pd/C. Regioselective iodination of (IV) by means of N-iodosuccinimide provides (V). Aryl iodide (V) is then subjected to palladium-catalyzed cross-coupling with trimethylsilylacetylene (VI), leading to the silylethynyl adduct (VII). Desilylation of (VII) employing tetrabutylammonium fluoride furnishes intermediate (VIII).

参考文献 中间体
合成目标
【1】 Gangjee, A.; Yu, J.; Kisliuk, R.L.; Haile, W.H.; Sobrero, G.; McGuire, J.J.; Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and. J Med Chem 2003, 46, 4, 591.
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) 14794 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide C11H14N4O2 详情 详情
(II) 63357 N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C11H13ClN4O 详情 详情
(III) 63358 N-(4-ethenyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C13H16N4O 详情 详情
(IV) 63359 N-(4-ethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C13H18N4O 详情 详情
(V) 63360 N-(4-ethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C13H17IN4O 详情 详情
(VI) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(VII) 63361 N-{4-ethyl-5-[2-(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-2,2-dimethylpropanamide C18H26N4OSi 详情 详情
(VIII) 63362 N-(4-ethyl-5-ethynyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C15H18N4O 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XI)

6-Bromo-1-indanone (VII) is reduced to alcohol (VIII) employing NaBH4. After chlorination of (VIII) with SOCl2, the resultant alkyl chloride (IX) is displaced by heating with ethanolic dimethylamine in a sealed vessel to produce the (dimethylamino)indan (X). Palladium-catalyzed coupling of aryl bromide (X) with trimethylsilyl acetylene (XI) furnishes the silyl acetylene (XII), which is then desilylated to (XIII) with Bu4NF in THF. Finally, condensation between acetylene (XIII), aryl iodide (VI) and carbon monoxide in the presence of palladium catalyst leads to the title quinolone derivative. (1,2)

参考文献 中间体
合成目标
【1】 Dhar, T.G.M.; Watterson, S.H.; Chen, P.; Shen, Z.; Gu, H.H.; Norris, D.; Carlsen, M.; Haslow, K.D.; Pitts, W.J.; Guo, J.; Chorba, J.; Fleener, C.A.; Rouleau, K.A.; Townsend, R.; Hollenbaugh, D.; Iwanowicz, E.J.; Quinolone-based IMPDH inhibitors: Introduction of basic residues on ring D and SAR of the corresponding mono, di and benzofused analogues. Bioorg Med Chem Lett 2003, 13, 3, 547.
【2】 Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H.; Watterson, S.H. (Bristol-Myers Squibb Co.); Heterocycles that are inhibitors of IMPDH enzyme. EP 1276739; JP 2003531205; WO 0181340 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 64043 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine C10H9IN2O2 详情 详情
(VII) 64044 6-bromo-2,3-dihydro-1H-inden-1-one C9H7BrO 详情 详情
(VIII) 64045 6-bromo-2,3-dihydro-1H-inden-1-ol C9H9BrO 详情 详情
(IX) 64046 6-bromo-1-chloro-2,3-dihydro-1H-indene C9H8BrCl 详情 详情
(X) 64047 6-bromo-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine; N-(6-bromo-2,3-dihydro-1H-inden-1-yl)-N,N-dimethylamine C11H14BrN 详情 详情
(XI) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XII) 64048 N,N-dimethyl-6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-1H-inden-1-amine; N,N-dimethyl-N-{6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-1H-inden-1-yl}amine C16H23NSi 详情 详情
(XIII) 64049 N-(6-ethynyl-2,3-dihydro-1H-inden-1-yl)-N,N-dimethylamine; 6-ethynyl-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine C13H15N 详情 详情

合成路线23

该中间体在本合成路线中的序号：(XVII)

Chiral cyclopropanesulfonyl chloride intermediate (VIII) can be prepared as follows. Lithiation of (trimethylsilyl)acetylene (XVII) with t-BuLi in THF at –78 °C, and subsequent coupling with TBDMS-protected (S)-glycidol (XVIII) in the presence of BF3·Et2O at –78 °C affords the (S)-pentynol derivative (XIX). Then, the TMS-protecting group of intermediate (XIX) is selectively removed by means of K2CO3 in MeOH to give alkyne (XX). Iodoboration of alkyne (XX) with B-I-9-BBN in CH2Cl2 at 0 °C followed by deborination with AcOH yields 4-iodo-4-pentene-1,2(S)-diol (XXI). O-Protection of diol (XXI) with TBDMSOTf and pyridine in THF provides the bis-silyl ether (XXII), which is then submitted to Simmons-Smith cyclopropanation with CH2I2 in the presence of Et2Zn and TFA in DCE to produce 1,2-O-bis-TBDMS-3-(1-iodocyclopropyl)propane-1,2(S)-diol (XXIII). Desilylation of compound (XXIII) using HCl in THF gives 3-(1-iodocyclopropyl)propane-1,2(S)-diol (XXIV), which by trans-ketalization with 2,2-dimethoxypropane (XXV) by means of PPTS in CH2Cl2 gives 4(S)-(1-iodocyclopropylmethyl)-2,2-dimethyl-1,3-dioxolane (XXVI). Finally, alkyl iodide (XXVI) is treated with t-BuLi in Et2O at –78 °C, followed by chlorosulfonation with SO2Cl2 in Et2O (3).
Alternatively, deprotonation of dicyclopropyl disulfide (XXVII) with BuLi in THF, followed by alkylation with 4(R)-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (XXVIII) at –78 °C affords the dimeric bis-acetonide (XXIX), which is reductively cleaved to the corresponding thiol monomer (XXX) by treatment with PPh3 and HCl in dioxane/H2O. Air oxidation of cyclopropanethiol derivative (XXX) in the presence of NaOH in DMF gives sodium cyclopropanesulfonate derivative (XXXI), which can also be obtained by direct oxidation of disulfide (XXIX) with H2O2 and NaOAc in AcOH at 80 °C. Finally, sulfonate (XXXI) is chlorinated using POCl3 at 80 °C. Alternatively, sulfonyl chloride (VIII) can be directly obtained from disulfide (XXIX) by oxidative cleavage with NCS in the presence of HCl in MeCN .

参考文献 中间体
合成目标
【1】 Maderna, A., Vernier, J., Barawkar, D., Chamakura, V., El Abdellaoui, H., Hong, Z. (Ardea Biosciences, Inc.). Derivatives of N-(arylamino)sulfonamides as inhibitors of MEK. US 2008058340, US 8101799.
【2】 Maderna, A., Vernier, J.-M., Barawkar, D., Chamakura, V., Abdellaoui, H.E., Hong, Z. (Ardea Biosciences, Inc.). N-(Arylamino)-sulfonamide inhibitors of MEK. EP 1912636, US 2012022076, WO 2007014011
【3】 Maderna, A., Vernier, J.-M. (Ardea Biosciences, Inc.). Preparation of (R)-and (S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl)cyclopropane-1-sulfonamide and protected derivatives thereof. EP 2462111, JP 2013500242, KR 2012032536, WO 2011009541.
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) 67911 (S)-1-((5,5-dimethyltetrahydrofuran-2-yl)methyl)cyclopropane-1-sulfonyl chloride 　 C10H17ClO3S 详情 详情
(XVII) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XVIII) 42416 tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether 123237-62-7 C9H20O2Si 详情 详情
(XIX) 67918 (S)-1-((tert-butyldimethylsilyl)oxy)-5-(trimethylsilyl)pent-4-yn-2-ol 　 C14H30O2Si2 详情 详情
(XX) 67919 (S)-1-((tert-butyldimethylsilyl)oxy)pent-4-yn-2-ol 　 C11H22O2Si 详情 详情
(XXI) 67920 (S)-4-iodopent-4-ene-1,2-diol 　 C5H9IO2 详情 详情
(XXII) 67922 (S)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane 　 C17H37IO2Si2 详情 详情
(XXIII) 67921 1,2-O-bis-TBDMS-3-(1-iodocyclopropyl) propane-1,2(S)-diol;(S)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane 　 C18H39IO2Si2 详情 详情
(XXIV) 67923 3-(1-iodocyclopropyl)propane-1,2(S)-diol 　 C6H11O2I 详情 详情
(XXV) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(XXVI) 67924 4(S)-(1-iodocyclopropylmethyl)-2,2-dimethyl- 1,3-dioxolane 　 C9H15IO2 详情 详情
(XXVII) 67925 dicyclopropyl disulfide;Dicyclopropyldisulfide 68846-57-1 C6H10S2 详情 详情
(XXVIII) 67926 4(R)-(bromomethyl)-2,2-dimethyl-1,3- dioxolane 14437-87-7 C6H11BrO2 详情 详情
(XXIX) 67927 1,2-bis(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropyl)disulfane 　 C18H30O4S2 详情 详情
(XXX) 67929 (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropanethiol 　 C9H16O2S 详情 详情
(XXXI) 67928 sodium (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonate 　 C9H15NaO5S 详情 详情

合成路线24

该中间体在本合成路线中的序号：(V)

Cyclization of 4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline (I) with ditosylate (II) [prepared by sulfonylation of triethylene glycol (III) with p-TsCl in the presence of NaOH in THF/H2O (1)] by means of K2CO3 in DMF at 80-90 °C yields the tetraoxacyclododecane derivative (IV), which is finally submitted to Sonogashira coupling with (trimethylsilyl)acetylene (V) using Pd(PPh3)4, CuI and K2CO3 in refluxing DMF .
The aryl bromide precursor (IV) can also be prepared by chlorination of the quinazolinone (VI) using POCl3 in the presence of a catalytic amount of DMF at reflux to afford the 4-chloroquinazoline derivative (VII), which is then coupled with 3-bromoaniline (VIII) in i-PrOH/DMF .
Alternatively, condensation of chloroquinazoline (VII) with 3-ethynyl-aniline (IX) in refluxing i-PrOH/DMF directly produces icotinib .

参考文献 中间体
合成目标
【1】 Wang, Y., Ding, L., Tan, F. et al. (Zhejiang Beta Pharma, Inc.). Icotinib hydrochloride, synthesis, crystallographic form, medical combination, and uses thereof. CN 10187818, EP 2392576, JP 2011527291, KR 2011031370, US 2011182882, WO 2010003313.
【2】 Zhang, D., Xie, G., Davis, C., Cheng, Z., Chen, H., Wang, Y., Kamal, M.(Beta Pharma, Inc.). Fused quinazoline derivatives useful as tyrosine kinase inhibitors. US 2004048883, US 7078409, WO 2003082830.
【3】 Hu, S., Xie, G., Zhang, D.X. et al. Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors. Bioorg Med Chem Lett 2012, 22(19): 6301-5.
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) 67978 4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline 　 C14H10BrN3O2 详情 详情
(II) 67980 (ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) 19249-03-7 C20H26O8S2 详情 详情
(III) 67979 2,2'-(ethane-1,2-diylbis(oxy))diethanol;Triethylene glycol 112-27-6 C6H14O4 详情 详情
(IV) 67981 N-(3-bromophenyl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine 　 C20H20BrN3O4 详情 详情
(V) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(VI) 67982 7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4(3H)-one 　 C14H16N2O5 详情 详情
(VII) 67983 4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline 　 C14H15ClN2O4 详情 详情
(VIII) 19136 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine 591-19-5 C6H6BrN 详情 详情
(IX) 56445 3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene 54060-30-9 C8H7N 详情 详情

合成路线25

该中间体在本合成路线中的序号：(V)

Condensation of 2-amino-3,5-dibromopyrazine (I) with neat 3-amino-pentane (II) under microwave irradiation at 150 °C yields the diaminopyrazine (III), which is then subjected to cyclization with CDI in refluxing THF to give 6-bromo-1-(3-pentyl)imidazo[4,5-b]pyrazin-2-ol (IV). Sonogashira cross-coupling of aryl bromide (IV) with (trimethylsilyl)acetylene (V) in the presence of PdCl2(PPh3)2, CuI and Et3N in DMF at 80 °C affords adduct (VI), which is finally desilylated by treatment with KF in MeOH/THF/H2O .

参考文献 中间体
合成目标
【1】 Muci, A., Finer, J.T., Lu, P.-P., Russell, A.J., Morgan, B.P., Morgans, D.J. Jr. (Cytokinetics, Inc.). Certain chemical entities, compositions and methods. EP 2069352, JP 2009545596, US 2008146561, US 7598248, US 8227603, US 8299248, WO 200801669.
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) 26178 3,5-dibromo-2-pyrazinamine 24241-18-7 C4H3Br2N3 详情 详情
(II) 25924 1-ethylpropylamine; 3-pentanamine 616-24-0 C5H13N 详情 详情
(III) 67991 6-bromo-N2-(pentan-3-yl)pyrazine-2,3-diamine 　 C9H15BrN4 详情 详情
(IV) 67992 6-bromo-1-(3-pentyl)imidazo[4,5-b]pyrazin-2-ol 　 C10H13BrN4O 详情 详情
(V) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(VI) 67993 1-(pentan-3-yl)-6-((trimethylsilyl)ethynyl)-1H-imidazo[4,5-b]pyrazin-2-ol 　 C15H22N4OSi 详情 详情

合成路线26

该中间体在本合成路线中的序号：(XI)

Bromination of 1-methyl-4-nitro-2-(trifluoromethyl)benzene (I) with NBS in the presence of AIBN in refluxing CCl4 gives the corresponding bromomethyl derivative (II), which is condensed with 1-methylpiperazine (III) by means of Et3N in CH2Cl2 to afford 1-methyl-4-[4-nitro-2-(trifluoromethyl)benzyl]piperazine (IV). Reduction of compound (IV) with Na2S2O4 in refluxing acetone/H2O yields the aniline (V), which by coupling with 3-iodo-4-methylbenzoyl chloride (VI) (prepared by chlorinating acid [VII] with SOCl2 at reflux) in the presence of DIEA and DMAP in THF provides the corresponding amide (VIII). Finally, the iodobenzene derivative (VIII) is submitted to Sonogashira coupling with 3-ethynylimidazo[1,2-b]pyridazine (IX) by means of CuI, Pd(PPh3)4 and DIEA in DMF .
Intermediate (IX) is prepared by Sonogashira coupling of 3-bromoimidazo[1,2-b]pyridazine (X) with trimethylsilyl acetylene (XI) in the presence of CuI, PdCl2(PPh3)4 and DCHA in acetonitrile at 80 °C or CuI, Pd(PPh3)4 and DIEA in DMF to give 3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine (XII), which is deprotected by cleaving the trimethylsilyl moiety by means of TBAF in THF .

参考文献 中间体
合成目标
【1】 Huang, W.S., Metcalf, C., Sundaramoorthi, R. et al. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-Abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 2010, 53(12): 4701-19.
【2】 Zou, D., Huang, W.-S., Thomas, R.M. et al. (Ariad Pharmaceuticals, Inc.).Bicyclic heteroaryl compounds. EP 1973545, JP 2009521462, US 2007191376, WO 2007075869.
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) 68863 1-methyl-4-nitro-2-(trifluoromethyl)benzene 　 C8H6F3NO2 详情 详情
(II) 68864 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene 　 C8H5BrF3NO2 详情 详情
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 68865 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine 　 C13H16F3N3O2 详情 详情
(V) 68866 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline 694499-26-8 C13H18F3N3 详情 详情
(VI) 68867 3-iodo-4-methylbenzoyl chloride 　 C8H6ClIO 详情 详情
(VII) 68868 3-iodo-4-methylbenzoic acid 　 C8H7IO2 详情 详情
(VIII) 68869 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide 　 C21H23F3IN3O 详情 详情
(IX) 68870 3-ethynylimidazo[1,2-b]pyridazine 　 C8H5N3 详情 详情
(X) 68871 3-bromoimidazo[1,2-b]pyridazine 18087-73-5 C6H4BrN3 详情 详情
(XI) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XII) 68872 3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine 　　 C11H13N3Si 详情 详情
Extended Information