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【结 构 式】

【分子编号】15926

【品名】2-methyl-1-propene; isobutylene

【CA登记号】115-11-7

【 分 子 式 】C4H8

【 分 子 量 】56.10752

【元素组成】C 85.63% H 14.37%
与该中间体有关的原料药合成路线共 15 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1

该中间体在本合成路线中的序号：(B)

The condensation of alanine tert-butyl ester (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (III), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (IV). The condensation of (IV) with tert-butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (VIII) [prepared from the corresponding acid (VI) and isobutylene (B) by means of H2SO4] as before gives tert-butyl-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (IX), which is finally hydrolyzed partially by treatment with trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Hoefle, M.L.; Klutchko, S. (Pfizer Inc.); Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. DD 201787; EP 0049605; EP 0096157; US 4344949 .
【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; CI-906. Drugs Fut 1983, 8, 12, 1014.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(I) 29385 tert-butyl (2S)-2-aminopropanoate C7H15NO2 详情 详情
(II) 20810 ethyl 2-bromo-4-phenylbutanoate C12H15BrO2 详情 详情
(III) 31121 ethyl 2-[[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate C19H29NO4 详情 详情
(IV) 31124 (2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid C15H21NO4 详情 详情
(VI) 13953 (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid 74163-81-8 C10H11NO2 详情 详情
(VIII) 31125 tert-butyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate C14H19NO2 详情 详情
(IX) 31126 tert-butyl 2-((2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate C29H38N2O5 详情 详情

合成路线2

该中间体在本合成路线中的序号：

L44 is prepared by alkylating p-cyclohexylphenol (I) with iosobutene using Aberlyst A 15 as a catalyst. The raw mixture (II) is esterified with nicotinoyl chloride hydrochloride (III). The product is purified by recristallization from ethanol.

参考文献 中间体
合成目标
【1】 Quack, G.; L44/L44-O. Drugs Fut 1987, 12, 4, 349.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(I) 22908 4-cyclohexylphenol 1131-60-8 C12H16O 详情 详情
(II) 22909 2-(tert-butyl)-4-cyclohexylphenol C16H24O 详情 详情
(III) 22910 nicotinoyl chloride 20260-53-1 C6H5Cl2NO 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

Reaction of isobutene (I) and diisopropyl phosphonylmethanol (II) in the presence of IBr as an electrophile afforded the phosphonate (III), which was converted to the desired 9-[2-methyl-2-(phosphonomethoxy)propyl]guanine (2',2'-dimethyl-PMEG).

参考文献 中间体
合成目标
【1】 Hwang, J.-T.; Choi, J.-R.; Novel phosphonate nucleosides as antiviral agents. Drugs Fut 2004, 29, 2, 163.
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) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(II) 63951 diisopropyl hydroxymethylphosphonate C7H17O4P 详情 详情
(III) 63952 diisopropyl (2-iodo-1,1-dimethylethoxy)methylphosphonate C11H24IO4P 详情 详情
(IV) 63953 2-amino-9-chloro-1,9-dihydro-6H-purin-6-one C5H4ClN5O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

A synthesis of L-692429 has been reported: The cyclization of isobutene (I) with chlorosulfonyl isocyanate (II) gives 1-(chlorosulfonyl)-4,4-dimethylazetidin-2-one (III), which is condensed with 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (IV) by means of triethylamine in methanol to yield 3-methyl-3-(methylsulfonamido)-N-[2-oxo-2,3,4,5-tetrahydro-1H-1-benzaze pin-3(R)-yl]butyramide (V). The reaction of (V) with 2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl bromide (VI) by means of NaH in THF/DMF affords protected L-692429, which is finally deprotected by a treatment with 5N HCl.

参考文献 中间体
合成目标
【1】 Bergan, J.J.; Reider, P.J.; McNamara, J.M.; Volante, R.P.; Bhupathy, M.; A convergent synthesis of a novel non-peptidyl growth hormone secretagogue, L-692,429. Tetrahedron Lett 1995, 36, 52, 9445.
【2】 Schoen, W.R.; et al.; A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429). J Med Chem 1994, 37, 7, 897.
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) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(II) 14101 Chlorosulfonyl isocyanate 1189-71-5 CClNO3S 详情 详情
(III) 15928 2,2-dimethyl-4-oxo-1-azetanesulfonyl chloride C5H8ClNO3S 详情 详情
(IV) 15929 (3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C10H12N2O 详情 详情
(V) 15930 3-methyl-3-[(methylsulfonyl)amino]-N-[(3R)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]butanamide C16H23N3O4S 详情 详情
(VI) 15538 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole 124750-51-2 C33H25BrN4 详情 详情
(VII) 15932 3-methyl-3-[(methylsulfonyl)amino]-N-((3R)-2-oxo-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)butanamide C49H47N7O4S 详情 详情

合成路线5

该中间体在本合成路线中的序号：

The treatment of D-leucine (I) with NaNO2, H2SO4 and NaBr gives 2(R)-bromo-5-methylpentanoic acid (II), which is esterified with isobutene and H2SO4 to the corresponding tert-butyl ester (III). The condensation of (III) with dibenzyl malonate (IV) by means of potassium tert-butoxide in DMF yields the malonyl derivative (V), which is treated with trifluoroacetic acid to hydrolyze the tert-butyl ester, and without isolation is condensed with L-phenylalanine methyl amide (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC), affording 4-benzyloxy-3-(benzyloxycarbonyl)-2(R)-isobutylsuccinyl-L-phenylalanine methylamide (VII). The elimination of the benzyl groups of (VII) by hydrogenolysis over Pd/C in ethanol gives the dicarboxylic acid (VIII), which by partial decarboxylation and reaction with aqueous formaldehyde and piperidine yields 4-hydroxy-2(R)-isobutyl-3-methylenesuccinyl-L-phenylalanine methylamide (IX). The addition of thiophene-2-thiol (X) to the double bond of (IX) affords 4-hydroxy-2(R)-isobutyl-3(S)-(2-thienylsulfanylmethyl)succinyl-L-phenylalanine methylamide (XI), which is finally treated with hydroxylamine and hydroxybenzotriazole in dichloromethane/DMF.

参考文献 中间体
合成目标
【1】 Ngo, J.; Graul, A.; Castaner, J.; Batimastat. Drugs Fut 1996, 21, 12, 1215.
【2】 Campion, C.; Davidson, A.H.; Dickens, J.P.; Crimmin, M.J. (British Biotech plc); Hydroxamic acid based collagenase inhibitors. US 5240958; US 5310763; WO 9005719 .
【3】 Beckett, R.P.; Crimmin, M.J.; Galloway, W.A.; Matrix metalloproteinase inhibitors in the treatment of rheumatoid arthritis and cancer. 205th ACS Natl Meet (March 28-April 2, Denver) 1993, Abst MEDI 147.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(I) 16010 D-leucine 328-38-1 C6H13NO2 详情 详情
(II) 16011 (2R)-2-bromo-4-methylpentanoic acid C6H11BrO2 详情 详情
(III) 16012 tert-butyl (2R)-2-bromo-4-methylpentanoate C10H19BrO2 详情 详情
(IV) 16013 dibenzyl malonate 15014-25-2 C17H16O4 详情 详情
(V) 16014 1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate C27H34O6 详情 详情
(VI) 16015 (2S)-2-amino-N-methyl-3-phenylpropanamide C10H14N2O 详情 详情
(VII) 16016 dibenzyl 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonate C33H38N2O6 详情 详情
(VIII) 16017 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonic acid C19H26N2O6 详情 详情
(IX) 16018 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]acrylic acid C19H26N2O4 详情 详情
(X) 16019 2-Thienylhydrosulfide; 2-Thiophenethiol 7774-74-5 C4H4S2 详情 详情
(XI) 16020 (2S,3R)-3-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-5-methyl-2-[(2-thienylsulfanyl)methyl]hexanoic acid C23H30N2O4S2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

Treatment of amino acid (I) with isobutylene (II) and H2SO4 in dioxane afforded tert-butyl ester (III), which was coupled with carboxylic acid (IV) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole (HOBT) to give (V). Removal of the benzyloxycarbonyl protecting group by hydrogenolysis provided amine (VI) which, on reaction with 2-bromotoluenesulfonyl chloride (VII) and pyridine in refluxing ethyl acetate was converted into sulfonamide (VIII). Deprotection of both tert-butyl groups was effected by treatment with trifluoroacetic acid in dichloromethane, to give (IX) as the trifluoroacetate salt. Tritium labeled compound was then obtained by reductive debromination with tritium gas, using Pearlman's catalyst in the presence of triethylamine.

参考文献 中间体
合成目标
【1】 Thorell, J.O.; et al.; Synthesis of a C-11-labelled nitrated 1,4-dihydroquinoxaline-2,3-dione, the NMDA glycine receptor antagonist ACEA 1021 (Licostinel). J Label Compd Radiopharm 1998, 41, 4, 345-353.
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) 18008 (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid 35761-26-3 C11H14N2O4 详情 详情
(II) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(III) 18009 tert-butyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate C15H22N2O4 详情 详情
(IV) 18010 5-[2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl]-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid C20H30N4O5 详情 详情
(V) 18011 tert-butyl 4-[2-[2-([[(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate C35H50N6O8 详情 详情
(VI) 18012 tert-butyl 4-[2-[2-([[(2S)-2-amino-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate C27H44N6O6 详情 详情
(VII) 18013 2-bromo-4-methylbenzenesulfonyl chloride C7H6BrClO2S 详情 详情
(VIII) 18014 tert-butyl 4-[2-[2-([[(2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate C34H49BrN6O8S 详情 详情
(IX) 18015 (2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-[([4-oxo-5-[2-(4-piperidinyl)ethyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl]carbonyl)amino]propionic acid C25H33BrN6O6S 详情 详情

合成路线7

该中间体在本合成路线中的序号：

Intermediate (VI) has been obtained as follows: The condensation of benzyloxycarbonyl-L-isoleucine (IX) with malonic acid monomethyl ester potassium salt (X) by means of carbonyldiimidazole (CDI) and MgCl2 in THF gives the ketoester (XI), which is reduced to the hydroxyester (XII) with NaBH4 in methanol. The methylation of (XII) with methyl iodide and silver oxide in DMF affords the N-methyl methoxyester (XIII). The hydrolysis of (XIII) with NaOH in dioxane/water followed by reesterification with isobutylene gives the tert-butyl ester (XIV), which is deprotected by hydrogenation over Pd/C, yielding the amino acid (XV). The condensation of (XV) with benzyloxycarbonyl-L-valine (XVI) by means of DCC in dichloromethane gives the protected dipeptide (XVII), which is debenzylated as usual, yielding (XVIII). The condensation of (XVIII) with N,N-dimethyl-L-valine (XIX) affords the tripeptide ter-butyl ester (XX). Finally, (XX) is hydrolyzed by treatment with trifluoroacetic acid to the free acid intermediate (VI).

参考文献 中间体
合成目标
【1】 Tsukagoshi, S.; Sakakibara, K.; Gondo, M.; Natsume, T.; Mikami, T.; Kobayashi, M.; Miyazaki, K.; Synthesis and antitumor activity of novel dolastat. Chem Pharm Bull 1995, 43, 10, 1706.
【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404.
【3】 Sakakibara, K.; Gondo, M.; Miyazaki, K. (Teikoku Hormone Manufacturing Co., Ltd.); Novel tetrapeptide derivs.. EP 0598129; JP 1993503479; US 5654399; WO 9303054 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(VI) 23505 (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid C22H43N3O5 详情 详情
(IX) 23508 (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid 3160-59-6 C14H19NO4 详情 详情
(X) 23509 3-methoxy-3-oxopropanoate C4H5O4 详情 详情
(XI) 23510 methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate C17H23NO5 详情 详情
(XII) 23511 methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylheptanoate C17H25NO5 详情 详情
(XIII) 23512 methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate C19H29NO5 详情 详情
(XIV) 23513 tert-butyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate C22H35NO5 详情 详情
(XV) 23514 tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate C14H29NO3 详情 详情
(XVI) 18092 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid C13H17NO4 详情 详情
(XVII) 23516 tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate C27H44N2O6 详情 详情
(XVIII) 23517 tert-butyl (3R,4S,5S)-4-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate C19H38N2O4 详情 详情
(XIX) 23518 (2S)-2-(dimethylamino)-3-methylbutyric acid C7H15NO2 详情 详情
(XX) 23519 tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate C26H51N3O5 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XVI)

The cyclization of D-penicillamine (I) with 1,2-dichloroethane by means of DBU and TMS-Cl in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid (XV), which is treated with isobutylene (XVI) and sulfuric acid in dioxane to yield the corresponding tert-butyl ester (XVII). The sulfonation of (XVII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid tert-butyl ester (XVIII), which is finally treated with HCl in refluxing dioxane to give the previously reported free acid intermediate (XIV). The cyclization of D-penicillamine methyl ester (XIX) with 1,2-dibromoethane by means of DBU in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid methyl ester (XX), which is sulfonated with the sulfonyl chloride (VI) as before, affording 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid methyl ester (XXI). Finally, this compound is hydrolyzed with refluxing aqueous HCl to yield the previously reported intermediate (XIV).

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150.
【2】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 .
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) 12567 (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine 1113-41-3 C5H11NO2S 详情 详情
(VI) 32887 4-(4-pyridinyloxy)benzenesulfonyl chloride C11H8ClNO3S 详情 详情
(XIV) 32894 (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylic acid C18H20N2O5S2 详情 详情
(XV) 32895 (3S)-2,2-dimethyl-3-thiomorpholinecarboxylic acid C7H13NO2S 详情 详情
(XVI) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(XVII) 32896 tert-butyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate C11H21NO2S 详情 详情
(XVIII) 32897 tert-butyl (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylate C22H28N2O5S2 详情 详情
(XIX) 32898 methyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate; methyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate C6H13NO2S 详情 详情
(XX) 32899 methyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate C8H15NO2S 详情 详情
(XXI) 32900 methyl (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylate C19H22N2O5S2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

8-Bromooctanoic acid (I) was treated with 2-methylpropene (II) in the presence of sulfuric acid to afford tert-butyl ester (III). Alkylation of the benzylidene derivative of glycine methyl ester (IV) with bromide (III) using lithium diisopropylamide (LDA) and hexamethylphosphoramide (HMPA) in THF at -78 C, followed by imine hydrolysis with aqueous citric acid provided the racemic aminoester (V). This was condensed with Boc-a-methyl(R)tryptophan (VI) using (benzotriazol-1-yloxy) tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as the coupling reagent, in the presence of diisopropylethylamine (DIEA) to give the protected dipeptide (VII) as a diastereomeric mixture, and further treatment with trifluoroacetic acid in dichloromethane and anisole removed both tert-butyl groups. The resulting linear compound (VIII) was cyclized by treatment with BOP and NaHCO3 in DMF to give (IX), which was then hydrolyzed with NaOH to afford acid (X). Coupling with the dipeptide Asp(OBzl)PheNH2 (XI) yielded (XII), and the obtained benzyl ester was finally deprotected by catalytic hydrogenolysis to provide the target compound, after separation of isomers by semipreparative HPLC.

参考文献 中间体
合成目标
【1】 Blommaert, A.G.S.; et al.; Structure-based design of new constrained cyclic agonists of the cholecystokinin CCK-B receptor. J Med Chem 1997, 40, 5, 647-658.
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) 18016 8-Bromooctanoic acid 17696-11-6 C8H15BrO2 详情 详情
(II) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(III) 18017 tert-butyl 8-bromooctanoate C12H23BrO2 详情 详情
(IV) 18018 methyl 2-[[(E)-benzylidene]amino]acetate C10H11NO2 详情 详情
(V) 18019 10-(tert-butyl) 1-methyl 2-aminodecanedioate C15H29NO4 详情 详情
(VI) 18020 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)-2-methylpropionic acid C17H22N2O4 详情 详情
(VII) 18021 10-(tert-butyl) 1-methyl 2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)-2-methylpropanoyl]amino]decanedioate C32H49N3O7 详情 详情
(VIII) 18022 9-[[(2R)-2-amino-3-(1H-indol-3-yl)-2-methylpropanoyl]amino]-10-methoxy-10-oxodecanoic acid C23H33N3O5 详情 详情
(IX) 18023 methyl (2R)-2-(1H-indol-3-ylmethyl)-2-methyl-3,13-dioxo-1,4-diazacyclotridecane-5-carboxylate C23H31N3O4 详情 详情
(X) 18024 (2R)-2-(1H-indol-3-ylmethyl)-2-methyl-3,13-dioxo-1,4-diazacyclotridecane-5-carboxylic acid C22H29N3O4 详情 详情
(XI) 18025 benzyl (3S)-3-amino-4-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-4-oxobutanoate C20H23N3O4 详情 详情
(XII) 18026 benzyl (3S)-4-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-3-([[(2R)-2-(1H-indol-3-ylmethyl)-2-methyl-3,13-dioxo-1,4-diazacyclotridecan-5-yl]carbonyl]amino)-4-oxobutanoate C42H50N6O7 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IX)

Conversion of amino acid (I) into its methyl ester derivative (II) by means of SOCl2 in MeOH, followed by coupling with ethyl isocyanatoacetate (III) and Et3N in CH2Cl2/THF yields derivative (IV). Cyclization of (IV) by means of H2O/HCl affords hydantoin (V), which reacts with 2-methylthio-2-imidazoline (VI) in an aqueous NaOH solution to provide cyclic guanidine derivative (VII). Treatment of amino acid (VIII) with isobutylene (IX) and H2SO4 in dioxane affords t-Bu ester (X), which then couples with (VII) by means of HOBt and DCC in DMF to furnish derivative (XI). Finally, tert-butyl ester is hydrolyzed by treatment with TFA in the presence of 1,2-dimercaptoethane.

参考文献 中间体
合成目标
【1】 Knolle, J.; Peyman, A.; Wehner, V.; et al.; RGD mimetics containing a central hydantoin scaffold: alphavbeta3 vs alphaIIbbeta3 selective requirements. Bioorg Med Chem Lett 2000, 10, 2, 179.
【2】 Wehner, V.; Knolle, J.; Stilz, H.U.; Carniato, D.; Gourvest, J.-F.; Gadek, T.; McDowell, R. (Aventis SA); Inhibitors of bone resorption and vitronectin receptor antagonists. DE 19626701; DE 19635522; EP 0796855 .
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) 30898 (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoic acid C13H18N2O4 详情 详情
(II) 42993 methyl (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoate C14H20N2O4 详情 详情
(III) 18312 ETHYL ISOCYANATOACETATE; ethyl 2-isocyanatoacetate 2949-22-6 C5H7NO3 详情 详情
(IV) 42994 12-ethyl 8-methyl (8S)-3,10-dioxo-1-phenyl-2-oxa-4,9,11-triazadodecane-8,12-dicarboxylate C19H27N3O7 详情 详情
(V) 42295 (2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]propanamide C25H32N4O2S 详情 详情
(VI) 42996 4,5-dihydro-1H-imidazol-2-yl methyl sulfide; 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole 5464-11-9 C4H8N2S 详情 详情
(VII) 42997 2-[(4S)-4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-2,5-dioxoimidazolidinyl]acetic acid C11H17N5O4 详情 详情
(VIII) 18008 (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid 35761-26-3 C11H14N2O4 详情 详情
(IX) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(X) 18009 tert-butyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate C15H22N2O4 详情 详情
(XI) 42998 tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-[(4S)-4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-2,5-dioxoimidazolidinyl]acetyl)amino]propanoate C26H37N7O7 详情 详情

合成路线11

该中间体在本合成路线中的序号：(D)

2) 7-ADCA (XVIII) is reacted with isobutylene and concentrated H2SO4 in DME to afford the corresponding tert-butyl ester (XIX), which on oxidation with Na2WO4 in presence of H2O2 gives the sulfone (XX). The sulfone (XX) on treatment with NaNO2 and 2.5 (N) H2SO4 in the presence of MeOH gives the 7alpha-methoxy cephem intermediate (XXI). Heating of compound (XXI) with dimethylamine hydrochloride and formaldehyde in a mixture of DMF and dioxane gives the 2-exomethylene cephem intermediate (XXII). Cycloaddition of (XXII) with diazo cyclopentane generated in situ by treatment of cyclopentyl hydrazone with silver (I) oxide, gives 7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl cephem derivative (XXIII). Deprotection of the tert-butyl ester group with formic acid gives the free acid (X). From the intermediate acid (X), the target molecule Syn-1390 and its corresponding sodium salt can be prepared, as described in Scheme 26506201a.

参考文献 中间体
合成目标
【1】 Maiti, S.N.; Woods, D.E.; Cantin, A.M.; 2-Spirocyclopropyl cephem sulfones: Human neutrophil elastase inhibitors Syn-1390 and Syn-1396. Drugs Fut 1998, 23, 6, 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
(D) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(B) 25055 cyclopentanone hydrazone C5H10N2 详情 详情
(X) 27617 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid S,S-dioxide C15H19NO6S 详情 详情
(XI) 27618 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carbonyl chloride S,S-dioxide C15H18ClNO5S 详情 详情
(XII) 27619 2-[4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazin-1-yl]acetic acid tert-butyl ester S,S-dioxide C25H37N3O7S 详情 详情
(XIII) 27620 2-[4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazin-1-yl]acetic acid S,S-dioxide C21H29N3O7S 详情 详情
(XVIII) 27626 (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C8H10N2O3S 详情 详情
(XIX) 27621 tert-butyl (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C12H18N2O3S 详情 详情
(XX) 27622 tert-butyl (7R)-7-amino-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C12H18N2O5S 详情 详情
(XXI) 27623 tert-butyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C13H19NO6S 详情 详情
(XXII) 27624 tert-butyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H19NO6S 详情 详情
(XXIII) 27625 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid tert-butyl ester S,S-dioxide C19H27NO6S 详情 详情
(C) 25056 tert-butyl 2-(1-piperazinyl)acetate C10H20N2O2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(D)

2) 7-ADCA (XVIII) is reacted with isobutylene and concentrated H2SO4 in DME to afford the corresponding tert-butyl ester (XIX), which on oxidation with Na2WO4 in presence of H2O2 gives the sulfone (XX). The sulfone (XX) on treatment with NaNO2 and 2.5 (N) H2SO4 in the presence of MeOH gives the 7alpha-methoxy cephem intermediate (XXI). Heating of compound (XXI) with dimethylamine hydrochloride and formaldehyde in a mixture of DMF and dioxane gives the 2-exomethylene cephem intermediate (XXII). Cycloaddition of (XXII) with diazo cyclopentane generated in situ by treatment of cyclopentyl hydrazone with silver (I) oxide, gives 7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl cephem derivative (XXIII). Deprotection of the tert-butyl ester group with formic acid gives the free acid (X). From the intermediate acid (X), the target molecule Syn-1396 and its corresponding sodium salt can be prepared, as described in Scheme 26506301a.

参考文献 中间体
合成目标
【1】 Maiti, S.N.; Woods, D.E.; Cantin, A.M.; 2-Spirocyclopropyl cephem sulfones: Human neutrophil elastase inhibitors Syn-1390 and Syn-1396. Drugs Fut 1998, 23, 6, 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
13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情
(D) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(B) 25055 cyclopentanone hydrazone C5H10N2 详情 详情
(X) 27617 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid S,S-dioxide C15H19NO6S 详情 详情
(XV) 27627 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid tert-butyl ester S,S-dioxide C24H35N3O7S 详情 详情
(XVI) 27628 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid S,S-dioxide C20H27N3O7S 详情 详情
(XVIII) 27626 (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C8H10N2O3S 详情 详情
(XIX) 27621 tert-butyl (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C12H18N2O3S 详情 详情
(XX) 27622 tert-butyl (7R)-7-amino-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C12H18N2O5S 详情 详情
(XXI) 27623 tert-butyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C13H19NO6S 详情 详情
(XXII) 27624 tert-butyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H19NO6S 详情 详情
(XXIII) 27625 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid tert-butyl ester S,S-dioxide C19H27NO6S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

The reaction of testosterone (I) with isobutylene (II) in dichloromethane catalyzed by trifluoromethanesulfonic acid gives the tert-butyl ether (III), which is ozonolyzed with O3 and H2O2 in AcOH/ethyl acetate to yield the seco-steroid (IV). The cyclization of (IV) by means of acetic anhydride and potassium acetate at 135 C affords the 4-oxa steroid (V), which is methylated with 14C-labeled methylmagnesium iodide in ether to provide the intermediate (VI). The rearrangement of (VI) by means of NaOH in ethanol gives the labeled testosterone tert-butyl ether (VII), which is deprotected by means of 6N HCl in refluxing ethanol to yield the labeled testosterone (VIII). The reduction of the double bond of (VIII) with Li in liquid ammonia affords the dihydro compound (IX), which is oxidized with Jones oxidant in acetone to provide the labeled androstane-3.17-dione (X). The selective reduction of the 3-oxo group of (X) by means of tri-tert-butoxy lithium aluminum hydride in hot THF gives the labeled 3-beta-hydroxyandrostan-17-one (XI), which is brominated with CuBr2 in refluxing methanol to yield the target alpha-bromo derivative, along with some beta-isomer that is separated by column chromatography

参考文献 中间体
合成目标
【1】 Han, M.C.; Hayes B.A.; Prendergast, P.T.; Gupta, S.; Inhibition of HIV replication: Synthesis of [4-14C]-5alpha-androstan-16alpha-bromo-3 beta-ol-17-one. J Label Compd Radiopharm 2000, 43, 12, 1149.
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) 54210 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon 58-22-0 C19H28O2 详情 详情
(II) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(III) 62424 (10R,13S,17S)-17-(tert-butoxy)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one C23H36O2 详情 详情
(IV) 62425 3-[(3S,3aS,6R)-3-(tert-butoxy)-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propanoic acid C22H36O4 详情 详情
(V) 62426 (4aR,6aS,7S)-7-(tert-butoxy)-4a,6a-dimethyl-4,4a,4b,5,6,6a,7,8,9,9a,9b,10-dodecahydroindeno[5,4-f]chromen-2(3H)-one C22H34O3 详情 详情
(VI) 62427 (1R,5S,6S)-6-(tert-butoxy)-13-hydroxy-1,5,13-trimethyltetracyclo[10.3.1.0~2,10~.0~5,9~]hexadecan-16-one C23H38O3 详情 详情
(VII) 62424 (10R,13S,17S)-17-(tert-butoxy)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one C23H36O2 详情 详情
(VIII) 54210 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon 58-22-0 C19H28O2 详情 详情
(IX) 62428 (5S,10S,13S,17S)-17-hydroxy-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one C19H30O2 详情 详情
(X) 62429 (5S,10S,13S)-10,13-dimethyldodecahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,4H)-dione C19H28O2 详情 详情
(XI) 62430 (3S,5S,10S,13S)-3-hydroxy-10,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one C19H30O2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VII)

By condensation of N-(perhydroazepin-1-ylcarbonyl)-L-leucine (V) with 4-O-benzyl-L-tyrosine tert-butyl ester (VIII) by means of HOBT and diisopropylethylamine in DMF. The two peptide intermediates (V) and (VIII) have been obtaines a follows: L-Leucine fragment (V): The carbonatation of perhydroazepine (I) with CO2 and pyridine followed by reaction with SOCl2 gives perhydroazepin-1-ylcarbonyl chloride (II), which is condensed with L-leucine benzyl ester (III) yielding the N-acylated leucine ester (IV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in THF to afford the target intermediate (V). Tyrosine fragment (VIII): By esterification of 4-O-benzyl-L-tyrosine (VI) with isobutylene (VII) by means of sulfuric acid in dioxane.

参考文献 中间体
合成目标
【1】 Malone, T.; et al.; Identification and SAR studies of PD 151307, a novel N-type calcium channel blocker. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 122.
【2】 Roth, B.D.; Connor, D.T.; Malone, T.C.; Hamilton, H.W.; Rafferty, M.F.; Hu, L.-Y.; Cody, W.L.; He, J.X.; Nadasdi, L.; Brogley, L.; Urge, L.; Silva, D.F.; Song, Y.; Szoke, B.G.; Booth, R.J.; Lescosky, J. (Neurex Corp.; Pfizer Inc.); Peptidyl calcium channel blockers. US 6423689 .
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) 18672 azepane 111-49-9 C6H13N 详情 详情
(II) 26713 1-azepanecarbonyl chloride C7H12ClNO 详情 详情
(III) 22252 Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate C13H19NO2 详情 详情
(IV) 26714 benzyl (2S)-2-[(1-azepanylcarbonyl)amino]-4-methylpentanoate C20H30N2O3 详情 详情
(V) 26715 (2S)-2-[(1-azepanylcarbonyl)amino]-4-methylpentanoic acid C13H24N2O3 详情 详情
(VI) 26716 (2S)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid 16652-64-5 C16H17NO3 详情 详情
(VII) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(VIII) 26717 tert-butyl (2S)-2-amino-3-[4-(benzyloxy)phenyl]propanoate C20H25NO3 详情 详情

合成路线15

该中间体在本合成路线中的序号：(B)

Coupling Method 1. Treatment of L-Arginine (XIII) with K2CO3 and assembling to intermediate (VII) affords derivative (XIV). After protection of the piperidine derivative (XV) as its tert-butyl ether (XVI) by means of isobutylene (B) in acidic media, (XVI) is condensed with (XIV) in the presence of Et3N to yield (XVII). Finally, elimination of the protecting groups with TFA, HBr gas or HCl in AcOH affords the desired product. 2. Alternatively, the coupling can be performed by reaction of nitro-protected L-arginine (XVIII) with isobutyl chloroformate in DMF in the presence of NMM, followed by reaction with protected piperidine derivative (XVI) to yield (XIX). Removal of the Boc group with HCl in AcOH or in dichloromethane/AcOH (2:1) and assembling to sulfonyl chloride intermediate (VII) with DIEA in DMF yields protected derivative (XX). Reductive cleavage of the nitro protecting group of (XX) with Pd/C, H2 in MeOH/AcOH/H2O (15:0.1:1), followed by elimination of the t-Bu protecting group in the conditions described above, yields the desired product.

参考文献 中间体
合成目标
【1】 Donovan, V.; Brundish, D.; Bull, A.; et al.; Design and synthesis of thrombin inhibitors: Analogues of MD-805 with reduced stereogenicity and improved potency. J Med Chem 1999, 42, 22, 4584.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 15926 2-methyl-1-propene; isobutylene 115-11-7 C4H8 详情 详情
(VII) 43006 6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride C11H13Cl2NO2S 详情 详情
(XIII) 22853 Arginine; 2-Amino-5-guanidinopentanoic acid C6H14N4O2 详情 详情
(XIV) 43011 N(5)-[amino(imino)methyl]-N(2)-[(3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]ornithine C17H27N5O4S 详情 详情
(XV) 43012 2-(4-piperidinyl)-1-ethanol 622-26-4 C7H15NO 详情 详情
(XVI) 43013 4-[2-(tert-butoxy)ethyl]piperidine; tert-butyl 2-(4-piperidinyl)ethyl ether C11H23NO 详情 详情
(XVII) 43014 N-[4-[[amino(imino)methyl]amino]-1-([4-[2-(tert-butoxy)ethyl]-1-piperidinyl]carbonyl)butyl]-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonamide C28H48N6O4S 详情 详情
(XVIII) 43017 　 C11H21N5O6 详情 详情
(XIX) 43015 　 C22H42N6O6 详情 详情
(XX) 43016 　 C28H47N7O6S 详情 详情
Extended Information