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【结 构 式】 
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【分子编号】27989 【品名】2-naphthalenesulfonyl chloride 【CA登记号】93-11-8 |
【 分 子 式 】C10H7ClO2S 【 分 子 量 】226.68308 【元素组成】C 52.99% H 3.11% Cl 15.64% O 14.12% S 14.15% |
合成路线1
该中间体在本合成路线中的序号：(VI)AY-31,637 may be synthesized by either of two routes: 1) Dilithiation of 2,4-thiazolidinedione (I) with two equivalents of n-butyllithium, followed by sulfonylation with 2-naphthylsulfonyl chloride (VI). 2) Coupling of 2-mercaptonaphthalene (III) and 5-bromo-2,4-thiazolidinedione (II) by the addition of two equivalents of lithium diisopropylamide gives 5-(2-naphthylthio)-2,4-thiazolidinedione (IV). Oxidation of this compound with excess hydrogen peroxide in acetic acid at 60 C gives the corresponding sulfone, AY-31,637.
| 【1】 Zask, A.; Jirkovsky, I. (American Home Products Corp.); 5-[(1- and 2-Naphthalenyl)sulfonyl]-2,4-thiazolidinediones and derivs. Thereof. US 4997948 . |
| 【2】 McCaleb, M.L.; Jirkovsky, I.; Zask, A.; Nowicki, J.W.; Synthesis and antihyperglycemic activity of 5-(naphthalenylsulfonyl)-2,4-thiazolidinediones. J Med Chem 1990, 33, 5, 1418-23. |
| 【3】 Zask, A.; McCaleb, M.L.; AY-31,637. Drugs Fut 1991, 16, 6, 505. |
| 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) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (II) | 13875 | 5-Bromo-1,3-thiazolidine-2,4-dione | C3H2BrNO2S | 详情 | 详情 | |
| (III) | 15234 | 2-Naphthalenethiol; 2-Naphthylhydrosulfide | 91-60-1 | C10H8S | 详情 | 详情 |
| (IV) | 13876 | 5-(2-Naphthylsulfanyl)-1,3-thiazolidine-2,4-dione | C13H9NO2S2 | 详情 | 详情 | |
| (V) | 13877 | 3,5-Dilithiothiazolidine-2,4-dione | C3HLi2NO2S | 详情 | 详情 | |
| (VI) | 27989 | 2-naphthalenesulfonyl chloride | 93-11-8 | C10H7ClO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The reaction of 4-chlorothieno[3,2-c]pyridine (I) with KOH in phenol at 140 C followed by ammonium acetate at 155 C gives thieno[3,2-c]pyridine-4-amine (II), which is benzoylated with benzoyl anhydride in pyridine yielding the benzamide (III). The formylation of (III) with DMF and LDA, followed by reduction with NaBH4 in methanol/THF affords the hydroxymethyl compound (IV), which is converted into the mesylate (V) with MsCl and TEA in dichloromethane. The reaction of (V) with LiCl in THF provides the chloromethyl compound (VI), which is condensed with the protected aminomalonate (VII) by means of sodium ethoxide in ethanol/dioxane to give the adduct (VIII). The selective decarboxylation and deprotection of (VIII) with HCl in hot acetic acid yields the amino acid (IX), which is esterified with SOCl2 and methyl to the corresponding methyl ester (X). The condensation of (X) with naphthalen-2-ylsulfonyl chloride (XI) by means of TEA in dichloromethane affords the sulfonamide (XII), which is finally condensed with 4-methylpiperidine (XIII) by means of NaOH and TBTU in DMF. Alternatively, the protection of the amino acid (IX) with Boc2O and TEA in methanol gives the carbamate (XIV), which is condensed with 4-methylpiperidine (XIII) by means of NaOH and TBTU in DMF yielding the piperidide (XV). Finally, this compound is deprotected with TFA and condensed with sulfonyl chloride (XI) and TEA to afford the target compound.
| 【1】 Rewinkel, J.B.M.; et al.; Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors. Bioorg Med Chem Lett 1999, 9, 19, 2837. |
| 【2】 Van Galen, P.J.M.; Rewinkel, J.B.M.; Van Boeckel, C.A.A. (Akzo Nobel N.V.); Heterocyclic derivs. and their use as antithrombotic agents. EP 0975600; WO 9847876 . |
| 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) | 38321 | 4-chlorothieno[3,2-c]pyridine | C7H4ClNS | 详情 | 详情 | |
| (II) | 38322 | thieno[3,2-c]pyridin-4-amine; thieno[3,2-c]pyridin-4-ylamine | C7H6N2S | 详情 | 详情 | |
| (III) | 38323 | N-thieno[3,2-c]pyridin-4-ylbenzamide | C14H10N2OS | 详情 | 详情 | |
| (IV) | 38324 | N-[2-(hydroxymethyl)thieno[3,2-c]pyridin-4-yl]benzamide | C15H12N2O2S | 详情 | 详情 | |
| (V) | 38325 | N-[2-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)thieno[3,2-c]pyridin-4-yl]benzamide | C18H18N2O2S2 | 详情 | 详情 | |
| (VI) | 38326 | N-[2-(chloromethyl)thieno[3,2-c]pyridin-4-yl]benzamide | C15H11ClN2OS | 详情 | 详情 | |
| (VII) | 30060 | diethyl 2-[(tert-butoxycarbonyl)amino]malonate | C12H21NO6 | 详情 | 详情 | |
| (VIII) | 38327 | diethyl 2-[[4-(benzoylamino)thieno[3,2-c]pyridin-2-yl]methyl]-2-[(tert-butoxycarbonyl)amino]malonate | C27H31N3O7S | 详情 | 详情 | |
| (IX) | 38328 | 3-(4-aminothieno[3,2-c]pyridin-2-yl)alanine | C10H11N3O2S | 详情 | 详情 | |
| (X) | 38329 | methyl 2-amino-3-(4-aminothieno[3,2-c]pyridin-2-yl)propanoate | C11H13N3O2S | 详情 | 详情 | |
| (XI) | 27989 | 2-naphthalenesulfonyl chloride | 93-11-8 | C10H7ClO2S | 详情 | 详情 |
| (XII) | 38330 | methyl 3-(4-aminothieno[3,2-c]pyridin-2-yl)-2-[(2-naphthylsulfonyl)amino]propanoate | C21H19N3O4S2 | 详情 | 详情 | |
| (XIII) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (XIV) | 38331 | 3-(4-aminothieno[3,2-c]pyridin-2-yl)-N-(tert-butoxycarbonyl)alanine | C15H19N3O4S | 详情 | 详情 | |
| (XV) | 38332 | tert-butyl 1-[(4-aminothieno[3,2-c]pyridin-2-yl)methyl]-2-(4-methyl-1-piperidinyl)-2-oxoethylcarbamate | C21H30N4O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Lithiation of 1-(N-N-dimethylsulfamoyl)imidazole (I) followed by reaction with tert-butyldimethylsilyl chloride produced the 2-silyl protected imidazole (II). Further lithiation of (II) allowed the introduction of a bromohexyl group at position 5 upon treatment with 1,6-dibromohexane yielding (III). Bromide (III) was subsequently converted into primary amine (VI) through a Gabriel synthesis involving condensation with potassium phthalimide (IV) with concomitant desilylation, and then hydrazinolysis of the resulting alkylated phthalimide (V). Condensation of amine (VI) with naphthalene-2-sulfonyl chloride (VII) furnished sulfonamide (VIII). The sulfamoyl protecting group of (VIII) was finally removed by hydrolysis with HCl.
| 【1】 Tozer, M.J.; Kalindjian, B.; Pether, M.J.; Watt, G.F.; Shankley, N.P.; Harper, E.A.; From histamine to imidazolylalkyl-sulfonamides: The design of a novel series of histamine H3-receptor antagonists. Bioorg Med Chem Lett 1999, 9, 13, 1825. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 | |
| (I) | 11036 | N,N-Dimethyl-1H-imidazole-1-sulfonamide | 78162-58-0 | C5H9N3O2S | 详情 | 详情 |
| (II) | 11037 | 2-[tert-Butyl(dimethyl)silyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide | C11H23N3O2SSi | 详情 | 详情 | |
| (III) | 27986 | 5-(6-bromohexyl)-2-[tert-butyl(dimethyl)silyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide | C17H34BrN3O2SSi | 详情 | 详情 | |
| (IV) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (V) | 27987 | 5-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hexyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide | C19H24N4O4S | 详情 | 详情 | |
| (VI) | 27988 | 5-(6-aminohexyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide | C11H22N4O2S | 详情 | 详情 | |
| (VII) | 27989 | 2-naphthalenesulfonyl chloride | 93-11-8 | C10H7ClO2S | 详情 | 详情 |
| (VIII) | 27990 | N,N-dimethyl-5-[6-[(2-naphthylsulfonyl)amino]hexyl]-1H-imidazole-1-sulfonamide | C21H28N4O4S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Condensation of S-(4-monomethoxytrityl)-L-cysteine (I) with 2-naphthalenesulfonyl chloride (II) under Schotten-Baumann conditions afforded sulfonamide (III). Cleavage of the trityl group of (III) by treatment with trifluoroacetic acid and triisopropylsilane gave thiol (IV), which was protected as the thiopyridyl derivative (V) using dithiodipyridine. Coupling of (V) with 4-amidinophenylalanyl piperidine (VI) by means of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide - HCl (EDC), 1-hydroxybenzotriazole (HOBt) and N-ethylmorpholine (NEM) furnished dipeptide (VII). The thiopyridyl group of (VII) was then deprotected by treatment with tributyl phosphine to afford thiol (VIII).
| 【1】 Buijsman, R.C.; van Boeckel, C.A.A.; van der Marel, G.A.; Basten, J.E.M.; van Dinther, T.G.; van Boom, J.H.; Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg Med Chem Lett 1999, 9, 14, 2013. |
| 【2】 Van Boeckel, C.A.A.; Basten, J.E.M.; Dreef-Tromp, C.M.; Buijsman, R.C. (Akzo Nobel N.V.; Universiteit Leiden); Antithrombotic cpds.. WO 9965934 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 22457 | 2,2'-Dithiodipyridine; 2-(2-pyridinyldisulfanyl)pyridine; 2,2'-Dipyridinyl disulfide | 2127-03-9 | C10H8N2S2 | 详情 | 详情 |
| (I) | 37316 | (2R)-2-amino-3-[[(4-methoxyphenyl)(diphenyl)methyl]sulfanyl]propionic acid | C23H23NO3S | 详情 | 详情 | |
| (II) | 27989 | 2-naphthalenesulfonyl chloride | 93-11-8 | C10H7ClO2S | 详情 | 详情 |
| (III) | 37317 | (2R)-3-[[(4-methoxyphenyl)(diphenyl)methyl]sulfanyl]-2-[(2-naphthylsulfonyl)amino]propionic acid | C33H29NO5S2 | 详情 | 详情 | |
| (IV) | 37318 | (2R)-2-[(2-naphthylsulfonyl)amino]-3-sulfanylpropionic acid | C13H13NO4S2 | 详情 | 详情 | |
| (V) | 37319 | (2R)-2-[(2-naphthylsulfonyl)amino]-3-(2-pyridinyldisulfanyl)propionic acid | C18H16N2O4S3 | 详情 | 详情 | |
| (VI) | 37320 | 4-[2-amino-3-oxo-3-(1-piperidinyl)propyl]benzenecarboximidamide | C15H22N4O | 详情 | 详情 | |
| (VII) | 37321 | (2R)-N-[1-[4-[amino(imino)methyl]benzyl]-2-oxo-2-(1-piperidinyl)ethyl]-2-[(2-naphthylsulfonyl)amino]-3-(2-pyridinyldisulfanyl)propanamide | C33H36N6O4S3 | 详情 | 详情 | |
| (VIII) | 37322 | (2R)-N-[1-[4-[amino(imino)methyl]benzyl]-2-oxo-2-(1-piperidinyl)ethyl]-2-[(2-naphthylsulfonyl)amino]-3-sulfanylpropanamide | C28H33N5O4S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)After activation of acid (IX) as the mixed anhydride with isobutyl chloroformate, coupling with the mono-protected diaminopropionate (X) leads to amide (XI). Subsequent removal of the N-carbobenzoxy group by catalytic hydrogenolysis gives amino ester (XII). This is then acylated by 2-naphthalenesulfonyl chloride (XIII), yielding sulfonamide (XIV).
| 【1】 Lesur, B.; Henry, M.; Yue, C.; Giboulot, T. (Laboratoires L. Lafon); Bispiperidines as antithrombotic agents. EP 1098878; FR 2781223; JP 2002520393; US 6333338; WO 0003986 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 63026 | 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoyl)amino]acetic acid | C28H49N3O7 | 详情 | 详情 | |
| (X) | 26615 | ethyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C13H18N2O4 | 详情 | 详情 | |
| (XI) | 63027 | tert-butyl 4-[(10S)-3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}-10-(ethoxycarbonyl)-4,7,12-trioxo-14-phenyl-13-oxa-5,8,11-triazatetradec-1-yl]-1-piperidinecarboxylate | C41H65N5O10 | 详情 | 详情 | |
| (XII) | 63028 | tert-butyl 4-{3-{[(2-{[(2S)-2-amino-3-ethoxy-3-oxopropyl]amino}-2-oxoethyl)amino]carbonyl}-5-[1-(tert-butoxycarbonyl)-4-piperidinyl]pentyl}-1-piperidinecarboxylate | C33H59N5O8 | 详情 | 详情 | |
| (XIII) | 27989 | 2-naphthalenesulfonyl chloride | 93-11-8 | C10H7ClO2S | 详情 | 详情 |
| (XIV) | 63029 | tert-butyl 4-[5-[1-(tert-butoxycarbonyl)-4-piperidinyl]-3-({[2-({(2S)-3-ethoxy-2-[(2-naphthylsulfonyl)amino]-3-oxopropyl}amino)-2-oxoethyl]amino}carbonyl)pentyl]-1-piperidinecarboxylate | C43H65N5O10S | 详情 | 详情 |