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【结 构 式】 
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【分子编号】31666 【品名】7-methoxy-2-naphthalenesulfonyl chloride 【CA登记号】 |
【 分 子 式 】C11H9ClO3S 【 分 子 量 】256.70936 【元素组成】C 51.47% H 3.53% Cl 13.81% O 18.7% S 12.49% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reduction of 5-bromothiophene-3-carbaldehyde (I) with NaBH4 in THF gives the corresponding carbinol (II), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to yield 4-(hydroxymethyl)thiophene-2-carbonitrile (III). The reaction of (III) with tetrabromomethane and triphenylphosphine affords the corresponding bromomethyl derivative (IV), which is condensed with 3(S)-(tert-butoxycarbonylamino)pyrrolidin-2-one (V) by means of NaH in THF/DMF to give the expected addition product (VI). The deprotection of the amino group of (VI) with HCl in ethyl acetate yields the primary amine (VII), which is acylated with 7-methoxynaphthalene-2-sulfonyl chloride (VIII) and triethylamine in dichloromethane providing the sulfonamide (IX). The methylation of (IX) with methyl iodide and K2CO3 in DMF affords the N-methylsulfonamide (X), which is finally treated first with HCl in ethanol, and then with NH3 in methanol to convert the cyano group of (X) into the amidino group of the target compound.
| 【1】 Ewing, W.R.; Manetta, V.E.; Becker, M.R.; et al.; Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa. J Med Chem 1999, 42, 18, 3557. |
| 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) | 31660 | 5-bromo-3-thiophenecarbaldehyde | C5H3BrOS | 详情 | 详情 | |
| (II) | 31661 | (5-bromo-3-thienyl)methanol | C5H5BrOS | 详情 | 详情 | |
| (III) | 31662 | 4-(hydroxymethyl)-2-thiophenecarbonitrile | C6H5NOS | 详情 | 详情 | |
| (IV) | 31663 | 4-(bromomethyl)-2-thiophenecarbonitrile | C6H4BrNS | 详情 | 详情 | |
| (V) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (VI) | 31664 | tert-butyl (3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinylcarbamate | C15H19N3O3S | 详情 | 详情 | |
| (VII) | 31665 | 4-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-2-thiophenecarbonitrile | C10H11N3OS | 详情 | 详情 | |
| (VIII) | 31666 | 7-methoxy-2-naphthalenesulfonyl chloride | C11H9ClO3S | 详情 | 详情 | |
| (IX) | 31667 | N-[(3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinyl]-7-methoxy-2-naphthalenesulfonamide | C21H19N3O4S2 | 详情 | 详情 | |
| (X) | 31668 | N-[(3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinyl]-7-methoxy-N-methyl-2-naphthalenesulfonamide | C22H21N3O4S2 | 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 7-methoxynaphthalen-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) | 31666 | 7-methoxy-2-naphthalenesulfonyl chloride | C11H9ClO3S | 详情 | 详情 | |
| (XII) | 38333 | methyl 3-(4-aminothieno[3,2-c]pyridin-2-yl)-2-[[(7-methoxy-2-naphthyl)sulfonyl]amino]propanoate | C22H21N3O5S2 | 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 |