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【结 构 式】 
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【药物名称】NNC-55-0118 【化学名称】6-Chloro-N-isopropyl-4H-thieno[3,2-e][1,2,4]thiadiazin-3- amine 1,1-dioxide 【CA登记号】 【 分 子 式 】C8H10ClN3O2S2 【 分 子 量 】279.7688 |
【开发单位】Novo Nordisk 【药理作用】ENDOCRINE DRUGS, ANTIDIABETIC DRUGS |
合成路线1
The title compound can be obtained by several synthetic procedures. Esterification of the thiophenecarboxylic acid (I) with simultaneous N-t-butyl group cleavage in ethanolic HCl affords (II). Ethyl ester (II) is then converted to hydrazide (III) with hydrazine hydrate. Reaction of (III) with NaNO2/HCl leads to the acyl azide (IV), which is subsequently subjected to Curtius rearrangement in boiling toluene to produce the thienothiadiazine derivative (V). Condensation of (V) with isopropylamine (VII) by heating with P2O5 furnishes the target compound in low yield. In an improved method, chlorination of (V) in the presence of POCl3 leads to (VI), which is further reacted with isopropylamine (VII) to afford the title compound
| 【1】 Nielsen, F.E.; Bodvarsdottir, T.B.; Worsaae, A.; et al.; 6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives potently and selectively activate ATP sensitive potassium channels of pancreatic beta-cells. J. Med. Chem. 2002, 45, 19, 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) | 61482 | 2-[(tert-butylamino)sulfonyl]-5-chloro-3-thiophenecarboxylic acid | C9H12ClNO4S2 | 详情 | 详情 | |
| (II) | 61483 | ethyl 2-(aminosulfonyl)-5-chloro-3-thiophenecarboxylate | C7H8ClNO4S2 | 详情 | 详情 | |
| (III) | 61484 | 5-chloro-3-(hydrazinocarbonyl)-2-thiophenesulfonamide | C5H6ClN3O3S2 | 详情 | 详情 | |
| (IV) | 61485 | 2-(aminosulfonyl)-5-chloro-3-thiophenecarbonyl azide | C5H3ClN4O3S2 | 详情 | 详情 | |
| (V) | 61486 | 6-chloro-1lambda~6~-thieno[3,2-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione | C5H3ClN2O3S2 | 详情 | 详情 | |
| (VI) | 56052 | 3,6-dichloro-1lambda~6~-thieno[3,2-e][1,2,4]thiadiazine-1,1(4H)-dione | C5H2Cl2N2O2S2 | 详情 | 详情 | |
| (VII) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线2
In an alternative procedure, metalation of thiophenesulfonamide (I) with butyllithium, followed by quenching with p-toluenesulfonyl azide affords azide (II), which is further reduced to amine (III) with NaBH4 in the presence of a quaternary phosphonium salt. The N-t-butyl group of (III) is then cleaved with fuming HCl to afford (IV). Condensation of sulfonamide (IV) with isopropyl isothiocyanate furnishes the sulfonyl thiourea (V). This is finally cyclized to the desired thienothiadiazine by treatment with phosgene in the presence of triethylamine
| 【1】 Nielsen, F.E.; Bodvarsdottir, T.B.; Worsaae, A.; et al.; 6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives potently and selectively activate ATP sensitive potassium channels of pancreatic beta-cells. J. Med. Chem. 2002, 45, 19, 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) | 61487 | N-(tert-butyl)-5-chloro-2-thiophenesulfonamide | C8H12ClNO2S2 | 详情 | 详情 | |
| (II) | 61488 | 3-azido-N-(tert-butyl)-5-chloro-2-thiophenesulfonamide | C8H11ClN4O2S2 | 详情 | 详情 | |
| (III) | 61489 | 3-amino-N-(tert-butyl)-5-chloro-2-thiophenesulfonamide | C8H13ClN2O2S2 | 详情 | 详情 | |
| (IV) | 61490 | 3-amino-5-chloro-2-thiophenesulfonamide | C4H5ClN2O2S2 | 详情 | 详情 | |
| (V) | 61491 | 3-amino-5-chloro-2-({[(isopropylamino)carbothioyl]amino}sulfonyl)thiophene | C8H12ClN3O2S3 | 详情 | 详情 |
合成路线3
In an alternative procedure, metalation of thiophenesulfonamide (I) with butyllithium, followed by quenching with p-toluenesulfonyl azide affords azide (II), which is further reduced to amine (III) with NaBH4 in the presence of a quaternary phosphonium salt. The N-t-butyl group of (III) is then cleaved with fuming HCl to afford (IV). Condensation of sulfonamide (IV) with isopropyl isothiocyanate furnishes the sulfonyl thiourea (V). This is finally cyclized to the desired thienothiadiazine by treatment with phosgene in the presence of triethylamine
| 【1】 Nielsen, F.E.; Bodvarsdottir, T.B.; Worsaae, A.; et al.; 6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives potently and selectively activate ATP sensitive potassium channels of pancreatic beta-cells. J. Med. Chem. 2002, 45, 19, 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) | 61482 | 2-[(tert-butylamino)sulfonyl]-5-chloro-3-thiophenecarboxylic acid | C9H12ClNO4S2 | 详情 | 详情 | |
| (II) | 61492 | ethyl 2-[(tert-butylamino)sulfonyl]-5-chloro-3-thiophenecarboxylate | C11H16ClNO4S2 | 详情 | 详情 | |
| (III) | 61493 | N-(tert-butyl)-5-chloro-3-(hydrazinocarbonyl)-2-thiophenesulfonamide | C9H14ClN3O3S2 | 详情 | 详情 | |
| (IV) | 61494 | methyl 2-(aminosulfonyl)-5-chloro-3-thienylcarbamate | C6H7ClN2O4S2 | 详情 | 详情 | |
| (V) | 61495 | methyl 5-chloro-2-({[(isopropylamino)carbothioyl]amino}sulfonyl)-3-thienylcarbamate | C10H14ClN3O4S3 | 详情 | 详情 | |
| (VI) | 61496 | methyl 6-chloro-3-(isopropylamino)-1,1-dioxo-1lambda~6~-thieno[3,2-e][1,2,4]thiadiazine-4(1H)-carboxylate | C10H12ClN3O4S2 | 详情 | 详情 |