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【结 构 式】 
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【分子编号】13067 【品名】ethyl 5,6-difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylate 【CA登记号】 |
【 分 子 式 】C15H9F2NO4S 【 分 子 量 】337.3036064 【元素组成】C 53.41% H 2.69% F 11.26% N 4.15% O 18.97% S 9.51% |
合成路线1
该中间体在本合成路线中的序号：(X)A new synthesis for KB-5246 has been described: The reaction of 2,3,4-trifluoroaniline (I) with carbon disulfide (II) and triethylamine gives the corresponding dithiocarbamate (III), which by cyclization with 1-acetoxy-3-chloro-2-propanone (IV) in ethyl acetate yields 4-(acetoxymethyl)-3-(2,3,4-trifluorophenyl)thiazole-2(3H)-thione (V). The cyclization of (V) with potassium hydroxide in refluxing ethanol-water affords 6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (VI), which is treated with trichloromethyl chloroformate in hot toluene to give the thiazolium chloride (VII), which is not isolated. The in situ reaction of (VII) with diethyl malonate by means of triethylamine in toluene gives (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonic acid diethyl ester (IX), which is cyclized again with polyphosphoric acid (PPA) at 115 C to afford 7,8-difluoro-5-oxo-9,1-(epoxymethano)-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester (X). The hydrolysis of (X) with oleum gives the corresponding acid (XI), which is finally condensed with N-methylpiperazine (XII) in hot DMSO.
| 【1】 Kondo, H.; Tsukamoto, G.; Taguchi, M.; Jinbo, Y.; Kawahata, Y.; Sakamoto, F.; Inoue, Y.; Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials. J Med Chem 1992, 35, 1, 94. |
| 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) | 13059 | 2,3,4-Trifluorophenylamine; 2,3,4-Trifluoroaniline | 3862-73-5 | C6H4F3N | 详情 | 详情 |
| (III) | 13060 | 2,3,4-trifluorophenylcarbamodithioate | C7H3F3NS2 | 详情 | 详情 | |
| (IV) | 13061 | 2-(chlorooxy)-2-oxoethyl acetate | C4H5ClO4 | 详情 | 详情 | |
| (V) | 13062 | [2-thioxo-3-(2,3,4-trifluorophenyl)-2,3-dihydro-1,3-thiazol-4-yl]methyl acetate | C12H8F3NO2S2 | 详情 | 详情 | |
| (VI) | 13063 | 6,7-Difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazine-1-thione | C10H5F2NOS2 | 详情 | 详情 | |
| (VII) | 13064 | 1-Chloro-6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-10-ium chloride | C10H5Cl2F2NOS | 详情 | 详情 | |
| (VIII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (IX) | 13066 | diethyl 2-(6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate | C17H15F2NO5S | 详情 | 详情 | |
| (X) | 13067 | ethyl 5,6-difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylate | C15H9F2NO4S | 详情 | 详情 | |
| (XI) | 13068 | 5,6-Difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylic acid | C13H5F2NO4S | 详情 | 详情 | |
| (XII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)The reduction of 2-octyn-1-ol (XII) with bis(2-methoxyethoxy)aluminum hydride in toluene/THF gives 2-octen-1-ol (XIII), which is treated with tert-butyl hydroperoxide, (+)-diethyl L-tartrate and titanium tetraisopropoxide in dichloromethane yielding epoxide (XIV). The latter is reduced with bis(2-ethoxyethoxy)aluminum hydride in toluene/THF, affording the chiral diol (XV). The selective monotosylation of (XV) with TsCl in pyridine provides the primary tosylate (XVI), which is treated with NaI in hot acetone to furnish 1-iodo-3-octanol (XVII). Protection of (XVII) with dihydropyran and pyridine hydrochloride gives the tetrahydropyranyl ether (XVIII), which is condensed with dimethyl methylphosphonate (XIX) by means of BuLi and TEA in THF to yield the phosphonate (XX). Condensation of compound (XX) with 5-methoxy-2,3,3a,4-tetrahydronaphtho[2,3-b]furan-2-one (XXI) by means of BuLi in THF affords the tricyclic adduct (XXII), which is hydrogenated with H2 over Pd/C in ethanol to provide compound (XXIII). Isomerization of (XXIII) with NaOH in refluxing ethanol gives diastereomer (XXIV). The reduction of the carbonyl group of (XXIV) with NaBH4 in methanol, followed by deprotection with HOAc in THF yields compound (XXV). The demethylation of compound (XXV) by means of BuLi and Ph2PH in THF affords the tricyclic phenol (XXVI), which is condensed with 2-chloroacetonitrile (XXVII) by means of K2CO3 in refluxing acetone to provide the precursor (XXVIII). Finally, the cyano group of (XXVIII) is hydrolyzed with KOH in refluxing water.
| 【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; UT-15. Drugs Fut 2001, 26, 4, 364. |
| 【2】 Aristoff, P.A. (Pharmacia Corp.); Carbacyclin analogues. EP 0159784; JP 1985208936; US 4683330 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 46559 | 2-octyn-1-ol | C8H14O | 详情 | 详情 | |
| (XIII) | 46560 | (E)-2-octen-1-ol | C8H16O | 详情 | 详情 | |
| (XIV) | 46561 | [(2R,3S)-3-pentyloxiranyl]methanol | C8H16O2 | 详情 | 详情 | |
| (XV) | 46562 | (3S)-1,3-octanediol | C8H18O2 | 详情 | 详情 | |
| (XVI) | 46563 | (3S)-3-hydroxyoctyl 4-methylbenzenesulfonate | C15H24O4S | 详情 | 详情 | |
| (XVII) | 46564 | (3S)-1-iodo-3-octanol | C8H17IO | 详情 | 详情 | |
| (XVIII) | 46565 | (1S)-1-(2-iodoethyl)hexyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-(2-iodoethyl)hexyl]oxy]tetrahydro-2H-pyran | C13H25IO2 | 详情 | 详情 | |
| (XIX) | 13067 | ethyl 5,6-difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylate | C15H9F2NO4S | 详情 | 详情 | |
| (XX) | 46566 | dimethyl (4S)-4-(tetrahydro-2H-pyran-2-yloxy)nonylphosphonate | C16H33O5P | 详情 | 详情 | |
| (XXI) | 46567 | (3aS)-5-methoxy-3a,4-dihydronaphtho[2,3-b]furan-2(3H)-one | C13H12O3 | 详情 | 详情 | |
| (XXII) | 46568 | (9aS)-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one | C27H38O4 | 详情 | 详情 | |
| (XXIII) | 46569 | (1S,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,3,3a,4,9,9a-hexahydro-2H-cyclopenta[b]naphthalen-2-one | C27H40O4 | 详情 | 详情 | |
| (XXIV) | 46570 | (1R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,3,3a,4,9,9a-hexahydro-2H-cyclopenta[b]naphthalen-2-one | C27H40O4 | 详情 | 详情 | |
| (XXV) | 46571 | (1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol | C22H34O3 | 详情 | 详情 | |
| (XXVI) | 46572 | (1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol | C21H32O3 | 详情 | 详情 | |
| (XXVII) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (XXVIII) | 46573 | 2-([(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl]oxy)acetonitrile | C23H33NO3 | 详情 | 详情 |