6-chloro-5-nitro-1,3-dihydro-2-benzofuran-1-ol -Drug Synthesis Database

【结构式】

【分子编号】18150

【品名】6-chloro-5-nitro-1,3-dihydro-2-benzofuran-1-ol

【CA登记号】

【分子式】C₈H₆ClNO₄

【分子量】215.59268

【元素组成】C 44.57% H 2.81% Cl 16.44% N 6.5% O 29.68%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

5-Chloro-4-nitro-2-methylaniline (I) was treated with NaNO2 and HCl, and to the intermediate diazonium salt (II) was treated with a mixture of NaCN and Cu2(CN)2 to afford nitrile (III). Benzylic bromination of III with N-bromosuccinimide (NBS) and a catalytic amount of benzoyl peroxide under light irradiation gave bromide (IV), which was converted into acetate (V) on reaction with sodium acetate in DMF. Basic hydrolysis of (V) with NaOH, followed by treatment with HCl, yielded isobenzofuranone (VI). Treatment with diisobutylaluminum hydride (Dibal) in toluene at -78 C effected partial reduction of lactone (VI) to the cyclic hemiacetal (VII), which was then converted into methyl acetal (VIII) by treatment with methanol and trimethyl orthoformate in the presence of p-toluenesulfonic acid. Further reaction with 2-mercapto-4-ethylthiazole (IX) and KOH in DMF provided thiazolyl thioether (X). Then, the methylacetal group was hydrolyzed with HCl in THF-acetone, and the resulting hemiacetal (XI) was oxidized with pyridinium dichromate in dichlorometane to the isobenzofuranone (XII). Reduction of the nitro group with iron powder and ammonium chloride in refluxing EtOH-H2O afforded aniline (XIII). This was condensed with mesyl chloride in the presence of triethylamine to give the bis(methanesulfonyl) compound (XIV), which was finally hydrolyzed with NaOH to the title sulfonamide.

参考文献中间体

合成目标

【1】 Guay, D.; Li, C.-S.; Ouimet, N. (Merck Frosst Canada Inc.); 5-Methanesulfonamido-3H-isobenzofuran-1-ones as inhibitors of cyclooxygenase-2. US 5968958; WO 9623786 .

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)	18144	5-chloro-2-methyl-4-nitroaniline; 5-Chloro-4-nitro-o-toluidine; 5-chloro-2-methyl-4-nitrophenylamine	13852-51-2	C₇H₇ClN₂O₂	详情	详情
(II)	18145	5-chloro-2-methyl-4-nitrobenzenediazonium		C₇H₅ClN₃O₂	详情	详情
(III)	18146	5-chloro-2-methyl-4-nitrobenzonitrile		C₈H₅ClN₂O₂	详情	详情
(IV)	18147	2-(bromomethyl)-5-chloro-4-nitrobenzonitrile		C₈H₄BrClN₂O₂	详情	详情
(V)	18148	4-chloro-2-cyano-5-nitrobenzyl acetate		C₁₀H₇ClN₂O₄	详情	详情
(VI)	18149	6-chloro-5-nitro-2-benzofuran-1(3H)-one		C₈H₄ClNO₄	详情	详情
(VII)	18150	6-chloro-5-nitro-1,3-dihydro-2-benzofuran-1-ol		C₈H₆ClNO₄	详情	详情
(VIII)	18151	6-chloro-1-methoxy-5-nitro-1,3-dihydro-2-benzofuran; 6-chloro-5-nitro-1,3-dihydro-2-benzofuran-1-yl methyl ether		C₉H₈ClNO₄	详情	详情
(IX)	18152	4-ethyl-1,3-thiazole-2-thiol; 4-ethyl-1,3-thiazol-2-ylhydrosulfide		C₅H₇NS₂	详情	详情
(X)	18153	6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-5-nitro-1,3-dihydro-2-benzofuran-1-yl methyl ether; 4-ethyl-2-[(3-methoxy-6-nitro-1,3-dihydro-2-benzofuran-5-yl)sulfanyl]-1,3-thiazole		C₁₄H₁₄N₂O₄S₂	详情	详情
(XI)	18154	6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-5-nitro-1,3-dihydro-2-benzofuran-1-ol		C₁₃H₁₂N₂O₄S₂	详情	详情
(XII)	18155	6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-5-nitro-2-benzofuran-1(3H)-one		C₁₃H₁₀N₂O₄S₂	详情	详情
(XIII)	18156	5-amino-6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-2-benzofuran-1(3H)-one		C₁₃H₁₂N₂O₂S₂	详情	详情
(XIV)	18157	N-[6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-1-oxo-1,3-dihydro-2-benzofuran-5-yl]-N-(methylsulfonyl)methanesulfonamide		C₁₅H₁₆N₂O₆S₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The nitrotoluene (I) was brominated with N-bromosuccinimide in boiling chlorobenzene to produce the benzyl bromide (II), which upon displacement with NaOAc provided the acetate ester (III). After basic hydrolysis, the resulting alcohol was cyclized in situ with HCl to give lactone (IV). The lactone was reduced as the acetal (VI) by reaction with DIBALH, followed by treatment of the resulting lactol (V) with trimethyl orthoformate and PPTS. Subsequent displacement of the chlorine atom of (VI) with the potassium salt of 4-ethyl-2-mercaptothiazole (VII) in DMF at 100 C furnished sulfide (VIII). Further deprotection of the acetal, followed by oxidation of the lactol (IX) with pyridinium dichromate provided lactone (X). The nitro group of (X) was then reduced with iron and NH4Cl to amine (XI). Finally, bis-sulfonation of (XI) with mesyl chloride, followed by selective hydrolysis of one sulfonyl group with NaOH afforded the title sulfonamide.

参考文献中间体

合成目标

【1】 Ouimet, N.; et al.; Substituted heterocyclic analogs as selective COX-2 inhibitors in the flosulide class. Bioorg Med Chem Lett 1999, 9, 2, 151.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	18146	5-chloro-2-methyl-4-nitrobenzonitrile	C₈H₅ClN₂O₂	详情	详情
(II)	18147	2-(bromomethyl)-5-chloro-4-nitrobenzonitrile	C₈H₄BrClN₂O₂	详情	详情
(III)	18148	4-chloro-2-cyano-5-nitrobenzyl acetate	C₁₀H₇ClN₂O₄	详情	详情
(IV)	18149	6-chloro-5-nitro-2-benzofuran-1(3H)-one	C₈H₄ClNO₄	详情	详情
(V)	18150	6-chloro-5-nitro-1,3-dihydro-2-benzofuran-1-ol	C₈H₆ClNO₄	详情	详情
(VI)	18151	6-chloro-1-methoxy-5-nitro-1,3-dihydro-2-benzofuran; 6-chloro-5-nitro-1,3-dihydro-2-benzofuran-1-yl methyl ether	C₉H₈ClNO₄	详情	详情
(VII)	18152	4-ethyl-1,3-thiazole-2-thiol; 4-ethyl-1,3-thiazol-2-ylhydrosulfide	C₅H₇NS₂	详情	详情
(VIII)	18153	6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-5-nitro-1,3-dihydro-2-benzofuran-1-yl methyl ether; 4-ethyl-2-[(3-methoxy-6-nitro-1,3-dihydro-2-benzofuran-5-yl)sulfanyl]-1,3-thiazole	C₁₄H₁₄N₂O₄S₂	详情	详情
(IX)	18154	6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-5-nitro-1,3-dihydro-2-benzofuran-1-ol	C₁₃H₁₂N₂O₄S₂	详情	详情
(X)	18155	6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-5-nitro-2-benzofuran-1(3H)-one	C₁₃H₁₀N₂O₄S₂	详情	详情
(XI)	18157	N-[6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-1-oxo-1,3-dihydro-2-benzofuran-5-yl]-N-(methylsulfonyl)methanesulfonamide	C₁₅H₁₆N₂O₆S₄	详情	详情
(XII)	18157	N-[6-[(4-ethyl-1,3-thiazol-2-yl)sulfanyl]-1-oxo-1,3-dihydro-2-benzofuran-5-yl]-N-(methylsulfonyl)methanesulfonamide	C₁₅H₁₆N₂O₆S₄	详情	详情

Extended Information