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【结 构 式】 
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【分子编号】27260 【品名】(2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate 【CA登记号】572-09-8 |
【 分 子 式 】C14H19BrO9 【 分 子 量 】411.20346 【元素组成】C 40.89% H 4.66% Br 19.43% O 35.02% |
合成路线1
该中间体在本合成路线中的序号：(II)Reaction of 2,6-dihydroxyacetophenone (I) with acetylated bromoglucose (II) in the presence of CdCO3 in refluxing toluene, with water removal using a Dean Stark apparatus, afforded glycoside (III). Potassium hydroxide-promoted condensation of acetophenone (III) with benzofuran-5-carboxyaldehyde (IV), with concomitant hydrolysis of acetate esters, gave enone (V), which was hydrogenated over Pt/C in the presence of DMAP to provide dihydrochalcone derivative (VI). Treatment of (VI) with benzaldehyde dimethylacetal (VII) and p-TsOH gave benzylidene acetal (VIII). This compound was acetylated with Ac2O and pyridine to yield (IX).
| 【1】 Tsujihara, K.; et al.; Na+-glucose cotransporter inhibitors as antidiabetics. I. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives based on a new concept. Chem Pharm Bull 1996, 44, 6, 1174. |
| 【2】 Hongu, M.; et al.; Na+-Glucose cotransporter inhibitors as antidiabetic agents. II. Synthesis and structure-activity relationships of 4'-dehydroxyphlorizin derivatives. Chem Pharm Bull 1998, 46, 1, 22. |
| 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) | 27511 | 1-(2,6-dihydroxyphenyl)-1-ethanone | 699-83-2 | C8H8O3 | 详情 | 详情 |
| (II) | 27260 | (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate | 572-09-8 | C14H19BrO9 | 详情 | 详情 |
| (III) | 27512 | (2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxyphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate | C22H26O12 | 详情 | 详情 | |
| (IV) | 27262 | 1-benzofuran-5-carbaldehyde | C9H6O2 | 详情 | 详情 | |
| (V) | 27513 | (E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one | C23H22O9 | 详情 | 详情 | |
| (VI) | 27514 | 3-(1-benzofuran-5-yl)-1-(2-hydroxy-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-1-propanone | C23H24O9 | 详情 | 详情 | |
| (VII) | 27515 | Methoxy(phenyl)methyl methyl ether; Dimethylacetal benzaldehyde; Benzaldehyde dimethylacetal | 1125-88-8 | C9H12O2 | 详情 | 详情 |
| (VIII) | 27516 | 1-(2-[[(4aR,6S,7R,8R,8aS)-7,8-dihydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-6-hydroxyphenyl)-3-(1-benzofuran-5-yl)-1-propanone | C30H28O9 | 详情 | 详情 | |
| (IX) | 27517 | (4aR,6S,7R,8S,8aR)-7-(acetoxy)-6-[3-(acetoxy)-2-[3-(1-benzofuran-5-yl)propanoyl]phenoxy]-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate | C36H34O12 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Reaction of 2,6-dihydroxyacetophenone (I) with acetylated bromoglucose (II) in the presence of CdCO3 in refluxing toluene, with water removal using a Dean Stark apparatus, afforded glycoside (III). Potassium hydroxide-promoted condensation of acetophenone (III) with benzofuran-5-carboxyaldehyde (IV), with concomitant hydrolysis of acetate esters, gave enone (V), which was hydrogenated over Pt/C in the presence of DMAP to provide dihydrochalcone derivative (VI). Treatment of (VI) with 4-nitrophenyl chloroformate (VII) and 2,4,6-collidine gave the intermediate 6-O-(4-nitrophenylcarbonyl) compound, which is cyclized to the cyclic carbonate (VIII) by heating at 50 C. The ring opening reaction of (VIII) with TsOH and methanol afforded the target 4-O-(methoxycarbonyl) compound along with some 6-O-methoxycarbonyl isomer, which is separated by column chromatography.
| 【1】 Hongu, M.; et al.; Na+-Glucose cotransporter inhibitors as antidiabetic agents. II. Synthesis and structure-activity relationships of 4'-dehydroxyphlorizin derivatives. Chem Pharm Bull 1998, 46, 1, 22. |
| 【2】 Tsujihara, K.; et al.; Na+-glucose cotransporter inhibitors as antidiabetics. I. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives based on a new concept. Chem Pharm Bull 1996, 44, 6, 1174. |
| 【3】 Hongu, M.; Funami, N.; Takahashi, Y.; Saito, K.; Arakawa, K.; Matsumoto, M.; Yamakita, H.; Tsujihara, K.; Na+-glucose cotransporter inhibitors as antidiabetic agents. III. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives modified at the OH groups of the glucose moiety. Chem Pharm Bull 1998, 46, 10, 1545. |
| 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) | 27511 | 1-(2,6-dihydroxyphenyl)-1-ethanone | 699-83-2 | C8H8O3 | 详情 | 详情 |
| (II) | 27260 | (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate | 572-09-8 | C14H19BrO9 | 详情 | 详情 |
| (III) | 27512 | (2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxyphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate | C22H26O12 | 详情 | 详情 | |
| (IV) | 27262 | 1-benzofuran-5-carbaldehyde | C9H6O2 | 详情 | 详情 | |
| (V) | 27513 | (E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one | C23H22O9 | 详情 | 详情 | |
| (VI) | 27514 | 3-(1-benzofuran-5-yl)-1-(2-hydroxy-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-1-propanone | C23H24O9 | 详情 | 详情 | |
| (VII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VIII) | 27520 | (4aR,6S,7R,8R,8aS)-6-[2-[3-(1-benzofuran-5-yl)propanoyl]-3-hydroxyphenoxy]-7,8-dihydroxyhexahydropyrano[3,2-d][1,3]dioxin-2-one | C24H22O10 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Orcinol (I) was acetylated with Ac2O in pyridine to give diacetate (II), which was submitted to a Fries rearrangement in the presence of AlCl3 in chlorobenzene at 90 C to afford acetophenone (III). Subsequent condensation of (III) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (IV) was effected either in the presence of CdCO3 in boiling toluene or K2CO3 and tributyl benzylammonium chloride in CH2Cl2 at r.t. The resulting (glucopyranosyloxy)acetophenone (V) was condensed with 5-formylbenzofuran (VI) in the presence of KOH to give chalcone (VII). Hydrogenation of (VII) over Pt/C then yielded the (benzofuranyl)propiophenone (VIII). After protection of the 6'-hydroxyl group of (VIII) as the allyl ether (X) with allyl bromide (IX) and K2CO3, the primary alcohol of (X) was acylated with ClCOOMe to furnish carbonate ester (XI). Finally, the O-allyl group of (XI) was cleaved with palladium catalyst and ammonium formate.
| 【1】 Doggrell, S.A.; Castañer, J.; T-1095. Drugs Fut 2001, 26, 8, 750. |
| 【2】 Tsujihara, K.; et al.; Na+-glucose contransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring. J Med Chem 1999, 42, 26, 5311. |
| 【3】 Hongu, M.; Matsumoto, M.; Oku, A.; Saito, K.; Tsujihara, K. (Tanabe Seiyaku Co., Ltd.); Propiophenone derivs. and process for preparing the same. EP 0850948; JP 1998237089; US 6048842 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 | |
| (I) | 27257 | 5-Methyl-1,3-benzenediol; Orcinol | 505-15-4 | C7H8O2 | 详情 | 详情 |
| (II) | 27258 | 3-(acetoxy)-5-methylphenyl acetate | C11H12O4 | 详情 | 详情 | |
| (III) | 27259 | 1-(2,6-dihydroxy-4-methylphenyl)-1-ethanone | C9H10O3 | 详情 | 详情 | |
| (IV) | 27260 | (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate | 572-09-8 | C14H19BrO9 | 详情 | 详情 |
| (V) | 27261 | (2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxy-5-methylphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate | C23H28O12 | 详情 | 详情 | |
| (VI) | 27262 | 1-benzofuran-5-carbaldehyde | C9H6O2 | 详情 | 详情 | |
| (VII) | 27263 | (E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one | C24H24O9 | 详情 | 详情 | |
| (VIII) | 27264 | 3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-1-propanone | C24H26O9 | 详情 | 详情 | |
| (IX) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (X) | 27265 | 1-(2-(allyloxy)-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-3-(1-benzofuran-5-yl)-1-propanone | C27H30O9 | 详情 | 详情 | |
| (XI) | 27266 | ((2R,3S,4S,5R,6S)-6-[3-(allyloxy)-2-[3-(1-benzofuran-5-yl)propanoyl]-5-methylphenoxy]-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl methyl carbonate | C29H32O11 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Orcinol (I) is acetylated with Ac2O in pyridine giving the diacetate (II), which is submitted to a Fries rearrangement with AlCl3 in hot chlorobenzene yielding acetophenone (III). Subsequent condensation of (III) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (IV) by means of CdCO3 in refluxing toluene (or K2CO3 and tributylbenzylammonium chloride in dichloromethane) affords the glycosylated acetophenone (V), which is condensed with benzofuran-5-carbaldehyde (VI) by means of KOH in ethanol affording deacetylated chalcone (VII). Finally, this compound is hydrogenated with H2 over Pt/C in ethanol.
| 【1】 Tsujihara, K.; et al.; Na+-glucose contransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring. J Med Chem 1999, 42, 26, 5311. |
| 【2】 Hongu, M.; Matsumoto, M.; Oku, A.; Saito, K.; Tsujihara, K. (Tanabe Seiyaku Co., Ltd.); Propiophenone derivs. and process for preparing the same. EP 0850948; JP 1998237089; US 6048842 . |
| 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) | 27257 | 5-Methyl-1,3-benzenediol; Orcinol | 505-15-4 | C7H8O2 | 详情 | 详情 |
| (II) | 27258 | 3-(acetoxy)-5-methylphenyl acetate | C11H12O4 | 详情 | 详情 | |
| (III) | 27259 | 1-(2,6-dihydroxy-4-methylphenyl)-1-ethanone | C9H10O3 | 详情 | 详情 | |
| (IV) | 27260 | (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate | 572-09-8 | C14H19BrO9 | 详情 | 详情 |
| (V) | 27261 | (2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxy-5-methylphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate | C23H28O12 | 详情 | 详情 | |
| (VI) | 27262 | 1-benzofuran-5-carbaldehyde | C9H6O2 | 详情 | 详情 | |
| (VII) | 27263 | (E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one | C24H24O9 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The condensation of 2,4,6-trihydroxyacetophenone (IV) with tetraacetylbromoglucose (V) by means of NaOH in acetone-water gives tetraacetylphloracetophenone-4-O-glucoside (VI), which is condensed with 4-hydroxybenzaldehyde (VII), by means of KOH in alcohol yielding the chalcone derivative (VIII). Finally, this compound is cyclized and deprotected by a treatment with refluxing aqueous HCl.
| 【1】 Zemplen, G.; Bognar, R.; Synthese eines phloracetophenon-glucosids, eines naringenin-glucosids und des p-phlorhizins. Ber 1942, 75, 645-655. |
| 【2】 Castaner, J.; Serradell, M.N.; Aboul-Enein, H.Y.; Naringenin. Drugs Fut 1984, 9, 9, 653-654. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 34293 | 1-(2,4,6-trihydroxyphenyl)-1-ethanone | 480-66-0 | C8H8O4 | 详情 | 详情 |
| (V) | 27260 | (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate | 572-09-8 | C14H19BrO9 | 详情 | 详情 |
| (VI) | 34294 | (2R,3R,4S,5R)-6-(4-acetyl-3,5-dihydroxyphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate | C22H26O13 | 详情 | 详情 | |
| (VII) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VIII) | 34295 | (E)-1-(2,6-dihydroxy-4-[[(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-3-(4-hydroxyphenyl)-2-propen-1-one | C21H22O10 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)Claisen condensation between 2'-hydroxyacetophenone (I) and 3,4-dibenzyloxybenzaldehyde (II) afforded chalcone (III) which was further subjected to the Agar-Flynn-Oyamada reaction to give flavonol (IV). The silver oxide-assisted glycosylation of (IV) with acetobromoglucose (V) in pyridine furnished the protected glucoside (VI). Removal of the acetyl protecting groups of (VI) was effected by methanolysis in the presence of potassium tert-butoxide to yield (VII). Subsequent catalytic hydrogenolysis of the benzyl groups of (VII) provided the title compound.
| 【1】 Frederique, A.; et al.; Synthesis of novel 3,7-substituted-2-(3',4'-dihydroxyphenyl) flavones with improved antioxidant activity. J Med Chem 2000, 43, 20, 3752. |
| 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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 49829 | 3,4-Dibenzyloxybenzaldehyde; 3,4-Bis(benzyloxy)benzaldehyde | 5447-02-9 | C21H18O3 | 详情 | 详情 |
| (III) | 49830 | (E)-3-[3,4-bis(benzyloxy)phenyl]-1-(2-hydroxyphenyl)-2-propen-1-one | C29H24O4 | 详情 | 详情 | |
| (IV) | 49831 | 2-[3,4-bis(benzyloxy)phenyl]-3-hydroxy-4H-chromen-4-one | C29H22O5 | 详情 | 详情 | |
| (V) | 27260 | (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate | 572-09-8 | C14H19BrO9 | 详情 | 详情 |
| (VI) | 49832 | (2R,3R,4S,5R)-3,5-bis(acetoxy)-2-[(acetoxy)methyl]-6-([2-[3,4-bis(benzyloxy)phenyl]-4-oxo-4H-chromen-3-yl]oxy)tetrahydro-2H-pyran-4-yl acetate | C43H40O14 | 详情 | 详情 |