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【结 构 式】 
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【分子编号】48874 【品名】2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid 【CA登记号】 |
【 分 子 式 】C12H11FO2 【 分 子 量 】206.2165432 【元素组成】C 69.89% H 5.38% F 9.21% O 15.52% |
合成路线1
该中间体在本合成路线中的序号：(VII)Condensation of p-fluorobenzaldehyde (I) with propionic anhydride (II) by means of sodium propionate at 140 C affords p-fluoro-alpha-methylcinnamic acid (III), which is then hydrogenated over Pd/C in EtOH to provide p-fluoro-alpha-methylhydrocinnamic acid (IV). Derivative (IV) is subjected to cyclization by treatment with polyphosphoric acid (PPA) to give 6-fluoro-2-methylindanone (V), which is converted into 5-fluoro-2-methylindenyl-3-acetic acid (VII) by first condensation with cyanoacetic acid (VI) by means of acetic acid and ammonium acetate in refluxing toluene, followed by hydrolysis with KOH in hot ethanol. Condensation of derivative (VII) with p-methylthiobenzaldehyde (VIII) by means of sodium methoxide in hot MeOH affords 5-fluoro-2-methyl-1-[p-(methylsulfanyl)benzylidene]-3-indenyl acetic acid (IX), which is then oxidized in MeOH/acetone by means of an aqueous solution of sodium periodate to yield methylsulfinylbenzylidene derivative (X). Finally, the target product is obtained by further oxidation of (X) with H2O2 in the presence of sodium methoxide and sodium bicarbonate in MeOH/acetonitrile at -10 C.
| 【1】 Mayle, M.J.; Menander, K.B. (Cell Pathways, Inc.); A method for treating patients with acne by administering a cyclic GMP PDE inhibitor. WO 0044372 . |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 48870 | (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid | C10H9FO2 | 详情 | 详情 | |
| (IV) | 48871 | 3-(4-fluorophenyl)-2-methylpropionic acid | C10H11FO2 | 详情 | 详情 | |
| (V) | 48872 | 6-Fluoro-2-methylindanone | C10H9FO | 详情 | 详情 | |
| (VI) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
| (VII) | 48874 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid | C12H11FO2 | 详情 | 详情 | |
| (VIII) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (IX) | 51940 | 2-(5-fluoro-2-methyl-1-[(E)-[4-(methylsulfanyl)phenyl]methylidene]-1H-inden-3-yl)acetic acid | C20H17FO2S | 详情 | 详情 | |
| (X) | 51941 | 2-(5-fluoro-2-methyl-1-[(E)-[4-(methylsulfinyl)phenyl]methylidene]-1H-inden-3-yl)acetic acid | C20H17FO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Heating p-fluorobenzaldehyde (I) with propionic anhydride (II) in the presence of sodium propionate affords methyl cinnamic acid derivative (III), which is then hydrogenated over Pd/C in EtOH to provide methyl hydrocinnamic acid derivative (IV). Ring closure of (IV) is then performed by heating with polyphosphoric acid to yield methylindanone derivative (V). Condensation of (V) with cyanoacetic acid (VI) by means of ammonium acetate and HOAc in refluxing toluene, followed by treatment with KOH in refluxing EtOH, provides acetic acid derivative (VII), which is then condensed with 3,4,5-trimethoxybenzaldehyde (VIII) by heating with NaOMe in MeOH to give substituted benzylidene derivative (IX). The target product can be finally obtained either by direct condensation of (IX) with benzylamine (XI) by means of DMAP and EDC in DMA or by first conversion of (IX) into the corresponding acetyl chloride by reaction with oxalyl chloride in refluxing THF, followed by coupling with benzylamine (XI) in CH2Cl2. Alternatively, the desired compound can also be obtained by coupling of acetic acid derivative (VII) with benzylamine (XI) by means of DMAP, EDC in DMA to afford N-benzyl acetamide derivative (XII), followed by condensation with 3,4,5-trimethoxybenzaldehyde (VIII) by heating with NaOMe in MeOH.
| 【1】 Sperl, G.; Gross, P.; Brendel, K.; Pamucku, R.; Piazza, G.A. (University of Arizona); Substd. benzylidene indenyl formamides, acetamides and propionamides. WO 9747303 . |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 48870 | (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid | C10H9FO2 | 详情 | 详情 | |
| (IV) | 48871 | 3-(4-fluorophenyl)-2-methylpropionic acid | C10H11FO2 | 详情 | 详情 | |
| (V) | 48872 | 6-Fluoro-2-methylindanone | C10H9FO | 详情 | 详情 | |
| (VI) | 48873 | 2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile | C3H3NO | 详情 | 详情 | |
| (VII) | 48874 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid | C12H11FO2 | 详情 | 详情 | |
| (VIII) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (IX) | 48875 | 2-[5-fluoro-2-methyl-1-[(E)-(3,4,5-trimethoxyphenyl)methylidene]-1H-inden-3-yl]acetic acid | C22H21FO5 | 详情 | 详情 | |
| (X) | 48876 | 2-[5-fluoro-2-methyl-1-[(E)-(3,4,5-trimethoxyphenyl)methylidene]-1H-inden-3-yl]acetyl chloride | C22H20ClFO4 | 详情 | 详情 | |
| (XI) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (XII) | 48877 | N-benzyl-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide | C19H18FNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Heating p-fluorobenzaldehyde (I) with propionic anhydride (II) in the presence of sodium propionate affords methyl cinnamic acid derivative (III), which is then hydrogenated over Pd/C in EtOH to provide methyl hydrocinnamic acid derivative (IV). Ring closure of (IV) is then performed by heating with polyphosphoric acid to yield methylindanone derivative (V). Condensation of (V) with cyanoacetic acid (VI) by means of ammonium acetate and HOAc in refluxing toluene followed by treatment with KOH in refluxing EtOH provides acetic acid derivative (VII), which is then converted into acetyl chloride compound (VIII) by reaction with oxalyl chloride in refluxing THF. Coupling of (VIII) with benzylamine (IX) in refluxing CH2Cl2 gives indenylacetamide derivative (X), which is finally condensed with 4-pyridinecarboxaldehyde (XI) by means of NaOMe in MeOH to furnish the desired compound.
| 【1】 Piazza, G.; Gross, P.; Brendel, K.; Sperl, G.; Pamukcu, R. (Cell Pathways, Inc.; University of Arizona); N-Benzyl-3-indenylacetamides derivs. for treating neoplasia. EP 1044187; US 5948779; US 6066634; WO 9931065 . |
| 【2】 Mayle, M.J.; Menander, K.B. (Cell Pathways, Inc.); A method for treating patients with acne by administering a cyclic GMP PDE inhibitor. WO 0044372 . |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 48870 | (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid | C10H9FO2 | 详情 | 详情 | |
| (IV) | 48871 | 3-(4-fluorophenyl)-2-methylpropionic acid | C10H11FO2 | 详情 | 详情 | |
| (V) | 48872 | 6-Fluoro-2-methylindanone | C10H9FO | 详情 | 详情 | |
| (VI) | 48873 | 2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile | C3H3NO | 详情 | 详情 | |
| (VII) | 48874 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid | C12H11FO2 | 详情 | 详情 | |
| (VIII) | 48878 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetyl chloride | C12H10ClFO | 详情 | 详情 | |
| (IX) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (X) | 48877 | N-benzyl-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide | C19H18FNO | 详情 | 详情 | |
| (XI) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The title compound is prepared by condensation between 5-fluoro-2-methylindene-3-acetic acid (I) and 3-furaldehyde (II) in the presence of NaOMe.
