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【结 构 式】

【分子编号】48873

【品名】2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile

【CA登记号】

【 分 子 式 】C3H3NO

【 分 子 量 】69.06296

【元素组成】C 52.17% H 4.38% N 20.28% O 23.17%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VI)

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2

该中间体在本合成路线中的序号:(VI)

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
Extended Information