6-Fluoro-2-methylindanone -Drug Synthesis Database

【结构式】

【分子编号】48872

【品名】6-Fluoro-2-methylindanone

【CA登记号】

【分子式】C₁₀H₉FO

【分子量】164.1792632

【元素组成】C 73.16% H 5.53% F 11.57% O 9.75%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

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.

参考文献中间体

合成目标

【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：(V)

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.

参考文献中间体

合成目标

【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：(V)

参考文献中间体

合成目标

【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