4-Chlorobutanal -Drug Synthesis Database

【结构式】

【分子编号】23428

【品名】4-Chlorobutanal

【CA登记号】

【分子式】C₄H₇ClO

【分子量】106.55168

【元素组成】C 45.09% H 6.62% Cl 33.27% O 15.02%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(II)

Almotriptan has been obtained by several related ways: 1) The hydrolysis of 4-chlorobutyraldehyde dimethylacetal (I) with HCl gives the corresponding aldehyde (II), which is condensed with 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) by means of HCl in methanol/water, giving 3-(2-aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole (IV). Finally, this compound is methylated with formaldehyde and NaBH4 in methanol. 2) The direct condensation of 4-chlorobutyraldehyde dimethylacetal (I) with 4-(1-pyrrolidinylsulfonylmethyl)phenylhydrazine (III) by means of HCl in water also yields intermediate 3-(2-aminoethyl)-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole (IV). 3) The decarboxylation of 3-[2-(dimethylamino)ethyl]-5-(1-pyrrolidinylsulfonylmethyl)-1H-indole-2-carboxylic acid (V) catalyzed by means of Cu2O in quinoline at 190 C also gives almotriptan.

参考文献中间体

合成目标

【1】 Fernandez Forner, D.; Puig Duran, C.; Prieto Soto, J.; Vega Noverola, A.; Moragues Mauri, J. (Almirall Prodesfarma, SA); Indol derivs. for the treatment of migraine. EP 0605697; JP 1994511261; US 5565447; WO 9402460 .
【2】 Fernandez Forner, M.D.; Puig Duran, C.; Crespo Crespo, M.I.; Moragues Mauri, J. (Almirall Prodesfarma, SA); Process for the preparation of indole derivs.. ES 2084560 .
【3】 Pujol Noguera, F.; Crespo Crespo, M.I.; Puig Duran, C.; Fernandez Forner, D.; Moragues Mauri, J. (Almirall Prodesfarma, SA); New indole derivs.. ES 2056025 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16870	4-Chlorobutyraldehyde dimethylacetal; 4-Chloro-1-methoxybutyl methyl ether; 4-Chloro-1,1-dimethoxybutane	C₆H₁₃ClO₂	详情	详情
(II)	23428	4-Chlorobutanal	C₄H₇ClO	详情	详情
(III)	23429	1-[(4-hydrazinobenzyl)sulfonyl]pyrrolidine	C₁₁H₁₇N₃O₂S	详情	详情
(IV)	23430	2-[5-[(1-pyrrolidinylsulfonyl)methyl]-1H-indol-3-yl]-1-ethanamine; 2-[5-[(1-pyrrolidinylsulfonyl)methyl]-1H-indol-3-yl]ethylamine	C₁₅H₂₁N₃O₂S	详情	详情
(V)	23431	3-[2-(dimethylamino)ethyl]-5-[(1-pyrrolidinylsulfonyl)methyl]-1H-indole-2-carboxylic acid	C₁₈H₂₅N₃O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded tryptamine (V). In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VIII) was prepared by treatment of amine (VI) with N-carbethoxyphthalimide (VII). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (IX), which was deprotected with hydrazine to furnish the corresponding tryptamine (V). Subsequent condensation of (V) with di-tert-butyl dicarbonate gave carbamate (X). This was finally reduced by means of LiAlH4 providing the target N-methyl tryptamine.

参考文献中间体

合成目标

【1】 Xu, Y.-C.; Schaus, J.M.; Walker, C.; Krushinski, J.; Adhamm, N.; Zgombick, J.M.; Liang, S.X.; Kohlman, D.T.; Audia, J.E.; N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist. J Med Chem 1999, 42, 3, 526.
【2】 Audia, J.E.; Cohen, M.L.; Gidda, J.S.; Nelson, D.L.G.; Baker, S.R.; Ezquerra-Carrera, J.; Lamas-Peteira, C.; Pedregal-Tercero, C. (Eli Lilly and Company); Method for treating 5HT2B receptor related conditions. EP 0749313; JP 1997510216; US 5663178; WO 9524200; WO 9624351 .
【3】 Audia, J.E.; et al. (Eli Lilly and Company); Intermediates to tetrahydro-beta-carbolines. US 5635528 .

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)	27492	4-(tert-butyl)aniline	769-92-6	C₁₀H₁₅N	详情	详情
(II)	29269	1-[4-(tert-butyl)phenyl]hydrazine		C₁₀H₁₆N₂	详情	详情
(III)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(IV)	23428	4-Chlorobutanal		C₄H₇ClO	详情	详情
(V)	29270	2-[5-(tert-butyl)-1H-indol-3-yl]-1-ethanamine		C₁₄H₂₀N₂	详情	详情
(VI)	23323	4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine	6346-09-4	C₈H₁₉NO₂	详情	详情
(VII)	10283	ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide	22509-74-6	C₁₁H₉NO₄	详情	详情
(VIII)	23325	2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione		C₁₆H₂₁NO₄	详情	详情
(IX)	29271	2-[2-[5-(tert-butyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione		C₂₂H₂₂N₂O₂	详情	详情
(X)	29272	tert-butyl 2-[5-(tert-butyl)-1H-indol-3-yl]ethylcarbamate		C₁₉H₂₈N₂O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded the target tryptamine. In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VII) was prepared by treatment of amine (V) with N-carbethoxyphthalimide (VI). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (VIII), which was deprotected with hydrazine to furnish the corresponding tryptamine.

参考文献中间体

合成目标

【1】 Xu, Y.-C.; Schaus, J.M.; Walker, C.; Krushinski, J.; Adhamm, N.; Zgombick, J.M.; Liang, S.X.; Kohlman, D.T.; Audia, J.E.; N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist. J Med Chem 1999, 42, 3, 526.
【2】 Audia, J.E.; Cohen, M.L.; Gidda, J.S.; Nelson, D.L.G.; Baker, S.R.; Ezquerra-Carrera, J.; Lamas-Peteira, C.; Pedregal-Tercero, C. (Eli Lilly and Company); Method for treating 5HT2B receptor related conditions. EP 0749313; JP 1997510216; US 5663178; WO 9524200; WO 9624351 .
【3】 Audia, J.E.; et al. (Eli Lilly and Company); Intermediates to tetrahydro-beta-carbolines. US 5635528 .

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)	27492	4-(tert-butyl)aniline	769-92-6	C₁₀H₁₅N	详情	详情
(II)	29269	1-[4-(tert-butyl)phenyl]hydrazine		C₁₀H₁₆N₂	详情	详情
(III)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(IV)	23428	4-Chlorobutanal		C₄H₇ClO	详情	详情
(V)	23323	4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine	6346-09-4	C₈H₁₉NO₂	详情	详情
(VI)	10283	ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide	22509-74-6	C₁₁H₉NO₄	详情	详情
(VII)	23325	2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione		C₁₆H₂₁NO₄	详情	详情
(VIII)	29271	2-[2-[5-(tert-butyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione		C₂₂H₂₂N₂O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded tryptamine (V). In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VIII) was prepared by treatment of amine (VI) with N-carbethoxyphthalimide (VII). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (IX), which was deprotected with hydrazine to furnish the corresponding tryptamine (V). Finally, dimethylation of (V) by means of methyl methanesulfonate provided the target N,N-dimethyl tryptamine.

参考文献中间体

合成目标

【1】 Xu, Y.-C.; Schaus, J.M.; Walker, C.; Krushinski, J.; Adhamm, N.; Zgombick, J.M.; Liang, S.X.; Kohlman, D.T.; Audia, J.E.; N-Methyl-5-tert-butyltryptamine: A novel, highly potent 5-HT1D receptor agonist. J Med Chem 1999, 42, 3, 526.
【2】 Audia, J.E.; Cohen, M.L.; Gidda, J.S.; Nelson, D.L.G.; Baker, S.R.; Ezquerra-Carrera, J.; Lamas-Peteira, C.; Pedregal-Tercero, C. (Eli Lilly and Company); Method for treating 5HT2B receptor related conditions. EP 0749313; JP 1997510216; US 5663178; WO 9524200; WO 9624351 .
【3】 Audia, J.E.; et al. (Eli Lilly and Company); Intermediates to tetrahydro-beta-carbolines. US 5635528 .

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)	27492	4-(tert-butyl)aniline	769-92-6	C₁₀H₁₅N	详情	详情
(II)	29269	1-[4-(tert-butyl)phenyl]hydrazine		C₁₀H₁₆N₂	详情	详情
(III)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(IV)	23428	4-Chlorobutanal		C₄H₇ClO	详情	详情
(V)	29270	2-[5-(tert-butyl)-1H-indol-3-yl]-1-ethanamine		C₁₄H₂₀N₂	详情	详情
(VI)	23323	4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine	6346-09-4	C₈H₁₉NO₂	详情	详情
(VII)	10283	ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide	22509-74-6	C₁₁H₉NO₄	详情	详情
(VIII)	23325	2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione		C₁₆H₂₁NO₄	详情	详情
(IX)	29271	2-[2-[5-(tert-butyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione		C₂₂H₂₂N₂O₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(III)

Nitrosation of 7-chloro-3,4-dihydro-2H-1,4-benzothiazine (I) by means of NaNO2 and H2SO4, followed by reduction with LiAlH4, affords amino derivative (II). Finally, Fischer indole cyclization of (II) with 4-chlorobutanal (III) in refluxing aqueous methanol yields the desired product.

参考文献中间体

合成目标

【1】 Slassi, A.; Isaac, M.; O'Brien, A.; et al.; Pyrrolo[3,2,1-ij]quinoline derivatives, a 5-HT2c receptor agonist with selectivity over the 5-HT2a receptor: Potential therapeutic applications for epilepsy and obesity. Bioorg Med Chem Lett 2000, 10, 9, 919.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	45612	7-chloro-3,4-dihydro-2H-1,4-benzothiazine	C₈H₈ClNS	详情	详情
(II)	45613	7-chloro-2,3-dihydro-4H-1,4-benzothiazin-4-ylamine; 7-chloro-2,3-dihydro-4H-1,4-benzothiazin-4-amine	C₈H₉ClN₂S	详情	详情
(III)	23428	4-Chlorobutanal	C₄H₇ClO	详情	详情

Extended Information