2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione -Drug Synthesis Database

【结构式】

【分子编号】23325

【品名】2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione

【CA登记号】

【分子式】C₁₆H₂₁NO₄

【分子量】291.34708

【元素组成】C 65.96% H 7.27% N 4.81% O 21.97%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(III)

4-Aminobutyraldehyde diethyl acetal (I) was treated with N-(ethoxycarbonyl)phthalimide (II) in THF to produce the phthalimido acetal (III), which was hydrolyzed to aldehyde (IV) with HCl in aqueous THF. Subsequent reductive alkylation of 7-methoxy-1,2,3,4-tetrahydroisoquinoline (V) with (IV) in the presence of sodium triacetoxyborohydride provided (VI). After conversion to the hydrochloride salt, the methyl ether of (VI) was cleaved using BBr3 in CH2Cl2 to give the phenol (VII), which was treated with trifluoromethanesulfonic anhydride in pyridine to afford triflate (VIII). The phthalimido group of (VIII) was then removed with ethanolic hydrazine and the resulting primary amine (IX) was finally coupled with 3-(3-indolyl)acrylic acid (X) in the presence of EDC and HOBt to yield the target amide.

参考文献中间体

合成目标

【1】 Nash, D.J.; Stemp, G. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. and their pharmaceutical use. EP 0922035; WO 9806699 .

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)	23323	4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine	6346-09-4	C₈H₁₉NO₂	详情	详情
(II)	10293	methyl (2R)-2-amino-3-(2-chloro-4-quinolinyl)propanoate		C₁₃H₁₃ClN₂O₂	详情	详情
(III)	23325	2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione		C₁₆H₂₁NO₄	详情	详情
(IV)	21620	4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butanal		C₁₂H₁₁NO₃	详情	详情
(V)	21619	7-methoxy-1,2,3,4-tetrahydroisoquinoline; methyl 1,2,3,4-tetrahydro-7-isoquinolinyl ether		C₁₀H₁₃NO	详情	详情
(VI)	21621	2-[4-[7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione		C₂₂H₂₄N₂O₃	详情	详情
(VII)	21622	2-[4-[7-hydroxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione		C₂₁H₂₂N₂O₃	详情	详情
(VIII)	21623	2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate		C₂₂H₂₁F₃N₂O₅S	详情	详情
(IX)	21624	2-(4-aminobutyl)-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate		C₁₄H₁₉F₃N₂O₃S	详情	详情
(X)	21625	trans-3-(3-Indolyl)-2-propenoic acid; trans-Indole-3-acrylic acid; trans-beta-Indoleacrylic acid; Indole-3-acrylic acid; 3-(3-Indolyl)acrylic acid; (E)-3-(1H-indol-3-yl)-2-propenoic acid	29953-71-7	C₁₁H₉NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

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：(VII)

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：(VIII)

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

Extended Information