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【结 构 式】

【分子编号】11883

【品名】1,4-Dibromobutane; 1,4-Butylene bromide

【CA登记号】110-52-1

【 分 子 式 】C4H8Br2

【 分 子 量 】215.91552

【元素组成】C 22.25% H 3.73% Br 74.01%
与该中间体有关的原料药合成路线共 27 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6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26合成路线27

合成路线1

该中间体在本合成路线中的序号：(II)

The condensation of 2,4-dihydroxy-3-prop ylacetophenone (I) with 1 4-dibromobutane (II) by means of K2CO3 in refluxing acetone gives 4-(4 acetyl 3-hydroxy-2-propylphenoxy)butyl bromide (III), which is treated with NaCN in hot DMF to yield 5-(4 acetyl-3-hydroxy-2-propylphenoxy)pen tanenitrile (IV). Finally, this compound is cyclized with sodium azide by means of NH4Cl in DMF at 125 C.

参考文献 中间体
合成目标
【1】 Marshall, W.S.; Verge, J.P. (Eli Lilly and Company); Leukotriene antagonists. EP 0108592 .
【2】 Chu, S.S.; LY-171883. Drugs Fut 1985, 10, 8, 632.
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) 13137 2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone 40786-69-4 C11H14O3 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 24757 1-[4-(4-bromobutoxy)-2-hydroxy-3-propylphenyl]-1-ethanone C15H21BrO3 详情 详情
(IV) 24758 5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentanenitrile C16H21NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

The quaternary salt (II), prepared from 1-(pyrimidin-2-yl)piperazine (I) and 1,4-dibromobutane (A), undergoes reaction with 3,3-dimethylglutarimide (III) in the presence of potassium carbonate in refluxing xylene to afford the free base (IV), which is isolated by acid extraction and basification of the extract. Treatment of the free base with HCl in isopropanol affords ttle compound as the monohydrochloride.

参考文献 中间体
合成目标
【1】 Temple, D.L. Jr. (Bristol-Myers Squibb Co.); 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyrimidines. BE 0895504; CH 656383; DE 3248160; FR 2518993; GB 2114122; JP 1983118582; JP 1994293753; US 4423049 .
【2】 Eison, M.S.; Yevich, J.P.; Farney, R.F.; Gepirone Hydrochloride. Drugs Fut 1985, 10, 6, 456.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(I) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 详情 详情
(II) 29661 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane bromide C12H19BrN4 详情 详情
(III) 29662 4,4-dimethyl-2,6-piperidinedione 1123-40-6 C7H11NO2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The reaction of 2-hydroxydiphenylmethane (I) with 1,4-dibromobutane (II) in a basic medium affords 2-(4-bromobutoxy)diphenylmethane (III), which is then condensed with methylamine in water - ethanol at room temperature.

参考文献 中间体
合成目标
【1】 Kikumoto, R.; et al.; Pharmaceutically active 2-omega-aminoalkoxydiphenylmethanes. US 4091114 .
【2】 Kikumoto, R.; et al.; 2-Substituted-1-(omega-aminoalkoxy)benzenes. DE 2627227; FR 2315913; NL 7606668 .
【3】 Kikumoto, R.; et al. (Mitsubishi Chemical Corp.); Process for preparation of 2-(omega-aminoalkyloxy)diphenylmethanes. JP 52033658 .
【4】 Serradell, M.N.; Blancafort, P.; Castaner, J.; MCI-2016. Drugs Fut 1980, 5, 12, 611.
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) 32707 2-benzylphenol 28994-41-4 C13H12O 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 32708 1-benzyl-2-(4-bromobutoxy)benzene; 2-benzylphenyl 4-bromobutyl ether C17H19BrO 详情 详情

合成路线4

该中间体在本合成路线中的序号：(A)

The condensation of 7-methoxy-3,4-dihydro-1(2H)-naphthalenone (I) with tetramethylene dibromide (A) by means of NaH in benzene gives 3,4-dihydro-7-methoxy-2,2-tetramethylene-1(2H)-naphthalenone (II), b.p.(0.05) = 120-3 C, which is treated with acetonitrile and butyllithium in THF yielding 1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene-1-naphthaleneacetonitrile (III), m.p. 140-2 C. This compound is reduced with LiAlH4 in THF to afford hydro-2,2-tetramethylene-1-naphthol (IV), m.p 178-80 C, and isomerized to 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxy-phenantrene (V), m.p. 187 C. This amine is cyclized by reaction with bromine in CHCl3 giving 3-methoxy-9a-bromonrhasybanan hydrobromide (VI), m.p. 207.0-8.5 C (decomp.), and isomerized with dehydrobromination by treatment with NaHCO3 in DMF affording 3-methoxy-DELTA(8,14)-morphinan (VII), m.p. 180-4 C. The acetylation of (VII) with trifluoroacetic anhydride (B) yields 3-methoxy-N-trifluoroacetyl-DELTA(8,14)-morphinan (VIII), m.p. 94-6 C, which is epoxidized with m-chloroperbenzoic acid in methylene chloride giving 8,14-epoxy-3-methoxy-N-trifluoroacetylmorphinan (IX), m.p. 102-5 C. The deacetylation of (IX) with NaSH4 in ethanol gives 8,14-epoxy-3-methoxymorphinan (X), oily product that is treated with LiAlH4 in THF to open the epoxide ring and yield 14-hydroxy-3-methoxymorphinan (XI) (HCl salt, m.p. 243-4 C (decomp.)). The condensation of (Xl) with cyclobutylcarbonyl chloride (C) by means of pyridine in CH2Cl2 affords N-cyclobutylcarbonyl-14-hydroxy-3-methoxymorphinan (XII), m.p. 183-5 C, which is reduced with LiAlH4 in refluxing THF giving N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan (XIII) (HCl salt, mp. 248-50 C (decomp.)). Finally, (XIII) is demethylated by treatment with refluxing 48% HBr.

参考文献 中间体
合成目标
【1】 Conway, T.T.; Monkovic, I.; J Am Chem Soc 1973, 95, 23, 7910-12.
【2】 Pachter, I.; et al.; 14-Hydroxymorphinan derivatives. DE 2243961; FR 2154481; GB 1412129; GB 1412130; US 3819635 .
【3】 Monkovic, I.; Conway, T.T.; Process for the preparation of 14-hydroxymorphinan derivatives. JP 49061169; NL 7306344; US 3775414 .
【4】 Paton, D.M.; Castaner, J.; Butorphanol. Drugs Fut 1977, 2, 4, 231.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(B) 33862 trifluoroacetic anhydride 407-25-0 C4F6O3 详情 详情
(I) 21385 7-methoxy-3,4-dihydro-1(2H)-naphthalenone 6836-19-7 C11H12O2 详情 详情
(II) 33856 　 C15H18O2 详情 详情
(III) 33857 RCL R15,507-1 C17H21NO2 详情 详情
(IV) 33858 　 C17H25NO2 详情 详情
(V) 33859 2-[6-methoxy-1,3,4,9-tetrahydro-4(2H)-phenanthrenyl]ethylamine; 2-[6-methoxy-1,3,4,9-tetrahydro-4(2H)-phenanthrenyl]-1-ethanamine C17H23NO 详情 详情
(VI) 33860 　 C17H22BrNO 详情 详情
(VII) 33861 (1S,9R)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraene; (1S,9R)-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraen-4-yl methyl ether C17H21NO 详情 详情
(VIII) 33863 2,2,2-trifluoro-1-[(1S,9R)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6,10-tetraen-17-yl]-1-ethanone C19H20F3NO2 详情 详情
(IX) 33864 2,2,2-trifluoro-1-[(1S,9R,10S,12S)-4-methoxy-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-trien-18-yl]-1-ethanone C19H20F3NO3 详情 详情
(X) 33865 (1S,9R,10S,12S)-4-methoxy-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-triene; methyl (1S,9R,10S,12S)-11-oxa-18-azapentacyclo[7.6.3.0(1,10).0(2,7).0(10,12)]octadeca-2,4,6-trien-4-yl ether C17H21NO2 详情 详情
(XI) 33866 (1S,9R,10S)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-10-ol C17H23NO2 详情 详情
(XII) 33867 cyclobutyl[(1S,9R,10S)-10-hydroxy-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-17-yl]methanone C22H29NO3 详情 详情
(XIII) 33868 (1S,9R,10S)-17-(cyclobutylmethyl)-4-methoxy-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-10-ol C22H31NO2 详情 详情
(C) 18589 cyclobutanecarbonyl chloride 5006-22-4 C5H7ClO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VIII)

Reaction of the dicarboxylic acid (I) with thionyl chloride in hot toluene gives the di-acid chloride (II). Treatment of (II) with Cl2 in CH2Cl2 gives the sulfenyl chloride (III), which upon reaction with NH4OH affords the benzisothiazole (IV). Chlorination of (IV) in heat POCl3 yields the chlorobenzisothiazole (V). Reaction of (V) and piperazine (VI) in excess molten pipeazine gives the monosubstituted piperazine (VII). Reaction of (VII) with the dibromide (VIII) in refluxing ethanol yields the spiroquaternary (IX). Finally, BMY-13859-1 is obtained by treatment of (IX) with the glutarimide (X) in refluxing xylene followed by treatment with HCl in isopropanol.

参考文献 中间体
合成目标
【1】 Eison, M.S.; Taylor, D.P.; New, J.S.; Minielli, J.L.; BMY-13859. Drugs Fut 1985, 10, 9, 731.
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) 10404 Ethyl vanillin; 3-Ethoxy-4-hydroxybenzaldehyde 121-32-4 C9H10O3 详情 详情
(II) 10405 2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile C15H20ClNO2 详情 详情
(III) 28018 2-(chlorosulfanyl)benzoyl chloride C7H4Cl2OS 详情 详情
(IV) 16278 1,2-benzisothiazol-3(2H)-one; 1,2-Benzisothiazolin-3-one 2634-33-5 C7H5NOS 详情 详情
(V) 16279 3-chloro-1,2-benzisothiazole C7H4ClNS 详情 详情
(VI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VII) 16280 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) 87691-87-0 C11H13N3S 详情 详情
(VIII) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(IX) 28019 8-(1,2-benzisothiazol-3-yl)-8-aza-5-azoniaspiro[4.5]decane bromide C15H20BrN3S 详情 详情
(X) 28020 8-azaspiro[4.5]decane-7,9-dione 1075-89-4 C9H13NO2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

The reaction of benzoisothiazole-3(2H)-one-1,1-dioxide (I) with 1,4-dibromobutane (II) by means of NaH in DMF gives 2-(4-bromobutyl)benzoisothiazole-3(2H)-one-1,1-dioxide (III), which is then condensed with 1-(2 pyrimidinyl)piperazine (IV) by means of K2CO3 in refluxing chlorobenzene.

参考文献 中间体
合成目标
【1】 Seidel, P.-R.; Horstmann, H.; Traber, J.; Dompert, W.; Glaser, T.; Schuurman, T. (Troponwerke GmbH & Co KG); 2-pyrimidinyl-1-piperazine derivatives, proceses for their preparation and medicaments containing them. EP 0129128; JP 60023373; US 4818756; US 4937343; US 4988809 .
【2】 Castaner, J.; Prous, J.; Ipsapirone. Drugs Fut 1986, 11, 7, 565.
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) 24826 3-oxo-2,3-dihydro-1H-1,2-benzisothiazole-1,1-diolate C7H5NO3S 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 24828 2-(4-bromobutyl)-3-oxo-2,3-dihydro-1H-1,2-benzisothiazole-1,1-diolate C11H12BrNO3S 详情 详情
(IV) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VII)

For the synthesis of umespirone the following synthesis pathway was chosen: Acetone is condensed with ethyl cyanoethanoate (I) to yield ethylisopropylidenecyanoacetate (II). This product is reacted with N-butylcyanoacetamide (III) in sodium methoxide solution to give N-butyl-2,4-dicyano-3,3-dimethylglutarimide (IV). The glutarimide (IV) is cyclized with phosphoric acid to yield 3-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraone (V). The quaternary salt (VIII) (R = CH3), prepared from 1-(2-methoxyphenyl)piperazine (VI) and 1,4-dibromobutane (VII), undergoes reaction with (V) in the presence of potassium carbonate to afford the free base KC-9172 (IX) (R = CH3).

参考文献 中间体
合成目标
【1】 Schon, U.; Kehrbach, W.; Benson, W.; Fuchs, A.; Ruhland, M. (Kali-Chemie AG); Novel tetraoxo cpds. AU 8661619; DE 3529872; EP 0212551; ES 8801271; ES 8801272; US 4771044 .
【2】 Krahling, H.; Krijzer, F.; Umespirone. Drugs Fut 1991, 16, 5, 437.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(I) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(II) 11878 ethyl 2-cyano-3-methyl-2-butenoate; 2-Butenoic acid, 2-cyano-3-methyl-, ethyl ester 759-58-0 C8H11NO2 详情 详情
(III) 11879 N-Butyl-2-cyanoacetamide C7H12N2O 详情 详情
(IV) 11880 1-Butyl-4,4-dimethyl-2,6-dioxo-3,5-piperidinedicarbonitrile C13H17N3O2 详情 详情
(V) 11881 3-Butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetrone C13H18N2O4 详情 详情
(VI) 11882 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine 35386-24-4 C11H16N2O 详情 详情
(VII) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(VIII) 11884 8-(2-Methoxyphenyl)-8-aza-5-azoniaspiro[4.5]decane bromide C15H23BrN2O 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VII)

Reaction of 1,3,5,7-cyclooctatetraene (I) with maleimide (Step a, b), or maleic anhydride (Step c), in refluxing toluene affords the imide (II) or the anhydride (III) in 78 and 85% yields, respectively. Reaction of imide intermediate (II) with 1,4-dibromobutane gives the omega-haloalkylimide, which subsequently is reacted with 1-(2-pyrimidinyl)piperazine to yield Wy-47846 (Method A). Alternatively, Wy-47846 can be prepared via the reaction of (III) with 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in refluxing pyridine (Method B), as shown in scheme. Wy-47846 is achiral.

参考文献 中间体
合成目标
【2】 Abou-Gharbia, M.; Moyer, J.A.; Haskins, J.T.; WY-47846. Drugs Fut 1989, 14, 5, 442.
【1】 Abou-Gharbia, M.; et al.; Polycyclic aryl- and heteroarylpiperazyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies. J Med Chem 1988, 31, 7, 1382.
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) 20923 1,3,5,7-cyclooctatetraene 629-20-9 C8H8 详情 详情
(II) 20924 bicyclo[4.2.0]octa-2,4-diene C8H10 详情 详情
(III) 20925 (2R,6S,8R,11S)-4-azatetracyclo[5.4.2.0(2,6).0(8,11)]trideca-9,12-diene-3,5-dione C12H11NO2 详情 详情
(IV) 20926 (2R,6S,8R,11S)-4-oxatetracyclo[5.4.2.0(2,6).0(8,11)]trideca-9,12-diene-3,5-dione C12H10O3 详情 详情
(V) 19711 1H-pyrrole-2,5-dione 541-59-3 C4H3NO2 详情 详情
(VI) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情
(VII) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(VIII) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 详情 详情
(IX) 11181 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine 33386-20-8 C12H21N5 详情 详情

合成路线9

该中间体在本合成路线中的序号：(III)

This compound can be obtained by two related ways: 1) The reaction of cis-octahydroisobenzofuran-1,3-dione (I) with ammonia in water at 180-90 gives cis-octahydro-1H-isoindole-1,3-dione (II), which is alkylated with 1,4-dibromobutane (III) and K2CO3 in refluxing acetone to yield cis-2-(4-bromobutyl)octahydro-1H-isoindole-1,3-dione (IV). The condensation of (IV) with piperazine (V) in refluxing toluene affords cis-2-(4-piperazinobutyl)octahydro-1H-isoindole-1,3-dione (VI), which is finally condensed with 3-chloro-1,2-benzisothiazole (VII) and K2CO3 in refluxing toluene. 2) The condensation of benzisothiazole (VII) with piperazine (V) by heating at 120 C gives 3-piperazino-1,2-benzisothiazole (VIII), which is then condensed with isoindole (IV) by means of K2CO3 and KI in hot DMF. 3) The 3-chloro-1,2-benzisothiazole (VII) is obtained as follows: The reaction of 2,2'-dithiobenzoic acid (IX) with refluxing SOCl2 gives the corresponding acyl chloride (X), which by treatment with methylamine in THF is converted into the diamide (XI). The reaction of (XI) with PCl5 in refluxing benzene affords 3-chloro-2-methyl-1,2-benzisothiazolium chloride (XII), which is finally heated in refluxing 1,2-dichlorobenzene to give (VII).

参考文献 中间体
合成目标
【1】 Ishizumi, N.; Antoku, F.; Maruyama, I.; Kojima, A. (Sumitomo Pharmaceuticals Co., Ltd.); Imide derivs., their production and use. EP 0196096; ES 8800219; JP 1987123179; JP 1987277355; JP 1987277356; US 4745117 .
【2】 Prous, J.; Castaner, J.; SM-9018. Drugs Fut 1991, 16, 2, 122.
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) 27329 (3aR,7aS)hexahydro-2-benzofuran-1,3-dione 13149-00-3 C8H10O3 详情 详情
(II) 31245 (3aR,7aS)hexahydro-1H-isoindole-1,3(2H)-dione 7506-66-3 C8H11NO2 详情 详情
(III) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(IV) 31246 (3aR,7aS)-2-(4-bromobutyl)hexahydro-1H-isoindole-1,3(2H)-dione C12H18BrNO2 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 31247 (3aR,7aS)-2-[4-(1-piperazinyl)butyl]hexahydro-1H-isoindole-1,3(2H)-dione C16H27N3O2 详情 详情
(VII) 16279 3-chloro-1,2-benzisothiazole C7H4ClNS 详情 详情
(VIII) 16280 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) 87691-87-0 C11H13N3S 详情 详情
(IX) 20404 2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid 119-80-2 C14H10O4S2 详情 详情
(X) 20405 2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride C14H8Cl2O2S2 详情 详情
(XI) 31248 N-methyl-2-([2-[(methylamino)carbonyl]phenyl]disulfanyl)benzamide 2527-58-4 C16H16N2O2S2 详情 详情
(XII) 31249 3-chloro-2-methyl-1,2-benzisothiazol-2-ium chloride C8H7Cl2NS 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

The condensation of 7-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (I) with 1,4-dibromobutane (II) by means of K2CO3 in hot DMF gives 7-(4-bromobutoxy)-1,2,3,4-tetrahydroquinolin-2-one (III), which is then condensed with 1-(2,3-dichlorophenyl)piperazine (IV) by means of NaI and triethylamine in refluxing acetonitrile.

参考文献 中间体
合成目标
【1】 Kikuchi, T.; Oshiro, Y.; Nishi, T.; Kurahashi, N.; Tottori, K.; Tanaka, T.; Sato, S.; Uwahodo, Y.; Novel antipsychotic agents with dopamine autoreceptor agonist properties: Synthesis and pharmacology of 7-[4-(4-phenyl-1-piperazinyl)butoxy]-3, 4-dihydro-2(1H)-quinolinone derivatives. J Med Chem 1998, 41, 5, 658.
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) 27883 7-hydroxy-3,4-dihydro-2(1H)-quinolinone 22246-18-0 C9H9NO2 详情 详情
(II) 13943 1-(2,3-Dichlorophenyl)piperazine 41202-77-1 C10H12Cl2N2 详情 详情
(IV) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(V) 13940 7-(4-Bromobutoxy)-3,4-dihydro-2(1H)-quinolinone 129722-34-5 C13H16BrNO2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

Lesopitron dihydrochloride was obtained following two related procedures. 1) Reaction of 4-chloropyrazole (I) with 1,4-dibromobutane (II) gives 1-(4-bromobutyl)-4-chloropyrazole (III). Compound (III) is refluxed with 2-(1-piperazinyl)pyrimidine (IV) and potassium carbonate in DMF to give lesopitron (V), which is treated with isopropyl alcohol saturated with hydrochloric acid to pH 4.5-5 . 2) 2-(1-Piperazinyl)pyrimidine (IV) reacts with 1,4-dibromobutane (II) to yield 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane bromide (VI). The quaternary salt (VI) undergoes reaction with 4-chloropyrazole (I) in DMF in the presence of potassium carbonate to afford the free base.

参考文献 中间体
合成目标
【1】 Merce-Vidal, R.; Frigola-Constansa, J.; Pares-Corominas, J. (Laboratorios del Dr. Esteve, SA); Process for the preparation of aryl (or heteroaryl) piperazinylbutylazole derivs. AU 9211429; CA 2062468; EP 0502786; ES 2036145; FR 2673628; JP 1993078313; NO 9200888; US 5227486; ZA 9201682 .
【2】 Frigola, J.; Farré, A.; Lesopitron Dihydrochloride. Drugs Fut 1994, 19, 7, 651.
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) 14132 4-Chloro-1H-pyrazole 15878-00-9 C3H3ClN2 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 14134 1-(4-Bromobutyl)-4-chloro-1H-pyrazole C7H10BrClN2 详情 详情
(IV) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 详情 详情
(V) 14136 2-[4-[4-(4-Chloro-1H-pyrazol-1-yl)butyl]piperazino]pyrimidine C15H21ClN6 详情 详情
(VI) 14137 8-(2-Pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane C12H19N4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

Alkylation of 2-pyrrolidinone (I) with 1,4-dibromobutane (II) in the presence of KOH and tetraethylammonium bromide gave the N-(4-bromobutyl)pyrrolidinone (III). This was condensed with 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine (IV) in the presence of Na2CO3 to produce the target disubstituted piperazine, which was then converted to the corresponding fumarate salt.

参考文献 中间体
合成目标
【1】 Carlier, P.; Combourieu, M.; Poisson, C.; Monteil, A.J.-C. (Akzo Nobel N.V.); 4-[4- or 6-(Trifluoromethyl-2-pyridinyl)]-1-piperazinyl-alkyl substd. lactams. EP 0482696; JP 1992282379; US 5180726 .
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) 27397 2-Pyrrolidinone 616-45-5 C4H7NO 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 59111 1-(4-bromobutyl)-2-pyrrolidinone C8H14BrNO 详情 详情
(IV) 59112 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine C10H12F3N3 详情 详情

合成路线13

该中间体在本合成路线中的序号：

The synthesis of BAY x 3702 was carried out as outlined: Chroman-2-carboxylic acid (I) was activated with thionyl chloride. The acid chloride (II) was treated with (S)-phenethylamine (III), affording a (1:1)-mixture of diastereomers. Fractional crystallization from ethanol gave the isomer (IV) in high diastereomerical purity; basic epimerization of the undesired diastereomer is feasible. The amide (IV) was reduced with diborane in THF, yielding the amine (V), which was submitted to catalytic hydrogenation over palladium-on-charcoal. The resulting optically pure (R)-2-aminomethyl chroman (VI) was alkylated with 4-bromobutyl saccharin (VII), which is easily available from saccharin sodium and 1,4-dibromobutane. BAY x 3702 was isolated as the hydrochloride salt. White, odorless crystals, m.p. 195 C, alpha(20,D) -42.2 (c 0.9, CHCl3). BAY x 3702 is soluble in water (2.1 g/100 ml), acetone (2.2 g/100 ml) and DMSO. The solid substance is heat-stable, nonhygroscopic and nonsensitive to light. It is unstable in alkaline medium (hydrolysis), sensitive to hydrolysis in aqueous dilute solutions/suspensions at weak acidic and neutral pH, but stable in acidic medium (pH less than or equal to 4). The UV spectrum shows maxima at 272 and 279 nm. BAY x 3702 can be assayed by HPLC.

参考文献 中间体
合成目标
【1】 Opitz, W.; Heine, H-G.; Mauler, F.; Schohe-Loop, R.; Maertins, T.; Jork, R.; Dietrich, H.; Glaser, T.; Horvath, E.; Scherling, D.; De Vry, J.; Bay-x-3702. Drugs Fut 1997, 22, 4, 341.
【2】 Junge, B.; Schohe, R.; Seidel, P.-R.; Glaser, T.; Traber, J.; Benz, U.; Schuurman, T.; De Vry, J.-M.-V. (Bayer AG); Substd. amino methyl tetralines, and their heterocyclic analogous cpds. EP 0352613; JP 1990096552; US 5137901; US 5506246 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
33704 1,1-Dioxide-1,2-benzisothiazol-3(2H)-one, sodium salt; 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt (1:1) 38279-26-4 C7H4NNaO3S 详情 详情
65068 2-(4-{[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione C21H24N2O4S 详情 详情
(I) 17037 2-chromanecarboxylic acid C10H10O3 详情 详情
(II) 17038 2-chromanecarbonyl chloride C10H9ClO2 详情 详情
(IV) 17040 (2R)-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide C18H19NO2 详情 详情
(V) 17041 (1S)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1S)-1-phenylethyl]amine C18H21NO 详情 详情
(VI) 17042 (2R)-3,4-dihydro-2H-chromen-2-ylmethanamine; (2R)-3,4-dihydro-2H-chromen-2-ylmethylamine C10H13NO 详情 详情
(VII) 17043 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione C11H12BrNO3S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

The adopted procedure for the preparation of HCT-1026 consisted in the reaction of flurbiprofen sodium salt (I) and 1,4-dibromobutane (II) in acetonitrile at reflux temperature to obtain HCT-1031 (III), the 4-bromobutyl ester of flurbiprofen. HCT-1031 was then converted into HCT-1026 by reaction with silver nitrate in acetonitrile at reflux temperature. The crude HCT-1026 thus obtained showed 85% HPLC purity with the presence of one major impurity (15%) that was identified as the bis-compound HCT-1028. The crude product was then purified by silica gel column chromatography using toluene as eluent to give a product with >99% HPLC purity in 57% overall yield. After cooling, pure HCT-1026 was obtained as a thick oil.

参考文献 中间体
合成目标
【1】 Benedini, F.; Burgaud, J.L.; Del Soldato, P.; Robinson, E.M.; HCT-1026. Drugs Fut 1999, 24, 8, 858.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 12280 Flurbiprofen; 2-(2-Fluoro[1,1'-biphenyl]-4-yl)propionic acid 5104-49-4 C15H13FO2 详情 详情
(I) 26005 sodium 2-(2-fluoro[1,1'-biphenyl]-4-yl)propanoate C15H12FNaO2 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 26006 4-bromobutyl 2-(2-fluoro[1,1'-biphenyl]-4-yl)propanoate C19H20BrFO2 详情 详情

合成路线15

该中间体在本合成路线中的序号：

Nibentan is obtained as illustrated in Scheme 22645801a: Phenylacetonitrile (I) is condensed with diethyl carbonate by means of sodium ethylate in toluene to give sodium (ethoxycarbonyl)cyanophenylmethanate (II). Subsequent alkylation of (II) with 1,4-dibromobutane provides 5-bromo-1-(ethoxycarbonyl)-1-cyano-1-phenylpentane (III). Treatment of (III) with diethylamine gives 1-(ethoxycarbonyl)-1-cyano-5-(diethylamino)-1-phenylpentane (IV), which is decarboxylated with aqueous KOH in the presence of triethylbenzylammonium chloride to 1-cyano-5-(diethylamino)-1-phenylpentane (V). The reaction of (V) with H2O2 in dimethylsulfoxide gives 1-carbamoyl-5-(diethylamino)-1-phenylpentane (VI), which is rearranged to 1-(methoxycarbonylamino)-5-(diethylamino)-1-phenylpentane (VII) according to Hoffman reaction by means of bromine and sodium methylate in methanol. Hydrolysis of (VII) with NaOH in ethanol provides amine (VIII). Subsequent coupling of (VIII) with 4-nitrobenzoyl chloride in acetonitrile yields nibentan.

参考文献 中间体
合成目标
【1】 Glushkov, R.G, Mashkovski, M.C.; Yuzhakov, S.D.; Nibentan. Drugs Fut 1997, 22, 1, 30.
【2】 L'vov, A.I.; Davydova, N.K.; Sizova, O.S.; Glushov, R.G.; Mashkovskiy, M.D.; Vinogradova, S.M.; Yurhakov, S.D.; Synthesis and antifibrillatory activity of nibentan and its analogues. Eur J Med Chem 2000, 35, 2, 205.
【3】 Glushkov, R.G.; Lvov, A.I.; Davidova, N.K.; Sizova, O.S.; Sanzarova, G.M.; Polakova, M.J.; Skachilova, S.J.; Zeltuchin, N.K.; Cherkasova, E.M.; The method of preparation of hydrochloride 1-phenyl-1-p-nitrobenzoylamino-5-N,N-diethylaminopentane and 1-phenyl-1-amino-5-N,N-diethylaminopentane. SU 2059612 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(I) 17046 Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide 140-29-4 C8H7N 详情 详情
(II) 17047 ethyl 2-cyano-2-phenylacetate 4553-07-5 C11H11NO2 详情 详情
(III) 17048 ethyl 6-bromo-2-cyano-2-phenylhexanoate C15H18BrNO2 详情 详情
(IV) 17049 ethyl 2-cyano-6-(diethylamino)-2-phenylhexanoate C19H28N2O2 详情 详情
(V) 17050 6-(diethylamino)-2-phenylhexanenitrile C16H24N2 详情 详情
(VI) 17051 6-(diethylamino)-2-phenylhexanamide C16H26N2O 详情 详情
(VII) 17052 methyl N-[5-(diethylamino)-1-phenylpentyl]carbamate C17H28N2O2 详情 详情
(VIII) 17053 N-(5-amino-5-phenylpentyl)-N,N-diethylamine; N(5),N(5)-diethyl-1-phenyl-1,5-pentanediamine C15H26N2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IV)

Ortho lithiation of sulfonamide (I) with n-butyllithium, followed by carbonation with CO2 afforded benzoic acid (II). Subsequent cyclization with PPA with concomitant elimination of the N-tert-butyl group provided the saccharin analogue (III). Alkylation of the sodium salt of (III) with 1,4-dibromobutane (IV) in DMF yielded bromide (V). The reductive alkylation of 2-aminophenol (VI) with 1-tert-butoxycarbonyl-4-piperidone (VII) in the presence of sodium tri(acetoxy)borohydride provided the aminopiperidine (VIII), which was cyclized with triphosgene to afford benzoxazolone (IX). Then, removal of the N-Boc protecting group provided piperidine (X), which was finally alkylated with bromide (V) in the presence of Et3N in DMF at 80 C to furnish the title compound.

参考文献 中间体
合成目标
【1】 Nerenberg, J.B.; Erb, J.M.; Thompson, W.J.; Lee, H.Y.; Guare, J.P.; Munson, P.M.; Bergman, J.M.; Huff, J.R.; Broten, T.P.; Chang, R.S.; Chen, T.B..; O'Malley, S.; Schorn, T.W.; Scott, A.L.; Design and synthesis of N-alkylated saccharins as selective alpha1-a adrenergic receptor antagonists. Bioorg Med Chem Lett 1998, 8, 18, 2467.
【2】 Lombardino, J.G.; Preparation of substituted 1,2-benzoisothiazolin-3-one 3 1,1-dioxides (o-benzoic sulfimides). J Org Chem 1971, 36, 13, 1843.
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) 18658 N-(tert-butyl)-4-chlorobenzenesulfonamide C10H14ClNO2S 详情 详情
(II) 18659 2-[(tert-butylamino)sulfonyl]-5-chlorobenzoic acid C11H14ClNO4S 详情 详情
(III) 18660 5-chloro-1H-1,2-benzisothiazole-1,1,3(2H)-trione C7H4ClNO3S 详情 详情
(IV) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(V) 18400 2-(4-bromobutyl)-5-chloro-1H-1,2-benzisothiazole-1,1,3(2H)-trione C11H11BrClNO3S 详情 详情
(VI) 18663 o-aminophenol; 2-aminophenol 95-55-6 C6H7NO 详情 详情
(VII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VIII) 18665 tert-butyl 4-(2-hydroxyanilino)-1-piperidinecarboxylate C16H24N2O3 详情 详情
(IX) 18666 tert-butyl 4-[2-oxo-1,3-benzoxazol-3(2H)-yl]-1-piperidinecarboxylate C17H22N2O4 详情 详情
(X) 18667 3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one C12H14N2O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

Tetrahydrobenzindole (I) was alkylated with 1,4-dibromobutane (II) in the presence of NaH to afford the bromobutyl derivative (III). This was then condensed with 4-phenyltetrahydropyridine (IV) to yield the title compound.

参考文献 中间体
合成目标
【1】 Kikuchi, C.; et al.; Tetrahydrobenzindoles: Selective antagonists of the 5-HT7 receptor. J Med Chem 1999, 42, 4, 533.
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) 25590 2a,3,4,5-tetrahydrobenzo[cd]indol-2(1H)-one 96933-21-0 C11H11NO 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 25591 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenzo[cd]indol-2(1H)-one C15H18BrNO 详情 详情
(IV) 25592 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride 1191-50-0 C11H14ClN 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

The condensation of perhydropyrrolo[1,2-c]imidazole-2,7-dione (I) with 1,4-dibromobutane (II) by means of NaH in DMF gives the expected 4-bromobutyl derivative (III), which is condensed with 1-(3-nitrophenyl)piperazine (IV) by means of triethylamine in hot acetonitrile yielding 2-[4-[4-(3-nitrophenyl)piperazin-1-yl]butyl]perhydropyrrolo[1,2-c]imidazole-2,7-dione (V). The reduction of the nitro group of (V) with H2 over Pd/C in methanol affords the corresponding amino derivative (VI), which is finally sulfonated with ethanesulfonyl chloride and pyridine in acetone.

参考文献 中间体
合成目标
【1】 López-Rodríguez, M.L.; et al.; Design and synthesis of 2-[4-[4-(m-(ethylsulfonamido)-penhyl)piperazin-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole (EF-7412) using neural networks. A selective derivative with mixed 5-HT1A/D2 antagonist properties. Bioorg Med Chem Lett 1999, 9, 12, 1679.
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) 25216 tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione C6H8N2O2 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 26724 2-(4-bromobutyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione C10H15BrN2O2 详情 详情
(IV) 26725 1-(3-nitrophenyl)piperazine C10H13N3O2 详情 详情
(V) 26726 2-[4-[4-(3-nitrophenyl)-1-piperazinyl]butyl]tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione C20H27N5O4 详情 详情
(VI) 26727 2-[4-[4-(3-aminophenyl)-1-piperazinyl]butyl]tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione C20H29N5O2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(I)

Grignard reagent (II), prepared from 1,4-dibromobutane (I), was added to lactone (III) to produce the cyclopentanol derivative (IV). Oxidation of the primary alcohol of (IV) with sulfur trioxide-pyridine complex in the presence of DMSO gave rise to lactone (V), which was reduced to the corresponding lactol (VI) by means of DIBAL at low temperature. Subsequent acid hydrolysis of the ketal group of (VI) afforded triol (VII). Mitsunobu coupling with 4-(diphenylmethoxy)-7-hydroxycoumarin (VIII) furnished ether (IX). After selective hydroxyl group protection of (IX) with chlorotriethylsilane to give (X), the remaining free hydroxyl was further protected as the tetrahydropyranyl ether (XI). Then, removal of the benzhydryl protecting group of (XI) was achieved by hydrogenation over Pd/C to give (XII).

参考文献 中间体
合成目标
【1】 Periers, A.-M.; Laurin, P.; Klich, M.; Musicki, B.; Haesslein, J.-L. (Aventis Pharma SA); Novel aromatic amides, preparation method and application as medicines. FR 2773369; WO 9935155 .
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) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(II) 38182 1,4-Bis(bromomagnesio)butane 23708-48-7 C4H8Br2Mg2 详情 详情
(III) 38183 (3aS,7R,7aR)-7-methoxy-2,2-dimethyltetrahydro-6H-[1,3]dioxolo[4,5-c]pyran-6-one C9H14O5 详情 详情
(IV) 38184 1-[(R)-[(4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl](methoxy)methyl]cyclopentanol C13H24O5 详情 详情
(V) 38185 　 C13H20O5 详情 详情
(VI) 38186 　 C13H22O5 详情 详情
(VII) 38187 (8R,9S,10R)-10-methoxy-6-oxaspiro[4.5]decane-7,8,9-triol C10H18O5 详情 详情
(VIII) 38188 4-(benzhydryloxy)-7-hydroxy-8-methyl-2H-chromen-2-one C23H18O4 详情 详情
(IX) 38189 4-(benzhydryloxy)-7-[[(7R,8R,9S,10R)-8,9-dihydroxy-10-methoxy-6-oxaspiro[4.5]dec-7-yl]oxy]-8-methyl-2H-chromen-2-one C33H34O8 详情 详情
(X) 38190 4-(benzhydryloxy)-7-([(7R,8R,9S,10R)-8-hydroxy-10-methoxy-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one C39H48O8Si 详情 详情
(XI) 38191 4-(benzhydryloxy)-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one C44H56O9Si 详情 详情
(XII) 38192 4-hydroxy-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one C31H46O9Si 详情 详情

合成路线20

该中间体在本合成路线中的序号：(IV)

The condensation of 3-cyanophenyl isocyanate (I) with N-Boc-4-aminopiperidine (II) produced the corresponding urea (III). The diazepinone system (V) was then obtained by dialkylation of the urea (III) functionality with 1,4-dibromobutane (IV) in the presence of NaH. After acid cleavage of the Boc protecting group of (V), the resulting piperidine (VI) was acylated with 2-thiophenesulfonyl chloride (VII) to give sulfonamide (VIII). Addition of methanol to the cyano group of (VIII) in the presence of anhydrous HCl in MeOAc furnished imidate (IX). This was then converted to the corresponding amidine by treatment with either methanolic ammonia or (NH4)2CO3, followed by conversion to the title hydrochloride salt.

参考文献 中间体
合成目标
【1】 Rossi, K.A.; Wells, B.L.; Galemmo, R.A. Jr.; et al.; The de novo design and synthesis of cyclic urea inhibitors of factor Xa: Optimization of the S4 ligand. Bioorg Med Chem Lett 2000, 10, 3, 301.
【2】 Maduskuie, T.P. Jr.; Galemmo, R.A. Jr.; Dominguez, C.; Quan, M.L.; Rossi, K.A.; Stouten, P.F.W.; Sun, J.H.; Wells, B.L. (DuPont Pharmaceuticals Co.); N-(Amidinophenyl)-N'-(substd.)-3H-2, 4-benzodiazepin-3-one derivs. as factor Xa inhibitors. EP 0960104; US 5925635; WO 9738984 .
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) 40756 3-isocyanatobenzonitrile 16413-26-6 C8H4N2O 详情 详情
(II) 28414 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine 87120-72-7 C10H20N2O2 详情 详情
(III) 40757 tert-butyl 4-[[(3-cyanoanilino)carbonyl]amino]-1-piperidinecarboxylate C18H24N4O3 详情 详情
(IV) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(V) 40758 tert-butyl 4-[3-(3-cyanophenyl)-2-oxo-1,3-diazepan-1-yl]-1-piperidinecarboxylate C22H30N4O3 详情 详情
(VI) 40759 3-[2-oxo-3-(4-piperidinyl)-1,3-diazepan-1-yl]benzonitrile C17H22N4O 详情 详情
(VII) 40760 2-thiophenesulfonyl chloride 16629-19-9 C4H3ClO2S2 详情 详情
(VIII) 40761 3-[2-oxo-3-[1-(2-thienylsulfonyl)-4-piperidinyl]-1,3-diazepan-1-yl]benzonitrile C21H24N4O3S2 详情 详情
(IX) 40762 methyl 3-[2-oxo-3-[1-(2-thienylsulfonyl)-4-piperidinyl]-1,3-diazepan-1-yl]benzenecarboximidoate C22H28N4O4S2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(III)

The condensation of 4-nitrophenylacetonitrile (I) with diethyl carbonate by means of sodium ethylate in toluene gave the intermediate arylcyanoacetate sodium salt (II) that was further alkylated with 1,4-dibromobutane (III) to yield the bromobutyl derivative (IV). Subsequent treatment of bromide (IV) with diethylamine provided amine (V). Decarbethoxylation of the cyanoester group of (V) to give (VI) was carried out using aqueous KOH in the presence of benzyltriethylammonium chloride. Partial hydrolysis of the nitrile group of (VI) by means of potassium hydroperoxide in DMSO afforded amide (VII). This was subjected to Hoffman rearrangement by means of Br2 and NaOEt to produce carbamate (VIII), which was subsequently hydrolyzed to amine (IX) with KOH. This was finally coupled with benzoyl chloride to furnish the title benzamide.

参考文献 中间体
合成目标
【1】 L'vov, A.I.; Davydova, N.K.; Sizova, O.S.; Glushov, R.G.; Mashkovskiy, M.D.; Vinogradova, S.M.; Yurhakov, S.D.; Synthesis and antifibrillatory activity of nibentan and its analogues. Eur J Med Chem 2000, 35, 2, 205.
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) 40948 2-(4-nitrophenyl)acetonitrile 555-21-5 C8H6N2O2 详情 详情
(II) 40949 　 C11H9N2NaO4 详情 详情
(III) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(IV) 40950 ethyl 6-bromo-2-cyano-2-(4-nitrophenyl)hexanoate C15H17BrN2O4 详情 详情
(V) 40951 ethyl 2-cyano-6-(diethylamino)-2-(4-nitrophenyl)hexanoate C19H27N3O4 详情 详情
(VI) 40952 6-(diethylamino)-2-(4-nitrophenyl)hexanenitrile C16H23N3O2 详情 详情
(VII) 40953 6-(diethylamino)-2-(4-nitrophenyl)hexanamide C16H25N3O3 详情 详情
(VIII) 40954 methyl 5-(diethylamino)-1-(4-nitrophenyl)pentylcarbamate C17H27N3O4 详情 详情
(IX) 40955 N-[5-amino-5-(4-nitrophenyl)pentyl]-N,N-diethylamine; N(5),N(5)-diethyl-1-(4-nitrophenyl)-1,5-pentanediamine C15H25N3O2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(IV)

Dibenzyl malonate (I) was alkylated with 3-(trifluoromethyl)benzyl bromide (II) in the presence of Na in DMF to yield the 3-(trifluoromethyl)benzylmalonate (III). Further alkylation of (III) with 1,4-dibromobutane (IV) provided the bromobutyl derivative (V). Condensation of the known 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8-one (VI) with bromide (V) in the presence of NaH and NaI furnished adduct (VII). The keto group of (VII) was then reduced to alcohol (VIII) employing NaBH4 in MeOH-CH2Cl2. Finally, hydrogenolysis of the benzyl ester groups of (VIII) in the presence of Pd/C and Et3N afforded the title dicarboxylate triethylammonium salt.

参考文献 中间体
合成目标
【1】 Bookser, B.C.; Kasibhatla, S.R.; Erion, M.D.; AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues: N3-alkylmalonates as ribose 5'-monophosphate mimetics. J Med Chem 2000, 43, 8, 1519.
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) 16013 dibenzyl malonate 15014-25-2 C17H16O4 详情 详情
(II) 40803 1-(bromomethyl)-3-(trifluoromethyl)benzene 402-23-3 C8H6BrF3 详情 详情
(III) 40804 dibenzyl 2-[3-(trifluoromethyl)benzyl]malonate C25H21F3O4 详情 详情
(IV) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(V) 40805 dibenzyl 2-(4-bromobutyl)-2-[3-(trifluoromethyl)benzyl]malonate C29H28BrF3O4 详情 详情
(VI) 40806 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one C6H6N4O 详情 详情
(VII) 40807 dibenzyl 2-[4-[8-oxo-7,8-dihydroimidazo[4,5-d][1,3]diazepin-3(6H)-yl]butyl]-2-[3-(trifluoromethyl)benzyl]malonate C35H33F3N4O5 详情 详情
(VIII) 40808 dibenzyl 2-[4-[8-hydroxy-7,8-dihydroimidazo[4,5-d][1,3]diazepin-3(6H)-yl]butyl]-2-[3-(trifluoromethyl)benzyl]malonate C35H35F3N4O5 详情 详情

合成路线23

该中间体在本合成路线中的序号：(II)

The lithium dianion of 9-fluorenecarboxylic acid (I) was alkylated with 1,4-dibromobutane (II) to afford bromo acid (III). After conversion of (III) to the corresponding acid chloride by treatment with oxalyl chloride, condensation with 2,2,2-trifluoroethylamine furnished the intermediate bromo amide (IV).

参考文献 中间体
合成目标
【1】 Sun, C.-Q.; Robl, J.A.; Sulsky, R.; et al.; A novel series of highly potent benzimidazole-based microsomal triglyceride transfer protein inhibitors. J Med Chem 2001, 44, 6, 851.
【3】 Sulsky, R.B.; Poss, M.A.; Slusarchyk, W.A.; Dickson, J.K.; Biller, S.A.; Tino, J.A.; Magnin, D.R.; Lawrence, R.M.; Robl, J.A.; Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method. US 5760246 .
【2】 Biller, S.A.; Dickson, J.K.; Lawrence, R.M.; Magnin, D.R.; Poss, M.A.; Robl, J.A.; Slusarchyk, W.A.; Sulsky, R.B.; Tino, J.A. (Bristol-Myers Squibb Co.); Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method. EP 0904262; JP 2000502355; WO 9726240 .
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) 47744 9H-fluorene-9-carboxylic acid; 9-Fluorenecarboxylic acid; Diphenyleneacetic acid; Fluorene-9-carboxylic acid 1989-33-9 C14H10O2 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 47745 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid C18H17BrO2 详情 详情
(IV) 47746 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide C20H19BrF3NO 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

4,4'-Dihydroxybenzophenone (I) is condensed with 1,4-dibromobutane (II) by means of KH in THF/DMF to afford monoalkylated compound (III), which is then subjected to a McMurry cross-coupling reaction with the organometallic compound (IV) in refluxing THF in the presence of TiCl4 and Zn to provide the isomeric mixture (V). Finally, bromo compound (V) is converted into the target product by first heating with dimethylamine (HNMe2) in MeOH followed by isomer separation by means of preparative HPLC chromatography.

参考文献 中间体
合成目标
【1】 Jaouen, G.; et al.; First anti-oestrogen in the cyclopentadienyl rhenium tricarbonyl series. Synthesis and study of antiproliferative effects. Chem Commun (London) 2001, 4, 383.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Z)-(V) 46772 　 C28H29BrO5Re 详情 详情
(E)-(V) 46773 　 C28H29BrO5Re 详情 详情
(I) 20637 bis(4-hydroxyphenyl)methanone 611-99-4 C13H10O3 详情 详情
(II) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(III) 46770 [4-(4-bromobutoxy)phenyl](4-hydroxyphenyl)methanone C17H17BrO3 详情 详情
(IV) 46771 　 C11H12O4Re 详情 详情

合成路线25

该中间体在本合成路线中的序号：(V)

Tetrahydrobenzo[cd]indol-2-one (IV) is selectively alkylated at position 2a with 1,4-dibromobutane (V) in the presence of NaH to provide the bromobutyl derivative (VI). Then, condensation of bromide (VI) with amine (III) employing K2CO3 in DMF leads to the title compound.

参考文献 中间体
合成目标
【1】 Kikuchi, C.; et al.; 2a-[4-(Tetrahydropyridondol-2-yl)butyl]tetrahydrobenzindole derivatives: New selective antagonists of the 5-hydroxytryptamine7 receptor. J Med Chem 2002, 45, 11, 2197.
【2】 Koyama, M.; Okuno, M.; Hiranuma, T.; Ando, T.; Fuji, K.; Ushiroda, O.; Kikuchi, C.; Shiiyama, M.; Satoh, E. (Meiji Seika Kaisha, Ltd.); Tetrahydrobenzindole derivs.. EP 1057814; JP 1999189585; US 6498251; WO 9933804 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 60193 N,N-dimethyl-1,2,3,4-tetrahydro-9H-beta-carboline-9-carboxamide C14H17N3O 详情 详情
(IV) 25590 2a,3,4,5-tetrahydrobenzo[cd]indol-2(1H)-one 96933-21-0 C11H11NO 详情 详情
(V) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(VI) 25591 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenzo[cd]indol-2(1H)-one C15H18BrNO 详情 详情

合成路线26

该中间体在本合成路线中的序号：(VI)

Claisen rearrangement of allyl ether (I) in refluxing o-dichlorobenzene affords (II). The allyl group of (II) is subsequently hydrogenated over Pd/C to provide the propyl derivative (III). Benzophenone (III) is converted into the corresponding oxime (IV) by means of hydroxylamine hydrochloride and NaOAc. Acetylation of oxime (IV), followed by refluxing in pyridine gives rise to the benzisoxazole (V). The phenolic hydroxyl group of (V) is then alkylated by 1,4-dibromobutane (VI) producing the bromobutyl ether (VII). 3-Hydroxyphenylacetic acid (VIII) is esterified with MeOH/H2SO4 to give the methyl ester (IX). This is then condensed with bromide (VII) in the presence of K2CO3 to furnish diether (X). Finally, saponification of the methyl ester group of (X) employing LiOH yields the target carboxylic acid (1,2)

参考文献 中间体
合成目标
【1】 Adams, A.D.; Yuen, W.; Hu, Z.; Santini, C.; Jones, A.B.; MacNaul, K.L.; Berger, J.P.; Doebber, T.W.; Moller, D.E.; Amphipathic 3-phenyl-7-propylbenzisoxazoles; human PPAR gamma, delta and alpha agonists. Bioorg Med Chem Lett 2003, 13, 5, 931.
【2】 Adams, A.D.; Berger, J.P.; Berger, G.D.; Fitch, K.J.; Graham, D.W.; Jones, A.B.; Von Langen, D.; Leibowitz, M.D.; Moller, D.E.; Patchett, A.A.; Santini, C.; Sahoo, S.P.; Tolman, R.L.; Toupence, R.B.; Walsh, T.F. (Merck & Co., Inc.); Heterocyclic derivs. as antidiabetic and antiobesity agents. EP 0882029; JP 2002503203; US 6090836; WO 9728137 .
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) 63548 [4-(allyloxy)-2-hydroxyphenyl](phenyl)methanone C16H14O3 详情 详情
(II) 63549 (3-allyl-2,4-dihydroxyphenyl)(phenyl)methanone C16H14O3 详情 详情
(III) 63550 (2,4-dihydroxy-3-propylphenyl)(phenyl)methanone C16H16O3 详情 详情
(IV) 63551 (2,4-dihydroxy-3-propylphenyl)(phenyl)methanone oxime C16H17NO3 详情 详情
(V) 63552 3-phenyl-7-propyl-1,2-benzisoxazol-6-ol C16H15NO2 详情 详情
(VI) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(VII) 63553 6-(4-bromobutoxy)-3-phenyl-7-propyl-1,2-benzisoxazole; 4-bromobutyl 3-phenyl-7-propyl-1,2-benzisoxazol-6-yl ether C20H22BrNO2 详情 详情
(VIII) 58561 2-(3-hydroxyphenyl)acetic acid C8H8O3 详情 详情
(IX) 58567 methyl 2-(3-hydroxyphenyl)acetate C9H10O3 详情 详情
(X) 63554 methyl 2-(3-{4-[(3-phenyl-7-propyl-1,2-benzisoxazol-6-yl)oxy]butoxy}phenyl)acetate C29H31NO5 详情 详情

合成路线27

该中间体在本合成路线中的序号：(XI)

6-O-Methylerythromycin A (I) is protected with benzoic anhydride in the presence of triethylamine and DMAP in ethyl acetate to afford 2’,4”-di-O-benzoyl-6-O-methylerythromycin A (II). Treatment of the protected intermediate (II) with 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) followed by 1,1-carbonyldiimidazole (CDI) (III) in DMF yields 10,11-anhydro-2’,4”-di-O-benzoyl-12-O-imidazolylcarbonyl-6-Omethylerythromycin A (IV), which is converted to the 2’,4”-di-O-benzoyl-11-N-(4-azidobutyl)-6-O-methylerythromycin A 11,12-cyclic carbamate (V) by treatment with 4-azidobutylamine (XIII) and DBU in DMF. The cladinose sugar is cleaved from carbamate (V) by hydrolysis with 1 N HCl in acetone to provide 11-N-(4-azidobutyl)-5-(2’-benzoyldesosaminyl)-3-hydroxy-6-O-methylerythronolide A 11,12-cyclic carbamate (VI). 1-N-(4-Azidobutyl)-5-(2’-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolide A 11,12-cyclic carbamate (VII) is prepared by oxidation of the secondary alcohol of intermediate (VI) with Dess-Martin periodinane (DMP).

参考文献 中间体
合成目标
【1】 Hwang, C., Duffield, J., Chiu, Y. et al. SAR of 11,12-carbamate macrolides/ketolides linked with 1,4-substituted-[1,2,3]-triazoles. 48th Intersci Conf Antimicrob Agents Chemother/Infect Dis Soc Am 46th Annu Meet (Oct 25-28, Washington, DC) 2008, Abst F1-3973.
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) 68888 (3S,4R,5R,6S,7S,9S,11S,12S,13R,14S)-6- (((2R,3S,4R,6S)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-12,13-dihydroxy-4-(((2S,4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-hexamethyloxacyclotetradecane-2,10-dione 　 C38H69NO13 详情 详情
(II) 68889 (2R,3R,4S,6S)-6-(((3S,4R,5R,6S,7S,9S,11S,12S,13R,14S)-6-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecan-4-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate 　 C52H77NO15 详情 详情
(III) 11353 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) 530-62-1 C7H6N4O 详情 详情
(IV) 68890 (2S,3R,7S,9S,10S,11R,12R,13S)-10-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-12-(((2S,4S,5R,6R)-5-(benzoyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradec-4-en-3-yl 1H-imidazole-1-carboxylate 　 C56H77N3O15 详情 详情
(V) 68891 (2R,3R,4S,6S)-6-(((3aR,4S,7S,8R,9R,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-10-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-8-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate 　 C57H83N5O15 详情 详情
(VI) 68892 (2R,3S,4R,6S)-2-(((3aR,4S,7S,8R,9R,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate 　 C42H65N5O11 详情 详情
(VII) 68893 (2R,3S,4R,6S)-2-(((3aR,4S,7S,9S,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate 　 C42H63N5O11 详情 详情
(XI) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(XII) 68896 1,4-diazidobutane 　 C4H8N6 详情 详情
(XIII) 68887 azidobutylamine;4-azidobutan-1-amine 　 C4H10N4 详情 详情
Extended Information