【结 构 式】 |
【分子编号】28017 【品名】cyanic bromide;cyanogen bromide 【CA登记号】506-68-3 |
【 分 子 式 】CBrN 【 分 子 量 】105.92174 【元素组成】C 11.34% Br 75.44% N 13.22% |
合成路线1
该中间体在本合成路线中的序号:(VIII)The nitration of 1,2,3-trichlorobenzene (I) with concentrated HNO3 gives 2,3,4-trichloronitrobenzene (II), which by reaction with cuprous cyanide in hot pyridine is converted to 2,3-dichloro-6-nitrobenzonitrile (III). The reduction of (III) with borane in THF yields 2,3-dichloro-6-nitrobenzylamine (IV), which by reaction with ethyl bromoacetate (V) by means of triethylamine in refluxing dioxane affords ethyl N-(2,3-dichloro-6-nitrobenzyl)glycinate (VI). The reduction of (VI) with SnCl2 in concentrated HCl gives ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.
【1】 Jenks, T.A.; Beverung, W.N.Jr.; Partyka, R.A. (Bristol-Myers Squibb Co.); Preparation of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one. CA 1137474 . |
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) | 29082 | 1,2,3-trichlorobenzene | 87-61-6 | C6H3Cl3 | 详情 | 详情 |
(II) | 29083 | 1,2,3-trichloro-4-nitrobenzene | 17700-09-3 | C6H2Cl3NO2 | 详情 | 详情 |
(III) | 29084 | 2,3-dichloro-6-nitrobenzonitrile | C7H2Cl2N2O2 | 详情 | 详情 | |
(IV) | 29085 | (2,3-dichloro-6-nitrophenyl)methanamine | 70380-49-3 | C7H6Cl2N2O2 | 详情 | 详情 |
(V) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
(VI) | 29086 | ethyl 2-[(2,3-dichloro-6-nitrobenzyl)amino]acetate | C11H12Cl2N2O4 | 详情 | 详情 | |
(VII) | 29087 | ethyl 2-[(6-amino-2,3-dichlorobenzyl)amino]acetate | C11H14Cl2N2O2 | 详情 | 详情 | |
(VIII) | 28017 | cyanic bromide;cyanogen bromide | 506-68-3 | CBrN | 详情 | 详情 |
(IX) | 29088 | ethyl 2-[5,6-dichloro-2-imino-1,4-dihydro-3(2H)-quinazolinyl]acetate | C12H13Cl2N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VIII)The reaction of 3-chloroaniline (X) with choral hydrate (XI) and hydroxylamine gives isonitroso-3-chloroacetanilide (XII), which is cyclized by means of H2SO4 to 4-chloroisatin (XIII). Chlorination of (XIII) with SO2Cl2 affords 4,5-dichloroisatin (XIV), which is oxidized with H2O2 yielding 5,6-dichloroanthranilic acid (XV). The reduction of (XV) with borane in THF gives 6-amino-2,3-dichlorobenzyl alcohol (XVI), which by reaction with SOCl2 in benzene is converted to 6-amino-2,3-dichlorobenzyl chloride (XVII). This compound is condensed with ethyl glycinate (XVIII) by means of triethylamine in refluxing methylene chloride to give ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.
【1】 Jenks, T.A.; Beverung, W.N.Jr.; Partyka, R.A. (Bristol-Myers Squibb Co.); Preparation of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one. CA 1137474 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII) | 29087 | ethyl 2-[(6-amino-2,3-dichlorobenzyl)amino]acetate | C11H14Cl2N2O2 | 详情 | 详情 | |
(VIII) | 28017 | cyanic bromide;cyanogen bromide | 506-68-3 | CBrN | 详情 | 详情 |
(IX) | 29088 | ethyl 2-[5,6-dichloro-2-imino-1,4-dihydro-3(2H)-quinazolinyl]acetate | C12H13Cl2N3O2 | 详情 | 详情 | |
(X) | 25239 | 3-chloroaniline; 3-chlorophenylamine | 108-42-9 | C6H6ClN | 详情 | 详情 |
(XI) | 14018 | 2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate | 302-17-0 | C2H3Cl3O2 | 详情 | 详情 |
(XII) | 29089 | N-(3-chlorophenyl)-2-(hydroxyimino)acetamide | C8H7ClN2O2 | 详情 | 详情 | |
(XIII) | 29090 | 4-chloro-1H-indole-2,3-dione | C8H4ClNO2 | 详情 | 详情 | |
(XIV) | 29091 | 4,5-dichloro-1H-indole-2,3-dione | C8H3Cl2NO2 | 详情 | 详情 | |
(XV) | 29092 | 6-amino-2,3-dichlorobenzoic acid | C7H5Cl2NO2 | 详情 | 详情 | |
(XVI) | 29093 | (6-amino-2,3-dichlorophenyl)methanol | C7H7Cl2NO | 详情 | 详情 | |
(XVII) | 29094 | 3,4-dichloro-2-(chloromethyl)aniline | C7H6Cl3N | 详情 | 详情 | |
(XVIII) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(A)The condensation of 2-nitro-6-chlorobenzyl chloride (I) with ethyl glycinate (II) by means of triethylamine in refluxing ethanol gives ethyl N-(2-nitro-6-chlorobenzyl)glycinate (III), which is reduced with H2 over Pd/C in ethanol yielding ethyl N-(2-amino-6-chlorobenzyl)glycinate (IV). The cyclization of (IV) with cyanogen bromide (A) in refluxing ethanol affords 6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (V), which is finally chlorinated with Cl2 and FeCl3 in hot nitromethane.
【1】 Beverung, W.N.Jr.; Partyka, A.; Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones. US 3932407 . |
【2】 Castaner, J.; Serradell, M.N.; Hillier, K.; Blancafort, P.; Anagrelide hydrochloride. Drugs Fut 1980, 5, 3, 117. |
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) | 28017 | cyanic bromide;cyanogen bromide | 506-68-3 | CBrN | 详情 | 详情 |
(I) | 32683 | 1-Chloro-2-(chloromethyl)-3-nitrobenzene | 15258-72-7 | C7H5Cl2NO2 | 详情 | 详情 |
(II) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
(III) | 32684 | ethyl 2-[(2-chloro-6-nitrobenzyl)amino]acetate | 50608-25-8 | C11H13ClN2O4 | 详情 | 详情 |
(IV) | 32685 | ethyl 2-[(2-amino-6-chlorobenzyl)amino]acetate | C11H15ClN2O2 | 详情 | 详情 | |
(V) | 32686 | 6-chloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one | 61834-95-5 | C10H8ClN3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(II)By cyclization of 6-(aminomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine (I) with cyanogen bromide (II) in THF, followed by a treatment with NaOH and acidification with HCl in ether.
【1】 Walther, G.; Schneider, C.S,, Weber, K.-H.; Fuegner, A. (Boehringer Ingelheim GmbH); Fused dibenzo imidazolo compounds, compositions and use. DE 3008944 . |
【2】 Serradell, M.N.; Castaner, J.; Epinastine Hydrochloride. Drugs Fut 1987, 12, 12, 1106. |
合成路线5
该中间体在本合成路线中的序号:(IX)Nitration of vanillin acetate (I) by means of HNO3 yields the 2-nitrobenzaldehyde derivative (II), which by hydrolysis of the acetate ester with K2CO3 in MeOH provides 2-nitrovanillin (III). Protection of phenol (III) by means of benzyl bromide and K2CO3 in DMF gives the corresponding benzyl ether (IV), which by reaction of the aldehyde moiety with iodine and excess NH3 in H2O/THF results in nitrile (V). Reduction of the nitro group in compound (V) using Fe and AcOH, followed by cyclization of the resulting aminonitrile (VI) with ethylenediamine (VII) in the presence of sulfur affords imidazoline (VIII). Subsequent ring closure of the aminoimidazoline derivative (VIII) with cyanogen bromide (IX) by means of Et3N in CH2Cl2 yields the imidazo[1,2-c] quinazoline derivative (X), which is then debenzylated by means of TFA to give the corresponding phenol (XI). Alkylation of phenol (XI) with 4-(3-chloropropyl)morpholine (XII) in the presence of Cs2CO3 in DMF affords the morpholinopropyl ether (XIII) (1), which is finally condensed with 2-aminopyrimidine-5-carboxylic acid (XIV) using PyBOP and DIEA in DMF .
2-Aminopyrimidine-5-carboxylic acid (XIV) is prepared by cyclization of sodium 2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1(Z)-en-1-olate (XV) with guanidine hydrochloride (XVI) to provide methyl 2-aminopyrimidine-5-carboxylate (XVII), which is then hydrolyzed with LiOH in MeOH .
【1】 Scott, W.J., Hentemann, S.M., Rowley, B. et al. Novel 2,3-dihydroimidazo[1,2-c]quinazolines PI3K inhibitors: Discovery and SAR. 22nd EORTCNCI-AACR Symp Mol Targets Cancer Ther (Nov 16-19, Berlin) 2010, Abst 444. |
【2】 Hentemann, M., Wood, J., Scott, W. et al. (Bayer Pharmaceuticals Corp.). Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis. EP 2096919, JP 2010511718, US 2011083984, US 8466283, US 201326113, WO 2008070150. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 68135 | 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bis(2,2,2-trifluoroacetate) | C11H12N4O2.2C2HF3O2 | 详情 | 详情 | |
(I) | 68127 | vanillin acetate;4-Acetoxy-3-methoxybenzaldehyde;4-Formyl-2-methoxyphenyl acetate | 881-68-5 | C10H10O4 | 详情 | 详情 |
(II) | 68128 | 4-formyl-2-methoxy-3-nitrophenyl acetate;4-O-Acetyl-2-nitrovanillin;4-(acetyloxy)-3-methoxy-2-nitro-Benzaldehyde | 2698-69-3 | C10H9NO6 | 详情 | 详情 |
(III) | 68129 | 2-nitrovanillin;4-Hydroxy-3-methoxy-2-nitrobenzaldehyde | C8H7NO5 | 详情 | 详情 | |
(IV) | 68130 | 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde | C15H13NO5 | 详情 | 详情 | |
(V) | 68131 | 4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile | C15H12N2O4 | 详情 | 详情 | |
(VI) | 68132 | 2-amino-4-(benzyloxy)-3-methoxybenzonitrile | C15H14N2O2 | 详情 | 详情 | |
(VII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
(VIII) | 68133 | 3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline | C17H19N3O2 | 详情 | 详情 | |
(IX) | 28017 | cyanic bromide;cyanogen bromide | 506-68-3 | CBrN | 详情 | 详情 |
(X) | 68134 | 8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine | C18H18N4O2 | 详情 | 详情 | |
(XIII) | 68137 | 7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine | C18H25N5O3 | 详情 | 详情 | |
(XIV) | 68136 | 2-aminopyrimidine-5-carboxylic acid;2-Amino-5-carboxypyrimidine;2-Amino-5-pyrimidinecarboxylic acid | 3167-50-8 | C5H5N3O2 | 详情 | 详情 |
(XV) | 68138 | sodium (Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate | C7H11NaO5 | 详情 | 详情 | |
(XVI) | 14262 | Guanidine hydrochloride | 50-01-1 | CH5N3.HCl | 详情 | 详情 |
(XVII) | 68139 | methyl 2-aminopyrimidine-5-carboxylate | 308348-93-8 | C6H7N3O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号:(IX)Reaction of 2-nitrovanillin (III) with NH4OH and I2 in H2O/THF yields nitrile (XVIII), which is then condensed with 4-(3-chloropropyl)morpholine hydrochloride (XII) —prepared by alkylation of morpholine (XIX) with 1-bromo-3-chloropropane (XX) in toluene at 84 °C— by means of Cs2CO3 in DMF at 75 °C to give the morpholinopropyl ether (XXI). Reduction of the nitro group in compound (XXI) with Fe and AcOH affords amine (XXII), which by cyclization with ethylenediamine (VII) and sulfur at 100 °C produces the imidazoline derivative (XXIII). Finally, aminoimidazoline (XXIII) is then subjected to ring closure with cyanogen bromide (IX) in the presence of Et3N in CH2Cl2 .
【1】 Hentemann, M., Wood, J., Scott, W. et al. (Bayer Pharmaceuticals Corp.). Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis. EP 2096919, JP 2010511718, US 2011083984, US 8466283, US 201326113, WO 2008070150. |
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) | 68129 | 2-nitrovanillin;4-Hydroxy-3-methoxy-2-nitrobenzaldehyde | C8H7NO5 | 详情 | 详情 | |
(VII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
(IX) | 28017 | cyanic bromide;cyanogen bromide | 506-68-3 | CBrN | 详情 | 详情 |
(XII) | 18691 | 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine | 7357-67-7 | C7H14ClNO | 详情 | 详情 |
(XIII) | 68137 | 7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine | C18H25N5O3 | 详情 | 详情 | |
(XVIII) | 68140 | 4-hydroxy-3-methoxy-2-nitrobenzonitrile | C8H6N2O4 | 详情 | 详情 | |
(XIX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
(XX) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
(XXI) | 66434 | 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile | 675126-26-8 | C15H19N3O5 | 详情 | 详情 |
(XXII) | 66435 | 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile | 675126-27-9 | C15H21N3O3 | 详情 | 详情 |
(XXIII) | 68141 | 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholinopropoxy)aniline | C17H26N4O3 | 详情 | 详情 |