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【结 构 式】 
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【分子编号】14262 【品名】Guanidine hydrochloride 【CA登记号】50-01-1 |
【 分 子 式 】CH5N3.HCl 【 分 子 量 】95.53156 【元素组成】C 12.57% H 6.33% Cl 37.11% N 43.99% |
合成路线1
该中间体在本合成路线中的序号：(XXII)The reduction of 4-bromophenylacetic acid (I) with boron hydride gives 2-(4-bromophenyl)ethanol (II), which is mesylated with methanesulfonyl chloride to the sulfonate (III). The condensation of (III) with diethyl malonate (IV) by means of NaH yields 2-[2-(4-bromophenyl)ethyl]malonic acid diethyl ester (V), which is reduced with LiAlH4 to the diol (VI). The enantioselective transesterification of (VI) with methyl acetate by means of porcine pancreatic lipase (PPL, Sigma type II, no. 3126) affords the (R)-enantiomer of monoester (VII), which is treated with tert-butyldimethylsilyl chloride in dichloromethane, giving the (S)-enantiomer of the silylated acetoxy derivative (VIII). The hydrolysis of (VIII) with methanolic NaOH yields the silylated alcohol (IX), which is mesylated with methanesulfonyl chloride as before affording the sulfonate (X). The reaction of (X) with sodium azide in hot DMF gives 1-azido-4-(4-bromophenyl)-2(S)-(tert-butyldimethylsilyloxymethyl)butane (XIII), which is deprotected with acetic acid in THF yielding 2(S)-(azidomethyl)-4-(4-bromophenyl)butanol (XII). Mesylation of (XII) as before affords sulfonate (XIII), which is condensed with diethyl malonate (IV) by means of NaH as before, giving the chiral malonate derivative (XIV). The cyclization of (XIV) by means of tributyl phosphine in THF yields (3RS,5R)-5-[2-(4-bromophenyl)ethyl]-2-oxopiperidine-3-carboxylic acid ethyl ester (XV), which is treated with trimethyloxonium tetrafluoroborate in CHCl3 to afford the methoxy derivative (XVI). Cyclization of (XVI) with guanidine hydrochloride (XXII) by means of sodium ethoxide in hot ethanol gives 2-amino-6(R)-[2-(4-bromophenyl)ethyl]-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (XVII), which is treated with copper cyanide in refluxing 1-methyl-2-pyrrolidone, yielding the nitrile (XVIII). Hydrolysis of (XVIII) with refluxing 6N HCl affords the corresponding benzoic acid (XIX), which is condensed with L-glutamic acid diethyl ester (XX) by means of N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine in DMF, affording the diethyl ester of the desired product (XXI). Finally, this compound is hydrolyzed with 1N NaOH.
| 【1】 Barnett, C.J.; Wilson, T.M. (Eli Lilly and Company); Enantioselective synthesis of antifolates. EP 0417212 . |
| 【2】 Barnett, C.J.; Wilson, T.M.; Asymmetric synthesis and absolute configuration of 5,10-dideaza-5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Tetrahedron Lett 1989, 30, 46, 6291. |
| 【3】 Castaner, J.; Prous, J.; Lometrexol. Drugs Fut 1993, 18, 2, 121. |
| 【4】 Wilson, T.M.; Barnett, C.J.; Asymmetric synthesis and absolute configuration of 5,10-dideaza-5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Chemistry and Biology of Pteridines (1989): Pteridines and Folic Acid Derivatives. H.-C. Curtius, S. Ghisla and N. Blau (Eds.). de Gruyter, New York 1990, 102. |
| 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) | 14247 | 2-(4-Bromophenyl)acetic acid; p-Bromophenylacetic acid; 4-Bromophenylacetic acid | 1878-68-8 | C8H7BrO2 | 详情 | 详情 |
| (II) | 14248 | 2-(4-Bromophenyl)-1-ethanol; 4-Bromophenethyl alcohol；2-(4-bromophenyl)ethanol；2-(4-Bromophenyl)ethan-1-ol | 4654-39-1 | C8H9BrO | 详情 | 详情 |
| (III) | 14249 | 4-Bromophenethyl methanesulfonate | C9H11BrO3S | 详情 | 详情 | |
| (IV) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (V) | 14251 | diethyl 2-(4-bromophenethyl)malonate | C15H19BrO4 | 详情 | 详情 | |
| (VI) | 14252 | 2-(4-Bromophenethyl)-1,3-propanediol | C11H15BrO2 | 详情 | 详情 | |
| (VII) | 14253 | (2R)-4-(4-bromophenyl)-2-(hydroxymethyl)butyl acetate | C13H17BrO3 | 详情 | 详情 | |
| (VIII) | 14254 | (2S)-4-(4-bromophenyl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)butyl acetate | C19H31BrO3Si | 详情 | 详情 | |
| (IX) | 14255 | (2S)-4-(4-Bromophenyl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-butanol | C17H29BrO2Si | 详情 | 详情 | |
| (X) | 14256 | (2R)-4-(4-bromophenyl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)butyl methanesulfonate | C18H31BrO4SSi | 详情 | 详情 | |
| (XI) | 14257 | [[(2S)-2-(Azidomethyl)-4-(4-bromophenyl)butyl]oxy](tert-butyl)dimethylsilane; (2S)-2-(Azidomethyl)-4-(4-bromophenyl)butyl tert-butyl(dimethyl)silyl ether | C17H28BrN3OSi | 详情 | 详情 | |
| (XII) | 14258 | (2S)-2-(Azidomethyl)-4-(4-bromophenyl)-1-butanol | C11H14BrN3O | 详情 | 详情 | |
| (XIII) | 14259 | (2S)-2-(azidomethyl)-4-(4-bromophenyl)butyl methanesulfonate | C12H16BrN3O3S | 详情 | 详情 | |
| (XIV) | 14260 | diethyl 2-[(2R)-2-(azidomethyl)-4-(4-bromophenyl)butyl]malonate | C18H24BrN3O4 | 详情 | 详情 | |
| (XV) | 14261 | ethyl (5R)-5-(4-bromophenethyl)-2-oxohexahydro-3-pyridinecarboxylate | C16H20BrNO3 | 详情 | 详情 | |
| (XVI) | 14268 | ethyl (5R)-5-(4-bromophenethyl)-2-methoxy-3,4,5,6-tetrahydro-3-pyridinecarboxylate | C17H22BrNO3 | 详情 | 详情 | |
| (XVII) | 14263 | (6R)-2-Amino-6-(4-bromophenethyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one | C15H17BrN4O | 详情 | 详情 | |
| (XVIII) | 14264 | 4-[2-[(6R)-2-Amino-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzonitrile | C16H17N5O | 详情 | 详情 | |
| (XIX) | 14265 | 4-[2-[(6R)-2-Amino-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoic acid | C16H18N4O3 | 详情 | 详情 | |
| (XX) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (XXI) | 14267 | diethyl (2S)-2-[(4-[2-[(6R)-2-amino-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate | C25H33N5O6 | 详情 | 详情 | |
| (XXII) | 14262 | Guanidine hydrochloride | 50-01-1 | CH5N3.HCl | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)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 |