7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine -Drug Synthesis Database

【结构式】

【分子编号】68137

【品名】7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine

【CA登记号】　

【分子式】C₁₈H₂₅N₅O₃

【分子量】359.4284

【元素组成】C 60.15% H 7.01% N 19.48% O 13.35%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIII)

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 .

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(XIII)

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 .

参考文献中间体

合成目标

【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

Extended Information