3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene -Drug Synthesis Database

【结构式】

【分子编号】56445

【品名】3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene

【CA登记号】54060-30-9

【分子式】C₈H₇N

【分子量】117.15032

【元素组成】C 82.02% H 6.02% N 11.96%

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：(IX)

Erlotinib can be obtained by three related ways: 1) Alkylation of 3,4-dihydroxybenzoic acid ethyl ester (I) with 2-bromoethyl methyl ether (II) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in refluxing acetone gives 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (III), which is nitrated with HNO3 in acetic acid to yield 4,5-bis(2-methoxyethoxy)-2-nitrobenzoic acid ethyl ester (IV). Reduction of ester (IV) with H2 over PtO2 in ethanol/HCl affords the corresponding aniline derivative (V), which is cyclized with ammonium formate (VI) in formamide at 165 C to provide 6,7-bis(2-methoxyethoxy)-quinazolin-4(3H)-one (VII). Reaction of quinazoline (VII) with oxalyl chloride in refluxing chloroform gives the expected 4-chloroquinazoline derivative (VIII), which is finally condensed with 3-ethynylaniline (IX) in refluxing isopropanol containing pyridine. 2) Reaction of the 4-chloroquinazoline derivative (VIII) with 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol (X) in refluxing acetonitrile gives the secondary amine (XI), which is finally treated with anhydrous solid NaOH in refluxing either 1-butanol, 2-butanol, isopropanol or 2-methoxyethanol. 3) Reaction of 3-bromonitrobenzene (XII) with trimethylsilylacetylene (XIII) by means of a Pd catalyst and Cu2I in hot TEA gives 3-(trimethylsilylethynyl)nitrobenzene (XIV), which is reduced with H2 over Pt/Al2O3 in isopropanol to provide 3-(trimethylsilylethynyl)aniline (XV). Condensation of the aniline (XV) with the quinazoline derivative (VIII) in refluxing isopropanol affords the silylated quinazoline derivative (XVI), which is finally deprotected with TBAF in THF.

参考文献中间体

合成目标

【1】 Bayes, M.; Castaner, J.; Sorbera, L.A.; Silvestre, J.S.; Erlotinib Hydrochloride. Drugs Fut 2002, 27, 10, 923.
【2】 Schnur, R.C.; Arnold, L.D. (Pfizer Inc.); Alkynyl and azido-substd. 4-anilinoquinazolines. US 5747498 .
【3】 Schnur, R.C.; Arnold, L.D. (Pfizer Inc.); Quinazoline derivs.. EP 0817775; EP 1110953; JP 1998506633; WO 9630347 .
【4】 Santafianos, D.P.; Norris, T.; Lehner, R.S. (Pfizer Inc.); Processes and intermediates for preparing anti-cancer cpds.. EP 1044969; JP 2000290262; US 6476040 .

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)	56439	3,4-Dihydrohybenzoic acid ethyl ester; Ethyl 3,4-dihydroxybenzoate; Ethyl Protocatechuate; Protocatechuic acid ethyl ester	3943-89-3	C₉H₁₀O₄	详情	详情
(II)	51459	2-Methoxyethyl bromide; 2-Bromoethyl methyl ether; 1-Bromo-2-methoxyethane; Methyl 2-bromoethyl ether	6482-24-2	C₃H₇BrO	详情	详情
(III)	56440	ethyl 3,4-bis(2-methoxyethoxy)benzoate	183322-16-9	C₁₅H₂₂O₆	详情	详情
(IV)	56441	ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate	179688-26-7	C₁₅H₂₁NO₈	详情	详情
(V)	56442	ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate	179688-27-8	C₁₅H₂₃NO₆	详情	详情
(VII)	56443	6,7-bis(2-methoxyethoxy)-4(3H)-quinazolinone	179688-29-0	C₁₄H₁₈N₂O₅	详情	详情
(VIII)	56444	4-chloro-6,7-bis(2-methoxyethoxy)quinazoline; 4-chloro-6-(2-methoxyethoxy)-7-quinazolinyl 2-methoxyethyl ether	183322-18-1	C₁₄H₁₇ClN₂O₄	详情	详情
(IX)	56445	3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene	54060-30-9	C₈H₇N	详情	详情
(X)	56446	4-(3-aminophenyl)-2-methyl-3-butyn-2-ol		C₁₁H₁₃NO	详情	详情
(XI)	56447	4-(3-{[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amino}phenyl)-2-methyl-3-butyn-2-ol		C₂₅H₂₉N₃O₅	详情	详情
(XII)	56448	1-Bromo-3-nitrobenzene; 3-Bromonitrobenzene; 3-Nitrobromobenzene; m-Bromonitrobenzene; m-Nitrobromobenzene	585-79-5	C₆H₄BrNO₂	详情	详情
(XIII)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(XIV)	56449	trimethyl[2-(3-nitrophenyl)ethynyl]silane		C₁₁H₁₃NO₂Si	详情	详情
(XV)	56450	3-[2-(trimethylsilyl)ethynyl]aniline; 3-[2-(trimethylsilyl)ethynyl]phenylamine		C₁₁H₁₅NSi	详情	详情
(XVI)	56451	N-[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]-N-{3-[2-(trimethylsilyl)ethynyl]phenyl}amine; 6,7-bis(2-methoxyethoxy)-N-{3-[2-(trimethylsilyl)ethynyl]phenyl}-4-quinazolinamine		C₂₅H₃₁N₃O₄Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

2-Chloroaniline (I) is diazotized with NaNO2/HCl and the resultant diazonium salt (II) is further coupled to 2,4-pentanedione (III) to furnish the diketo hydrazone (IV). Subsequent bromination of (IV) with Br2 in Ac2O/AcOH gives rise to the hydrazonyl bromide (V). This is finally condensed with 3-ethynylaniline (VI) in DMF to provide the corresponding aryl amidrazone.

参考文献中间体

合成目标

【1】 Wilson, D.M.; Termin, A.P.; Mao, L.; Ramirez-Weinhouse, M.M.; Molteni, V.; Gootenhuis, P.D.J.; Arylamidrazones as novel corticotropin releasing factor receptor antagonists. J Med Chem 2002, 45, 11, 2123.

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)	35804	2-chloroaniline; 2-chlorophenylamine	95-51-2	C₆H₆ClN	详情	详情
(II)	63682	2-chlorobenzenediazonium chloride		C₆H₄Cl₂N₂	详情	详情
(III)	11620	2,4-Pentanedione;acetylacetone	123-54-6	C₅H₈O₂	详情	详情
(IV)	63683	2,3,4-pentanetrione 3-[N-(2-chlorophenyl)hydrazone]		C₁₁H₁₁ClN₂O₂	详情	详情
(V)	63684	N-(2-chlorophenyl)-2-oxopropanehydrazonoyl bromide		C₉H₈BrClN₂O	详情	详情
(VI)	56445	3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene	54060-30-9	C₈H₇N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

Cyclization of 4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline (I) with ditosylate (II) [prepared by sulfonylation of triethylene glycol (III) with p-TsCl in the presence of NaOH in THF/H2O (1)] by means of K2CO3 in DMF at 80-90 °C yields the tetraoxacyclododecane derivative (IV), which is finally submitted to Sonogashira coupling with (trimethylsilyl)acetylene (V) using Pd(PPh3)4, CuI and K2CO3 in refluxing DMF .
The aryl bromide precursor (IV) can also be prepared by chlorination of the quinazolinone (VI) using POCl3 in the presence of a catalytic amount of DMF at reflux to afford the 4-chloroquinazoline derivative (VII), which is then coupled with 3-bromoaniline (VIII) in i-PrOH/DMF .
Alternatively, condensation of chloroquinazoline (VII) with 3-ethynyl-aniline (IX) in refluxing i-PrOH/DMF directly produces icotinib .

参考文献中间体

合成目标

【1】 Wang, Y., Ding, L., Tan, F. et al. (Zhejiang Beta Pharma, Inc.). Icotinib hydrochloride, synthesis, crystallographic form, medical combination, and uses thereof. CN 10187818, EP 2392576, JP 2011527291, KR 2011031370, US 2011182882, WO 2010003313.
【2】 Zhang, D., Xie, G., Davis, C., Cheng, Z., Chen, H., Wang, Y., Kamal, M.(Beta Pharma, Inc.). Fused quinazoline derivatives useful as tyrosine kinase inhibitors. US 2004048883, US 7078409, WO 2003082830.
【3】 Hu, S., Xie, G., Zhang, D.X. et al. Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors. Bioorg Med Chem Lett 2012, 22(19): 6301-5.

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)	67978	4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline		C₁₄H₁₀BrN₃O₂	详情	详情
(II)	67980	(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate)	19249-03-7	C₂₀H₂₆O₈S₂	详情	详情
(III)	67979	2,2'-(ethane-1,2-diylbis(oxy))diethanol;Triethylene glycol	112-27-6	C₆H₁₄O₄	详情	详情
(IV)	67981	N-(3-bromophenyl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine		C₂₀H₂₀BrN₃O₄	详情	详情
(V)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(VI)	67982	7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4(3H)-one		C₁₄H₁₆N₂O₅	详情	详情
(VII)	67983	4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline		C₁₄H₁₅ClN₂O₄	详情	详情
(VIII)	19136	3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine	591-19-5	C₆H₆BrN	详情	详情
(IX)	56445	3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene	54060-30-9	C₈H₇N	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IX)

Fluorination of the keto intermediate (VII) is accomplished with potassium tert-butoxide and N-fluo-robenzenesulfonamide (NFSI) in THF/CH2Cl2 at –20 °C to –15 °C to afford the fluoro-azide intermediate (VIII). The triazole intermediate (X) is prepared by a copper-catalyzed azide-alkyne cycloaddition reaction between the fluoro-azide intermediate (VIII) and 3-ethynylaniline (IX) in the presence of copper(I) iodide and DIEA in acetonitrile. Deprotection of the triazole intermediate (X) is accomplished by refluxing in methanol to yield solithromycin . 4-Azidobutylamine (XIII) is prepared by substitution of 1,4-dibromobutane (XI) with sodium azide in DMF/H2O at 80 °C to produce 1,4-diazidobutane (XII), which, without isolation, is subjected to partial reduction with triphenylphosphine in MTBE to afford 4-azidobutylamine (XIII) .

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
(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
(VIII)	68894	(2R,3S,4R,6S)-2-(((3aR,4S,7R,9S,10S,11S,13S,15S,15aS)-1-(4-azidobutyl)-4-ethyl-7-fluoro-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		C₄₂H₆₂FN₅O₁₁	详情	详情
(IX)	56445	3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene	54060-30-9	C₈H₇N	详情	详情
(X)	68895	(2R,3S,4R,6S)-2-(((3aR,4S,7R,9S,10S,11S,13S,15S,15aS)-1-(4-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)butyl)-4-ethyl-7-fluoro-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		C₅₀H₆₉FN₆O₁₁	详情	详情

Extended Information