(E)-4-bromo-2-butenoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】50564

【品名】(E)-4-bromo-2-butenoyl chloride

【CA登记号】

【分子式】C₄H₄BrClO

【分子量】183.43186

【元素组成】C 26.19% H 2.2% Br 43.56% Cl 19.33% O 8.72%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IX)

The condensation of 3-ethoxy-4-nitroaniline (I) with 2-(ethoxymethylene)cyanacetic acid ethyl ester (II) in refluxing toluene gives the adduct (III), which is further cyclized in Dowtherm at 258 C to yield 7-ethoxy-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile (IV). The reaction of (IV) with refluxing POCl3 affords the 4-chloroquinoline (V), which is condensed with 3-chloro-4-fluoroaniline (VI) in refluxing isopropanol to provide the secondary amine (VII). The reduction of the nitro group of (VII) with Fe and NH4Cl in refluxing methanol/water gives the corresponding amino derivative (VIII), which is condensed with the acid chloride (IX) by means of t-BuOCOCl and NMM in THF to yield the amide (X). Finally, this compound is treated with dimethylamine in THF to afford the target quinoline-3-carbonitrile.

参考文献中间体

合成目标

【1】 Wissner, A.; Overbeek, E.; Reich, M.F.; Floyd, B.; Johnson, B.D.; Mamuya, N.; Rosfjord, E.C.; Discafani, C.; Davis, R.; Shi, X.; Rabindran, S.K.; Gruber, B.C.; Ye, F.; Hallett, W.A.; Nilakantan, R.; Shen, R.; Wang, Y.-F.; Greenberger, L.M.; Tsou, H.-R.; Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epi. J Med Chem 2003, 46, 1, 49.

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)	61513	3-ethoxy-4-nitroaniline; 3-ethoxy-4-nitrophenylamine		C₈H₁₀N₂O₃	详情	详情
(II)	61514	ethyl (Z)-2-cyano-3-propoxy-2-propenoate		C₉H₁₃NO₃	详情	详情
(III)	61515	ethyl (E)-2-cyano-3-(3-ethoxy-4-nitroanilino)-2-propenoate		C₁₄H₁₅N₃O₅	详情	详情
(IV)	61516	7-ethoxy-6-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile		C₁₂H₉N₃O₄	详情	详情
(V)	61517	4-chloro-7-ethoxy-6-nitro-3-quinolinecarbonitrile		C₁₂H₈ClN₃O₃	详情	详情
(VI)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情
(VII)	61518	4-(3-chloro-4-fluoroanilino)-7-ethoxy-6-nitro-3-quinolinecarbonitrile		C₁₈H₁₂ClFN₄O₃	详情	详情
(VIII)	61519	6-amino-4-(3-chloro-4-fluoroanilino)-7-ethoxy-3-quinolinecarbonitrile		C₁₈H₁₄ClFN₄O	详情	详情
(IX)	50564	(E)-4-bromo-2-butenoyl chloride		C₄H₄BrClO	详情	详情
(X)	61520	(E)-4-bromo-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-2-butenamide		C₂₂H₁₇BrClFN₄O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Methyl 4-bromocrotonate (VI) was hydrolyzed with barium hydroxide under controlled conditions and the resulting bromocrotonic acid (VII) was converted to the corresponding acid chloride (VIII) by treatment with oxalyl chloride. Condensation of acid chloride (VIII) with amino quinazoline (V) produced the bromocrotonamide (IX). Finally, nucleophilic displacement of the allylic bromine with dimethylamine provided the title compound.

参考文献中间体

合成目标

【1】 Tsou, H.-R.; et al.; 6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity. J Med Chem 2001, 44, 17, 2719.
【2】 Wissner, A.; Johnson, B.D.; Zhang, N.; Tsou, H.-R.; Hamann, P.R. (American Cyanamid Co.); Substd. quinazoline derivs. and their use as tyrosine kinase inhibitors. EP 1000039; JP 2001515071; WO 9909016 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	23222	N(4)-(3-bromophenyl)-4,6-quinazolinediamine; N-(6-amino-4-quinazolinyl)-N-(3-bromophenyl)amine		C₁₄H₁₁BrN₄	详情	详情
(VI)	26358	methyl (E)-4-bromo-2-butenoate	1117-71-1	C₅H₇BrO₂	详情	详情
(VII)	50563	(E)-4-bromo-2-butenoic acid	13991-36-1	C₄H₅BrO₂	详情	详情
(VIII)	50564	(E)-4-bromo-2-butenoyl chloride		C₄H₄BrClO	详情	详情
(IX)	50565	(E)-4-bromo-N-[4-(3-bromoanilino)-6-quinazolinyl]-2-butenamide		C₁₈H₁₄Br₂N₄O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Acetylation of the diarylamine (I) with Ac2O yields acetamide (II), which is reduced at the nitro group by means of H2 over Raney Ni in THF to give 6-aminoquinazoline derivative (III). Condensation of amine (III) with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA affords the butenamide derivative (V), which is then deacetylated with NaOH, yielding anhydrous dacomitinib (VI). Finally, crude dacomitinib (VI) is recrystallized in dichloroethane/water .
Anhydrous dacomitinib (VI) can also be obtained as follows: Reduction of the 6-nitroquinazoline derivative (I) with H2 over Raney Ni in THF yields the 6-aminoquinazoline derivative (VII), which is then condensed with 4-bromo-2-butenoyl chloride (VIII) in the presence of Et3N in THF to give the 4-bromo-2-butenamide derivative (IX). Finally, 4-bromoamide (IX) is condensed with piperidine (X) using Et3N in DMA .
4-Bromo-2-butenoyl chloride (VIII) is obtained by hydrolysis of methyl 4-bromocrotonate (XI) with Ba(OH)2 in EtOH/H2O to produce acid (XII), which is finally treated with (COCl)2 in the presence of DMF in CH2Cl2 .
Anhydrous dacomitinib (VI) is also obtained by N-deprotection of its 3,4-dimethoxybenzyl derivative (XIII) with TFA in THF .

参考文献中间体

合成目标

【1】 Fakhoury, S.A., Lee, H.T., Reed, J.E., Schlosser, K.M., Sexton, K.E., Tecle, H., Winters, R.T. (Pfizer, Inc.). 4-Phenylamino-quinazolin-6-yl-amides. EP 1746999, JP 200753668, JP 2009007363, US 2005250761, US 7772243, WO 2005107758.

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)	68469	N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine		C₁₅H₁₀ClFN₄O₃	详情	详情
(II)	68470	N-(3-chloro-4-fluorophenyl)-N-(7-methoxy-6-nitroquinazolin-4-yl)acetamide		C₁₇H₁₂ClFN₄O₄	详情	详情
(III)	68471	N-(6-amino-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)acetamide		C₁₇H₁₄ClFN₄O₂	详情	详情
(IV)	68473	4-(piperidin-1-yl)-2-butenoyl chloride；(E)-4-(piperidin-1-yl)but-2-enoyl chloride		C₉H₁₄ClNO	详情	详情
(V)	68472	(E)-N-(4-(N-(3-chloro-4-fluorophenyl)acetamido)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide		C₂₆H₂₇ClFN₅O₃	详情	详情
(VI)	68474	(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide	1110813-31-4	C₂₄H₂₅ClFN₅O₂	详情	详情
(VII)	68475	N⁴ -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine		C₁₅H₁₂ClFN₄O	详情	详情
(VIII)	50564	(E)-4-bromo-2-butenoyl chloride		C₄H₄BrClO	详情	详情
(IX)	68476	(E)-N⁶-(5-bromopenta-1,3-dien-2-yl)-N4-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine		C₂₀H₁₇BrClFN₄O	详情	详情
(X)	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情
(XI)	26358	methyl (E)-4-bromo-2-butenoate	1117-71-1	C₅H₇BrO₂	详情	详情
(XII)	50563	(E)-4-bromo-2-butenoic acid	13991-36-1	C₄H₅BrO₂	详情	详情
(XIII)	68477	(E)-N-(4-((3-chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide		C₃₃H₃₅ClFN₅O₄	详情	详情

Extended Information