(E)-4-bromo-2-butenoic acid -Drug Synthesis Database

【结构式】

【分子编号】50563

【品名】(E)-4-bromo-2-butenoic acid

【CA登记号】13991-36-1

【分子式】C₄H₅BrO₂

【分子量】164.9865

【元素组成】C 29.12% H 3.05% Br 48.43% O 19.39%

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：(II)

Acylation of 6-amino-4-(3-chloro-4-fluorophenylamino)-7-[tetrahydrofuran-3(S)-yloxy]quinazoline (I) with the acid chloride generated from bromocrotonic acid (II) and oxalyl chloride leads to the bromocrotonamide (III), which is finally submitted to bromide displacement with dimethylamine (1). Scheme1.
In an alternative method, aminoquinazoline (I) is acylated with diethylphosphonoacetic acid (IV) by means of carbonyldiimidazole in THF to give the phosphonoacetamide (V), which is finally condensed with (dimethylamino)acetaldehyde diethyl acetal (VI) under basic conditions (2). Scheme 1.

参考文献中间体

合成目标

【1】 Himmelsbach, F., Langkopf, E., Solca, F., Jung, B., Baum, A., Blech, S. (Boehringer Ingelheim Pharma GmbH & Co., KG). Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof. DE 10063435, EP 1345910, JP 2004516283, US 2002173509, US 2006100223, US 7019012, WO 0250043.
【2】 Soyka, R., Rall, W., Kulinna, C., Sieger, P., Schnaubelt, J. (Boehringer Ingelheim Pharma GmbH & Co., KG). Process for preparing amino crotonyl compounds. DE 10349113, EP 1678165, JP 2007510624, US 2005085495, WO 2005037824.

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)	65710	N4-(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furanyl]oxy]-4,6-quinazolinediamine	314771-76-1	C₁₈H₁₆ClFN₄O₂	详情	详情
(II)	50563	(E)-4-bromo-2-butenoic acid	13991-36-1	C₄H₅BrO₂	详情	详情
(III)	65711			C₂₂H₁₉BrClFN₄O₃	详情	详情
(IV)	36512	2-(diethoxyphosphoryl)acetic acid	3095-95-2	C₆H₁₃O₅P	详情	详情
(V)	65712			C₂₄H₂₇ClFN₄O₆	详情	详情
(VI)	65713	2,2-Diethoxy-N,N-dimethylethylamine; (Dimethylamino)acetaldehyde diethyl acetal	3616-56-6	C₈H₁₉NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

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：(XII)

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