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【结 构 式】 
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【分子编号】26358 【品名】methyl (E)-4-bromo-2-butenoate 【CA登记号】1117-71-1 |
【 分 子 式 】C5H7BrO2 【 分 子 量 】179.01338 【元素组成】C 33.55% H 3.94% Br 44.64% O 17.88% |
合成路线1
该中间体在本合成路线中的序号：(II)Raxofelast has been synthesized by a short route involving Friedel-Crafts alkylation of trimethylhydroquinone (I) by methyl 4-bromocrotonate (II). The crude reaction mixture containing methyl 4-(2,5-dihydroxy-3,4,6-trimethylphenyl)-2(E)-butenoate (III) was directly submitted to a hydrolytic cyclization in alkaline environment in the presence of a strong reducing agent to afford (±)-2,3-dihydro-5-hydroxy-4,6,7-trimethyl-2-benzofuranacetic acid (IV) (IRFI-005). Acetylation of phenolic hydroxyl by routine methods, followed by recrystallization by isopropyl acetate, gave the final product.
| 【1】 De Vellis, P.; Scuri, R.; Zanarella, S.; Ceccarelli, S.; Synthesis of novel 2-substituted 5-oxycoumarans via a direct route to 2,3-dihydro-5-hydroxy-2-benzofuranacetic acids. J Heterocycl Chem 1993, 30, 679. |
| 【2】 Cuzzocrea, S.; Ceccarelli, S.; Raxofelast. Drugs Fut 1999, 24, 7, 735. |
| 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) | 26357 | 2,3,5-trimethyl-1,4-benzenediol | 700-13-0 | C9H12O2 | 详情 | 详情 |
| (II) | 26358 | methyl (E)-4-bromo-2-butenoate | 1117-71-1 | C5H7BrO2 | 详情 | 详情 |
| (III) | 26359 | methyl (E)-4-(2,5-dihydroxy-3,4,6-trimethylphenyl)-2-butenoate | C14H18O4 | 详情 | 详情 | |
| (IV) | 26360 | 2-(5-hydroxy-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-2-yl)acetic acid | C13H16O4 | 详情 | 详情 | |
| (V) | 26361 | methyl (E)-2-butenoate | 623-43-8 | C5H8O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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.
| 【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：(XI)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 .
| 【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 |
合成路线4
该中间体在本合成路线中的序号：(XI)Compound (XIII) can be obtained by reductocondensation of 3-chloro-4-fluoroaniline (XIX) with 3,4-dimethoxybenzaldehyde (XXI) using NaCNBH3 or NaBH(OAc)3 in AcOH/i-PrOH to yield the benzylaniline derivative (XXII), which by condensation with 4-chloro-7-fluoro-6-nitroquinazoline (XVIII) in i-PrOH gives the tertiary amine (XXIII) . Substitution of fluoroquinazoline (XXIII) with NaOMe in refluxing MeOH affords the 7-methoxyquinazoline derivative (XXIV), which is reduced to the quinazoline-4,6-diamine (XXV) by means of H2 over Raney Ni in THF. Finally, compound (XXV) is coupled with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA .
4-(Piperidin-1-yl)-2-butenoyl chloride (IV) can be prepared by condensation of methyl 4-bromocrotonate (XI) with piperidine (X) to yield methyl 4-(piperidin-1-yl)-2-butenoate (XXVI), which is then hydrolyzed with HCl to give 4-(piperidin-1-yl)-2-butenoic acid (XXVII). Finally, acid (XXVII) is reacted with (COCl)2 in the presence of DMF in CH2Cl2 .
| 【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. |
| 【2】 Bridges, A.J., Horne, N.M., Jacks, T.E. et al. (Pfizer, Inc.). Preparation of substituted quinazolines. JP 2006517959, US 2004158065, WO 2004069791. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （XXVI) | 68482 | (E)-methyl 4-(piperidin-1-yl)but-2-enoate | C10H17NO2 | 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 | |
| (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 |
| (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 | |
| (XVIII) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
| (XIX) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (XXI) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (XXII) | 68478 | 3-chloro-N-(3,4-dimethoxybenzyl)-4-fluoroaniline | C15NClFO2 | 详情 | 详情 | |
| (XXIII) | 68479 | N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-6-fluoro-7-nitroquinazolin-4-amine | C23H17ClF2N4O4 | 详情 | 详情 | |
| (XXIV) | 68480 | N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-6-methoxy-7-nitroquinazolin-4-amine | C24H20ClFN4O5 | 详情 | 详情 | |
| (XXV) | 68481 | N4-(3-chloro-4-fluorophenyl)-N4-(3,4-dimethoxybenzyl)-6-methoxyquinazoline-4,7-diamine | C24H22ClFN4O3 | 详情 | 详情 | |
| (XXVII) | 26709 | (E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid | C9H15NO2 | 详情 | 详情 |