4-amino-2-fluoro-N-methylbenzamide -Drug Synthesis Database

【结构式】

【分子编号】67496

【品名】4-amino-2-fluoro-N-methylbenzamide

【CA登记号】　

【分子式】C₈H₉FN₂O

【分子量】168.17074

【元素组成】C 57.14% H 5.39% F 11.3% N 16.66% O 9.51%

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：(XV)

Iodination of 3-(trifluoromethyl)-2-pyridinol (I) with NIS in acetonitrile/DMF at 80 °C gives 5-iodo-3-(trifluoromethyl)-2-pyridinol (II), which is treated with POCl3 in DMF at 110 °C under microwave to yield 2-chloro-5-iodo-3-(trifluoromethyl)pyridine (III). Condensation of iodide (III) with 4-methoxybenzylamine (IV) in the presence of Pd2dba3, xantphos and t-BuONa in refluxing toluene or using Pd(OAc)2, BINAP, Et3N and Cs2CO3 in toluene under microwave provides secondary amine (V), which is reacted with Zn(CN)2 in the presence of Pd2dba3 and dppf in DMF at 130 °C to obtain nitrile (VI). N-Deprotection of compound (VI) by means of TFA in CH2Cl2 affords 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (VII), which is condensed with thiophosgene (VIII) in CHCl3/H2O to yield 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (IX). Finally, isothiocyanate (IX) is submitted to cyclocondensation with nitrile (X) in DMF at 80 °C under microwave, followed by treatment with HCl in refluxing MeOH .
Synthesis of intermediate (X): Condensation of 2,4-difluorobenzoyl chloride (XI) with methylamine (XII) in THF produces 2,4-difluoro-N-methylbenzamide (XIII), which is condensed with 4-methoxybenzylamine (IV) in acetonitrile (1, 3, 4) or DMSO at 190 °C under microwave (2) to give the secondary amine (XIV). N-Deprotection of compound (XIV) by means of TFA in CH2Cl2 provides 4-amino-2-fluoro-N-methylbenzamide (XV), which is finally condensed with cyclobutanone (XVI) and NaCN in AcOH at 80 °C . Alternatively, amino nitrile (X) is obtained by direct condensation of fluoride (XIII) with 1-aminocyclobutanecarbonitrile (XVII) (prepared by Strecker reaction of cyclobutanone (XVI) with NaCN, NH4Cl and NH3 in the presence of MgSO4) .

参考文献中间体

合成目标

【1】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 8802689; EP 2004181; US 2011003839; WO 2007126765; EP 2656842; EP 2656841; EP 2368550; JP 2009531439.
【2】 Ouerfelli, O., Dilhas, A., Yang, G., Zhao, H. (Sloan-Kettering Institute for Cancer Research). Synthesis of thiohydantoins. US 2013225821; US 8461343; WO 2008119015.
【3】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 2013072511.
【4】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 2013072511.

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)	67484	3-(trifluoromethyl)pyridin-2-ol		C₆H₄F₃NO	详情	详情
(II)	67485	5-iodo-3-(trifluoromethyl)pyridin-2-ol		C₆H₃F₃INO	详情	详情
(III)	67486	2-chloro-5-iodo-3-(trifluoromethyl)pyridine		C₆H₂ClF₃IN	详情	详情
(IV)	15098	4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine	2393-23-9	C₈H₁₁NO	详情	详情
(V)	67487	6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine		C₁₄H₁₂ClF₃N₂O	详情	详情
(VI)	67488	5-((4-methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile		C₁₅H₁₂F₃N₃O	详情	详情
(VII)	67489	5-amino-3-(trifluoromethyl)picolinonitrile		C₇H₄F₃N₃	详情	详情
(VIII)	67490	Thiophosgene;Thiocarbonyl chloride	463-71-8	CCl₂S	详情	详情
(IX)	67491	5-isothiocyanato-3-(trifluoromethyl)picolinonitrile		C₈H₂F₃N₃S	详情	详情
(X)	67492	4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide		C₁₃H₁₄FN₃O	详情	详情
(XI)	67493	2,4-difluorobenzoyl chloride	72482-64-5	C₇H₃ClF₂O	详情	详情
(XII)	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
(XIII)	67494	2,4-difluoro-N-methylbenzamide		C₈H₇F₂NO	详情	详情
(XIV)	67495	2-fluoro-4-((4-methoxybenzyl)amino)-N-methylbenzamide		C₁₆H₁₇FN₂O₂	详情	详情
(XV)	67496	4-amino-2-fluoro-N-methylbenzamide		C₈H₉FN₂O	详情	详情
(XVI)	26374	cyclobutanone	1191-95-3	C₄H₆O	详情	详情
(XVII)	67497	1-aminocyclobutanecarbonitrile		C₅H₈N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Oxidation of 2-fluoro-4-nitrotoluene (I) by means of periodic acid and CrO3 affords 2-fluoro-4-nitrobenzoic acid (II), which by chlorination with SOCl2 in DMF at –5 °C, followed by condensation with methylamine, yields 2-fluoro-N-methyl-4-nitrobenzamide (III). Reduction of the nitro group in compound (III) with Fe in refluxing AcOH/EtOAc gives amine (IV), which is then condensed with pure acetone cyanohydrin (V) in the presence of anhydrous MgSO4 at 80 °C to provide 4-(1-cyano-1-methylethylamino)-2-fluoro-Nmethylbenzamide (VI). Finally, compound (VI) is condensed with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (VII) (prepared by reaction of 4-amino-2-(trifluoromethyl)benzonitrile (VIII) with thiophosgene in H2O) in DMF heated to 100 °C under microwave irradiation, and then cyclized by means of HCl in refluxing MeOH .

参考文献中间体

合成目标

【1】 Sawyers, C.L., Jung, M.E., Chen, C.D., Ouk, S., Welsbie, D., Tran, C., Wongvipat, J., Yoo, D. (University of California, Oakland). Diarylhydantoin compounds. EP 1893196, JP 2008540523, US 2007004753, US 7709517, WO 2006124118.
【2】 Jung, M., Yoo, D., Sawyers, C.L., Tran, C. (University of California, Oakland). Diarylthiohydantoin compounds. EP 2013187, JP 2009531449, US 2007254933, US 2008139634, WO 2007127010.
【3】 Jung, M.E., Ouk, S., Yoo, D., Sawyers, C.L., Chen, C., Tran, C., Wongvipat, J. Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem 2010 53(10): 2779-96.

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)	55902	2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene	1427-07-2	C₇H₆FNO₂	详情	详情
(II)	55903	2-Fluoro-4-nitrobenzoic acid	403-24-7	C₇H₄FNO₄	详情	详情
(III)	68796	2-fluoro-N-methyl-4-nitrobenzamide		C₈H₇FN₂O₃	详情	详情
(IV)	67496	4-amino-2-fluoro-N-methylbenzamide		C₈H₉FN₂O	详情	详情
(V)	18029	Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile	75-86-5	C₄H₇NO	详情	详情
(VI)	68797	4-(1-cyano-1-methylethylamino)-2-fluoro-N-methylbenzamide		C₁₂H₁₄FN₃O	详情	详情
(VII)	68798	4-isothiocyanato-2-(trifluoromethyl)benzonitrile；4-Cyano-3-trifluoromethylphenylisothiocyanate	143782-23-4	C₉H₃F₃N₂S	详情	详情
(VIII)	18743	4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride	654-70-6	C₈H₅F₃N₂	详情	详情

Extended Information