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【结 构 式】

【分子编号】21925

【品名】[4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine

【CA登记号】3300-51-4

【 分 子 式 】C8H8F3N

【 分 子 量 】175.1534696

【元素组成】C 54.86% H 4.6% F 32.54% N 8%
与该中间体有关的原料药合成路线共 5 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5

合成路线1

该中间体在本合成路线中的序号：(III)

D-11208 is obtained in a five step synthesis: 2,6-Dichloro-3-nitropyridine (I) reacts with ammonia to give 2-amino-3-nitro-6-chloropyridine (II). Subsequent condensation with 4-trifluoromethyl benzylamine (III) yields 2-amino-3-nitro-6-(4-trifluoromethyl)aminopyridine (IV). Hydrogenation with Raney Nickel as catalyst and reaction with ethyl chloroformiate yields D-11208.

参考文献 中间体
合成目标
【1】 Bebengurg, W.; Engek, J.; Heese, J.; Thiele, K. (Degussa AG); 2-Amino-3-acylamino-6-benzylaminopyridine derivatives having antiepileptic action. DE 3337593 .
【2】 Engel, J.; Molliere, M.; Emig, P.; Szelenyi, I.; D-11208. Drugs Fut 1988, 13, 9, 817.
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) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(II) 13575 6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine 27048-04-0 C5H4ClN3O2 详情 详情
(III) 21925 [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine 3300-51-4 C8H8F3N 详情 详情
(IV) 23270 N-(6-amino-5-nitro-2-pyridinyl)-N-[4-(trifluoromethyl)benzyl]amine; 3-nitro-N(6)-[4-(trifluoromethyl)benzyl]-2,6-pyridinediamine C13H11F3N4O2 详情 详情
(V) 23271 2-amino-6-[[4-(trifluoromethyl)benzyl]amino]-3-pyridinylamine; N(6)-[4-(trifluoromethyl)benzyl]-2,3,6-pyridinetriamine C13H13F3N4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(V)

1) The Knoevenagel condensation of aldehyde (I) with rhodanine (II) using NH4OAc and AcOH afforded benzylidene- thiazolidine (III). The methyl ester group of (III) was hydrolyzed with HCl in AcOH, and the resulting carboxylic acid (IV) was coupled to 4-(trifluoromethyl)benzylamine (V) in the presence of diethyl phosphorocyanidate and Et3N to produce amide (VI). Subsequent hydrogenation of the olefinic double bond of (VI) over Pd/C provided the target benzylthiazolidine.

参考文献 中间体
合成目标
【1】 Nomura, M.; et al.; (3-Substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents. Bioorg Med Chem Lett 1999, 9, 4, 533.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 21921 methyl 5-formyl-2-methoxybenzoate C10H10O4 详情 详情
(II) 10883 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione 2295-31-0 C3H3NO2S 详情 详情
(III) 21923 methyl 5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxybenzoate C13H11NO5S 详情 详情
(IV) 21924 5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxybenzoic acid C12H9NO5S 详情 详情
(V) 21925 [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine 3300-51-4 C8H8F3N 详情 详情
(VI) 21926 5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide C20H15F3N2O4S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(V)

2) An alternative method starting from aniline (VII) employed the Meerwein arylation of methyl acrylate (IX) with the intermediate diazonium salt (VIII) in the presence of cuprous oxide. The resulting bromoester (X) was cyclized with thiourea (XI) in Et2O, followed by hydrolysis with HCl in sulfolane to afford (XIII). Finally, acid (XIII) was coupled to benzylamine (V) in the presence of (EtO)2POCN and Et3N.

参考文献 中间体
合成目标
【1】 Nomura, M.; et al.; (3-Substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents. Bioorg Med Chem Lett 1999, 9, 4, 533.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(V) 21925 [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine 3300-51-4 C8H8F3N 详情 详情
(VII) 21927 methyl 5-amino-2-methoxybenzoate C9H11NO3 详情 详情
(VIII) 21928 methyl 5-(1lambda(5)-diazynyl)-2-methoxybenzoate C9H10N2O3 详情 详情
(IX) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(X) 21930 methyl 5-(2-bromo-3-methoxy-3-oxopropyl)-2-methoxybenzoate C13H15BrO5 详情 详情
(XI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XII) 21932 methyl 5-[(2-imino-4-oxo-1,3-thiazolidin-5-yl)methyl]-2-methoxybenzoate C13H14N2O4S 详情 详情
(XIII) 21933 5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-2-methoxybenzoic acid C12H11NO5S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VI)

5-Formyl-2-methoxybenzoic acid (I) is converted to the corresponding benzyl ester (II) upon treatment with benzyl bromide and potassium bicarbonate. Subsequent Wadsworth-Emmons condensation between aldehyde (II) and triethyl 2-phosphonobutyrate (III) gives the unsaturated ester (IV). Double bond hydrogenation in (IV) with concomitant hydrogenolysis of the benzyl ester affords acid (V), which is subsequently coupled with 4-(trifluoromethyl)benzyl amine (VI), via the mixed anhydride with ethyl chloroformate, to produce amide (VII). The ethyl ester group of (VII) is finally hydrolyzed to the title carboxylic acid employing NaOH in aqueous ethanol.

参考文献 中间体
合成目标
【1】 Tanase, T.; Nomura, M.; Miyachi, H.; et al.; Design, synthesis and evaluation of substituted phenylpropanoic acid derivatives as peroxisome proliferator-activated receptor (PPAR) activators: Novel human PPARalpha-selective activators. Bioorg Med Chem Lett 2002, 12, 1, 77.
【2】 Murakami, K.; Takahashi, Y.; Nomura, M.; Miyachi, H.; Ide, T.; Tsunoda, M.; Tanase, T. (Kyorin Pharmaceutical Co., Ltd.); Substd. phenylpropionic acid derivs. as agonists to human peroxisome proliferator-activated receptor (PPAR) alpha. EP 1184366; JP 2001055367; WO 0075103 .
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) 57501 5-formyl-2-methoxybenzoic acid C9H8O4 详情 详情
(II) 57502 benzyl 5-formyl-2-methoxybenzoate C16H14O4 详情 详情
(III) 20274 ethyl 2-(diethoxyphosphoryl)butanoate 17145-91-4 C10H21O5P 详情 详情
(IV) 57503 benzyl 5-[(E)-2-(ethoxycarbonyl)-1-butenyl]-2-methoxybenzoate C22H24O5 详情 详情
(V) 57504 5-[2-(ethoxycarbonyl)butyl]-2-methoxybenzoic acid C15H20O5 详情 详情
(VI) 21925 [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine 3300-51-4 C8H8F3N 详情 详情
(VII) 57505 ethyl 2-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)benzyl]butanoate C23H26F3NO4 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VI)

In an enantioselective synthesis of the (S)-enantiomer, asymmetric alkylation of the chiral N-butyryl oxazolidinone (I) with benzyl 5-bromomethyl-2-methoxybenzoate (II) in the presence of lithium hexamethyldisilazide leads to isomer (III) in high diastereomeric excess. Subsequent benzyl ester hydrogenolysis in (III) employing Pd/C affords carboxylic acid (IV), which is further converted to the mixed anhydride (V) with ethyl chloroformate and triethylamine. Coupling of anhydride (V) with 4-trifluoromethylbenzylamine (VI) furnishes the corresponding amide (VII). The chiral auxiliary is then removed from (VII) by hydrolysis with lithium peroxide to yield the target (S)-enantiomer.

参考文献 中间体
合成目标
【1】 Nomura, M.; Tanase, T.; Miyachi, H.; Efficient asymmetric synthesis of (S)-2-ethylphenylpropanoic acid derivative, a selective agonist for human peroxisome proliferator-activated receptor alpha. Bioorg Med Chem Lett 2002, 12, 16, 2101.
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) 10794 (4S)-4-Benzyl-3-butyryl-1,3-oxazolan-2-one C14H17NO3 详情 详情
(II) 61874 benzyl 5-(bromomethyl)-2-methoxybenzoate C16H15BrO3 详情 详情
(III) 61875 benzyl 5-((2S)-2-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxybenzoate C30H31NO6 详情 详情
(IV) 61876 5-((2S)-2-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxybenzoic acid C23H25NO6 详情 详情
(V) 61877 　 C26H29NO8 详情 详情
(VI) 21925 [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine 3300-51-4 C8H8F3N 详情 详情
(VII) 61873 5-((2R)-2-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide C31H31F3N2O5 详情 详情
Extended Information