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【结 构 式】

【药物名称】M-5011, T-3788, M-5010

【化学名称】2(R)-[4-(3-Methyl-2-thienyl)phenyl]propionic acid

【CA登记号】76604-64-3

【 分 子 式 】C14H14O2S

【 分 子 量 】246.33048

【开发单位】Maruho (Licensee)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Non-Steroidal Antiinflammatory Drugs

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6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

The Darzen's condensation of 4-iodoacetophenone (I) with methyl chloroacetate (II) in the presence of NaOMe afforded the glycidic ester (III), which was further hydrolyzed to the corresponding glycidic acid (IV) with NaOH in aqueous ethanol. Subsequent decarboxylation of (IV) under acidic conditions furnished 2-(4-iodophenyl)propionaldehyde (V). After oxidation of aldehyde (V) with sodium chlorite, the resultant carboxylic acid was converted to the corresponding zinc salt (VI) upon treatment with ZnCl2 and NaOH. Coupling of aryl iodide (VI) with the Grignard reagent (VIII) (prepared from 2-bromo-3-methylthiophene (VII)) in the presence of PdCl2 gave rise to the racemic biarylpropionic acid (IX)). The title (R)-enantiomer was then resolved via formation of the diastereoisomeric salts with D-phenylglycine methyl ester (X)

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
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) 51497 4'-Iodoacetophenone; 4-Iodoacetophenone; 1-(4-Iodophenyl)ethanone 13329-40-3 C8H7IO 详情 详情
(II) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(III) 62683 methyl 3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylate C11H11IO3 详情 详情
(IV) 62684 3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylic acid C10H9IO3 详情 详情
(V) 62685 2-(4-iodophenyl)propanal C9H9IO 详情 详情
(VI) 62686 　 C18H16I2O4Zn 详情 详情
(VII) 12443 2-Bromo-3-methylthiophene 14282-76-9 C5H5BrS 详情 详情
(VIII) 36973 bromo(3-methyl-2-thienyl)magnesium C5H5BrMgS 详情 详情
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(X) 10717 methyl (2S)-2-amino-2-phenylethanoate C9H11NO2 详情 详情

合成路线2

Preparation of the racemic arylpropionic acid (IX) has been reported through a number of different procedures. 4-Aminoacetophenone (XI) was diazotized to (XII) employing isoamyl nitrite and either acetic or fluoboric acid. Then, the Gomberg-Bachmann coupling of diazonium salt (XII) with 3-methylthiophene (XIII) furnished 4-(3-methyl-2-thienyl)acetophenone (XIV). Subsequent Darzen's condensation of acetophenone (XIV) with methyl chloroacetate (II) afforded the glycidic ester (XV), which was further hydrolyzed to acid (XVI), and then decarboxylated to aldehyde (XVII). Oxidation of (XVII) to the key carboxylic acid was performed by treatment with potassium permanganate

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XI) 27847 1-(4-aminophenyl)-1-ethanone 99-92-3 C8H9NO 详情 详情
(XII) 62688 4-acetylbenzenediazonium C8H7N2O 详情 详情
(XIII) 12442 3-Methylthiophene 616-44-4 C5H6S 详情 详情
(XIV) 62689 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone C13H12OS 详情 详情
(XV) 62690 methyl 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate C16H16O3S 详情 详情
(XVI) 62691 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylic acid C15H14O3S 详情 详情
(XVII) 62692 2-[4-(3-methyl-2-thienyl)phenyl]propanal C14H14OS 详情 详情

合成路线3

Alternatively, Darzen's condensation of acetophenone (XIV) with methyl 2-chloropropionate (XVIII) produced glycidic ester (XIX), which was hydrolyzed and decarboxylated to the 3-arylbutanone (XX). The haloform reaction of ketone (XX) with sodium hypobromite generated acid (IX)

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XIV) 62689 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone C13H12OS 详情 详情
(XVIII) 35742 methyl (2S)-2-chloropropanoate C4H7ClO2 详情 详情
(XIX) 62693 methyl 2,3-dimethyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate C17H18O3S 详情 详情
(XX) 62694 3-[4-(3-methyl-2-thienyl)phenyl]-2-butanone C15H16OS 详情 详情

合成路线4

Acetophenone (XIV) was converted to oxirane (XXI) by treatment with the in situ-generated dimethylsulfonium methylide. Rearrangement of epoxide (XVII) in the presence of molecular sieves furnished aldehyde (XVII), which was converted to acid (IX) by oxidation with sodium chlorite.

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XIV) 62689 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone C13H12OS 详情 详情
(XVII) 62692 2-[4-(3-methyl-2-thienyl)phenyl]propanal C14H14OS 详情 详情
(XXI) 62695 2-methyl-2-[4-(3-methyl-2-thienyl)phenyl]oxirane C14H14OS 详情 详情

合成路线5

In an alternative procedure, acetophenone (XIV) was condensed with KCN in the presence of ammonium carbonate to produce hydantoin (XXII). Basic hydrolysis of (XXII) led to amino acid (XXIII), which was converted to the dimethylamino analogue (XXIV) by reductive alkylation under Eschweiler-Clarke conditions. The desired arylpropionic acid (IX) was obtained from (XXIV) by hydrogenolysis in the presence of Pd/C

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XIV) 62689 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone C13H12OS 详情 详情
(XXII) 62696 5-methyl-5-[4-(3-methyl-2-thienyl)phenyl]-2,4-imidazolidinedione C15H14N2O2S 详情 详情
(XXIII) 62697 2-[4-(3-methyl-2-thienyl)phenyl]alanine C14H15NO2S 详情 详情
(XXIV) 62698 N,N-dimethyl-2-[4-(3-methyl-2-thienyl)phenyl]alanine C16H19NO2S 详情 详情

合成路线6

In a different approach, the precursor aldehyde (XVII) was obtained by addition of the Grignard reagent prepared from chloromethyl ethyl ether (XXV) to acetophenone (XIV), and then rearrangement of the resultant ethoxy alcohol (XXVI) in refluxing AcOH

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 62689 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone C13H12OS 详情 详情
(XVIII) 62692 2-[4-(3-methyl-2-thienyl)phenyl]propanal C14H14OS 详情 详情
(XXV) 13149 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether 3188-13-4 C3H7ClO 详情 详情
(XXVI) 62699 1-ethoxy-2-[4-(3-methyl-2-thienyl)phenyl]-2-propanol C16H20O2S 详情 详情

合成路线7

The thienyl bromobenzene (XXVII) was converted to the corresponding Grignard reagent and subsequently treated with ZnCl2 to afford the organozinc derivative (XXVIII). Condensation of (XXVIII) with ethyl bromopropionate (XXIX) led to the arylpropionic ester (XXX), which was further hydrolyzed to acid (IX) under basic conditions.

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XXVII) 62700 2-(4-bromophenyl)-3-methylthiophene C11H9BrS 详情 详情
(XXVIII) 62701 chloro[4-(3-methyl-2-thienyl)phenyl]zinc C11H9ClSZn 详情 详情
(XXIX) 19460 ethyl 2-bromopropanoate; 2-Bromopropionic acid ethyl ester 535-11-5 C5H9BrO2 详情 详情
(XXX) 62702 ethyl 2-[4-(3-methyl-2-thienyl)phenyl]propanoate C16H18O2S 详情 详情

合成路线8

Glycidonitrile (XXXII) was prepared by condensation of ketone (XIV) with chloroacetonitrile (XXXI) under Darzens conditions. Epoxide ring opening in (XXXII) by HCl in toluene provided the chlorohydrin (XXXIII). Acetylation of (XXXIII), followed by dehydrohalogenation led to the acetoxy acrylonitrile (XXXIV). Hydrolysis and decarbonylation of (XXXIV) provided an alternative access to the arylpropionic acid (IX)

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XIV) 62689 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone C13H12OS 详情 详情
(XXXI) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(XXXII) 62703 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarbonitrile C15H13NOS 详情 详情
(XXXIII) 62704 3-chloro-2-hydroxy-3-[4-(3-methyl-2-thienyl)phenyl]butanenitrile C15H14ClNOS 详情 详情
(XXXIV) 62705 (Z)-1-cyano-2-[4-(3-methyl-2-thienyl)phenyl]-1-propenyl acetate C17H15NO2S 详情 详情

合成路线9

The glycidic ester (XV), obtained as in Scheme 2, was alternatively rearranged to the alpha-keto ester enol form (XXXV) under acidic conditions. Hydrolysis and decarbonylation of (XXXV) employing NaOMe furnished acid (XI)

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XV) 62690 methyl 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate C16H16O3S 详情 详情
(XXXV) 62709 methyl (E)-2-cyano-3-[4-(3-methyl-2-thienyl)phenyl]-2-butenoate C17H15NO2S 详情 详情

合成路线10

The chlorohydrin (XXXIII), obtained as in Scheme 8, was converted to enol ether (XXXVI) via O-alkylation with bromoethane and sodium amide, followed by basic dehydrohalogenation. Acid hydrolysis of enol ether (XXXVI) produced the keto nitrile (XXXVII), which was then hydrolyzed and decarbonylated to acid (IX)

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XXXIII) 62704 3-chloro-2-hydroxy-3-[4-(3-methyl-2-thienyl)phenyl]butanenitrile C15H14ClNOS 详情 详情
(XXXVI) 62707 (Z)-2-ethoxy-3-[4-(3-methyl-2-thienyl)phenyl]-2-butenenitrile C17H17NOS 详情 详情
(XXXVII) 62708 3-[4-(3-methyl-2-thienyl)phenyl]-2-oxobutanenitrile C15H13NOS 详情 详情

合成路线11

A different strategy was based on the Knoevenagel condensation of ketone (XIV) with methyl cyanoacetate (XXXVIII) to produce the alkylidene cyanoacetate (XXXIX). Double-bond epoxidation by means of H2O2 led to (XL), which was further rearranged to keto amide (XLI). Decarboxylation of (XLI) under Hofmann rearrangement conditions furnished the arylpropionic acid (IX)

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XIV) 62689 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone C13H12OS 详情 详情
(XXXVIII) 34458 Cyanoacetic acid methyl ester; methyl 2-cyanoacetate 105-34-0 C4H5NO2 详情 详情
(XXXIX) 62709 methyl (E)-2-cyano-3-[4-(3-methyl-2-thienyl)phenyl]-2-butenoate C17H15NO2S 详情 详情
(XL) 62710 methyl 2-(aminocarbonyl)-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate C17H17NO4S 详情 详情
(XLI) 62711 3-[4-(3-methyl-2-thienyl)phenyl]-2-oxobutanamide C15H15NO2S 详情 详情

合成路线12

Methylation of arylacetic ester (XLII) was accomplished via Claisen condensation with diethyl carbonate and alkylation of the resultant arylmalonate (XLIII) with iodomethane and NaOMe. The methylated compound (XLIV) was further subjected to hydrolysis and decarboxylation to give (IX)

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XLII) 62712 ethyl 2-[4-(3-methyl-2-thienyl)phenyl]acetate C15H16O2S 详情 详情
(XLIII) 62713 diethyl 2-[4-(3-methyl-2-thienyl)phenyl]malonate C18H20O4S 详情 详情
(XLIV) 62714 diethyl 2-methyl-2-[4-(3-methyl-2-thienyl)phenyl]malonate C19H22O4S 详情 详情

合成路线13

2-(4-Iodophenyl)-2-methyloxirane (XLV) was obtained by addition of dimethylsulfonium methylide to 4-iodoacetophenone (I). Rearrangement of epoxide (XLV) in the presence of molecular sieves led to aldehyde (V), which was protected as the dimethyl acetal (XLVI) upon treatment with trimethyl orthoformate. Palladium-catalyzed condensation of the Grignard reagent (VIII) with aryl iodide (XLVI) furnished the biaryl adduct (XLVII). This was subsequently hydrolyzed to the key aldehyde (XVII) employing AcOH

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
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) 51497 4'-Iodoacetophenone; 4-Iodoacetophenone; 1-(4-Iodophenyl)ethanone 13329-40-3 C8H7IO 详情 详情
(V) 62685 2-(4-iodophenyl)propanal C9H9IO 详情 详情
(VIII) 36973 bromo(3-methyl-2-thienyl)magnesium C5H5BrMgS 详情 详情
(XVII) 62692 2-[4-(3-methyl-2-thienyl)phenyl]propanal C14H14OS 详情 详情
(XLV) 62715 2-(4-iodophenyl)-2-methyloxirane C9H9IO 详情 详情
(XLVI) 62716 1-(2,2-dimethoxy-1-methylethyl)-4-iodobenzene; 2-(4-iodophenyl)-1-methoxypropyl methyl ether C11H15IO2 详情 详情
(XLVII) 62717 1-methoxy-2-[4-(3-methyl-2-thienyl)phenyl]propyl methyl ether; 2-[4-(2,2-dimethoxy-1-methylethyl)phenyl]-3-methylthiophene C16H20O2S 详情 详情

合成路线14

The iodophenyl propionic acid (XLVIII) was protected as the oxazoline (LII) via activation as the corresponding acid chloride (XLIX), which was condensed with 2-amino-2-methylpropanol (L) to yield amide (LI). Subsequent cyclization of hydroxy amide (LI) by treatment with phosphorus oxychloride led to oxazoline (LII). Palladium coupling between aryl iodide (LII) and the Grignard reagent (VIII) provided the biaryl adduct (LIII). The oxazoline (LIII) was then hydrolyzed to (IX) with sulfuric acid and AcOH

参考文献 中间体
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 36973 bromo(3-methyl-2-thienyl)magnesium C5H5BrMgS 详情 详情
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XLVIII) 62718 2-(4-iodophenyl)propanoic acid C9H9IO2 详情 详情
(XLIX) 62719 2-(4-iodophenyl)propanoyl chloride C9H8ClIO 详情 详情
(L) 21513 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol 124-68-5 C4H11NO 详情 详情
(LI) 62720 N-(2-hydroxy-1,1-dimethylethyl)-2-(4-iodophenyl)propanamide C13H18INO2 详情 详情
(LII) 62721 2-[1-(4-iodophenyl)ethyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole C13H16INO 详情 详情
(LIII) 62722 4,4-dimethyl-2-{1-[4-(3-methyl-2-thienyl)phenyl]ethyl}-4,5-dihydro-1,3-oxazole C18H21NOS 详情 详情

合成路线15

In an asymmetric synthesis of the title compound, aldehyde (V) was oxidized with sodium chlorite to afford the corresponding racemic acid, which was resolved via formation of the diastereoisomeric salts with cinchonidine. The target (R)-2-(4-iodophenyl)propionic acid (LIV) was then converted to the zinc salt and subsequently coupled to 3-methyl-2-thienylmagnesium bromide (VIII) in the presence of palladium catalyst to provide the desired chiral arylpropionic acid

参考文献 中间体
【1】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
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) 62685 2-(4-iodophenyl)propanal C9H9IO 详情 详情
(VIII) 36973 bromo(3-methyl-2-thienyl)magnesium C5H5BrMgS 详情 详情
(LIV) 62723 (2R)-2-(4-iodophenyl)propanoic acid C9H9IO2 详情 详情
Extended Information