Patent GB-1397647-A (GB)
Title: Thiophene derivatives
IPC: C07D333/32
Filed: 1972-08-02
Abstract: 1397647 Thiophen derivatives SANDOZ Ltd 2 Aug 1972 [6 Aug 1971 (10)] 36095/72 Heading C2C Novel compounds I and salts thereof in which R 1  is H or 1-4 C alkyl; R 2  is OH, 1-4 C alkoxy, 3-6 C cycloalkoxy, 3-6 C cycloalkyl-1-4 C alkoxy, NH 2 , 1-4 C alkylamino or di-(1-4 C alkyl) amino; or R 1  and R 2  together form a single band; R 3  is H, Cl, or 1-4 C alkyl or if R 1  is H or if R 1  and R 2  are together a single bond then R 3  may be OH, or if R 1  is 1-4 C alkyl then R 3  may be 1-4 C alkoxy; R 4  is H, Cl, Br or 1-4 C alkyl or if R 1  is H or if R 1  and R 2  are together a single bond then R 4  may be OH, or if R 1  is 1-4 C alkyl then R 4  may be 1-4 C alkoxy, or if R 3  is H, then R 4  may be F or CF 3  ; R 5  is H or 1-4 C alkyl and R 6  is H or CH 3 ; are prepared by (i) solvolysing -CN to -COR<SP>1</SP> 2  (R<SP>1</SP> 2  is OH, NH 2 , alkoxy, cycloalkoxy or cycloalkyl-alkoxy) in a compound II (in which R<SP>AT</SP> is H or alkyl; R<SP>1</SP> 3  is H, Cl or alkyl or if R<SP>1</SP> 1  is H, R<SP>1</SP> 3  may be OH or if R<SP>1</SP> 1  is alkyl, R<SP>1</SP> 3  may be alkoxy; R<SP>1</SP> 4  is H, Cl, Br or alkyl or if R<SP>1</SP> 1  is H, R<SP>1</SP> 4  may be OH or if R<SP>1</SP> 1  is alkyl, R<SP>1</SP> 4  may be alkoxy or if R<SP>1</SP> 3  is H, R<SP>1</SP> 4  may be F or CF 3 ) to give a compound Ia (ii) hydrolysing a compound Ic (in which R<SP>11</SP> 2  is alkoxy, cycloalkoxy or cycloalkyl-alkoxy) to give a compound Ib (iii) esterifying a compound Ib to give a compound Ic; (iv) reacting a compound Ie (in which R<SP>IV</SP> 2  is OH, alkoxy, cycloalkoxy, cycloalkyl-alkoxy, NH 2 , or mono- or di-alkylamino) with a compound R<SP>1</SP> 5 X (in which R<SP>1</SP> 5  is alkyl and X is iodo, Cl, Br, R<SP>1</SP> 5 SO 2  or an organic sulphonate group) to give a compound Id (in which R<SP>11</SP> 1  is alkyl, R<SP>111</SP> 2  is as R<SP>IV</SP> 2 , R<SP>11</SP> 3  is H, Cl, alkyl or alkoxy; and R<SP>11</SP> 4  is H, Cl, Br, alkyl or alkoxy or if R<SP>11</SP> 3  is H, R<SP>11</SP> 4  may be F or CF 3 ); (v) reacting an acid Ib or a reactive derivative thereof with a compound HR<SP>v</SP> 2  (in which R<SP>V</SP> 2  is NH 2  or mono or dialkylamino) to give a compound If  (vi) splitting the ether groups in a compound Ih to give a compound Ig (in which R<SP>111</SP> 3  is H, Cl, alkyl or OH and R<SP>111</SP> 4  is H @  Cl, Br, alkyl or OH or if R<SP>111</SP> 3  is H, R<SP>111</SP> 4  may be F or CF 3 ) ; or (vii) cyclizing a compound Ij to give a compound Ii 4 - Methoxy - 5 - phenyl - 3 - thiophene - carboxylic acid ethyl ester is prepared by reaction of the corresponding 4-hydroxy compound with NaH and CH 3 I. On reduction of the 4 methoxy compound with LiAlH 4  4-methoxy-5-phenyl-3- thenyl alcohol is produced. This may be reacted with SOCl 2  to give 4-methoxy-5-phenyl-3-thenyl chloride which may then be reacted with NaCN to give 4-methoxy-5-phenyl-3-thiophene-acetonitrile. Compounds similar to the above intermediates but in which the phenyl moiety is substituted by F, Cl, CH 3  or OCH 3  are prepared similarly. Ethyl 5-(3-chlorophenyl)-4-hydroxy-3-thiophene carboxylate is prepared by reaction of ethyl #- mercaptopropionate with ethyl α-bromo-3- chlorophenylacetate to give ethyl α-[2-(carbethoxy)ethylthio]-3-chlorophenyl acetate, reaction of this with sodium ethylate to give ethyl 5-(3- chlorophenyl)-tetrahydro-4-oxo-3-thiophene carboxylate and reaction of this with H 2 O 2 . Compounds similar to these intermediates but in which the phenyl moiety is unsubstituted or substituted, not by Cl, but by CF 3 , CH 3 , two Cl atoms, F, two OCH 3  groups &c, are prepared similarly.  4-Hydroxy-5-phenyl-3-thiophene-acetonitrile is prepared by reaction of 4-methoxy-5-phenyl-3- thiophene-acetonitrile with sodium ethylate mercaptide solution. Compounds in which the phenyl moiety is substituted by F, Cl, CH 3  &c. are prepared similarly. 2 - (4 - methoxy - 5 - phenyl - 3 - thienyl)- propionyl chloride is prepared by reaction of the appropriate acid with SOCl 2 . Pharmaceutical compositions having antiphlogistic properties and arthritis-inhibiting effect comprise a compound I or a suitable salt together with a carrier or diluent.