Patent GB-1215132-A (GB)
Title: Physiologically active amine derivatives of thiophthalane
Inventor: PETERSEN POVL VIGGO
IPC: C07D333/72
Filed: 1967-09-29
Abstract: 1,215,132. Amine derivatives of thiophthalone- KEFALAS A.S. 15 Jan., 1968 [16 Jan., 1967; 29 Sept., 1967], Nos. 2327/67 and 44560/67. Heading C2C. [Also in Division A5] The invention comprises compounds of formula wherein R<SP>1</SP> and R<SP>2</SP> are H or C 1-8  alkyl, R<SP>3</SP> and R<SP>4</SP> are H, C 1-8  alkyl or benzyl, or NR<SP>3</SP>R<SP>4</SP> is a 5- or 6- membered saturated heterocyclic ring, "alkylene" is C 2-6  alkylene having at least 2 C atoms in the direct chain between the ring C and N atoms, R<SP>5</SP> is CONHR<SP>6</SP>, CO 2 R<SP>7</SP>, COR<SP>8</SP>, CHOHR<SP>8</SP> or Ph (optionally substituted with Y (halogen), C 1-8  alkyl, C 1-8  alkoxy or CY 3 ), R<SP>6</SP> is H, C 1-8  alkyl or Ph (optionally substituted with C 1-8  alkyl or C 1-8  alkoxy), R<SP>7</SP> is H or C 1-8  alkyl, R<SP>8</SP> is C 1-8  alkyl, Ph or Ph-C 1-8 -alkyl, and X is H, Y, C 1-8  alkyl, C 1-8  alkoxy or CY 3 ; and acid addition salts thereof with pharmaceutically acceptable acids. These compounds may be prepared by (a) condensing the corresponding thiophthalane having H instead of 'alkylene NR<SP>3</SP>R<SP>4</SP>', with Y-alkylene-NR<SP>3</SP>R<SP>4</SP>, (b) reacting the corresponding thiophthalane having Y instead of 'NR<SP>3</SP>R<SP>4</SP>', with HNR<SP>3</SP>R<SP>4</SP>, (c) reacting with H 2 S the corresponding #-(o-alkenylphenyl)- alk-#-enylamine, (d) monodealkylating the above compound (R<SP>3</SP>=C 1-8  alkyl, R<SP>4</SP>=C 1-8  alkyl or benzyl) by reaction with a C 1-8  alkyl or benzyl chloroformate followed by hydrolysis; (e) (for R<SP>5</SP>=CONHR<SP>6</SP>), reacting the above compound (R<SP>5</SP>=CO 2 R<SP>7</SP>) with R<SP>6</SP>NHMgY, (f) (for R<SP>5</SP>=COR<SP>8</SP> or CHOHR<SP>8</SP>) reacting the above compound (R<SP>5</SP> = CONH 2 ) with R<SP>8</SP>MgY, hydrolysing the mixture with dilute acid and optionally reducing the COR<SP>8</SP> group to CHOHR<SP>8</SP>. Starting materials and intermediates.- α-Phenylphthalyl dibromide (reacting o-benzoylbenzoic acid with LiAlH 4  and the product with PBr 3 ) reacts with Na 2 S to give 1-phenylthiophthalane; the 3-methyl homologue is made analogously. 2 - Benzylthio - 2 - (o - chlorophenyl)- propane (from benzylthiol and 2-(o-chlorophenyl)propan-2-ol (I)) reacts with NaH to give 1,1 - dimethyl - 3 - phenylthiophthalane (II). II is also made by (a) reducing its 3-hydroxy derivative (from o-isopropenylbenzophenone (III) and H 2 S) with formic acid, or (b) reacting III directly with H 2 S. o-Acetylbenzhydrol (from 3-phenylphthalide and MeMgI) is reduced with LiAlH 4  to α-methyl-α<SP>1</SP> -phenylphthalyl alcohol. 1 - (o - isopropenylphenyl) - 1 - phenyl - 4 - dimethylaminobut-1-ene is made by dehydrating the corresponding benzhydrol with SOCl 2 / pyridine. 1,1 - Dimethyl - 3 - N - ethoxycarbonyl- N - methylaminopropyl - 3 - phenylthiophthalane is made from the dimethylamino analogue with ClCO 2 Et. 2 - (Carboxymethylthio)- 2 - (o-chlorophenyl) propane (from thioglycollic acid and I) is ring-closed with NaH/Me 2 SO to 1,1-dimethylthiophthalane - 3 - carboxylic acid; the latter is converted conventionally to its acid chloride, amide, and methyl and ethyl esters.