Patent GB-1471620-A (GB)
Title: Pyrazolidine and pyrazolidinone derivatives
IPC: C07C57/58
Filed: 1974-10-29
Abstract: 1471620 Pyrazolidine derivatives; Grignard intermediate E I DU PONT DE NEMOURS & CO 29 Oct 1974 46770/74 Addition to 1428431 Headings C2C and C2J [Also in Division C3] The invention comprises pyrazolidine derivatives of the Formula I wherein A is vinylene, ethynylene or phenylene; R is H, C 1-12  alkyl, C 3-12  cycloalkyl or C 4-12  cycloalkylalkyl ; m is 0 or 1; n and p each are 0 or 6; Y and Z are O or H 2 , with the proviso that where one is O, the other is H 2 ; R<SP>1</SP> is H, methyl or ethyl; R<SP>2</SP> is H, methyl, ethyl, vinyl, or ethynyl; R<SP>3</SP> is H or C 2-4  alkanoyl; R<SP>4</SP> and R<SP>5</SP> each are H, F, methyl or ethyl; and Q is H, methyl, ethyl, trifluoromethyl or 1,1-difluoroethyl; with the provisos that (i) R<SP>1</SP>, R<SP>4</SP> and R<SP>5</SP> are each H when R<SP>2</SP> is methyl, ethyl, vinyl or ethynyl; and (ii) when A is vinylene or ethynylene and m is 1, or when m is 0, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP> and R<SP>5</SP> are not all 11 when Q is H or CH 3  except that Q may be methyl when p is 6; alkali metal and amine salts and pharmaceutically acceptable acid addition salts thereof; and processes for their preparation. Compounds of the above formula wherein Y is O, Z is H 2  and R<SP>3</SP> is H are prepared by reacting compounds of the Formula II with ketones of the formulae or to yield compounds of the formulae and reducing the oxo group in the side chain, and, if necessary, the olefinic grouping in said side chain, or when R<SP>1</SP>, R<SP>3</SP>, R<SP>4</SP> and R<SP>5</SP> are H, reacting the ketones above with the saturated oxo side chain with compounds of the formula R<SP>8</SP>MgX or R<SP>8</SP>Li, wherein R<SP>8</SP> is methyl, ethyl, vinyl or ethynyl and X is Cl, Br or I. Compounds of the above formula in which Z is O, Y is H 2  and R 3  is H are prepared by (a) reacting compounds of the formulae with compounds of the formula wherein X is Cl, Br or I, to yield compounds of the formulae and reducing the oxo group in the side chain, and, if necessary the olefinic grouping in said side chain, or when R<SP>1</SP>, R<SP>2</SP>, R<SP>4</SP>, R<SP>5</SP> are H, reacting the above ketones with the saturated oxo side chain with compounds of the formula R<SP>8</SP>MgX or R<SP>8</SP>Li. Compounds of the above formula wherein Y and Z are H 2  are prepared by reacting pyrazole with ketones of the formula to produce pyrazoles of the formula reducing the oxo group or reacting said pyrazoles with compounds of the formulae R<SP>8</SP>MgX or R<SP>8</SP>Li, heating the resulting pyrazoles with compounds of the formula and reducing the thus obtained pyrazolium salts of the formula or reacting pyrazole with compounds of the formula reacting the resulting monosubstituted pyrazoles with ketones of the formula and either before or after the previous step reducing the ring unsaturation and reducing the oxo group in the thus obtained pyrazolidines, or reducing the corresponding compounds of the Formula I above wherein one of Y and Z is O. Compounds of the Formula I above in which R<SP>2</SP> is C 2-40  alkanoyl are obtained by acylating the corresponding compounds in which R<SP>2</SP> is H. The following intermediates are also prepared: 8,8,8 - trifluoro - 1 - octen - 3 - ol; ketones of the formula N - (4 - chlorophenyl) - 2 - [4 - (2 - isopropoxycarbonylethyl) - benzyl] - 3 - oxo - I - pyrazolidinecarbothioamide; ethyl 4 - mesyloxy - 2- butynoate; 8 - bromo - 1,1,1 - trifluorooctane; 1,1,1 - trifluoro - 7 - iodoheptane; 5 - bromo- 1,1,1 - trifluoropentane; 5 - chloro - 1,1,1 - trifluoro - 5 - methylhexane; 2,2 - difluoro - 5- iodohexane; 2 - bromo - 2 - methylheptane; 2- bromohexane; 3 - chloro - 3 - ethylpentane; ethyl 4 - hydroxy - 2 - butynoate; ethyl p- (iodomethyl) - phenylacetate; ethyl p - (chloromethyl) - phenylacetate; p - (chloromethyl)- phenylacetic acid; 3 - (p - bromomethylphenyl)-propionic acid and its methyl ester; 4- (p - bromomethylphenyl) - butyric acid and its methyl and isopropyl esters; methyl p-bromomethylbenzoate; pyrazoles of the Formula II above and of the formulae wherein P is H or benzyloxycarbonyl; 2,2,2-trichloroethyl 2 - {4 - [(2 - isopropoxycarbonyl)- ethyl] - benzyl} - 3 - oxo - 1 - pyrazolidinecarboxylate; isopropyl 3-{p-[(3-oxopyrazolidin-2- yl) - methyl] - phenyl} - propionate; isopropyl 3 - {p - [(1 - (3 - oxo - octyl) - 3 - oxopyrazolidin- 2 - yl) - methyl] - phenyl} - propionate; 1 - (3- oxo - octyl) - pyrazole; 1 - (3 - hydroxyoctyl)- pyrazole; 1 - (6 - ethoxycarbonylhexyl) - 2 - (3- hydroxyoctyl) - pyrazolium iodide; and 2 - (3- hydroxyoctyl) - 1 - pyrazolidineheptanoic acid and its ethyl ester and sodium salt. 5,5,5 - Trifluoropentylmagnesium bromide is prepared by reacting 1,1,1-trifluoro-5-bromopentane with magnesium in diethyl ether. Pharmaceutical compositions, suitable for nasal, oral, parenteral, rectal or topical administration, contain the above pyrazolidine derivatives or salts thereof with pharmaceutically acceptable carriers. The compounds possess prostaglandin-like activities.