GB1563573A

GB1563573A - Heterocyclic phosphonium salts

Info

Publication number: GB1563573A
Application number: GB4715377A
Authority: GB
Original assignee: GD Searle LLC
Current assignee: GD Searle LLC
Priority date: 1976-11-15
Filing date: 1977-11-11
Publication date: 1980-03-26
Also published as: FR2370751B2; FR2370751A2; JPS5387357A; AU3060677A; AU521135B2; AU3064077A; AU518955B2; DE2750526A1

Description

(54) HETEROCYCLIC PHOSPHONIUM SALTS (71) We, G. D. SEARLE & CO., a corporation organised and existing under the laws of the State of Delaware and whose full post office address is P.O. Box 5110, Chicago, Illinois 60680, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to a dass of novel heterocyclic phosphonium compounds having pharmacological activity.

The specification of our copending application No. 20128/76 (Serial No. 1498774) to which this is an addition, describes and claims a compound of the formula

wherein X is a pharmacologically acceptable anion.

It has now been found that the compounds of application No. 20128/76 (Serial No.

1498774) are members of a broader class of compounds prepared in like manner and having similar pharmacological activity. The broader class of compounds may be defined by the following formula:

wherein R, is hydrogen or an alkyl group R2, Rs and Rs which can be the same or different are alkyl or cycloalkyl radicals or aryl radicals optionally substituted by pharmacologically acceptable atoms or radicals; X is a pharmacologically acceptable anion; and n is 4 or 5, with the proviso that the com pound is not a said compound wherein R1 is hydrogen, R2, R, and R4 are each unsubstituted phenyl and n is 5.

Compounds falling within the scope of formula II are prepared by heating a phosphorane compound of the formula:

wherein Y is a radical released from the phosphorane compound as it undergoes cyclization, the heating being effected in an inert solvent.

In the compounds of formula II, the anion xe is preferably bromide or chloride. However, it can be any other pharmacologically acceptable anion, examples of which are the trifiuoromethanesulphonate and tetrafluoroborate anions.

The reaction by which the compounds of formula II are produced is carried out with heating in an inert solvent. Preferred solvents are aromatic hydrocarbons such as benzene and toluene. The anion of the salt obtained will correspond to Y. Salts involving other anions can be obtained readily by ion exchange procedures or by mixing an aqueous solution of the phosphonium salt with a mineral salt. Silver salts of the anions has been found to be particularly satisfactory to use as the mineral salt.

It is ordinarily unnecessary to have isolated the indicated phosphorane starting material.

It can simply be used in the solution in which it is prepared.

Two methods are available for the preparation of the phosphorane starting material.

Thus, for example, an -halopentanoyl or in-halohexanoyl halide can be reacted with imidazole to give the corresponding 1 - ( halopentanoyl or -halohexanoyl) imidazole which is then reacted with a phosphorane of general formula:

ro give the desired starting material. Alterna tively, an ej halopentanoyl or -halohexanoyl halide is reacted with diazomethane to give a 1,6-dihalo-2-hexanone or 1,7 dihalo-2-hepta- none respectively which is then reacted with a phosphine of general formula:

to give a phosphonium halide of general formula.

which is then reacted with a base to give the desired phosphorane.

In the compounds of formula II, R1 is hydrogen or an alkyl group. When an alkyl group Rl generally contains from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms and is more preferably methyl. Insofar as R2, R, and R4 may be alkyl radicals, such alkyl radicals generally contain from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms. Preferred cycloalkyl radicals R2 and/or R3 and/or Rl are cyclohexyl. Preferred aryl radicals R2 and/or R3 and/or Rç are phenyl.

Radicals which may substitute aryl radicals R to R, are exemplified by alkyl, generally containing from 1 to 3 carbon atoms, preferably methyl, alkoxy, generally containing from 1 to 3 carbon atoms, preferably methoxy, and halo, preferably chloro or fluoro.

The compounds of formula II are useful as analgesic agents. Thus, these compounds show analgesic activity but, at the same time, they show activity as morphine antagonists and they would appear to possess a particularly useful combination of these effects.

The analgesic utility of the novel compounds may be demonstrated by the test procedure set out in the specification of application No.

20128/76 (Serial No. 1498774). Morphine antagonism for the present compounds has been demonstrated in the standard hotplate procedure.

For therapeutic use, the compounds of forfula II can be made up in accordance with well known pharmaceutical techniques, into compounds having as an essential active ingredient, a compound of the invention in association with a non-toxic pharmaceutical carrier therefor. If desired, the compositions can be made up in a dosage unit form suitable for the particular mode of administration, the quantity of active ingredienr in each dosage unit being such that one or more unit are required for each therapeutic administration.

This dosage unit may exist, for example, in the form of a tablet, pill sachet, package powder, or encapsulated powder for oral administration or in the form of a sterile injectable solution or suspension, if desired contained in an ampoule for parenteral administration.

Ampoules can thus be prepared containing 100 mg of the novel compounds. The useful dose for a single administration would be 50 to 3000 mg parenterally.

The compounds of formula II are also useful in organic synthesis. Thus, the preparation of the novel phosphonium salts can be used as a method of purifying the phosphoranes from which they are obtained. Regeneration of the phosphorane can be accomplished by treating the phosphonium salts with an acid such as hydrochloric acid to give the corresponding ( - chloro - 2 - oxohexyl or - heptyl) phosphonium salt which is then treated with base to give the phosphorane.

Also, depending on the acid used to open up the cyclic compound, this can serve as a method for obtaining other substituted phosphoranes which are different from the original compound. The substituted phosphoranes themselves can be reacted with an appropriate aldehyde or ketone by standard procedure to give the corresponding product.

The compounds of formula II are usually produced in admixture with their isomers of formula:

and will usually be separated from these isomers.

The following Examples illustrate or relate to the present invention. In the Examples, quantities are indicated in parts by weight unless otherwise indicated. The relationship of parts by weight and parts by volume is the same as that existing between grams and millilitres.

EXAMPLE 1 To an ethereal solution of diazomethane (prepared by the reaction of 90 parts of N nitrosomethylurea with 175 parts by volume of 45 aqueous potassium hydroxide in 375 parts by volume of ether) is added dropwise, at OOC., 50 parts of 5-chlorovaleryl chloride and the resulting reaction mixture is allowed to warm to room temperature with stirring, then stirred for an additional 16 hours. A saturated solution of dry hydrogen chloride in ether is then added portionwise to the point at which the solution becomes colorless.

This solution containing the diazoketone and hydrogen chloride is stirred at room temperature for about 16 hours, then is washed successively with water, saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure affords 1,6 - dichloro2 - hexanone.

To a solution of 41 parts of 1,6 - dichloro 2 - hexanone in 400 parts by volume of benzene is added 44 parts of triphenylphosphine and the resulting solution is stored, in the absence of light for about 6 days, at the end of which time the crude product has crystallized from the mixture. That material is collected by filtration and is purified by recrystallization from acetone to afford (6 chloro - 2 - oxohexyl)triphenylphosphonium chloride. This product melts at 158-1610C.

and is characterized by 60-MHz nuclear magnetic resonance peaks in CDCI3 (deuterated chloroform) at 100 cps (multiplet), 140 cps (multiplet), 180 cps (multiplet), 208 cps (multiplet) and 357 cps (doublet, 5--12) in addition to the aromatic protons. The C, protons at 375 cps exchange with D2O (deuterated water).

A solution of 20 parts of (6 - chloro 2 - oxo - hexyl) - triphenylphosphonium chloride in 200 parts of water is made alkaline by the addition of a 50% aqueous sodium hydroxide solution and extracted with benzene. The combined organic extracts are dried over anhydrous sodium sulfate, then stripped of solvent under reduced pressure to afford (5 - chloropentanoylmethylene)triphenylphosphorane.

A solution containing 20 parts of 5 - chloropentanoylmethylene)triphenylphosphorane in 200 parts of benzene is heated at the reflux temperature for about 16 hours.

Evaporation of the solvent affords a product which is a mixture of [(tetrahydro - 2H pyran - 2 - ylidene)methyl]triphenylphospho- nium chloride and [(5,6 - dihydropyran 2 - yl)methyl j triphenylphosphonium chloride.

The mixture is separated by low pressure liquid chromatography. A column packed with Merck Silica 60, 230v00 mesh (Merck is Registered Trade Mark)). is equilibrated with 500 parts of 95% ethanol-S O/o water and then 2000 parts ethyl acetate. 1 part of the product is combined with 1000 parts eluent consisting of approximately 25% ethanol, 2% water and 73% benzene, and is passed through the column. The flow rate is maintained by a Milroyal D pump (Milroyal is a Registered Trade Mark).

The first of the two compounds eluted is [(5,6 - dihydropyran - 2 - yl)methylltriphenyl- phosphonium chloride. This product is characterized by 60 MIIz nuclear magnetic resonance peaks in CDCl: at 108 cps (multiplet), 162 cps (triplet), 216 cps (triplet), 246 cps (doublet, J-13 cps), 294 cps (multiplet) and 462 cps (mulltiplet) and is represented by the following structure

The second compound, [(tetrahydro - 2H pyran - 2 - ylidene)methyl]triphenylphospho- nium chloride, is characterized by 60 MHz nuclear magnetic resonance peaks in CDCI3 at about 107 cps (multiplet), 170 cps (multiplet), 228 cps (multiplet) and 329 cps (doublet, J-18 cps) in addition to the aromamatic protons. This compound melted at about 215-2210C. and is represented by the following structure

EXAMPLE 2 A solution consisting of 18.5 parts of [(tetrahydro - 2H - pyran - 2 - ylidene) methyl]triphenylphosphonium chloride in 100 parts by volume of concentrated hydrochIoric acid is heated at the reflux temperature for about 36 hours, then is cooled to room temperature. The solvent is removed by distillation under reduced pressure to afford (6 chloro - 2 - oxohexyl)triphenylphosphonium chloride, identical with the product of paragraph 2 of Example 1.

EXAMPLE 3 A solution consisting of 2.1 parts of [(tetrahydro - 2H - pyran - 2 - ylidene)methyl]- triphenylphosphonium chloride in 50 parts of water is added with stirring to 2 parts of sodium bromide. At the end of about 5 minutes an additional 4 parts of sodium bromide is added and the mixture is stirred until precipitation is complete. The precipitate is isolated by filtration, thus affording [(teura- hydro - 2H - pyran - 2 - ylidene)methylj tri- phenylphosphonium bromide. This product melts at 205--2090C. and is characterized by 60 MHz nuclear magnetic resonance peaks in CDC1 (deuterated chloroform) at 107 cps (multiplet), 170 cps (multiplet), 228 cps (multiplet), 329 cps (doublet, 5--18 cps) in addition to the aromatic protons, and by microanalytic determination of bromide.

EXAMPLE 4 A solution of 68 parts of imidazole in 225 parts of tetrahydrofuran is cooled to 50C.

and a solution of 99.3 parts of 5 - bromovaleryl chloride in 175 parts of ether is added slowly over 30 minutes with stirring. The mixture is then stirred an additional 30 minutes at room temperature before it is filtered quickly to remove the imidazole hydrochloride. The resulting filter cake is washed with ether and the combined filtrate which is a solution of 1 - (5 - bromopentanoyl)imidazole, is kept under nitrogen.

To a slurry of 180 parts of methyltriphenylphosphonium bromide in 280 parts of ether is added 500 parts by volume of an ether-hexane solution containing 42 parts of phenyllithium at room temperature with stirring under nitrogen. The resulting mixture is stirred for one hour under nitrogen and then cooled to --700C. and the amide solution prepared in the preceding paragraph is added slowly over a period of 30 minutes. Stirring is continued at -700C. for 30 minutes and the mixture is allowed to warm up to 100 C.

over 30 minutes before it is poured into 5000 parts by volume of 1M hydrochloric acid.

The aqueous layer is separated and made alkaline with potassium carbonate. An oil forms and this is extracted well with toluene. The toluene solution is filtered through infusorial earth and concentrated to a volume of 500 parts to provide a toluene solution of (5 - bromopentanoylmethylene)triphenylphosphorane.

The toluene solution of (5 - bromopenta noylmethylene)triphenylphosphorane obtained in the preceding paragraph is heated at reflux for 16 hours with stirring. Evaporation of the solvent affords a product which is a mixture of [(tetrahydro - 2H - pyran - 2 - ylidene) methylitriphenyl phosphonium bromide and [(5,6 - dihydropyran - 2 - yl) - methylitri- phenylphosphonium bromide which are separated by low pressure liquid chromatography.

EXAMPLE 5 A solution consisting of 1.6 parts of [(tetrahydro - 2H - pyran - 2 - ylidene)methyl]triphenylphosphonium bromide in 25 parts by volume of 48% hydrobromic acid was heated at the reflux temperature for about 5 hours, then was stripped of solvent under reduced pressure affording the crude product as an amber colored oil. Trituration of that oily material with benzene, followed by evaporation of the benzene under an atruosphere of nitrogen afforded (6 - bromo - 2 - oxohexyl)triphenylphosphonium bromide. This product exhibited 60 MHz nuclear magnetic resonance peaks in CDCI, (deuterated chloroform) at about 100 cps (muluplet), 180 cps (multiplet), 200 cps (multiplet), 357 cps (doublet, J-l2 cps) in addition to the aromatic protons.

EXAMPLE 6 When an equivalent quantity of tri(p methoxyphenyl) - phosphine is substituted for the triphenylphosphine in Example 1, and the procedure detailed therein is substantially repeated, there is obtained [(5,6 - dihydropyran - 2 - yl)methyl]tri(p methoxyphenyl)phosphonium chloride which is characterized by 60 MHz nuclear magnetic resonance peaks in CDC13 at 108 cps (multiplet), 221 cps (triplet), 237 cps (singlet), 257 (doublet, J--13 cps), and 438 cps (multiplet) and is represented by the structure

and [(tetrahydro - 2H - pyran- 2 - ylidenef methyl]tri(p - methoxyphenylphosphonium chloride which is characterized by 60 MHz nuclear magnetic resonance peaks in CDCI3.

at 111 cps (multiplet), 172 cps (triplet), 232 cps (multiplet), 256 cps (singlet), 444 cps (multiplet), and 329 cps (doublet, J-17 cps) and is represented by the structure

EXAMPLE 7 When an equivalent quantity of tri(p methylphenyl) - phosphine is substituted for the triphenylphosphine in Example 1, and the procedure detailed therein is substantially repeated, there is obtained [(5,6 - dihydropyran - 2 - yl) - methyl] tri(p - methylphenyl)- phosphonium chloride which is represented by the structure

and [(tetrahydro - 2H - pyran - 2 - ylidene) methyl] tri(p - methylphenyl)phosphonium chloride which melts at 210-2120C. and is represented by the suucture

EXAMPLE 8 When an equivalent quantity of methyl (diphenyl) - phosphine is substituted for the triphenylphosphine in Example 1, and the procedure detailed therein is substantially repeated, there is obtained [(5,6 - dihydropyran - 2 - yl) - methyl]methyl(diphenyl)phosphonium chloride which is represented by the structure

and [(tetrahydro - 2H - pyran - 2 - ylidene)methyl)methyl(diphenyl) - phosphonium chloride which is represented by the structure

EXAMPLE 9 When an equivalent quantity of triethylphosphine is substituted for the triphenylphosphine in Example 1, and the procedure detailed therein is substantially repeated, there is obtained [(5,6 - dihydropyran - 2 - yl) methyl J triethylphosphonium chloride which is very hydrophilic having a melting range of 100--125SC. and is represented by the struc

and [(tetrahydro - 2H - pyran - 2 - ylidene) methyl]triethylphosphonium chloride which is represented by the structure

EXAMPLE 10 When an equivalent quantity of tri(p fluorophenyl) - phosphine is substituted for the triphenylphosphine in Example 1, and the procedure detailed therein is substantially repeated, there is obtained [(5,6 - dihydropyran - 2 - yl)methyl]tri(p - fluorophenyl)phosphonium chloride which is represented by the structure

and [(tetrahydro - 2H - pyran - 2 - ylidene9- methyl] tri(p - fluorophenyl)phosphonium chloride which melts at 199-2020C. and is represented by the structure

EXAMPLE 11 When an equivalent quantity of ethyltriphenylphosphonium chloride is substituted for the methyltriphenylphosphonium bromide in Example 4, and the procedure detailed therein is substantially repeated, there is obtained [(5,6 - dihydropyran - 2 yl,ethyl]triphenyl- phosphonium chloride which is characterized by 100 MHz nuclear magnetic resonance peaks in CDCI3 at 740 cps imuldplet), 540 cps (multiplet), two multiplets symmetrical about 362 cps, and four singlets arising above the methylene envelope symmetrical about 163 cps (J7 cps and J-19 cps) and is represented by the structure

and [1 - (tetrahydro - 2H - pyran - 2 - ylidene)ethyl] triphenylphosphonium chloride which is represented by the structure

EXAMPLE 12 When an equivalent quantity of 6 - chlorohexanoyl chloride is subjected to the successive processes described in Example 1 there is obtained [(4,5,6,7 - tetrahydrooxepin - 2 yl)methyl] triphenylphosphonium chloride which is characterized by 60 MIIz nuclear magnetic resonance peaks in CDCIo at 213 cps itripletv, 243 cps (doublet J 13 cps), 288 cps (multiplet) and 446 cps (multiplet) and is represented by the structure

and [(2 - oxepanylidene)methyl triphenyl phosphonium chloride which is represented by the structure

These compounds were separated from each other.

Substitution of an equivalent quantity of [(2 - oxepanylidene)methyl] triphenylphosphonium chloride in the procedure of Example 3 resulted in [(2 - oxepanylidene) methyl]triphenylphosphonium bromide, melting at about 223-2260C.

EXAMPLE 13 Following the procedure of Example 12 substituting an equivalent quantity of tri(pmethoxyphenyl)phosphine for triphenylphosphine and 6 - bromohexanoyl chloride for 6chlorohexanoyl chloride provides [(2 - oxe panylidene)methyl]tri - p - methoxyphenylphosphonium bromide, m.p. 187-1890C and having the following structural formula

Using tri(p - methylphenyl) - phosphine provides [(2 - oxepanylidene)methyl]tri(p methylphenyl)phosphonium bromide, melting at 200--2030C and having the following suuaural formula

Using tri(m - methylphenyl)phosphine pro vides [(2 - oxepanylidene)methyljtri(m methylphenyl)phosphonium bromide, melting at 188189 C, having the following structural formula

In a similar manner tri(p - chlorophenyl)phosphine provides [(2 - oxepanylidene)methyl]tri(p - chlorophenyl)phosphonium bromide, melting at 212-2140C and having the following structural formula

Using cyclohexyl diphenyl phosphine pro- vides [(2 - oxepanylidene)methyljdiphenyl cyclohexyl phosphonium bromide, melting at 210-213 C and having the following structural formula

Using diphenylmethylphosphine provides [(2 - oxepanylidene)methyl] diphenylmethyl phosphonium bromide melting at 115-1380C and having the structural formula

EXAMPLE 14 One part of silver trifluoromethyisulfonate is added with stirring to a solution of one part af [(tetrahydio - 211 - pyran - 2 - ylidene)- methyljtriphenylphosphonium chloride in nitromethane until precipitation is complete.

The precipitate is isolated by filtration and the liquid phase evaporated under a stream of nitrogen gas, thus affording [(tetrahydro 21? - pyran - 2 - ylidene)methyl]triphenylphosphonium trifluoromethanesulfonate, melting at 145-146 C and represented by the structural formula

EXAMPLE 15 When an equivalent quantity of silver tetra fluoroborate is substituted for the silver tri fiuoromethanesulfonate in Example 14, and the procedure detailed therein substantially.

repeated, there is obtained [(tetrahydro 211 - pyran - 2 - ylidene)methylitriphenyl- phosphonium tetrafluoroborate. The product is characterized by its proton nuclear magnetic resonance spectrum, as in Example 3, and by microanalytic determination of carbon and hydrogen and is represented by the structure

WHAT WE CLAIM IS:1. A compound of the formula:

wherein R1 is hydrogen or an alkyl group; R2, R8 and R4 which can be the same or different are alkyl or cycloalkyl radicals or aryl radicals optionally substituted by pharmacologically acceptable atoms or radicals; X is a pharmacologically acceptable anion; and n is 4 or 5, with the proviso that the com- pound is not a said compound wherein R1 is hydrogen, R2, R, and R are each unsubstituted phenyl, and n is 5.

2. [(Tetrahydro - 2H- pyran - 2 - ylidene) methyl]triphenylphosphonium chloride.

3. [(Tetrahydro - 2H - pyran - 2 - ylidene)- methyl] triphenylphosphonium bromide.

4. [(Tetrahydro - 211- pyran - 2 - ylidene)- methyl] tri(p - methoxyphenyl)phosphonium chloride.

5. [(Tetrahydro - 2H - pyran - 2 - ylidene)- methyl [tri(p - methylphenyl)phosphonium chloride.

6. [(Tetrahydro - 211- pyran - 2 - ylidene) mehyl]methyl(diphenyi) - phosphonium chloride.

7. [(Tetrahydro -211- pyran -2 - ylidene)- methyl] triethyiphosphonium chloride.

8. [(Tetrahydro -211- pyran -2 - ylidenek methyl]tri(p - fluorophenyl)phosphonium chloride.

9. [1 - (Tetrahydro - 211 - pyran - 2 - ylidene)ethyl]triphenylphosphonium chloride.

10. [(2 - Oxepanylidene)methyl]tri(p methylphenyl)phosphonium bromide.

11. [2 - Oxepanylidene)methyl)tri(m methylphenyl)phosphonium bromide.

12. [2- Oxepanylidene)methyl]tri(p chlorophenyl)phosphonium bromide.

13. [(2 - Oxepanylidene(methyl)diphenylcyclohexyl phosphonium bromide.

14. [2 - Oxepanylidene)methyl]di phenylmethyl pnosphonium bromide.

15. [Tetrahydro - 2H - pyran 2 - ylidene)methyl)triphenylphosphonium trifluoromethane sulfonate.

16. [(Tetrahydro - 2H - pyran 2 - ylidene)methyl] triphenylphosphonium tetrafluoroborate.

17. A process for the preparation of a com- pound of the formula

wherein R1 to Rr, n and X have the meanings given in claim 1, with the proviso that

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

210-213 C and having the following structural formula

Using diphenylmethylphosphine provides [(2 - oxepanylidene)methyl] diphenylmethyl phosphonium bromide melting at 115-1380C and having the structural formula

EXAMPLE 14 One part of silver trifluoromethyisulfonate is added with stirring to a solution of one part af [(tetrahydio - 211 - pyran - 2 - ylidene)- methyljtriphenylphosphonium chloride in nitromethane until precipitation is complete.

The precipitate is isolated by filtration and the liquid phase evaporated under a stream of nitrogen gas, thus affording [(tetrahydro 21? - pyran - 2 - ylidene)methyl]triphenylphosphonium trifluoromethanesulfonate, melting at 145-146 C and represented by the structural formula

EXAMPLE 15 When an equivalent quantity of silver tetra fluoroborate is substituted for the silver tri fiuoromethanesulfonate in Example 14, and the procedure detailed therein substantially.

repeated, there is obtained [(tetrahydro 211 - pyran - 2 - ylidene)methylitriphenyl- phosphonium tetrafluoroborate. The product is characterized by its proton nuclear magnetic resonance spectrum, as in Example 3, and by microanalytic determination of carbon and hydrogen and is represented by the structure

WHAT WE CLAIM IS:1. A compound of the formula:

wherein R1 is hydrogen or an alkyl group; R2, R8 and R4 which can be the same or different are alkyl or cycloalkyl radicals or aryl radicals optionally substituted by pharmacologically acceptable atoms or radicals; X is a pharmacologically acceptable anion; and n is 4 or 5, with the proviso that the com- pound is not a said compound wherein R1 is hydrogen, R2, R, and R are each unsubstituted phenyl, and n is 5.
2. [(Tetrahydro - 2H- pyran - 2 - ylidene) methyl]triphenylphosphonium chloride.
3. [(Tetrahydro - 2H - pyran - 2 - ylidene)- methyl] triphenylphosphonium bromide.
4. [(Tetrahydro - 211- pyran - 2 - ylidene)- methyl] tri(p - methoxyphenyl)phosphonium chloride.
5. [(Tetrahydro - 2H - pyran - 2 - ylidene)- methyl [tri(p - methylphenyl)phosphonium chloride.
6. [(Tetrahydro - 211- pyran - 2 - ylidene) mehyl]methyl(diphenyi) - phosphonium chloride.
7. [(Tetrahydro -211- pyran -2 - ylidene)- methyl] triethyiphosphonium chloride.
8. [(Tetrahydro -211- pyran -2 - ylidenek methyl]tri(p - fluorophenyl)phosphonium chloride.
9. [1 - (Tetrahydro - 211 - pyran - 2 - ylidene)ethyl]triphenylphosphonium chloride.
10. [(2 - Oxepanylidene)methyl]tri(p methylphenyl)phosphonium bromide.
11. [2 - Oxepanylidene)methyl)tri(m methylphenyl)phosphonium bromide.
12. [2- Oxepanylidene)methyl]tri(p chlorophenyl)phosphonium bromide.
13. [(2 - Oxepanylidene(methyl)diphenylcyclohexyl phosphonium bromide.
14. [2 - Oxepanylidene)methyl]di phenylmethyl pnosphonium bromide.
15. [Tetrahydro - 2H - pyran 2 - ylidene)methyl)triphenylphosphonium trifluoromethane sulfonate.
16. [(Tetrahydro - 2H - pyran 2 - ylidene)methyl] triphenylphosphonium tetrafluoroborate.
17. A process for the preparation of a com- pound of the formula

wherein R1 to Rr, n and X have the meanings given in claim 1, with the proviso that

the compound to be produced is not a said compound wherein R, is hydrogen, R2, R3 and R, are each unsubstituted phenyl and n is 5 which comprises heating a phosphorane compound of the formula

wherein Y is a radical released from the phosphorane compound as it undergoes cyclization, the heating being effected in an inert solvent.
18. A process as claimed in claim 17, wherein Y is a chloro or bromo radical.
19. A process for the production of a com- pound as defined in claim 1, wherein X is an anion other than a halide anion, which com- prises adding a salt of formula Ag+XI- wherein X1- is the anion other than halide to a solution of a compound of formula I, wherein X- is halide, produced by the process claimed in claim 17 or 18.
20. A process as claimed in any one of claims 17 to 19, wherein said compound is separated from its coproduced isomer of formula

wherein R1 to Ri, n and X have the aforesaid meanings.
21. A process for the preparation of a compound as defined in claim 1, substantially as described in any one of the foregoing Examples 1, 3, 4, 6 to 11 and 13 to 15.
22. A process for the preparation of [(2 - oxepanylidene)methyl)triphenylphosphonium chloride substantially free from [(4,5,6,7 - tetrahydroxepin - 2 - yl)-methyl]triphenylphosphonium chloride, substantially as described in the foregoing Example 12.
23. A compound as defined in claim 1, whenever produced by the process as claimed in any one of claims 17 to 21.
24. [(2 - oxepanylidene)methylj triphenyl- phosphonium chloride whenever produced substantially free from [(4,5,6,7 - tetrahydroxepin - 2 - yl)methyl]triphenylphosphonium chloride by the process claimed in claim 22.
25. A pharmaceutical composition compris ine; a compound as claimed in any one of claims 1 to 16 and 23 and 24 in association with a non-toxic pharmaceutical carrier.
26. A pharmaceutical composition as claimed in claim 25, substantially as described herein.