Novel tri-phenyl alkane and alkene derivatives and their preparation and use

Claim 2

A process for the preparation of a compound of the general formula or wherein n is 0 to 4, R 1 and R 2 , which can be the same or different are H or OH, R 3 is H, OH, halogen, alkoxy of 1 to 4 carbon atoms, benzyloxy, methoxymethoxy, 2,3-dihydroxypropoxy or wherein m is 1 or 2, R 5 and R 7 , which can be the same or different are H or an alkyl group of 1 to 4 carbon atoms, or can form an N-containing three-, four-, five- or six-membered heterocyclic ring; R 4 is OH, F, Cl, Br, I, mesyloxy, tosyloxy, formyloxy, alkylcarbonyloxy of 1 to 4 carbon atoms or CH 2 R 4 is replaced by CHO; R 5 is H or OH; or R 4 and R 5 together form an ―0― bridge between the carbon atoms to which they are attached, provided that a) when n is 0, then R 2 and R 3 are not both simultaneously hydrogen b) when n is 0, then R 3 must be other than halogen c) when n is 1 and R 4 and R 5 both are OH or together form an―O― bridge between the carbon atoms to which they are attached, then R 1 , R 2 and R 3 are not all simultaneously hydrogen d) when n is 2 and R 4 and R 5 together form an ―0― bridge between the carbon atoms to which they are attached, then R 1 , R 2 and R 3 are not all simultaneously hydrogen and its non-toxic pharmaceutically acceptable salts N-oxides and esters which comprises reacting a compound of the formula: wherein n is as hereinbefore defined, R 1 is the same as R 1 as hereinbefore defined or is a hydroxyl group protected as a mixed acetal group, R' 4 is the same as R 4 as hereinbefore defined or is a protected hydroxyl group, and R 9 is a group R 2 or R 3 as hereinbefore defined or is a hydroxyl group protected as a mixed acetal group, with an organo-metallic compound of the formula: wherein M is ―MgHal or―Li and R 10 is a group R 2 or R 3 as hereinbefore defined or is a hydroxyl group protected as a mixed acetal group, to give a compound of the formula: which is then treated, if necessary, to convert the radicals R' 1 , R' 4 , R 9 and R 19 into the radicals R 1 , R 2 , R 3 and R 4 to provide a compound of formula II in which R 5 is hydroxyl, and optionally dehydrating the product to give a compound of formula I or treating the product to provide a compound of formula II in which R 5 is hydrogen, or one in which R 4 and R 5 together form an ―0― bridge, and/or optionally treating the product to convert a radical R 1 , R 2 , R 3 , R 4 or R 5 into another such radical as hereinbefore defined, and/or optionally treating the product to convert it into a non-toxic pharmaceutically acceptable salt, N-oxide or ester thereof.

Claim 3

A process according to claim 1 which comprises 1) reacting a compound of the formula wherein R 1 and R 2 are as defined in claim 1 or a mixed acetal group, n is as defined in claim 1 and OR 8 is a mixed acetal, benzyloxy or hydroxy, either by a Grignard reaction with a phenylmagnesiumhalide derivative of the formula or with a corresponding lithium compound of the formula wherein R 3 is as defined in claim 1 or a mixed acetal group to give a protected or unprotected triphenyldiol of the formula from which compound any protecting group R 8 and protecting group in a phenyl ring are removed, to give a compound of formula (III wherein R 4 and R 5 are OH; 2) reacting a compound of the formula wherein R 1 and R 3 are as defined in claim 1 or a mixed acetal, n is as defined in claim 1 and OR a is a mixed acetal, benzyloxy or hydroxy, either by a Grignard reaction with a phenylmagnesiumhalide derivative of the formula or with a corresponding lithium compound of the formula wherein R 2 is as defined in claim 1 or a mixed acetal to give a protected or unprotected triphenyldiol of the formula from which compound any protecting group R 8 and protecting group in a phenyl ring are removed, to give a compound of formula (II) wherein R 4 and R 5 are OH; 3) dehydrating a compound of formula (II) wherein R 4 and R 5 both are OH, to give a compound of formula (II) wherein R 4 and R 5 together form an ―0― bridge between the carbon atoms to which they are attached; 4) dehydrating a compound of formula (II) wherein R 4 and R 5 are both OH, to give a compound of formula (II) wherein R 4 is OH; 5) removing the protecting group R 8 , which is other than hydrogen, and/or protecting group in a phenyl ring, and dehydrating a compound of the formula wherein R 1 , R 2 and R 3 are as defined in claim 1 or mixed acetal, n is as defined in claim 1 and OR 8 is a mixed acetal, benzyloxy or hydroxy, to give a compound of formula (II) wherein R 4 and R 5 together form an -0- bridge between the carbon atoms to which they are attached; 6) removing the protecting group R a , which is other than hydrogen and/or a protecting group in a phenyl ring, and dehydratiung a compound of the formula wherein R 1 , R 2 , R 3 , n and OR 8 are as defined in step 5), to give a compound of formula (I) wherein R 4 is OH; 7) ring opening a compound of formula (II), wherein R 4 and R 5 together form an -0- bridge between the carbon atoms to which they are attached, to give a compound of formula (I) wherein R 4 is OH or halogen; 8) reacting an AI-complex of the formula wherein R 1 is as defined in claim 1 and n 1 is 0 to 3, with a benzophenone derivative of the formula wherein R 2 and R 3 are as defined in claim 1, to give a compound of formula (II) wherein R 4 and R 5 are OH; 9) esterifying a compound of formula (I) or (II) wherein R 4 is OH, with a carboxylic acid of 1 to 5 carbon atoms or with the corresponding carboxylic acid derivative, to give a compound of formula (I) or (II) wherein R 4 is formyloxy or alkylcarbonyloxy of 1 to 4 carbon atoms; 10) dehydrating a compound of formula (II) wherein R 5 is OH, to give a corresponding compound of formula (I); 11) hydrolysing a compound of formula (I), wherein R 4 is formyloxy or alkylcarbonyloxy of 1 to 4 carbon atoms, to give a compound of formula (I) wherein R 4 is OH; 12) reacting a compound of formula (II) wherein R 4 and R s are both OH or together form an ―0― bridge between the carbon atoms to which they are attached, with an acid catalyst in a carboxylic acid containing 1 to 5 carbon atoms, to give a compound of formula (I) wherein R 4 is formyloxy or alkylcarbonyloxy of 1 to 4 carbon atoms; 13) reacting a compound of the formula wherein R 1 , R 2 , R 3 , OR 8 and n are as defined in step 1) and 2), with an appropriate acid catalyst in a carboxylic acid containing 1 to 5 carbon atoms, to give a compound of formula (I) wherein R 4 is formyloxy or alkylcarbonyloxy of 1 to 4 carbon atoms; 14) dealkylating a compound of formula (I) or (II), wherein at least one of R 1 , R 2 and R 3 is alkoxy or aralkoxy, to give a compound okf formula (I) or (II) wherein at least one of R 1 , R 2 and R 3 is OH; 15) alkylating a compound of formula (I) or (II) wherein R 3 is OH, with diazomethane or alkylhalide derivative of the formula wherein R 11 is an alkyl group of 1 to 4 carbon atoms, benzyl, methoxymethyl, 2,3-dihydroxypropyl or ; wherein R 6 , R 7 and m are as defined in claim 1, to give a compound of formula (I) or (II) wherein R 3 is alkoxy of 1 to 4 carbon atoms, benzyloxy, methoxymethoxy, 2,3-dihydroxypropoxy or wherein m, R 6 and R 7 are as defined in claim 1; 16) alkylating a compound of formula (I) wherein R 3 is OH, with a dihaloalkane of the formula wherein m is as defined in claim 1 and the radicals hal are halogen atoms, which can be the same or different, to give a 4-(haloalkoxy)phenyldiphenylalkane of the formula: wherein R 1 , R 2 , R 4 and n and m are as defined in claim 1 and hal is halogen, which is further reacted with an amine of the formula: wherein R 6 and R 7 are as defined in claim 1, to give a compound of formula (I) wherein R 3 is aminoalkoxy as defined in claim 1; 17) alkylating a compound of formula (II), wherein R 3 is OH, with dihaloalkane of the formula: wherein m is as defined in claim 1 and the radicals hal are halogen atoms, which can be the same or different, to give a 4-(haloalkoxy)phenyldiphenylalkane of the formula: wherein R 1 , R 2 , R 4 , R 5 , n, m are as defined in claim 1 and hal is halogen, which is further reacted with an amine of the formula wherein R 6 and R 7 are as defined above, to give a compound of formula (II) wherein R 3 is aminoalkoxy as defined in claim 1; 18) substituting the hydroxy group R 4 in a compound of formula (I) or (II) by halogen, to give the corresponding compound of formula (I) or (II) wherein R 4 is halogen; 19) reacting a compound of formula (I) or (II) wherein R 4 is OH, with methane sulfonic acid chloride or toluene sulfonic acid chloride, to give a compound of formula (I) or (II) wherein R 4 is mesyloxy or tosyloxy; 20) dehydrating and substituting the hydroxy group of a compound of formula (II), wherein R 4 and R 5 both are OH, to give a compound of formula (I) wherein R 4 is halogen; 21) treating a compound of formula (II), wherein R 4 and R 5 both are OH, with thionyl chloride, to give a compound of formula (I) wherein R 4 is Cl; 22) substituting a compound of formula (I) or (II), wherein R 4 is mesyloxy, tosyloxy or halogen, with halogen, to give a compound of formula (I) or (II) wherein R 4 is halogen; 23) reacting a compound of the formula: wherein R 1 and R 2 are as defined in claim 1 or mixed acetal, n is as defined in claim 1 and hal is halogen, either by a Grignard reaction with a phenylmagnesiumhalide derivative or with the corresponding lithium compound as defined in step 1) to give a triphenylhydroxyhalide of the formula: from which compound a possible protecting group in a phenyl ring is removed, to give a compound of formula (II) wherein R 4 is halogen and R 5 is hydroxy; 24) carrying out the same reactions as in step 23) except that the groups R 2 and R 3 of the starting material and the reagent are interchanged, to give a compound of formula (II) wherein R 4 is halogen and R 5 is hydroxy; 25) dehydrating and removing any protecting group in a phenyl ring of a compound of formula (II), wherein R 5 is OH and R 3 is as defined in step 23), to give a compound of formula (I) wherein R 3 is OH and R 4 is halogen; 26) converting a compound of the formula: wherein R 1 , R 2, R 3 and n are as defined in claim 1, Z is H, Y is H or OH or Z and Y together form a bond, and X is halogen to the corresponding Grignard-complex or lithium salt wherein X is Mghal or Li, respectively, and reacting this complex or salt with formaldehyde, ethylene oxide or trimethylene oxide, to give a compound of formula (I) or (II) wherein R 4 is OH and n is 1 to 4; 27) reacting a compound of formula (1) or (II) wherein n is 0 to 3 and R 4 is halogen, mesyloxy or tosyloxy, with a cyano group to give a triphenyl nitrile of the formula: wherein R 1 , R 2 and R 3 are as defined in claim 1, Z and Y as defined in step 26) and n is 0 to 3, hydrolysing this compound to the corresponding triphenylcarboxylic acid, and reducing the said carboxylic acid in one step or via an intermediate, to give a compound of formula (I) or (II) wherein R 4 is OH and n is 1 to 4; 28) converting a compound of the formula as defined in step 26), wherein X is Mghal or Li, with carbon dioxide to give the corresponding triphenylcarboxylic acid, which is finally reduced, in one step or via an intermediate to give a compound of formula (1) or (II) wherein R 4 is OH and n is 1 to 4; 29) reacting a protected diphenyloxoaldehyde of the formula: wherein R 1 , R 2 and n are as defined in claim 1 or a mixed acetal, and R 13 and R 14 , which can be the same or different, are alkyl groups or form together a 1,3-propylene group, with a compound of the formula wherein R 3 is as defined in claim 1 or a mixed acetal and X is Mghal or Li, to give a protected triphenylhydroxyaldehyde of the formula: and finally removing the protecting group, and also any protecting group in a phenyl ring, to give a compound of formula (II) wherein CH 2 R 4 is replaced by CHO and R 5 is OH; 30) carrying out the same reaction as in step 29) except that the grups R 2 and R 3 of the starting material and the reagent are interchanged, to give a compound of formula (II) wherein CH 2 R 4 is replaced by CHO and R 5 is OH; 31) dehydrating a compound of the formula: or or a mixture of said compounds wherein R 1 , R 2 , R 3 and n are as defined in claim 1, to give a compound of formula (I) wherein CH 2 R 4 is replaced by CHO; 32) dehyhdrating a protected triphenylaldehyde of the formula: wherein R 1 , R 2 , R 3 n, R 13 and R 14 are as defined in step 29), to give a compound of the formula: and finally removing the protecting group from this compound, to give a compound of formula (I) wherein CH 2 R 4 is replaced by CHO; 33) oxidizing a compound (I) or (II) wherein R 4 is OH, to give a compound of formula (I) or (II) wherein CH 2 R 4 is replaced by CHO; 34) reducing a compound of formula (I) or (II), wherein R 4 is COOH, in a single step or via an intermediate, to give a compound of formula (I) or (II) wherein CH 2 R 4 is replaced by CHO; 35) hydrogenating a compound of formula (I) or a compound of formula (II) wherein R 5 is other than hydrogen, to give a compound of formula (II) wherein R 5 is H; or 36) alkylating a compound of formula (I) or (II) wherein at least one of R 1 , R 2 and R 3 is OH, with a suitable alkylating agent, to give a compound of formula (I) or (II) wherein at least one of R 1 , R 2 and R 3 is alkoxy of 1 to 4 carbon atoms, benzyloxy, or methoxymethoxy.

Claim 4

A process according to claim 1 or 2, followed by the separation of the pure (Z)- and (E)-isomers of compound (I) from their mixtures as well as pure (RR, SS)- and (RS, SR)-enantiomer pairs of compound (II) from the corresponding mixtures, by fractional crystallization, fractional dissolution, chromatography or a combination thereof.