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Generated: August 16, 2017

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Title: Palladium catalyzed vinylic substitution reactions with 2-substituted-pyridines
Abstract:This invention involves a coupling reaction involving an organo-metallic catalyst, preferably a palladium catalyst involving reacting 2-halo-3-hydroxy-6-hydroxymethylpyridine, acrylic acid or its alkali metal salt and benzyl or a phenylalkyl derivative in presence of a dipolar aprotic solvent producing none other than the expected 2-propenoate-3-benzyl or phenylalkylether-6-hydroxymethyl-pyridine product. Said products are converted into medicaments useful for treating psoriasis.
Inventor(s): Sheldrake; Peter William (Tunbridge Wells, GB2), Powling; Laurence Charles (Maidstone, GB2), Bickle; Peter William (Tunbridge Wells, GB2)
Assignee: SmithKline Beecham plc (GB2)
Filing Date:May 26, 1995
Application Number:08/452,200
Claims:1. A process for the preparation of a compound of formula (I): ##STR14## in which n is 1 to 20; R.sup.1 is hydrogen, C.sub.1-6 alkyl or hydroxyC.sub.1-6 alkyl; and R.sup.2 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or trifluoromethyl, which process comprises coupling a compound of formula (II): ##STR15## in which n and R.sup.2 are as defined in formula (I) and R.sup.3 is halogen with a compound of formula (III): ##STR16## in which R.sup.1 is as defined in formula (I) in the presence of palladium catalyst.

2. A process for the preparation of a compound of formula (IA) or a salt or N-oxide thereof: ##STR17## in which: R.sup.1 is hydrogen, benzyl or a group of formula (A): ##STR18## where n is 1 to 20 and R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or trifluoromethyl; m is 0 to 5;

R.sup.8 and R.sup.9 are independently hydrogen, halogen, CO.sub.2 H, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; and

R.sup.10 is a group CR.sup.2 =CR.sup.3 --R.sup.4 or CHR.sup.2 --CHR.sup.3 --R.sup.4 where R.sup.2 and R.sup.3 are independently hydrogen or C.sub.1-6 alkyl and R.sup.4 is cyano or CO.sub.2 R.sup.6 where R.sup.6 is hydrogen or C.sub.1-6 alkyl, which process comprises:

coupling a compound of formula (II): ##STR19## in which R.sup.1 is as defined in formula (IA) and R.sup.7 is a leaving group with a compound of formula (III) or a salt thereof: ##STR20## in which R.sup.2, R.sup.3 and R.sup.4 are as defined in formula (IA) in the presence of a palladium catalyst, to give a compound of formula (I): ##STR21## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in formula (IA), and thereafter: converting the compound of formula (I) into a compound of formula (IA), or converting a compound of formula (IA) into another compound of formula (IA), or forming a pharmaceutically acceptable salt or N-oxide.

3. A process according to claim 1 in which the palladium coupling is carried out in aqueous DMF.

4. A process according to claim 3 in which R.sup.1 is a group of formula (A) where n is 2 to 8.

5. A process according to claim to 4 in which R.sup.4 is CO.sub.2 R.sup.6 where R.sup.6 is hydrogen or C.sub.1-6 alkyl.

6. A process according to claim 5 in which R.sup.5 is methoxy.

7. A process according to claim 1 in which the compound prepared is: n-butyl 3-{6-hydroxymethyl-3-[8(4-methoxyphenyl)octyloxy]pyridin-2-yl}prop enoate, methyl 3-[6-hydroxymethyl-3-[8(4-methoxyphenyl)octyloxy]pyridin-2-yl}propenoate, methyl 3-{6-hydroxymethyl-3-(phenylethyloxy)pyridin-2-yl}propenoate, t-butyl 3-{6-hydroxymethyl-3-[8(4-methoxyphenyl)octyloxy]pyridin-2-yl)propenoate, 3-{6-hydroxymethyl-3-[8(4-methoxyphenyl)octyloxy]pyridin-2-yl }propenoic acid, n-butyl 3-{6-hydroxymethyl-3-(phenylethyloxy)pyridin-2-yl}propenoate, ethyl (3-hydroxy-6-methylpyridin-2-yl)propenoate, ethyl 3-{3-hydroxy-6-hydroxymethylpyridin2-yl}propenoate, ethyl (3-benzyloxy-6-hydroxymethylpyridin-2-yl)propenoate, n-butyl (3-benzyloxy-6-hydroxymethylpyridin-2-yl)propenoate, methyl (3-benzyloxy-6-hydroxymethylpyridin-2-yl)propenoate, and and salts and N-oxides thereof.

8. A process according to claim 2 in which the compound of formula (IA) is 3[2-thia-3-[2-(E-2-carboxyethenyl-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridy l]propyl]benzoic acid, [[1-thia-2-[6-(2-carboxyethyl)-5-phenylethyloxy-2-pyridyl]]ethyl]-2,6-dich lorobenzene, or [[1-thia-2-[6-(E-2-carboxyethenyl)-5-phenylethyloxy-2-pyridyl]]ethyl]-2,6- dichlorobenzene, or pharmaceutically acceptable salts or N-oxides thereof.

9. The process of claim 1 wherein the palladium catalyst is palladium (II) catalyst selected from the group consisting of Pd(OAc).sub.2, Pd(OAc).sub.2 /(o-tol).sub.3 P, Pd(OAc).sub.2 / Ph.sub.3 P, Pd(OAc).sub.2 /tri(2-furyl)phosphine, (Ph.sub.3 P).sub.2 PdCl.sub.2, and PdCl.sub.2 /Ph.sub.3 P.

10. The process according to claim 9 wherein the catalyst is bis(triphenylphosphine)palladium dichloride or palladium acetate.

11. The process of claim 2 wherein the palladium catalyst is a palladium (II) catalyst selected from the group consisting of Pd(OAc).sub.2, Pd(OAc).sub.2 /(o-tol).sub.3 P, Pd(OAc).sub.2 /Ph.sub.3 P, Pd(OAc).sub.2 /tri(2-furyl)phosphine, (Ph.sub.3 P).sub.2 PdCl.sub.2, and PdCl.sub.2 /Ph.sub.3 P.

12. The process according to claim 11 wherein the catalyst is bis(triphenylphosphine)palladium dichloride.
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