Patent GB-1243213-A (GB)
Title: Improvements in or relating to phosphorylated phosphonium ylids
IPC: C07F9/655
Filed: 1968-07-11
Abstract: 1,243,213. Phosphonium ylids. SYNTEX CORP. 11 July, 1968 [18 July, 1967; 29 Feb., 1968]; No. 33243/68. Heading C2C. - Novel phosphonium ylids of the general Formula A in which R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are independently alkyl having 1 to, 6 carbon atoms, aryl, substituted aryl, aralkyl, or substituted aralkyl, or R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are all three N-piperidyl, N-morpholinyl or cyclohexyl, R<SP>4</SP> is hydrogen, alkyl having 1 to 6 carbon atoms, cyclohexyl, optionally substituted aryl or. optionally substituted aralkyl, Y is oxygen or sulphur, Z<SP>1</SP>and Z<SP>2</SP> are independently N-piperidyl, N-morpholinyl or the group OR<SP>5</SP>, SB<SP>6</SP> or NR<SP>7</SP>R<SP>8</SP> where R<SP>5</SP> and R<SP>6</SP> are alkyl having 1 to, 6 carbon atoms, alkenyl, optionally, substituted aryl or optionally substituted aralkyl, and R<SP>7</SP> and, R<SP>8</SP> are alkyL having 1 to 6 carbon atoms, aryl or aralkyl or Z<SP>1</SP> and Z<SP>2</SP> together are the group -0-R<SP>9</SP>-O-, -O-R<SP>9</SP>-S-,or-S-R<SP>9</SP>-S- in which R<SP>9</SP> is alkylene or arylene, are prepared by one of the following methods: (1) A monosubstituted phosphonium ylid of the Formula (I) is condensed under substantially anhydrous conditions with an appropriately disubstituted phosphonyl or thionophosphonyl halide of the Formula (11) in which X is chloro or bromo, in an inert solvent, at a temperature from 0 C. to the reflux temperature of the solvent, optionally in the presence of an inert atmosphere. (2) A trisubstituted phosphine of the Formula III  is reacted under the same conditions as above with an appropriately disubstituted halomethylphosphonic ,  acid of halpmethylthioi.iophosphonic acid of the Formula IV in which Z<SP>1</SP>' and. Z<SP>2</SP>' are N-piperidyl, N-morpholinyl, NR<SP>7</SP>R<SP>8</SP> or OR<SP>5</SP>', where R<SP>5</SP>' is optionally substituted aryl or aralkyl to give a salt, which is treated with an aqueous solution, of a base to. give an ylid of Formula A in which R,<SP>4</SP> is hydrogen, Z1 is'Z<SP>1</SP>'' and Z<SP>2</SP> is Z<SP>2</SP>'. This may he, reacted with an alkyl or cyclohexyl halide to obtain the ylids in which R<SP>4</SP> is alkyl or cyclohexyl. (3) To give ylids of the Formula A in which Y is oxygen, a monosubstituted phosphonium ylid of the Formula (I) is reacted with an appropriately tetrasubstituted pyrophosphate of the formula VII.  The novel phosphonium ylids (A) can be reacted with a wide variety of aldehydes and ketones to give unsaturated phosphonate and thiophosphonate derivatives which can be converted into the corresponding saturated phosphonic and thiophosphonic acids. In particular nucleoside.-6<SP>1</SP>-phosphonic acids, are, prepared by the steps of (a) reacting a phosphonium ylid of Formula A with a nucleoside'- 51-aldehyde to give, a nuclepside-5<SP>1</SP> -6<SP>1</SP>unsaturated 61-phosphonate; (b) catalytic hydrogenation or di-imide reduction to give the corresponding saturated nucleoside 61-phosphonate; and (c) removing the ester groups (i.e. Z<SP>1</SP> and Z<SP>2</SP>) by hydrolysis, hydrogenolysis, anionic dealkylation, enzymatic action, or combinations thereof to give the corresponding nucleoside-61- phosphonic acid. Examples are given of the preparation of phenyl [1 - (5,6 - dideoxy - (3- D - ribo hexofuranosyl)uracil] 6<SP>1</SP> - phosphonic acid from 2<SP>1</SP>,31  -  0 - anisylidene uridine - 5<SP>1</SP> - aldehyde.; of a salt of [9 - (5,6- dideoxy - # - D - ribo - hexofuranosyl) adenine] 6<SP>1</SP>-phosphonic acid from 21,3<SP>1</SP>-0-isopropyl idene adenosine-51-aldehyde, and of the acids from 31-O-acetylthymidine 5<SP>1</SP>-aldehyde, 1-(N<SP>4</SP>, O<SP>2'</SP>,<SP>3'</SP>-tribenzoyl-#-D-arabinofuranosyl-): [ cytosine 5<SP>1</SP> aldehyde; and others.