There is a need in the art for alternative processes for preparing cyanophosphonate derivatives and novel cyanophosphonate derivatives to be used in the synthesis of phosphorus species. There is a further need for such novel processes and compounds that are economical and have an improved environmental impact over conventional processes using halogen-containing starting materials.

SUMMARY OF THE INVENTION This invention relates to a process for preparing cyanophosphonate derivatives.

More particularly, the invention is directed to a process that involves contacting phosphoric anhydride (P401o) and a cyanide, preferably in the presence of a Lewis base, in a reaction mixture under sufficient conditions to produce a cyanophosphonate

derivative. The cyanophosphonate derivative can be subsequently hydrogenated to produce an aminomethylphosphonate derivative. In a further preferred embodiment, the cyanophosphonate derivative and the aminomethylphosphonate derivative are used as precursors for the production of N-phosphonomethylglycine.

The processes according to the invention offer significant advantages in that they provide a novel, economic route to synthesize cyanophosphonate derivatives having improved environmental impact over conventional processes using halogen-containing phosphorus starting materials.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The invention is broadly directed to a process that involves contacting phosphoric anhydride (P40lo) and a cyanide, preferably in the presence of a Lewis base, in a reaction mixture under sufficient conditions to produce a cyanophosphonate derivative. That cyanophosphonate derivative can be subsequently hydrogenated to produce an aminomethylphosphonate derivative. In a further preferred embodiment, the cyanophosphonate and aminomethylphosphonate derivatives are used as precursors for the production of N-phosphonomethylglycine.

In a preferred embodiment, the process according to the invention involves charging a reaction vessel with phosphoric anhydride, optionally with a nonreactive, polar solvent. A Lewis base is then added, preferably in an amount ranging from about 1 to about 10 molar equivalents relative to phosphoric anhydride, more preferably about 2 to about 8 molar equivalents, and most preferably about 3 to about 6 molar equivalents.

That mixture is then heated under suitable conditions to dissolve or partially dissolve the phosphoric anhydride, e. g., preferably at a temperature of about 40°C and for about 10 minutes. Subsequently, a cyanide compound is added, preferably in an amount ranging from about 1 to about 15 molar equivalents relative to phosphoric anhydride, more preferably about 2 to about 10 molar equivalents and most preferably about 3.5 to about

8.5 molar equivalents. This mixture is then heated under suitable conditions to carry out the reaction. The reaction temperature can be between about-20°C and about 150°C, and is preferably between about 0°C and about 150°C, and more preferably between about 30°C and about 90°C. The reaction time preferably ranges from about 0.1 to about 50 hours, more preferably from about 0.5 to about 20 hours and most preferably from about 1 to about 6 hours. The Lewis base and any solvent can subsequently be removed from the product mixture, for example, under reduced pressure. The remaining reside can then be quenched with water, alcohol or buffer to yield one or more cyanophosphonate derivatives. The amount of water, alcohol or buffer added to the reaction mixture in the quenching step is preferably at a least stoichiometric amount and more preferably an excess amount.

Phosphoric anhydride is commercially available, for example, from Aldrich Chemical Co. in assays in excess of 99.99%. Phosphoric anhydride is generally available in the form of a powder and can be added to the reaction mixture in various forms. For example, phosphoric anhydride can be added directly as a powder or as a slurry in a solvent or cosolvent.

The cyanide reagent can be hydrogen cyanide or a cyanide salt that is sufficiently reactive with phosphoric anhydride to produce a cyanophosphonate derivative according to the inventive process. For example, the cyanide salt can be an alkali metal cyanide, an alkaline earth metal cyanide, a tetraaryl phosphonium cyanide, an ammonium cyanide, a tetraalkyl ammonium cyanide, tetraalkyl phosphonium cyanide, a tetraaryl phosphonium cyanide, a trialkyl sulfonium cyanide, a cyanide of a cationic form of an organic amine or mixtures thereof. The cyanide reagent is preferably hydrogen cyanide, potassium cyanide, sodium cyanide, lithium cyanide, silver cyanide, gold cyanide, copper cyanide, tetrabutylammonium cyanide or mixtures thereof. More preferably, the cyanide compound is hydrogen cyanide, potassium cyanide, sodium cyanide, tetrabutyl- ammonium cyanide or mixtures thereof.

The Lewis base is generally any base suitable for promoting the production of the cyanophosphonate derivative according to the inventive process. In a preferred embodiment, the Lewis base is triethylamine, diglyme, 4-isopropylpyridine, dibenzylamine, 4-dimethylaminopyridine, tris [2- (2-methoxyethoxy) ethyl] amine, 4-tert- butylpyridine, 4- (5-nonyl) pyridine, trimethylamine, 1, 8-bis (dimethylamino) naphthalene, 4-ethylpyridine, phenanthroline, N, N, N', N'-tetramethylethylenediamine, 1,4,7,10,13- pentamethyl-1,4,7,10,13-pentaazacyclopentadecane, quinuclidine, N-methylpyrrolidine, 1, 4-diazobicyclo [2.2.2] octane, 1-butylimidazole, 3-benzylpyridine, 1,5-pentamethylene- tetrazole, tris [2 (2-methoxyethoxy) ethyl] amine, N, N-dimethylaniline, collidine, N- benzylidine aniline, triphenylphosphine or mixtures thereof. More preferably, the Lewis base is 4-tert-butylpyridine, 4- (5-nonyl) pyridine, quinuclidine or N-methylpyrrolidine.

The Lewis base can be added to the reaction mixture in an amount ranging from about 1 to about 10 molar equivalents, more preferably from about 2 to about 8 molar equivalents and most preferably from about 3 to about 6 molar equivalents relative to phosphoric anhydride.

The solvent can be any material which enhances the solubility of the reactants or promotes the formation of the desired products. Preferably the solvent is a polar solvent, for example, a nitrile such as acetonitrile, phenylacetonitrile, adiponitrile, propionitrile, dimethylacetonitrile or mixtures thereof. More preferably, the solvent is acetonitrile, phenylacetonitrile or adiponitrile.

The step of contacting phosphoric anhydride and a cyanide can produce a variety of intermediate products, including those disclosed in the co-pending U. S. patent application serial no., entitled"Cyanophosphorus Compounds and Their Preparation,"by Patrick J. Lennon and Sergey G. Vulfson, filed December 23,1997, which is incorporated by reference. For example, the intermediate products can include one or more dicyanophosphinates, cyanopolyphosphates, tricyanocyclotriphosphonates and/or tetracyanocyclotetraphosphates.

Upon quenching of the intermediate product solution with water or a buffer, the product solution preferably contains a cyanophosphonate derivative of cyanophosphonic acid or a cyanophosphonate monosalt monoacid, such as potassium hydrogen cyanophosphonate, sodium hydrogen cyanophosphonate or lithium hydrogen cyanophosphonate. Upon quenching with an alcohol, the product solution preferably contains a cyanophosphonate derivative of cyanophosphonic acid, a cyanophosphonate monosalt monoester, a cyanophosphonate diester, a cyanophosphonate monoacid monoester, a cyanophosphonate monosalt monoacid or a cyanophosphonate disalt. In a further preferred embodiment, the cyanophosphonate derivative is potassium benzyl cyanophosphonate, potassium methyl cyanophosphonate, potassium ethyl cyanophosphonate, sodium benzyl cyanophosphonate, sodium methyl cyanophosphonate, sodium ethyl cyanophosphonate, disodium cyanophosphonate, dipotassium cyano- phosphonate, dilithium cyanophosphonate, bis (2-hydroxyethylammonium) cyanophos- phonate, bis (ammonium) cyanophosphonate, bis (isopropylammonium) cyanophosphonate, bis (dimethylammonium) cyanophosphonate, mono (isopropylammonium) cyanophospho- nate or bis (trimethylsulfonium) cyanophosphonate.

In another preferred embodiment, the cyanophosphonate derivative is a cyclic cyanophosphonate anhydride, a linear cyanophosphonate anhydride, a mixed linear cyanophosphonate-phosphate anhydride or a mixed cyclic cyanophosphonate-phosphate anhydride. For example, the cyanophosphonate derivative can be monocyanopyro- phosphate, dicyanopyrophosphate, dicyanotripolyphosphate, dicyanotetrapolyphosphate, monocyanotetrapolyphosphate, monocyanopentapolyphosphate, cyanophosphate cyclo- trimer or cyanophosphate cyclotetramer.

The cyanophosphonate derivative product or products are preferably produced in at least 50% yield with respect to the phosphoric anhydride reagent, more preferably at a 55-95% yield, for example, at a 60-90% yield.

The cyanophosphonate derivatives produced by the inventive process can be used as precursors for producing other organophosphorus species. In a preferred embodiment, the cyanophosphonate derivative product can be hydrogenated to produce an aminomethylphosphonate derivative. The hydrogenation may take place by contacting the cyanophosphonate derivative with hydrogen in the presence of a suitable catalyst under sufficient conditions to produce an aminomethylphosphonate derivative. The cyanophosphonate derivative can be provided alone or in a mixture of compounds, including a product mixture or portion of a product mixture from the reaction of a pyrophosphate or polyphosphate ester and cyanide.

The solvent can be any material that enhances the solubility of reactants or promotes the formation of the desired products. In a preferred embodiment, the solvent is water, acetic acid, an alcohol, dimethylacetamide, an anhydride, e. g., acetic anhydride, an amide, sulfolan or mixtures thereof.

Hydrogen pressure can be maintained at a level suitable for the formation of an aminomethylphosphonate derivative, and consistent with the safety limitations of the experimental system. In a preferred embodiment, the hydrogen pressure is between about 0.25 and 5000 psi, more preferably between about 0.5 and about 3000 psi and most preferably between about 1 and about 1000 psi, for example, between about 25 and about 300 psi.

The catalyst is generally any material effective at catalyzing the formation of aminomethylphosphonate derivatives according to the inventive method. In a preferred embodiment, the catalyst is a transition metal catalyst. For example, the hydrogenation step can use a catalyst of a cobalt-containing compound, a nickel-containing compound, a

platinum-containing compound, a palladium-containing compound or a rhodium- containing compound. More preferably, the catalyst is Raney cobalt, Raney nickel, a platinum promoted Raney nickel such as platinum tetrachloride (PtCl4) promoted Raney nickel, platinum on carbon, palladium on carbon or rhodium on carbon. The catalyst can be used at a stoichiometric amount or catalytic amount with respect to the cyanophosphonate derivative. The stoichiometric amount is preferably between about 1 molar equivalent and about 5 molar equivalents with respect to the cyanophosphonate derivative, and more preferably between about 1 molar equivalent and about 2 molar equivalents with respect to the cyanophosphonate derivative. The catalytic amount is preferably between about 0.1 molar percent and about 100 molar percent with respect to the cyanophosphonate derivative, and more preferably between about 0.5 molar percent and about 50 molar percent with respect to the cyanophosphonate derivative.

In the event that a catalyst of platinum on carbon, palladium on carbon or rhodium on carbon is used, the hydrogenation reaction mixture preferably further contains an acid in an amount sufficient to promote formation of the desired product. The acid can be an inorganic acid or an organic acid. The inorganic acid is preferably hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or hydrocyanic acid and, more preferably, is hydrochloric acid. The organic acid is preferably acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid. The acid is preferably added to the hydrogenation reaction mixture at a concentration between about 0.1 and 5 molar equivalents with respect to the cyanophosphonate derivative, more preferably at a concentration between about 0.5 and about 2.5 molar equivalents with respect to the cyanophosphonate derivative, and most preferably at a concentration of about 1 molar equivalent or about 2 molar equivalents with respect to the cyanophosphonate derivative, depending on the nature of the cyanophosphonate derivative.

In a preferred embodiment the reaction product mixture from the hydrogenation step is heated under sufficient conditions to further promote the formation of the amino- methylphosphonate derivative. For example, a product mixture that has been partially or

substantially hydrogenated can be heated to a temperature in the range of about 135°C to about 200°C, and more preferably to a range of about 135°C to about 160°C. This heating step may be conducted for any amount of time that further promotes the aminomethylphosphonate derivative formation, preferably about 1 to about 12 hours. The heating time for optimum aminomethylphosphonate derivative formation can depend on the pH and the nature of the cations in the reaction mixture.

The products of the hydrogenation step can be isolated from the reaction mixture by conventional methods or can be used for some purposes without isolation from the reaction product mixture. Further details regarding cyanophosphonate derivative hydrogenation are provided in co-pending U. S. application Serial No., entitled"Method for Preparing Aminomethylphosphonate Derivatives Via Hydrogenation of Cyanophosphonate Derivatives,"by Patrick J. Lennon, filed December 23,1997, which is incorporated herein by reference.

The aminomethylphosphonate derivative product of the inventive process can be used as a precursor for producing other organophosphorus species. In a preferred embodiment, aminomethylphosphonic acid can used for producing N-phosphono- methylglycine. Methods for producing N-phosphonomethylglycine from aminomethyl- phosphonic acid are disclosed, for example, in U. S. Patent No. 4,221,583 (Monsanto Co.), which is incorporated herein by reference.

The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments

which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

EXAMPLES Example 1. Preparation of Cyanophosphonate Derivatives from Phosphoric Anhydride and Cyanides for NMR Analysis Preparation 1. Under inert atmosphere, 0.07 g (0.25 mol) of P40, o was mixed with 1 ml of dry CH3CN and 0.10 g (1.0 mmol) of triethylamine were added. The mixture was then heated at 40°C for 5 minutes, after that 0.07 g (1.06 mmol) of KCN were added to this solution. The solid KCN was crushed with a spatula around the walls of the glass vial under the surface of the reaction mixture. The mixture was heated at 40°C overnight.

After removal of the solvent under reduced pressure, the resulting powder was dissolved in D20 and the NMR spectra were recorded. The pH was adjusted as needed by the addition of acid or base.

Preparation la. The reaction was carried out according to the procedure in Example 1 using the same molar quantities of reagents, except that K 13 CN was used instead of K12CN.

Preparation 2. Under inert atmosphere, 0.07 g (0.25 mol) of P4010 was mixed with 1 ml of dry CH3CN and 0.135 g (1.0 mmol) of 4-tert-butylpyridine were added. The mixture was then heated at 40°C for 5 minutes, after that 0.07 g (1.06 mmol) of KCN were added to this solution. The solid KCN was crushed with a spatula around the walls of the glass vial under the surface of the reaction mixture. The mixture was heated at 40°C overnight. After removal of the solvent under reduced pressure, the resulting powder was dissolved in D20 and the NMR spectra were recorded. The pH was adjusted as needed by the addition of acid or base.

Preparation 3. Under inert atmosphere, 0.07 g (0.25 mol) of P40, o was mixed with 1 ml of dry CH3CN and 0.10 g (1.0 mmol) of triethylamine were added. The mixture was then heated at 40°C for 5 minutes, after that 0. 269 g (1. 0 mmol) of (C4H9) 4NCN were added to this solution. The mixture was heated at 40°C overnight. A small quantity of dry CD3CN was added to the solution before the NMR spectra were run.

The product mixtures for Preparations 1,1A, 2 and 3 were then evaluated by NMR, the results of which are summarized in Tables I-VI.

Species Assignment Key for Tables I-IV, VI Molecule ID Assignment Formula A Cyclic trimer or tetramer (CN)3 (PO,), or (CAl) (PO.), B Symmetrical linear trimer [NCPO3 PO, PO2CN]' C Symmetrical linear tetramer [NCPOjPOjPOjPO.. CN]' D Unsymmetrical linear tetramer E Unsymmetrical linear pentamer [NCPO3PO3PO3PO3PO3]0- L Cyanophosphonate (monomer A) [NCPO3]2- Table V 1 Dicyanophosphinate (monomer B) [(NC)2PO2]1 12 Cyclic trimer or tetramer (CN)3(PO2)3 or (CN)4 (PO2)4

TABLE ! "P NMR Data for Preparation I (pH-2.5,3 day solution) Molecule ID Approx. Highest Field Pattern Coupled Partner Pattern % Chemical Shift (ppm) Chemical Shift (ppm) Jpp (Hz) Jpp (Hz) A 25.3 S P 253 -33.69 B 10.0 D T -33.02 -23.63 20.9 20.9 C 3.9 HOP HOP -32.6-22.9 D 3. 4 D DD HOP HOP -32.42-22.43-22.27-21.77 18.9 18.8 E 9. 5 D DD DD HOP HOP -32.38-22.21-21.56-21.1 aprox-20. 9 aprox 19.3 19.2,16.8 F <1 D D -32. 17-9. 83 20.9 20.7 G <1 D -31.54 partner not 12.3 located H 2.1 S -22.36 1 <1S -22.51 J 3. 2 D O -21. 37-9. 49 15.3 K 6. 2 -20. 25 L 35. 6 -14.38 M <1 S -1.13 S = singlet T = triplet DD = doublet of doublets D = doublets HOP = higher order pattern O = obscured

TABLE II "P NMR Data for Preparation I (pH = 8.2,1 hr solution) Molecule ID Approx. Highest Fieid Pattern Coupled Partners Pattern % Chemical Shift (ppm) Chemical Shift (ppm) Jp-p (Hz) Jpp (Hz) A 28. 9 S -33.64 B 12.4 D T -33.90-23.50 20.9 20.9 C 4.9 HOP HOP -32.47-22.73 D 3. 8 D DD HOP -32.31-22. 27-21.09 18.7 18.3 E 11.7 D DD DD HOP HOP -32.27-22.05-21.39-20.74-20.74 19.3 19.1,16.9 16.3,15.3 X <1 D TOSCY sw did -31.50 not include 12 90 coupled portion aY <1 D " " -30.53 22.66 H 1.1 S 22.66 H 1.1 S -22.44 1 1. 2 S -22.21 J 7.6 D " " -21.20 14.8 K 26.5 S -20.14 LS -14.25 S = singlet D= doublet T = triplet HOP = higher order pattern DD = doublet of doublets SW = sweep width 'X and Y may be identical to F and G (Table I) but shifts are notably different.

TABLE III 31P NMR Data for Preparation 2 (pH = 3.2,24 hr solution) Molecule ID Approx. Highest Field Pattern Coupled Partners Pattern % Chemical Shift (ppm) Chemical Shift (ppm) Jp-p (Hz) Jpp (Hz) A 39.2 S -33.75 B 6. 6 D T -33.05-23. 66 20. 9 20. 9 C 2.5 HOP HOP -32.64-22.92 D <I D DD HOP HOP -32. 47 -22.24 -21. 28-21.78 19.3 E 6.0 D DD DD HOP HOP -32.43 22.24 -21.60 -21.16 -20.95 19.3 F 9.5 D-9. 81 -32. 19 21. 1 21.1 G Absent H <1 S I 1.4 S -22. 39 -22.39 J 2.6 D O -21.46 -9.46 K 5.4 S -20.30 L 23. 4 S -15.67 M 1. 0 S +1. 13 N <1 S -21.82 S = singlet D = doublet T = triplet DD = doublet of doublets O = obscured HOP= higher order pattern

TABLE IV 31P-13C Coupling Constants from Preparation 1a Molecule JP-C coupling constant in hertz ID A'JPC= 204.7 Hz 3JPC = 11.04 Hz B 200. 5 Hz C 199.9 Hz 199. 2 Hz E 198.9 Hz L 157.3 Hz

Table V Chemical shifts and coupling constants for P containing molecular species in Preparation 3 Molecule Approx Pattem Coupled ID % Chem Shift Partner (s) (ppm) J, _, (Hz) 16.8 -47. 36 peak at -37.68-19.47 24.5 observed by #18 3 <1 Q #7 -34. 90 -34.90 22.7 4 <1 S -33.62 <1 S -33.44 <1 DX 6A -32.92 25.88 7 2.1 S #3 -32.75 23 -32. 75 2 M 15, 16 -32.55 D CNL -21.82 10 <1 D CNL -32.18 It 7.2 D 13. 18 -31.8 19.1 12 9.2 S -30.9 13 7.3 HOP 11.18 29. 86 Molecule Approx Pattern Coupled ID % Chem Shift Partner (s) (ppm) JP-P (Hz) 14 20. 4 D 17 -29.71 20.6 15 1. 4 HOP 8, 16 -22, 32 16 <1 T 15, 8 -21.48 24.0 17 10 T 14 -20. 28 21.05 18 16 D 11.13 -19.54 22.6 19 3 D obscured -19. 08 peak 22. 5 at 30. 2 ppm obscured -18.11 peak 22.5 at 29. 5 6A <1 D 6 -31.17 25.88 S = singlet D = doublet T = triplet Q = quartet HOP= higher order pattern CNL = cannot locate

TABLE VI "C Chemical Shifts and C-P Coupling Constants for CN Containing Species in Preparation la with Triethylamine Base (5 day solution) Molecule Approx. 13C Chemical 1JCP 3JCP ID % Shift' (ppm) Hz Hz A 12. 3 116. 34 204.7 11. 0 B 7. 1 116. 80 200.5 C 3.8 117. 01 199.9 D 2. 9 117.09 199.2 E 5.5 117. 10 198.9 bF 1.2 117.10 196. 2 bG <1 117. 40 174.4 L 35.0 119.71'166.7 O 31. 6 110. 80 'referenced to CH. CN at 118. 2 ppm bassignment speculative Cthis'Jcp is time dependent

General Procedure for Examples 2-6 Under an inert atmosphere, 1 molar part of P4Olo was mixed with dry polar solvent (CH3CN is preferred, 4 ml per mmol P4Olo) and four molar parts of dry Lewis base were added. The mixture was then heated at 40°C to effect partial or total dissolution Of P4010 (about 5-10 minutes), after which 4.3 molar parts of Kl3CN were added to this solution. The solid KCN was crushed with a spatula around the walls of the glass vessel, e. g., a glass vial, under the surface of the reaction mixture. The mixture was heated at the specified temperature, usually between 40-80°C, for the specified time period, often between 2-20 hours. At the end of this time period, the solvent and organic base were removed using a vacuum pump. The solid residue contained one or more cyanophosphonate derivatives and was hydrolyzed by water or buffer, thereby yielding cyanophosphonate derivatives.

Example 2 The reaction was carried out in 4 ml of CH3CN with Prolo (0.28 g, 0.986 mmol), 4-tert-butylpyridine (0.54 g, 4 mmol) and K'3CN (0.28 g, 4.234 mmol) at 48°C for 20 hours. The solvent and part of the 4-tert-butylpyridine were removed (oil pump, 40°C, for 2 hours). The solid residue was hydrolyzed in water or buffer at pH = 2, yielding 87.4% or 86.5% of cyanophosphonate derivatives, respectively. Several products with P-C bonds are evident from the large coupling constants (>140 Hz) in the region around-35 ppm, as well as cyanophosphonate in the-18 to-20 ppm region as a doublet (lJpC=146. 6 Hz). On standing, the amount of the latter product increased.

Example 3 The reaction was carried out in 1 ml of CH3CN with P4010 (0.07 g, 0.25 mmol), 4- tert-butylpyridine (0.135 g, 1.0 mmol), and K 13 CN (0. 07 g, 1.06 mmol) at 80°C for 2 hours. CH3CN and part of the 4-tert-butylpyridine were removed (oil pump). The residue was hydrolyzed by water, and two layers were formed. The top (organic) layer was extracted by CH2Cl2 and showed no significant signals in the 3lP NMR spectrum.

According to 31P NMR, the bottom (water) layer contained 83% cyanophosphonate derivatives.

Example 4 This reaction was carried out in 1 ml of CH3CN with P4010 (0.07 g, 0.25 mmol), 4- (5-nonyl) pyridine (0.21 g, 1.02 mmol) and K 13 CN (0.07 g, 1.06 mmol) at 48°C for 16 hours (overnight), then at 80°C for 1 hour. The solvent was removed under reduced pressure, and the residue was hydrolyzed with water producing two layers. The top (organic) layer, diluted with methanol, contained only two signals in the 31P NMR spectrum corresponding to cyanophosphonate derivatives, one of which was cyanophosphonate. The bottom (water) layer yielded 84.5% of cyanophosphonate derivatives with cyanophosphonate accounting for 24%.

Example 5 The reaction was carried out in 1 ml of CH3CN with P401o (0.07 g, 0.25 mmol), triethylamine (0.10 g, 1.0 mmol) and K13 CN (0.07 g, 1.06 mmol) at 80°C for 1 hour. The solvent and amine were removed under reduced pressure. The solid residue was hydrolyzed with water yielding 63% of cyanophosphonate derivatives (23% as cyanophosphonate).

Example 6 In dry acetonitrile (7 ml), Pro (0.5 g, 1.76 mmol), triethylamine (0.7 g, 6.9 mmol) and K'3CN (0.5 g, 7.56 mmol) were combined and heated at 40°C for 16 hours.

Then the solvent and triethylamine were removed under reduced pressure. The solid residue was hydrolyzed with water yielding 64% of cyanophosphonate derivatives (32% as cyanophosphonate; the remainder as compounds with chemical shifts in the range-31.5 to-34. 9 ppm (large doublets of varying multiplicities)) in the 3'P NMR spectrum.

Further, representative conditions and yields are indicated below in Table VII.<BR> <P>Table VII. Reactions of P4O10 and Cyanide CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCN1 H2O2 Comments Molar Molar Equiv. Equiv. % P4O10:CN P4O10:Base K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 84 <1h K13CN was powdered in 85 17h react. mixture, buffer w 81 73h pH=4.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 87 <1h K13CN was powdered in 69 73h react. mixture, H2O K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 87 <1h K13CN was powdered in 64 73h react. mixture, buffer w pH=2.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 86 <1h K13CN was powdered in 80 73h react. mixture, buffer w pH=5.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 86 <1h K13CN was powdered in 78 73h react. mixture, buffer w pH=10.0 1 PCN % is the percent yield of cyanophosphonate derivatives.<BR> <P>2H2O time is the hydrolysis time. CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCN1 H2O2 Comments Molar Molar Equiv. Equiv. % P4O10:CN P4O10:Base K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 85 <1h K13CN was powdered in 80 73h react. mixture, buffer w pH=12.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 84 <1h K13CN was powdered in 74 73h react. mixture, buffer w pH=8.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 84 <1h K13CN was powdered in 73 73h react. mixture, buffer w pH=6.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 20 84 <1h K13CN was powdered in 67 73h react. mixture, buffer w pH=7.0 K+ 4-t-butylpyridine 1:8 1:4 CH3CN 40°C 16 60 <1h K13CN, D2O 60 K+ triethylamine 1:4 1:4 CH3CN 40°C 16 56 <1h K13CN, D2O 53 25h K+ triethylamine 1:8 1:4 CH3CN 40°C 16 55 <1h K13CN, D2O 53 25h K+ triethylamine 1:2 1:4 CH3CN 40°C 16 46 <1h K13CN, D2O 44 25h K+ N,N,N',N'- 1:4 1:4 CH3CN 40°C 7 18 <1h K13CN, D2O tetramethyl 19 17h ethylenediamine CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCN1 H2O2 Comments Molar Molar Equiv. Equiv. % P4O10:CN P4O10:Base K+ 4-t-butylpyridine 1:4 1:4 CH3CN 48°C 16+1 89 <1h K13CN was powdered in +80°C react. mixture, buffer w pH=2.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 52°C 17 86 <1h K13CN was powdered in react. mixture, buffer w pH=2.0 K+ 4-(5-nonyl)- 1:4 1:4 CH3CN 48°C 16+1 85 K13CN was powdered in pyridine +80°C react. mixture, D2O K+ 4-t-butylpyridine 1:5 1:5 CH3CN 78°C 2.75 84 <1h K13CN was powdered in react. mixture, D2O pH=5.5 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 80°C 2 82 <1h K13CN was powdered in react. mixture, D2O pH=5.9 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 80°C 1.5+1 82 <1h K13CN was powdered in +40°C react. mixture, D2O K+ 4-(5-nonyl)- 1:4 1:4 BzCN+ 50°C 20+1 79 <1h K13CN was powdered in pyridine CH3CN +85°C react. mixture, D2O K+ Me5[15]aneN5 1:4 1:4 CH3CN 50°C 16 78 K13CN was powdered in react. mixture, D2O pH=9.45 K+ quinuclidine 1:4 1:4 CH3CN 48°C 16+1 77 <1h K13CN was powdered in +80°C react. mixture, D2O CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCN1 H2O2 Comments Molar Molar Equiv. Equiv. % P4O10:CN P4O10:Base K+ 4-t-butylpyridine 1:4 1:4 CH3CN 80°C 1+24 75 <1h K13CN was powdered in +50°C react. mixture, buffer w pH=2.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 50°C 16 73 <1h K13CN was powdered in react. mixture, buffer w pH=2.0 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 45°C 72 71 <1h K13CN was powdered in react. mixture, buffer w pH=2.0 K+ 4-(5-nonyl)- 1:4 1:4 adipoCN 80°C 3 70 <1h K13CN, D2O pyridine K+ 4-t-butylpyridine 1:4 1:4 BzCN+ 50°C 20+1 67 <1h K13CN was powdered in CH3CN +85°C react. mixture, H2O K+ 4-t-butylpyridine 1:4 1:2 CH3CN 80°C 2 66 <1h K13CN was powdered in react. mix, buffer pH=8.0 pH=3.4 (real) K+ 4-t-butylpyridine 1:4 1:2 CH3CN 80°C 2 65 <1h K13CN was powdered in react. mixture, buffer pH=6.0 pH=2.9 (real) K+ triethylamine 1:4 1:4 CH3CN 40°C 16 64 <1h K13CN was powdered in react. mixture, D2O K+ 1,4-diazabicyclo 1:4 1:4 CH3CN 40°C 16 63 <1h K13CN was powdered in [2.2.2]octane react. mixture, D2O pH=8.1 CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCN1 H2O2 Comments Molar Molar Equiv. Equiv. % P4O10:CN P4O10:Base K+ triethylamine 1:4 1:4 CH3CN 80°C 1 63 <1h K13CN was powdered in rect. mixture, D2O pH=7.8 K+ 4-t-butylpyridine 1:4 1:4 sulfolane 85°C 72+ 63 <1h K13CN was powdered in +50°C 24 react. mixture, buffer w pH=2.0 K+ 4-t-butylpyridine 1:4 1:2 CH3CN 80°C 2 62 <1h K13CN was powdered in react. Mix, D2O pH=2.4 K+ 4-t-butylpyridine 1:4 1:2 CH3CN 80°C 2 62 <1h K13CN was powdered in react. mixture, D2O +K2CO3 pH=10.1 K+ 4-t-butylpyridine 1:4 1:4 CH3CN 87°C 0.25 61 <1h K13CN was powdered in react. mixture, D2O pH=3.85 K+ triethylamine 1:4 1:4 CH3CN 40°C 7 59 <1h K13CN, D2O K+ 1-butylimidazole 1:4 1:4 CH3CN 48°C 16+1 59 <1h K13CN, D2O +80°C K+ triethylamine 1:4 1:4 CH3CN 40°C 16 59 <1h K13CN was powdered, dried oil pump 80°C, 24h. D2O k+ 4-benzylpyridine 1:4 1:4 CH3CN 50°C 16 59 <1h K13CN was powdered in react. mixture, buffer w pH=2.0 CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCN H202 Comments MolarMolar (hr) Time Equiv.Equiv. % P401o : CN P4010 : Base 11 4 triethylamine 1 : 4+2 1 : 4 CH3CN DMSO 40°C 16 58 <lh K 13 CN was added in 2h; NBu4++2K+ polymer or gel, DMSO was added with KCN K+ triethylamine 1: 4 1 : 4 CH3CN 2 eq. 40°C 16 57 <I h D2O Zn (CN) 2 K+ triethylamine 1: 4 1: 8 CH3CN 40°C 16 57 <lh buffer pH=7.4 K+ 3-benzylpyridine 1: 4 1 : 4 CH3CN 50°C 16 55 <lh K 13 CN was powdered in react. mixture, H20 K+ triethylamine 1: 4 1 : 4 CH3CN 1.1 eq 40°C 16 54 <Ih K 13 CN, D20 Bu4NI 4 triethylamine 1 : 4+2 1: 4 CH3CN dimethyl 40°C 16+2 54 <Ih K 13 CN was added in 16h NBu4++2K+formamide Only PCN before hydrolysis DMF was added with KCN K+ tributylamine 1: 4 1: 4 CH3CN 50°C 16 53 <lh K 13 CN was powdered in react. mixture, D2O pH=4.03 K+ 1,5-penta 1: 4 1: 4 CH3CN 50°C 16 52 <lh K 13 CN was powdered methylene under CH3CN, D20 tetrazolpH=9.6 4 triethylamine 1: 1+4 1: 4 CH3CN 40°C 2+2 52 <lh K 13 CN was added in 2h; NBu4++4K+ polymer or gel, after hydrolysis by H20 pH=9. 1 CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCN1 H2O2 Comments Molar Molar Equiv. Equiv. % P4O10:CN P4O10:Base K+ 4-t-butylpyridine 1:4 1:4 BzCN 50°C 24 52 <1h K13CN was powdered in react. mixture, H2O 4 triethylamine 1:4+2 1:4 CH3CN 50°C 16+2 51 <1h K13CN was added in 16h Only PCN before hydrolysis, though gel is possible 4Na+ triethylamine 1:4 1:4 CH3CN 4eq 40°C 1 51 <1h buffer pH=7.4 5-crown-15 K+ tributylamine 1:8 1:4 CH3CN 40°C 48 50 <1h K13CN, D2O K+ tris[2(2-methoxy 1:8 1:4 CH3CN 40°C 16 49 K13CN, D2O ethoxy)ethyl] amine 4 triethylamine 1:2+4 1:4 CH3CN 40°C 2+2 47 <1h K13CN was added in 2h; NBu4++4K+ polymer or gel, after hydrolysis by H2O pH=9.4 K+ diglyme 1:4 1:4 CH3CN 4 HCl 40°C 16 46 <1h K13CN, D2O -dioxane NBu4+ triethylamine 1:4 1:4 cH3CN 40°C 16 44 <1h K+ N,N-dimethyl 1:8 1:4 CH3CN 40°C 48 42 K13CN, D2O aniline 4K+ diglyme 1:4 1:4 CH3CN 40°C 16 40 <1h CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCNI Ha02 Comments Molar Molar (hr) Time Equiv. Equiv. % P401o : CN P4010 : Base K tributylamine 1: 8 1: 4 CH3CN Cap (C8HI7) 3 40°C 16 40 <Ih Kl3CN, D2O MINCI 4K triethylamine 1 : 4 1 : 4 adipoCN 80°C 16 39 <lh buffer pH=7. 4 K+ triethylamine 1 : 8 1 : 4 CH3CN 82°C 72 38 <Ih Kl3CN, D2O 2K++3 triethylamine 1 : 5 1 : 4 CH3CN 40°C 16 37 <lh Mixt. K++NBu+ was NBu4+ used, there is precipitate 11 K collidine 1 : 8 1: 4 CH3CN 40°C 24 37 <lh K3CN, D2O K tribenzylamine 1 : 4 1 : 4 CH3CN 50°C 16 37 <lh K 13 CN was powdered in react. mixture, H20 K none 1 : 4 1 : 4 CH3CN 40°C 72 37 <lh 13 CN was powdered in react. mixture, H20 K+ triethylamine 1 : 4 1: 4 CH3CN 0. 15LaCI3 40°C 16 36 <lh K 13 CN, D20 K+ triethylamine 1: 4 1 : 4 CH3CN 4 HCI-40°C 16 35 <Ih Kl3CN, D2O pH=8. 34 dioxane K+ N-benzylidine 1 : 4 1: 4 CH3CN 50°C 16 35 <lh K 13 CN was powdered in aniline react. mix., buffer pH=2.0pH=4.03 K+ isoquinoline 1 : 4 1 : 4 CH3CN 40°C 16 27 <lh K 13 CN was powdered in react. mix., D2O K+ tris [2 (2-methoxy 1: 4 1: 4 CH3CN 40°C 16 26 <lh K 12 CN, D20 ethoxy)ethyl] amine CN Cation Base Ratio of Ratio of Solvent Additive Temp Time PCNI H202 Comments Molar Molar (hr) Time Equiv.Equiv. % P401o : CN P40I0 : Base K+ triethylamine 1 : 4 1 : 4 CH3CN I eq. 40°C 16 25 < I h K13CN, D2O Pd (CN) 2 K+ 1 : 8 1 : 0 CH3CN 40°C 72 24 <lh K3CN, D20 K+ 1,3,5-tribenzyl 1: 4 1 : 4 CH3CN 50°C 16 24 <lh K 13 CN was powdered in hexahydro-1,3,5-react. mixture, H20 triazine K 1, 8-diazabicyclo 1: 4 1: 4 CH3CN 40°C 16 23 <lh K 13 CN, D20 pH= 10. 0 [5.4.0] undec-7- ene K+ 1,5-diazabicyclo 1 : 4 1: 4 CH3CN 40°C 16 22 <lh K'CN, D20pH= ! 0. 0 [5.4.0]undec-7- ene triphenyl 1 : 4 1 : 4 CH3CN 50°C 16 16 <I h Kl3CN was powdered in phosphine react. mixture, H20 K 4-dimethylamino I : 8 1 : 4 CH3CN 40°C 48 12 <lh K 13 CN, D20 pyridine K+ dibenzylamine 1 : 4 1 : 4 CH3CN 40°C 16h 5 <lh K+ Benzotriazole 1 : 4 1 : 4 CH3CN 48°C 16+1 4 <lh +80°C

Example 7. Reaction of P4OIo with K 13 CN and Triethylamine, Followed by Hydrolysis and Catalytic Hydrogenation Using 5% Rh/C and HCI to Produce AMPA In dry acetonitrile (7 mL), phosphoric anhydride (0.35 g, 1.233 mmol) was stirred with triethylamine (0.70 g, 6.9 mmol) for 10 minutes. At the end of this time, K CN (0.35 g, 5.3 mmol) was added and stirring was continued for 16 hours at 25°C. The volatile components were removed under reduced pressure, and pH 2 buffer (2 mL) was added. This mixture was shaken until homogeneous, then allowed to stand for 3 days at room temperature. After this time, the solution was stored at 4°C for 3 days. The 31p NMR spectrum showed the presence of cyanophosphonate (30.2%) and cyano- polyphosphates (16.8%). This mixture was placed in an autoclave, after which water (100 ml) was added, followed by 5% Rh/C (Strem, 140 mg), then HCl-dioxane (4N, 2.5 mL, 10 mmol). The autoclave was then sealed, purged once with nitrogen, and pressurized with hydrogen to 1000 psi. The reaction was stirred overnight (19 hours). At the end of this time, the hydrogen pressure was released, the autoclave was pressurized once with nitrogen, the pressure was released and the autoclave was opened. The collected reaction mixture was filtered, stirred with Chelex resin, filtered again and analyzed by HPLC (phosphate detection method). The yield of AMPA was 32.6% by HPLC, based on phosphorus equivalents charged as phosphoric anhydride. The P NMR was consistent with this formulation. It is expected that the AMPA yield in this product solution will increase with further treatment, for example, with the addition of a suitable amount of acid or base and appropriate heating.

Example 8. General Procedure for Low Pressure Hydrogenations Dipotassium cyanophosphonate (0.133 g, 1.0 mmol) was added to Raney nickel (0.118 g, as a 50% slurry in water, W2 form) in a Fisher Porter bottle containing a stir bar.

Water (5 mL) was added, and platinum tetrachloride (0.105 g, 0.31 mmol) was added.

The pressure bottle was immediately connected to a hydrogen manifold, and three purges with hydrogen at 75 psi were done, and the bottle was pressurized to 75 psi. The reaction

mixture was vigorously stirred for 25.5 hours at room temperature. The pressure was then released and the reaction mixture was filtered. HPLC analysis determined a 63% yield of aminomethylphosphonic acid.

Example 9. General Procedure for Hydrogenation in Autoclave In a 300 mL Autoclave Engineers autoclave, Na203PCN (H2O) 049 (0. 80 g, 5.0 mmol) was added, followed by 10% Pt/C (0.15 g), water (100 mL) and then HCI'dioxane (2.5 mL, 4 N, 10.0 mL). The autoclave was sealed, pressured once with nitrogen above 500 psi, vented and pressured with hydrogen to 1001 psi. Stirring at about 1500 rpm was started. Within about 10 minutes, the internal pressure was about 996 psi, and the autoclave internal temperature was about 26°C. After stirring overnight, the hydrogen was vented, the autoclave was repressurized with nitrogen and vented, and then the reactor was opened and the reaction mixture removed. The reaction mixture was filtered, and the resulting solution analyzed by HPLC. The yield by HPLC of aminomethylphosphonic acid was 85%, and the yield by P NMR was 87%.

Example 10. Preparation of Phosphonitrile Derivatives from Phosphoric Anhydride and Hydrocyanic Acid As a general example, under an inert atmosphere, 1 molar part of Prolo was mixed with a dry polar solvent (CH3CN is preferred, 4 mL per mmol P40, o) and a few molar parts (four parts are preferable) of a dry aprotic base were added. The mixture was then heated at 30-40°C to effect partial or total dissolution of Prolo (about 5 to 10 minutes), after which several molar parts (four parts are preferable) of dry liquid H12 CN or H CN or a mixture of both were added to this solution cooled in an ice bath with magnetic stirring. The mixture was heated at the specified temperature, usually between 30 and 80°C, for the specified time period, often between 2 and 20 hours. At the end of this time period, the solution was purged by nitrogen for 2 hours to remove free HCN. The rest of the volatile compounds were removed using a vacuum pump then the viscous residue was hydrolyzed by water or buffer. The yield of cyanophosphonate derivatives was analyzed before and after hydrolysis.

In a particular example, the reaction was carried out in 8 ml of CH3CN with P4010 (0.56 g, 1.97 mmol), quinuclidine (0.89 g, 8.0 mmol) and H'CN (0.4 mL, 10 mmol) at 48°C for 16 hours, giving a homogeneous solution. After purging with nitrogen, P NMR showed the presence of 87.6% of P-CN containing species (major signals correspond to cyclic tricyanotripolyphosphonate : 3'P NMR (CH3CN)-35 ppm (dt,'Jpc= 187.7 Hz, 3JPC= 11.0 Hz),'C NMR (CH3CN) 120.3 ppm (doublet of triplets,'Jcp= 187.2 Hz, 3JCP= 11. 0 Hz) and dicyanotripolyphosphate 31 P NMR (CH3CN)-34. 5 ppm (dd, 1JPC= 184.6 Hz, 3JPP= 19.8 Hz), 13C NMR (CH3CN) 121.3 ppm (dd, 1JCP= 184.4 Hz, 3JCP= 2.0 Hz). Part of the CH3CN solution was hydrolyzed in water (4: 1, CH3CN : H20) yielding the same ratio of products. The solvent of another portion of unhydrolyzed reaction mixture was removed under reduced pressure. A portion of this solid, 0.1 g, was hydrolyzed in 1 mL of buffer at pH = 2 (final pH of medium, 5.0), giving 87.2% of P-CN containing species (cyclic tricyanotripolyphosphonate: 3P NMR (H2O)-34 ppm (dt, 1JPC= 202.9 Hz, 3Jpc= 11.0 Hz),'C NMR (H2O) 117.2 ppm (dt,'Jcp= 201.8 Hz, 3JCP= 11.0 Hz) and dicyanotripolyphosphate P NMR (H20)-33. 2 ppm (dd,'Jpc= 198.4 Hz, 3JPP= 21.4 Hz), 13 C NMR (H2O) 117.6 ppm ('Jcp= 198.4 Hz).

Additional representative conditions and yields are shown in Tables VIII-XI.

Table VIII. Reactions of HCN and P4010 mmol mmol Additive Temp Time Solvent Yield P-CN Yield P-CN (%) of of (mmol) °C before (%) before after hydrolysis HCN P401o hydro-hydrolysis (final pH or lysis solvent) 12.95 3.0 NEt3 (12) 40 16h CH3CN 62 60 (pH = 3. 0) 51 (pH = 9. 0) 12.95l 3.0 NEt3 (12) 40 7d CH3CN 66 62 (pH = 3. 0) 12.95 3.17 4-t-BuPy 40 18h CH3CN 63 36 (pH = 3. 0) (12. 6) 47 (pH = 6. 0) 15.5 1.50 4-t-BuPy (6.0) 70+4 1+16h CH3CN 40 22 (pH = 7. 0) 0 5.18 0.50 none 40 16h CH3CN 0 0 12.95 3.0 NEt3 (2.0) 50 48h C6HsCN 0 0 46.6 0.5 none 34 20h none 0 0 15.6 3.0 TMED (12.0) 80 16h CH3CN 72 68.2 (in CH3CN) 28.6 (pH = 1.0) Same reaction as above at different reaction times

15.6 3.0 TMED (12.0) + 70 + 1 + CH3CN 64.6 62.1 (in CH3CN) NEt3 (12. 0) 40 16 h 15.6 3.0 Proton-Sponge 80 16h CH3CN 67 48.7 (in CH3CN) (11.7) 14.26 2.47 TEED (8.84) 45 16h CH3CN 55.7 51. 0 (in CH3CN) 10.37 3.24 DBU (10.0) 80 16h CH3CN 41.8 41.2 (in CH3CN) 9.07 1.80 Quinuclidine 48 16h CH3CN 84.9 84.7 (in CH3CN) (7. 1) 79.1 (pH = 6. 0) 11.7 2.22 NBu3 (9.12) 40 64h CH3CN 68.3 61.6 (in CH3CN) 17.5 2.22 Quinuclidine 48 16h CH3CN 82.2 75.4 (in (8.02) CH3CN) 10.0 1.97 Quinuclidine 48 16h CH3CN 87.6 87.6 (in CH3CN) (8. 0) 87.2 (pH = 5) NEt3 is triethyl amine. 4-t-BuPy is 4-tert-butylpyridine. TMED is N, N, N', N'- tetramethylethylenediamine. Proton sponge@ is 1, 8-bis (dimethylamino) naphthalene.

TEED is N, N, N', N'-tetraethylethylenediamine. DBU is 1, 8-diazabicyclo [5.4.0] undec-7- ene. NBu3 is tri-n-butylamine.

Table IX. Reactions of HCN and P401o in acetonitrile Run P401o HCN Base Base Temp Time P-CN% P-CN% Yield Eq. Eq. Eq. °C h Yield After Before hydrolysis hydrolysis 1 1 5 4 N-Methyl 48 19 85. 3 85 (MeCN) Pyrrolidine 2 1 5. 07 4.0 TMED 48 19 80 78 (MeCN) 74 (+10 min) 70 (+1 h) 3 1 7 4 TMED 48 19 65 43 (MeCN) 4 1 6.1 3.7 t-Butyl-48 19 43 27 (MeCN) N=P [N (CH2)4]3 5 1 5. 24 4.0 MeN (C6H,) 2 30 19 41 34 (MeCN) Table X. Reactions of HCN and P4O10 in acetonitrile with quinuclidine Run P4010 HCN Base Base Temp Time P-CN% P-CN% Yield Eq. Eq. Eq. °C h Yield After Before hydrolysis hydrolysis 11 1 4. 7 3. 9 Quinuclidine 46 19 88. 2 87 (MeCN) 2 1 4. 9 4.1 Quinuclidine 45 19 87. 2 86 (MeCN) 3 1 5. 6 4.0 Quinuclidine 48 19 87. 1 nd 4 1 4.0 4.0 Quinuclidine 48 19 83.8 79 (in 10 min) 43 (6 h, pH 1. 5) 52 1 5.0 4.0 Quinuclidine 48 19 82 nd 'Hydrogenation step used I eq HCl 2 P40lo and HCN and quinuclidine at 0°C initially

Table XI. Hydrogenation of HCN, P401o and quinuclidine reaction mixtures at 1000 psi with 5% Rh/C catalyst according to conditions of hydrolysis. Reaction & Temp. Time, h Hydrolysis % Yield AMPA % Yield Hydrolysis Condition HPLC NMR Phosphate HPLC NMR lA'RT 20+1 wk pH= 1. 7 27.7 4.7 as HPLC sample IB 138° 2 pH= 1. 7 79.3 (avg. of 3) 82 21.5 18 2A2 RT pH= 5. 6 21.7 33 0 0 2B 134 2 pH = 5. 6 59.4 58 16.0 16 2C 134 5 pH = 5. 6 70.5 68 18.0 17 (avg. of 2) 2D 134 8 pH = 5. 6 74.1 70 18.3 17 2E 100 16 pH = 5. 6 71.7 73 17 18 2F 130 2 pH = 11. 8 75. 5 71 8. 5 9 2G 130 39 pH= 11. 8 80.0 78 14.1 13 2H 130 3 pH= 1. 5 80.7 80 19.4 20 (avg. of 2) Runs beginning with number"I"are from HCN/P40, o reaction of Run 2 in Table X 2 Runs beginning with number"2"are from HCN/P40, o reaction of Run 1 in Table X Example 11. Conversion of Phosphoric Anhydride to AMPA Phosphoric anhydride was treated with potassium cyanide and amine following the procedure No. 6 using about 1.25 mmol of phosphoric anhydride. At the end of this reaction, the solvent was removed under reduced pressure. For the 1 h hydrolyses, the resulting powder was added to water (100 mL) in an autoclave containing hydrogen chloride-dioxane (10 mmol) and 5% Rh/C (122 to 139 milligrams), and was hydrogenated at about 1000 psi overnight at room temperature following the procedure No. 8. For the 2 and 3 day hydrolyses, hydrolysis took place at room temperature, then, the hydrolysis mixture was kept at the indicated temperature for the rest of the hydrolysis time. The hydrogenation was then performed as for the short hydrolysis time experiments. After the pressure was released and the system purged with

nitrogen, the reaction mixture was filtered, and the amount of AMPA was determined by HPLC.

The reaction mixtures were then heated to the temperature specified below for the period of time indicated, and the amount of AMPA was determined. In the following Table IX, the hydrolysis time refers to the duration of the hydrolysis prior to the start of the hydrogenation; n. d. indicates that a yield was not determined.

Table XII. Reaction Conditions and Yield for Conversion of P401o to AMPA P4Ol o Amine Hydrolysis Yield Yield AMPA AMPA Temp Time Expt. Time 03PCN Cyanopoly-Yield, Yield, °C phosphates no with heating heating NEt3 3 days, rt 30% 17% 33% 38% 85 4 h 46% 85 1 day 2 t-BuPyr 1 h, rt 10% 61% 32% 56% 85 1 day 2 days, rt, 38% 29% 44% 57% 85 1 day then 4°C 3 t-BuPyr Ih, rt n. d. n. d. 21% 66% 118 2 h 73% 118 4. 5 h While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations can be applied to the process described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention.