AP163A

AP163A - Process for purifying aminomethylenephosphonic acids.

Info

Publication number: AP163A
Application number: APAP/P/1990/000202A
Authority: AP
Inventors: Joseph R Garlich; Jaime Simon; Tipton T Masterson
Original assignee: Dow Chemical Co
Priority date: 1989-08-04
Filing date: 1990-08-03
Publication date: 1992-01-11
Also published as: KR0178779B1; AP9000202A0; NZ247888A; IL110861A0; FI105033B; DK0411941T3; IE902812A1; GR3020932T3; DE69027818D1; CN1049351A; EP0411941B1; IL95094A0; CZ290556B6; LV10718B; AU6023790A; SA90110175B1; BR9003694A; NO178196B; RO105967B1; IL95094A

Abstract

High purity ethylenediaminetetra (methylenephosphonic acid) and

Description

PROCESS FOR PURIFYING AMINOMETHYLENEPHOSPHONIC ACIDS

Many organic aminopnosphonic acids and their salts are well known compounds, especially for their use in chelating metal ions. Some of these organic aminophosphonic acids and their salts are used as threshold inhibitors. U. S. Patent 2,599,807 discloses some of these compounds and describes methods for their preparation. An example of the preparation given in this patent discloses heating an aqueous solution of ethyienediamine and then adding to it a solution of the sodium salt of chloromethylenephosphonic acid and an θ excess of a base. e.g. Ua2CO3, to maintain a pH of from 10 to 11.5. After adding at least a stoichiometric amount of the ohosphonating reagent, i.e. sufficient to form the completely phosphorated amine salt [i.e.. the sodium salt of ethylenediaminetetra(methylenephosphonic acid), (known as NaEDTMP)], the solution is refluxed at its boiling point for from one to five hours. The solution is then cooled and neutralized to a pH of from 5 to 7 and evaporated to dryness to recover the desired ethyienediaminetetra(methylenephosphonic acid), 'known as ΞΟΤΜΡ).

Another process which makes the symmetrical ethyienediaminedi th_z lenephosphonic acid) in good yield involves treating an aqueous solution of two molar

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-2portions of aminomethylenephosphonic acid with one molar portion of an alkylene dihalide at an elevated temperature for a time sufficient to insure complete reaction. This reaction can be accomplished in a few hours under reflux in 50 percent ethanol.

In another patent, U. S. Patent 3.738,987, the reaction to form the aminophosphonic acid is begun by introducing PCI3 into water to form phosphorous acid and ‘0 hydrochloric acid (HC1). The polyamine is then introduced intS this acid solution. It is preferred to have a 5 to 10 percent excess of the PCI3. When the amine is added, the reaction medium is at a temperature of about 38 to 50°C. When all the amine has been added, c

the temperature is raised to about 93 to 104’C and an aqueous solution of formaldehyde is sparged into the reaction mixture, during which time the temperature is maintained at that level and for several hours ₂Q thereafter and finally cooled.

In a more recent published patent, Japanese No. 55-150501, it is disclosed that much higher yields of the desired product are obtained by adding the amine to a mixture of phosphorous and hydrochloric acids in which the H3PO3 is in excess with respect to the amine, preferably from about 4.3 to 5.5 moles of the acid per mole of amine. Concentrated HC1 is used, preferably about 2.2 moles HC1 per mole of amine. Too much acid will tend to increase the amount of water in the system, which is undesirable. No additional water is added to the reaction mixture, which is apparently the reason for the improved yields, since all the other processes use water and dilute acids.

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It has recently been discovered that certain of the methyle.nephosphonated amines are useful for imaging and other Radiopharmaceutical uses when complexed as chelates with radioactive metals. Use of the compounds for such purposes requires the highest purity materials.

It has now been found that, even when using the preferred processes of the known art. impurities are formed, e.g. the N-methylated species in which an amine hydrogen is replaced by a methyl group rather than by the methylenephosphonic acid moiety.

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While a process to obtain high purity amincphosphcr.ic acids is known, a process to make an even higher puriay of suc.o products is the sue;ec t cf this invention. The present process involves certain procedures for r«crystallization to oocain the desired high purity produces.

curor:sin co a ervstciiization crccess has now

Peer, found which produces certain very high purity (99* bad original

35,080-r percent) aminomethylenephosphonic acids, e.g.

ethylenediaminetetra(methylenephospnonic acid), [known as cDTMP],. and 1, 4 ,7 , 10-tetraazacyclododecane-1,4,7,10t tetra(methylenephospnonic acid), [known as DOTMP]. FDTMP and DOTMP may each be complexed to various metals to form pharmaceutical products (see, for example, U.S. Patents 4,898,724 and 4,882,142, respectively). Other aminophospnonic acids are not easily purified in this manner because of their greater solubility in water at low pH valued. For example, diethylenetriaminepenta(methyle.nephospnonic acid) [known as DTPMP] and r.i tr ilotri (methylenepnospnonic acid) [known as NTMP] cannot be purified by the present process.

The present process of recrystallizaticr. is icccmplished by the steps of:

(a) dissolving the aminophospnonic acid in an

G U U C W «Ρ W C. .b C 9 (b) adding the solution from step (a) to an acid solution optionally maintained at an elevated temperature to reprecipitate the aminophosphonic acid;

(c) optionally heating the solution for a period of time sufficient to assure that precipitation cf the aminophospnonic acid has begun:

(d) filtering the aminophospnonic acid crystals; and (e) washing the crystals with wacer.

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-0The first step (a) dissolves the aminophosphonic acid in an aqueous base, preferably ammonium hydroxide, which is followed by acidifying the solution with an acid, preferably a mineral acid, to a pH within the range of from 0 to 4 (step b). The acidic solution is then refluxed, preferably at a temperature of from 35 to 1Q5°C, more preferably from 70 to 105°C, for a period of time, preferably of from 0.5 to 3 hours, more preferably from 0.5 to 1 hour (step c). The solution can then optionally be cooled, preferably of from about ambient temperature to about 95°C, more preferably from 25 to 45°C, and allowed to remain at that temperature for a period of time to permit precipitation, preferably of .- from l to 24 hours, more preferably from 12 to 24 hours. The precipitated, i.e. recrystallized, aminophosphonic acid is then filtered at the lower temperature to obtain the desired purified crystals (step di wnich are then washed thoroughly with water to remove any solution which might contain undesired impurities (step e). The process is repeated one or more times, if the desired purity has not been attained. A product containing 0.1 percent or less impurities can be obtained by the above process.

Of course, the number of times the recrystaliization process of this invention is repeated will depend on the purity desired in the final product and also on the purity of the starting aminomethyieneohcs- 0 pnonic acid.

it has now been determined that, in the case of

Ξ0ΤΜΡ. if the reaction medium is filtered prior to substantial cooling, the resulting E0^TMP product has a • 5 * higher purity than if the reaction medium is cooled

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AP 0 0 0 1 6 3 before filtering. Best results are obtained if the filtration is done while the reaction medium is at reflux temperature. It is believed that this is because the impurities are more soluble in the hot solution.

The following example illustrates the method of preparation which results in the purest EDTMP product. Additional examples below show the recrystallization process to provide the products which can be used for pharmaceutical purposes.

Exampie 1. Preferred Preparation of EDTMP

A 5-L 3-neck flask equipped with a mechanical stirrer fitted with a Teflon paddle was charged with phosphorous acid (755 g) to which was added concentrated (cone.) HC1 (1.2 L). After vigorous stirring, the phosphorous acid dissolved, causing the solution temperature to drop to 0°C. To this cold solution was added ethylenediaminedihydrochloride (271 g) and heat was applied with vigorous stirring. At about 60°C, a Large volume of HC1 gas was given off, which was conveniently recovered with a water gas trap. At about 38°C ail· the ethylenediaminedihydrochloride was dissolved and heating was continued to 100°C (reflux). Once the reaction had reached IQO’C, a 37% aqueous solution of formaldehyde (902 mL) was added dropwise via a peristaltic pump over a 22-24 hour period (rate was 3.65 mL/min). After an additional four hour reflux time, the boiling suspension was vacuum filtered (1.5 L s intered glass filter) and washed with two 300 mL portions of water. This solid was air dried and 607 g (70¾ yield) of EDTMP, m.p. 216-217 decomposition (d)

'.lit. m.p. 214 d) is recovered. H-ι and ?-31*NMR

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I '5 analyses of this sample indicated the impurities were at a Level of Less than 1J.

Example 2. Purification of EDTMP

A quantity of 1050 g of the EDTMP prepared by the procedure of Example 1 was added to 1050 mL water in a 2-L round-bottomed flask and stirred with a mechanical stirrer fitted with a Teflon' paddle. Concentrated NH4OH (325 mL) was added in 25-mL increments over a one hour period, /kfter all the NH4OH was added, almost all the EDTMP had gone into solution. The small amount that was not soluble was removed by vacuum filtration. The clear filtrate was then poured with stirring into 2100 mL of refluxing 3M hydrochloric acid in a 5-L roundbottomed flask equipped with a heating mantle and thermometer (set at 100°C). The resulting stirred solution was clear and the temperature had dropped to 68°C. Stirring was continued and after six minutes the temperature had risen to 72°C and a slight precipitate was visible. Within 16 minutes, with continued stirring, the temperature was 87°C and the precipitate was heavy. After 20 minutes, the temperature was again at reflux (1Q0^JC). After 30 minutes at reflux temperature, the thermometer setting was lowered to 43°C. After stirring for 21 hours at 43°c, the suspension was vacuum filtered through a sintered glass funnel while still warm. Water (500 mL) was used to transfer the heavy solid from the flasx to the filter funnel. The filter cake thus obtained was washed with three 500-mL portions of water and air dried overnight to give 984.3 g of EDTMP, m.p. 214-215°C. A P-3¹ NMR spectrum of this samDle indicated about 0.6* impurity. The EDTMP used as starting material had impurity levels of about 1£.

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3b

-8Zxample 3» Purification of EDTMP in

A sample of EDTMP prepared in Example 2 (970 g,

0.6% impurity) was dissolved in 970 mL of water in a 2-L round-bottomed flask by the addition of 323 mL of concentrated NH4OH in 25-mL portions. After all solids ^Gwere dissolved, the solution was poured with stirring into ’9^u0 mL of refluxing 3N aqueous HC1. The temperature dropped to 74°C and after seven minutes, had risen to 32°C with a faint precipitate visible. After 30 minutes, more precipitate had formed and the temperature had reacned 100°C. The suspension was left '5 at reflux for an additional hour after which the temperature was lowered to 43°C and stirred for an additional 13 hours. At the end of this time, the suspension was vacuum filtered using 450 mL of water to transfer, washed with three 400-mL portions of water and ²⁰ air dried to give 920.4 g of EDTMP, m.p. 214-215°C. A P-31 MMR spectrum of this sample indicated about 0.4% impurity level.

The following Examples illustrate the purification of EDTMP from different sources.

Example -. Purification of EDTMP

The product of Example 3 (0.4% impurity, 900 g) 30 was dissolved in 900 mL of water in a 2-L round-bottomed flasx by the addition of 300 mL cone. NH4OH over a 20mi nute period. The solution was poured with stirring into ‘300 mL of refluxing 3N aqueous HC1. The temperature of the resulting solution rironnpd -o 72°C and after five minutes of stirring wit?» ί;=αι it had risen to 78°C with some precipitate present. Within 30 minutes the d5,C8O-F

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-9temperature was back to lOO'O and was left there for one hour after which the temperature was lowered to 43°C. After stirring overnight (17.5 hours) at 43°C, the heavy precipitate was vacuum filtered using 400 mL of water to transfer, washed with three 400-tnL portions of water and air dried to give 805.62 g of EDTMP, m.p. 215-217°C. A high field P-31 NMR spectrum indicated an impurity level of around 0.15 for this sample of EDTMP.

‘0 Example 5. Purification oi' EDTMP

A sample (50 g, 115 mmoles) of EDTMP containing 5.315 impurities 'ey ?-*' NMR was dissolved in 50 mL of water by the addition of 13-5 mL (193 mmoles) cone.

’5 NH4OH in small portions over a period of 15 minutes.

This solution of the ammonium salt of EDTMP was then poured with stirring into 100 mL (300 mmoles) of refluxing 3N HCl. The temperature, which dropped ’o 73°C, was brought back to reflux (100°C) with application of additional heat and vigorous stirring. The EDTMP began precipitating from solution almost immediately and continued to precipitate with continued stirring and heating. The solution was maintained at reflux for one hour after which the temperature was lowered to 43°C and the suspension allowed to stir for 21 hours, after wnicn the heavy white precipitate was vacuum filtered at that temperature, using 25 mL of water to transfer and three additional 25 ML corticns of water to wash the precipi30 tate. The precipitate was air dried to give 44.2 g (101 mmoles, 395 yield) of EDTMP. Analysis of this precipitate oy P-31 'IMP, indicated the impurity level had drooped to 2.335.

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-9-’0Examole 5. Purification of EDTMP

A sample (50 g, 115 mmoles) of EDTMP containing ³ 5.81% impurities by P-31 NMR was dissolved in 50 mL of water by the addition of 13 mL (186 mmoles) cone. NH4OH in small portions over a period of 15 minutes. This solution of the ammonium salt of EDTMP was then poured •₀ with stirring into 100 mL (300 mmoles) of refluxing 3N HC1. The temperature, which dropped to 72°C, was brought back to reflux (100°C) with application of additional heat and vigorous stirring. The EDTMP began precipitating from solution almost immediately, and continued to precipitate with continued stirring and heating. The solution was maintained at reflux with stirring for 22 hours, after which the heavy white precipitate was vacuum filtered at that temperature, using 25 mL of water to transfer and three additional 25 mL portions of water to wash the precipitate. The precipitate was air dried to give 34.3 g (79 mmoles, 69% yield) of EDTMP. Analysis of this precipitate by P-31 NMR indicated the impurity level had dropped to 1.45%.

Example . Purification of EDTMP

A sample (50 g, 115 mmoles) of EDTMP containing 5.81% impurities by P-31 NMR was dissolved in 50mL of water by the addition of '· 3 mL ( 136 mmoles) cone. NH4OH « Q in small portions over a period of 15 minutes. This solution of the ammonium salt of EDTMP was then poured with stirring into 100 mL (300 mmoles) of refluxing 3N HC1. The temperature, which dropped to 72°C, was

-),-. brought back co reflux (lOG’C) with application of.

additional heat and vigorous stirring. The EDTMP began bad ORIGIN^

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-10-ι 1precipi.tati.ng from solution almost immediately, and continued to precipitate with continued stirring and heating. The solution was maintained at reflux for one hour, after which the temperature was lowered to 70°C and the suspension allowed to stir for 21 hours, after which the heavy white precipitate was vacuum filtered at that temperature, using 25 mL of water to transfer and three additional 25 mL portions of water to wash the precipitate. The precipitate was air dried to give 41.4

9 g (95 mmole, 83* yield) of EDTMP. Analysis of this precipitate by P-31 NMR indicated the impurity level had dropped to 2.05$.

Example 3. Purification of EDTMP

A sample (50 g, 115 mmoles) of EDTMP containing

5-3136 impurities by P-31 NMR was dissolved in 50 mL of water by the addition of 13 mL (186 mmoles) cone. NH4OH in small portions over a period of 15 minutes. This solution of the ammonium salt of EDTMP was then poured with stirring into 100 mL (300 mmoles) of refluxing 3N HC1. The temperature, which dropped to 72°C, was brought back to reflux (100°C) with application of additional heat and vigorous stirring. The EDTMP began precipitating from solution almost immediately and continued to precipitate with continued stirring and heating. The solution was maintained at reflux for one hour after which the heat source was removed and the suspension allowed to stir at room temperature for 2¹ hours after which the heavy white precipitate was vacuum filtered at that temperature, using 25 mu of water to transfer ar.d three additional 25 mL portions of water to wash the precioitate. The precipitate was air dried to give 41.2 g (94 mmole, 32$ yield) of EDTMP. Analysis’of

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-12this precipitate by P-31 NMR indicated the impurity Level had dropped to 2.11%.

Example 9. Purification of EDTMP

A sample (50 g, 115 mmole) of EDTMP (DEQUEST'* 2041, a commercial sample from the Monsanto Company for a series of aminophosphonic acid chelating agents) containing 3-65% impurities by P-31 NMR was dissolved in 50 mL of water by the addition of 16 mL (229 mmoles) cone. NH4OH ini small portions over a period of 15 minutes. This solution of the ammonium salt of EDTMP was then poured with stirring into 100 mL (300 mmoles) of refluxing jN HC1. The temperature, which dropped to 72°C, was brought back to reflux (100°C) with application of additional heat and vigorous stirring. The EDTMP began precipitating from solution almost immediately and continued to precipitate with continued stirring and heating. The solution was maintained at reflux for one hour after which the temperature was lowered to 43°C and the suspension allowed to stir for 21 hours after which the heavy white precipitate was vacuum filtered at that temperature, using 25 mL of water to transfer*^- and three additional 25 ML portions of water to wash the precipitate. The precipitate was air dried to give 44.3 g (102 mmoie, 39% yield) of EDTMP. Analysis of this precipitate cy P-31 NMR indicated the impurity level· had dropped to ’.35%.

Example Ό. Purification of EDTMP

A sample (50 g, 115 mmoles) of EDTMP containing 5.31% impurities by P-31 NMR was dissolved in 50 mL of water by the addition of '5 mL (</9 mmoles) cone. NHuCiH in small portions over a period of 15 minutes. This

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-12-17solution of the ammonium salt of EDTMP was then poured with stirring into 100 mL (300 mmoles) of refluxing 3N HC1. The temperature, which dropped to 72°C, was allowed to cool to 43°c with continued vigorous stirring. The EDTMP began precipitating from solution almost immediately and continued to precipitate while the suspension was allowed to stir for 21 hours at 43°C. The heavy white precipitate was then vacuum filtered at that temperature, using 25 mL of water to transfer and θ three additional 25 mL portions of water to wash the precipitate. The precipitate was air dried to give 42.7 g (98 mmole, 35% yield) of EDTMP. Analysis of this precipitate by P-31 NMR indicated the impurity level had dropped to 2.95J.

Examples A and 3 following are comparative.

Examnle A. Comparative of DTPMP

A 5 g (8.73 mmoles) sample of diethylenetriaminepenta(methylenephosphonic acid), DTPMP, was dissolved in 4 mL of water by the addition of 1.526 mL (21.82 mmoles) cone. NH4OH in small portions over a period cf '5 minutes. This solution of the ammonium salt of DTPMP was then poured with stirring into 9.'5 mL (27.45 mmoles) of refluxing 3N HC1. The temperature, which dropped to 75’C, was orougrtt back to reflux (100°C5 with application of additional heat and vigorous

-θ stirring. The solution was maintained at reflux for one hour after wnich the temperature was lowered to 43°C and the suspension allowed to stir for 91 hours. Even at the end of this lengthy period of stirring, no precipitate had formed. The solution was allowed to remain at room temperature without stirring for an

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35,O8O-F-13- -,4additional 3 days with periodic observation. No precipitate had formed at the end of this time.

Example B. Comparative of NTMP ⁵ A sample of nitrilotri(methylenephosphonic acid), NTMP, (3 g, 10 mmoles) was dissolved in 4.32 mL of water by the addition of 1.049 mL (15.0 mmoles) cone. NH4OH in small portions over a period of 15 minutes.

.g This solution of the ammonium salt of NTMP was then poured with starring into 6.3 mL (18.9 mmoles) of refluxing 3N HCl. The temperature, which dropped to 33°C, was brought back to reflux (100°C) with application of additional heat and vigorous stirring. The solution '5 was maintained at reflux for one hour after which the temperature was lowered to 43°C and allowed to stir at that temperature for 89 hours. Even at the end of this lengthy period of stirring, no precipitate had formed. The solution was allowed to remain at room temperature ²⁰ without stirring for an additional 8 days with periodic observation. No precipitate had formed at the end of this time.

Example '1. Preparation of DOTMP

Into a '00 mL. shree-necked, round-bottomed flask, equipped with a thermometer, reflux condenser and heating mantle, was placed 3-48 g (20.2 mmoles) of '.4.7,10-tetraazacyclododecane (a commercial product obtained from Parish Chemical Company, Crem. Utah) and '4 mL water. To this solution was added 17.2 mL of cone. HCl and 7.2 g of H3PO3 (87.7 mmoles) and the solution was heated to iO5°C. The refluxing solution was stirred vigorously while 13 g (160.2 mmoles) of formaldehyde (37* aa. soln.) was added over a period of

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-15one hour. The refluxing solution was stirred an additional two hours. The heat was then removed and the solution allowed to cool to room temperature and stand for 62.5 hours. The reaction solution was concentrated by heating at 40°C in uacuo to a reddish brown semi-solid. A 30-mL portion of water was added which produced a suspension. This suspension was then poured into 400 mL of acetone with vigorous stirring. The resulting offwhite precipitate was vacuum filtered and dried over⁰ night to give 10.69 g (97ί yield) of DOTMP.

Example 12. Purification of DOTMP

A 2.0 g ( 3*65 mmoles) sample ox¹ DOTMP from ’5 Example 11 was dissolved in 2 mL of water by the addition of 700 pL cone. NH4OH in 100 pL portions to give a solution having a pH of 2-3· This solution was then added all at once to 4.5 mL of 3N HC1 (¹3.5 mmoles), mixed well, and allowed to stand. Within one ²⁰ hour, small nearly square crystals had begun to form on the sides of the glass below the surface of the liquid. The crystal growth was allowed to continue and the crystals were gently bumped off the vessel walls, filtered, washed with four 3—fnL portions of water and air dried to constant weight to give 1.19 g (60t yield) of white crystalline solid m.p. 270 (d)°C.

The DOTMP signal in the decoupled P-31 NMR spectrum of the starting material represented 78.1’ of the total phosphorous signals present while that of the product obtained after the base/acid recrystallization, represented 94.7* of the total phosphorous present.

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-15-16Example 13. Preparation of DOTMP

Into a 250-mL three-necked, round-bottomed flask, fitted with a thermometer, temperature control- ler, addition funnel and stirring bar and attached to a reflux condenser was placed 6.96 g (0.04 mole) 1,4,7,10tetraazacyclododecane (a commercial product obtained from Parish Chemical Company, Orem, Utah). To this was added 14.5 g (1.77 moles) phosphorous acid, 30 mL deion10 ized water and 28 mL (0.336 mole) cone. HC1. After the solution had b*een brought to reflux temperature (105°C), aqueous (37%) formaldehyde (26.0 g, 0.32 mole) was introduced into the flask through the addition funnel during a 30 to 40-minute period. The solution was heated and stirred for three more hours at reflux and then permitted to cool to ambient temperature.

The reaction solution was then transferred to a 500 mL round bottomed flask an attached to a rotoevaporator apparatus. The solution was evaporated to an amber, viscous semi-solid, the temperature never exceeding 40°C in the heating bath. To the viscous material was added about 300 mL HPLC grade acetone, producing a light brown, sticky, viscous oil which was then dissolved in 22 mL of water and added slowly with vigorous stirring to 1 L of acetone. The acetone was decanted and the light colored oil dried under vacuum to give '6.6 g (76% yield) of crude DOTMP. A portion (13.1 g) of the crude DOTMP was dissolved in 39-3 g deionized water, treated with a seed crystal and allowed to stand overnight. The resulting precipitate was vacuum filtered, washed with cold water and dried under vacuum to give 4.75 g (36% yield) of DOTMP.

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-16-17Example 14. Purification of DOTMP id

A quantity (3.0 g, 5.47 mraoies) of the DOTMP prepared in Example 13 was recrystaiiized by dissolving it in 3 mL of water by the addition of 2.2 mL (31.5 mmoles) of cone. NH4OH. This solution was added with stirring to 2.4 mL (28.8 mmoles) of cone. HC1 at which time a white solid precipitated. This precipitate was vacuum filtered and dried to give 2.42 g (815 yield) of DOTMP, m.p. 280 (d)^cC.

The DOTMP signal in the decoupled P-31 NMR spectrum of the starting material represented 97.25 of the total phosphorous signals present. The DOTMP signal in the decoupled 31-P NMR spectrum of the product after the Pase/acid recrystallization, represented 98.25 of the total phosphorous signals present.

Example 15. Preparation of DOTMP

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Into a 250-mL beaker containing 85.77 g (.871 mole) cone. HC1 was added (57.11 g, 0.696 mole) solid phosphorous acid and dissolved with stirring. A 250 mL three-necKed. round-bottomed flask was loaded with '.4,7,10-tetraazacyclododecane (10.00 g, 0.58 mole) and attached to a reflux condenser. This apparatus was placed on a heater/stirrer and fitted with a thermometer which controlled an infra-red lamp through a temperature controller. The acid solution was carefully added to the reaction flask containing ',4,7,1O-tetraazacyclododecane.

The reaction mix. which had become a white slurry, was hrnijght 'ό reflux temperature (about 105°C). Aqueous 375 foiuiaxueuyde solution (94.12 g, 1.16 moles) was added all at once to the reaction mix. The slurry

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-17-18iaunediately turned to a clear solution. The reaction was continued at reflux with constant stirring for approximately five hours. The reaction solution was cooled and 188 mL transferred to a one liter Erlenmeyer flask and diluted with 470 mL of 0.1M hydrochloric acid solution (1 to 3.5 dilution). The solution was seeded with a few grains of DOTMP and placed in the refrigera-* tor overnight. The resulting white solid precipitate (1.35 g) was collected 17 hours later by filtration on a medium glass fritted funnel. The filtrate was transferred from the filter flask back into the one liter Erlenmeyer, seeded again with a few grains of DOTMP, and placed in the refrigerator overnight. The next day the ₁₅ white precipitate was filtered (2.70 g) and the filtrate concentrated under vacuum to 80 mL. This filtrate was then diluted with 200 mL of water, seeded as above and allowed to stand in a refrigerator for i2 hours, after which the white solid was filtered and dried to give

3.85 g (28% yield) of DOTMP.

Example '6. Purification of DOTMP

In the reactor of Example 15 a 50 mL threenecked flask was loaded with 15.6 mL οί' 3N HC1 solution i5 (46.3 mmoles) and placed on a heater/stirrer. This solution was taken up to reflux temperature (about ’03°C). A separate solution was made by placing DOTMP (3.00 g, 4.6 mmoles), prepared in Example 15, into a 50 mL beaker and dissolving it by adding 3.00 g HPLC grade water and (2.52 mL, 36.0 mmoles) of concentrated (’4.3M) ammonium hydroxide.

The DOTMP/NH-j solution was added all at once with constant stirring to the re^f1”^v’ⁿ3 3N HC1 solu- * tion. The temperature dropped to about 75°C and was

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-· 9quickly brought back to reflux and maintained there for about one hour. The temperature was lowered to 43°c and maintained there for a period of 21 hours. Thi3 slurry was then filtered through a glass medium filter funnel, transferring it with about 4 raL water and washing the filter cake additionally with about 4 mL of water. The filter cake was air dried to give 6.79 g (85% yield) of a fine, white solid. Analysis showed that the coproducts were reduced from 6.85% in the original DOTMP ' Q sample of example 15 to 3.11% in this sample.

example 17. Purification of DOTMP

Into a 50-mL three-necked flask, fitted with a thermometer and water jacketed condenser, was introduced a 3N HCl solution (13.25 mL, 39.76 mmoles). This apparatus was placed on a heater/stirrer and heated to reflux.

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A separate solution of DOTMP was prepared by adding the DOTMP (6 .79 g, 12.38 mmoles), prepared in example 12, to a 50 mL beaker and dissolving it by adding 6.8 g of water and 2.14 mL (30.59 mmoles) of concentrated ammonium hydroxide. This solution was

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filtered through a paper filter to remove trace solids; then added ail at once to the refluxing hydrocnloric acid solution prepared above. The resulting white suspension was heated for one hour at reflux and then

-θ the temperature was lowered to 43°C. After allowing the suspension to stir at this temperature for a total of about 21 hours the white solid was filtered through a fine glass fritted funnel, washed with about 3 mL of deionized water, then allowed to air dry. A total of

5.14 g*(90% yield) of DOTMP was thus recovered as a* fir?

white solid. Analysis by P-31 NMR showed an increase in

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-20purity from 96.89% for the DOTMP used as starting material to 98.37% for the DOTMP product recovered.

Example *8. Purification of DOTMP

A 50 mL three-necked, round bottomed flask was loaded with 12.0 g (36.0 mmoles) of 3N hydrochloric acid solution. A stir bar was added and the HC1 solution was brought up to reflux temperature with constant stirring.

⁰ A 50 mL beaker was loaded with 6.14 g (11.2 mmoles) of DOTMP prepared in Example 17. An equal weight of deionized water was added (341.1 mmoles) and the DOTMP was brought into solution through the addition of 1.94 mL (27.7 mmoles) of concentrated ammonium hydroxide. This solution was filtered through a paper filter to remove undissolved solids, then added all at once with vigorous stirring to the refluxing hydrochloric acid solution. A white precipitate formed immediately from the addition of the two water-clear solutions. The suspension was heated to reflux and allowed to stir for about one (1) hour at this temperature. The temperature of the flask was then lowered to acout 43^0 and allowed to stir at this temperature for a total· of about 21 hours.

The white solid was filtered at this temperature, washed with 3 mL of water and air dried to give 5.90 g (37* yield) of purified DOTMP. Analysis by

-θ P-3¹ NMR indicated greater that 99% purity of DOTMP had been acnieved.

Example Purification of DOTMP

The '.75 g sample and the 2.7 sample of DOTMP prepared in Example 15 were combined and ground to a

35,O8O-F

-20B AD ORIGINAL

I

-21flne powder. A P-31 NMR analysis of this sample indicated 6.40$ non-DOTMP phosphorous-containing byproducts were present. A 1.00 g (1.32 mmoles) sample of this DOTMP was added to a 3-dram vial along with a 1.00 g portion of water and a stir bar. This slurry was stirred while adding concentrated ammonium hydroxide (315 pL, 4.5 mmoles) in small portions (42 pL) until completely dissolved.

A 4-dram vial was loaded with 1.95 mL of 3N HC1 solution (5.85 mmoles) and equipped with a stirring bar and reflex condenser. This solution was brought to reflux temperature using a mineral oil bath. The DOTMP solution from above was added to the refluxing HC1 solution with stirring dropping the temperature to 75°C.

This solution was again brought to reflux and held for one hour with constant stirring. The temperature wa3 then lowered to 43°C and held there with constant

2Q stirring for a total of 21 hours. The white precipitate was then filtered and washed with 4 portions of 0.5 mL of cold water. The 0.72 g (72$ yield) of DOTMP thus purified showed only 2.28$ phosphorous containing byproducts when analyzed by P-31 NMR.

Example 20. Purification of DOTMP

The recrystallization of Example 19 was repeated except that after the one hour reflux period the solid was filtered while hot, washed with hot water, and dried to give 0.34 g (34$ yield) of DOTMP. This material was analyzed by P-31 NMR and found to contain only 1.TJ$ phosphorous containing by-products as compared to 6.40$ present in the starting DOTMP.

__ >

bad ORIGINAL

35,080-?

-21-22Example C. Comparative for EDTMP

In the apparatus of Example 13 was placed 7.51g (0.125 mole) ethylenediamine, 47.3g (0.5 mole) phos- phorous acid, 59 mL cone. HC1 (0.737 mole) and 80 mL water. The solution was heated to reflux with stirring and treated with 16.6g (0.5 mole) paraformaldehyde, added in small portions over a one hour period. The solution was then refluxed an additional 2.5 hours and '0 allowed to cool to room temperature overnight. The resulting whit*e solid EDTMP was then vacuum filtered and washed with two 50-mL portions of water. This procedure gave 32.27g (60% yield) EDTMP. Analysis of this sample by P-31 NMR indicated a 6.4% level of by-products ³ present.

Example 21.

The procedure of Comparative Example C above was repeated using half the above amounts. After all the paraformaldehyde had been added, a portion of the reaction solution was maintained at 9O-97°C overnight after which a voluminous white precipitate had appeared. The suspension was filtered while still hot and washed with two 40-mL portions of hot 3N HC1. The solid thus isolated was air-driea to give 5.25 g EDTMP, containing only 1.4% by-product level.

Claims

1 . A process for purifying ethyler.ediamir.etstraiaethylenephcsphonic acid) or 1,4.7,IC-tetraazacyciododecane-1.4,7,10-terra(methylenephosphoric acid) which comorises the steos of:

(a) dissolving the aqueous base:

(b) adding the sol'.

aincpnosphonic aci ion from step (a)

APO 0016 3 acid solution optionally maintained at an elevated temperature to reorecipitats the aaincphosphcric acic:

(c) optionally heating the solution for a period of time sufficient to assure that precipitation cf the aaincphosphonic acid has oegun:

id) filtering the aainoohcsoncnic acid crystals: and (e) washinz the crystals w

CcO- =

-2in

2. The process of Claim 1 wherein the aqueous case in step (a) is ammonium hydroxide.

3. The process of Claim 1 or 2 wherein the acid solution in step (b) is a solution of a mineral acid .

4. The process of Claim 3 wherein the mineral acid is hydrochloric acid.

5. The process of Claim 4 wherein the pH is from 0 to 4.

δ. The process of Claim 1 wherein the period of time for heating in step (c) is from 0.5 to 3 hours. 1 5

7. The process of Claim 6 wherein the heating period is from 0.5 to 1 hour.

3. The process of Claim 1 wherein the

20 temperature of step (c) is from 35 to 105°C.

9. The process cf Claim 3 wherein the temperature is from 70 to 1O5°C.

29 t OOOdV

Ό. The process of Claim 1 wherein steps (a) through (e), inclusive, are repeated at least once.

1'. A process of Claim including the step of cooling the solution after step (c), and before the filtration step, and allowing it to remain cooled for a period of time sufficient to assure precipitaticn cf the amir.ophosohcr.ic acid;

.n the range of from ambient temperature to ?5°C.

35.C8O-F bad original <* •3

13. The process of Claim 12 wherein the temperature is in the range of from 25 to 45°C.

14. The process of Claim 12 or 13 wherein the time period is from 1 to 24 hours.

15. The process of Claim 14 wherein the time period is from 12 to 24 hours.

10 16. jin the process for preparing ethylenediaminetetraimethylenephosphonic acid) which comprises reacting ethylenediamine, phosphorous acid, hydrochloric acid and formaldehyde or paraformaldehyde and heating the reaction medium to reflux temperature, the

15 improvement comprises filtering the product from the reaction medium prior to cooling.

17. The process of Claim 16 wherein the filteration is accomplished while the reaction medium is

20 at reflux temperature.

18. The process of Claim 16 wherein the ethylenediamine is in the form of the hydrochloride.