AU599950B2

AU599950B2 - Method of preparing 1-functionally-substituted-alkylidene-1, 1-diphosphonic acids and mixtures thereof

Info

Publication number: AU599950B2
Application number: AU67607/87A
Authority: AU
Inventors: Ivan Sergeevich Alferiev; Izrail Lvovich Kotlyarevsky; Aza Vasilievna Krasnukhina; Nikolai Vasilievich Mikhalin
Original assignee: INST KHIM KINETIKI I GORENIA S
Current assignee: INSTITUT KHIMICHESKOI KINETIKI I GORENIA SIBIRSKOGO OTDELENIA AKADEMII NAUK SSSR
Priority date: 1987-01-13
Filing date: 1987-01-15
Publication date: 1990-08-02
Anticipated expiration: 2007-01-15
Also published as: AU6760787A; BE1000075A4; DE8804948U1; DE3700772A1

Description

*I

5 9950 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 Form COMPLETE SPECIFICATION FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: This document contains the amendments made under Section 49 and is correct for printing.

Related Art: TO BE COMPLETED BY APPLICANT C C C c c v Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: INSTITUT KHIMICHESKOI KINETIKI I GORENIA SIBIRSKOGO OTDELENIA AKADEMII NAUK SSSR Ulitsa Institutskaya 3, Novosibirsk,

U.S.S.R.

Ivan Sergeevich Alferiev Nikolai Vasilievich Mikhalin Izrail Lvovich Kotlyarevsky and Aza Vasilievna Krasnukhina GRIFFITH HASSEL FRAZER 71 YORK STREET SYDNEY NSW 2000

AUSTRALIA

Complete Specification for the invention entitled: METHOD OF PREPARING 1-FUNCTIONALLY-SUBSTITUTED- ALKYLIDENE-1,1-DIPHOSPHONIC ACIDS AND MIXTURES THEREOF The following statement is a full description of this invention, including the best method of performing it known to me/us:- 2368A:rk T T x i i: 1 t -1A- The present invention relates to the chemistry of organophosphorus compounds with a C-P bond, particularly, to mthods of preparing 1-functionally-substituted-alkylidene-1,1-diphosphonic acids and their i-retu a' Said products find extensive application as complexforming agents for flotation dressing of non-suphide ores, e.g. such as cassiterite, anatite, phosphorite, fluorite, and others. Some of these' acids find application in the medicine.

There is a number of methods for preparing 1-functionally-substituted-alkylidene-1,1-diphosphonic acids, miAxtue-e9 and salts thereof by reacting carboxylic acids or their derivatives with compounds of trivalent phosphorus under dehydrating conditions (see FRG Patent No. 2943, 498).

Usually as inorganic compounds of trivalent phosphorus use is made of a mixture of phosphorous acid ard phosphorus trichloride; quite often phosphorous acid is obtained in the course of synthesis, a portion of phosphorus trichloride being hydrolyzed with a calculated amount of water.

A characteristic feature common to these methods is the necessity of using a carboxylic acid or its derivatives in a considerable excess. This is due to the C C.

CE~r r C Ct C C .I 9 a" :a j; ii r el. ~i~ii L 1 sm~ I r 2 fact that in the course of reaction under dehydrating conditions polycondensation products of polyphosphonic acids are formed, which are very viscous or solid compounds.To preclude thickening of the reaction mass because of formation of polycondensates, one has to use carboxylic acids or their derivatives in excessive amounts, this involving serious technological difficulties associated with the removal of said excessive amounts.

Attempts to use inert diluents for the same purpose prove to be either inefficient (for instance, in the case of hydrocarbons or chlorinated hydrocarbons which are poorly miscible with the polycondensation mass) or add Ji too much to the cost of the technological process, as in the case of sulphone, which is difficult to isolate from the reaction mixture and makes the isolation of the desired product more difficult. Moreover, under the reaction conditions sulphones become to a certain extent reduced to volatile organosulphur compounds (Ese D. Curry, D. et Nicholson, O.J. Quimbly, Topics in Phosphorus Chemistry, 1972, 7.75).

o One more method is known for preparing derivatives of 1-functionally-substituted-alkylidene-1,1-diphosphonic acids, namely, 1-hydroxyalkylidenediphosphonic acids.

The method resides in that a mixture of carboxylic acids Scomprising from 6 to 10 carbon atoms and used in twofold excess is mixed with compounds of phosphorus trichloride under dehydrating conditions. The resulting mixture is heated gradually for 4-5 hours to a temperature ;B I: r Ir -3on the order of 110-150°C.

Such long and gradual heating is dictated by an extreme temperature-sensitivity of the reaction. A more rapid heating leads to the reaction becoming uncontrollable, and this creates serious difficulties.

On completion of the heating the reaction mixture is kept at the above-stated temperature for a period of from 5 hours to 15 minutes.

As a result, polycondensates of 1-hydroxyalkylidene- Sdiphosphonic acids are formed. Then the resulting polycondensates are subjected to hydrolysis with excess water at a temperature of 80-110°C during 5-12 hours.

The hydrolysis gives 1-bydroxyalkylidene-1,1-diphpohonic acids, which are precipitated with the aid of sodium hydroxide in the form of disodium salts with a yield S of up to The method allows the desired reaction products to be isolated from excess carboxylic acids, but filtering and subsequent washing of the precipitated dioo sodium salts are quite difficult operations, requiring much time and considerable consumption of the solvent.

Furthermore, regeneration of excess carboxylic acids also involves technological difficulties (see UK Patent No. 1,469,894 of 1974).

1i i, >4 I- 1XII,~:_

II:

r h 1 t The invention provides such a method of preparing 1-functionally-substituted-alkylidene-1,1-diphosphonic acids and salts thereof,which would make it possible to simplify the process technology, to increase the process efficiency, and to obtain the desired products with a sufficiently high yield.

Thus a method of preparing 1-functionally-substitutedalkylidene-1,1-diphosphonic acids and salts thereof is provided, by reacting carboxylic acids or their derivatives with phosphorous acid under dehydrating conditions created by the addition of phosphorus trichloride in the presence of hydrochlorides of organic nitrogen bases to dilute the reaction mixtures.

**3 t 0 -4 t c S -4-

I

0329s/MS 1 l I t ta r uce C IC I rt 111 It IL 'I 11 I It DiI I I p.oano of hydroohI-or-ido of nitrogen basos.

As carboxylic acids one can use mono- and dicarboxylic aliphatic acids C -C20, as well as carboxylic acids with an amino acid or halide substituent in the hydrocarbon chain. As derivatives of carboxylic acids via the carboxylic group it is possible to use their chlorides, anhydrides, amides, and substituted amides. In some cases said derivatives of carboxylic acids via the carboxyl group are formed at the initial stage of the process, when the initial compounds are carboxylic acid and phosphorus trichloride.

As inorganic compounds of trivalent phosphorus is possible to use, for example, phosphorus trichloride, the latter being partically hydrolysed with water in a molar ratio of PC13:H20 equal to 1:1.55-2.21. It is possible to use phosphorous acid. Phosphorus acid may be introduced in combination with phosphorus trichloride. It may be not introduced at all, since this acid is formed during the reaction of phosphorus trichloride with water.

As stated above, the reaction of carboxylic acids or their derivatives via the carboxyl group is effected at a temperature of 20-1800C. The choice of the process temperature depends on the stability of the initial and final products of the reaction. Thus, in the case of unsubstituted carboxylic acids the reaction should preferably be carried out at higher temperatures, since the react.,n i time till be materially cut down and the process efficiency will be appreciably increased.

Bii ii:;

AU

7 NT 6 The use of hydrochlorides of nitrogen bases as diluents makes it possible to diminish the quantity of carboxylic acids or their derivatives and to utilize them in the reaction practically completely, bringing the yield of desired products, as calculated for the carboxylic acids, up to 100%. Furthermore, the use of said diluents makes the reaction less temperature-sensitive, the process thus becoming easily controllable.

Though said hydrochlorides of aitrogen bases are solid, and sometimes even very high-melting compounds, they not only efficiently dilute reaction mixtures, but provide a pocsibility for carrying out reactions at high temperatures (so that the reaction rates can be increased sharply) and with no excess of carboxylic acids or their derivatives via the carboxyl group.

For preparing salts of 1-functionally-substituted alkylidene-1,1-diphosphonic acids and their mixtures,to a hydrolysate containing the target product a caustic I F alkali is added to the pH of the medium of 9-12, a solution being thus formed, containing salts of 1-functionalc, ly-substituted-alkylidene-1,1-diphosphonic acids and ni- SCt trogen bases, the latter being then removed from the reaction mixture.

As to their purpose, particularly for flotation dressing of non-sulphide ores, the acids proposed herein ~and their .ixtures are equivalent to their salts, but it is reasonable to convert the acids and rmixtures thereof into salts, since then the product is easier to transl l i l l r r l .4 7 -7port.

As a caustic alkali it is recommendable to use potassium hydroxide or sodium hydroxide.

As hydrochlorides of nitrogen bases it is recommendable to use hydrochlorides of aliphatic-amines or hydrochlorides of heterocyclic nitrogen bases.

The herein-proposed method of preparing 1-functionally-substituted-alkylidene-1,1-diphosphonic acids and their mixtures allows an essential simplification of the process technology without requiring the use of carboxylic acids in excess and their subsequent isolation from the reaction products; the method also makes it possible to easily control the process (to run it at a higher temperature) and to raise the process efficiency due to the specific action of the hydrochlorides of nitrogen bases.

The realization of the present method ensures a sufficiently high yield of the desired product, that reaches 90-100%.

C' 'It The possibility of converting the target acids into salts, which are equivalent to the acids in application C r allows one to transport them to the user in steel tanks.

S *I The present method of preparing 1-functionally-sub- S stituted-alkylidene-1,1-diphosphonic acids and their mixtures is simple tecLnologically and is effected in the Sfollowing manner.

A carboxylic acid or its derivatives via the carboxyl group, water, hydrochloride of a nitrogen base,and sometimes, instead of water, also a certain quantity 1 C t

C

1~

C

Cs

C

r S ii' S I

C,

44 '1 4 I 4 4 I 1.040 4 4 41

S

III 4 4 4 0 -8 of phosphorous acid, are charged into an enamel-coated steel or steel-titanium reactor; then phosphorus trichloride is gradually introduced into the reactor at a temperature of 20 to 1800C, end the mixture is kept from two minutes to several hours. As a result, a reaction mixture is formed, containing polycondensates of polyphosphonic acids. The reaction mixture thus obtained is transferred to another reactor, excess water is added thereto, and at a temperature of 100-1300C the polycondensates of polyphosphonic acids are hydrolyzed to desired products: 1-flunctionally-substituted-alkylidene-1 ,1-phosphonic acids or their mixtures.

Depending on their purpose, these acids or mixtures thereof are isolated by conventional methods, for instance, by changing the solvent.

If the desired products are employed for ore decreasing, the former are converted into salts. This is done by adding sodium hydroxide of potassium hydroxide to the hydrolysate to p1H 9-12. The nitrogen base is isolated from the resultir solution, and an aqueous solution of salts of the desired acids thus obtained is used as such.

The nitrogen base is isolated quantitatively. It is converted into hydrochloride and reused at the stage of preparing the desired product.

For a better understanding of the present invention, specific examples of its embodiment are given h~re*nb- 4w.by way of illustration.

1 1 1 -9- Pr P C C, .I r 4- P. t 20 Example 1 To a mixture of 37.2 g (0.250 mole) of synthetic fatty acids of C 7

-C

9 fraction, having an average molecular weight of 148.5, 20 ml (0.19 mole) of diethylamine and 15.1 g (0.840 mole) of water are added under stirring and at a temperature gradually increasing from 2000 C to 1250C 73.0 g (0.532 mole) of phosphorus trichloride. Then the resulting reaction mass is kept at a temperature of 125- -130 0 °C for 1 hour. Hydrogen chloride that evolves upon mixing the reagents in the course of condensation is absorbed with water. Iodometric determination of the ohosphorous acid content in an absorption bottle has shown 0.025 mole of PC1 3 to be entrained with the stream of HC1. Thus, the overall quantity thereof, with allowance for losses, is 0.507 mole. The RCOOH:H 2 0:PC1 3 ratio is 0.47:1.58:1.

To the reaction mixture 40 ml of water and 10 ml of concentrated hydrochloric acid are added, and the mixture thus obtained is hydrolyzed at low boiling (105-1080C) for 10 hours. The resulting hydrolysate is alkalized with an aqueous solution of sodium hydroxide (about 45 g of NaOH), and then diethylamine is distilled off till the temperature in the vapours becomes 990 C. As a result, pH of the mixture is 9. The content of the desired 1-hydroxyalkylidene-1,1-diphosphonic acids in the solution of sodium salts thus obtained is determined by the NMR (31P) method. The solution contains 0.21 mole of 1-hydroxyalkylidene-1,1-diphosphonic acids. The yield is 83%.

_li 10 If 1-hydroxyalkylidene-1,1--diphosphonic acids are prepared in accordance with the procedure described above by using 15 ml (0.11 mole) of triethylamine instead of diethylamine, the yield of the 1-hydroxylidene-1,1-diphosphonic acids is 78%; with the use of 14.5 g (0.15 mole) of trimethylamine hydrochloride the yield is while with the use of 20.8 g (0.19 mole) of n-butylamine hydrochloride the yield is 73%.

In case the content of PC13 is lowered to 52.2 g (0.380 mole) and the reaction is carried out in the presence of 15 ml of diethylamine, the yield drops down to

RCOOH:H

2 0:PC1 3 0.66:2.21:1.

Example 2 Under the same conditions as in Example 1 a mixture of synthetic fatty acids of C -C fraction, water, and ml (0.42 mole) of tri-n-butylamine are introduced into the reaction with PCI3.PCI 3 losses arc U.032 mole, 0.500 <mole of PCI 3 has entered into the reaction.

The RCOOH:H 2 0:0:PC1 3 ratio is 1.47:1.58:1.

The hydrolyzed mixture is alkalized with NaOH and the liberated tributylamine is extracted with carbon tetrachloride. 0.209 mole of 1-hydroxyalkyl-1,1-diphosphonic acids is found in the aqueous layer; the yield is 84%.

I- C~ 4. *C 4 Example 3 To a mixture consisting of 169.1 g (0.884 mole) of synthetic fatty acids of C10 -C13 fraction, having a 11 aa a a a aaa a aeat a La a a ~aa aa a a a (at a a ata( aa at a tat a ta a I I a La

I

4 an average molecular weight of 191.3, and 93.2 g of 35.4% hydrochloric acid comprising 60.2 g (3.340 mole) of water and 33 g (0.905 mole) of HCl 100 ml (0.965 mole) of diethylamine is added with stirring; and cooling with water.

Then 286.6 g (2.072 mole) of phosphoris trichioride are introduced into the mixture at a temperature of 20-125 0C and the mixture is kept for 1 more hour at a temperature of 125-130 0C. P01 losses are U.118 mole, 1.964 mole of PCi 3 as entered into the reaction. The ,-ZCJH:H 2 O:PCl 3 10 ratio is 0.42:1.60:1.

50 ml of concentrated hydrochloric acid and 130 ml of water are added to the mixture, Pnd then it is :iydrolyzed at a boil (about 10500C) during 10 h. A 25,, aqueous solution of potassium hydroxide (about 330 e, of X01I) is added to the hydrolyzed mixture, and diethylamine is distilled off till the temperature in the vapours becomes 9900C. A solution of ot-assium salts of 1-hydroxyalkylidene-1,1dichosphonic acids C0oC 13 is obtained. In this solution the 14'1'.R .(31p) spectrum analysis reveals t',he following 20 1,h1osphorus-containin- compounds (the values of chemical shlifts are cvlculated with respect to 85 1APO4): 19.6 p.p*m. tJ 11 11-z), 85%, R-C(OH< 2 3.6 p.p.m.

Jyr 563 Iliz) H 3

PO

3 3.4 2% 3 P0 4 nonidentified compounds, about If synthetic fatty acids of 010-0 16 ar Ie introduced into the reaction, under the sa-me conditions a solution of potassium salts of 1-hydroalkylidene-1,1-diphosphonic acids is obtained with the yield of 82% for the reacted PC1 3 and of 91% for the syn- .1.

.0 0 a. 4 ill i :L -mrru 12 thetic fatty acids.

Example 4 Synthetic fatty acids of C10-C16 fraction, having an average molecular weight of 224.6, are chlorinated with gaseous 012 at a temperature of 95-105 0 C till a 49;L gain in weight. The reaction mass thus obtained is kept at the temperature of 100 C in a vacuum of 1 mm Hg, the gaseous and low-boiling products are removed. An elementary analysis of the resulting chlorinated synthetic fatty acids has shown the content of 33.59% Cl, this corresponding to the introducing of 3.16 Cl atoms per molecule of the synthetic fatty acids and giving an average molecular weight of the chlorinated synthetic fatty acids of 333.4.

To a mixture of 161.8 g (0.485 mole) of the chlorinated synthetic fatty acids and 51.1 g of 35.4% hydrochloric acid comprising 33.0 g (1.832 mole) of water, 55 ml

C

(0.53 mole) of diethylamine is added with stirring rnd cooling; then 160.0 g (1.164 mole) of phosphorus trichloride is introduced at a temperature of 20-1150C, and the S m20 mixture is kept at a temperature of 110-1150C for 8 E C hours more. PC13 losses are U.123 mole, 1.041 mole of PC01 ias reacted. RCOOHi: 2 0:PC1 3 0.42:1.57:1. The mixture is hydrolyzed with aqueous HC1, and amine is isolated by alkalyzing the hydrolysate with a solution of KOI as in the preceding Example. A solution of potassium salts of a mixture of 1-hydroxychloralkylidene-1,1-diphosphonic acids is thus obtained, containing 0.485 mole of desired compounds, the yield being 79% for PC1 and 85% for the C. 3 vow, 7j

I:

R

1 I 13 chlorinated synthetic fatty acids.

Example 37.2 g (0.250 mole) of synthetic fatty acids of C7-

-C

9 fraction, 20 ml (0.14 mole) of triethylamine, 15.1 g (0.840 mole) of water are mixed under the copditions of Example 1, and 73.0 g (0.532 mole) of phosphorus trichloride is introduced into the mixture at a temperature of 20-150 0 C. Then the mixture is kept for 15 min at the temperature of 1500C. After that the mixture is hydrolyzed and amine is isolated from the hydrolyzate as in Example 1. RCOOH:H 2 0:PC1 0.47:1.58:1. The yield of 1-hydroxyalkylidene-1,1-diphosphonic acids is 77%.

S An increase in the temperature of the mixture while adding PC13 to 170-180°C and subsequent keeping at this temperature for 2 minutes make the yield of 1-hydroxyalkylidene-1,1-diphosphonic acids Carrying out the reaction with synthetic fatty acids in excess, at a temperature of 170-180 C has the yield of 1-hydroxyalkylidene-1,1-diphosphonic acids to 20 (3 min keeping) and to 32% (10 min keeping).

Example 6 To a mixture of 25.6 g (0.100 mole) of palmitic acid, 6.81 g (0.378 mole) of water and 10 ml (0.095 mole) of diethylamine 32.5 g (0.237 mole) of PC1 is added with stirring at a temperature of 20-1350C, the resulting mixture is kept for 40 min at a temperature of 130-135 C,and hydrolyzed with dilute aqueous hydrochloric acid. PC1 3 losses with exit gases is 0.010 mole, 0.227 mole of PC1 3 I li i.

r I 14 tf r c: r(I has reacted.

RCOOH:H

2 0:PC13 0.42:1.59:1.

A sample of the reaction mixture is dissolved in water, triethylamine is acded thereto (pH 11.5), and the resultant mixture is analyzed NMR (1P)-spectrometrically.

The following phosphorus-containing compounds are present in the mixture: 19.0 p.p.m. Jpy 13 Hz), 68%, (OH) 3CPO 2 2.4 p.p.m. JP 613 Hz), 7%, HPO: 0.4 p.p.m. H3PO 4 unidentified compounds, about 3%.

Thus, the yield of the desired l-hydroxyhexadecylidene-l,l-diphospaonic acid is 88% for PC13 and about 100% for palmitic acid.

The reaction mixture is diluted with 200 ml of methanol and a solution of 49 g (0.6 mole) of sodium acetate in 110 ml of water is added thereto at boiling.The precipitated disodium salt on completion of crystallization is filtered off, washed with a mixture consisting of 5 volumes of methanol and 1 volume of water, then 20 with boiling methanol. After drying in a vacuum at the temperature of 100 0 C 38.2 g of disodium salt of 1-hydroxyhexadecylidene-ll-diphosphonic acid are obtained, this corresponding to the yield of 75% for the reacted PC3 and 86% for palmitic acid.

For preparing an analytic sample, the product is dissolved in hot water, auding a two-fold molar quantity of NaOH, the mixture is filtered and precipitated, acidulating it with a small excess of acetic acid. The t c r c t t Ct(! 8 tt &ro a~ i', P i:i: 9 i i r 15 precipitate is washed with water and methanol, then dried in a vacuum at the temperature of 100 0

C.

Elementary analysis data: Found, C 45.40; H 7.66,C 1 6

H

4 0P 2 Na 2 Calculated, C 43.05; H 7.68.

For preparing i-hydroxyhexadecylidene-l,l-diphosphonic acid 5.0 g of its purified disodium salt are suspended in 30 ml of ether, 20 ml of 307 aqueous H 2 S0 4 is added thereto, and the mixture is stirred till the solid phase disappears. The ethereal layer is separated, riltered to remove droplets of the aqueous layer, and the other is evaporated. The residue crystallizes after short-term standing. 4.3 g of crystalline 1-hydroxyhexadecylidene- 1,1-diphosphonic acid are obtained (about 100% for the disodium salt). For preparing an analytic sample, the product is recrystallized twice from acetone.

M 107-108°C(sinters).

Elementary analysis data: Found, C 47.15; H 9.05. C 16

H

6 0 7

P

2 20 Calculated, C 47.75; H 9.02.

Example 7 Under the conditions of Example 1 33.0 g (0.250 mole) of enanthic acid, 15.1 g (0.840 mole) of water, ml (0.14 mole) of triethylamine and 73.0 g (0.532 mole) of phosphorus trichloride are entered into the reaction. PC13 losses are 0.027 mole, 0.505 mole of PCl3 has reacted. The RCOOH:H 2 0:PCl 5 ratio is 0.47:1.58:1.

The reaction mixture is bydrolyzed with 50 ml of

I~,

I

16 water for 11 hours at boiling (100-105C), neutralized with a solution of 40 g NaOH in 80 ml of water, triethylamine is distilled off. The solution of disodium salts thus obtained contains 0.202 mole of 1-hydroxyheptylidene- -1,1-diphosphonic acid, the yield being 80% for the reacted PC1. The solution is acidulated at a temperature of 80-100 0 C with 150 ml of acetic acid, 100 ml of ethanol is added thereto, and the mixture is allowed to stand

S

r till crystallization of the disodium salt ceases. Then the precipitate is tiltered off, washed with acetic acid, ethanol, and boiling toluene. After drying in a vacuum at the temperature of 100°C 58.8 g of disodium salt of 1-hydroxyheptylidene-l,1-diphosphonic acid are obtained, this corresponding to the 73% yield for PC1.

For a final purification the salt is converted to £ree l-bydroxyheptylideae-l,1-dirosphonic acid. To this end, the salt is suspended in isopropanol, saturated with gaseous hydrogen chloride, the NaCl precipitate is filtered off, the Ziltrate is evaporatea in vacuum. To remove, c 20 isopropanol, HC1 and traces of water, the syrup-like residue is dissolved in ethylacetate, an equal volume of I benzene is added thereto, and the solvents are distilled off in vacuum. This operation is repeated till the product has crystallized, the crystals are dried in vacuum S* over H 2 S,0, then they are recrystallized from an ace- :i tate-chloroform mixture. M.p. 144-1460C (siaters).

Elementary analysis data: Found, C 50.37; H 6.74.C 17

H

18 2 i 1 17 et C t c crr Ctt 1 t i Ci r c r

SF-

C c.

r' r C C C Ct.

1.S j t tti e: r Calculated, C 30.44; H 6.57.

Example 8 Under the conditions of Example 7 22.0 g (0.250 mole) of n-butjric acid are introduced into the reaction.

PC1 3 losses are 0.017 mole, 0.515 mole of PCI 3 has reacted. RCOOH:H 2 0:PC1l 0.47:1.58:1. After hydrolysis, alkalizing and removal of amine, 0.210 mole of 1-hydroxybutylidene-l,l-diphosphonic acid is identified in the resulting solution, the yield being 81% for the reacted PC1 3 The solution is acidulated with acetic acid to pH evaporated in a vacuum till a viscous crystalline suspension is obtained, diluted with an equal volume of ethanol, and crystals of a sodium salt are filtered off.

The crystals are washed with ethanol and dried in a vacuum. 52.3 g of disodium salt of l-hydroxybutylidene-1,1diphosphonic acid monohydrate are obtained, the yield being 68% for PC1 3 An analytic sample is repricipitated with ethanol from water.

Elementary analysis data: Found, C 16.27; H 4.09. C 4

H

10 0 P 2 Na 2

H

2 0.

Calculated, C 16.32; H 4.06.

1-Hydroxybutylidene-ll-diphosphonic acid is obtained by passing an aqueous solution of sodium salts through a column with a cation-exchange resin. After evaporating an aqueous eluate free acid is obtained in the form of a non-crystallizing syrup.

Example 9 To a mixture comprising 19.7 g (71 mmole) of synrtsit

-I:

18 c I thetio fatty acids of C17-C20 fraction, having an average molecular weight of 274.3, and 7.48 g of 35.0% hydrochloric acid containing 4.86 g (270 mmole) of water and 2.62 g (72 mmole) of HC1 11.1 ml (80 mmole) of triethylamine are added dropwise, and then at a temperature of -120 0 C 23.9 g (74 mmole) of phosphorus trichloride are introduced, the mixture is kept at a temperature of 115- -120°C for 2 hours, then excess water (18 ml) is added thereto, and the mixture is hydrolyzed at a temperature of 100-105 0 C (low boiling). After that it is neutralized with 0OH and triethylamine is distilled off in a manner similar to that described in Examples 3 and 4.

An NMR 3 1 P)-spectrometric analysis of the reaction mixture has shown the yield of hydroxyalkylidenediphosphonic acids C 1 7

-C

2 0 to be 86% (19.5 JPH 12 Hz)j of phosphorous acid, 8% (3.4 d., JPH 565 Hz); of phosphoric acid, 6% (3.3 p.p.m.).PC1 3 losses are 4.8 mmole, 169 mmole of PC13 have reacted.

The RCOOH:H 2 0:PCl 3 ratio is 0.43:1.6:1. The yield of l-hydroxyalkylidene-l,l-diphosphonic acids for the synthetic fatty acids C 1 7

-C

2 0 is practically quantitative.

Example To a mixture comprising 16.3 g (125 mmole) of enanthic acid, 10.0 g (73 mmole) of anhydrous triethylamine hydrochloride and 7.5 g (416 mmole) of water 36.8g (268 mmole) of PC1 3 are added with stirring at a temperature of 20-180 0 C. PCl3 having been added and the temperature having reached 180 C, the reaction mixture is t

"'I

1 .i tt -f'~ff fl*!.A

I

11 1* 19 cooled rapidly to a temperature of 100-110 0 °C by immersing the flask into a water bath, then 20 ml of water are added into the flask, and its contents are hydrolyzed and treated as in Example 7. PC13 losses are 15 mmole, 253 mmole of PC1 3 have reacted. The C 6

H

1 3

COOH:H

2 0:PC13 ratio is 0.47:1.55:1.0 for the introduced PC1. and 0.49:1.64: for the reacted PC1. The yield of 1-hydroxyheptylidene-l,l-diphosphonic acid is 96.5 mmole 28.5g of its disodium salt are isolated.

Example 11 To a mixture comprising 37.2 g (0.250 mole) of synthetic fatty acids of C 7

-C

9 fraction and 37.0 g of an aqueous 59.2% solution of pyridine nydrochloride, consisting of 15.1 g (0.858 mole) of water and 21.9 g (0.190 *mole) of pyridine hydrochloride, 73.2 g (0.533 mole) of phosphorus triculoride are added, as in example 1. PC1 3 losses are 0.031 mole, 0.502 mole of PC1 nas reacted.

The RCOOH:H 2 0:PC1 3 ratio is 0.47:1.57:1.0 for the introduced PC1 3 and 0.50:1.67:1.0 for the reacted PC1 3 The mixture is hydrolyzed with aqueous hydrochloric acid as in Example 1, the yield of 1-hydroxyalkylidenediphosphonic acids is 0.198 mole Example 12 To a mixture comprising 35 g of anhydrous dimethylamine hydrochloride, 15.2 g (0.185 mole) of anhydrous phosphorous acid and 11.7 g (0.26 mole) of formamide 32.7 g (0.238 mole) of phosphorus trichloride is added dripwise, with stirring and the temperature rising gra- C C c .1 20

I'

L

I

dually from 20 to 8000°C. The mixture immediately becomes liquid and homogeneous. After adding PC1 3 the temperature of the mixture is kept at 80-85°C for 10 h, then the resulting viscous mass is hydrolyzed with 60 ml of 7% hydrochloric acid for 12 hours at boiling. The NMR (31p) spectrometric analysis of the hydrolyzed mixture gives a 79% yield of aminomethylenediphosphonic acid for the reacted trivalent phosphorus, whose quantity with allowance for the losses of PC01 3 with the evolved hydrogen chloride (0.083 mole), is 0.34 mole. After diluting the mixture with methanol 25.0 g of crystalline aminomethylenediphosphonic acid are obtained (77.6% for the reacted trivalent phosphorus).

The same results are obtained if calculated quantities of water and phosphorus trichioride are used instead of phosphorous acid.

Example 13 To a mixture comprising 6.58 g of trimethylamine hydrochloride, 3.88 g (47.3 mmole) of phosphorous acid o 20 and 9.13 g (42.8 mmole) of dodecylformamide 6.73 g (49.0 mmole) of phosphorus trichloride is added at a temperature of 20-90 0 C, then the mixture is heated at a temperature of 90-95 0 C for 10 h and hydrolyzed with 30 ml of hydrochloric acid for 5 hours at boiling. To the hydrolyzed mixture 100 ml of isopropanol is added, and upon cooling a precipitate is filtered off, which is then washed with isopropanoi and acetone. The yield of N-dodecylarinomethylenediphosphonic acid is 12.77 g or, h. :1 c 21 with allowance for the PCI 3 losses (10.7 mmole), 6ad for the reacted trivalent phosphorus.

The same results are obtained if a mixture of water and phosphorus trichloride is used instead of phosphorous acid.

Example 14 To a mixture comprising 22.2 g (0.2>v mole) of J3- -alanine, 28.9 g of trimethylamine ydrochloride and 14.6 g (0.810 mole) of water 77.0 g (0.561 mole) of phosphorus trichloride is added with stirring and at a temperature of 20 to 9000. The resulting mixture is stirred at the temperature of 9000°C for 1 hour more and then it is hydrolyzed with excess hydrochloric acid. The NMR 3 1 P)-spectrometry gives the yield of 3-amino-l-hbydroxy- ,propylidene-l,l-diphosphonic acid to be 727 for the reacted PC1 3 (the quantity of which, with allowance for the PC13 losses with exit gases, is 0.488 mole). Crystals precipitate from the reaction mixture when the latter is allowed to stand. These crystals are filtered off, washed with water and dried. 37.5 g of 3-amino-l-hydroxypropylidene-l,l-diphosphonic acid are obtained, the yield being 65% (for the reacted PC13). An analytic sample is recrystallized from water. At a temperature above 20000 the product decomposes without melting.

Elementary analysis data: Found, C 15.56; H 4.88. C 3

H

1 1 N0 7 2 Calculated, C 15.33; H 4.72.

*'1 r I II e 22 Example To a mixture comprising 56.5 g (0.250 mole) of adipic acid and 115.6 g of an aqueous solution of trimethylamine hydrochloride, consisting of 85.4 g of Me3N-C1 and 30.2 g (1.676 mole) of water, 165.0 g (1.201 mole) of phosphorus trichloride is added at a temperature of -125 0 C. The mixture is kept for 30 min at a temperature of 125-130 0 C, then it is hydrolyzed with excess water. The r o NMR P)-spectrometric analysis of the hydrolysate gives the yield of the desired tetraphosphonic acid to be 68% for the reacted PC13 (whose quantity with allowance for the losses is 1.024 mole). l,6-Dihydroxyhexane-l,l,6,6- -tetrayltetraphosphonic acid is isolated in the form of a trisodium salt dihydrate and recrystallized from water.

pH-metric titration data: Found: Equiv.

1 554.0; Equiv.

2 180.5.

Calculated: Equiv., 540.1; Equiv., 180.0.

Example 16 STo a mixture comprising 66.2 g of anbydrous pyri- 20 dine hydrochloride, 36.9 g (0.450 mole) o anhydrous phosphorous acid and 35.9 g (0.491 mole) of dimethylformamide 61.7 g (0.449 mole) of phosphorus trichloride is Sadded dropwise with stirring and at a temperature of 20-85°C. The resulting homogeneous mass is stirred for h at a temperature of 85-90°C and then hydrolyzed 31 P)-pecsco-1 t with excess water at boiling. The NMR (31P)-spectroscopic analysis of the hydrolysate shows the yield of dimethylaminomethylenediphosphonic acid to be 92% for the '4 23 reacted trivalent phosphorus (whose quantity with allowance for the PC13 losses is 0.802 mole). The major quantity of the dimethylaminomethylenediphosphonic acid crystallizes from the reaction mixture when the latter is left to stand. An analytic sample is recrystallized from water, and after drying it in a vacuum at room temperature dimethyl aminomethylenediphosphonic acid monohydrate is obtained.

I pH-metric titration data: Found: Equiv.

l 239.4; Equiv.

2 119.2 Calculated: Equiv. 237./1 Equiv.

2 118.6 1 SThe same results are obtained when equivalent quantities of water and phosphorus trichloride are used instead of phosphorous acid and an equivalent quantity of picoline hydrochloride is used instead of pyridine hy- S* drochloride.

Example 17 To a mixture of 30.0 g (0.500 mole) of acetic acid f r c and 43.2 g of an aqueous solution-of diethylamine hydrochloride consisting of 31.7 g of an anhydrous substance, and 11.5 g (0.658 mole) of water 73.5 g (0.535 mole) of phosphorus trichloride is added at a temperature of S!e -125°C, the resulting mixture is kept for 5 min at a tem- Sperature of 125-130 C, and then hydrolyzed with excess of dilute hydrochloric acid. The NMR (3 1 P)-spectrometric I analysis of the hydrolysate shows the yield of 1-hydroxyethylidene-l,l-diphosphonic acid to be 75% for the rer^ acted phosphorus trichioride (whose quantity with allow- 1 ance for the PU 3 losses is 0.510 mole).

The solution is acidul.ated with NaUH, diethylamine is distilled off, and trisodium salt of 1-hydroxyethylidene-l,1-diphosphonic acid is isolated from the residue.

After drying in a vacuum at the temperature of 100 0 C zhe salt has the cowposition of a monochydrate. 50.5 g of pure salt-are obtained.

Elementary analysis data: Found, C 8.51; H 2.49. C 2

H,

7 0 8

P

2 Na 3.

Calculated, C 8.28; H 2.43.

C C C ;4 V C V 4t C C I CCI I C I C I C I I '-1

"I

Claims

1. A method of preparing 1-functionally-substituted alkylidene-l,l-diphosphonic acids and salts thereof by reacting carboxylic acids or their derivatives with phosphorous acid under dehydrating conditions created by the addition of phosphorus trichloride in the presence of hydrochlorides of organic nitrogen bases to dilute the reaction mixtures.

2. A method according to claim 1, wherein the hydrochlorides of organic nitrogen bases are hydrochlorides of aliphatic amines, and of nitrogen-containing heterocyclic compounds.

3. A method of preparing 1-functionally-substituted alkylidene-l,l-diphosphonic acids and salts thereof substantially as herein described with reference to any one of Examples 1 to 17.

4. 1-functionally-substituted alkylidene-l,1-diphosphonic acids and salts thereof when prepared by any one of claims 1 to 3.

5. A method of preparing 1-functionally-substituted alkylidene-l,1-diphosphonic acids and salts thereof as defined in claim 1 and substantially as herein described. DATED this 14th day of May 1990 INSTITUT KHIMICHESKOI KiNETIKI I GORENIA SIBIRSKOGO OTDELENIA AKADEMII NAUK SSSR By their Patent Attorneys GRIFFITH HACK CO. .1 I L tt It t 25 C t t 2 .r e 11C To 9s/MS