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Publication numberUS2447715 A
Publication typeGrant
Publication dateAug 24, 1948
Filing dateJun 12, 1947
Priority dateJun 12, 1947
Publication numberUS 2447715 A, US 2447715A, US-A-2447715, US2447715 A, US2447715A
InventorsGordon Rose William
Original AssigneeUs Agriculture
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Esters of diacyl-glycerophosphoric acids
US 2447715 A
Abstract  available in
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Description  (OCR text may contain errors)

Patented Aug. 24, 1948 UNITED STATES PATENT OFFICE 2,447,715 ESTERS OF DIACYL-GLYCEROPHO SPHORIC ACIDS William Gordon Rose, Berkeley, Calif assignor to the United States of America as represented by the Secretary of Agriculture No Drawing. Application June 12, 1947, Serial No. 754,257

13 China.

(Granted under the act of March a, 1883, as

amended April 30,

More particularly, the invention relates to thepreparation of aminoethyl esters of dlacyl-glycerophosphoric acids wherein the acyl groups are aliphatic and contain at least eight carbon atoms. These compounds may be illustrated by the following formulae:

(Aminoethyl ester of alpha, gamma-diacyl-glycerophosphoric acid) (Aminoethyl ester of alpha, beta-diacyl-glycerophoa' phoric acid) wherein represents an aliphatic acyl radical containing at least 8 carbon atoms.

Cephalin is a naturallyoccurring mixture 0! aminoethyl esters of diacyl-glycerophosphoric acids. Thus, these esters can also be named with respect to their relationship to cephalin. For instance, the following compound can be named the amlnoethyl ester of alpha, gamma-dipal:

5 mitoglycerophosphoric acid or alpha, gammadipalmitocephalin:

and the following compound can be named the aminoethyl ester of alpha, gamma-distearoglycerophosphoric acid or alpha, gamma-distearocephalin.

This invention relates with further particularity to the preparation of novel compounds, namely, phthalimidoethyl esters of diacyl-glycerophosphoric acids wherein the acyl groups are aliphatic and contain at least eight carbon atoms. These compounds may be illustrated by the formulae:

(Phthalimidoethyl ester of alpha, gamma-diacyl-glycerophosphoric acid) (Phthalimidoethyl ester of alpha, beta-diacyl-glycerophosphoric acid) wherein represents an aliphatic acyl radical containing at least 8 carbon atoms.

These novel compounds can also be named with respect to'their relationship to cephalin. Thus, for instance, the phthalimidoethyl ester of alpha, gamma-dipalmitoglycerophosphoric acid can be referred to as alpha, gamma-dipalmitophthalylcephalin.

Accordingly, an object of this invention is to prepare aminoethyl esters of diacyl-glycerophosphoric acids wherein the acyl groups are allphatic and contain at least eight carbon atoms.

Another object of this invention is to prepare phthalimidoethyl esters of diacyl-glycerophosphoric acids wherein the acyl groups are aliphatic and contain at least eight carbon atoms.

A further object of this invention is to provide novel compounds, namely, phthalimidoethyl esphoric acid amide instead of the desired ester.

Another method involves the heating together of brometbylamine picrate and the monosilver salt of dipalmitoglycerophosphoric acid. This procedure gives very poor yields probably due to formation of piperazlne derivatives.

I have found that the aminoethyl esters can be obtained in good yield by the reaction of a diacylglycerophosphoryl chloride with beta-hydroxyethylphthalimide. The resulting compound, phthalimidoethyl ester of diacyl-glyceromonochlorophosphoric acid, is subjected to a limited hydrolysis to remove the chlorine atom attached to the phosphorus atom whereby the phthalimidoethyl ester of the diacyl-glycerophosphoric acid is produced. This material is then cleaved by reaction under refluxing conditions with hydrazine, hydrazine hydrate, or the mineral acid salts of hydrazine to produce the aminoethyl ester of the diacyl-glycerophosphorlc acid. The reactions can be demonstrated by the following equations:

o mo -o- -a The following example, which describes the (A) Preparation of alpha, gamma-dipalmitophthalylcephalin Phosphorus oxychloride in the quantity of 9.18 grams was placed in a two-necked flask with 30 ml. oil dry pyridine and 40 ml. of chloroform. The flask was provided with an agitator adapted to scrape the bottom of the flask and was surrounded by a water bath at 10-15 C. The agitator was started and then 34.2 grams of alpha, gamma-dipalmitin in 200 ml. of alcohol-free chloroform was added during the course of 1 hour. The solution was stirred at 25 C. for 30 minutes, then at 30-35 C. for 30 minutes, then cooled to 10-15 C. again, and 11.45 grams betahydroxyethylphthalimide in 200 m1. chloroform added during the course of 1 hour. The solution was then stirred at 25 C. for 30 minutes and at 30-35 C. for 30 minutes to complete the reaction. After cooling to 28 C., 1.15 ml. of water in 4 ml. pyridine was added. This step causes the hydrolysis of the chlorine atom. Most of the aid of ether, and was shaken moderately. The

emulsified aqueous layer was withdrawn, acidified, and'the ether that separated added to the main ether solution. The ether layer was washed with dilute hydrochloric acid and with water and was then filtered through a thick soft paper or through cotton and left overnight at C.

Filtration removed 3.4 grams of material that melted at -50-60 C., but did not become-clear until 160 C. To obtain the principal reaction- 1 product, the filtratewas next left for 5 hours at -18 C. and filtered at this temperature. The precipitate retained much ether and was airdried overnight, as it melted in the retained solvent when it was dried in a vacuum desiccator without preliminary air drying. The dried product weighed 39.5 grams and melted at 43-46 C. It was found later to be largely phthalylcephalin, but contained several other substances.

The crude material was purified by dissolving it in 600 ml. of hot hexane, filtered hot and allowed to stand 18 hours at room temperature. Filtration gave 4.8 grams of impure phthalylcephalin that sintered at 63 C. and melted from 70-76 C. This was dissolved in 50 ml. of methanol, filtered hot and allowed to stand at room temperature overnight. Filtration gave 3.0 grams of crystals of phthalylceph'alin that sintered at 64 C. and melted at 67-68 C. The hexane filtrate (above) contained still more phthalylcephalin. It was concentrated to 200 ml., seeded with some of the crystals from the methanol crystallization and thereupon deposited more crystals when allowed to stand at room temperature for 3 hours with occasional stirring. Filtration gave 14.7 grams that sintered at 60 C. and melted at 64-73 C. This product was dissolved in 150 ml. of hot methanol and the hot solution was filtered through cotton and allowed to stand for 16 hours at room temperature. Filtration gave 12.5 grams that sintered at 69 C. and melted at 70-72 C. The two products that had been recrystallized from methanol were combined and recrystallized from 200 ml. of hexane,

the solution being filtered after standing 1 hour at room temperature. The yield was 13.25 grams of product (alpha, gamma-dipalmitophthalylceph'alin or phthalimidoethyl ester of alpha, gamma-dipalmitoglycerophosphoric acid) that melted at 71-72 C.

Analysis: Calcd. for C45H'1sOioNP: N, 1.70; P, 3.77; C, 65.74; H, 9.32; equiv, wt. 822.1. Found:

N, 1.66; P, 3.85; C, 66.09; H, 9.47; equiv. wt. 825.

(B) Preparation of alpha, gamma-dipalmitocephalin Four and eleven-hundredths grams of phthalylcephalin prepared as described above was dissolved in 100 ml. of hot neutral monomethyl ether of glycol and neutralized by the addition of 10 4 ml. of 0.5 N N aOH. Hydrazine hydrate in monolln was accomplished by taking advantage of the unexpected property that it is insoluble in ether but is very readily suspended therein. The water suspension was transferred to a separator-y funnel with 300 ml. of ether, shaken and the aqueous layer removed. The ether layer and the solid that collected at the ether-water interface were washed with water until the washings were neutral; The ether containing the suspended solid was then filtered, washed with ether and dried. The dry residue amounted to 2.9 grams and melted at 178-200 C. Recrystallization from 190 ml. absolute alcohol gave 2.47 grams that sintered at 187 C. and melted with decomposition at 192-193 C., depending on the rate of heating. Further recrystallization from alcohol did not alter the melting point. The product was alpha, gamma-dipalmitocephalin or aminoethyl ester of alpha, gamma-dipalmitoglycerophosphoric acid.

Analysis: Calcd. for alpha, gamma-dipalmitocephalin, CmI-I'uOsNP: N, 2.02; P, 4.48; C, 64.22; H, 10.78 percent; equiv. wt. 692.0. Found: N (Dumas), 2.07; Amino N (Van Slyke in acetic acid), 1.86; P, 4.50; C, 63.75; H, 10.52 percent;

equiv. wt. (titration in neutral alcohol), 689.

It was necessary to add vanadium pentoxide t0 the substance, as described for phosphoric acid esters by Wagner-Jauregg and Griesshaber (Berichte Deut. Chem. Geseil, vol. 70, p, 1458 (1937) to obtain correct carbon analyses. Combustion of the substance alone, or with copper ox ide gave carbon values that were 2 to 3 percent As set forth above the first step in the process involves the reaction of beta-hydroxyethylphthalimide with a diacyl-glycerophosphoryl chloride. As the latter reactant, many different compounds can be used wherein the acyl radicals are aliphatic and contain at least eight carbon atoms. The acyl radicals can be attached at the alpha and gamma positions of the glycerine nucleus, in which case the phosphoryl chloride group is at the beta position; or, the acyl groups can be attached at the alpha and beta positions, in which case the phosphoryl chloride group is attached at the gamma position.

These diacyl-glycerophosphoryl chlorides are most conveniently prepared by reacting a diacyl ester of glycerine with phosphorus oxychloride. For example, by reacting alpha, gamma-dipalmitin with phosphorus oxychloride in the presence of pyridine, alpha, gamma-dipolmitoglycerophosphoryl chloride can be prepared. Thus, one can employ as the diacyl-glycerophosphoryl chloride reactant the phosphorus oxychloride reaction product with any of the following diacyl esters of glycerine, i, e.', alpha, gamma-dicaprylin; alpha, beta-dicaprylin; alpha, gamma-dipelargonic ester of glycerine; alpha, beta-dipelargonic ester of glycerine; alpha, gamma-dicaprin; alpha, beta-dicaprin; alpha, gamma-diundecylic ester of glycerine; alpha, beta-diundecylic ester of glycerine; alpha, gamma-dilaurin; alpha, betadilaurin; alpha, gamma-ditridecylic ester of glycerine; alpha, beta-ditridecylic ester of glycerine;

alpha, gamma-dimyristin; alpha, beta-dimyristin;

alpha, gamma-dipentadecylic ester of glycerine; alpha, beta-dipentadecylic ester of glycerine; alpha, gamma-dipalmitin; alpha, beta-dipalmitin; alpha, gamma-dimargarin; alpha, beta-dimergarin; alpha, gamma-distearin; alpha, beta-distearin; alpha, gamma-dinondecylic ester of glycerine; alpha, beta-dlnondecylic ester of glycerine; alpha, gamma-diarachadin; alpha, beta- V insure complete reaction.

diarachadin; alpha,gamma-dlolein; alpha. beta-.-

. iolein; alpha, gamma-dielaidin; alpha, beta-dielaidin; alpha, gamma-dipalmitolein; alpha. betadipalmitolein; alpha, gamma-dilinolein; alpha, beta-dilinolein; and so forth.

Further, it is possible to use glycerine esters wherein the two acyl groups are dissimilar, for instance-alpha-stearic, beta-palmitic ester of glycerine; alpha-lauric. gamma-palmitic ester of glycerine: alpha-stearic, gamma-oleic ester of glycerine; alpha-palmitic, gamma-linoleic ester of glycerine; and so forth.

Further, if it is not desired to prepare an individuual final compound but mixtures, one can employ mixtures of different diesters of glycerine. For instance. one could employ the mixtures of diglycerides formed by heating glycerlne and a catalyst with a triglyceride. Thus, mixtures of digiycerides suitable for use in the process could be prepared by heating glycerine with a catalyst and with coconut oil, palm-kernel oil, olive oil, taliow. suet, cottonseed oil, peanut oil, lard, olive oil,-whale oil, sardine oil. corn oil, soybean oil, and so forth. Mixtures of diglycerides can also be prepared by reacting an excess of giycerine, in

' ed to 59.2 grams of phthalic anhydride, and after the initial heat of reaction had subsided, the mixture was heated at 150 C. for 30 minutes. It was then allowed to cool to about 90 C. and poured into-800 ml. of water. The crystals so obtained were chilled in ice and filtered, giving 46.7 grams of beta-hydroxyethylphthalimide,

Analysis: Calcd. for CioHeOaN: C. 62.82; H, 4.74; N, 7.33. Found: C, 62.81; H, 4.65; N. 7.40.

In the reaction of the diacyl glycerine ester with phosphorus oxychloride to prepare the diacyl-glycerophosphoryl chloride, it is necessary to add a hydrogen chloride acceptor to the reaction mixture. For this purpose, pyridine, quinoline, dimethyl aniline or other tertiary amines are suitable. The temperature of the reaction should be kept low. It has been found that temperatures from about to about 35 C. are suitable. Preferably, the reaction should be conducted at the lower temperature, about 10-45 C., and then heating toabout 30-35 C. for a short time to The diacyi-glycerine ester and phosphorus oxychloride should be employed in approximately equimolar proportions. It is preferable to employ a solvent in this reaction. Organic solvents such as chloroform, di-

chloromethane, benzene and so forth are suitable. Any other inert liquid which will dissolve the diacyl-glycerine ester-phosphorus oxychloride complex and the tertiary amine hydrochloride can be used.

ride with the beta-hydroxyethylphthalimide, it is necessary I to employ a hydrogen chloride acceptor (quinoline, pyridine, diemethylaniline, or other tertiary amine). It has been found to be convenient to add an excess of the hydrogen chloride acceptor in the first reaction (diacylglycerine ester and phosphorus oxychloride) whereby sufliclent acceptor will remain in the reaction mixture for the second reaction (diacylglycerophosphorylchloride and beta-hydro ethylphthalimide). In regard to the latter reaction. the same temperature, proportions, and

solvents are applicable as to the former reaction.

In the hydrolysis step involving the removal of the chlorine atom from the complex phthalimidoethyl ester of diacylglyceromonochlorophosphoric acid. the amount of water is not critical. At least an equimolar proportion of water I should be added but an excess will not be disadvantageous. The temperature during-this step should be kept at about 25 C, or less to prevent hydrolysis of the ester linkages. No solvent is necessary in the hydrolysis, but a solvent such as pyridine can be used if desired to assist in transfer of the water to the mixture.

The expression limited hydrolysis," as used herein, means a controlled hydrolysis whereby only the chlorine atom on the phosphorus atom is hydrolyzed and the ester linkages are not affected. h I t In the cleavage step, hydrazine is heated with the phthalylcephalin. One mol of the phthalylcephalin requires 1 to 2 mols of hydrazine. In this cleavage step, the hydrazine can be replaced by hydrazine hydrate, hydrazine hydrochloride, hydrazine sulphate, or other hydrazine mineral acid salts. It is preferable to use a solvent; monomethyl glycol ether, monoethyl glycol ether, ethanol and methanol are suitable. The reactants are preferably refluxed to bring about the reaction and to prevent loss of solvent and/or hydrazine.

The aminoethyl'esters produced according to the described process can be used to replace lecithin in a variety of pharmaceutical preparations and cosmetics where they are useful as emulsifying and skin-softening agents. These products are also useful as antiblushing agents in chocolates and as water-binding and dispersing agents in oleomargarine. Because of their surface-active properties, the aminoethyl esters are also useful in preparing oil-in-water emulsions of insecticldes and fungicides and in promoting the reaction of hydrophilic materials with hy--v drophobic materials.

are useful as a convenient source for the preparation of the corresponding aminoethyl esters. The phthalimidoethyl esters are quite stable and can be kept for; long periods contrary to the amimethyl esters. The former can be readily cleaved with hydrazine when aminoethyl esters are required. The phthalimidoethyl esters are generally useful as intermediates from whichto prepare many different glycerophosphoric acid derivatives. I

The foregoing example indicates methods of purifying the product and intermediates. These steps can, of course, be omitted if it is not desired to obtain a chemically pure grade of material.

In a copending application, Serial No. 754,256,

' filed June 12, 1947, now U. S. Patent 2,436,699, I

have disclosed a method of preparing aminoethyl esters of diacyl-glycerophosphoric acids involving reaction of carbobenzoxyaminoethanol with a diacyl-glycerophosphoryl chloride, followed by 9 limited hydrolysis, and cleavage with phosphonium iodide. Having thus described the invention, what is claimed is:

1. A process comprising reacting a diacyi-glycerophosphoryl chloride, wherein the acyl radicalsare aliphatic and contain at least 8 carbon atoms, with beta-hydroxyethylphthalimide in the presence of a tertiary amine at a temperature of about from 10 C. to '5" C., subjecting the resulting phthallmidoethyl ester of diacyl-glyceromonochlorophosphoric acid to limited hydrolysis by reaction with water at a temperature not exceeding about 25 C. to form the phthalimidoethyl ester of diacyl-glycerophosphoric acid, and refluxing this last-formed ester with a member selected from the group consisting of hydrazine, hydrazine hydrate, and the mineral acid salts of hydrazine to produce an aminoethyl ester of a diacyl-giyeerophosphorlc acid.

2. A process comprising reacting a diacylglycercphosphoryl chloride, wherein the acyl radicals are aliphatic and contain at least 8 carbon atoms, with beta-hydroxyethylphthalimide in the presence oi a tertiary amine at a temperature of about from 10 C. to 35 C., subjecting the resulting phthalimidoethyl ester of diacylglyceromonochlorophosphoric acid to limited hydrolysis by reaction with water at a temperature not exceeding about 25 C. to form the phthalimidoethyl ester of diacyl-glycerophosphoric acid, and refluxing this last-formed ester with hydrazine hydrate to produce an aminoethyl ester of a diacyl-glycerophosphoric acid.

3. A process comprising reacting an alpha, gamma-diacylglycerophosphoryl chloride, wherein the acyl radicals are aliphatic and contain at least 8 carbon atoms, with'beta-hydroxyethylphthalimide in the presence or a tertiary amine at a temperature of about from 10 C. to 35 C., subjecting the resulting phthalimidoethyl ester of a l p h a, gamma diacylglyceromonochlorophosphoric acid to limited hydrolysis by reaction with water at a temperature not exceeding about 25 C. to form the phthalimidoethyl ester of alpha, gamma-diacylglycerophosphoric acid, and refluxing this last-formed ester with a member selected from the group consisting of hydrazine, hydrazine hydrate, and the mineral acid salts of hydrazine to produce the aminoethyl ester of an alpha, gamma-diacylglycerophosphoric acid.

4. A process comprising reacting alpha. Eamma -dipalmitoglycerophosphoryl chloride with beta-hydroxyethylphthalimide in the presence of.

l0 sisting of hydrazine, hydrazine hydrate, and the mineral acid salts of hydrazine to produce the aminoethyl ester of alpha, gamma-dipalmitoglycerophosphoric acid.

5. The process of claim 1 wherein the tertiary amine is pyridine.

6. A process comprising reacting a diacylglycerophosphoryl chloride, wherein the acyl radicals are aliphatic and contain at least 8 carbon atoms, with beta-hydroxyethylphthalimide in the presence of a tertiary amine at a temperature of about from 10 C. to 35 C. and subjecting the resulting phthalimidoethyl ester of diacyl-glyceromonochiorophosphoric acid to limited hydrolysis by reaction with water at a temperature not exceeding about 25 C. to form the phthallmidoethyl ester of diacyl-glycerophosphoric acid.

7. A process comprising reacting an alpha, gamma diacyl glycerophosphoryl c h 1 o rid e, wherein the acyl radicals are aliphatic anacontain at least 8 carbon atoms, with beta-hydroxyethylphthalimide in the presence of a tertiary amine at a temperature of about from 10 C. to 35 C. and subjecting the resulting phthalimidoethyl ester of alpha, gamma-diacyl-giyceromonochlorophosphoric acid to limited hydrolysis by reaction with water at a temperature not exceeding about 25 C. to form the phthalimidoethyl ester of alpha, gamma-diacyl-glycerophosphoric acid.

8. A process comprising reacting alpha, gamma dipalmitoglycerophosphoryl chloride with beta-hydroxyethylphthalimide in the presence of a tertiary amine at a temperature or about from 10 C. to 35 C. and subjecting the resulting phthalirnidoethyl ester of alpha, gamma-dipalmitogiyceromonochlorophosphoric acid to limited hydrolysis by reaction with water at a tempera.- ture not exceeding about 25 C. to form the phthalimidoethyl ester of alpha, gamma-dipalmitoglycerophosphorlc acid.

9. The process or claim 6 wherein the tertiary amine is pyridine.

10. A phthalimidoethyl ester or a diacyl-glycerophosphoric acid wherein the acyl radicals are aliphatic and contain at least 8 carbon atoms.

11. A phthalimidoethyl ester of an alpha, gamma-diacylglycerophosphorlc acid wherein the acyl radicals are aliphatic and contain at least 8 carbon atoms.

12. Phthalimidoethyl ester of dipalmitoglycerophosphoric acid.

v13. Phthalimidoethyl ester of alpha, gammadipalmitoglycerophosnhoric acid. 4

WILLIAM GORDON ROSE.

.REFERENCES CITED The following references are of record in the file of this patent:

Sidgwick, "Organic Chemistry oi Nitrogen," new edition, 1937, Oxford University Press (London), pages 14 and 15.

Non-Patent Citations
Reference
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US2767194 *Mar 18, 1955Oct 16, 1956Stauffer Chemical CoCompositions of matter
US2885414 *Oct 16, 1957May 5, 1959Beal Robert EPreparation of partial glycerides
US2914530 *May 28, 1957Nov 24, 1959Bayer AgThiophosphoric acid esters and their production
US3336188 *Jan 6, 1964Aug 15, 1967Dow Chemical CoPhosphorus containing pesticidal composition and method of use
US3960905 *Aug 28, 1974Jun 1, 1976Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V.Diacylglycerophosphoric acid esters of aminoethanol and methylaminoethanol and method of preparing the same
US4104403 *Dec 21, 1976Aug 1, 1978Witco Chemical CorporationWater-oil emulsions and method of preparing same
US4742051 *Jul 17, 1981May 3, 1988University Of Tennessee Research CorporationAntihypertensive compounds
US4788182 *Oct 23, 1987Nov 29, 1988Ciba-Geigy CorporationPhosphatidyl compounds, processes for their manufacture, and their use
US4873322 *Jan 16, 1987Oct 10, 1989Ciba-Geigy CorporationSaccharide derivatives and processes for their manufacture
US4885285 *Sep 9, 1985Dec 5, 1989Ciba-Geigy CorporationPhosphorus compounds, processes for their manufacture, and their use
US5189017 *Oct 17, 1990Feb 23, 1993Ciba-Geigy CorporationUse of sugar derivatives for the prophylaxis and treatment of virus infections
US5334583 *Dec 2, 1992Aug 2, 1994Ciba-Geigy Corp.Use of sugar derivatives for the prophylaxis and treatment of virus infections
EP0307175A2 *Sep 7, 1988Mar 15, 1989Ciba Corning Diagnostics Corp.Method for preparing phosphodiester conjugates useful for preparing immunoactive liposomes
Classifications
U.S. Classification548/415, 987/233, 987/364, 554/80
International ClassificationC07F9/10, C07F9/553, C07F9/00
Cooperative ClassificationC07F9/10, C07F9/5537
European ClassificationC07F9/553A9, C07F9/10