DE1113937B - Process for the preparation of heterocyclic amides of phosphoric acid - Google Patents

Description

GERMAN

PATENT OFFICE

S 65826 IVd / 12p

REGISTRATION DATE: NOVEMBER 13, 1959

NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL: SEPTEMBER 21, 1961

The invention relates to a process for the preparation of heterocyclic amides of phosphoric acid.

It is known (see J. Chem. Soc, 1956, p. 2812) that an important representative of this class of compounds, namely the phosphoric acid diesterimidazolide, is formed when diphenylphosphoric acid chloride Reacts with imidazole; however, the substance was not isolated, but processed further in solution. This method has for the preparation of phosphoric acid diesterimidazolides Disadvantage that you have to start from phosphoric acid diester chlorides, which are the sensitive esters Phosphoric acid, e.g. B. sugar phosphates and biologically important phosphates do not represent permit. In Chem. Abstracts, 50 (1956), p. Ρ 10826 g, and 51 (1957), p. Ρ 3702 i, works by Rathiev and Rosenberg gave a lecture, with a reaction between aminophosphate and imidazole partial phosphorylation of nitrogen takes place. Furthermore, in a publication in Angew. Chemistry, 71 (1959), p. 195, it has been reported that NN'-carbonyldi-imidazole (easy to manufacture from phosgene and imidazole according to German patent specification 1033 210) with Carboxylic acids can be converted to imidazolides.

The object of the invention is now to produce heterocyclic amides of phosphoric acid using of NN'-carbonyl derivatives of five-membered unsaturated heterocyclic - so-called quasi aromatic - nitrogen compounds with at least two ring nitrogen atoms and their substitution products as reaction components.

It has now been found that heterocyclic amides of phosphoric acid can be prepared by reaction of the above-mentioned NN'-carbonyl compounds with orthophosphoric acid or its mono- and diesters. As examples of these NN'-carbonyl compounds can be mentioned: carbonyl-di-imidazole, carbonyl-di- (4 or 5-methyl-imidazole), Carbonyl-di- (triphenyl-imidazole), carbonyl-di-1,2,3-triazole, carbonyl-di- (1,2,4-triazole), carbonyl-dibenzimidazole, Carbonyl-dibenz-1,2,3-triazole, carbonyldi- (3,5-dimethyl-pyrazole). As examples of the mono- and diesters of orthophosphoric acid may be mentioned: benzylphosphoric acid, p-nitrobenzylphosphoric acid, Adenosine phosphoric acid, cyclohexyl phosphoric acid, diphenyl phosphoric acid and their ring-substituted ones Derivatives, dibenzyl phosphoric acid, di-p-nitrobenzyl phosphoric acid, Diethyl phosphoric acid, dicyclohexyl phosphoric acid.

In terms of formula, the reaction can be represented as follows using the example of the imidazole compound:

Method of manufacture

of heterocyclic amides

of phosphoric acid

Applicant:

Shell Internationale Research Maatschappij N.V., The Hague

Representative: Dr.-Ing. F. Wuesthoff, Dipl.-Ing. G. Pulse and DipL-Chem. Dr. rer. nat. E. Frhr. v. Pechmann, patent attorneys, Munich 9, Schweigerstr. 2

N N— C — N N + HO -

, OR ₁ OR ₂

, OR ₁

ν ν-ρ;

4- CO ₂ + HN N

-OR,

wherein R ₁ and R _{2 represent} hydrogen, alkyl, aryl, aralkyl, cycloalkyl or nucleotide radicals.

The heterocyclic amides of phosphoric acid according to the invention can be represented in three types, namely unesterified phosphoric acid amides of the formula

N-

-P-OH

OH

Phosphoric acid monoester amides of the formula

NP-OR ₁ OH

109 689/225

and phosphoric acid diester amides of the formula blended with butylamine and was made in this way

characterized.

⁰ example 2

j ρ Qj ^ ₅ monophenylphosphoric acid imidazolide

3.05 g of monophenyl phosphoric acid were dissolved in 3 cm ^{3 of} OR ₂ acetonitrile and 10 cm ^{3 of} benzene and 3.5 g of car-

bonyldiimidazole added. After 15 minutes at

where R ₁ and R _{2 have} the abovementioned meaning and room temperature, the evolution of CO ₂ ceased.

ίο It was briefly heated to boiling, cooled and 5 cm ^{3 of} cyclohexylamine, 0.2 cm ^{3 of} water and

N— 30 cm ^{3 of} ether added. The one not implemented

Monophenylphosphoric acid crystallized out in the cold (cyclohexylammonium salt 0.75 g). The heterocyclic residue of the 15 given above was filtered and the filtrate was evaporated in vacuo, which corresponds to the definition. If R ₁ and / or R _{2 represent} water remaining oil taken up in 50 cm ^{3 of} acetone, it is possible that a second molecule and ^{mixed with 50 cm 3 of} ether. After 2 hours at the N, N'-carbonyl compound with one of the hydroxyl 0 ⁰ C were 4.45 g (79% of theory) reacts further to cyclohexyl groups to form hetero- ammonium salt of Monophenylphosphorsäure-imidcyclischen diamides of the formula 20 azolide crystallized. Mp. 115 ⁰ C. The substance

is easily soluble in water and hydrolyzes in the course O of a few days, sparingly soluble in pyridine, acetone,

0 ether, benzene.

² 5 Example 3

O Rj, 2 diimidazolide of orthophosphoric acid

Anhydrous orthophosphoric acid was with 2 mol

The compounds produced according to the invention, carbonyldiimidazole in dimethylformamide at room temperature, are very reactive and can be reacted with alcohols at 30 temperature. It developed rapidly to esters with amines to amides and with acids to CO ₂ , and the imidazolium salts of phosphoric acids anhydrides of phosphoric acid are converted. failed. They contained the phosphoric acid diimide-The heterocyclic amides of phosphoric acid are azolid, which is used directly for further reactions. B. it reacts with alcohols to the reaction equation given above in 70 to 90% 35 diesters.
the theory arise. These connections will

preferably isolated in the form of their salts and are in Example 4

durable in this form. _,. .,. ,,,,,,,,

The heterocyclic amides of phosphoric acid Monoimidazohd of monobenzylphosphoric acid

can by reaction with phosphoric acid, Phos- 4 ° 528 mg monobenzylphosphoric acid were in 8 cm ³

phosphoric acid monoester or diester dissolved to the corresponding tetrahydrofuran and 502 mg carbonyl diester

added imidazole to the pyrophosphates in almost quantitative yield. After 10 minutes the stormy

implemented. These reactions are therefore _{terminated mixed CO 2} evolution, weight loss

particularly interesting because they are preparatively in a lot of 110 mg CO ₂ . The solvent was in vacuo

Wrong way the synthesis of coenzymes and evaporated away, the remaining oil with 25 cm ³

should allow borrowed connections. It is also absorbed by acetone and in the cold with 0.2 cm ³

in this process it is particularly advantageous that water, 1 cm ^{3 of} cyclohexylamine and 25 cm ^{3 of} ether

can obtain pure asymmetrical pyrophosphates, added. After 12 hours at 0 ^° C., 580 mg des

which in the previously known methods usually imidazolide crystallizes out as the cyclohexylammonium salt

is not easily possible. 50%, yield: 60% of theory; Mp 112 ° C; Loosening

The compounds according to the invention react like the monophenyl derivative. with carboxylic acids to form phosphoric acid carboxylic acid

anhydrides, which z. B. As a mild acetic agent Example 5

particularly suitable for peptide synthesis. _,. .,,.,, _ ,. ,. ,,

Monoimidazohd of p-chlorophenylphosphoric acid

Example 1 415 mg of p-chlorophenylphosphoric acid were in

■ n. , - 1 ■. , ... ., f , 8 cm ^{3 of} benzene and 2 cm ^{3 of} acetonitrile dissolved and 340 mg

Diphenylphosphoric acid imidazolide carbonyldümidazole added. After 10 minutes (end

2 moles of diphenylphosphoric acid and 1 mole of carbonyl gas evolution) was concentrated in vacuo,

diimidazole were placed in a sealed flask. The remaining oil solidified after 12 hours

combined with calcium chloride tube and at 0 ⁰ C and was recrystallized from acetone-ether,

warmed up in the water bath. From 50 ⁰ C there is a stormy yield: 438 mg (67% of theory); Mp 87 ° C.
CO ₂ evolution and 75% of theory CO ₂

escape. The residue was dissolved in tetrahydrofuran Example 6

recorded, with most of the imidazoüum- 65 .., - ■,., ■■ _o - ^ r ■, -, -, ι

salt remains undissolved. When distilling off the Monoimidazohd der ^ -Naphtylphosphorsaure

Tetrahydrofuran remained behind in vacuo, the di- 450 mg of ß-naphthylphosphoric acid were in 5 cm ³

phenylphosphorylimidazole as an oil. It reacted dissolved tetrahydrofuran and 345 mg carbonyldiimide

azole added. After the evolution of gas had ceased, the mixture was evaporated in vacuo, taken up in acetone and then 0.2 cm ^{3 of} water and 500 mg of sodium iodide, dissolved in acetone, were added. The immediately precipitating sodium salt of the imidazolide was recrystallized from water-acetone. Yield: 422 mg (71% of theory); Mp> 250 ° C.

Example 7

Monoimidazolide of monomethylglycol phosphoric acid

246 mg of the acid were dissolved in 4 cm ^{3 of} tetrahydrofuran and 120 mg of imidazole and then 308 mg of carbonyldiimidazole were added. The weight loss due to the evolution of CO ₂ was 71 mg after 15 minutes. The resulting imidazolide was isolated as in Example 4 as the cyclohexylammonium salt. Yield: 295 mg (56% of theory); Mp 126 ° C.

Example 8
Monoimidazolide of monothymyl phosphoric acid

589 mg of monothymylphosphoric acid in 8 cm ^{3 of} tetrahydrofuran were mixed with 280 mg of carbonyldiimidazole and, after the _{evolution of CO 2} (85 mg of CO ₂ ) had ended, the mixture was evaporated in vacuo. The residue was ^{recrystallized from 2 cm 3 of} acetonitrile and the imidazolide was obtained in analytically pure form. Yield: 736 mg of the imidazolium salt (82% of theory); Mp 91 ° C. The substance is very hygroscopic and easily soluble in polar solvents such as water, acetone, pyridine, and poorly soluble in non-polar solvents such as benzene and ether.

Example 9
Monoimidazolide of orthophosphoric acid

310 mg of orthophosphoric acid were dissolved in 3 cm ^{3 of} dimethylformamide and 500 mg of carbonyldiimidazole were added. There was a stormy development of CO ₂ , and the imidazolium salts of phosphoric acids precipitated. The imidazolium salt of the imidazolide was obtained in pure form by recrystallization from water-acetone. Yield: 362 mg (54% of theory); Mp 164 ° C.

Example 10
Phenylphosphoric acid benzotriazolide sodium salt

1.7 g (0.65 mM) carbonyldibenz-1,2,3 are added to the solution of 0.9 g (0.5 niM) phenylphosphoric acid and 2.5 ml (1.8 mM) triethylamine in 10 ml absolute acetone -triazole added and left to stand for about ₂ hours at room temperature with frequent shaking. The mixture is then heated to the boil for a short time, allowed to cool and diluted with 30 ml of acetone. The sodium salt is precipitated as an amorphous precipitate with the solution of 1 g of NaI in ml of acetone, filtered off, washed very well and finally dried in vacuo or on clay. Soluble in H ₂ O, alcohol and dimethylformamide, insoluble in acetone, chloroform and pyridine.

Yield: chromatographically over 90%, isolated%. The substance gives the same reactions as the other phosphoric imidazolides.

Analysis of the sodium salt C ₁₂ H ₉ N ₃ O ₃ PNa:
Calculated ... C 48.50, H 3.05, N 14.14, P 10.42; Found ... C 47.98, H 2.96, N 13.89, P 9.67.

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of heterocyclic amides of phosphoric acid, characterized in that NN'-carbonyl derivatives of five-membered unsaturated heterocyclic nitrogen compounds with at least two ring nitrogen atoms and their substitution products are allowed to react with orthophosphoric acid or their mono- and diesters. 2. The method according to claim 1, characterized in that one with orthophosphoric acid or their monoester formed heterocyclic amide with a second molecule of the NN'-carbonyl compound lets react. 3. Process according to claims 1 and 2, characterized in that the formed heterocyclic amides of phosphoric acid isolated in the form of their salts. © 109 689/225 9.61