PROCESS FOR PREPARING N-(DIBENZYLOXYPHOSPHORYL)-CYANAMIDE AND PROCESSES USING SAID COMPOUNDS AS INTERMEDIATE FOR THE SYNTHESIS OF PHOSPHAGEN SUBSTANCES

Abstract: The invention relates to a process for preparing com­ pounds of general formula: wherein R = Hydrogen, halogen, alkyl, nitro-group; said com­ pounds, which are indicated hereinunder with the general term «N-(dibenzyloxyphosphoryl)-cianamide» are useful as inter­ mediates in the synthesis of phosphagen compounds such as phosphocreatine, phosphocreatinine and similar compounds. Such process is characterized in that dibenzyloxyphosphoryl chloride is reacted with cyanamide, N-(dibenzyloxyphosphor­ yl)-cyanamide being produced; this latter can react with sub­ stances provided with a primary or secondary amine function, to give the corresponding guanidinoderivatives; e.g., with a sarcosine derivative to give N-(dibenzyloxyphosphoryl)-crea­ tine or N-(dibenzyloxyphosphoryl)-creatinine.

Description: Disclosure It is well known that phosphocreatine is a compound of fundamental importance in the mechanism of muscular contraction in vertebrates. It is indeed a phosphagen substance: it is namely a stock of high-energy phosphor ic groups. As such, it is prevailingly present in muscular tissue, wherein it is capable of promptly transforming ADP into ATP, in a reaction catalyzed by creatine kinase. Similarly interesting are- compounds such as N-phosphoryl-creatinol, phosphoarginine and other molecules of similar structure. Several industrial syntheses are known of these compounds, which proceed through the preparation of an in termediate, N-(dibenzyloxyphosphoryl)-cyanamide, from which e.g. N-(dibenzyloxyphosphoryl)-creatinine of for mula (I) can be obtained, from which then phosphocreatine (II) can be obtained via the following reaction scheme A: EMI1.1 and phosphocreatinine (III) via the following reaction scheme B: EMI2.1 The preparation of the intermediate N-(dibenzyloxyphosphoryl)-creatinine (I) is presently carried out most ly by means of the synthesis which is summarized by the reaction scheme C shown hereunder: C) Preparation according to known methods of an inter mediate, dibenzyloxyphosphoryl chloride (IV); then reaction of this latter according to the following steps: EMI2.2 EMI3.1 In other terms, according to the presently known reac tion summarized in scheme C, the intermediate (IV) is reacted with S-methylisothiourea (V), and then the soobtained corresponding N-dib < yloxyphosphoryl)-deriva- tive (VI) is cleaved by means of mercury oxide and sodium carbonate, sodium N-(dibenzyloxyphosphoryl)-cyana mide (VII) being obtained, which is separated from mercury mercaptide, poorly soluble, by filtering. The subsequent reaction of (VII) with sarcosine meth ylester hydrochloride (VIII) supplies then the derivative (I). The synthesis of scheme C suffers from several drawbacks: one of such drawbacks is due to the circumstance that in the synthesis toxic, and hence of dangerous handl ing and environmental polluting reactants and products are involved; we refer in particular to the use of mercury oxide and of S-methylisothiourea, and to the mercaptan and to the mercury mercaptide produced in the synthesis. It is clear that it would be very desirable to be able to avoid the use, or the formation, in the reaction ambient of so muxh toxic compounds, and this is precise ly a purpose of the present invention. A second problem of the known synthesis hereinabove recalled is connected with the low overall yield of the reaction, with consequent high incidence on the cost of the process of some reactants, in the first place of N (dibenzyloxyphosphoryl)-S-methylisothiourea, whose pres ence therefore, also due to this latter reason, it would be desirable to avoid. A further drawback of the preparation technology of the known art heretofore discussed consists in that N (dibenzyloxyphosphoryl)-creatinine so produced is polluted by impurities (mainly by mercury and mercaptan) hindering the subsequent hydrogenolytic reaction, in that they poison the catalyst. Such a phenomenon makes it necessary to perform repeated recristallizations of the intermediate which, in addition to increasing the overall cost of the process, lower still more the yields. Purpose of the present invention is therefore also to solve the further problems of the known art just men tioned, by providing a substantially original new synthesis, cheaper and characterized by higher yields. To the purpose of achieving the purposes mentioned, the present invention provides a process for preparing N (dibenzyloxyphosphoryl)-cyanamide, useful as intermediate in the synthesis of phosphagen compounds such as phosphocreatine, phosphocreatinine and similar compounds, characterized in that dibenzyloxyphosphoryl chloride is reacted with cyanamide, dibenzyloxyphosphoryl-cyanamide being produced. This latter can be then reacted with a compound bear ing a primary or secondary aminic function, to give a guanidine derivative. For instance, by reaction with a derivative of sarcosine, the corresponding derivative of N-(dibenzyloxyphosphoryl)-creatine or -creatinine can be obtained. The invention consists therefore essentially in pro viding a step of direct synthesis of N-(dibenzyloxyphos phoryl)-cyanamide from dibenzyloxyphosphoryl chloride (it being possible to obtain this latter by any one of several known methods) and cyanamide: the fact that such a reaction gives favourable results may be defined as surprising and unexpected aspect of the invention, in that such a reaction, never described before, takes place in heterogeneous phase, as dibenzyloxyphosphoryl chloride is soluble in organic solvents, and sodium cyanamide is only soluble in water or in polar solvents. It is moreover known that cyanamide has a strong inclination to instability, and, in alkaline medium, it easily forms a dimer, so that from the reaction step under discussion, the formation would be expectable not of dibenzyloxyphosphoryl-cyanamide, but on the contrary of N-(dibenzyloxyphosphoryl)- '-cyanoguanidine. According to the invention, it is a crytical condition for such a step of direct synthesis to succeed, that the reaction temperature be maintained under +50C, and that an adequate stirring be provided. The synthesis process according to the invention takes place advantageously within the same reaction ambient, it being not necessary that intermediates be isolated. To the purpose of better understanding characteris tics and advantages of the invention, in following Ex ample 1, a summarizing but not limitative scheme is re ported, followed by a description of the reactions there in shown. Example 1 EMI7.1 <tb> <SEP> a\ <SEP> O <tb> <SEP> '0 <SEP> II <SEP> Q, <tb> <SEP> h <SEP> ,1 <SEP> CH <SEP> c) <tb> <SEP> O <SEP> E <SEP> V <SEP> I <tb> <SEP> Ln <SEP> Ln <SEP> rt <SEP> X <SEP> <tb> t <SEP> + <SEP> 2 <SEP> u\ <SEP> Ln <SEP> n <SEP> n <SEP> u <SEP> h <tb> <SEP> 3 <SEP> 65 <SEP> o <SEP> = <SEP> 2 <SEP> m <SEP> II <SEP> h <tb> <SEP> v <SEP> v <SEP> W <SEP> CH2 <SEP> h <SEP> o <tb> <SEP> Ln <SEP> m <SEP> rl <SEP> U <SEP> U <SEP> O <SEP> C <tb> <SEP> X <SEP> X <SEP> a, <SEP> I <SEP> I <SEP> h <SEP> I <SEP> U <SEP> ---- <SEP> '4 <SEP> PI <tb> <SEP> Dibenzylpho <SEP> h <SEP> I <SEP> I <SEP> I <SEP> I <SEP> m <tb> <SEP> U <SEP> U <SEP> rl <SEP> CU <SEP> C\I <SEP> O <SEP> rl <SEP> X <SEP> 'u <SEP> o <tb> <SEP> I <SEP> I <SEP> C <SEP> X <SEP> X <SEP> C <SEP> CV <SEP> CU <SEP> h <SEP> O <SEP> R <SEP> rT <SEP> A <tb> <SEP> A <SEP> v <SEP> v <SEP> - <SEP> CH2 <SEP> x <SEP> C6H5 <SEP> x <SEP> ·O <SEP> h <SEP> CH2 <SEP> 5 <SEP> C6H5 <tb> <SEP> (U <SEP> (V <SEP> m <SEP> m <SEP> U <SEP> U <SEP> o <SEP> h <tb> <SEP> X <SEP> Xoi <SEP> lo <SEP> C <SEP> P <SEP> X <tb> <SEP> U <SEP> UC <SEP> C <SEP> I <SEP> I <SEP> F4 <SEP> o <tb> <SEP> A <SEP> o <SEP> o <SEP> A <SEP> xa <SEP> / <SEP> m <tb> <SEP> I <SEP> H <SEP> + <SEP> SO2Cl2 <SEP> r <SEP> P <tb> o <SEP> O <SEP> s <SEP> CH2 <SEP> - <SEP> C <SEP> o <SEP> Cl <SEP> \ <SEP> / <SEP> CH2 <SEP> - <SEP> C <SEP> H <tb> <SEP> \ <SEP> / <SEP> A <SEP> A <SEP> H <SEP> A <SEP> h <SEP> u <SEP> u <SEP> d <tb> <SEP> CP <SEP> x" <SEP> x" <tb> <SEP> / <SEP> \ <SEP> CH2 <SEP> -C6H5 <SEP> O <SEP> H <SEP> NaOH <SEP> o <SEP> Sz <SEP> I <SEP> .Z <SEP> h <SEP> c) <SEP> v <tb> <SEP> ot <SEP> . <tb> <SEP> o <tb> <SEP> -rl <SEP> A <SEP> CH2 <SEP> -C <SEP> O <tb> <SEP> ll <SEP> ç <SEP> a) <SEP> g: <SEP> \ <SEP> v <tb> <SEP> 2 <SEP> w <SEP> a <SEP> uo <SEP> O <tb> <SEP> a, <SEP> C <SEP> R <SEP> o <SEP> r <SEP> 10 <SEP> c <tb> <SEP> H <SEP> dibenzyloxyphosphoryl <SEP> = <SEP> o <SEP> ' <SEP> < 1&commat; ;o <tb> c <SEP> H <SEP> a) <SEP> v <SEP> 0 <SEP> H3C-NH-CH2-COX <SEP> Toluene/ <SEP> C6H <SEP> CH <SEP> 0 <SEP> 0 <tb> <SEP> h <SEP> g <SEP> ò <tb> <SEP> V <SEP> O <SEP> O <SEP> a <SEP> F <SEP> bOP <tb> <SEP> gh <SEP> O <SEP> Ed <SEP> I <SEP> CD <SEP> O <SEP> A <SEP> M <tb> <SEP> " <SEP> " <SEP> qg-P <SEP> OR <SEP> m <SEP> H <SEP> G) <SEP> H <tb> a <SEP> u <SEP> -CH2O <SEP> NH <SEP> d <SEP> C <SEP> rt <SEP> N <SEP> Me <SEP> = <SEP> physiological <SEP> 80O5oC <SEP> C6H5CH2O <SEP> NH-C=N <tb> <SEP> ly <SEP> acceptable <tb> <SEP> metal <SEP> C=O <tb> <SEP> H <SEP> cu <SEP> O <SEP> u <tb> <SEP> H <SEP> 1 <SEP> 11 <tb> <SEP> u <SEP> U <SEP> II <SEP> II <tb> <SEP> CU <SEP> III <SEP> c <SEP> a, <tb> <SEP> O <SEP> O <SEP> m <SEP> H <SEP> E <SEP> PR <tb> <SEP> tinine <tb> <SEP> ocM <SEP> zcM <tb> <SEP> uz <SEP> n <SEP> 111 <tb> <SEP> o <SEP> ± <SEP> Q <SEP> m <SEP> t <SEP> c <tb> <SEP> N <SEP> V <SEP> V <SEP> \ <tb> <SEP> > <SEP> V <SEP> V <tb> <SEP> V <tb> <SEP> m <tb> <SEP> to <SEP> N <SEP> C\J <SEP> CU <SEP> CM <SEP> O <SEP> Z <tb> <SEP> m <SEP> m <SEP> x <SEP> m <SEP> m <SEP> s <tb> <SEP> t0 <SEP> V <SEP> V <SEP> V <SEP> V <SEP> \ <SEP> / <tb> <SEP> C) <SEP> X <tb> <SEP> o <SEP> O <SEP> O <SEP> O <SEP> O <SEP> o <tb> <SEP> A <SEP> A <tb> <SEP> V <SEP> fi <tb> <SEP> Pq <SEP> o <SEP> x <SEP> o <SEP> C > <SEP> V <SEP> V <tb> Example NO 1 N-(dibenzyloxyphosphoryl)-cyanamide: Into a glass equipment, of suitable volume, 250 ml of toluene and 106,76 g of phosphorus trichloride are added. The reaction mass is cooled, and at the temperature of 8 - 10 C, a mixture is added of 65 g of benzyl alcohol and 130,5 ml of pyridine in 250 ml of toluene. The reac tion mass is maintained at 8 - tOOC for 30 minutes, and is then cautiously treated with 200 ml of water. The tem erature is then allowed to rise to 200C, the mass is stirred for 30 minutes, and the aqueous phase is separated. Such phase is extracted with 100 ml of toluene. The combined toluenic phases are concentrated to a small volume in vacuo. To this solution, cooled at 10 C and kept under a nitrogen atmosphere, a solution is slowly added of 80 ml of sulphuryl chloride in 280 ml of tolu ene, the mass is then stirred for 1 hour at 100C, under a flow of nitrogen. The reaction mass is cooled, and to it concentrated NaOH (density 1,33) is slowly added, un der strong stirring, until pH 5 is reached in the aque ous phase. To the reaction mass, 40 g of cyanamide and 140 ml of a NaOH solution at d = 1,33 are added. The reaction is allowed to proceed for 1 hour and 30 minutes at 0 C. Sodium N-(dibenzyloxyphosphoryl)-cyanamide is so obtained, dissolved in the aqueous phase. Example N02 Crude dibenzyloxyphosphoryl-creatinine To the reaction mass outcoming from a process as described in Example NO 1, 95 g of sarcosine methyles ther hydrochloride dissolved in 270 ml of ethanol are added. pH Is adjusted at 6 with acetic acid, and the mass is refluxed for 5 hours. The solvents are distilled off under vacuum, until an oily residue is obtained, which is mixed with 600 ml of water. The aqueous mixture is cooled and filtered. About 200 of white-grey precipitate are obtained, of crude and moist N-dibenzyl oxyphosphoryl-creatinine. Example NO 3 Pure dibenzyloxyphosphoryl-creatinine The preceding product, still wetted with water, is dissolved upon warming in 360 ml of isopropanol. The reaction mass is filtered with activated charcoal, and the filtrate is cooled. The product crystallizes, which is filtered and dried. Are obtained 128 g of white, crys talline N-(dibenzyloxyphosphoryl)-creatinine, melting point 91 - 94OC. Assay value with HClO4 of 100,210. Moisture (K.F.) of 0,2% Example NO 4 S-di-(p-chlorobenzyloxy)-phosphoryl-cyanamide Into a glass equipment, of adequate volume, 50 ml of toluene and 21,32 g of phosphorus trichloride are intro duced. The raction mass is cooled, and while keeping it at the temperature of 8 - 100C, a mixture is added of 43,6 g of p-chlorobenzyl alcohol and 39,33 g of 5-ethyl2-methylpyridine in 70 ml of toluene. When the admixture is ended, the mass is further stir red for 30 minutes at 10 - 150C, it is then cautiously treated with 40 ml of H20, and the reaction is allowed to proceed for 30 minutes at room temperature. The phases are separated; the organic phase is concentrated, until an oily residue is obtained. This re sidue is diluted with 50 ml of toluene, and is then treat ed with 16 g of sulphuryl chloride diluted with 55 ml of toluene, under a nitrogen blanket. The reaction is allow ed to proceed for 1 hour, always under a nitrogen flow, and the reaction mass is then cooled. A toluenic solution is thus obtained of di-(p-chlorobenzyloxy)-phosphor yl chloride. To the preceding reaction mass, cooled to OOC, 35 ml of NaOH solution (density 1,33) are added, up to pH 5 - 6. 8 Grams of NH2CN are then added, and subsequently another 30 ml are added of NaOH solution (d = 1,33). The mass is further stirred for 1 hour and 30 minutes. An aqueous solution is so obtained of sodium N-(di-p-chlorobenzyloxyphosphoryl)-cyanamide, which dees not require to be isolated. Example NO 5 N- ( di-p-chlorobenzyloxyphosphoryl )-creatinine: To the reaction mass, outcoming from a process as described in Example NO 4, 126 g are added of a 38,9* solution of sarcosine methylester hydrochloride in ethyl alcohol. The reaction mass is refluxed for 5 hours. The solvents are distilled off in vacuo, until an oily residue is obtained, with is mixed withmdhanol. Some en trapped salts are filtered off upon warming. By cooling of the filtrate, the product crystallizes. It is separated by filtration, and dried. An amount of 14 g of N-(di-p-chlorobenzyloxyphosphoryl)-creatinine is obtained. Example N0 6 A-Phosphocreatinol To a solution of sodium N-(dibenzyloxyphosphoryl)- cyanamide, prepared as described in Example NO 1, 80 g of 2-methylamino-ethanol are added, and the reaction mass is buffered at pH 5 - 6 with 73 ml of acetic acid. The reaction mass is stirred for 10 minutes, and its pH is checked adjusting it with snother 15 ml of CH3-COOH to remain at pH 6. The mass is heated to reflux tem perature, and is refluxed for 1 hour, and is then cooled. The reaction mass is extracted with water made acid with CH3-COOH, to extract the excess of 2-methylaminoethanol. The toluenic phase is collected, is concentrated to a small volume, and is diluted with 400 ml of methanol. An amount of 30 g of aniline is added thereto. The obtained solution is submitted to hydrogenolysis in an autoclave, using 1 g of 10% Pd on C. The hydrogenolysis is carried out at room temperature, and under a 4 atm pressure. When the absorption of hydrogen ceases, the mass is discharged and filtered. The precipitate is con stituted by the product, by the catalyst and by salts. The precipitate is suspended in 100 ml of cold water, is stirred for 5 minutes, and is filtered. The filtrate, treated with 400 ml of acetone, allows 25 g of N-phosphocreatinol to separate. With reference to heretofore reported Examples, many different embodiments can be provided, without thereby going out of the invention domain, as it was substantially defined hereinabove. In particular, different to those exemplified may be the syntheses of dibenzyl phos phite and of dibenzyloxyphosphoryl chloride, which will be suitably selected by one skilled in the art among all those described in the technical literature, as well as different to those shown in the Examples may be the working conditions of the end steps in the synthesis of the intermediate N-(dibenzyloxyphosphoryl)-creatinine provided that the heretofore disclosed conditions are respected, which are the object of the present invention, in the synthesis step of N-(dibenzyloxyphosphor yl)-cyanamide. A first advantage of the invention is clear, i.e., the avoiding of the use of toxic reactants, such as S-methylisothiourea and mercury oxide, and hence of the consequent risks of toxicity in the working ambient, and of pollution and environmental damaging. The danger is also avoided of poisoning of the catalyst by toxic reactants or reaction products in the end synthe sis step of phosphocreatine and of phosphocreatinine, and of obtaining a product not pure, and hence to be pu rified. For understanding how the invention additional ly efficaciously reaches also the purpose of providing a synthesis process financially more advantageous than the known art reminded in the introduction to the dis closure, it is useful to take into account the high o verall yields of N-(dibenzyloxyphosphoryl)-guanidino- derivative obtainable in that way; the working simple ness, which does not require that any intermediate pre ceding the N-(dibenzyloxyphosphoryl)-guanidino-derivati ve be isolated; the purity of the product, obtained by means of a simple crystallization, not requiring any further purification steps1 nor poisoning possible hz drogenation catalysts used in the hydrogenolysis of benz yl groups, giving high yields of de-benzylated product. An object of the present invention is also the preparation from the intermediate produced, as described hereinabove, of phosphagen compounds of general formula EMI13.1 wherein: R1 n X Resulting compound CH3 1 -COOH Phosphoryl-creatine H 3 -CH(NH2)CO0H Phosphoryl-arginine H 2 -S03H Phosphoryl-taurocyamine H 1 -COOH Phosphoryl-glycocyamine H 2 -OPO(OH)OCH2CH(NH2)COOH Phosphoryl-lombricine CH3 2 -OH Phosphoryl-creatinol and Me = H or a metal forming a physiologically accept able salt and the products of intramolecular condensation between the group X and the group NH of the compounds of formula (IX), such as e.g. phosphoryl-creatinine sodium salt. EMI13.2 For the synthesis of such compounds of formula (IX), and of their condensation derivatives, starting from the intermediate N-(dibenzyloxyphosphoryl)-cyanamide prepar ed according to the invention, reference is made to the known techniques described in technical literature.

Claims: Claims 1. Process for the preparation of N-(dibenzyloxyphos phoryl)-cyanamide, useful as intermediate in the synthe sis of phosphagen compounds such as phosphocreatine, phos phocreatinine and similar compounds, characterized in that dibenzyloxyphosphoryl chloride is reacted with cyanamide with production of N-(dibenzyloxyphosphoryl)cyanamide. 2. Process as claimed in claim 1, characterized in that the reaction ambient is alkaline, and that the tem perature is not higher than +50C. 3. Process as claimed in claim 1, characterized in that the reaction between dibenzyloxyphosphoryl chloride and cyanamide is carried out in mixtures of solvents or in immiscible solvents, wherein dibenzyloxyphosphoryl chloride and cyanamide are respectively soluble. 4. Process as claimed in claim 1, characterized in that the process is carried out within the same reaction ambient, without isolating intermediates. 5. N-(dibenzyloxyphosphoryl)-cyanamide prepared by means of the process as claimed in one or more preceding claims. 6. Process for the preparation of guanidino-derivatives, characterized in that N-(dibenzyloxyphosphoryl)cyanamide prepared by means of the process as claimed in one or more preceding claims is reacted with substances bearing a primary or secondary amine function. 7. Process for preparing phosphagen compounds of gen eral formula EMI15.1 wherein: R1 n X CH3 1 -COOH H 3 -CH(NH2)COOH H 2 -SO3H H 1 -COOH H 2 -OPO(OH)OCH2CH(NH2)COOH CH3 2 -OH and Me = H or a metal forming a physiologically accept able salt, and the intramolecular condensation products between said group X and said group =NH, such as phosphoryl-creatinine disodium salt of formula EMI15.2 characterized in that as intermediate of synthesis, N (dibenzyloxyphosphoryl)-cyanamide is used, prepared ac cording to the process as claimed in one or more preced ing claims. 8. Compounds of general formula IX as defined in claim 5, characterized in that they are prepared accord ing to the process of claim 5. C L A I M S FOR AUSTRIA 1. Process for the preparation of N-(dibenzyloxyphosphoryl)-cyanamide, useful as intermediate in the synthesis of phosphagen compounds such as phosphocreatine, phosphocreatinine and similar compounds, characterized in that dibenzyloxyphosphoryl chloride is reacted with cyanamide with production of N- ( dibenzyloxyphosphoryl ) -cyanamide. 2. Process as claimed in claim 1, characterized in that the reaction ambi is alkaline, and that the temperature is not higher than +50C. 3. Process as claimed in claim 1, characterized in that the reaction between dibenzyloxyphosphoryl chloride and cyanamide is carried out in mixtures of solvents or in immiscible solvents1 wherein dibenzyloxyphosphoryl chloride and cyanamide are respectively soluble. 4. Process as claimed in claim 1, characterized in that the process is carried out within the same reaction ambient, without isolating intermediates. 5. Process for the prepartion of guanidino-derivatives, characterized in that N-(dibenzyloxyphosphoryl)-cyanamide prepared by means of the process as claimed in one or more preceding claims is reacted with substances bearing a primary or secondary amine function. 6. Process for preparing phosphagen compounds of general formula EMI16.1 wherein: R1 n X CH3 1 -COOH H 3 -CH(NH2)COOH H 2 -SO3H H 1 -OOH H 2 -OPO(OH)OCH2CH(NH2)COOH CH3 2 -OH 3 and Me=H or a metal forming a physiologically acceptable salt, and the intramolecular condensation products between said group X and said group = NH, such as phosphoryl-creatinine disodium salt of formula EMI17.1 characterized in that as intermediate of synthesis, N-(dibenzyloxyphosphoryl)-cyanamide is used, prepared according to the process as claimed in one or more preceding claims.

Inventors: GUERRATO, ALFREDO, RIZZI, AMLETO VIA CALESELLA 65
Applicants: F.I.S.  FABBRICA ITALIANA SINTETICI S.P.A.
Application year: 1985
Main classification: C07F9
IPC codes: C07F9