DE1793730A1 - INTERMEDIATE IN THE MANUFACTURING OF PHOSPHORYL CREATININE AND PHOSPHORYL CREATINE - Google Patents

Description

DR. BERG DIPL.-ING. STAPF PATENTANWXlTK

8 MUNICH BO. MAUERKIRCHERSTIT.

179373Q

Dec 21, 1371

Lawyer file 21 993 ■ ^:

UGINE KÜHLMANN Paris / PRANCIA

"Intermediate product for the production of phosphoryl creatinine and phosphoryl creatine. "

Inventor: Jesus ANATOL, Paris. · ·

The present invention relates to a new intermediate for the preparation of phosphoryl creatinine and of the phosphoryl creatine, namely the dibenzyloxyphosphory! creatinine the formula:

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IV / ßl - 2 -

- CH - O ^ .NH - CO

It is known that the O-substituted derivatives of isoureas, the S-substituted derivatives of iso'thiourea φ substances or the substituted cyanamides are capable of with Amines react to form guanidines'; so e.g. have P. CRAMER and A. VOLLMAN, see Chemical Reports, Vol. 9.1, 1958, page 92o - diesters of phosphorylisothioureide with Amino derivatives condensed and thereby the ", - possibility '" of Condensation withoCr amino acids or esters of u ^ amino acids established. In fact, the applicant was able to state that such condensation allows Trieste of phosphorylated and by a one. COOH group containing chain substituted guanidines. So, following this procedure, one arrives at that Ethyl ester of dibenzyloxyphosphoryl creatine of the formula:

C ₆ H ₅ - CH ₂ -

-NH-CN- CH ₂ -.COOC ₀ H ^ (II) 3

I - CH - Q ^ i · 'I

5 2 0 NH C

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BATHROOM, ORIGWNAL

It has been found that this triester can be carefully subjected to hydrolysis
such that only the carboxylic acid ester group is hydrolyzed. ·

The contact of this Trieste in an aqueous-alcoholic medium with dilute cold caustic soda hydrolyzes
the ester function of the carboxyl group.

The sodium salt of dibenzyloxy-phosphoryl creatine obtained in this way is transformed into dibenzyloxy-phosphoryl creatinine under the action of even weak acids
converted, according to, the following reaction:

NH COONa P - NH-

- CH ₂

.NH - CO

.- "■ <■ i

^X N - CH ₀ (III)

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For the production of Dibenzyloxyphosphorylkreatinin der Formula (I) can be the ethyl ester of Dibenzyloxyphosphorylkreatins Treat in an aqueous-alcoholic medium with dilute cold sodium hydroxide and the obtained Treat the sodium salt of the diester with equimolar amounts of acid based on the sodium hydroxide to be released.

The constitution of the derivative of the formula (III) was determined by centesimal analysis and also by comparison with the results obtained when one was made from ethyl-diphenoxyphosphoryl ran out of. If this triester is treated in a similar way, diphenoxy-phosphorylcreatinine is produced after the following reaction:.

P-NH-C

COOC ₁ H-

Γ H OH

^υ 6 -5 0 N-CH ₂ NaOH χ

I H +

Am - co

-N = C ^

- CH- (VII)

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■ .- ■ - 5 -

This substance was made by H * R. ING (Journal of the Chemical Society, 1952, page 2054) and by K. ZEILE and H. MEYER (Hoppe-Seyler's Zeitschrift für Physiologische Chemie _} 252, 1938, page löl); these researchers obtained the substance by methods entirely different from that of the present invention.

In contrast to the esters and the salts of the alkali metals des dibenzyloxyphosphoryl creatine, which cannot be crystallized and are difficult to isolate from the reaction medium used for their preparation, is dibenzyloxyphosphory! creatinine crystallizable, easy to isolate and easy to clean «

These remarkable properties allow its Derivatives are easy to manufacture, even on a technical scale and enable a very high degree of purity as far as the products themselves are concerned. This is a very significant advantage because phosphocreatine or Phosphocreatinine administered to humans.

The triester of the formula (II) can be derived from the N-dibenzyloxy-phosphoryl derivative

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of the S ^ methyl-isothiourea of the formula

O ₆ H ₅ -CE ₂ -O

O ■ KH -

produced, which by -the-.action of the in Carbon tetrachloride dissolved dibenzyl phosphite (A «K« üA vol u * a * -Journal of the Chemical Society, 1945, page 662) on the S-methyl-isothiouronium sulfate in the presence of Sodium hydroxide was obtained *

This ii-dibenzyl-oxy-phosphoryl-S-ethyl-isothiourea was subjected to the action of mercury oxide (HgO) in order to produce the corresponding cyanamide, - taking into account the work of H, J. BACHER. And .H. 1- «IOLD (Collection of the chemical works of the Kiederlsndo, 66, page 335) and by H, J. BACKER and SK ₄ VkODKAK der Chemischen Arbeit der Netherlands, 66, 595) "These authors have observed the low lipophilicity of p-nitro-phenyl-sulfonyl-cyanafiiide * On the other hand, they have shown the possibility of working with its sodium salt. For this reason, it is advisable to add sodium carbonate to the desulphurizing medium, so that the dibenzyl-

^ cyanaiaids dtgsen iTatriuüidgrivat is formed, 209886/1241

BADORiGlNAL

^ P-K-CK

y ¹

C ₆ H-CH-O- [I.

This salt reacts in alcoholic fcedium with the chlorohydrate of ethyl sarcosinate, whereby - '' λ thy 1-dibenzyl-oxyphosphoryl-creatinat is formed according to the following scheme:

^ F- N - 0N + (ClIi) .KH - CH ₂ -COOC ₂ H ₅ - ^ (H)

j ■■ 1

Ka C

0 Ka

In the example below that the search scope In no way intended to restrict, the parts specified are molded parts, unless otherwise stated will.

In one equipped with a stirrer and a cooler 175 parts of dibenzyloxyphosphoryl-O-methylisothiohsrnstoff are introduced into the apparatus, 3000 parts of 80% alcohol, 26.5 parts Sodium carbonate and 54 parts of red mercury (II) oxides. Iisn heated for two hours while stirring at the boiling temperature After cooling, the mercury acid captide is filtered off and removed the solvent under reduced pressure. The residue is taken up in 1000 parts of absolute alcohol. 7-175 parts of the chlorohydrate are added to this solution

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BAD RlQWAL

of the ethyl ester of sarcosine with a melting point of 121 ~ 122 °, dissolved in 200 parts of alcohol. Ivan lets stand overnight and then refluxes the genius for two hours. After cooling and filtering off the sodium chloride, the alcohol contained in the filtrate is removed. The residue is dissolved in 250 parts of alcohol, whereupon 60 parts by volume of 10N sodium hydroxide solution are added. The whole thing is left in contact for an hour, then 250 parts of water are added and the filter is filtered .. Tue? The solution is acidified with 36 parts of acetic acid; it is left to crystallize overnight, filtered, the precipitate is washed with 5C alcohol, then with water and finally with 50% alcohol, whereupon it is dried in the oven at $ 0. This gives 132 reile dibenzyloxyphosphoryl creatinine with a melting point of 91-92 °, i.e. a yield of 71>·> ·

This dibenzyloxyphosphoryl creatinine is suitable without further purification very good for the production of Ih.osphocreatinine. as well as phosphocreatine.

For the purpose of analysis, the product is allowed to recrystallize from Oyjigea I-.othanol, the yield being 90 ° and the melting point being 93 °.

Analysis for C ,, oH ^ qN., 0.p:

Calculated: 57.900 C, 5.40 ^ H, 11.25 p N, 8.30 /; ϊ Found: 57.68 ^ C, 5.96 # H, 10.89 # N, .8.54 # F.

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BAD ORiOIWAL

The Ii-dibenzyloxyphodphoryl-u-ine used in the previous example thy! -isothiourea (IV) as manufactured under:.

In an apparatus which is provided with a mechanical stirrer, a thermometer and a metering device, 99 ropes of S-methyl-isothiourea sulfate are dissolved in 294 parts of v / water, which is produced as described in "Organic Syntheses' ¹ , Vol. XIi, öeite 52.'l'kin adds parts of dibenzyl phosphite (preparation according to TODD - Journal of the Chemical Soc, 1945, page 384 and 1946, page 662), dissolved in 750 parts of carbon tetrachloride. Under good stirring and means Dian adds 56/8 parts of sodium hydroxide, dissolved in 1? 0 parts of water, to the metering device and maintains the temperature at 5-10 ° by means of a cooling bath. The sodium hydroxide solution is introduced over the course of about an hour. The mixture is stirred for another hour and then left to stand until the next day. 300% chloroform are then added to dissolve the solid and then decanted. The organic phase is dried over sodium sulfate. It is filtered and evaporated to dryness under reduced pressure. The I-roduct that clumps together to form a cash register is filtered off with the aid of petroleum ether. In this way, 225 parts of K-dibenzyloxj'phosphoryl-S-methyl-isothiourea are obtained, ie a yield of 90%. The product melts

■ - 10 -

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BADORlQiNAL

in the capillary tube at 85 ?. fran it can be from mixtures of Recrystallize ethanol and water or benzene and ± etrolether, the melting point then being '86 °. Analysis for C ^ H lyXl- .S

Calculated *: 7.99> 3 N, 8 _r 84> 5 F, -9.14 *> 3 Found: 7.652 N, 8.75 ^ F, 9, x 27 £ 8.

Claim. :

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BATH

Claims (1)

Claim: Dibenzyloxyphosphoryl creatinine of the formula j-- CH ₂ - (K --CH ₂ -O H- CO N CH CH. 2098SC / 1246