SI8211067A8 - Process for preparing of 9-(1,3-dihydroxy-2-prophoxy-methyl)guanine - Google Patents

Description

Process for the preparation of novel 9- (1,3-dihydroxy-2-propoxymethyl) guanine

Technical field of the invention

The present invention relates to the field of synthesis chemistry, and specifically relates to a process for the preparation of a novel, antiviral-effective 9- (1,3-dihydroxy-2-propoxymethyl) guanine.

A technical problem

There was a need to find a new, technologically advanced process for the preparation of novel 9- (1,3-dihydroxy-2-propoxymethyl) guanine, suitable for the control of viral infections, in good yields and with a satisfactory purity.

The state of the art

9- (1,3-Dihydroxy-2-propoxymethyl) guanine is a new compound, so the process for its preparation has not yet been described.

Viral infections are widespread and are reflected in a variety of symptoms. Some viral infections are easily overcome by the body's defense mechanism, while others are more serious in nature and lead to permanent damage, e.g. blindness and even death.

- 2'Bia of these virus families that can cause serious infections is the Herpes virus group.

Drugs used to treat viral infections today are in many cases ineffective but, if effective, required in large and / or continuous doses that cause serious side effects and / or toxicity. Therefore, there is a need for an effective antiviral agent that is effective at lower dosages, such as the drugs available today, reducing the risk of possible side effects and toxicity

U.S. Pat. 4 199 574 describes the compounds shown by the following generic formula:

d in which X is sulfur or oxygen, H is hydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, alkylamino or dialkylamino,

R is hydrogen, halogen, alkylthio, acylamino, amino or azide, R- ² is hydrogen, straight or branched or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl, R is hydrogen, hydroxy or alkyl, R is hydrogen, hydroxy, amino, alkyl , hydroxyalkyl, benzyloxy, benzoyl oxy, benzoyloxymethyl, sulfamoyloxy, phosphate, carboxypropyamyloxy, straight or cyclic acyloxy of 1 to 8 carbon atoms, acetoxy or substituted carbamoyl group of formula NHCO-Z, wherein Z is alkyl, aryl or aralkyl substituted by one or more sulfonyls, amines, carbamoyls or halogens, R is water:

Or alkyl, with the proviso that when X is oxygen and R, R, R and

hydroxy, but salts thereof.

The class of compounds shown by the formula above and the pharmaceutically acceptable acid addition salts have been shown to exhibit anti-viral activity. GL e j also Tetrahedron Letters. 21,327-30 (1980).

Description of solution to a technical problem with implementation examples

We have now found, however, that surprisingly, compound 9 (1,3-dihydroxy-2-propoxymethyl) guanine and its salts are a particularly effective anti-viral agent. The selective activity of this compound is emphasized when comparing the compound with the most structurally broad compound shown in U.S. Pat. 4 199 574 and in the antivirus experiment, as shown in more detail in the γ case -.- 5.

According to the invention, a process for the preparation of 9- (1,3dihydroxy-2-propoxymethyl) guanine of the formula is proposed

(I) and its pharmaceutically acceptable salts.

Pharmaceutical compositions containing the compound of the invention as an essential ingredient are also described. These compositions may contain other pharmaceutically effective ingredients of the same indication. In most cases, these compositions will contain suitable pharmaceutical carriers or excipients.

We also describe a method for treating viral infections comprising administering a compound of formula (I) or a composition containing it.

The process for the preparation of a compound of formula (I) and its pharmaceutically acceptable salts comprises:

a) deacylating a compound of formula ύτΛ

R-N ^ ir

H CH ~ OCHCH ₀ OH i 2 ch ₂ oh where R is defined as an acyl group,

R ”8, wherein R is a straight or branched hydrocarbon chain of one to ten carbon atoms to give 9- (1,3-dihydroxy-2-propoxy methyl) guanine, or

b) dearalkylating a compound of formula

wherein R 'is defined as a protecting group, such as benzyl, which is optionally substituted by 1 or 2 alkoxy groups, where alkyl has the above defined meaning, preferably 4® methoxy, or lower alkyl groups, where alkyl is defined as straight or a branched hydrocarbon having from 1 to 4 carbon atoms, preferably methyl, to give 9- (1,3-dihydroxy-2-propoxymethyl) guanine, or

- 5 c) dealkylation and deacylation of a compound of formula

where E and E 'have the above meaning to give 9- (1' 3-dihydroxy-2-propoxymethyl) guanine, or

d) conversion of 9- (1,5-dihydroxy-2-propoxymethyl) guanine into a pharmaceutically acceptable salt, or

e) converting the salt of 9- (1, S - dihydroxy-2-propoxymethyl) guanine into 9- (1,5 'dihydroxy-2-propoxy) guanine, or

f) converting the salt of 9- (1 '3-dihydroxy-2-propoxymethyl) guanine into its pharmaceutically acceptable salt.

Compounds of formula IX in which.

in which R represents an acyl group RCO, wherein R is a straight or branched chain hydrocarbon having 1 to 10 carbon atoms, and their salts, prepared by:

a) dearalkylating a compound of formula

wherein R has the above meaning and R 'is a protecting group, such as benzyl, optionally substituted by 1 or 2 alkoxy groups, or lower alkyl groups, where alkyl is defined as a straight or branched chain hydrocarbon having 1 to 4 carbon atoms, or

b) metabolizing a compound of formula (VIII) with Lewis acid,

c) metabolism, compounds of formula (Vlil) with acetic acid,

d) converting a compound of formula (IX) into a salt thereof, or

I

e) converting the salt to the corresponding free compound of formula (IX).

Those compounds of formula IX wherein R is an acyl group as defined above are used as intermediates for a compound of formula I, wherein in this process the compounds are deacylated as described in more detail below.

- 7 In the text of the description and the appended claims, the following terms have an indicated meaning unless otherwise indicated.

Pharmaceutically acceptable salts refer to those salts which have the biological efficacy and properties of the free compound and which are not biologically or otherwise undesirable. The salts may be either acid addition salts or inorganic metal salts, preferably alkali metal salts. Suitable acids for the formation of salts are inorganic acids such as hydrochloric, hydrobromic, sulfuric, hydrochloric, phosphoric acid and the like, of organic! acids are trifluoroacetic, methanesulfonic, ethanesulfonic and p-toluenesulfonic acid and the like. Suitable bases for the formation of salts are organic bases, inorganic metal bases such as copper or silver bases and alkali bases such as alkali hydroxides, e.g. sodium hydroxide, potassium hydroxide, and the like.

The compound of the invention, characterized by the above formula (I), and its pharmaceutically acceptable salts, are characterized in that the substitution with the 1,3-dihydroxy-2-propoxymethyl group in position 9 of the guanine nucleus has a surprisingly strong active compound.

The present compound of formula (I) and its pharmaceutically acceptable salts exhibit potent antiviral efficacy when administered to animals, in particular mammals (humans or animals), cold-blooded animals such as fish, further birds and especially humans. So e.g. the compound of the invention exhibits excellent efficacy against Herpes Simplex viruses I and II and related viruses such as cytomegalovirus,

Epstein-Barr virus and varicella Zoster virus.

- 8 Pharmaceutical compositions, both for veterinary and human medicine, containing a compound suitable for antiviral use, are prepared by methods and may contain fillers well known in the art. A widely recognized collection of such methods and ingredients is listed in Remington's Pharmaceutical Sciences,

E. W. Martin, (Mark Publ. Oo., 15 · ed. 1975) ·

Pharmaceutical compositions may also contain other antiviral agents. Generally, the pharmaceutical composition may contain from 0.1 to 9θ wt. % effective substance.

The compound of formula (I) may be administered parenterally (eg by intravenous, intraperitoneal or intramuscular injection), orally, externally or rectally, depending on whether the preparation is used to treat internal or external viral infections.

For internal infections, the compositions are administered orally or parenterally at dosage levels calculated as free base, about 0.1 to 300 mg / kg, preferably 1.0 to JO mg / kg, of mammalian body weight, and can be used in humans in the form of a dosage form It is given once to four times daily in an amount of 1 to 250 mg per dosage unit. For oral administration, however, fine powders or granules may contain diluents, dispersants and / or surfactants, and may be provided in the form of a drink in water or syrup} in capsules or bags in the dry state or in a non-aqueous solution or suspension, where they may be included suspend agents in tablets where binders and lubricants may be included, or in suspension in water or in syrup. Optional flavors, preservatives, suspending agents, thickeners or emulsifiers may also be included in the price, if desired or necessary. Tablets and granules are preferred and may be coated.

For parenteral or drip administration, such as e.g. for ocular infections, compounds in aqueous solution at a concentration of about 0.1 to 10%, more preferably about 0.1 to 7%, can be provided. The solution may contain antioxidants, buffers, etc.

Alternatively for infections of the eye or other external tissues, e.g. mouth and skin, preferably apply the compositions to the infected portion of the patient's body locally as a lubricant, cream, aerosol or powder, preferably as a lubricant or cream. The compounds may be provided as a lubricant, e.g. with a water-soluble lubricant base, or in a cream, e.g. with an oil in an aqueous cream base at a concentration of about 0.01 to 10%, preferably 0.1 to 7%, most preferably about 0.5 wt./vol.%. Additionally, viral eye infections such as herpes keratitis can be treated using a delayed-release drug system as described in U.S. Pat. 4 217 ^ 898.

The proposed compositions are also useful in the treatment of non-human mammals, birds, e.g. chickens and turkeys and cold-blooded animals as fish. Avian viral diseases such as Nev Oastle disease, Marek's disease, etc. can be prevented and / or treated with compounds of formula (U, by methods well known in the veterinary field, such as the movement of hatching eggs into a solution containing the compound, injection of a composition containing the compound to birds, or and adding a compound of the present invention to feed or drinking water.

Fish that are in a restricted area, such as a pond, aquarium or tank, can also be treated for viral infections such as herb-10. similar viruses, e.g. channel catfish virus (CCV), herpesvirus salomones, Nerka virus, etc., by adding the compound directly into the water of a pond, aquarium or tank, or by incorporating the compounds into the feed.

The exact regimen for administration of the compounds and compositions shown herein will necessarily depend on the needs of the individual subject treated, the type of treatment and, of course, the judgment of a physician.

The compound of formula (I) can be prepared by the following reaction scheme, wherein R is defined as an acyl group,

H

R is 0, where R is a straight or branched chain hydrocarbon having 1 to 10 carbon atoms and R 'is defined as a protecting group such as benzyl which is optionally substituted by 1 or 2 alkoxy groups where alkyl is straight or a branched chain hydrocarbon having from 1 to 4 carbon atoms, preferably methoxy, or lower alkyl groups, where alkyl has the above defined meaning, preferably methyl.

-11 / ° \ ch ₂ chch ₂ ci (II)

CH ~ OR '

I 2

CH ~ OCH ~ C1 and Z 2 ch ₂ or '(IV)

(VI)

CH _o 0R 'I ² ^ ^Η 2 ^0Η CH ₉ 0R' (III)

CH _o 0R '

I ²

CH "OCH" OCCH_

I ^{2 2} II ³ °

CH ₂ OR '(V)

(x)

(IX): hch ₂ oh: h ₂ oh

The compound of formula (III) is prepared by dropwise addition of an epi chlorohydrin (II) to a solution of an alkali salt, preferably a benzyl alcohol sodium salt, optionally substituted as defined above, in a solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphorylphosphoxamide, hexamethylphosphorylphosphuidamide, and dioxane, at a temperature of about 0 to 100 ° 0, preferably about 15 to 40 ° 0. The reaction mixture is stirred for about 10 hours to 24 hours, preferably about 12 hours to 18 hours, at a temperature of about 0 ° C to 100 ° C, preferably about 20 to 5θ ° θ.

The compound of formula (III) is chloromethylated to the compound of formula (IV) by blowing dry hydrogen chloride gas in a solution of the compound and paraformaldehyde dissolved in a halogenated hydrocarbon solvent such as dichloroethane, chloroform, dichloromethane and 1,1,2-trichloroethane, ° 0 to 25 ° 0, preferably at a temperature of about 0 ° C. Hydrogen chloride gas is added over 3θ minutes to 5 hours, preferably over a period of 1 hour to 2 hours, until paraformaldehyde has dissolved. The solution is maintained at a temperature of about 0 ° to 10 ° C for about 12 to 48 hours, preferably from about ⁰ to 5 ° θ for about 16 hours to 24 hours.

The compound of formula (V) is prepared by the metabolism of alkali acetate as sodium acetate, with a compound of formula (IV) dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, temperature, in sulfolane, in sulfolane, in sulfolane, in sulfolane, in sulfanol C to 45 ° 0, preferably about 0 ° C to 25 ° 0. The solution is stirred for about 5 to about 24 hours, preferably about 10 hours to about 18 hours, at a temperature of about 10 ° C to about 3θ ° 0 and preferably at a temperature of about 15 ° ^G to 25 ° 0.

The compound of formula (VII) is prepared by heating guanine (VI) with a carboxylic acid anhydride of 2 to 20 carbon atoms, such as acetiuhydride-butyric anhydride, valer anhydride, caprylanhydride, preferably pure acetal anhydride, at reflux for about 10 to 24 hours. , preferably about 12 to 18 hours.

N ^2, 9 -diacilgvanin of formula (VII) is reacted with a compound of formula (V) to form a compound of formula (VIII) alone or in a solvent such as dioxane, sulfolane and the like, in the presence of a catalytic amount of acid ery as bis (p- nitrophenyl) phosphate, toluene sulfonic acid, methylphosphonic acid or dichloroacetic acid, preferably bis (p-nitrophenyl) phosphate at a temperature of about 75 ° ^G to 200 ° C, preferably at about 110 to 180 ° 0. The reaction is generally carried out using 0.8 mol to 1.2 mol of the compound of formula (V) per 1 mol of compound of formula (Vil).

The protecting groups can be removed both at once, optionally substituted benzyl then acyl, or acyl, and then optionally substituted benzyl.

The benzyl protecting (R *) groups can be first removed from the compound of formula (VIII) by one of several methods; catalytic hydrogenation reaction with Lewis acids or acetolysis to form a compound of formula (IX).

- 14 Catalytic hydrogenation is generally carried out in the presence of a hydrogenation catalyst such as palladium, platinum, rhodium or nickel on a support, such as carbon, and in the presence of an inert solvent for a compound of formula IX. Hydrogen is added to the solution at a pressure of 718.20 pa (15 psi) to 957θ, 06 Pa (200 psi), preferably at a pressure of 1426.41 Pa (50 psi) to 5850.42 Pa (80 psi). Typically, the reaction temperature is in the range 0 to 50 ° 0. Under preferred conditions, palladium-on-charcoal is added to a solution of a compound of formula (VIII) dissolved in the solvent as an aqueous lower alkyl alcohol, wherein alkyl is defined as a straight or branched hydrocarbon having 1 to 4 carbon atoms, preferably aqueous methanol.

The compound of formula I can be prepared by deacylating compound IX by removing the protecting group R in a manner known per se. This removal can be carried out under salt-like conditions whereby a suitable solvent restores the amino function in position 2 of the guanine ring system. Such solvents include water or lower alkanols having 1 to 4 carbon atoms. Solvolysis can be performed under acidic or basic conditions. The reaction temperatures are usually selected in the range 0 to 5θ ° 0, preferably 10 to 5θ ° 0. Most preferably, the range is 15 to 25 ° 0. Basic solvolysis is preferred. Suitable bases include alkali hydroxides, alkali carbonates or ammonia. Preferred solvents are lower alkanols, especially methanol. Under preferred conditions, the solution of the compound of formula (IX) and the base is stirred for about 1 hour to 5θ, preferably about 10 hours to 24 hours, at a temperature of about 10 ° C to 5 ° C, preferably at a temperature of about 15 ° 0 to 25 ° C.

The acyl protecting group may first be removed under the same conditions as described above.

The benzyl (R ') protecting groups can be removed in a manner known per se from the compound of formula (X) by one of several methods: catalytic hydrogenation, reaction with Leuis acids (eg as follows:

To a solution of 9- (1,3-dibenzyloxy-2-propoxymethyl) guanine (0.87 g, 2 mmol) in methylene chloride (100 ml) at -78 ° C was added BBr ^ (4 mmol). After 24 hours, methanol (5 ml) was poured into the solution and evaporated. The residue was washed twice with methylene chloride (20 ml) and recrystallized from water to give 9- (1,3-dihydroxy-2-propoxymethyl) guanine) or aoetholysis to form a compound of formula (I). Catalytic hydrogenation is generally carried out in the presence of a hydrogenation catalyst such as palladium, platinum, rhodium or nickel on a support as charcoal and in the presence of an inert solvent for a compound of formula X. (0.82 g; 2 mmol). Hydrogen is added to the solution at a pressure of 718.20 Pa (15 psi) to 9576.06 Pa (200 psi), preferably at a pressure of 1436.41 Pa (30 psi) to 3830.42 Pa (80 psi). The reaction temperature is usually in the range 0 to 50 ° C.

Under preferential conditions, palladium on charcoal in slurry (20%, 19 ml of ethanol (20 ml) and cyclohexane (10 ml) is added to a solution of a compound of formula (X) dissolved in a solvent such as aqueous lower alkyl alcohol, where alkyl is defined as a straight or branched hydrocarbon having from 1 to 4 carbon atoms, preferably as aqueous methanol The solution was diluted with water (100 ml) and filtered hot, the filtrate cooled and the crystals were collected to give 9- (1,315a dihydroxy-2-propoxymethyl ) guanine.

Both acyl and benzyl protecting groups can be removed from the compound of formula (VIII) in one step to form the compound of formula (I).

The compound of formula (VIII) (0.31 g, 0.65 mmol) was refluxed (temperature between -25 and -40 ° C) in a solution of sodium in liquid ammonia (10 ml), with sodium present in a small excess, however, a small amount of proton source is added to the solution, such as lower alkyl alcohol, where the alkyl is straight or branched and has 1 to 4 carbon atoms, preferably ethanol or methanol. The ammonia was evaporated and the residue was triturated with ammonium chloride (0.3 g) to form a residue, which is a compound of formula (I).

The pharmaceutically acceptable salts of compound I are prepared with

- 16 metabolizing a compound of formula I with a suitable base or acid as defined above. This conversion is carried out in a solvent, adding approximately stoichiometric equivalents of base or acid to the compound of formula I in a suitable inert solvent at a temperature between 0 and 5θ ° θ ·

Similarly, salts of compounds of formula I can be removed from the compounds of formula I by delivering a stoichiometric equivalent of base b to an acid addition salt or an acid to a salt of a compound of formula I with a base, in a solvent at a temperature between 0 and 50 ° θ ·

Similarly, a salt of a compound of formula I can be converted to a pharmaceutically acceptable salt of formula I, e.g. by conventional salt double decomposition, wherein the anion or cation of the starting material is replaced by a pharmaceutically acceptable anion or cation. Salt double decomposition usually takes advantage of the fact that less soluble salt is prepared from more soluble salt at double decomposition temperatures 0 to 50 ° 0 ·

The following specific description is provided in order to enable the person skilled in the art to better understand and implement the invention. However, it is by no means to be understood as limiting the scope of the invention, but merely as an explanation thereof.

PREPARATION I

Preparation of 1,5-di-O-benzylglycerol

Sodium hydride (100 g (50% mineral oil dispersion), 2.08 moles) was washed twice with one liter of hexane and then dried under nitrogen. Then dry dimethylformamide (1.5 L) was added · Benzyl alcohol (400 ml) was then added at a rate sufficient to maintain the temperature below 50 ° C. The addition took 2 hours. Epichlorohydrin (92.5 6, 1 mol) was then added dropwise

- 17 for half an hour under ice-cooling to keep the temperature below 40 ° 0. The solution was then stirred for 16 hours at 21 ° C and then

2.5 hours at 50 ° 0. Dimethylformamide was then removed by evaporation under reduced pressure. The oily residue was dissolved in

2.5 1 diethyl ether. The organic solution was washed with 2 l of water,

1 2% acid, 2 11% sodium bicarbonate and 1 1 brine, dried over sodium sulfate and concentrated as a brown oil. Distillation gave us 147.8 g of 1,3-di-O-henzylglycerol (boiling point 170 to 180 ° C / 133 »322 Pa).

PREPARATION II

Preparation of 1,5-di-O-benzyl-2-O-chloromethyl glycol erol

Dry hydrogen chloride gas was bubbled into the solution of 1,3-di-O-henzylglycerol from Preparation I (15 g »55 mmol) and paraformaldehyde (3.3 g, 110 mmol) in 175 ml for 1.5 hours. dichloro ethane at 0 ° 0. The solution was then stored in a closed flask for 21 hours at 4 ° 0. The solution was then dried over. of magnesium sulfate under heating at 21 ° C, then filtered and concentrated to give 17 »5 g of 1,3-di-O-henzyl-2-o-chloro til glycerol a.

PREPARATION III

Preparation of 2-0-ac e t oxime t il-1.5-di-O-benzyl glyc erol

To a solution of 1,3-di-O-benzyl-2-O-chloromethyl-glycerol from Preparation II (17.5 g < 55 > mmol) in 400 ml of dimethylformamide at 0 DEG C. sodium acetate (6 g) was added. The solution was then warmed to 21 ° 0 and stirred magnetically for 15 hours. The solvent was removed by evaporation under reduced pressure and the oily residue was dissolved in 0.45 kg (1 ft.) Of diethyl ether. Etmo solution

- 18 was washed once with 75 ° ml of water, twice with 250 ml of water and once with 25O ml of brine, dried over sodium sulfate and concentrated to give 19 g of 2-0-acetoxymethyl-1,3-di-O-benzylglycerol like oil.

PREPARATION IV

Preparation of N ^ .9-diacetylguanine

Guanine (20 g, 0.132 mol) was combined with 3θθ ml of acetahydride and the mixture was heated at reflux for 16 hours. The mixture was cooled and the excess acetanhydride removed by evaporation under reduced pressure. The residue was recrystallized from dimethyl sulfoxide to give 25.6 g of N ^2, 9-Giacetilgvanina.

EXAMPLE 1

A) Preparation of N, N -acetyl-9- (1,5-dibenzyloxy-2-propoxymethyl) guanine

1- ^ -9-Diacetylguanine from Preparation IV (15.61 g, 66 mmol), 2-0-Acetoxymethyl-1,3-di-O-benzylglycerol from Preparation III (19 g, 55 mmol) and bis (p-nitrophenyl) ) phosphate (0.5 g) was mixed with 150 ml of diethyl ether. The solvent was removed by evaporation and the residue was heated on an oil bath at 175 ° C for 1.5 hours under a stream of nitrogen. Column chromatography eluting with 1: 9 methanol / methylene chloride followed by recrystallization from ethyl acetate, p

afforded 4.76 g of N -acetyl-9- (1,3-dibenzyloxy-2-propoxymethyl) guanine from m.p. 145 to 146 ° 0.

p

B) Preparation of N -acetyl-9- (1,3-dihydroxy-2-propoxymethyl) guanine

To a solution of N, N -acetyl-9- (1,3-dibenzyloxy-2-propoxymethyl) guanine (4.62 g, 9.6 mmol) in 15θ ml of methanol and 40 ml of water was added 20% palladium hydroxide on charcoal as slurry in 10 ml of water. The mixture was hydrogenated on a Parr hydrogenator pi 2872,82 Pa

- 19 (60 psi) hydrogen for 38 hours, then filtered through Celite and concentrated to a white solid. Recrystallization from methanol / ethyl acetate gave us 1.4 g of N, N -acetyl-9- (1,3-dihydroxy-2propoxymethyl) guanine and m.p. 205 to 208 ° C.

The mother liquor was further reduced with 10% palladium on charcoal (1 g) in 150 ml of methanol and 5θ ml of water at 2872,82 Pa (60 psi) for 47 hours. i The overall yield of N - acetyl ~ 9- (1,3 'dihydroxy-propoxymethyl) guanine was 2.11 g.

C) Preparation of 9- (1 '3-dihydroxy-2-propoxymethyl) guanine

N, N -acetyl-9-d, 3-dihydroxy-2-propoxymethyl) guanine (721.9 mg, 2.4 mmol) was mixed with 5θ ml of methanolic ammonia solution (methanol saturated with ammonia at 0 ° 0) for 17 hours at 21 ° C. The solution was concentrated to a white solid and the residue was recrystallized from methanol to give 582.3 mg of 9- (1,3-dihydro · oxy-2-propoxymethyl) guanine from the ground. 250 ° C. (diff).

EXAMPLE 2

9- (1,3-dihydroxy-2-propoxymethyl) guanine was dissolved in an aqueous solution containing 1 molar equivalent of sodium hydroxide. The solution was then lyophilized to give the sodium salt of 9- (1,3-dihydroxy-2-propoxy name til) guanine as a white wash UV: X max ' ^{265 nra; E = l1400} ·

EXAMPLE 3

The sodium salt of 9- (1 »3-dihydroxy-2-propoxymethyl) guanine was dissolved in a minimal amount of water and dilute hydrochloric acid was added to adjust the pH to 7 · From the solution, blood20 stabilized 9- (1,3" dihydroxy-2 -propoxymethyl) guanine from m.p. 250 ° C (dec).

Salt conversion to 30I

To a solution of the sodium salt of 9- (1,3-dihydroxy-2-proxymethyl) guanine (0.83 g, 3 mmol) in water (10 ml) was added ammonium chloride (0.48 g, 9 mmol) and the resulting solution cooled. at 0 ° C. The crystals were collected by filtration and dried. They were then dissolved in water (100 ml) containing KOH (0.17 g, 3 mmol). The resulting solution was frozen and then lyophilized to give the 9- (1,3-dihydroxy-2-propoxymethyl) guanine potassium salt.

-24An indication of the best known applicant for the economic exploitation of the invention p

A) Preparation of N -acetyl-9- (1,5-dibenzyloxy-2-propoxymethyl) guanine

N ^ -9 ~ diacetylguanine from Preparation IV (15 »61 S» 66 mmol), 2-0-acetoxymethyl-1,3-di-O-benzylglycerol from Preparation III (* 19 6 »55 mmol) and bis (p- nitrophenyl) phosphate (0.5 g) was stirred together with 150 ml of diethyl ether. The solvent was removed by evaporation and the residue was heated on an oil bath at 175 ° C for 1.5 hours under a stream of nitrogen. Column chromatography eluting with 1: 9 methanol / methylene chloride followed by recrystallization from ethyl acetate »gave 4.76 g of N, N -acetyl-9- (1,3-dibenzyloxy-2-propoxymethyl) guanine from m.p. 145 to 146 ° C.

p

B) Preparation of N -acetyl-9- (1,3-dihydroxy-2-propoxymethyl) p: vanine

To a solution of N, N -acetyl-9- (1,3-dibenzyloxy-2-propoxymethyl) guanine (4.62 g, 9.67 mmol) in 150 ml of methanol and 40 ml of water was added 20% palladium hydroxide on carbon as sludge in 10 ml of water. The mixture was hydrogenated on a Parr hydrogenator at. 2872.82 Pa (60 psi) of hydrogen for 38 hours, then filtered through Celite and concentrated to a white solid. Recrystallization from methanol / ethyl acetate gave us 1.4 g of N ² -acetyl-9- (1,3-dihydroxy-2propoxymethyl) guanine from m.p. 205 to 208 ° 0.

The mother liquor was further reduced with 10% palladium on charcoal (1 g) in 150 ml of methanol and 50 ml of water at 2872,82 Pa (60 psi) for 47 hours. The overall yield of N, N -acetyl-9- (1,3-8hydroxy-2-propoxymethyl) guanine was 2.11 g.

21C) Preparation of 9- (1 '5-dihydroxy-2-propoxymethyl) guanine

N, N -ac ethyl-9- (1 »3-dihydroxy i-2-propoxymethyl) guanine (721.9 mg» 2.4 mmol) was mixed with 50 ml of methanolic ammonia solution (methanol saturated with ammonia at O ° 0) for 17 hours at 21 ° 0 The solution was concentrated to a white solid and the residue was recrystallized from methanol to give 582.5 mg of 9- (1 '5-dihydroxy-2-propoxymethyl) guanine from m.p. 250 ° C. (diff).

Claims (2)

PATENT APPLICATION Preparation procedure 9- ( 3-dihydroxy-2-propoxymethyl) guanine and its pharmaceutically acceptable salts, characterized in that it deacylates a compound of formula wherein R is an acyl group R ”CO, wherein R” is a straight or branched chain hydrocarbon having 1 to 10 carbon atoms as methyl , ethyl, isopropyl, Npropyl, isobutyl, n-butyl, tert-butyl, n-hexyl, isohekdyl, n-octyl, isooctyl, n-nonyl, isononyl, n-decyl or isodecyl, under solvolytic conditions such as in aqueous or C Or a dearalkylated compound of the formula wherein R 'is a protecting group as a benzyl group optionally substituted by 1 or 2 alkyl or alkoxyl groups, in the presence of an acid or base such as ammonia. groups of 1 to 4 carbon atoms in the alkyl or alkoxyl moiety as a methoxyl or methyl group under catalytic hydrogenation conditions such as in the presence of palladium, platinum, rhodium or nickel, on a carbon support, with an inert solvent such as C ₁ -C 4 -alcohol , with Lewis or acetic acid, or dearylalkyl mo or deacylated a compound of the formula wherein R and R 'have the above meaning, by refluxing at reduced temperature as -25 ° to -40 ° C, with sodium in liquid ammonia, in the presence of a proton source such as C 1 -C 4 -alcohol, or convert 9- (1,3-dihydroxy-2-propoxymethyl) -guanine into a pharmaceutically acceptable salt using the base as sodium hydroxide or potassium hydroxide for conversion to an inorganic metal salt, or suitable acids as hydrochloric or trifluoroacetic acids for conversion to an acid addition salt, or converting a salt of 9- (1,3-dihydroxy-2-propoxymethyl) guanine into a pharmaceutically acceptable salt under double salt degradation conditions, where a less soluble salt of a more soluble salt is usually prepared than the potassium salt of the sodium salt. For SYNTEX (U.S.A.) INC .: 1818O-VIII-88 / KA P O V Z E TE K We propose a process for the preparation of a novel 9- (1,3dihydroxy-2-propoxymethyl) guanine and its pharmaceutically acceptable salts, having the formula by deacylation, dearalkylation or dearylalkylation and deacylation of the corresponding derivatives of compound (I) and conversion to salts or conversion of the salt to compound (I ). The products are antivirus efficient.