FI97970C - Process for the preparation of 9- (1,3-dihydroxy-2-propoxymethyl) -guanine derivatives - Google Patents

Description

97970

Process for the preparation of 9- (1,3-dihydroxy-2-propoxymethyl) -guanine derivatives This application is divided by patent application No. 5 854879 (Patent Publication 91959).

This invention relates to a process for the preparation of 9- (1,3-dihydroxy-2-propoxymethyl) guanine derivatives.

10- (1,3-dihydroxy-2-propoxymethyl) guanine (hereinafter DHPG) and its esters are effective antiviral agents and have been prepared by the methods described in U.S. Patent 4,355,032 and European Patent Applications 49,072, 72,027 and 74,306. Similar compounds with similar side chains are disclosed in U.S. Patents 4,347,360 and 4,199,574. The present invention relates to an improved process for preparing a novel DHPG ether or ester side chain intermediate using fewer steps than other currently used processes and producing fewer unwanted by-products.

Side chain intermediates for the preparation of DHPG and its ethers and esters have previously been prepared by reacting epichlorohydrin with benzyl alcohol to give a symmetrically substituted 1,3-dibenzylglycerol which is then chloromethylated. The chloromethyl compound is converted to the acetate or formate ester, which is then reacted with guanine 30 to join the 9-position of guanine. See. U.S. Patent 4,355,032. An alternative synthesis is disclosed in U.S. Patent 4,347,360, in which 1,3-dichloro-2-propanol is reacted with sodium benzylate to form a chloromethoxy derivative which is further reacted with 35 purine bases.

These syntheses are multi-step methods involving complex separation and purification techniques and do not use the intermediates of this invention.

97970 2 EP patent 74,306 and in particular example 7 thereof represent the closest prior art. In it, unsubstituted guanine and hexamethyldisilazane are reacted in the presence of a catalyst, with acetoxymethyl-1,3-diacetoxy-2-propyl ether being added at a later stage. However, our invention differs from the process shown in this example in that the reaction is carried out in the presence of an aprotic solvent. Due to the solvent, no viscous substance is formed, less hexamethyl-10-lydisilazane is required, the reaction time is shortened and the yields are improved.

In the prior art process related to FI patent 79851, guanine is first converted to a diacetylated compound, which must be isolated before reaction with 2-O-acetoxymethyl-1,3-di-O-benzylglycerol. The method according to the invention is a one-pot method using silyl protection.

In the process described in FI patent application 823195, gua-20ine reacts with hexamethyldisilazane in the first step without additional solvent and in the second step silylated guanine reacts with the 2-chloromethoxypropane derivative. The process differs from the process according to the invention in the starting materials and the yields are inferior.

25

The process of the invention is straightforward (requires fewer steps), uses readily available starting materials, does not form undesired isomers, and can be easily substituted for terminal esters. In particular, a wide variety of 1,3-diesters and 1,3-diethers of DPHG can be readily prepared using the process of this invention.

This invention relates to a process for the preparation of 9- (1,3-dihydroxy-2-pro-35-poxymethyl) -guanine derivatives of formula (I). 97970 3

O

II

HN "V" V m

2 H2 <: \ _ r0 ~ R

Lo-R 3 wherein R 1 and R 3 are selected from the group consisting of hydrogen, C 1-4 alkyl-C 10-20 alkyl-CO-, phenyl-CO-, 1-Adamant anoyl, phenyl or phenyl-C 1-4 alkyl wherein all alkyl and phenyl groups may be substituted by halogen atoms, C 1-4 alkyl groups and phenyl groups, in which process (a) a guanine compound of formula (II) is reacted in an aprotic hydrocarbon solvent in the presence of a catalyst in the presence of a catalyst with N-alkyldisilazane, followed by a compound of formula A.

O

II-O-R 1 R 4 - C - OO - (A) 30 - O - R 3 wherein R 1 and R 3 are as defined above, and R 4 is C 1-4 alkyl which may be substituted by halogen atoms, C 1-4 alkyl groups or with phenyl groups, (b) treating the resulting mixture with a C 1-4 alkyl alcohol; followed optionally by 4,97970 (c) if R 1 and R 3 are not hydrogen, treating the resulting mixture with ammonium hydroxide and water.

In this specification and claims, the following terms have the meanings given, unless otherwise stated.

"Lower alkyl" means any straight-chain or branched hydrocarbon group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, i-propyl, butyl, t-butyl, and the like.

"Optionally substituted" means a substitution on an alkyl or phenyl group with halogen atoms, lower alkyl groups and phenyl groups.

"Optionally substituted guanine" means a guanine molecule optionally substituted with acyl and / or (alkyl) 3 Si groups at the 2-position amino group and the 20-position nitrogen.

"Acyl" as used herein is optionally substituted alkyl-C (O) having from 4 to 20 carbon atoms in the alkyl chain, optionally substituted phenyl-C (O), or optionally substituted alkylphenyl-C (O), wherein the optional substitution is on the phenyl ring. Examples are n-hexanoyl, n-heptanoyl, palmitoyl, steracanoyl, arachidoyl, pivaloyl, 1-methyl-1-cyclohexanecarboxyl, 2-octyl-decanoyl, benzoyl, p-chlorobenzoyl, toluoyl-3'-phenyl, phenyl -phenylpropanoyl and 4-phenylbutanoyl.

"Pivalic acid" is 2,2-dimethylpropionic acid.

35 "1-adamantanoyl" means a radical having the following structure 5,97970 t * ° ζΧ 1-adamantanoyl "Phenyl" is a six membered carbon ring containing three double bonds.

"Alkylphenyl" means a phenyl group substituted with an alkyl chain, wherein alkyl has the same meaning as previously defined.

"Hydrogen donor" means any substance that can serve as a source of active hydrogen. Some examples of hydrogen donors include hydrogen gas, cyclohexene, 1,4-cyclohexadiene and the like. In some cases, catalysts may be used with the hydrogen donors, for example precious metals, for example platinum, palladium and rhodium may be used as a finely divided metal or a metal supported on a conventional catalyst support, for example supported on carbon, alumina or silica.

"Acid" as used herein is usually associated with either a specifically named acid, for example, pivalic acid, or is modified, such as a protic acid or a Lewi's acid.

"Lewis acid" means any acid having no leaving proton. Examples are Be (CH3) 2, BF3, B (O-alkyl) 3, Al (CH3), A1 (C1) 3, Fe3 +, Mg2 *, Ca2 *, Cu *, TiCl4, Hg2 *, Cn2 *, Fe2 * , Zn2 * and the like. A comprehensive list of Lewis acids can be found in Chem. Rev. , 75, 1, (1975), p. 35 2.

6,97970 "Protic acid" means any Bronsted acid having a pKa of less than 2.0 and preferably less than 1.0 and having a leaving proton. Examples are mineral acids, for example nitric acid, sulfuric acid, phosphoric acid, hydrogen halides, for example hydrochloric acid; organic acids, for example trifluoroacetic acid, organic sulfonic acids, for example phenylsulphonic acid, and particularly preferred para-toluenesulphonic acid, and acidic resins, for example Amberlyst (B) (Rohm and Haas).

"Protecting group" means any group that can protect the functionality of a compound and can be removed by hydrolysis or hydrogenation. Examples of protecting groups useful in this invention include sterically hindered groups (where the term "sterically hindered" refers to a particular atomic moiety that prevents or inhibits the expected chemical reaction due to its size), such as benzyl or optionally substituted benzyl or alkyl groups, and R 3 Si (R 2) sterically hindered silyy-20 groups.

"Alkoxymethyl ether" means a compound of the formula

A 0-CH2-0-B

Wherein A and B are optionally substituted lower alkyl groups.

The compound of formula A can be prepared by the following reaction scheme I.

II

35 7 97970

REACTION SCHEME

0 0

Il II

, C h

5 CH2 (0R6)? + R ^ "Cr R

K aa v a G

Formula F

A

10 0

II

R ^ '^' 0 '^^ DR6 + R1-q 0-R3 \ /

Formula D ^

15 K a a v a E

V

CH OR1 Ϊη-O-R7 iH OR 3

20 I Z

0 7 A 11 7

If R = R 2 O- ^ H 2 if R = CH 2 OR 6 J, the compound is reacted then this is with the formula A ^ 25 '(R ^ c) 0 i i'

Formula A

0 1 „CHOR1

A "I

30 R -CCT ^ 0-C

HOR 3 wherein R 1 and R 3 are as defined above and R 7 is R 4 C (O) OCH 2 or R 6 OCH 2, wherein R 4 and R 6 are independently selected from optionally substituted lower alkyls.

8 97970

In Reaction Series A, a dialkyl oxymethane of formula F is reacted with an anhydride of formula G in the presence of a protic acid catalyst. The two reaction components are present in a molar ratio of about 1: 1 when a catalytic amount of a protic acid, for example organic sulphonic acids, for example para-toluenesulphonic acid, or catalytic amounts of a mineral acid, for example hydrochloric acid or sulfuric acid, are present. The reaction may be carried out in a protic hydrocarbon solvent, for example benzene or as such, typically at the reflux temperature of the solution. The solution is allowed to react for 1-12 hours, giving a fairly typical length of 6 hours. See Method in J. Am. Chem. Soc .. 76. page 5161 (1954).

15

It is recommended that the anhydride and dialkyloxymethane be symmetrical because the number of possible products is dramatically reduced by using symmetrical reagents. Naturally, asymmetric anhydrides or asymmetric alkyloxymethanes can also be reacted with one another in the process of this invention. In some cases, asymmetric anhydrides may be selective for any potential product.

1,3-Dialkanoylglycerol of formula E can be prepared in one of two ways. Treatment of glycerol with slightly more than two equivalents of acid chloride or acid anhydride in aprotic solvents in the presence of an organic base such as trialkylamines and a nucleophilic catalyst such as pyridine can give 1,3-dialkanoyl glycerol of formula E.

Alternatively, these compounds can be obtained from dihydroxyacetone in J. Orq. Chem. , 35, 2082, (1970), 35. Treatment of dihydroxyacetone in pyridine with the equivalent of the fatty acid chloride in question followed by reduction of the middle keto group

II

9,97970 with borohydride in tetrahydrofuran can give 1,3-dialkanoylglycerol of formula E.

In Reaction Series B, compounds D and E are reacted together in the presence of a protic acid catalyst, for example organic sulfonic acids, for example para-toluenesulphonic acid, or in the presence of catalytic amounts of a mineral acid, for example hydrochloric acid or sulfuric acid, to give a mixture (formula C). This mixture consists of a compound of formula A 10 and a compound of formula C '. The compounds of formula D and formula E are mixed as such together with a catalytic amount of a protic acid catalyst. It is preferred that an excess of the compound of formula D be used, as the excess is useful as a reaction solvent. The reaction components can be mixed together without the need for an external heat source, although the use of heat accelerates the reaction. Reaction B may be exothermic. The reaction has taken place when the temperature drops to ambient temperature. The reaction takes 1-6 hours, typically about 2 hours, for the lop-20 tree.

The mixture (formula C) varies depending on the starting material. For example, if R1 and R3 are benzyl, Reaction Series B essentially produces a compound of Formula A, but if R1 and R2 are pivaloyl, Reaction Series B essentially produces a compound of Formula C '. Reaction series C may be omitted if the product of reaction series B is a compound of formula A. Otherwise, the compounds are reacted according to Reaction Series C.

30

In Reaction Series C, a mixture of compounds of formula C is then further reacted in the presence of an alkyl anhydride and a Lewis acid catalyst. It is preferred that the anhydride used in this reaction be a symmetrical anhydride to reduce the potential number of products formed, although this is not a prerequisite for this reaction.

10 97970

The catalyst acid is preferably a non-protic Lewis acid catalyst, for example boron trifluoride or aluminum trichloride. The reaction temperature rises from ambient temperature to about 50 ° C, at which point the temperature begins to be adjusted.

The reaction temperature is generally maintained between about 45 and 65 ° C, preferably between about 50 ° C and about 60 ° C.

The progress of the reaction is typically monitored by thin layer chromatography (TLC) to determine the amount of reaction.

The reaction is usually complete after about 60 to 180 minutes. The reaction mixture is extracted as an organic solvent, which is washed with sodium carbonate and water. The organic layer is then dried and the product of formula A is obtained by evaporating the solvent.

15

Once compound A is obtained, esters or ethers of DPHG or DPHG itself can then be readily obtained, if desired.

According to the invention, 9- (1,3-dihydroxy-2-propoxymethyl) -20 guanine derivatives can be prepared as follows.

REACTION SCHEME

0 O n 25 H - O - R1 + ΗΝ'ΛΛ R4 - C - O O - I I / - 0 - R3 H ^ N 'N' "

B

(A) (II) 30 + [(lower alkyl) 3Si] 20

II

-.r · HN _v

35 I A (I) -7 DHPG

N 2 H, N / 2 h 2c / j-O-H 1

Lo-R ’li 11 97970

The compound of formula A can be reacted directly with trialkylsilyl-protected guanine to give a DHPG ester or ether. Guanine is heated in an aprotic hydrocarbon solvent, for example toluene or xylenes and the like, with more than 3 molar equivalents of hexa-lower alkylsilazane, for example hexamethylsilazane, hexaethylsilazane and the like and a catalyst. The catalyst is selected from the group consisting of trialkylsilyl sulfates, chloro-10 silanes, ammonium sulfate, and pyridines. The resulting solution is removed by vacuum distillation with an equal volume of volatiles equal to the volume of the hydrocarbon solvent. The compound of formula A is then added and the mixture is heated to above ambient temperature until TLC analysis of the mixture shows that the compound of formula A is consumed and a DHPG ester or ether (Formula I) is formed. When all trimethylsilyl groups are then removed from the reaction mixture, for example by heating with lower alkyl alcohols, for example methanol, ethanol or isopropanol, a DHPG ester or ether is obtained which can be purified by standard methods. If DHPG is desired, the compound of formula I can be deprotected (R1 and R3) by reacting it with, for example, a mixture of ammonium hydroxide and water.

25

EXAMPLES

The following non-limiting examples illustrate various aspects of this invention.

30 Manufacture of starting materials 1 12 97970

EXAMPLE A

1,3-di (1-adamantanowli) glycerol 5 1.053 g of glycerol are dissolved in a flask under nitrogen in a mixture of 4 ml of pyridine and 6 ml of methylene chloride and cooled to about -10 ° C. 5.00 g of (1-adamantanoyl) chloride (Aldrich Chemical Co.) are then added in one portion and stirring is continued for about half an hour under cooling and then for a further 2 hours at ambient temperature. The resulting solid is filtered and washed with methylene chloride. The combined organic layers are washed twice with dilute aqueous hydrochloric acid and then once with water and dried over magnesium sulfate. 1,3-di (1-adaman-15 tanoyl) glycerol is isolated as an oil.

Proton NMR, CDCl 3 1.5-2.2 (m 30H); 2.3-2.7 (br s, 1H); 4.1-4.3 (m. 5H).

Using a similar procedure but substituting the corresponding compound for (1-adamantanoyl) chloride, the following compounds were prepared: 1,3-di-benzoylglycerol; 1,3-di-pivaloylglycerol; 1,3-di-butanoylglycerol; 1,3-di-s-butanoylglycerol; 1,3-di-t-butanoylglycerol; 1,3-di-propanoylglycerol; 1,3-di-hexanoylglycerol; 1,3-di-heptanoylglycerol, -β, 3-dioctanoylglycerol; 1,3-di-nonaoylglycerol; 1,3-di-decanoylglycerol; 35 1,3-di-undecanoylglycerol; 1,3-di-dodecanoylglycerol; 1,3-di-tridecanoylglycerol;

II

13,97970 1,3-di-1-tetradecanoylglycerol; 1,3-di-pentadecanoylglycerol; 1,3-di-hexadecanoylglycerol; 1,3-di-heptadecanoylglycerol; 5,3-di-octadecanoylglycerol; 1,3-di-nonadecanoylglycerol; 1,3-di-eicosanoylglycerol; 1,3-di-p-chlorobenzoylglycerol; 1,3-di-o-chlorobenzoylglycerol; 1,3-di-m-chlorobenzoylglycerol; 1,3-di-p-bromobenzoylglycerol; 1,3-di-o-bromobenzoylglycerol; 1,3-di-m-bromobenzylglycerol; 1,3-di-p-fluorobenzoylglycerol; 15,3-di-o-fluorobenzoylglycerol; 1,3-di-m-fluorobenzoylglycerol; 1,3-di-p-iodobenzoylglycerol; 1,3-di-o-iodobenzoylglycerol; 1,3-di-m-iodobenzoylglycerol; 1,3-di-toluoylglycerol; 1,3-diphenylacetylglycerol; 1,3-di-3-phenylpropanoylglycerol; 1,3-di-4-phenylbutanoylglycerol.

1,3-Dialkylglycerols can be prepared by the method described in U.S. Patent 4,355,032.

EXAMPLE B

1,5-Diisopropyl-4-propanoyloxymethylcerol 30,154 g of 1,3-diisopropylglycerol and 616 ml of methoxymethylpropionate and 9.98 g of para-toluenesulfonic acid were stirred in a 2-liter round-bottomed flask equipped with a magnetic stirrer and an internal heat stirrer. meter. A temperature rise of 6 ° C occurred within 10 minutes. This was followed by a steady drop in temperature back to ambient temperature. After 45 minutes of reaction, a TLC check (97% ethyl acetate / 75% hexane rf = 0.69, silica) performed 14 97970 showed almost complete consumption of the starting alcohol.

The reaction mixture was added to a separatory funnel with 500 ml of hexane as the organic phase, after which the organic layer was washed with 500 ml of water and twice with 500 ml of saturated aqueous sodium bicarbonate and finally with 500 ml of water. The organic layer was then dried over anhydrous magnesium sulfate and stripped on a rotary evaporator, and 1,3-diisopropyl-2-propanoyloxymethylglycerol was isolated.

Proton NMR, CDCl 3, 1.1 (complex, 9H); 2.3 (q, 2 H); 3.4-4.0 (complex, 7H); 5.2 (s. 2H).

In a similar manner, the following compounds were prepared by substituting the relevant compound of Example A: 1,3-dimethyl-2-propanoyloxymethylglycerol; 1,3-diethyl-2-propanoyloxymethylglycerol; 1,3-di-propyl-2-propanoyloxymethylglycerol; 1,3-di-butyl-2-propanoyloxymethylglycerol; 1,3-di-s-butyl-2-propanoyloxymethylglycerol; 1,3-di-1-butyl-2-propanoyloxymethylglycerol; 1,3-di-phenyl-2-propanoyloxymethylglycerol; 1,3-Di-benzyl-2-propanoyloxymethylglycerol.

Similarly, methoxymethyl butanoate 30 or methoxymethyl pentanoate can be used to prepare the corresponding 1,3-di-alkyl-2-alkanoyloxymethyl glycerol.

EXAMPLE C

1,3-Dipropanowl-2-propanoyloxymethylcerol 35 339 g of propionic anhydride and 185 g of the crude oil obtained from the reaction of Example 2 (1,3-diisopropyl-2-yl-97970 15 propanoyloxymethylglycerol) were added to a 2-liter round-bottomed 2-liter round-bottomed flask. equipped with a magnetic stirrer, a reflux condenser, an internal thermometer and a nitrogen supply and assembled in such a way that it could be heated or cooled rapidly. 17.9 g of boron trifluoride etherate were then added in one portion. The temperature of the reaction mixture immediately rose from about 20 ° C (ambient temperature) to about 50 ° C, at which point cooling began. The reaction temperature was carefully maintained between 50 and 60 ° C by heating or cooling as needed. The progress of the reaction was monitored by analyzing the reaction mixture by TLC (25% ethyl acetate / 75% hexane rf = 0.31, silica).

After 100 minutes, the reaction mixture was added to a separatory funnel along with 500 mL of toluene. The organic layer was washed with 500 ml of saturated aqueous sodium carbonate and twice with 500 ml of water. The organic layer was then dried over anhydrous sodium sulfate, filtered and stripped on a rotary evaporator at 76 mmHg in vacuo. The crude black oil was collected and then purified by passing twice through a distillation apparatus (wiped film). The purified oil was 1,3-dipropanoyl-2-propanoyloxymethylglycerol.

25

Proton NMR, CDCl 3, 1.1 (t, 9H); 2.3 (q, 6 H); 4.1 (complex 5H); 5.2 (s. 2H).

In a similar manner, the corresponding 1,3-di-alkyl-2-propanyloxymethylglycerols of Example B can be reacted to prepare 1,3-di-propanoyl-2-propanoyloxymethylglycerol.

In a similar manner, the corresponding 1,3-di-35-alkyl-2-acetyloxymethylglycerol, 1,3-di-alkyl-2-butanoyloxymethylglycerol or 1,3-di-alkyl-2-pentanoylmethylglycerol can be reacted to form the corresponding 1,3-di-acyl compound.

EXAMPLE D

1,3-Dibenzyl-2-acetoxymethylcerol 75 g of dibenzylglycerol, 5.25 g of paratoluenesulfonic acid, 300 ml of hexane and 300 ml of methoxymethyl acetate were added to a 2-liter round-bottomed flask equipped with a magnetic stirrer and an internal heat stirrer. The reaction mixture was heated to 60-65 ° C for 90 minutes, monitored by TLC (20% ethyl acetate / 80% hexane rf = 0.31, silica), then cooled, transferred to a separatory funnel, washed once with 15,700 mL: 11a of water and once 700 ml of saturated aqueous sodium carbonate solution. Then 150 ml of methylene chloride were added and finally washed with 700 ml of water. The organic layer was dried over sodium sulfate, filtered and stripped under high vacuum to give 1,3-di-benzyl-2-acetoxymethylglycerol as a clear oil.

Proton NMR CDCl 3 1.9 (s, 3H); 3.6 (complex, 4H); 4.0 (m, 1 H): 4.5 (s, 4 H); 5.2 (s. 2H); 7.2 (complex, 10H).

In a similar manner the following compounds were prepared using the corresponding 1,3-disubstituted glycerols of Example A: 1,3-dimethyl-2-acetoxymethylglycerol; 1,3-diethyl-2-acetoxymethylglycerol; 1,3-di-propyl-2-acetoxymethylglycerol; 1,3-diisopropyl-2-acetoxymethylglycerol; 1,3-di-butyl-2-acetoxymethylglycerol; 1,3-s-butyl-2-acetoxymethylglycerol; 1,3-di-t-butyl-2-acetoxymethylglycerol; 1,3-Di-phenyl-2-acetoxymethylglycerol.

35

II

17 97970

EXAMPLE E

1,3-Dipivaloyl-2-methoxymethylcerol 50.45 g of 1,3-dipivaloylglycerol was dissolved in 200 ml of 5-methoxymethyl acetate. 2.5 g of p-toluenesulfonic acid monohydrate were added, after which the mixture was stirred for 1 hour, then diluted with 200 ml of hexane and washed twice with 200 ml of saturated aqueous sodium carbonate and once with aqueous NaCl solution. It was then dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1,3-dipivaloyl-2-methoxymethylglycerol as a colorless oil.

Proton NMR, CDCl 3, 1.2 (s, 18H); 3.4 (s. 3H); 4.1 (m, 1 H); 4.2 (m. 4H); 4.7 (s. 2H).

In a similar manner the following compounds were prepared using the corresponding 1,3-di-substituted glycerols from Example A: 1,3-di (1-adamantanoyl) -2-methoxymethylglycerol

Proton NMR, CDCl 3, 1.6-2.1 (complex, 30H); 3.4 (s. 3H); 4.1 (complex, 1H); 4.2 (complex, 4H); 4.8 (s. 2H).

1,3-di-benzoyl-2-methoxymethylglycerol; 1,3-di-pivaloyl-2-methoxymethylglycerol; L, 3-di-butanoyl-2-methoxymethyl; 1,3-di-s-butanoyl-2-methoxymethylglycerol; 1,3-di-t-butanoyl-2-methoxymethylglycerol; 1,3-di-propanoyl-2-methoxymethylglycerol, - 1,3-di-heptanoyl-2-methoxymethylglycerol; 1,3-di-octanoyl-2-methoxymethylglycerol; 1,3-di-nonanoyl-2-methoxymethylglycerol; 1,3-dl-decanoyl-2-methoxymethylglycerol, 1,3-di-undecanoyl-2-methoxymethylglycerol; 1,3-di-dodecanoyl-2-methoxymethylglycerol; 18,97970 1,3-di-tridecanoyl-2-methoxymethylglycerol; 1,3-di-tetradecanoyl-2-methoxymethylglycerol 1,3-di-pentadecanoyl-2-methoxymethylglycerol; 1,3-di-hexadecanoyl-2-methoxymethylglycerol; 1,3-di-heptadecanoyl-2-methoxymethylglycerol; 1,3-di-octadecanoyl-2-methoxymethylglycerol, -β, 3-nonadecanoyl-2-methoxymethylglycerol; 1,3-di-eicosanthyl-2-methoxymethylglycerol; 1- (3-di-p-chlorobenzoyl-2-methoxymethylglycerol 1,3-di-o-chlorobenzoyl-2-methoxymethylglycerol 1,3-di-m-chlorobenzoyl-2-methoxymethylglycerol 1,3-di-p-bromobenzoyl-2-methoxymethylglycerol) di-o-bromobenzoyl-2-methoxymethylglycerol 1,3-di-m-bromobenzoyl-2-methoxymethylglycerol 1,3-di-p-fluorobenzoyl-2-methoxymethylglycerol 1,3-di-o-fluorobenzoyl-2-methoxymethylglycerol 1,3-di -m-fluorobenzoyl-2-methoxymethylglycerol 1,3-di-pyrodibenzoyl-2-methoxymethylglycerol 1,3-di-o-iodobenzoyl-2-methoxymethylglycerol 1,3-di-m-iodobenzoyl-2-methoxymethylglycerol 1.3 toluoyl-2-methoxymethylglycerol, 1,3-di-phenylacetyl-2-methoxymethylglycerol, 1,3-di-3-phenylpropanoyl-2-methoxymethylglycerol, 1,3-di-4-phenylbutanoyl-2-methoxymethylglycerol.

25

In a similar manner, ethoxymethyl acetate, propoxymethyl acetate or butoxymethyl acetate can be prepared from the corresponding 1,3-diacyl-2-alkoxymethylglycerol.

30 EXAMPLE F

1,3-Dipivaloyl-2-acetoxymethylcerol 50 g of 1,3-dipivaloyl-2-methoxymethylglycerol, 150 ml of methylene chloride and 17 ml of acetic anhydride were cooled to about -5 ° C. 0.3 ml of boron trifluoride etherate was then added and the mixture was stirred for a further 1 hour at about 0 ° C and then allowed to warm to 25 ° C.

II

19,97970 for another 1.5 hours. After this period, 100 mL of saturated aqueous Na 2 CO 3 was added to the mixture, followed by 100 mL of methylene chloride. After vigorous stirring for 5 minutes, the organic layer was separated and washed once with 100 ml of water, once with aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1,3-dipivaloyl-2-acetoxymethylglycerol as a weakly colored oil.

10

Proton NMR, CDCl 3, 1.2 (s, 18H); 2.1 (s. 3H); 4.1-4.3 (m. 5H); 5.3 (s. 2H); 4.7 (s. 2H).

In a similar manner, 1,3-di (1-adamantanoyl) -15 2-acetoxymethylglycerol was prepared.

Proton NMR, CDCl 3, 1.6-2.1 (complex, 30H); 2.1 (s. 3H); 4.1 (complex, 5H); 5.3 (s. 2H).

1,3-di-benzoyl-2-acetoxymethylglycerol; 1,3-di-pivaloyl-2-acetoxymethylglycerol; 1,3-di-butanoyl-2-acetoxymethylglycerol; 1,3-di-s-butanoyl-2-acetoxymethylglycerol; 1,3-di-t-butanoyl-2-acetoxymethylglycerol; 1,3-di-propanoyl-2-acetoxymethylglycerol; 1,3-di-hexanoyl-2-acetoxymethylglycerol; 1,3-di-heptanoyl-2-acetoxymethylglycerol; 1,3-di-octanoyl-2-acetoxymethylglycerol; 1,3-di-nonaoyl-2-acetoxymethylglycerol; 1,3-di-decanoyl-2-acetoxymethylglycerol; 1,3-di-undecanoyl-2-acetoxymethylglycerol; 1,3-di-dodecanoyl-2-acetoxymethylglycerol; 1,3-di-tridecanoyl-2-acetoxymethylglycerol; 1,3-di-tetradecanoyl-2-acetoxymethylglycerol; 1,3-di-pentadecanoyl-2-acetoxymethylglycerol; 1,3-di-hexadecanoyl-2-acetoxymethylglycerol; 1,3-di-heptadecanoyl-2-acetoxymethylglycerol; 20,97970 1,3-di-octadecanoyl-2-acetoxymethylglycerol; 1,3-di-nonadecanoyl-2-acetoxymethylglycerol; 1,3-di-eicosanoyl-2-acetoxymethylglycerol; 1,3-di-p-chlorobenzoyl-2-acetoxymethylglycerol; 1,3-di-o-chlorobenzoyl-2-acetoxymethylglycerol; 1,3-di-m-chlorobenzoyl-2-acetoxymethylglycerol, 1,3-di-p-bromobenzoyl-2-acetoxymethylglycerol; 1,3-di-o-bromobenzoyl-2-acetoxymethylglycerol; 1,3-di-m-bromobenzoyl-2-acetoxymethylglycerol; 1,3-di-p-fluorobenzoyl-2-acetoxymethylglycerol; 1,3-di-o-fluorobenzoyl-2-acetoxymethylglycerol; 1,3-di-m-fluorobenzoyl-2-acetoxymethylglycerol; 1,3-di-p-iodobenzoyl-2-acetoxymethylglycerol, - 1,3-di-o-iodobenzosyl-2-acetoxymethylglycerol; 1,3-di-m-iodobenzoyl-2-acetoxymethylglycerol; 1,3-di-toluoyl-2-acetoxymethylglycerol; 1,3-diphenylacetyl-2-acetoxymethylglycerol; 1,3-di-3-phenylpropanoyl-2-acetoxymethylglycerol; 1,3-di-4-phenylbutanoyl-2-acetoxymethylglycerol.

20

In a similar manner, the corresponding 1,3-di-acyl-2-acyloxymethylglycerol can be prepared by substituting ethoxymethyl acetate, propoxymethyl acetate or butoxymethyl acetate.

25

EXAMPLE I

ETHERS AND ESTERS OF DHPG

Dipivalowli-DHPG 9- (1,3-dipivalowloxy-2-propoxymethyl) quanine) 8.00 g of guanine, 40 ml of hexamethyldisilazane, 80 ml of xylene and 0.64 g of ammonium sulfate are refluxed for about 20 hours. 80 ml of the clear solution obtained are then distilled off and discarded. 23.1 g of 1,3-dipivaloyl-2-acetoxymethylglycerol are then added to the resulting solution and the mixture is refluxed for about 20 hours. After cooling, the volatiles are removed in vacuo. The residue is refluxed with 40 ml of isopropanol and then the volatiles are stripped off in vacuo and then chromatographed on silica gel to give 14.9 g of dipivaloyl-DHPG, yield 66%.

Proton NMR, DMSO-d 6 1.1 (s, 18H); 3.9-4.3 (m. 5H); 5.4 (s, 2 H): 6.4 (S, 2 H); 7.8 (s, 1 H); 10.68 (s, H).

In a similar manner, 1,3-dibenzyl-DHPG, (9- (1,3-10 dibenzyloxy-2-propoxymethyl) -guanine) was prepared.

Proton NMR, DMSO-d 6 3.5 (m, 4H); 4.1 (m, 1 H); 4.4 (s. 4H); 5.5 (s. 2H); 6.7 (s. 2H); 7.3 (complex, 10H); 7.9 (s, 1 H); 10.9 (s, 1H) using 1,3-dibenzyl-2-acetoxymethylglycerol as starting material. Yield 60-70%.

In a similar manner, the following ethers and esters of DHPG can be prepared using the corresponding 1,3-dialkyl or 1,3-diacyl-2-alkanoyloxymethylglycerols: 20- (1,3-dimethyloxy-2-propoxymethyl) -guanine; 9- (1,3-dietyylioksi-2-propoxymethyl) guanine; 9- (1,3-dipropyylioksi-2-propoxymethyl) guanine; 9- (1,3-di-isopropyloxy-2-propoxymethyl) guanine; 25- (1,3-dibutyloxy-2-propoxymethyl) -guanine; 9- (1,3-di-s-butoxy-2-propoxymethyl) guanine; 9- (1,3-di-t-butyloxy-2-propoxymethyl) guanine; 9- (1,3-difenyylioksi-2-propoxymethyl) guanine; 9- (1,3-dibentsoyylioksi-2-propoxymethyl) guanine; 30- (1,3-di-hexanoyloxy-2-propoxymethyl) -guanine; 9- (1,3-di-heptanoyloxy-2-propoxymethyl) guanine; 9- (1,3-di-octanoyloxy-2-propoxymethyl) guanine; 9- (1,3-di-nonanoyloxy-2-propoxymethyl) guanine; 9- (1,3-di-decanoyloxy-2-propoxymethyl) guanine; 35 22 97970 9- (1,3-di-undecanoyloxy-2-propoxymethyl) -guanine; 9- (1,3-di-dodecanoyloxy-2-propoxymethyl) guanine; 9- (1,3-di-tridekanoyylioksi-2-propoxymethyl) guanine; 9- (1,3-di-tetradekanoyylioksi-2-propoxymethyl) guanine; 59- (1,3-di-pentadecanoyloxy-2-propoxymethyl) -guanine; 9- (1,3-di-heksadekanoyylioksi-2-propoxymethyl) guanine; 9- (1,3-di-heptadekanoyylioksi-2-propoxymethyl) guanine; 9- (1,3-di-oktadekanoyylioksi-2-propoxymethyl) guanine; 9- (1,3-di-nonadekanoyylioksi-2-propoxymethyl) guanine; 109- (1,3-di-eicosanoyloxy-2-propoxymethyl) -guanine; 9- (1,3-di-p-chlorobenzoyloxy-2-propoxymethyl) guanine; 9- (1,3-di-o-chlorobenzoyloxy-2-propoxymethyl) guanine; 9- (1,3-di-m-chlorobenzoyloxy-2-propoxymethyl-guanine; 9- (1,3-di-p-bromobenzoyloxy-2-propoxymethyl) -guanine; 9- (1,3-di-m-chlorobenzoyloxy-2-propoxymethyl) -guanine; -o-bromobenzoyloxy-2-propoxymethyl) -guanine-20-n; 9- (1,3-di-m-bromobenzoyloxy-2-propoxymethyl) -guanine; 9- (1,3-di-p-fluorobenzoyloxy-2- propoxymethyl) guanine; 9- (1,3-di-o-fluorobenzoyloxy-2-propoxymethyl) guanine; 9- (1,3-di-m-fluorobenzoyloxy-2-propoxymethyl) guanine; 1,3-di-p-iodobenzoyloxy-2-propoxymethyl) guanine 9- (1,3-di-o-iodobenzoyloxy-2-propoxymethyl) guanine 9- (1,3-di-m-iodobenzoyloxy) 2-propoxymethyl) guanine, 9- (1,3-di-toluoyloxy-2-propolmethyl) guanine, 9- (1,3-diphenylacetyloxy-2-propoxymethyl) guanine, 9- (1,3 -di-phenylpropanoyloxy-2-propoxymethyl) -guanine-35; 9- (1,3-diphenylbutanoyloxy-2-propoxymethyl) -guanine, 23,97970 9- (1,3-diacetyloxy-2-propoxymethyl) -guanine , yield 66%, mp 234-247 ° C, nmr: 1.9 (s, 6H), 3.9-4.1 (complex, 5H) , 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H), 10.6 (s, 1H) (reference compound, see EP-74,306, e.g. 7). 5

Claims (4)

97970 Claim A process for the preparation of 9- (1,3-dihydroxy-2-propoxymethyl) -guanine derivatives of the formula (I) according to 5 0 II HN | ^ \\ (1) Η-, Ν /, 10. H2C <C-R 10 Lo-R 3 wherein R 1 and R 3 are selected from the group consisting of hydrogen, C 1-4 alkyl, C 4-20 alkyl-CO-, phenyl-CO-, 1-Adamant anoyl, phenyl or phenyl-C 1-4 -alkyl, in which all the alkyl and phenyl groups may be substituted by halogen atoms, C 1-4 -alkyl groups and phenyl groups, characterized in that 20 (a) guanine of the formula (II) ) "" H2N NH is reacted in an aprotic hydrocarbon solvent in the presence of a catalyst with hexa-C1-4-alkyldisilazane, and then with a compound of formula A O II I-o-R1 R4-C-OO - (A) -O-R3 35 wherein R 1 and R 3 are as defined above, and II 97970 R 4 is C 1-4 alkyl which may be substituted by halogen atoms, C 1-4 alkyl groups or phenyl groups, (b) treating the resulting mixture with a C 1-4 alkyl alcohol; then optionally 5 (c) if R 1 and R 3 are not hydrogen, treating the resulting mixture with ammonium hydroxide and water. 10 For the preparation of 9- (1,3-dihydroxy-2-propoxymethyl) -guanine derivatives of formula (I) 0 to 15 / Hf [\ (I) LI / 2 h2c <^ o- Lo — n 3 20 i and R3 and R3 are selected from the group consisting of C1-4alkyl, C1-4alkyl, C4.20-alkyl-CO-, phenyl-CO-, 1-adamantanoyl, phenyl or phenyl-C1-4-alkyl, an alkyl-phenyl group having 25 substituents on a halogen atom, a C 1-4 -alkyl group and a phenyl group, a rotary substituent, (a) guanine with formula (II) 0 30 II ΗΝΛΛ I ^ (II) A Av H2N "N / g 1 is provided as an aprotic piston medium with a catalyst containing hexa-C 1-4 alkyldisilazane and a dehydrated formulation with the form AO 97970 Il - O - R1 R4 - C - OO - (A) - O - R3 5. each of R1 and R3 is selected from the group consisting of halo, C1-4-alkyl, C1-4-alkyl or phenyl, (b) reacting with a C1-4 alkylal-10 alcohol, followed by (c) reacting R1 and R3 with ammonium hydroxide and water.