FI91746C - The process prepares alkoxymethyl ether derivatives - Google Patents

Description

91746

This invention relates to a process for the preparation of intermediate 5 for the preparation of 9- (1,3-dihydroxy-2-propoxymethyl) guanine and its esters and ethers.

9- (1,3-dihydroxy-2-propoxymethyl) guanine (hereinafter DHPG) and its esters are potent antiviral agents and have been prepared 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 15 new intermediates and to an even better process for preparing a new DHPG ether or ester side chain intermediate using fewer steps than other currently used processes and producing less undesirable side-by-side.

20

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-di-benzylglycerol which is then chloromethylated.

The chloromethyl compound is converted to the acetate or formate ester, which is then reacted with guanine to give the 9-position of quanine. See U.S. Patent 4,355,032.

30

An alternative synthesis is disclosed in U.S. Patent No. 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 a purine-35 base.

2,91746

The third method is disclosed in European Patent Application 74,306, published March 3, 1983. In this application, the side chain is prepared starting from glycerol formal, which is a mixture of 1,3-dioxan-5-ol and 1,3-dioxolane-4-methanol. The glycerol formal is acylated and the mixture is separated. The acylated compound is then reacted with acetic anhydride in the presence of ZnCl 2 to give a compound that can be reacted with a purine.

All of these syntheses are multi-step methods that involve complex separation and purification techniques and do not use the intermediates of this invention.

Such a process would be preferred, which would be straightforward (fewer steps required), using readily available starting materials, without the formation of undesired isomers, and easily substituting terminal esters. The subject invention has all these features. In particular, using the intermediates and process of this invention, DHPG and a wide variety of 1,3-diesters and 1,3-diethers of DPHG can be readily prepared.

A summary of Chemical Abstracts vol 68, (1968), 12384v 25 discloses a one-step process for the preparation of alkoxymethyl ethers of 1,3-dipropoxy-2-propanol starting from 1,3-dipropoxy-2-propanol and chloromethylalkyl ethers.

In the known method, chloromethyl ether is used as the reaction component, the reaction is carried out at an elevated temperature and in the presence of N, N-dimethylaniline and benzene. Benzene is also used to extract the final product. Thus, additional heating 35 is required in this method, and in addition, special equipment is required to recover and treat reagent components that are harmful to the environment. 1 3 91746

Our process does not use chlorine-containing feedstocks, and the process does not require an external heat source to complete the reaction. In addition, our process does not use a solvent such as benzene, nor aniline type-5 compounds.

The invention provides a process which has a lower energy consumption than the known process and which does not use carcinogenic solvents such as benzene.

10 Since no dialkylanilines are used in the process, odor problems are detrimental to the environment while the overall yield of the process is high.

The present invention provides a process for the preparation of a compound of formula C '- O - R 1 r 6och 2 -o- - O - R 3 Formula C' 20 wherein R 1 and R 3 are selected from the group consisting of hydrogen, halogen, lower alkyl or phenyl optionally substituted lower alkyl, acyl, 1-adamantanoyl, halogen, lower alkyl or phenyl optionally substituted phenyl or halogen, lower alkyl or phenyl optionally substituted phenyl-lower alkyl and R 6 represents halogen, lower alkyl or phenyl lower alkyl.

In this specification and claims, the following terms have the meanings assigned to them, unless otherwise stated.

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

4,91746 "Acyl" as used herein means 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 substituent 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 phenylpropanoyl and 4-phenylbut-10 tanoyl.

"1-Adamantanoyl" means a radical having the structure 15 C = 0 20 1-Adamantanoyl. 25 "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 such as nitric acid, sulfuric acid, phosphoric acid, hydrogen halides. , for example hydrochloric acid, organic acids, for example trifluoroacetic acid, organic sulphonic acids, for example phenylsulphonic acid, and particularly preferred para-toluenesulphonic acid, and acidic resins, for example Amberlyst (R) (Rohm and Haas).

35

One method of the present invention is shown in Reaction Scheme I.

li 5 91746

REACTION SCHEME I

0 O

II II

5 c c CH 2 (OR 6) 2 + R 4 ^ NR 4

Formula F Formula G

A

0 I

io || i R V X o OR6 + R1 - O O - R3

15 Formula D OH

B

Formula E

C ^ OR 1

20 I

CH-O-R7 ch2or3 25 if R7 = CH2OR6 1 is reacted with compound O ·: ii (R4C) 90 30 1

Formula A

O CHOR1

35 II I

R4 - CO O - C

CHOR3 40 wherein R1 and R3 are selected from the group consisting of hydrogen, optionally substituted lower alkyl, 1-adamantanoyl, acyl, optionally substituted phenyl or optionally substituted phenyl-lower alkyl, and R7 is R4C (O) OCH2 or R 6 OCH 2, wherein R 4 and R 6 are independently selected from optionally substituted lower alkyls.

In Reaction Series A, a dialkyloxymethane of formula F is reacted with an anhydride of formula G in the presence of a protic acid catalyst. The two reactants are present in a molar ratio of about 1: 1 in the presence of a catalytic amount of a protic acid, for example organic sulphonic acids, for example paratoluenesulphonic acid, or a catalytic amount of a mineral acid, for example hydrochloric acid or sulfuric acid. 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).

20

It is recommended that the anhydride and dialkyloxymethane be symmetrical, as the use of symmetrical reagents dramatically reduces the number of possible products. In the process of the present invention, naturally, asymmetric anhydrides or asymmetric alkyloxymethanes can also be reacted with one another. In some cases, asymmetric anhydrides may be selective for any 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 produce 1,3-dialkanoyl glycerol of formula E.

7,91746 Alternatively, these compounds can be obtained from dihydroxyacetone J. Orcr. Chem. . 35. 2082, (1970).

Treatment of dihydroxyacetone in pyridine with the equivalent of the fatty acid chloride in question followed by reduction of the middle keto group 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 a catalytic amount 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 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 the compound of formula D be used in excess, as the excess is useful as a solvent for the reaction. The reaction components can be mixed together without the need for an external heat source, although the use of heat will accelerate the reaction. Reaction B may be exothermic. The reaction has taken place when the temperature drops to ambient temperature. The reaction takes 1 to 6 hours, typically about 2 hours.

The mixture (formula C) varies depending on the starting material. For example, if R 1 and R 3 represent benzyl, Reaction Series B essentially produces a compound of formula A, but if R 1 and R 3 represent pivaloyl, Reaction Series B essentially produces a compound of formula C '. Reaction series C can be omitted if the product of reaction series 8 is a compound of formula A. Otherwise, the compounds are reacted according to Reaction Series C.

In Reaction Series C, a mixture of compounds of formula C is then further reacted with alkyl anhydride and 35,91746 8

In the presence of a Lewis acid catalyst. It is preferable that the anhydride used in this reaction is a symmetrical anhydride in order to reduce the possible number of products formed, although this is not a prerequisite for this reaction.

The catalyst acid is preferably a non-protic Levis acid catalyst, for example boron trifluoride or aluminum trichloride. The reaction temperature rises from ambient temperature 10 to about 50 ° C, at which point the temperature begins to be controlled.

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 extent of the reaction. The reaction is usually complete after about 60 to 180 minutes. The reaction mixture is extracted with an organic solvent, which is washed with sodium carbonate and water. The organic layer is then dried and the product of kaftva 20 A is obtained by evaporating the solvent.

Once compound A is obtained, esters or ethers of DPHG or DPHG itself can be readily obtained, if desired. This method is shown in Reaction Schemes II and III.

25

REACTION SCHEME II

o g κ .... λ. τΎ> ^ FYN> r5 I 5 <-0 —R1 R5 1) - 3

1_0-R

Formula H Formula J

i.

35 91746 9

The compound of formula A can be converted to 2-haloalkyl-1,3-diacylglycerol using HX, wherein X is a fluorine, chlorine, bromine or iodine atom, in methylene chloride.

5

A protected guaninine of formula H prepared, for example, by Shido'n et al. methods, Bull. Chem. Soc. Japan. 37. 1389 (1964), is reacted with Compound A isolated in Reaction Scheme I. R 5 is acyl or hydrogen and, if acyl, together with the nitrogen of guaninine protected by R 5, forms preferably a monoamide of a lower alkanoic acid, for example acetamide or propionamide. The reaction is carried out at elevated temperature under vacuum in the presence of an acid catalyst, for example para-toluenesulphonic acid. A DHPG derivative of formula J is then formed, wherein R1 and R3 have the same meaning as before. If the ester or ether derivative is directly useful, for example dipivaloyl-DPHG or di-adamantanoyl-DHPG, then no further reactions are required if R5 was hydrogen. If R 5 was acyl, then the ester or ether of DHPG can be prepared by reacting a compound of formula J, for example with methanolic ammonia.

If DHPG is desired, the compound of formula J can be deprotected (removal of R1, R3 and R5) to form DHPG by reacting the compound. 25 countries with, for example, a mixture of ammonium hydroxide and water.

REACTION SCHEME III

0 ♦ 30 Formula A Z (lower alkyl) Si /

K aa va K

Ύ 0 35 OHPG 4- I I / ^ u HN /

'*> <\ - r0_R

Lo-R

K a a va J

10 91746

Alternatively, a compound of formula A may be reacted directly with trialkylsilyl protected guanine to give a DHPG ester or ether. Guanine or an optionally substituted guanine derivative is heated in an aprotic hydrocarbon solvent, for example toluene or xylenes and the like, with more than 3 molar equivalents of hexa-lower alkyl-silazane, for example hexamethylsilazane, with hexane-ethylsilazane. The catalyst is selected from the group consisting of trialkylsilyl sulfates, chlorosilanes, ammonium sulfate and pyridines. The resulting solution is removed by vacuum distillation with an equal volume of volatiles as the volume of the hydrocarbon solvent. The compound of formula A is then added and the mixture is heated to a temperature 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 J) 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 normal methods. If R5 is acyl, then R5 can be removed with, for example, methanolic ammonia to give a DHPG ester or ether. If DHPG is desired, the compound of formula J can be deprotected (R1, R3 and R5) by reacting, for example, a mixture of ammonium hydroxide and water.

30 EXAMPLES

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

I; 11 91746 EXAMPLE 1 1,3-di (1-adamantanowli) alvserol 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 10 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-adamantanoyl) glycerol is isolated as an oil, yield 67%.

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; yield 50%; nmr: 4.5 pp, (complex, 5H); 7.5 (complex, 6H); 8.0 (multiplet, 4H) 1,3-di-pivaloylglycerol; yield 70%; nmr: 1.7 ppm (5.18η); 3.2 (s, 1H), 4.1 (complex, 5H) 1,3-di-butanoylglycerol; 1,3-di-s-butanoylglycerol, 1,3-di-t-butanoylglycerol, -β, 3-di-propanoylglycerol; 1,3-di-hexanoylglycerol; 1,3-di-heptanoylglycerol; 1,3-di-octanoylglycerol; 1,3-di-nonaoylglycerol; 12,91746 1,3-di-decanoylglycerol; 1,3-di-undecanoylglycerol; 1,3-di-dodecanoylglycerol; 1,3-di-tridecanoylglycerol; 5,3-di-tetradecanoylglycerol; 1,3-di-pentadecanoylglycerol; 1,3-di-hexadecanoylglycerol; 1,3-di-heptadecanoylglycerol; 1,3-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; 1,3-di-o-fluorobenzoylglycerol; 1,3-di-m-fluorobenzoylglycerol; 1,3-di-p-iodobenzoylglycerol; 1,3-di-o-iodobenzosylglycerol; 1,3-dira-iodobenzosylglycerol; 1,3-di-toluoylglycerol; 1,3-diphenylacetylglycerol; 1,3-di-3-phenylpropanoylglycerol; 1,3-di-4-phenylbutanoylglycerol.

1,3-Dialkyl glycerols can be prepared by the method described in U.S. Patent 30 4,355,032.

EXAMPLE 2 1,2-Diisopropanoyl-2-propanoyloxymethylcerol 35,154 g of 1,3-diisopropylglycerol and 616 g of methoxymethylpropionate and 9.98 g of para-toluenesulfonic acid were mixed in a 2-liter round bottom flask equipped with a 2-liter round bottom flask. with stirrer and internal thermometer. A temperature rise of 6 ° C occurred within 10 minutes. This was followed by a steady drop in temperature back to 5 ambient temperatures. After 45 minutes of reaction, TLC (25% ethyl acetate / 75% hexane rf = 0.69, silica) 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 subject compound of Example 1: 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-t-butyl-2-propanoyloxymethylglycerol; 1,3-di-phenyl-2-propanoyloxymethylglycerol; 1,3-di-benzyl-2-propanoyloxymethylglycerol, yield 74%; nMR; 1.05 ppm (t, 3 H); 2.2 (quartet, 2H); 3.6 (d, 4H), 4.5 (s, 4H); 5.4 (s, 2H), 7.7 (s, 10H) 35 14 91746

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

EXAMPLE 3 1,3-DiproDanowli-2-propanoyloxymethylsulcerol 339 g of propionic anhydride and 185 g of crude oil from the reaction of Example 2 (1,3-diisopropyl-2-propanoyloxymethylglycerol) were added to a 3-liter 3-pyrore-3-pyrore oil equipped with a magnetic stirrer, a reflux condenser, an internal thermometer and a nitrogen inlet and assembled in such a way that it could be heated or cooled rapidly. Subsequently, 17.9 g of boron trifluoride etherate were 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-30a, 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.

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

• · 35 15 91746

Similarly, the corresponding 1,3-di-alkyl-2-propanyloxymethylglycerols of Example 2 can be reacted to prepare 1,3-di-propanoyl-2-propanoyloxymethylglycerol.

5

In a similar manner, the corresponding 1,3-di-alkyl-2-acetyloxymethylglycerol, 1,3-di-alkyl-2-butanoyloxymethylglycerol or 1,3-di-alkyl-2-pentanoyloxymethylglycerol can be reacted to form the corresponding 10 l , 3-di-acyl compound.

EXAMPLE 4 1,3-Dibenzyl-2-acetoxymethylalcerol 15 75 g of dibenzylglycerol, 5.25 g of paratoluenesulphonic 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 equipped with a magnetic stirrer. The reaction mixture was warmed 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 700 mL. water and once 700 ml of saturated aqueous sodium carbonate .25 solution. Thereafter, 150 ml * of methylene chloride was 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-dibenzyl-2-acetoxymethylglycerol as a clear oil.

30

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

In a similar manner the following compounds were prepared using the corresponding 1,3-di-substituted glycerols of Example 1: 1,3-dimethyl-2-acetoxymethylglycerol; 1,3-diethyl-2-acetoxymethylglycerol; 16,91746 1,3-di-propyl-2-acetoxymethylglycerol; 1,3-diisopropyl-2-acetoxymethylglycerol; yield quantitative; nmr: 1.1 ppm (d, 12H), 2.05 (s, 3H), 3.4-4.0 (complex, 7H), 4.8 (s, 2H), 5.3 (s, 2H) ) 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; 1,3-di-adamantoyl-2-acetoxymethylglycerol; yield 62%, 10 nmr: 1.7-2.1 (mult, 3OH), 2.1 (s, 3H), 4.1 (complex, 5H), 5.3 (s, 2H).

EXAMPLE 5 1,3-Dipivaloyl-2-methoxymethylglycerol 50.45 g of 1,3-dipivaloylglycerol were dissolved in 200 ml of methoxymethyl acetate. 2.5 g of p-toluenesulfonic acid monohydrate were added, after which the mixture was stirred for 20 hours, 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-dipi-25-valoyl-2-methoxymethylglycerol as a colorless oil.

Proton NMR, CDCl 3, 1.2 (s, 18H); 3.4 (s. 3H); 4.1 (m, 1H); 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 1: 1,3-di (1-adamantanoyl) -2-methoxymethylglycerol 35

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 · 17,91746 1,3-di-benzoyl-2-methoxymethylglycerol, yield 51%, nmr: 3.4 ppm (s, 3H), 4.2-4.9 (complex, 7H), 7.5 ( mult., 6H), 8.0 (mult., 4H); 1,3-di-pivaloyl-2-methoxymethylglycerol; 1,3-di-butanoyl-2-methoxymethylglycerol; 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-di-decanoyl-2-methoxymethylglycerol; 1,3-di-undecanoyl-2-methoxymethylglycerol; 1,3-di-dodecanoyl-2-methoxymethylglycerol; 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; 1,3-di-nonadecanoyl-2-methoxymethylglycerol; 1,3-di-eicosanyl-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; 1,3-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-p-iodobenzoyl-2-methoxymethylglycerol; 1,3-di-o-iodobenzoyl-2-methoxymethylglycerol; 1,3-di-m-iodobenzoyl-2-methoxymethylglycerol; 3,5-di-toluoyl-2-methoxymethylglycerol; 1,3-diphenylacetyl-2-methoxymethylglycerol; • 1,3-di-3-phenylpropanoyl-2-methoxymethylglycerol; 18,91746 1,3-di-4-phenylbutanoyl-2-methoxymethylglycerol; 1,3-di-adamantoyl-2-methoxymethylglycerol; yield quantitative, nmr: 1.7-2.1 ppm (mult., 30H), 3.5 (s, 3H), 3.8-4.4 (complex, 5H), 4.8 (s, 2H).

5

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

EXAMPLE 6 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 for a further 1.5 hours. After this period, 100 ml of saturated aqueous Na 2 CO 3 were added to the mixture 20, 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 glycerol.

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

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

35 Proton NMR, CDCl 3, 1.6-2.1 (complex, 30H); 2.12 (s, 3H); 4.1 (complex, 5H); 5.3 (s. 2H).

I: 19,91746 1,3-di-benzoyl-2-acetoxymethylglycerol, yield 65%; nmr: 2.0 ppm (s, 3H); 4.5 (complex, 5H), 5.4 (s, 2H); 7.5 (mult. 6H), 8.0 (mult., 4H); 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-dodedecanoyl-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; 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; 20,91746 1,3-di-3-phenylpropanoyl-2-acetoxymethylglycerol; 1,3-di-4-phenylbutanoyl-2-acetoxymethylglycerol.

In a similar manner, the corresponding 1,3-diacyl-2-5 acyloxymethyl glycerol can be prepared by substituting ethoxymethyl acetate, propoxymethyl acetate or butoxymethyl acetate.

EXAMPLE 7

10 ETHERS AND ESTERS OF DHPG

Dipivalowli-DHPG

8.00 g of quanine, 40 ml of hexamethyldisilazane, 80 ml of xylene and 0.64 g of ammonium sulphate at reflux for about 15 hours. It is then distilled off from the clear solution obtained in 80 ml of volatile matter 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 dipivaloyl-DHPG.

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

Similarly, 1,3-dibenzyl-DHPG

Proton NMR, DMSO-d 6 3.5 (m, 4H); 4.1 (m, 1H); 4.4 (s. 4H); 5.5 (s. 2H); 6.7 (s. 2H); 7.3 (complex, 10H); 7.9 (s, 1H); 10.9 (s, 1H) was prepared using 1,3-dibenzyl-2-acetoxymethyl-35 glycerol as starting material.

21 91746

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: 59- (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; 9- (1,3-dibutyylioksi-2-propoxymethyl) guanine; 109- (1,3-di-s-butyloxy-2-propoxymethyl) -guanine; 9- (1,3-di-t-butyloxy-2-propoxymethyl) guanine; 9- (1,3-difenyylioksi-2-propoxymethyl) guanine; 9- (1,3-dibenzoyl-2-propoxymethyl) guanine; 9- (1,3-dibutanoyl-2-propoxymethyl) -guanine, yield 53%; 15 colors 205-207 ° C, nmr: 0.8-0.4 ppm (t, 6H), 1.5 (mult., 4H), 2.2 (t, 4H), 4.0-4.2 (complex) , 5H), 5.4 (s, 2H), 6.4 (2, 2H), 7.8 (2, 1H); 9- (1,3-di-p-butanoyl-2-propoxymethyl) guanine; 9- (1,3-di-t-butanoyl-2-propoxymethyl) guanine; 20- (1,3-di-propanoyl-2-propoxymethyl) -guanine, yield 25%, m.p. 190-192 ° C, nmr: 0.9-1.0 (t, 6H), 2.15-2.25 (quartet, 4H), 3.4-4.2 (complex, 5H), 5.4 (s , 2H), 7.8 (s, 1H), 6.5 (s, 1H); 9- (1,3-di-hexanoyl-2-propoxymethyl) -guanine, yield 30%, m.p. 184-186 ° C, nmr: 0.8-0.9 (t, 6H), 1.15-1.35 (mult, 8H), 1.4-1.5 (mult., 4H) 2.1 - 2.2 (t, 4H), 3.0-4.1 (complex, 5H), 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H), 10, 6 (s, 1H); 9- (1,3-di-heptanoyl-2-propoxymethyl) guanine; 30- (1,3-di-octanoyl-2-propoxymethyl) -guanine, yield 61%, m.p. 165-166 ° C, nmr: 1.15-1.3 (complex, 16H), 1.4-1.5 (complex, 4H), 2.1-2.2 (t, 4H), 3.9 - 4.2 (complex, 5H), 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H), 10.7 (s, 2H); 35- (1,3-di-nonanoyl-2-propoxymethyl) -guanine; 9- (1,3-di-decanoyl-2-propoxymethyl) -guanine, yield 58%, m.p. 158-160 ° C, nmr: 0.8-0.9 (t, 6H), 22,91746 1.1-1.3 (complex, 28H), 1.4-1.5 (complex, 4H), 2.1-2 , 2 (t, 4H), 3.4-4.1 (complex, 5H), 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H), 10, 6 (s, 1H); 9- (1,3-di-undecanoyl-2-propoxymethyl) guanine; 59- (1,3-di-dodecanoyl-2-propoxymethyl) -guanine, yield: 51%, nmr: 0.8-0.9 (t, 6H), 1.2-1.4 (complex, 32H ), 1.4-1.5 (complex, 4H), 2.1-2.2 (t, 4H), 3.9-4.1 (complex, 5H), 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H), 10.6 (s, 1H); 109- (1,3-di-tridecanoyl-2-propoxymethyl) -guanine; 9- (1,3-di-tetradecanoyl-2-propoxymethyl) -guanine, yield 66%, m.p. 137-140 ° C, nmr: 0.8-0.9 (t, 6H), 1.2-1.4 (complex, 40H), 1.4-1.5 (complex, 4H), 2.1-2.2 (t, 4H), 3.9-4.1 (complex, 5H), 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H), 10.6 (s, 2H) 9- (1,3-di-pentadecanoyl-2-propoxymethyl) -guanine; 9- (1,3-di-hexadecanoyl-2-propoxymethyl) -guanine, yield 85%, m.p. 154-158 ° C, nmr: 0.8-0.9 (t, 6H), 1.1-1.3 (complex, 48H), 1.4-1.5 (complex, 4H), 2.1- 2.2 (t, 4H), 3.9-4.1 (complex, 5H), 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H), 10 , 6 (s, 1H); 9- (1,3-di-heptadecanoyl-2-propoxymethyl) guanine; 9- (1,3-di-octadecanoyl-2-propoxymethyl) guanine; 9- (1,3-di-nonadecanoyl-2-propoxymethyl) guanine; 25- (1,3-di-eicosanoyl-2-propoxymethyl) -guanine; "· 9- (1,3-di-p-chlorobenzoyl-2-propoxymethyl) guanine; 9- (1,3-di-o-chlorobenzoyl-2-propoxymethyl) guanine; 9- (1,3-di -m-chlorobenzoyl-2-propoxymethyl) -guanine; 9- (1,3-di-p-bromobenzoyl-2-propoxymethyl) guanine; 9- (1,3-di-o-bromobenzoyl-2-propoxymethyl) guanine 9- (1,3-di-m-bromobenzoyl-2-propoxymethyl) guanine, 9- (1,3-di-p-fluorobenzoyl-2-propoxymethyl) guanine, 9- (1,3-di-o- fluorobenzoyl-2-propoxymethyl) guanine; 9- (1,3-di-m-fluorobenzoyl-2-propoxymethyl) guanine; 35- (1,3-di-p-iodobenzoyl-2-propoxymethyl) guanine; 9- ( 1,3-di-o-iodobenzoyl-2-propoxymethyl) guanine; 9- (1,3-di-m-iodobenzoyl-2-propoxymethyl) guanine; 23,91746 9- (1,3-di-toluoyl- 2-propoxymethyl) guanine, 9- (1,3-diphenylacetyl-2-propoxymethyl) guanine, 9- (1,3-diphenylpropanoyl-2-propoxymethyl) guanine, 9- (1,3-di -phenylbutanoyl-2-propoxymethyl) guanine, 5,9- (1,3-di-adamantoyl-2-propoxymethyl) -guanine, yield 65%, mp 283-285 ° C; 9- (1,3-di-acetyloxy-2-propoxymethyl) -guanine, yield 65%, m.p. 234-237 ° C, nmr: 1.9 (s, 6H), 3.9-4.1 (complex, 5H), 5.4 (S, 2H), 6.5 (s, 2H), 10 , Δ (s, 1H), 10.6 (s, 1H); 9- (1,3-dipentanoyl-2-propoxymethyl) -guanine, yield 70%, m.p. 198-203 ° C, nmr: 0.8-0.9 (t, 6H), 1.2-1.3 (complex, 4H), 1.4-1.5 (complex, 4H), 2.1 - 2.2 (t, 4H), 3.9-4.1 (complex, 5H), 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H) , 10.6 (s, 1H).

• ·

Claims (3)

24 91746 A process for the preparation of a compound of formula C ' Formula C 'wherein R 1 and R 3 are selected from the group consisting of hydrogen, lower alkyl, acyl, 1-adamantano optionally substituted with halogen, lower alkyl or phenyl. phenyl, phenyl optionally substituted by halogen, lower alkyl or phenyl, or phenyl-lower alkyl optionally substituted by halogen, lower alkyl or phenyl, and R 6 represents lower alkyl optionally substituted by halogen, lower alkyl or phenyl, characterized in that Formula D wherein R 4 is lower alkyl optionally substituted by halogen, lower alkyl or phenyl and R 6 is as defined above is reacted in the presence of a protic acid with a compound of formula E R 1 - 0 0 - R3 3 0 \ -j_ / Formula E OH where R1 and R3 have the same meaning as above. 35 Process according to Claim 1, characterized in that the protic acid is p-toluenesulphonic acid. 25 91746 Process according to Claim 1, characterized in that the reaction mixture is allowed to heat without external heating. «· 26 91746