FI91746B - Process for the preparation of alkoxy methyl ether derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of a compound of the formula C <IMAGE> Formula C wherein R1 and R3 are hydrogen, lower alkyl, which can be substituted, acyl, 1-adamantanoyl, phenyl, which can be substituted, or phenyl-lower alkyl, which can be substituted, and R6 is lower alkyl, which can be substituted. In the process a compound of the formula D <IMAGE> Formula D wherein R4 is lower alkyl, which can be substituted, and R6 is as defined above, is reacted in the presence of a protic acid with a compound of the formula E <IMAGE> Formula E wherein R1 and R3 are as defined above. The invention further relates to a compound of the formula C' <IMAGE> Formula C' wherein R1, R3 and R6 are optionally substituted lower alkyl, with the exception that R1 and R6 cannot both be propyl.

Description

91746

The present invention relates to a process for the preparation of intermediate-5 products 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 novel intermediates and 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.

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 join the 9-position of the 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.

91746 2

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 properties. 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.

From the abstract Chemical Abstracts can 68, (1968), 12384v 25, 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 is known.

The known process uses chloromethyl ether as a 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. This method therefore requires the use of additional heating 35 and in addition requires special equipment for the recovery and treatment of environmentally harmful reagent components.

li 3 91746

Our process does not use chlorine-containing starting materials, and the process does not require an external heat source to complete the reaction. In addition, our method 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 harmful to the environment are avoided 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, lower optionally substituted with halogen, lower alkyl or phenyl alkyl, acyl, 1-adamantanoyl, 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 optionally substituted by halogen, lower alkyl or phenyl lower alkyl.

In this specification and claims, the following references are given unless otherwise indicated.

"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.

91746 4 "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, 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 the 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 0

II II

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

Formula F Formula G

A

0 I

io || J

R V X o OR6 + R1 - O 0 - 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 · il (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-91746, acyl, optionally substituted phenyl or optionally substituted phenyl-lower alkyl, and R7 is R4C (O) OCH2 or R6OCH2 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 reaction components are present in a molar ratio of about 1: 1 in the presence of a catalytic amount of a protic acid, for example organic sulfonic acids, for example paratoluenesulphonic acid, or catalytic amounts 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 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 according to the invention. 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 just over 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 These compounds can alternatively be obtained from dihydroxyacetone J. Ora. Chem., 35, 2082, (1970).

Treatment of the dihydroxyacetone in pyridine with an equivalent of the fatty acid chloride in question followed by reduction of the middle keto group with borohydride in tetrahydrofuran can afford the 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 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 to 6 hours, typically about 2 hours.

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 R3 are pivaloyl, Reaction Series B essentially produces a compound of Formula C '. Reaction series C may 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 preferred that the anhydride used in this reaction be a symmetrical anhydride in order to reduce the possible number of products formed, although this is not a condition 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 adjusted.

The reaction temperature is generally maintained between about 45 and 65 ° C, most 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 20 A is obtained by evaporating the solvent.

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

25

REACTION SCHEME II

Q 0

Formula A, YYS- * Ϊ 30 HN-VV HnK / Sn / r5 & I, <-0 — R1 R \) - 3

1_0-R

Formula H Formula J

i.

35 9 91746

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 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, preferably forms a monoamide of a lower alkanoic acid, for example acetamide or propionamide. The reaction is carried out at elevated temperature in vacuo in the presence of an acid catalyst, for example para-toluenesulphonic acid. In this case, a DHPG derivative of the formula J is formed, in which R1 and R3 have the same meaning as above. If an 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 / "(former alkyl) Si / Ä *

Formula K

Ύ 0 35 OHPG 4- I I / ^ n HN /

Lo-R

Formula J

91746 10

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 alkylsilazane, for example hexamethylsilazane, with hexylethylsilazane. 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 equal to the volume of the hydrocarbon solvent. The compound of formula A is then added and the mixture is heated at 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 this invention.

I; 11 91746 EXAMPLE 1 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 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; 91746 12 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-Dialkylglycerols can be prepared by the method described in U.S. Patent 30 4,355,032.

EXAMPLE 2 1,2-Diisopropanoyl-2-propanoyloxymethylsalicerol 35,154 g of 1,3-diisopropylglycerol and 616 ml 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. TLC checking after 45 minutes of reaction (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 relevant 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, 2 H), 7.7 (s, 10 H) 35,91746 14

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

EXAMPLE 3 1,3-Dipropanoyl-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 2-liter 3-necked round-bottomed flask. equipped with a magnetic stirrer, a reflux condenser, an internal thermometer and a nitrogen supply and assembled so 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.

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

• · h 35 15 91746

The corresponding 1,3-di-alkyl-2-propanyloxymethylglycerols of Example 2 can be reacted in a similar manner 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 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 700 mL. water and once 700 ml of saturated aqueous sodium carbonate .25 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-dibenzyl-2-acetoxymethylglycerol as a clear oil.

30

Proton NMR CDCl 3 1.9 (s, 3H); 3.6 (complex, 4H); 4.0 (m, 1 H); 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; 91746 16 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).

1,3-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; 1,3-di-toluoyl-2-methoxymethylglycerol; 1,3-diphenylacetyl-2-methoxymethylglycerol; • 1,3-di-3-phenylpropanoyl-2-methoxymethylglycerol; 91746 18 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-Diivalival-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 over a further 1.5 hours. After this period, 100 mL of saturated aqueous Na 2 CO 3 was added to 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 as a pale colored oil.

Proton NMR, CDCl 3, 1.6-2.1 (complex, 30H); 2.1 (s. 3H); 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; 91746 20 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

Dipivalovvli-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. 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 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 (comp, 5H), 5.4 (s, 2H), 6.5 (s, 2H), 7.8 (s, 1H), 10, 6 (s, 1 H); 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), 91746 22 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, 1 H); 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, 2 H), 7.8 (s, 1 H), 10.6 (s, 1 H); 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, 1 H); 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-di-phenylpropanoyl-2-propoxymethyl) guanine, 9- (1,3-diphenylpropanoyl) phenylbutanoyl-2-propoxymethyl) guanine, 59- (1,3-dihydamantoyl-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, 1 H).

• ·

Claims (3)

91746 24 A process for the preparation of a compound of formula C ' 5 I-O - R 1 r 6och 2 -o - * - O - R 3 Formula C 'wherein R 1 and R 3 are selected from the group consisting of hydrogen, lower alkyl, acyl, 1-adamantanoyl optionally substituted with halogen, lower alkyl or 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 the compound of formula D: R 4 - C - O 2 R 2 OR 6 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 with a compound of formula E in the presence of a protic acid R 1 - OO - 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. «· 91746 26