IL100956A - Glycerol ester and ether compounds and their preparation - Google Patents

Description

GLYCEROL ESTER AND ETHER COMPOUNDS AND THEIR PREPARATION mom 7Π! 7;ι 7ω ΊΠΝΊ ΊΌΌΚ mimri The present invention rel ates to compounds represented by the formul a ; Formula C wherein R1, R3 and R6 are defined as optionally substituted Ci-4 alkyl, the substituents being selected from halogen atoms, Ci-4 alkyl groups and phenyl groups, with the proviso that when R6 is an unsubstituted C1-4 alkyl, R1 and R3 cannot be both propyl or iso-propyl.

The invention further relates to a process for the production of compounds of Formul a C : Formula C wherein R1 and R3 which are identical, are selected from the group consisting of hydrogenl optionally substituted lower alkyl, acyl, 1 -adamantanoyl, optionally substituted phenyl or optionally substituted phenyl lower alkyl and R7 is defined as R4C(0)OCH2 and as R6OCH2 wherein R4 and R6 are defined as optionally substituted lower alkyl, by reacting a compound of Formula D: Formula D are as previously defined with a compound of 1 Formula ε 1 3 wherein R and R are as previously defi ned , in the presence of a protic acid .

The present patent appl ication has been divided out from patent appl ication No . 77298, which relates to certain intermediates for the production of 9- (l ,3-di hydroxy-2-propoxymethy"i ) guanine and to a process for their production.

The said patent appl ication No. 77298 provides a process for preparing a compound of Formul a A: „ — Formula A wherein R1 and R3 are identical, and which are selected from the group consisting of hydrogen, optionally substituted lower alkyl, acyl, 1 -adamantanoyi, optionally substituted phenyl or optionally substituted phenyl lower alkyl and R4 is optionally substituted lower alkyl, comprising: reacting a compound represented by the Formula: 0 4 " (R — C — ) -0 Formula B wherein each i s i dependently sel ected from the group as defined above, with a compound represented by the Formul a Formula C wherein R and R are as previously defined, and R is defined as optionally substituted lower alkyl, in the presence of a catalytic amount of a Lewis acid for time sufficient to form a compound represented by Formula A.

I DETAILED DESCRIPTION OF THE INVENTION As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated.

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

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

"Optionally substituted guanine" refers to a guanine molecule which is optionally substituted with acyl and/or (alkyDjSi groups on the amino group at position 2 and on the nitrogen at position 9. j "Acyl" is defined herein as optionally substituted alkyl-C(O) having four to twenty carbon atoms in the alkyl chain, optionally substituted phenyl-C(O), or optionally substituted alkyl phenyl-C(O) where the optional substitution is on the phenyl ring. Examples include n-hexanoyl, n-heptanoyl, palmitoyl, Stearoyl arachidoyl, pivaloyl, 1-methyl-l-cyclohexane-carboxoyl , 2- octyl-decanoyl, benzoyl, p-chlorobenzoyl, toluoyl, phenylacetyl, 3-phenylpropanoyl, and A-phenylbutanoyl .

"Pivalic acid" is 2,2-dimethyl propionic acid. ' "1-adamantanoyl" refers the radical having the structure identified below.

Phenyl refers to a six-member carbon ring which contains 3 double bonds.

Alkyl phenyl refers to a phenyl group which has an alkyl chain substituted on it wherein alkyl is as defined above .

"Lewis acid" refers to any species which has a vacant orbital that can be used to form covalent bond with the electron pair of a base. Examples include Be(CH3)2, and the like. A comprehensive list of Lewis acids can be found at Chem. Rev., 75, 1, (1975), on page 2.

As used herein the term "Protic acid" refers to any Bronsted acid having a pK less than 2.0, and preferably less than 1.0 that has an abstractable proton. Examples include mineral acids, for example, nitric acid, sulfuric acid, phosphoric acid, hydrogen halides, for example, hydrochloric acid; organic acids, for example, t rifloroacetic acid, organic sulfonic' acids, for example phenyl sulfonic acid, and particularly preferred, para-toluene sulfonic acid; and acidic resins, for example Amberlyst" (Rohm and Haas).

REACTION SCHEME I Formula F Formula G A 0 Formula E -4a- Formula C wherein R 1 and R3 are identical , and are selected from the group consisting of hydrogen, optionally substituted lower alkyl, 1 -adamantanoyl , acyl, optionally substituted phenyl ! - 5 - i 7 or optionally subtituted phenyl lower alkyl, and R is R4C(0)0CH2 or R60CH2 wherein RA and R6 are independently selected from optionally subtituted lower alkyl.

In Reaction Sequence A a dialkyloxy methane Formula F is reacted with an anhydride Formula G in the presence of a protic acid catalyst. The two reactants are present in about a one to one molar ratio in the presence of a catalytic amount of a protic acid, for example, organic sulfonic acids, for example, para-toluene sulfonic acid, or catalytic amounts of a mineral acid, for example, hydrochloric acid or sulfuric acid. The reaction can be done in an aprotic hydrocarbon solvent, for example benzene, or neat, typically at reflux temperature of the solution. The solution is reacted for 1 to 12 hours, 6 hours being about typical. See the method of , Am. Chem. Soc. , 76, page 5161 (1954).

I It is preferred that1 the anhydride and dialkyloxy methane be symmetric because the number of possible products is dramatically reduced by using symmetrical reagents. Asymmetrical anhydrides or asymmetrical alkyloxy methanes can, of course, be reacted together in the process of this invention. In certain cases asymmetrical anhydrides can be selective for one of the possible products.

The 1,3-dialkanoyl glycerol Formula E.can be prepared in one of two ways. Treatment of glycerol with slightly more than two equivalents of an acid chloride or an acid anhydride in aprotic solvents in the presence of organic base, for example, trialkylamines, and a nucleophilic catalyst, for example, pyridine can afford the 1,3-dialkanoyl glycerol Formula E.

Alternatively these compounds are accessible from dihydroxyacetone using the method of J. Org. Chem., 35, 2082, (1970). Treatment of dihydroxyacetone in pyridine with an equivalent of the appropriate fatty acid chloride followed by reduction of the central keto group with borohydride in tetrahydrofuran can afford the 1, 3-dialkanoyl glycerol Formula E.

In Reaction Sequence B compound Formula 0 and compound Formula E are reacted together in the presence of a protic acid catalyst, for example, organic sulfonic acids, for example, para-toluene sulfonic acid, or catalytic amounts of a mineral acid, for example, hydrochloric acid or sufuric acid , to produce a mixture (Formula C). This mixture is composed of compound of Formula A and compound of Formula C . Compounds of Formula D and Formula E are mixed together neat with a catalytic amount of a protic acid catalyst. It is preferable that an excess of the compound of Formula D be used, the excess being useful as a solvent for the reaction. The reactants can be mixed together without the necessity of an external heat source, although the application of heat will speed the reaction. Reaction B can be exothermic, and when the temperature drops to ambient temperature the reaction is over. The reaction takes between 1 and 6 hours, typically about 2 hours to complete.

The mixture (Formula C) will vary depending on the 1 3 starting materials. For example, if R and R are benzyl, reaction sequence B produces mostly Formula A, but- if fl1 and R3 are pivaloyl reaction sequence B produces mostly Formula C\.

EXAMPLES The following nonlimiting examples show various aspects of this invention.

The correct formal designation of the compound of Example 1 is: ,3-Di(1-adamantanoyloxy) propan-2-ol propan-2-oi For brevity Applicants designate this compound as 1,3-di (1-adamantanoyl) glycerol, and also the further compounds exemplified and listed are designated according to this nomenclature.

EXAMPLE 1 1.3-Di (1-adamantanoyl) Glycerol In a flask qnder nitrogen 1.053 gms of glycerol is dissolved in 4 ml of pyridine and 6 ml of methylene chloride and cooled to about -10°C. Then 5.00 gms of (l-adamantanoyl)-chloride (Aldrich Chemical Co.) is added in one portion and stirring is continued for about half an hour with cooling and then another two hours at ambient temperature. The resulting solid is filtered and washed with methylene chloride. The combined organic layers are washed twice with dilute aqueous HC1 and then once with water and dried over magnesium sulfate. l,3-di(l-adamantanoyl) glycerol is isolated as an oil.

Proton NMR , CDC1? 1.5-2.2(m, 30H) ; 2.3-2.7(br. s, 1H) ; 4.1-4.3(m, 5H) .

Using a similar method but substituting the appropriate compound for ( l-adamantanoyl)chloride , the ,3-di-benzoyl glycerol; , 3-dl-pivaloyi glycerol; , 3-di-butanoy 1 glycerol; , 3-di-s-butanoyl glycerol; , -di-t-butanoyl glycerol; ,3-di-propanoyl glycerol; , 3-di-hexanoyl glycerol; , -di-heptanoyl glycerol; ,3-di-octanoyl glycerol; , 3-di-nonanoyl glycerol; ,3-di-decanoyl glycerol; ,3-di-undecanoyl glycerol; , 3-di-dodecanoyl glycerol; , 3-di-tridecanoyl glycerol; , 3-di-tetradecanoyl glycerol; ,3-di-pentadecanoyl glycerol; ,3-di-hexadecanoyl glycerol; , 3-di-heptadecanoyl glycerol; , 3-di-octadecanoyl glycerol; , -di-nonadecanoyl glycerol; ,3-di-eicosanoyl glycerol; ,3-di-p-chlorobenzoyl glycerol; ,3-di-o-chlorobenzoyl glycerol; ,3-di-m-chlorobenzoyl glycerol; , 3-di-p-bromobenzoy 1 glycerol ; , 3-di-o-bromobenzoyl glycerol; ,3-di-m-bromobenzoyl glycerol; , 3-di-p-fluorobenzoyl glycerol; ,3-di-o-fluorobenzoyl glycerol; , 3-di-m-fluorobenzoyl glycerol; ,3-di-p-iodobenzoyl glycerol; ,3-di-o-iodobenzoyl glycerol; ,3-di-m-iodobenzoyl glycerol; ,3-di-toluoyl glycerol; ,3-di-phenylacetyl glycerol; 1, 3-di-3-phenylpropanoyl glycerol ; 1 , 3-di-4-phenylbutanoyl glycerol.

The 1,3-di-alkyl glycerols can be prepared according to the method described in U.S. Patent 4,355,032.

KXAMPLR 2 1.3 Diisopropoxy 2-propanoyloxy-methoxypropane * 154 g of 1, 3-di-isopropyl glycerol and 616 ml of methoxymethylpropionate plus 9.98 g para-toluene sulfonic acid were mixed in a 2-liter round bottom flask equipped with magnetic stirring and an internal thermometer. A 6° temperature rise occurred over 10 minutes. This was followed by a steady drop in temperature back to ambient temperature. A TLC (25¾ ethyl acetate / 75% hexane rf=0.69, silica) check after 45 minutes of reaction showed a nearly complete consumption of the starting alcohol.

The reaction mixture was added to a separatory funnel with 500 ml of hexane as an organic phase followed by washing the organic layer with 500 ml of water and washing it twice with 500 ml of saturated aqueous sodium bicarbonate and a final 500 ml wash of water. The organic layer was then dried over anhydrous magnesium sulfate and stripped on a rotary evaporator and 1,3-di- isopropyl-2-propanoyloxymethyl glycerol isolated.

Proton NMR, CDC13, l.Kcomplex, 9H); 2.3(q, 2H); 3.4-4.0(complex, 7H); 5.2(s, 2H) .

Similarly, substituting the appropriate compound of Example 1, the following compounds were prepared: 1 , 3-di-methyl-2-propanoyloxymethyl glycerol; 1, 3-di-ethy1-2-propanoy loxymethyl glycerol ; 1 , 3-di-propyl-2-propanoyloxymethyl glycerol; 1, -di-buty 1-2-propanoy loxymethy 1 glycerol ; 1 , 3-di-s-butyl-2-propanoyloxymethyl glycerol; l,3-di-t-butyl-2-propanoyloxymethyl glycerol; * hereinafter referred to as l^-diisopropyl^-propanoyloxymethyl glycerol - 10 - 1 , 3-di-phenylr2-propanoyloxymethyl glycerol; 1 , 3-di-benzyl-2-propanoyloxymethyl glycerol.

In a similar manner, methoxymethy lbutanoate , or methoxymethylpentanoate can be used to prepare the appropriate 1 , 3-di-alkyl-2-alkanoyloxymethyl glycerol.

KXAMPLB 3 1.3-Diurotttnoylo∑ -2-uropanoyXo y Met oxyurouane * 339 g of propionic anhydride and 185 g of the crude oil produced from the reaction of Example 2 ( 1, -di-isopropyl-2-propanoyloxymethyl glycerol) and were added to a 2-liter, 3-neck, round bottom flask equipped with a magnetic stirrer, a reflux condenser, an internal thermometer and a nitrogen inlet set up so that heating or cooling could be applied rapidly. 17.9 g of borontrif luoride etherate was then added in one portion. The reaction temperature immediately climbed from about 20°C (ambient) to about 50°C at which point cooling was applied. The reaction temperature was carefully kept between 50°C and 60°C by heating or cooling as necessary. Reaction progress was followed by TLC (25% ethyl acetate / 75% hexane rf=0.31, silica)of the reaction mixture.

After 100 minutes the reaction mixture was added to a separatory funnel 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 under a 26 inches of mercury vacuum. A crude black oil was recovered and then purified by 2 passes through a wiped film distillation apparatus. The purified oil was 1, 3-dipropanoyl-2-propanoyloxymethyl glycerol.

Proton NMR, CDC13, l.Kt, 9H) ; 2.3(q, 6H) ; 4.1(complex, 5H); 5.2(s, 2H) .

* Hereinafter referred to as 1,3-dipropanoy!-2-propanoyloxymethyl glycerol In a similar manner the appropriate l,3-di-alkyl-2-propanoyloxymethyl glycerols of Example 2 can be reacted to prepare 1 , 3-di-propanoy 1- 2-propanoyloxymethyl glycerol.

In a similar manner the appropriate 1 , -di-alkyl-2-acetyloxymethy 1 glycerol, 1, 3-di-alkyl-2-butanoyloxymethy 1 glycerol, or 1 , 3-di-alkyl-2-pentanoyloxymethyl glycerol can be reacted to form the corresponding 1,3-di-acyl compound.

EXAMPLE 4 1, 3-dibenzyl-2-acetoxymethyl glycerol 75 g di-benzyl glycerol, 5.25 g paratoluene sulfonic acid, 300 ml hexane, and 300 ml methoxymethy1 acetate were added to a 2-1 round bottom flask with magnetic stirring, internal thermometer and drying tube. The reaction mixture was brought to 60-65°C for 90 minutes, followed by TLC (20% ethyl acetate/ 80% hexane rf=0.31, silica)followed by cooling, transferring to a separatory funnel, washing once with 700 ml H20, and once with 700 ml saturated aqueous sodium carbonate solution. 150 ml CH2C12 was then added followed by a final wash with 700 ml H20. The organic layer was dried over sodium sulfate, filtered, and stripped at high vacuum to give 1, 3-dibenzyl-2-acetoxymethyl glycerol as a clear oil. . > Proton NMR, CDC13 l.?(s, 3H) ; 3.6(complex, 4H) ; 4.0(m, 1H) ; 4.5