IE46399B1 - 9-(2,6-dihalobenzyl)-adenines and their production - Google Patents
9-(2,6-dihalobenzyl)-adenines and their productionInfo
- Publication number
- IE46399B1 IE46399B1 IE253/78A IE25378A IE46399B1 IE 46399 B1 IE46399 B1 IE 46399B1 IE 253/78 A IE253/78 A IE 253/78A IE 25378 A IE25378 A IE 25378A IE 46399 B1 IE46399 B1 IE 46399B1
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- adenine
- isomer
- dihalobenzyl
- chloro
- liquid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Alkali metal salts or alkaline earth metal salts of adenine are alkylated with a 2,6-dihalobenzyl halide and with the production of a mixture of isomers of (2,6-dihalobenzyl)adenines, which consist to at least 70 % by weight of 9-(2,6-dihalobenzyl)adenines. The alkylation is carried out in a solid/liquid or liquid/liquid two-phase system. 9-(2,6-Dihalobenzyl)adenines, which are practically free of 3-isomers, are prepared from the isomeric mixture which is obtained by subjecting this mixture to a transalkylation in the presence of concentrated sulphuric acid and a carbenium ion acceptor. A further process for preparing 9-(2,6-dihalobenzyl)adenines, which are practically free of isomers, is based on first preparing a mixture of isomers of 9-(2,6-dihalobenzyl)adenines and then subjecting this mixture to an extraction with dilute mineral acid and then carrying out a transalkylation in the presence of concentrated sulphuric acid and a carbenium ion acceptor. The 9-(2,6-dihalobenzyl)adenines, which are practically free of 3-isomers, may be used for the therapy and prophylaxis of coccidiosis.
Description
This invention relates to the preparation and purification of 9-(2,6-dihalobenzyl)adenines. Included in the present invention are pure 9-(206-dihalobenzyl)adenines substantially free of the mutagenic 3-ioomer. Said adenines are described in U.S. Patent No 3,846,426 as being useful in the treatment and prevention of coccidlosis.
Coccidiosis ic a widespread poultry disease which is produced by infections of protozoa of the genus Eimeria which causes severe disorders in the intestines and ceca of poultry. Some of the most significant of these species are E. tenella, E. acervullna, E. necatrix,
E, brunetti and £. maxima. This disease is generally spread by the birds picking up the infectious organism in droppings on contaminated litter or ground, or by way of contaminated food or drinking water. The disease
hemorrhage, accumulation of blood in the ceca, passage of blood in the droppings, weakness and digestive disturbances. The disease often terminates in the death of the animals, but fowl that survive severe infections have had their market value substantially reduced as a result of the infection. Coccidiosis is, therefore, a disease of great economic importance and extensive work has been done to find new and improved methods for controlling and treating coccidial infections in poultry.
It has teen reported that 9-(2,fi-dihalobenzyl) adenines, viiich are useful for the control and treatment of coccidial infections, have been prepared by base-catalysed nonselective alkylations of a salt of adenine in aqueous solvents or protie organic solvents. These reactions are homogenous and rapid but suffer from the disadvantage that the mixtures of 3-isomer and 9-isomer obtained contain a high proportion of the 3-isomer.
Screening in the Ames test revealed that the 3isomer gives a weak positive test, and is deemed to be probably mutagenic. The presence of the 3-isomer side product in the 9-(2,6-dihalobenzyl)adenine thus renders the mixture unusable as a coccidiostat because of the problem of residues persisting in the poultry meat.
To get a usable product it is desirable that it be substantially free of the 3-isomer, defined as below the detectable level of 100 ppm.
Base-catalysed alkylations of adenine carried out in aprotic solvents such as dimethylformamide and dimethylsulfoxide provide a higher ratio of 9-isomer with respect to 3-isomer but suffer from the disadvantage that these solvents are costly. The isolation of the product is also made more difficult. The reaction mixture has to be
- 34039® quenched in water and the product, which is collected by filtration, has to be repeatedly washed to remove solvent. This results in a reduction of yield.
The product obtained by the alkylation reaction 5 is only partially purified by conventional methods such as washing with ethanol or water and recrystallizing from solvents such as acetic acid, aqueous acetic acid, dimethylformamide or dimethylsulfoxide. Swishing the product with dilute nitric acid or tetrafluoroboric acid also results in some purification.
The conventional purification methods recited above,such as washing or recrystallization of crude 9-(2,6dihalobensyl)adenine,result in a product containing up to about 4% of the 3-isomer. Thus, for example, extraction of crude 9-(2-chloro-6-fluor0benzyl)adenine containing 20¾ of the 3-isomer with a dilute aqueous solution of nitric acid produces 9-(2-chloro-'6-fluorobensyl)adenine containing 3-4% of the 3-isomer with a 96-97% recovery of 9-(2-chloro-6fluorobenzyl)adenine. Repeating this procedure on the enriched 9-(2-chloro-6-fluorobenzyl)adenine sample fails to reduce the 3-isomer level below 0.3-0.5% (3000-5000 ppm). This is due to the pronounced tendency toward solid solutions involving the 9-isomer and 3-isomer. The same problem is encountered when 3-isomer removal is attempted 25 using two acetic acid recrystallizations. The 3-isomer level remains in the range of 0.05-0.1% (500-1000 ppm) even though the liquid phase is not saturated with the 3-isaner.
E. C. Taylor, et al., J. Org. Chem. 36, 3211 (1971) have reported that 9-substituted adenines (2) may be prepared by reductive cleavage and subsequent cyclization of 7-amidofurazano[3,4-d]pyrimidines (1).
46338
Although a wide variety of adenine derivatives was prepared, the authors were unable to effect the conversion of 5-unsubstituted 7-amldofurazano £3,4~£/jyrimioinea (_!, R»H, Y0) to 2-unsubstituted adenines (_2. R«H) due t·’ the hydrolytic instability of the former compounds.
The present invention is based on the discovery that the 9(2,6-dihalobenzyl)adenines substantially free of the 3-isomer can be obtained by the alkylation of a salt of adenine in a two-phase system in the presence of an onlum salt phase-transfur catalyst, and selectively transalkylating the 3-isomer by-product with sulfuric acid in the presence of a carbenium ion trap.
In accordance with the present invertion, 9-(2,6-dihalobenzyl) adenines are prepared by alkylating an alkali metal or alkaline-earth metal salt of adenine with a 2,6-dihalobenzyl compound of formula:
where X^ and X^ are, independently, halogens and Y is a halogen, dimethylsulfonium halide or tosyl leaving group, in a solid-liquid two-phase system in which the solid phase comprises the salt of adenine and the liquid phase comprises a solution of the said 2,5-dihalobenzyl compound and an onium salt phase-transfer catalyst having the formula
Φ <£ Θ (R)^^ Z or (ap-jPE z where R is C4_lg alkyl, is alkyl and ls a chloride« bromide or iodide anion; or a liquid-liquid two phase system in which one liquid phase comprises an aqueous solution of the adenine salt and a second liquid phase canprises a solution of the said dihalobenzyl ccnpound and the said onium salt; followed by selectively transalkylating the 3-isater byproduct with sulfuric acid in the presence of a carbanium ion trap. The transalkylation is optionally preceded by acid extraction to remove part of the 3-(2,6-dihaiobenzyl)adenines. The onium salt is used as a catalyst to transport the salt of adenine from the solid phase into the liquid organic phase or from the aqueous liquid phase to the organic liquid phase where alkylation of adenine takes place. The process is generally referred to as phase transfer catalysis and the onium salt referred to as a phase transfer catalyst. The preferred value of Y is β halogen atom.
The alkylation is carried out in the said solid-liquid twophase system in an aprotic water-miscible or water-immiscible organic solvent in which the water-miscible solvent contains from 0 to 5 moles of water per mole of adenine salt, (excessive amounts of water tend to
63 9 8 result ln a higher proportion of 3-isoracr) or in the said liquidliquid two-phase system in an aprotic water-immiscible organic solvent, the quantity of water in the aqueous phase not being critical.
The alkylation normally results in a mixture of isomers of 5 (2,6-dihalobenzyl)adenine in which at least 70% by weight is 9(2,6-dihalobenzyl)adenine.
The compounds prepared are represented by the following structural formula;
where X^ and X^ are independently halogen, i.e. fluorine, chlorine, bromine or iodine. Specific examples of compounds represented by the foregoing structural formulasre 9-(2,6-dichlorobenzyl)adenine and 9(2-chloro-6-£luorobenzyl)adeninc. The 9-(2,6-dlhalobenzyl)adenines of the present invention must be substantially free of positional isomers,
IL and by this term is meant less than 100 ppm of positional Isomers.
Specifically, the present Invention provides 9-(2,6-dlhalobenzyl)adenines containing less than 100 ppm of the 3-isomer. A preferred embodiment of this aspect of the invention is the compound 9-(2-chloro-6-fluorobenzyl)~ adenlne containing less than 100 ppm of the 3-isomer.
Suitable solvent systems for the process of the present invention
O' are aprotic solvents that are inert, i.e. non-reactive with the components of the reaction mixture under the reaction conditions chat are maintained. Aprotic solvents are preferred for the reason that a high ratio of 9-isomer with respect to 3-isomer is obtained.
The alkali metal or alkaline-earth metal salt of adenine has the formula:
vW «here M is an alkali or alkaline-earth metal cation; b and c are integers such that the negative charge of £ moles of anion is neutralized by £ moles of cation 11®. The 3alt is suspended in an aprotic organic solvent or dissolved in an aqueous solution. To this is added a solution containing the 2,6-dihalobenzyl compound (the alkylating agent) which has the formula already given, and the onium salt phase-transfer catalyst in an aprotic solvent. The 2,6-dihalobenzyl compound is added in an equimolar amount with respect to adenine or in a slight excess.
The resulting heterogeneous reaction mixture io stirred rapidly until completion of the reaction.
According to one method of carrying cut the process of the present invention, adenine is suspended in a suitable aprotic solvent. To this is added an equivalent amount of a base derived from an alkali metal or alkaline-earth metal. Preferred bases are those having a pK^ greater than
46398
.5 so that the adenine is substantially completely converted to its anion. Examples of suitable bases include carboietes, e.g. alkali metal carbonates such as sodium carbonate and potassium carbonate, hydroxide^ e.g. alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alcoholates, e.g. potassium ethoxide and sodium ethoxide. In general, suitable alkall-and-alkaline-earth-metal-derived bases include all those that have a sufficient basicity to generate the adenine anion in the solvent system used.
The adenine salt may be prepared in situ by the addition of an equivalent amount of base, or the adenine salt may conveniently be prepared by dissolving the adenine in an aqueous solution containing an equivalent amount of strong base, evaporating the water, and using the residue containing the adenine salt hydrate in the alkylation.
A preferred way of carrying out tne first step of the present invention Is by alkylation of an alkaline-earth metal salt of adenine with 2chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide, thus producing a mixture of Isomers of (2-chloro-6-fluorobenzyl)adenlne or (2,6-dichlorobenzyl) adenine in which at least 70% by weight is 9-(2-chloro-6-fluorobenzyl)adenine or 9-(2,6-dichlorobenzyl)adenine, in a solid-liquid two-phase system comprising as solid phase an alkaline-earth metal salt of adenine and as liquid phase a solution of 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide and a quaternary ammonium salt phase transfer catalyst having the formula:
© o (R)3NRt - Z where R, and Z® are as defined above, in acetone, acetonitrile or hexamethylphosphoramide containing from 0 to 5 moles of water per mole of adenine salt, or in hexane, benzene, toluene, methylene chloride, chloroform or petroleum ether; or in a liquid-liquid two-phase system in which one liquid phase is an aqueous solution of an alkaline-eartli metal salt of adenine and the second liquid phase is a solution of 2-chloro-6-fluorobenzyl halide or
S 3 9 Θ
2,6-dichIorobenayl halide and c quaternary ammonium salt phase transfer catalyst having the formula:
where R, and Z^-' are as defined above in hexane, benzene, toluene, methylene chloride, chloroform or petroleum ether.
Another preferred method of carrying out the first step of the present invention is the alkyaltion of sodium adeninate with 2-chloro-6fluorobenzyl chloride to produce a mixture of Isomers of(2-chloro-6fluorobenaylladenine in which nt least 70% by weight is 9-(2-chloro-6fluorobenzyDadenine, tha alkylation being effected in a solid-liquid two-phase reaction system in which the aolid phase comprises sodium adeninate and the liquid phase comprises en acetone solution of 2-cliloro-6 fluorobenzyl chloride and a quaternary-ammonium-selt phaae-transfer cataljj having the formula:
(n-Rft)3HCH3 Cl where R* is a mixture of normal alkanes containing 8 to 12 carbon atoms, together with from 0 to 5 moles of water per mole of sodium adeninate; or in a liquid-liquid two-pho3e reaction system in which one liquid phase comprises an aqueous solution of sodium adeninate and the liquid phase comprises a hexane solution of 2-chloro-6-fluorobenzyl chloride and a quaternary ammonium salt phase transfer catalyst having the structure;
(R*)3NCH3 z ©
where R* is as defined above'and Z is a chloride, bromide or iodide anion, me mixture of tetraalkylammonium chlorides in which R* is primarily caprylyl (Cg) is known as Aliquat 336 and is manufactured by General Mills, Inc., Chemical Division, 4620 West 77th Street, Minneapolis,
Minnesota.
The relative proportions of the adenine and alkylating agent may 5 vary over a relatively wide range. The reactants may be used in stoichlometri
i.e. equimolar amounts or an excess e.g. a 2 to 107. or even greater molar excess of the alkylating agent may be used. A preferred excess is about 2 mole 7.. It is preferred that the phase transfer catalyst be used in an amount from 1 mole ’/. to 10 mole 7. relative to adenine. The amount of the solvent used may also vary over a wide range. The solvent is used in a quantity sufficient to permit of stirring the heterogeneous reaction mixture to allow the reaction to proceed at a reasonable rate and facilitate isolation of the reaction product. In most cases a 5 to 15 weight % solution of adenine salt in solvent is suitable for carrying out the reaction.
The components of the reaction mixture are combined in the reaction medium in any convenient manner and in any order. As illustrative of a suitable manner of combining the components of the reaction mixture, the adenine is added to a solution of the base in the reaction medium, after which the 2,6-dihalobenzyl compound is added, either neat or in a suitable solvent, and finally the phase transfer catalyst is added.
Other methods of combining the reactants and catalyst will be obvious but iL is preferred that they be combined so that the anion of the adenine forms no later than the time when the 2,6-dihalobenzyl compound fa added, a:d particularly prior to that time. The phase-transfer catalyst is preferably aided last.
The reaction time and temperature conditions are not unduly criticalThe time of the reaction will, however, decrease as the reaction temperature increases. The reaction will most conveniently be conducted between a temperature in the range of from room temperature to 150°C, However, it is preferred to carry out the reaction at the reflux temperature of the selected solvent. In the case of the solvent hexamethylphosphoramide, temperatures in excess of 155°C are to be avoided as the selectivity of the alkylation decreases with excessively high temperatures. The reaction may be carried out for from one hour to 24 hours but in most eases alkylation is complete after 4 to 6 hours.
Upon completion of the reaction, the reaction mixture ia cooled to about room temperature to precipitate a solid product.
The product is then collected in the usual manner, such as by filtration and the second stage of the method is carried out as set forth below.
It should be noted that the teachings set forth with respect to the purification of 9-(2-chloro-6-fluorobenzyl)adenine are equally applicable to other 9-(2,6-dihalobenzyl)adenines.
There are two chemical differences between the 9-isomer and the 3-isomer which form the basis for the purification of the present invention. First, the 3-isoraer (pKa 5.6) is 40 times more basic than 9-(2-chloro-6-fluorobenzyl)adenlne (pKQ 4.0) and secondly the 3-isomer is chemically less stable than 9-(2-chloro-6-fluorobenzyl)adenine in strong acid solutions.
Advantage is taken of the pK difference to effect a partial reduction of the amount of 3-isomer in the crude reaction mixture by simply extracting the solid crude with dilute mineral acid solution. Thus extraction of crude 9-(2-chlora-6-fluorobenzyl)adenine containing 20% of the 3-isomer with a dilute aqueous solution of nitric acid produces 9-(2-chloro-6-fluorobenzyl)adenine containing 3-4% of the 3-isomer with a 96-97% recovery of 9-(2-chloro-6-fluorobenzyl)adenine.
Virtually complete removal of the 3-isomer ( 100 ppm , and substantially pare” herein is defined accordingly), has been achieved by selective chemical transformation of the 3-isaner, taking advantage of its inherent lower thermodynamic stability. The 3-isomsr can be totally and selectively transformed to adenine and a benzyl polymer by treatment with 967. sulfuric acid without affecting the 9-isomer according to the following equation:
3-isomer
(hso4 carbeniuni ion sl· polymer
Under the same conditions 9-(2-chloro-6-f luorobenzyDadenine ia unreactive.
Thus, treatment of 9-(?-chloro-6-fluorobenzyl)adenine containing 3-4Ϊ of 3-isomer with 967. sulfuric acid results in a 967. recovery of
9-(2-chloro-6-£luorobenzyl)adenine containing 100 ppm of the 3- isomer. It has proved very difficult to completely separate the polymer from the 9-(2-chloro-6-£luorobenzyl)adenine. This problem ia overcome in the present invention, by carrying out the sulfuric acid treatment in the presence of a suitable carbenium ion trap which reacts with the carbenium ion and prevents formation of the polymer.
Suitable carbenium ion traps include dl(C^ $ alkyl)sulfidesj
benzene, toluene, xylene, mixed xylenes, mesitylene, (C^ j alkoxy)benzenes such as anisole? thiophene, iodobenzene, naphthalene or triphenylphosphine. Out of several substances examined, toluene and mixed xylenes were found to be the most suitable for this purpose. Toluene reacts rapidly with the intermediate carbenium ion to form the transalkylation product, according to the following equation:
ο-, m- and £transalkylation product thus preventing the polymerization. Utilizing the method of sulfuric acid transalkylation in the presence of toluene, 9(2-chloro-6-£luorubenzyl)adenine containing 3-4% of 3-isomer provides high purity 9-(2-chloro-6-fluorobenzyl)adenine containing no polymer and < 100 ppm of the 3-isomer in 9715 98% yield.
Crude 9-(2-chloro-6-fluorobenzyl)adenine contain4ng about 20% of 3-isomer may be extracted with a solution of dilute mineral acid to achieve a partial removal of tha vndesired 3-isomer and particularly to remove trace:
0: the 7-isomer, if desired, prior to treatment with sulfuric a id.
The mineral acid used is not Critical provided it react with the 9-isomer. Suitable mineral acids —15 —
463 are hydrochloric, phosphoric and nitric acids. Nitric acid is preferred. To avoid excessive loss of the 9-isomer during the extraction, best results are obtained if the quantity of the 3-isomer is determined by liquid chromatography assay (L.C. assay) as described below under the heading Assay and an equimolar (or a slight excess) of acid with respect to 3isomer is added, The extraction may be carried out between room temperature and about 100°c. The preferred conditions are reflux temperature with vigorous stirring. Extraction with vigorous stirring for about 1 hour to about 5 hours is sufficient. An optimal time is about 2 hours. The hot mixture is collected by filtration and washed with hot water, with base to remove excess acid and finally with hot water again. The resulting partially purified material enriched in the 9-isomer is subjected to treatment with sulfuric acid in the presence of a carbenium trap to obtain pure 9-(2-chloro-6-fluorobenzyl)adenine.
In. treating the crude 9»(2-chloro-6-fluorobenzyl) adenine with concentrated sulfuric acid (96% assay) to selectively dealkylate the 3-isomer and regenerate adenine, at least a twice molar excess of sulfuric acid with respect to the 3-isomer is required. The concentration of the 3-isomer is determined by liquid chromatography assay (L.C. assay) as described below under the heading Assay.
The excess of sulfuric acid used is not critical. For ' . example, an equal weight of crude 3-(2-chloro-6-fluorobenzyl) adenine to volume of sulfuric acid or up to 10 x volume sulfuric acid with respect to weight of crude 9-(2-chloro6-fluorobenzyl)adenine may be used. A preferred ratio is 1 g. of crude 9-(2-chloro-6-fluorobenzyl)-1646399 adenine for each 2 ml. of sulfuric acid.
The quantity of carbenium ion trap used is not critical, provided there is at least an equimolar amount with respect to the 3-i3omer. However, a large excess is preferred because it acts as both a reagent and a solvent.
The crude 9-(2-chloro-6-fluorobenzyl)adenine is treated with concentrated sulfuric acid at a temperature in the range of frcm rocpi temperature to 90°C. A preferred temperature is room temperature with an approximately 1010 minute final heating period at about 80°C. to ensure complete reaction. The reaction time is not critical provided that a minimum of 2 hours has elapsed. After the initial 2 hours, the reaction is essentially complete and may be terminated when convenient. No deleterious effects are observed even if the reaction is allowed to proceed for 36 hours. A convenient optimal time is about 5 hours for laboratory-scale reactions and about 24 hours for productionscale reactions.
The aqueous layer is separated . Warming may be necessary up to a temperature of 50°C. to
100’C. depending on the amount of solvent and acid present to facilitate the separation of the aqueous phase. The aqueous phase is made basic by the addition of base. Any base is suitable provided only that it forms a water-soluble sulfate. Suitable bases are sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, and potassium carbonate. The preferred base is sodium hydroxide. After the aqueous phase is made strongly basic the pure product precipitates and is collected by filtration and
3U cashed with water or an aqueous alcoholic solution and dried in vacuo.
-17An added advantage of this process is that the costly adenine can be recovered from the alkaline filtrate by neutralizing the filtrate and collecting the precipitated adenine by filtration.
ASSAY
X. Assay for weight % of 9-isomer, 3-isomer and 7-isomer when 3-isomer is present in excess of 1¾
The weight % of 9-isomer, 3-isomer and 7-isomer in the product is determined by high-pressure liquid chromatography (L.C.) and U.V. The weight % of 9-isomer and 7-isomer is determined by a high-pressure liquid chromatography assay (L.C.) using a 15 cm., 5 micron totally porous silica column (DuPont, Zorbax-SIL) eluted with
CHCl-jjMeOH (95:5) and measuring the absorbance of each component at 254 nm, 9-benzyladenine was used as an internal standard (accurate to +0.3%). The weight % of the 3-isomer is determined by U.V. assay. The sample is assayed in O.lN methanolic base at 310 nm, the.3-isomer has an € of 2300 at this wave-length and the 9-isomer does not absorb (accurate to +0.1%).
II. Assay for weight % of trace amounts of 3-isomer after sulfuric acid treatment
The weight % of 3-isomer in the product is determined by high-pressure liquid chromatography (L.C.) using a 10 micron, 30 cm., microporous, octadecylsilane bonded phase column (Waters' Associates Micro Bondapak C-18 No. 27324) with a methanol aqueous phosphate mobile phase at 35°C. The mobile phase is prepared from 30 parts methanol plus 70 parts 0.01M adjusted to pH 7 with
HgPO^. Detection is by U.V. at 280 nm. The limit of detection is 100 ppm.
-1846399
C. zUtemative Process for Preparing 9- (2,6-Dihalobenzyl)adenines
According to an alternative preparation of the present invention 9-(2,6-dihalobenzyl)adenines, unsub5 stituted at the 2-position, are prepared by treating 7-(Nformyl-N-2,6-dihalobenzylamino)[1,2,5]thiadiazolo[3,4d]pyrimidines, i.e., compounds having the structure (7_) in Table I, with Raney nickel.
-19TABLE I
where X^ and X2 are independently halogen.
-2046399
According to Table I, 4,5,6-triaminopyrimidine (3), obtained by the process set forth in A. fihrage et al., J. Org. Chem., 16, 207 (1951), with thionyl chloride affords 7-amino/l,2,57thiadiazolo/3,4-d7pyrimldlne (4). Nucleophilic displacement of the 7-amino group of (4) by the process of Y.F. Shealy et al., J. Org. Chem., 27, 2135 (1964), at
100°C with 2,6-dihalobenzylamine (5) provides the compounds (6) Alternatively, (6) can be prepared from (4) by treatment of (4) with ammonia and 2,6-dihalobenzyl chloride in a sealed vessel at 100°C. Formylation of (6) at room temperature with formic acetic anhydride yields tne compounds (7) as stable solids. Treatment of a solution of (7) with Raney nickel results in smooth desulfurization and formation of (9). The desulfurization may be carried out in an aqueous alcohol solvent wherein the alcohol preferably contains 1 to 6 carbon atoms. The reaction may be conducted at a temperature range of about room temperature to about 125°C for a period of about 1 hour to hours. Preferred conditions are ethanol-water at about room
40S98
The following non-limiting Exanples will serve to further illustrate the invention. Proportions of liquid mixtures are given on a volume basis. EXAMPLE 1
Process for Alkylating Adenine with a,2-Dichloro-65 fluorotoluene in the Presence of Aliquat 336 in HexaneWater (Liquid-liquid Heterogeneous Reaction Mixture)
A one-liter three-necked round bottom flask equipped with a thermometer, condenser, nitrogen inlet and an overhead mechanical stirrer was charged sequentially with 40 ml, of water, 8.0 g. of sodium hydroxide (0.20 mole) and, after the sodium hydroxide had dissolved, 27.60 g of adenine (98% pure, 0.20 mole). After the adenine had dissolved, a solution of 39.95 g. of a,2-dichloro-6-fluorotoluene (91.5% pure by G.C. assay, 0.20 mole plus 2%) and
IS 5.04 g. of Aliquat 336 (0,01 mole, 5 mole %) in 300 ml. of hexane was added as phase-transfer catalyst, (No reaction takes place if the phase-transfer catalyst is emitted.) The mixture was stirred at reflux for six hours and cooled to roan temperature by and the solids were collected/filtration. The solids xiere xiashed twice with 100 ml. of water and dried in vacuo (100°C.
overnight) to give 52.32 g. of 2-chloro-6-fluorobenzylated adenines (94%). U.V, (ti/10 HCl) U^max = 264, E% = 535;
L.C. wt. % 9-isomer = 69.9; U.V, wt, % 3-isomer = 25.0, Purification of Crude 2-Chloro-6-fluorobenzylated Adenines
g. of the above crude material was added to
6Q ml. of hot acetic acid (65°C.). The temperature was raised to 100°C. at which point all the material had dissolved. The hot acetic acid solution was filtered through a preheated glass fritted funnel and the filtrate was added dropwise over a tan minute period to 240 ml. of well-stirred water at 95°C. (addition of water to the acetic acid solution gives the acetate salt of the product which is a cotton-like material). When the solution had cooled to 37°C
-2246399 the bulk of the product precipitated. The product was collected by filtration, washed once with 25 ml. of acetic acid-water (1:4), twice with 25 ml. of water and dried in vacuo (95eC. for 6 hours) to give 20.83 g. of 9-(2-chloro-6fluorobenayl)adenine (69.5%). U.V. wt. % 3-isomer = 3.0;
L.C. wt. % 9-isomer 89.
EXAMPLE 2
Process for Alkylating Adenine with a,2-Dichloro-6fluorotoluene in the Presence of Aliquat 336 in Acetone (Solid-liquid Reaction Mixture)
A 250 ml. round bottom flask was sequentially charged with 100 ml. of acetone, 6.95 g. of adenine 97% pure, 50 mmole) and 4.0 g. of sodium hydroxide solution {assay 50%, SO mmole) and the suspension refluxed for l·1; hours. The suspension was charged with a solution of 9.8 g. of a,2-dichloro-6-fluorotoluene (91.4% pure, 50 mmole) and 1.25 g. of Aliquat 336 (2.5 mmole, 5 mole %) in 10 ml. of acetone and refluxed, with rapid stirring, for six hours. (Xn the absence of the phase transfer catalyst the reaction takes about five tines as long).
The reaction mixture was cooled to room temperature and the solids collected by filtration. The solids were washed twice with 15 ml. of acetone and then swished with 50 ml. of 0.1N sodium hydroxide solution for 15 minutes (this removes any unreacted adenine and the NaCl formed during the alkylation) . The solids were collected by filtration,-washed twice with 20 ml. of water and dried in vacuo (100°C. fcr 4.5 hours) to give 13.12 g. of 2-chloro-6-fluorobenzylated adenines (94.4%). U.V. (N/10 HCUT'-max « 262, E% « 534; L.C. wt. % 9-isomer = 77.4; U.V. wt. % 3-isomer = 20.4.
-23Purification
g. of the above material was added to 18 ml. of hot glacial acetic acid (zj-60°C.). The mixture was heated to 110°C. (solution occurred between 60 and 90°C.),and filtered 5 and the filtrate was added to 80 ml. of hot water (95°C.) over a five minute period with rapid stirring (2 more ml. of acetic acid was used for rinses). When the temperature had dropped to 37°c. the suspended solids were collected by filtration end washed once with 10 ml. of 4:1 H20:H0Ac and
Ιθ twice with 15 ml. of water. Vacuum oven drying (100°C. for 6 hours) gave 7.64 g. of 9-(2-ehloro-6-fluorobenzvl)adenine, 76.4%. U.V. (N/10 HCl) T^max = 260, E% 570; DSC = 0.5 mole % impurity (5000 ppm), m.p, (uncor) = 244.5-246°C.; tic on silica gel in CHCI,: MeOH (10:1) showed one minor impurity at Rf - 0.57 and a main spot at Rf = 0.86.
EXAMPLE 3
Process for Alkylating Sodium Adeninate Hydrate with a,2-Dichloro-6-fluorotoluene in the Presence of Aliquat 336 in Hexamethylphosphoramide (Solid-liquid Reaction Mixture)
Step 1: Sodium adeninate hydrate was conveniently prepared by dissolving one mole of adenine in 400 ml. of
2.5m sodium hydroxide (1.0 mole). The solution was concentrated on a rotary evaporator in vacuo at steam bath temperature until it became supersaturated. The solution was poured into a glass pan and after the sodium adeninate had crystallized, the material was dried in vacuo overnight at 75“C. The dried material was ground into a free flowing powder; KP = 8.3%; Eq. Wt. (HC104) = 85.4 (MW = 170.8) (eq. Wt. titrations with HCl gave values of 172-173).
24A6399
Step 2; Alkylation
A 103 ml. flask was charged with 50 ml. of hexamethylphosphoramide (HMPA) (no special drying was done) and 8.55 g. (50 mmole) of sodium adeninate hydrate (prepared by the process set forth in Example 3, Step 1). After all the sodium adeninate had teen uniformly suspended, 9.9 g. of o,2dichloro-6-fluorotoluene (92.3% pure, 50 raiaole plus 2%) was added over a 10-15 minute period. The reaction snixture was stirred ove.’-nicht (four hours was adequate for complete conversion) and then slowly poured (3 minutes) into 100 ml. of water with rapid stirring (pH * 7.9 after about 5 minutes).
Sodium hydroxide solution, 0.6 g. (assay 50%, 7.5 mole), was added to the suspension to ensure removal of unreacted adenine. After stirring for 15 minutes, the suspended solids were collected by filtration, washed twice with 25 ml. of water and dried xn vacuo (4 hours, 75*C.) to give 13.29 g. of 2-chloro-6-fluorobenzylated adenines (95.8%). U.V. wt. % 3-isomer 11.7; L.C. wt. % 9-isomer * 84.8.
Step 3; Purification
g. of the above material was dissolved in 14 ml. of acetic acid at 95°C. The solution was filtered hot and the filtrate added dropwise within a few minutes to 80 ml. of water at 95°C with rapid stirring (2 additional ml. of hot acetic acid was used to rinse all remaining material into the hot water). After cooling to 37eC., the suspended solids were collected by filtration, washed once with 10 ml. of acetic acid-water (1-.5), twice with 10 ml. of water and dried in vacuo (overnight, 75’C.) to give 8.45 g, of f-(2-chloro-6~fluorobenzyl)adenine (84.5%). Tic on silica30 gel in CHCl3:MeOH (10;l) indicated a single spot; m.p. 243-254 6 399
245°C.; DSC => 0.8 mole % impurity; U.V. (N/10 HCl)“X.max 259, E% = 562; U.V. wt. % 3-i5O;uer · 4. 2.
EXAMPLE 4
Process for Alkylating Sodium Adeninate Hydrate with a, 25 Dichloro-6-fluorotoluene in the Presence of Aliquat 336 in Acetone (Solid-liquid Reaction Mixture)
A 250 ml. round bottom flask was sequentially charged with 100 ml. of acetone, and'8.54 g. of sodium adeninate hydrate (50 mmole, prepared by the process set forth in Example 3, Step 1). The suspension was charged uith a solution of 9.8 g. of a,2-dichloro-6-fluorotoluene (91.4% pure, 50 mmole) and 1.25 g. of Aliquat 336 (2.5 mmole, 5 mole %) in 10 ml. of acetone and refluxed with rapid stirring for six hours. The reaction mixture was cooled to room temperature and the solids collected by filtration, washed twice with 15 ml. of acetone and then swished with 50 ml. of O.lN sodium hydroxide solution for 15 minutes (this removes any unreacted adenine and the NaCl formed during the alkylation). The solids were collected 20 by filtration, washed twice with 20 ml. of water and dried in vacuo (100°C., 4.5 hours) to give 13.2 g. of 2chloro-6-fluorobeazylated adenines (95%). U.V. (N/10 HClfX max = 262, E% “ 534; L.C. wt. % 9-isomer = 83; U.V. wt. % 3isomer ® 16.
EXAMPLE 5
Process for Alkylating Potassium Adeninate Hydrate with a,2Dichloro-6-fluorotoluene in the Presence of Aliquat 336 in Acetone (Solid-liquid Reaction Mixture)
The process was carried out as set forth in
Example 4, with the exception that the sodium adeninate was replaced by an equivalent amount of potassium adeninate. The
-2 646398 potassium adeninate was prepared by the process set forth in Example 3, Step 1 with the exception that an equivalent amount of potassium hydroxide was substituted for the sodium hydroxide.
The yield of 2-chloro-6-fluorobenzylated adenines was 94%. L.C. wt. % 9-isomer » 82; U.V. wt. % 3-isomer »
18.
EXAMPLE 6
Process for Alkylating Sodium Adeninate Hydrate with 10 α-(Y)-2-chloro-6-fluorotoluene in the Presence of Aliquat
336 in Acetone (Solid-liquid Reaction Mixture)
Th= process was carried out as set forth in Example 4, with the exception that the a,2-dichloro-6fluorotuluene tas replaced by an equivalent amount of an
TABLE I
Y a I 85% 7:3
Y ” i“(CH3)2 Cl® 31% 3:1
Y = Br 85% 4:1
Sr
In some cases small amounts of up to 10% of other products, presumably other isomers were obtained (l-isomer and 7-isomer).
-27EXAMPLE 7
Process for Alkylating Sodium Adeninate Hydrate with a,2,6-Trichlorotoluene in the Presence of Aliquat 336 in Acetone (Solid-liquid Reaction Mixture)
A 250 ml. round bottom flask was sequentially charged with 100 ml. of acetone and 8.54 g. of sodium adeninate hydrate (50 mmole, prepared by the process set forth in Example 3, Step 1). The suspension was charged with a solution of 10 g. of a,2,6-trichlorotoluene (98% pure, 50 mmole) and 1.25 g. of Aliquat 336 (2.5 mmole, 5 mole %) in 10 ml. of acetone and refluxed, with rapid stirring, for six hours. The reaction mixture was cooled to room temperature and the solids collected by filtration, washed twice with 15 ml. of acetone and then swished with 50 ml. of 0.1N sodium hydroxide solution for 15 minutes (this removes any unreacted adenine and the NaCl formed during the alkylation). The solids were collected by filtration, washed twice with 20 ml. of water and dried in vacuo (100°c.,
4.5 hours) to give 13.8 g. of 2,6-dichlorobenzylatad adenines (94%). U.V. (N/10 HCl) 'T*· max = 262, E% » 434;
L.C. wt. % 9-isomer = 81; U.V. wt. % 3-isomer - 17.
EXAMPLE 8
Process for Alkylating Sodium Adeninate Hydrate with a,2,6-Trichlorotoluene in the Presence of Aliquat 336 in Toluene (Solid-liquid Reaction Mixture)
A 250 ml. round bottom flask was sequentially charged with 100 ml. of toluene and 8.54 g. of sodium adeninate hydrate (50 mmole, prepared by the process set forth in Example 3, Step 1). The suspension was charged with a solution of 10 g. of a,2,6-trichlorotoluene (98% pure, 50 mmole) and 1.25 g. of Aliquat 336 (2.5 mmole,
-2846399 mole %) in 10 ml. of toluene and refluxed with rapid stirring for six hours. The reaction mixture was cooled to room temperature and the solids collected by filtration, washed twice with 15 ml. of toluene and then swished with 50 ml. of 0.IN sodium hydroxide solution for 15 minutes (this removes any unreacted adenine and the NaCl formed during the alkylation). The solids were collected by filtration, washed twice with 20 ml. of water and dried in vacuo (100°C.,
4.5 hours) to give 10.2 g. of 2,6-dichlorobenzylated adenines (76%). U.V. (N/10 HCl) Τ'-max = 262, E% = 498; L.C. wt. % 9-isomer = 80; U.V. wt. % 3-isomer = 20.
EXAMPLE 9
One Stap p’-rification of Crude 9-(2-Ch)oro-6-fluorobenzyl)adenine by Treatment with Sulfuric Acid
To a stirred suspension of crude 2-chloro-6fluorobenzylated adenines (2.0 g., L.C. assay wt. % of
9-/3-/7-isomer = 79.7/17.8/1.2) in xylene (4 ml.) was added dropwise concentrated sulfuric acid (96%, 4 ml.) at room temperature. The mixture was stirred for 12 hours at room temperature and then for an additional 10 minutes at 80°C. After the reaction mixture had cooled to room temperature, the mixture was poured into ice water (25 ml., containing xylene (10 ml.). The resulting mixture was transferred to a steam-jacketed separatory funnel and heated to 85OC. in order to redissolve the precipitate. The aqueous layer was separated and made basic by addition of concentrated ammonium hydroxide. The precipitated solids were filtered and washed with hot water (2 x 10 ml.). Yield, 1.53 g.
(95.6% based on available 9-isomer). L.C. assay 9-isomer 30 100.07%; 3-isomer, none detectable (<100 ppm,; 7-isomer /v 0,8%.
-29EXAMPLE 10
Two Step Purification of Crude 9-(2-Chloro-6-fluorobenzyl)adenine by Extraction with Dilute Nitric Acid and Treatment with Sulfuric Acid
Step A. - Extraction with Dilute Nitric Acid
A suspension of 40.0 g. (0.144 mole) crude
2-chloro-6-fluorobenzylated adenines (wt. % of 9-/3-isomers =
79.1/19.3 determined by L.C. assay) representing 31.64 g, of
9-isomer and 7.72 g. of 3-isomer in 440 ml. water containing
19.0 ml. (0.0285 mole) of 1.5N nitric acid was heated under reflux for 2 hours with vigorous stirring. The mixture was filtered while hot onto a pre-heated funnel, washed with hot water (3 x 50 ml. slurries), cono. HH^OH (2 x 25 ml.) and hot water (3 x 50 ml.). The product was sucked damp-dry and finally dried in vacuo at 65-70°C. overnight to yield 31.67
g. (97.1% yield) of 9-isomer enriched 2-chloro-6-fluorobenzylated adenines. This yield is based on available 9isomer and is corrected for purity. L.C. assay 9-isomer
97.2% and 3-isomer 3.0%.
Step B. - Dealkylation of 3-(2-Chloro-6-fluorobenzyl)adenine with Sulfuric Acid
To a vigorously stirred suspension of 50.0 g.
(0.18 mole) of 9-isomer enriched 2-chloro-6-fluorobenzylated adenines (wt. % of 9-/3-isomers = 96.8/3.2 by L.C. assay) representing 48.4 g. of 9-isomer and 1.6 g. of 3-isomer in
100 ml. of toluene (reagent grade) was added dropwise 100 ml. of concentrated sulfuric acid (assay = 96.02%) with ice/water cooling as required to maintain a temperature of
50-60°C. The mixture was heated with stirring at 50-60’C.
for 18 hours (all the solid dissolved in the acid to give a two-phase system). The batch was cooled to room temperature and poured into ice/water (300 ml.) whereupon the product
-3046398 precipitated as the suliate salt. The mixture was transferred to a steam-jacketed separatory funnel using hot water rinses and heated to 80-85°C in order to redissolve the precipitate and effect separation of the aqueous layer from the toluene layer. The aqueous layer (650 ml) was separated and washed with 50 ol of hot toluene using the same apparatus. The aqueous layer (while still warm) was made basic (pH
) by the cautious addition of concentrated ammonium hydroxide solution. The precipitated white solid was aged with stirring for 1 hour and collected while the batch was still warm. The product was washed with hot water (3 x 100 ml) and 50% aqueous methanol (2 x 100 ml). Tha batch was sucked damp-dry and finally dried lu vacuo at 7O°C. overnight co give pure 9-(2-chloro-6-fluorobenzyl)adenine. The yield was 47.8 g (98.8% based on available 9-isomer), m.p. 247-248°C; tic on silica gel in CHCljiMeoll (9:1) showed essentially a single spot,
Rj “ 0.48. Ho polymer or other impurity was detected. L.C. assay «flowed 9-isomer 100.68%; 3-isamer, none detected. Overall yield
- 95.9%.
Preparation of 2-Clloro-6-fluorobenzylamine starting material
An autoclave was charged with 89,0 g (0.5 mole) of 2-chloro-6fluorober.zyl chloride, 170.0 g (10 mole) ammonia and 50 ml benzene.
The reaction vessel was sealed and the contents heated at 100°C for 15 hours. The excess of ammonia was carefully evaporated off from the cooled contents of the autoclave with a stream of nitrogen. The residue was washed with water and the organic phase, after drying with anhydrous MgSO^, fractionated to afford 72.4 g (90%) of product as a clear liquid; b.p. 99-100°C/20 mm; NMR (CDClj)
Claims (14)
1 A process for alkylating an alkali raetal or alkaline-earth metal salt of adenine with a 2,5-dihalobenzyl compound of general formula: where X^ and ora, independently, halogens and Y is a halogen, 5 dimethylsulfonium halide or tosyl leaving group, to produce a mixture of isomers of (2,6-dihalobenayl)adenine in which at least 707. by weight is 9-(2,6-dihalobenzyl)adenine, in which the alkylation is carried out in (a) a solid-liquid two-phase system made up of a solid phase comprising the alkali metal or alkaline-earth metal salt of adenine and 10 a liquid phase comprising a solution of the 2,6-dihalobenzyl compound and an onium salt phase-transfer catalyst having the formula: © O (RJjNRj 2 or © 0 (R^PR Z Θ where R is C^-18 °lkyl, Rj i3 θ alkyl and Z is a chloride, bromide 15 or iodide anion, in an aprotic water-miscible or water-immiscible organic solvent in which the wateremiscible solvent contains from 0 to 5 moles of water per mole of adenine salt, or (b) in a liquid-liquid two-phnse system made up of one liquid phase comprising an aqueous solution of the alkali metal or alkaline-earth 20 metal salt of adenine and a second liquid phase comprising a solution of the 2,6-dihalobenzyl compound and an onium salt phase transfer catalyst having the formula stated above, in an aprotic water-immiscible organic solvent; and in which the alkylation is followed by selectively transalkylating the 3-isomer by-product with sulfuric acid in the presence of a carbenium ion trap, to produce a substantially pure (as hereinbefore defined) 9-(2,6dihalobenzyl)-adenine.
2. A process as claimed in claim 1 ln which Che 2,6-dihalobenzyI compound is a 2-chloro~6-fluorobenzyl halide or a 2,6-dichlorobenzyl $ halide, the onium salt is a quaternary ammonium salt of formula (R),NR.Z β J 1 , „ . , „ are as defined in claim 1, the aprotic waterwhere R, R^ and Z r miscible solvent (if used) is acetone, acetonitrile or hexamethylphosphnramide, the water-immiscible solvent (IE used) is hexane, Benzene, toluene, methylene chloride, chloroform or petroleum ether, end the final product is substantially pure (as hereinbefore defined) 9-(2-chloro-b-fluorobenzyl)adenine or 9-(2,6-dichlorooenzyl)adenine.
3. A process as claimed ln claim 2 in which the salt of adenine is sodium adeninate, the 2,6-dihalobcnzyl compound is 2-chloro-6fluorobenzyl chloride, the alkylation is carried out in the solidliquid two-phase system and the quaternary ammonium salt phase transfer catalyst has the structure; & © (n-R) 3 NCH 3 Cl where R is ti-alkyl containing 8 to 12 carbon atoms, the solvent being acetone containing from 0 to 5 moles of water per mole of sodium adeninate,
4. A process as claimed in claim 2 in which the salt of adenine is sodium adeninate, the 2,6-dihalobcnzyl compound is 2-chloro-6fluorobenzyl chloride, the alkylation is carried out in the liquid-liquid a o a » » two-phnse system, tho quaternary ammonium salt has the formula I (r) 3 NCU 3 Z& where Jl is alkyl having 8 to 12 carbon atoms and Z ®is a chloride, bromide or iodide anion, and the solvent ie hexane.
5. « A process according to any one of claims 1 to 4 in which the carbenium ion trap is a dilc^ alkyl)sulfide, a di(C^g aryl)aulfide, benzene, toluene, xylene, mixed xylenes, mesitylene, a (c^ alkoxy)benzene, thiophene, iodobenzene, naphthalene or triphenylphosphine.
6. O A process as claimed in claim 3 or 4 in which the transalkylation is carried out using an excess of concentrated sulfuric acid in the presence of an excess of toluene or mixed xylenes.
7. · A process as claimed in claim 6 in which the transalkylation io carried out at between room temperature and 90 e C for from 2 to 36 hours.
8. A proceso as claimed in any one of claims 1 to 7 in which the oelectivo transalkylation is preceded by partial extraction of 3-(2,6dihnlobenzyl)adenines by use of a dilute mineral acid.
9. A process as claimed in claim 8 in which the dilute mineral acid is dilute nitric, hydrochloric or phosphoric acid.
10. A process as claimed in claim 3 or 4 or any claim dependent on claim 3 or b in which the partial extraction of 3-(2-chloro-6-fluorobenzyl)adenine is carried out with dilute nitric acid solution containing an approximately equimolar amount of acid with respect to the 3-isomer at a temperature between room temperature und reflux temperature with rapid stirring. A compound having Lhe formula :
11. where each of and X., is fluorine, chlorine, bromine or iodine, substantially free (as hereinbefore defined) of the 3-isomer,
12. Λ compound having the formula: substantially free (aa hereinbefore defined) of the 3-isomer.
13. A process for producing a compound as claimed in claim 11 carried out by a procedure substantially as hereinbefore described in any one of Examples 1 to 8 followed by a procedure substantially as 5 hereinbefore described in Example 9 or 10.
14. A compound aa claimed in claim 13. when prepared by a process as claimed in any one of claims 1 to 10 and 13.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/766,326 US4100159A (en) | 1977-02-07 | 1977-02-07 | Process for preparation of 9-(2,6-dihalobenzyl)adenines |
| US05/768,235 US4098787A (en) | 1977-02-14 | 1977-02-14 | Process for preparation of 9-(dihalobenzyl) adenines |
| US84391977A | 1977-10-20 | 1977-10-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE780253L IE780253L (en) | 1978-08-07 |
| IE46399B1 true IE46399B1 (en) | 1983-06-01 |
Family
ID=27419624
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE253/78A IE46399B1 (en) | 1977-02-07 | 1978-02-06 | 9-(2,6-dihalobenzyl)-adenines and their production |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS53124294A (en) |
| AR (1) | AR225000A1 (en) |
| AT (1) | AT361008B (en) |
| CH (1) | CH636614A5 (en) |
| DD (1) | DD136744A5 (en) |
| DE (1) | DE2804723A1 (en) |
| DK (1) | DK36078A (en) |
| EG (1) | EG13333A (en) |
| ES (1) | ES466647A1 (en) |
| FI (1) | FI64596C (en) |
| FR (1) | FR2379536A1 (en) |
| GB (1) | GB1586537A (en) |
| GR (1) | GR64457B (en) |
| IE (1) | IE46399B1 (en) |
| IL (1) | IL53922A (en) |
| IT (1) | IT1105174B (en) |
| NL (1) | NL7800896A (en) |
| NO (1) | NO148374C (en) |
| NZ (1) | NZ186357A (en) |
| PL (1) | PL118655B1 (en) |
| PT (1) | PT67606B (en) |
| SE (1) | SE440355B (en) |
| YU (1) | YU27778A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4900826A (en) * | 1981-09-24 | 1990-02-13 | Kohjin Co., Ltd. | Process for preparing N6,9-disubstituted adenine |
| EP0411467A3 (en) * | 1989-08-01 | 1992-03-04 | Lonza Ag | Process for the preparation of pure adenin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3846426A (en) * | 1971-03-03 | 1974-11-05 | Int Minerals & Chem Corp | 6-amino-9-(substituted benzyl) purines and their n{11 oxides |
-
1978
- 1978-01-23 FI FI780200A patent/FI64596C/en not_active IP Right Cessation
- 1978-01-25 NL NL7800896A patent/NL7800896A/en not_active Application Discontinuation
- 1978-01-25 DK DK36078A patent/DK36078A/en not_active Application Discontinuation
- 1978-01-26 SE SE7800977A patent/SE440355B/en not_active IP Right Cessation
- 1978-01-26 NO NO780284A patent/NO148374C/en unknown
- 1978-01-30 IL IL53922A patent/IL53922A/en unknown
- 1978-01-31 AR AR270912A patent/AR225000A1/en active
- 1978-01-31 NZ NZ186357A patent/NZ186357A/en unknown
- 1978-02-02 GR GR55327A patent/GR64457B/en unknown
- 1978-02-02 PT PT67606A patent/PT67606B/en unknown
- 1978-02-03 FR FR7803115A patent/FR2379536A1/en active Granted
- 1978-02-03 DD DD78203555A patent/DD136744A5/en unknown
- 1978-02-03 ES ES466647A patent/ES466647A1/en not_active Expired
- 1978-02-03 DE DE19782804723 patent/DE2804723A1/en active Granted
- 1978-02-03 CH CH124478A patent/CH636614A5/en not_active IP Right Cessation
- 1978-02-04 PL PL1978204447A patent/PL118655B1/en unknown
- 1978-02-06 AT AT79778A patent/AT361008B/en not_active IP Right Cessation
- 1978-02-06 GB GB4691/78A patent/GB1586537A/en not_active Expired
- 1978-02-06 YU YU00277/78A patent/YU27778A/en unknown
- 1978-02-06 IT IT47941/78A patent/IT1105174B/en active
- 1978-02-06 IE IE253/78A patent/IE46399B1/en unknown
- 1978-02-06 EG EG76/78A patent/EG13333A/en active
- 1978-02-07 JP JP1290178A patent/JPS53124294A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ATA79778A (en) | 1980-07-15 |
| AT361008B (en) | 1981-02-10 |
| EG13333A (en) | 1981-06-30 |
| FR2379536B1 (en) | 1983-10-07 |
| CH636614A5 (en) | 1983-06-15 |
| AR225000A1 (en) | 1982-02-15 |
| FR2379536A1 (en) | 1978-09-01 |
| PT67606B (en) | 1980-03-03 |
| NO148374B (en) | 1983-06-20 |
| DD136744A5 (en) | 1979-07-25 |
| PL118655B1 (en) | 1981-10-31 |
| YU27778A (en) | 1983-12-31 |
| GR64457B (en) | 1980-03-24 |
| GB1586537A (en) | 1981-03-18 |
| SE7800977L (en) | 1978-08-08 |
| NZ186357A (en) | 1981-03-16 |
| SE440355B (en) | 1985-07-29 |
| DE2804723A1 (en) | 1978-08-10 |
| FI780200A (en) | 1978-08-08 |
| IL53922A0 (en) | 1978-04-30 |
| ES466647A1 (en) | 1980-12-16 |
| PT67606A (en) | 1978-03-01 |
| PL204447A1 (en) | 1979-06-04 |
| JPS53124294A (en) | 1978-10-30 |
| IL53922A (en) | 1981-02-27 |
| IT7847941A0 (en) | 1978-02-06 |
| IT1105174B (en) | 1985-10-28 |
| IE780253L (en) | 1978-08-07 |
| DK36078A (en) | 1978-08-08 |
| NO780284L (en) | 1978-08-08 |
| FI64596C (en) | 1983-12-12 |
| NO148374C (en) | 1983-09-28 |
| DE2804723C2 (en) | 1990-11-29 |
| NL7800896A (en) | 1978-08-09 |
| FI64596B (en) | 1983-08-31 |
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