GB1586537A - 9-(2,6-dihalobenzyl)-adenines and their production - Google Patents
9-(2,6-dihalobenzyl)-adenines and their production Download PDFInfo
- Publication number
- GB1586537A GB1586537A GB4691/78A GB469178A GB1586537A GB 1586537 A GB1586537 A GB 1586537A GB 4691/78 A GB4691/78 A GB 4691/78A GB 469178 A GB469178 A GB 469178A GB 1586537 A GB1586537 A GB 1586537A
- Authority
- GB
- United Kingdom
- Prior art keywords
- isomer
- adenine
- chloro
- dihalobenzyl
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- 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
(54) 9-(2,6-DIHALOBENZYL)-ADENINES AND
THEIR PRODUCTION
(71) We, MERCK & CO. INC., a corporation duly organized and existing
under the laws of the State of New Jersey, United States of America, of Rahway,
New Jersey, United States of America, do hereby declare the invention for which
we pray that a patent may be granted to us and the method by which it is to be
performed to be particularly described in and by the following statement:- This invention relates to the preparation and purification of 9-(2,6
dihalobenzyl)adenines. Included in the present invention are pure 9-(2,6
dihalobenzyl)adenines substantially free of the mutagenic 3-isomer. Said adenines
are described in U.S. Patent No. 3,846,426 as being useful in the treatment and
prevention of coccidiosis.
Coccidiosis is 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.
acervulina, E. necatrix, E. brunetti and E. 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 is
manifested by 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 been reported that 9-(2,6-dihalobenzyl)adenines, which are useful for the
control and treatment of coccidial infections, have been prepared by base
catalysed non-selective alkylations of a salt of adenine in aqueous solvents or
aprotic organic solvents. These reactions are homogenous and rapid but suffer
from the disadvantage that the mixture of 3-isomer and 9isomer obtained contain a
high proportion of the 3-isomer.
Screening in the Ames test revealed that the 3-isomer 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 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 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 (HBF4) also results in some purification.
The conventional purification methods recited above, such as washing or recrystallization of crude 9-(2,6-dihalobenzyl)adenine, result in a product containing up to about 4% of the 3-isomer. Thus, for example, extraction of crude 9-(2-chloro-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 34% of the 3-isomer with a 9697 /^ recovery of 9-(2-chloro-6fluorobenzyl)adenine. Repeating this procedure on the enriched 9-(2-chloro-6fluorobenzyl)adenine sample fails to reduce the 3-isomer level below 0.3-0.5% (30005000 ppm). This is due to the pronounced tendency toward solid solutions involving the 9-isomer and 3-isomer. The same problem is encountered when 3isomer removal is attempted 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 in the 3-isomer.
E. C. Taylor, et al., J. Org. Chem. 36, 3211 (1971) have reported that 9substituted adenines (2) may be prepared by reductive cleavage and subsequent cyclization of 7-amidofurazano[3,4-d]pyrimidines (1).
Although a wide variety of adenine derivatives was prepared, the authors were unable to effect the conversion of 5-unsubstituted 7-amidofurazano[3,4- d]pyrimidines (I, R=H, Y=O) to 2-unsubstituted adenines (2, R=H) due to the hydrolytic instability of the former compounds.
The present invention is based on the discovery that the 9-(2,6dihalobenzyl)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 onium salt phase-transfer 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 invention, 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 X2 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 2,6-dihalobenzyl compound and an onium salt phase-transfer catalyst having the formula o e e (R)3NR1 Z or (R1)3PR Z where R is C4~,8 alkyl, R1 is C18 alkyl and Ze is 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 comprises a solution of the said dihalobenzyl compound and the said onium salt; followed by selectively transalkylating the 3-isomer by-product with sulfuric acid in the presence of a carbenium ion trap. The transalkylation is optionally preceded by acid extraction to remove part of the 3-(2,6-dihalobenzyl)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 a halogen atom.
The alkylation is carried out in the said solid-liquid two-phase system in an aprotic water-miscible or water-immiscible organic solvent in which the -watermiscible solvent contains from 0 to 5 moles or water per mole of adenine salt, (excessive amounts of water tend to result in a higher proportion of 3-isomer) or in the said 'liquid-liquid 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 (2,6dihalobenzyl)adenine in which at least 70% by weight is 9-(2,6dihalobenzyl)adenine.
The compounds prepared are represented by the following structural formula:
where X1 and X2 are independently halogen, i.e. fluorine, chlorine, bromine or iodine. Specific examples of compounds represented by the foregoing structural formula are 9-(2,6-dichlorobenzyl)adenine and 9-(2-chloro-6-fluorobenzyl)adenine.
The 9-(2,6-dihalobenzyl) adenines of the present invention must be substantially free of positional isomers, and by this term is meant less than 100 ppm of positional isomers. Specifically, the present invention provides 9-(2,6-dihalobenzyl)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)adenine containing less than 100 ppm of the 3-isomer.
Suitable solvent systems for the process of the present invention are aprotic solvents that are inert, i.e. non-reactive with the components of the reaction mixture under the reaction conditions that 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:
where MO is an alkali or alkaline-earth metal cation; b and c are integers such that the negative charge of b moles of anion is neutralized by c moles of cation MO. The salt is suspended in an aprotic organic solvent or dissolved in an aqueous solution.
To this is added 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 is stirred rapidly until completion of the reaction.
According to one method of carrying out 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 10.5 so that the adenine is substantially completely converted to its anion. Examples of suitable bases include carbonates, e.g. alkali metal carbonates such as sodium carbonate and potassium carbonate, hydroxides, 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 alkali-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 the first step of the present invention is by alkylation of an alkaline-earth metal salt of adenine with 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide, thus producing a mixture of isomers of (2chloro-6-fluorobenzyl)adenine or (2,6-dichlorobenzyl)adenine in which at least 70% by weight is 9-(2-chloro-6-fluorobenzyl)adenine or 9-(2,6dichlorobenzyl)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 2chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide and a quaternary ammonium salt phase transfer catalyst having the formula: a e
(R)3NR1-z where R, R, and Zs 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-earth metal salt of adenine and the second liquid phase is a solution of 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide and a quaternary ammonium salt phase transfer catalyst having the formula: a a
(R)3NR1 Z where R, R1, and ze 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 alkylation of sodium adeninate with 2-chloro-6-fluorobenzyl chloride to produce a mixture of isomers of (2-chloro-6-fluorobenzyl)adenine in which at least 70 /n by weight is 9-(2-chloro-6-fluorobenzyl)adenine, the alkylation being effected in a solid-liquid two-phase reaction system in which the solid phase comprises sodium adeninate and the liquid phase comprises an acetone solution of 2-chloro-6-fluorobenzyl chloride and a quaternary-ammonium-salt phase-transfer catalyst having the formula: (nR*)3NCH3 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-phase reaction system in which one liquid phase comprises an aqueous solution of sodium adeninate and the second 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 Zs is a chloride, bromide or iodide anion. The mixture of tetraalkylammonium chlorides in which R* is primarily caprylyl (Ca) 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 vary over a relatively wide range. The reactants may be used in stoichiometric i.e. equimolar amounts or an excess e.g. a 2 to 10% or even greater molar excess of the alkylating agent may be used. A preferred excess is about 2 mole /n. It is preferred that the phase transfer catalyst be used in an amount from 1 mole /n to 10 mole /n 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 /n 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 it 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 is added and particularly prior to that time. The phase-transfer catalyst is preferably added last.
The reaction time and temperature conditions are not unduly critical. The 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 1500C.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 cases alkylation is complete after 4 to 6 hours.
Upon completion of the reaction, the reaction mixture is 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 bases for the purification of the present invention First, the 3isomer (pKa 5.6) is 40 times more basic than 9-(2-chloro-6-fluorobenzyl)adenine (pK, 4.0) and secondly the 3-isomer is chemically less stable than 9-(2-chloro-6fluorobenzyl)adenine in strong acid solutions.
Advantage is taken of the pK, difference to effect 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-chloro-6fluorobenzyl)adenine containing 20% of the 3-isomer with a dilute aqueous solution of nitric acid produces 9-(2-chloro-6-fluorobenzyl)adenine containing 34 /n 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 pure" herein is defined accordingly) has been achieved by selective chemical transformation of the 3-isomer, taking advantage of its inherent lower thermodynamic stability. The 3-isomer can be totally and selectively transformed to adenine and a benzyl polymer by treatment with 96 / > sulfuric acid without affecting the 9-isomer according to the following equation:
NH2 NH2 H, H2 C $)i;NINN) INN CH H 2 odenine C I [ F adenine (HSO,O ) k W J (HSO4f) ) 3 - isomer carbenium ion polymer Under the same conditions 9-(2-chloro-6-fluorobenzyl)adenine is unreactive. Thus, treatment of 9-(2-chloro-6-fluorobenzyl)adenine containing 34 /n of 3-isomer with 96% sulfuric acid results in a 960/, recovery of 9-(2-chloro-6-fluorobenzyl)adenine containing < 100 ppm of the 3-isomer. It has proved very difficult to completely separate the polymer from the 9-(2-chloro-6-fluorobenzyl)adenine. This problem is 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 di(C1~s alkyl)sulfides; di(C618 aryl)sulfides; benzene, toluene, xylene, mixed xylenes, mesitylene, C13 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:
0 CH,O cH CH, ( HSO4 } totuene CH29 o-, m- and p
transalkylation
product thus preventing the polymerization. Utilizing the method of sulfuric acid transalkylation in the presence of toluene, 9-(2-chloro-6-fluorobenzyl)adenine containing 3-4% of 3-isomer provides high purity 9-(2-chloro-6fluorobenzyl)adenine containing no polymer and < 100 ppm of the 3-isomer in 97-98% yield.
Crude 9-(2-chloro-6-fluorobenzyl)adenine containing about 20% of 3-isomer may be extracted with a solution of dilute mineral acid to achieve a partial removal of the undesired 3-isomer and particularly to remove traces of the 7-isomer, if desired, prior to treatment with sulfuric acid.
The mineral acid used is not critical provided it does not react with the 9isomer. Suitable mineral acids 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 3-isomer 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-6fluorobenzyl)adenine.
In treating the crude 9-(2-chloro-6-fluorobenzyl)adenine with concentrated sulfuric acid (96 /n 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 exampe, an equal weight of crude 9-(2-chloro-6-fluorobenzyl)adenine to volume of sulfuric acid or up to 10volume sulfuric acid with respect to weight of crude 9-(2-chloro-6fluorobenzyl)adenine may be used. A preferred ratio is 1 g. of crude 9-(2-chloro-6fluorobenzyl)adenine for each 2 ml. of surfuric acid.
The quantity of carbenium ion trap used is not critical, provided there is at least an equimolar amount with respect to the 3-isomer. 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 from room temperature to 900 C. A preferred temperature is room temperature with an approximately 10 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 production scale reactions.
The aqueous layer is separated. Warming may be necessary up to a temperature of 50"C. to 1000C. 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 washed with water or an aqueous alcoholic solution and dried in vacuo.
An 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
I. Assay for weight % of 9-isomer, 3-isomer and 7-isomer when 3-isomer is present
in excess of 1%
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 ClICl3:MeOH (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 0.1N 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 l0.l%).
II. Assay for weight % of trace amounts of 3-isomer after sufuric 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 350C. The mobile phase is prepared from 30 parts methanol plus 70 parts 0.01M Na2HPO4 adjusted to pH 7 with H3PO4.
Detection is by U.V. at 280 nm. The limit of detection is 100 ppm.
C. Alternative Process for Preparing 9-(2,6-Dihalobenzyl)adenines
According to an alternative preparation of the present invention 9-(2,6dihalobenzyl)adenines, unsubstituted at the 2-position, are prepared by treating 7 (N - formyl - N - 2,6 - dihalobenzylamino)[l,2,5]thiadiazolo[3,4-d]pyrimidines, i.e., compounds having the structure (7) in Table I, with Raney nickel.
TABLE I
where X1 and X2 are independently halogen.
According to Table I, 4,5,6-triaminopyrimidine (3), obtained by the process set forth in A. Shrage et al., J. Org. Chem., 16, 207(1951), with thionyl chloride affords 7-amino[l,2,5]thiadiazolo[3,4-dlpyrimidine (4). Nucleophilic displacement of the 7amino group of (4) by the process of Y.F. Shealy et al., J. Org. Chen., 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 1000C. Formylation of (6) at room temperature with formic acetic anhydride yields the 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 I 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 24 hours. Preferred conditions are ethanolwater at about room temperature for about 2 hours.
The following non-limiting Examples will serve to further illustrate the invention. Proportion of liquid mixtures are given on a volume basis.
EXAMPLE 1
Process for Alkylating Adenine with a,2-Dichloro-6-fluorotoluene in the Presence of Aliquat 336 in Hexane-Water (Liquid-liquid Heterogeneous Reaction Mixture)
A one-liter three-necked round-bottom flask equipped with a thermometer, condenser, nitrogen inlet and 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 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 omitted). The mixture was stirred at reflux for six hours and cooled to room temperature, and the solids were collected by filtration. The solids were washed 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. (N/10 HCI) A 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
30 g. of the above crude material was added to 60 ml. of hot acetic acid (650 C.). The temperature was raised to 1000C. at which point all the material had dissolved. The hot acetic acid solution was filtered through a pre-heated glass fritted funnel and the filtrate was added dropwise over a ten-minute period to 240 ml. of well stirred water at 950C. (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 370C. the bulk of
Step 2: Alkylation
A 100-ml. flask was charged with 50 ml of hexa-methylphosphoramide (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 been uniformly suspended, 9.9 g. of o,2-dichloro-6- fluorotoluene (92.3% pure, 50 mmole plus 2%) was added over a lel5-minute period. The reaction mixture was stirred overnight (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 in vacuo (4 hours, 75"C.) to give 13.29 g. of 2-chloro-6-fluorobenzylated adenines (95.8 /"). U.V. wt. /,1 3 isomer=l 1.7; L.C. wt. % 9-isomer=84.8.
Step 3: Purification
10 g. of the above material was dissolved in 14 ml. of acetic acid at 950C. The solution was filtered hot and the filtrate added dropwise within a few minutes to 80 ml. of water at 950C with rapid stirring (2 additional ml. of hot acetic acid was used to rinse all remaining material into the hot water). After cooling to 370 C., 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, 750C.) to give 8.45 g. of 9-(2-chloro-6-fluorobenzyl)adenine (84.5 /,). TIc on silica-gel in
CHCI3:MeOH (10:1) indicated a single spot; m.p. 243-2450C.; DSC=0.8 mole ,/, impurity; U.V. (N/10 HCI) A max=259, E%=562; U.V. wt. /O 3-isomer= < 2.
EXAMPLE 4
Process for Alkylating Sodium Adeninate Hydrate 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 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 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 0.1N sodium hydroxide solution for 15 minutes (this removes any unreacted adenine and the NaCI 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 13.2 g. of 2-chloro-6-fluorobenzylated adenines (95 /").
U.V. (N/10 Hcl) A 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,2-Dichloro-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 potassium adeninate was prepared by the process set forth in
Example 3, Step I 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. % 9isomer=82; U.V. wt. % 3-isomer=18.
EXAMPLE 6
Process for Alkylating Sodium Adeninate Hydrate with a-(Y)-2-chloro-6fluorotoluene 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 a,2-dichloro-6-fiuorotoluene was replaced by an equivalent amount of an a (Y)-2-chloro-6-fluorotoluene in which Y has the values set forth in Table I below:
TABLE I
CH2Y Yield of 2 C [\J/F Chloro-6- Ratio of fluorobenzylated 9-isomer adenines to 3-isomer* o Y-o-0s11 CH3 85 /n 2:1 o (tosyl) Y=l 85 /,, 7:3 a Y=S(CH3)2 Cl 31% 3:1
Y=Br 85% 4:1
* In some cases small amounts of up to 10% of other products, presumably
other isomers were obtained (I-isomer and 7-isomer).
EXAMPLE 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 NaCI 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-dichlorobenzylated adenines (94%). U.V.
(N/10 HCl) A max=262, E%=494: 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,.
5 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 0.1N sodium hydroxide solution for 15 minutes (this removes any unreacted adenine and
the NaCI formed during the alkylation). The solids were collected by filtration,
washed twice with 20 ml. of water and dried in vacuo (1000C., 4.5 hours) to give 10.2
g. of 2,6-dichlorobenzylated adenines (76%). U.V. (N/10 HCI) A max=262, E%=498;
L.C. wt. % 9-isomer=80; U.V. wt. % 3-isomer=20.
EXAMPLE 9
One-Step Purification of Crude 9-(2-Chloro-6-fluorobenzyl)adenine by Treatment
with Sulfuric Acid
To a stirred suspension of crude 2-chloro-6-fluorobenzylated 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 850C. 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 (2x10 ml.). Yield, 1.53 g. (95.6 based on available 9-isomer). L.C. assay 9-isomer 100.07%; 3-isomer, none detectable ( < 100 ppm); 7-isomer NO.8%.
EXAMPLE 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 (3x50 ml. slurries), conc. NH4OH (2x25 ml.) and hot water (3x50 ml.).
The product was sucked damp-dry and finally dried in vacuo at 65--700C. overnight to yield 31.67 g. (97.1% yield) of 9-isomer enriched 2-chloro-6-fluorobenzylated adenines. This yield is based on available 9-isomer 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 5060 C. The mixture was heated with stirring at 5(600C. 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 precipitated as the sulfate salt. The mixture was transferred to a steam-jacketed separatory funnel using hot water rinses and heated to 8O850C 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 ml of hot toluene using the same apparatus. The aqueous layer (while still warm) was made basic (pH 10) 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 (3x 100 ml) and 50 aqueous methanol (2x 100 ml). The batch was sucked damp-dry and finally dried in vacuo at 70"C. overnight to give pure 9-(2-chloro-6-fluorobenzyl)adenine. The yield was 47.8 g (98.8% based on available 9-isomer), m.p. 247-2480C; tIc on silica gel in CHCl3:MeoH (9:1) showed essentially a single spot, Rf=0.48. No polymer or other impurity was detected. L.C. assay showed 9-isomer=100.68%; 3-isomer, none detected. Overall yield=95.9%.
Preparation of 2-Chloro-6-fluorobenzylamine starting material
An autoclave was charged with 89.0 g (0.5 mole) of 2-chloro-6-fluorobenzyl chloride, 170.0 g (10 mole) ammonia and 50 ml benzene. The reaction vessel was sealed and the contents heated at 1000C 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 MgSO4, fractionated to afford 72.4 g (90%) of product as a clear liquid; b.p. 99-l000C/20 mm; NMR (CDCl3) a 1.46 (s, 2H); 3.88 (d, 2H; 7.00 (m, 3H).
WHAT WE CLAIM IS:
1. A process for alkylating an alkali metal or alkaline-earth metal salt of adenine with a 2,6-dihalobenzyl compound of general formula:
where X, and X2 are, independently, halogens and Y is a halogen,
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (14)
1. A process for alkylating an alkali metal or alkaline-earth metal salt of adenine with a 2,6-dihalobenzyl compound of general formula:
where X, and X2 are, independently, halogens and Y is a halogen,
dimethylsulfonium halide or tosyl leaving group, to produce a mixture of isomers of (2,6-dihalobenzyl)adenine in which at least 70% by weight is 9-(2,6dihalobenzyl)adenine, in which the alkylation is carred 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 a liquid phase comprising a solution of the 2,6-dihalobenzyl compound and an onium salt phase-transfer catalyst having the formula: a o (R)3NR, Z or a e (R,)3PR Z where R is C4~,8 alkyl, R, is C18 alkyl and Zeis a chloride, bromide or iodide anion, 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, or
(b) in a liquid-liquid two-phase system made up of one liquid phase comprising an aqueous solution of the alkali metal or alkaline-earth 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-(2,6-dihalobenzyl)-adenine.
2. A process as claimed in claim 1 in which the 2,6-dihalobenzyl compound is a 2-chloro-6-fluorobenzyl halide or a 2,6-dichlorobenzyl halide, the onium salt is a quaternary ammonium salt of formula
a e (R)3NR,Z where R, R, and Ze are as defined in claim 1, the aprotic watermiscible solvent (if used) is acetone, acetonitrile or hexamethylphosphoramide, the water-immiscible solvent (if used) is hexane, benzene, toluene, methylene chloride, chloroform or petroleum ether, and the final product is substantially pure (as hereinbefore defined) 9-(2-chloro-6-fluorobenzyl)adenine or 9-(2,6-dichlorobenzyl)adenine.
3. A process as claimed in claim 2 in which the salt of adenine is sodium adeninate, the 2,6-dihalobenzyl compound is 2-chloro-6-fluorobenzyl chloride, the alkylation is carried out in the solid-liquid two-phase system and the quaternary ammonium salt phase transfer catalyst has the structure:
a a (n-R)3NCH3 Cl where R is n-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-dihalobenzyl compound to 2-chloro-6-fluorobenzyl chloride, the alkylation is carried out in the liquid-liquid two-phase system, the quaternary ammonium salt has the formula: (R)3NCH3 e (R)3NCH3 Z where R is alkyl having 8 to 12 carbon atoms and za is a chloride, bromide or iodide anion, and the solvent is hexane.
5. A process according to any one of claims 1 to 4 in which the carbenium ion trap is a di(C,~s alkyl)sulfide, a di(C8~,8 aryl)sulfide, benzene, toluene, xylene, mixed xylenes, mesitylene, a (C,~3 alkdxy)benzene, thiophene, iodobenzene, naphthalene or triphenylphosphine.
6. 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 whichthe transalkylation is carried out at between room temperature and 90"C for from 2 to 36 hours.
8. A process as claimed in any one of claims 1 to 7 in which the selective transalkylation is preceded by partial extraction of 3-(2,6-dihalobenzyl)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 4 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 and reflux temperature with rapid stirring.
11. A compound having the formula:
where each of X; and X2 is fluorine, chlorine, bromine or iodine, substantially free (as hereinbefore defined) of the 3-isomer.
12. A compound having the formula:
substantially free (as 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 I to 8 followed by a procedure substantially as hereinbefore described in Example 9 or 10.
14. A compound as claimed in claim 11 when prepared by a process as claimed in any one of claims I 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 (1)
Publication Number | Publication Date |
---|---|
GB1586537A true GB1586537A (en) | 1981-03-18 |
Family
ID=27419624
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB4691/78A Expired GB1586537A (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) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2513254A1 (en) * | 1981-09-24 | 1983-03-25 | Kohjin Co | PROCESS FOR THE PREPARATION OF N6,9-DISUBSTITUTED ADENINS |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2513254A1 (en) * | 1981-09-24 | 1983-03-25 | Kohjin Co | PROCESS FOR THE PREPARATION OF N6,9-DISUBSTITUTED ADENINS |
Also Published As
Publication number | Publication date |
---|---|
ATA79778A (en) | 1980-07-15 |
IE46399B1 (en) | 1983-06-01 |
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 |
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 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4361699A (en) | Novel process for the preparation of N6 -alkyl-arprinocid | |
US4767859A (en) | Process for the preparation of pteridine derivatives | |
CZ20013658A3 (en) | Synthesis and crystallization of compounds containing piperazine ring | |
CA1105461A (en) | Process for alkylating adenine a mixture of isomers of (2,6-dihalobenzyl)adenine | |
GB1586537A (en) | 9-(2,6-dihalobenzyl)-adenines and their production | |
US4171440A (en) | Process for purification of 9-(2,6-dihalobenzyl)adenines | |
KR100281313B1 (en) | Improved method of synthesis of 2,6-dichloro-5-fluoronicotinic acid and 2,6-dichloro-5-fluoronicotinoyl chloride | |
EP1560833B1 (en) | Preparation of codeine from morphine | |
US6545149B2 (en) | Synthesis and crystallization of piperazine ring-containing compounds | |
CA1111423A (en) | Process for purification of 9-(2,6- dihalobenzyl)adenines | |
EP0052959B1 (en) | Production of purine derivatives and intermediates therefor | |
US8063217B2 (en) | Process for preparation of methyl-(+)-(S)-alpha-(2-chlorophenyl)-6, 7-dihydrothieno[3,2-C]pyridine-5(4H) -acetic acid methyl ester or salts thereof having higher chiral purity and products thereof | |
JP3528699B2 (en) | Method for producing hexahydro-2-oxo-1H-thieno [3,4-d] imidazole-4-pentanoic acid | |
US4091013A (en) | Process for preparing 1-amino-naphthalene-7-sulphonic acid | |
CS211355B2 (en) | Method of preparation of the isomeres 2,6-dihalogenbenzynladenine mixture | |
HU180866B (en) | Process for producing pure 9-bracket-2,6-dihalogeno-benzyl-bracket closed-adenines free of 3-isomere | |
US20030135043A1 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
KR800000976B1 (en) | Process for the preparation of 3,3'-triarylmethane-dicaboxylic acid derivatives | |
US4127721A (en) | Derivatives of thiadiazolo[3,4-d]pyrimidine | |
US7002034B2 (en) | Method for the production of biphenyl-4-carbonitrile | |
US4803283A (en) | Preparation of 4(5)-nitroimidazole-5(4)-carboxylic acids | |
Rasmusson et al. | Novel process for the preparation of N 6-alkyl-arprinocid | |
NZ211831A (en) | The preparation of 3-cyano-4-aminoacetophenones and their use as intermediates in preparing 2-amino-5-(1-hydroxy-2-(alkyl- or dialkyl-amino)ethyl) benzonitriles | |
JPS61268688A (en) | Production of 2,6-diaminobenzo-(1,2-d:4,5-d')-bisthiazole |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed [section 19, patents act 1949] | ||
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19940206 |