US3385857A - Cycloaliphatic pyrimidines - Google Patents

Cycloaliphatic pyrimidines Download PDF

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Publication number
US3385857A
US3385857A US592314A US59231466A US3385857A US 3385857 A US3385857 A US 3385857A US 592314 A US592314 A US 592314A US 59231466 A US59231466 A US 59231466A US 3385857 A US3385857 A US 3385857A
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Prior art keywords
amino
methyl
pyrimidine
filtered
solution
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US592314A
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English (en)
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Mizzoni Renat Herbert
Stevens George De
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BASF Corp
Novartis Corp
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Ciba Geigy Corp
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Priority to IL26554A priority Critical patent/IL26554A/xx
Priority to CH1392966A priority patent/CH484168A/de
Priority to DE19661670389 priority patent/DE1670389A1/de
Priority to FI662586A priority patent/FI45115C/fi
Priority to GB44046/66A priority patent/GB1116388A/en
Priority to GB44047/66A priority patent/GB1116389A/en
Priority to AT929366A priority patent/AT277653B/de
Priority to NL6613986A priority patent/NL6613986A/xx
Priority to FR78652A priority patent/FR1533208A/fr
Priority to DK511466AA priority patent/DK122326B/da
Priority to NO164999A priority patent/NO122650B/no
Priority to FR78651A priority patent/FR1503663A/fr
Priority to BE687779A priority patent/BE687779A/xx
Priority to BE687778A priority patent/BE687778A/xx
Priority to SE13371/66A priority patent/SE331786B/xx
Priority to AT994368A priority patent/AT281040B/de
Priority to NL6613987A priority patent/NL6613987A/xx
Priority to BR183424/66A priority patent/BR6683424D0/pt
Priority to BR183425/66A priority patent/BR6683425D0/pt
Application filed by Ciba Geigy Corp filed Critical Ciba Geigy Corp
Priority to US592314A priority patent/US3385857A/en
Application granted granted Critical
Publication of US3385857A publication Critical patent/US3385857A/en
Priority to US819459A priority patent/US3663695A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2

Definitions

  • the invention concerns and has for its object the provision of quarternary -ammoniummethyl-4-amino-Z-cycloaliphatic-lower alkyl-pyramidine salts in which the ammonium nitrogen atom is part of a monoor bicyclic heterocyclic radical containing at least one double bond extending from the ammonium nitrogen, as well as methods for their preparation.
  • this invention relates to compounds having the formula in which R stands for cycloalkyl or cycloalkenyl, or any such radical substituted by lower alkyl groups, halogen atoms or etherified hydroxy or mercapto groups, alk for lower alkylene, R for an ammonium group of which the nitrogen atom is part of a 5- or 6-ring-membered monocyclic heterocyclic radical or an 8- to -ring-membered bicyclic heterocyclic radical containing up to 3 hetero atoms and at least one double bond extending from the ammonium nitrogen, and X for the anion of an acid, and acid addition salts thereof.
  • R stands for cycloalkyl or cycloalkenyl, or any such radical substituted by lower alkyl groups, halogen atoms or etherified hydroxy or mercapto groups, alk for lower alkylene, R for an ammonium group of which the nitrogen atom is part of a 5- or 6-ring-membered monocyclic heterocycl
  • 'A cycloalkyl group representing R more particularly contains 3 to 8 ring-carbon atoms and preferably stands for cycloalkyl or (lower alkyl)-cycloalkyl with 3 to 6 ringcarbon atoms, such as cyclopropyl, Z-methyl-cyclopropyl, 2,2- or 2,3-dimethyl-cyclopropyl, 2,2,3,3-tetramethyl-cyclopropyl, 2-ethyl-cyclopropyl, cyclobutyl, 2,2,3-trimethylcyclobutyl, 3-ethyl-cyclobutyl, cyclopentyl, 2- or 3-methylcyclopentyl, 2,5- or 3,4-dimethyl-cyclopentyl, cyclohexyl, 2-, 3- or 4-methyl-cyclohexyl, 2,3-, 2,4- or 3,5-dimethyl-cyclohexyl, 2,4,6-trimethyl-cyclohexyl, cycloheptyl or
  • a cycloalkenyl group R has at most 2 double bonds and, more particularly, contains 3 to 8 ring-carbon atoms. It preferably stands for cycloalkenyl or (lower alkyl)- cycloallienyl wiih S to 6 ringcarbon atoms and represents, for example, 2-cyclopropenyl, 1- or 2-cyclopentenyl, 2,4- cyclopentadienyl, 2- or 3-methyl-2-cyclopentenyl, 4,5-dimethyl-Z-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 2,5-cycyclohexadienyl, 2-, 3- or 4-methyl-1- or 2-cyclohexenyl, 2,4- or 3,5-dimethyllor 2-cyclohexenyl, 2,4,6-trimethyl- 2,5-cyclohexadienyl, 1-, 2- or 3-cycloheptenyl, 2,6-cycloheptadienyl or Z-cycloocten
  • cycloaliphatic radicals may additionally be substituted by one or more than one halogen atoms, such as fluoro or chloro, or etherified hydroxy or mercapto groups, such as lower alkoxy or lower alkylmercapto, e.g. methoxy, ethoxy, nor i-propoxy, n-, i, sec. or tert.-but0xy, methylor ethylmercapto.
  • halogen atoms such as fluoro or chloro
  • etherified hydroxy or mercapto groups such as lower alkoxy or lower alkylmercapto, e.g. methoxy, ethoxy, nor i-propoxy, n-, i, sec. or tert.-but0xy, methylor ethylmercapto.
  • the lower alkylene portion alk separating said cycloaliphatic group from the 2-position of the pyrimidine nucleus preferably has 1 to 4 carbon atoms and especially represents methylene, but also 1,1- or 1,2-ethylene, 1,l,
  • the ammonium group R represents, for example a pyridinium, quinolinium, isoquinolinium, pyridazinium, pyrimidinium, pyrazinium, quinazolinium, phthalazinium, 1,5-, 1,6-, 1,7- or 1,8-naphthyridinium, N-lower alkyl-N'- pyrazoli um, N-lower alkyl-N-imidaz-olium, thiazolium, oxazolium, 1,3,5-triazinium, l-lower alkyl-lH-pyrrolo [3,- 2-b pyridinium, 6-lower alkyl-6H-pyrrolo [3 ,4-b pyridinium, thieno[3,2-b]pyridinium, thieno[2,3-b]pyridinium, pyrido[3,2-b] pyrimidinium or pyrido [2,3-b]pyrazinium
  • lower alkyl groups such as those mentioned above
  • free or functionally converted hydroxy or mercapto groups such as lower alkoxy or alkylmercapto, e.g. that mentioned above
  • halogen e.g. fiuoro, chloro or bromo
  • trifluoromethyl or amino especially di-lower alkylamino, e.g. dimethylamino or diethylamino.
  • the anion X as well as the acid addition salts mentioned in the beginning, are preferably derived from therapeutically useful inorganic or organic acids, such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, for example, formic, acetic, pripionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salocylic, p-aminosalicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic, tol
  • the compounds of this invention possess valuable pharmacological properties. For example, they exhibit antiprotozoal activity, especially against parasites causing coccidiosis, such as Eimeria tenella, acerv'ulina, adenoz'des, agridis, brmzetti, hagani, maxima and necalrix. This can be demonstrated, for example, by the curative effect of a feed, containing about 0.001 to about 0.02% of the compounds of this invention, given to chickens one or two days prior till 8 days after their inoculation with sporulated oocysts of Eimeria tenella, acervulina, maxima or necatrix.
  • coccidiosis such as Eimeria tenella, acerv'ulina, adenoz'des, agridis, brmzetti, hagani, maxima and necalrix.
  • the curative effect can also be demonstrated at doses between about 0.001 to 0.02% applied after inoculation with said oocysts.
  • the compounds of this invention are, therefore, useful agents in the control of coccidiosis, which is one of the most important goals in the poultry raising industry. Furthermore, they are useful intermediates in the manufacture of other valuable compounds, especially medicines.
  • R stands for cycloalkyl (lower alkyl)-cycloalkyl, (lower alkoxy)-cycloalkyl or (halo)-cycloalkyl with 3 to 6 ring-carbon atoms, alk for alkylene with 1 to 4 carbon atoms, R for pyridinum, quinolinium, isoquinolinium, pyridazinium, pyrimidinium, pyrazinium, thiazolium, thiazolinium, oxazolium, oxazolinium, imidazolium, imidazolinium or such radical substituted by up to 2 lower alkyl groups, and X for the anion of an acid, and acid addition salts thereof.
  • the compounds of the invention are prepared by methods in themselves known. Advantageously they are obtained by reacting a reactive ester or ether of a S-hydroxymethyl 4-amino-2-cycloaliphatic-lower alkyl-pyrimidine with a monoor bicyclic heterocyclic compound containing at least One ring-nitrogen atom and double bond, and/or converting a quaternary S-ammonium-methyl-4- amino 2-cycloaliphatic-lower alkyl-pyrimidine base or pseudobase into its quaternary salt and/or, if desired, converting a resulting free 4-amino-compound into its acid addition salt or converting a resulting acid addition salt into the free 4-amino-compound or into another salt and/ or converting a resulting quaternary salt into another quaternary salt.
  • a reactive ester of said S-hydroxymethyl compound is, for example, that of a strong inorganic or organic acid, such as a hydrohalic, sulfuric, sulfonic or carbamic acid, e.g. hydrochloric, hydrobromic, sulfuric or lower alkyl sulfuric acid, a lower alkane or benzene sulfonic acid, e.g. methane, ethane, benzene or p-toluene sulfonic acid, or unsubstituted or N-substituted carbamic acid, e.g. N,N- dimethylor N-phenyl-carbamic acid.
  • a strong inorganic or organic acid such as a hydrohalic, sulfuric, sulfonic or carbamic acid, e.g. hydrochloric, hydrobromic, sulfuric or lower alkyl sulfuric acid, a lower alkane or benzene sulfonic acid, e.g. methane
  • An ether of said 5- hydroxymethyl compound is preferably a lower alkyl or phenyl-lower alkyl ether, e.g. the methyl, ethyl, isopropyl or benzyl ether.
  • the quaternary base or pseudobase may contain hydroxy as an anion or as substituent of the heterocyclic ring containing the ammonium nitrogen.
  • the esters of the S-hydroxymethyl compound are reacted in the form of their acid addition salts with the free heterocyclic compound, whereas the corresponding ethers are reacted in the free form with an acid addition salt of the heterocyclic reagent.
  • the compounds of the invention are obtained in the free form, i.e. that having a free 4-amino group, or in the form of their acid addition salts, depending on the conditions under which the process is carried out; these salts are also included in the present invention.
  • Acid addition salts that are obtained can be converted into the free compounds in known manner, for example, with weak alkalies, e.g. alkali metal carbonates or bicarbonates, or into other salts, for example with ion exchangers.
  • Free compounds that are obtained, as well as the quaternary bases or pseudobases, can be converted into acid addition salts or quaternary salts respectively, by reacting them with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful salts, for example those listed for the anion X
  • the transquaternization is carried out in the usual manner, advantageously with an excess of the corresponding heterocyclic base.
  • the above reactions are carried out according to stand ard methods, in the presence or absence of diluents, preferably such as are inhert to the reagents and are solvents thereof, of catalysts, condensing agents and/or inert atmospheres, at low temperatures, room temperature or advantageously elevated temperatures, at atmospheric or superatmospheric pressure.
  • diluents preferably such as are inhert to the reagents and are solvents thereof, of catalysts, condensing agents and/or inert atmospheres, at low temperatures, room temperature or advantageously elevated temperatures, at atmospheric or superatmospheric pressure.
  • the invention further includes any variant of the present process in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts.
  • the reactive ester ofthe S-hydroxymethyl compounds e.g. a sulfonic acid ester
  • the reaction conditions i.e. in the presence of the heterocyclic compound.
  • those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being especially valuable.
  • the starting materials are known, or if they are new, may be prepared by methods in themselves known.
  • the 5-hydroxymethyl-4-amino-2-cycloaliph-atic-lower alkyl-pyrimidines may be prepared by reacting a cycloaliphatic-lower alkanoic acid amidine or imido ester with a lower alkoxy-methylidene-malodinitrile, reducing the resulting 5-cyano-4-amino-2-cycloaliphatic-lower alkyl-pyrimidine to the corresponding 5- amino-methyl compound, for example with catalytically activated hydrogen, and converting it into the corresponding S-hydroxymethyl compounds, for example by the reaction of nitrous acid.
  • Said alcohol can be reactively esterified or etherified according to known methods, for example with a thionylh'alide or phosphorus halide, a sulfuric or sulfonic acid halide, e.g. sulfuryl, tosyl or brosyl chloride.
  • a S-halomethyl compound obtained may then be reacted with an anhydrous alcohol or mercaptan in order to obtain the desired ethers.
  • the latter may also be prepared by reacting an acid addition salt of a cyloaliphatic-lower alkanoic acid amidine with an a-alkoxymethylene- 3-alkoxy-propionitrile.
  • the quaternary bases or pseudobases may be obtained by reduction of the corresponding oxo-compounds, i.e. the cyclic amides, for example with the use of complex light metal hydrides, such as lithium aluminum hydride or sodium borohydride.
  • the compounds of the invention may be used, for example in the form of veterinary compositions, animal feedingstuffs or additives to feedingstutfs, which are a further object of the present invention.
  • the former contain said compounds in admixture with organic or inorganic, solid or liquid pharmaceutical excipients suitable especially for enteral administration.
  • Suitable excipients are substances that do not react with the new compounds, for example water, gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propylene glycol and other known medicinal excipients.
  • the compositions may be, for example, tablets or pills, e.g.
  • microphills or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure or butters. They are prepared by conventional methods.
  • the feedingstuffs and additives for feedingstuffs or for the drinking water contain the compounds of the invention together wit-h conventional extenders, diluents and/or nutrients, such as sucrose, glucose, molasses, fermentation residues, cornmeal, ground and rolled oats, wheat shorts and middlings, meat scrap, oil cake, soybean and fish metal, alfalfa, clover, grass clippings and the like, mineral supplements, such as bone meal, calcium carbonate, iodized salt and the like, vitamins, such as vitamins A, B, C and D and other suitable substances, such as preservants, e.g. benzoic acid.
  • nutrients such as sucrose, glucose, molasses, fermentation residues, cornmeal, ground and rolled oats, wheat shorts and middlings, meat scrap, oil cake, soybean and fish metal, alfalfa, clover, grass clippings and the like
  • mineral supplements such as bone meal, calcium carbonate, iodized salt and the
  • the feedingstufis contain the compounds of the invention in an amount ranging between about 0.000l and 0.1% preferably bet-ween about 0.001 and 0.02%, whereas the additives may contain the pure substances, when used, for example, for the drinking water, but usually contain between about 1 and 50% thereof.
  • the amount of the compounds of the invention administered via the veterinary compositions or the drinking water corresponds to that given with the medicated feedingstuffs shown above.
  • compositions, feedingstufis and additives may contain other therapeutically valuable substances, for example, sulfonamides, such as N'-(6-chloro-2-pyraziny1)-sulfanilamide, N'-(2,6-dimethoxy-4-pyrimidyl)-sulfanilamide, N'- -ethyl- 1 ,3 ,4-thiadiazol-2-yl) -sulfanilarnide, N'-(5-methyl-3-isoxazolyl)-sulfanilamide, N'-( 6-methoxy-3-pyridazinyl) -sulfanilamide and the N-acetyl derivative thereof, N-(4-methyl-2-pyrimidinyl)-sulfanilamide, N'-(2,6-dimethyl-4-pyrimidinyl)-sulfanilamide, N'-(S-methyl-1,3,4'thiadiazol-2-yl)-sulfanilamide, N-(6-
  • compositions, feedingstuffs and additives of the invention may contain antibiotics, e.g. penicillin, streptomycin, aureomyein, Terramycin, tetracycline and the like, antiparasitic agents, e.g.
  • methyl-4-acetamino-Z-ethoxy-benzoate 2-amino-5- nitro-thiazole or 1-(5-nitro-thiazolyl-2)-2-oxotetrahydroimidazole and/or tranquilizers, such as reserpine, methyl 18-epi-O methyl-reserpate, meprobamate and the like.
  • the Amberlite IRA- 400 resin to which reference is made below, is a strong basic quaternary ammonium ion exchange resin of the type covered in US. Patent No. 2,591,573.
  • Example 1 2.2 g. 5-hydroxymethyl-4-amino-2-cyclopropylmethylpyrimidine are dissolved in ml. of freshly distilled 2,4- lutidine, and to this solution 2.24 g. p-toluenesulfonyl chloride are added. The mixture is allowed to stand at room temperature for 4 days. It is then diluted with diethyl ether to yield a precipitate of which the supernatant solution is decanted. The residue is dissolved in isopropanol and the product 4 times precipitated With diethyl ether until the odor of 2,4-lutidine disappears.
  • the crystalline 5 (2,4-dimethyl-pyridinium)-methyl-4-amino-2- cyclopropylmethyl-pyrimidine salt is dissolved in 100 ml. water and the solution is passed through an Amberlite IRA400 resin column present in the chloride form. The aqueous eluate is concentrated in vacuo and the residue recrystallized from methanol-isopropanol to yield the 5- (2,4 dimethyl pyridinium)-methyl-4-amino-2-cycl0propylmethyl-pyrimidine chloride hydrochloride of the formula
  • the starting material is prepared as follows:
  • the precipitated yellow solid is filtered, ground in a mortar with diethyl ether, filtered and vacuum dried at 50 to yield the 5-hydroxymethyl-4-amino-2-cyclopropylmethyl-pyrimidine hydrochloride.
  • the hydrochloride obtained is dissolved in the minimum amount of water and solid potassium carbonate is added while cooling and stirring until an oily layer separates. It is extracted with n-butanol until the last extract is virtually colorless. The combined extracts are dried over potassium carbonate, filtered and evaporated in vacuo. The residue is trituratml with diethyl ether, filtered, washed with ether and dried in vacuo at 50 to yield the 5 hydroxymethyl-4-amino-2-cyclopropylmethyl-pyrimidine.
  • Example 2 19.0 g. S-hydroxymethyl-4-amino-2-cyclopropylrnethylpyrimidine are dissolved in ml. 2,4-lutidine with warming. Hereupon 20.4 g. p-toluenesulfonyl chloride are added portionwise while cooling, the solution is filtered and allowed to stand at 20 for 18 hours and at room temperature for 5 /2 days.
  • EXAMPLE 3 18.5 g. 5-hydroxymethyl-4-amino-2-cyclopropylmethylpyrimidine are dissolved in 100 ml. 2-picoline and to the solution 19.9 g. p-toluenesulfonyl chloride are added. The mixture is worked up as described in Example 1 to yield the 5 (2 methyl-pyridinium-methyl)-4-amino-2cyclopropylmethyl-pyrimidine chloride hydrochloride of the formula Nin J] Ha melting at 225.5 to 226.5.
  • the starting material is prepared as follows: The solution of 50.0 g. cyclobutylcarboxylic acid in 500 ml. diethyl ether is added to the mixture of 23.6 g. lithium aluminum hydride and 500 ml. diethyl ether while stirring and refluxing. The mixture is refluxed and stirred for 3 hours, then cooled in an ice bath and 71.6 ml. 15% aqueous sodium hydroxide are added under nitrogen. The precipitate formed is filtered off, washed with diethyl ether and the filtrate evaporated. The residue is distilled and the fraction boiling at -143 collected; it represents the cyclobutylmethanol.
  • the starting material is prepared as follows: To the solution of 5.8 g. 5 hydroxymethyl 4 amino 2 cyclopropylmethyl-pyrimidine in 10 ml. dimethylformamide, 2.45 ml. thionyl chloride are added dropwise while stirring and keeping the temperature below 5. After stirring for 2 hours in the ice bath, the mixture is allowed to stand at 0 for 18 hours. Upon dilution with diethyl ether, the precipitate is filtered off, triturated with diethyl ether and acetone and recrystallized from isopropanoldiethyl ether to yield the 5-chloromethyl-4-amino-2-cyclopropylmethyl-pyrimidine hydrochloride melting at 191l95 with decomposition.
  • Example 7 The mixture of 6.5 g. 5-chloromethyl-4-amino-2-cyclopropylmethyl-pyrimidine hydrochloride and 30 ml. 2,4- lutidine is heated at the steam cone for 3 hours. It is allowed to stand overnight at room temperature, then diluted with acetone and the precipitate formed filtered off. It is washed with acetone until the odor of 2,4-lutidine disappears and recrystallized from aqueous isopropanol, to yield the 5-(2,4-dimethyl-pyridinium)-methyl-4-amino-2- cyclopropylmethyl pyrimidine chloride hydrochloride melting at 252253 with decomposition; it is identical with the product shown in Example 1.
  • the starting material is prepared as follows: To the solution prepared from 7.6 g. sodium and 200 ml. anhydrous ethanol, 61.2 g. cyclopropyl-acetamidine hydrobromide are added while stirring at 0l0. Stirring is continued for /2 an hour and hereupon 53.0 g. oc-IllB'tllOXY- methylidene-fi-isopropoxy-proponitrile (containing about 71% of the cis-isomer) are added in one portion and the mixture is stirred for 20 hours at room temperature. The precipitate formed is filtered olf, the filtrate evaporated in vacuo and the residue dissolved in methylene chloride.
  • p-toluenesulfonyl chloride are added while cooling.
  • the mixture is then filtered and the filtrate allowed to stand at 20 for 2 days and at room temperature for 4 days. It is then diluted with acetone, the precipitate formed filtered off, washed with acetone and recrystallized from isopropanoldiethyl ether to yield the 5-(2,4-dimethyl-pyridinium)- 1 1 methyl 4 amino-2-(2-chloro-cyclopropyl)methyl-pyridine chloride hydrochloride of the formula
  • the starting material is prepared as follows: The stirred mixture of 35.64 g. phenyl-(trichlorornethyl)-rnercury, 21 ml.
  • Example 9 In the manner described in the previous examples, the following compounds are prepared by using the equivalent amounts of the corresponding starting materials: 5-quinoliniummethyl-4-amino-2-cyclopropylmethylpyrimidine, S-isoquinoliniummethyl-4-amino-2-cyclopentylmethyl pyrimidine,
  • Example 10 A poultry feed containing 0.005% of the active ingredient may be prepared as follows.
  • the ingredients are mixed thoroughly until uniformity is obtained.
  • Feed formula Grams Corn meal 1,062.875 Fat 80.000 Fish meal, 60% protein 100.000 Soybean meal, 50% protein 500.000 Corn gluten meal 100.000 Dehydrated alfalfa meal 50.000 Corn distillers solubles 40.000 Dicalcium phosphate 28.000 Calcium carbonate 20.000 Iodized salt 10.000 Vitamins A and D (1,000,000 Int. units A and 250,000 D/pound 4.000 Calcium pantothenate 0.250 Butylated hydroxytoluene 0.250 Choline chloride, 25% 2.500 Riboflavin conc. (24 g. per pound) 0.125 Vitamin B (0.02 g. per pound) 1.000 Methionine 0.500 Manganese sulfate 0.500
  • the feed formula is prepared as follows: A portion of the corn meal is introduced into the blending machine (about half of the amount to be added). The remaining corn meal, previously blended with the pre-heated, liquified fat, is added thereto and mixing is continued until uniformity is obtained. The maganese sulfate, dicalcium phosphate, calcium carbone and iodized salt are then added with mixing, followed by the addition of the fish,
  • soybean, corn gluten and alfalfa meal and the corn distiller solubles After a uniform mixture has been obtained, vitamins A and D, calcium pantothenate, choline chloride, riboflavin, vitamin B and methionine are added in that order. Mixing is continued after the addition of butylated hydroxytoluene, and maintained until a uniform product is obtained.
  • the premix is added to the feed formula prepared as described above in an amount sufiicient to provide a concentration of 0.005 g. of the active ingredient per 100 g. of feed in the uniformly blended mix.
  • Another premix which may be used accordingly is the following An aqueous solution containing 0.01% of the active ingredient may be prepared from said additive.
  • Example 12 A poultry feed containing 0.0005 of the active ingredient is prepared as follows.
  • lb. of the vitamin composition contain: 16,000,000 I.U. vit. A, 1,000,000 I.U. vit. D 5,000 I.U. vit. E acetate, 6 g. vit. K 6 mg. vit. B 3 g. riboflavin, 30 g. niacin, 5 g. calcium pantothenate and 100 g. ethoxyquin, made up to 10 lb. with corn meal.
  • the 5 (2,4-dimethyl-pyridiniurn-methyl)-4-amino-2- cyclopropylmethyl-pyrimidine chloride hydrochloride is first premixed with about 1 kg. of the finely ground feed mixture (which is supplied as such by the manufacturer). The premix is increased to about 25 kg. with the feed and then thoroughly mixed with the main batch in a horizontal mixer.
  • Example 13 A poultry feed, containing 0.003% each of two active ingredients, is prepared as follows.
  • the thoroughly mixed ingredients are added to 99 kg. of the feed formula shown in Example 10 and the whole is homogenized in a horizontal mixer.
  • Example 14 A poultry feed is prepared as follows.
  • the premix is prepared by t-riturating I and II with III and the mixture is then screened through a 30 mesh screen, U.S. standard sieze size; the screened material is then blended with IV in a mixer and the thoroughly mixed ingredients are added to 910 kg. of the feed formula shown in Example 10 and the whole is homogenized in a horizontal mixer.
  • Example 15 A poultry feed is prepared as follows:
  • IV About one third of the amount of IV is combined with I and II, mixed and then screened through a 30 mesh screen, U.S. standard sieve. The remainder of IV is then put into a mixer, III is added and the materials mixed to form a uniform dispersion to which the screened material is added and then mixed until uniformity is obtained. The resulting mixture is then added to 910 kg. of the feed formula shown in Example 8 and the whole is homogenized in a horizontal mixer.
  • the sulfanilamide may be present in the final composition in an amount of about 0.0003 to 0.005% per 0.0125 of the quaternary component. Actually, one can utilize an amount of sulfanilamide in the range of 0.001 to 0.010% for the intended purposes.
  • Quaternary 5 ammoniummethyl-4-amino-2-cyclo aliphatic-lower alkyl-pyrimidine salts having the formula in which R is a member selected from the group consisting of 3 to 8 ring membered cycloalkyl, cycloalkenyl, and any such radical substituted by a member selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower alkylmercapto, alk is lower alkylene, R is pyridinium, quinolinium, isoquinolinium, pyridazinium, pyrimidinium, pyrazinium, quinazolinium, phthalazinium, 1,5-naphthyridinium, 1,6-naphthyridinium, 1,7-

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US592314A 1965-10-05 1966-11-07 Cycloaliphatic pyrimidines Expired - Lifetime US3385857A (en)

Priority Applications (21)

Application Number Priority Date Filing Date Title
IL26554A IL26554A (en) 1965-10-05 1966-09-21 Compositions containing pyrimidine derivatives for treatment of coccidiosis
CH1392966A CH484168A (de) 1965-10-05 1966-09-27 Verfahren zur Herstellung neuer Pyrimidine
DE19661670389 DE1670389A1 (de) 1965-10-05 1966-10-01 Neue quaternaere 5-Ammonium-methyl-4-amino-pyrimidinsalzverbindungen
GB44047/66A GB1116389A (en) 1965-10-05 1966-10-03 Compositions for treatment of coccidiosis
FI662586A FI45115C (fi) 1965-10-05 1966-10-03 Antikokkidioosiainetta sisältävä rehuaine siipikarjan kasvun edistämis eksi.
GB44046/66A GB1116388A (en) 1965-10-05 1966-10-03 Cycloaliphatic pyrimidines and process for their manufacture
FR78652A FR1533208A (fr) 1965-10-05 1966-10-04 Aliments complémentaires pour les animaux
DK511466AA DK122326B (da) 1965-10-05 1966-10-04 Analogifremgangsmåde til fremstilling af kvaternære 5-pyridinium-methyl-4-amino-pyrimidinsaltforbindelser eller syreadditionssalte deraf.
NO164999A NO122650B (is") 1965-10-05 1966-10-04
FR78651A FR1503663A (fr) 1965-10-05 1966-10-04 Procédé de préparation de nouvelles pyrimidines
AT929366A AT277653B (de) 1965-10-05 1966-10-04 Verfahren zur Herstellung eines Futtermittels mit anticoccidischer Wirkung
BE687778A BE687778A (is") 1965-10-05 1966-10-04
SE13371/66A SE331786B (is") 1965-10-05 1966-10-04
NL6613986A NL6613986A (is") 1965-10-05 1966-10-04
NL6613987A NL6613987A (is") 1965-10-05 1966-10-04
AT994368A AT281040B (de) 1965-10-05 1966-10-04 Verfahren zur Herstellung von neuen, quaternären 5-Ammoniummethyl-4-amino-2-R-pyrimidinsalzverbindungen oder Säureadditionssalzen davon
BE687779A BE687779A (is") 1965-10-05 1966-10-04
BR183424/66A BR6683424D0 (pt) 1965-10-05 1966-10-05 Processo para a fabricacao de pirimidinas cicloalifaticas
BR183425/66A BR6683425D0 (pt) 1965-10-05 1966-10-05 Composicao de racoes terapeuticas para prevencao e/ ou tratamento de infeccoes de coccidiose na avicultura
US592314A US3385857A (en) 1965-10-05 1966-11-07 Cycloaliphatic pyrimidines
US819459A US3663695A (en) 1965-10-05 1969-04-25 Anticoccidial compositions containing quaternary 5 - ammoniummethyl - 4-amino - 2 - cycloaliphatyl-pyrimidine salts

Applications Claiming Priority (4)

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US49323365A 1965-10-05 1965-10-05
US53466666A 1966-03-16 1966-03-16
US57267166A 1966-08-16 1966-08-16
US592314A US3385857A (en) 1965-10-05 1966-11-07 Cycloaliphatic pyrimidines

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BR (2) BR6683424D0 (is")
CH (1) CH484168A (is")
DE (1) DE1670389A1 (is")
DK (1) DK122326B (is")
FI (1) FI45115C (is")
FR (1) FR1503663A (is")
GB (2) GB1116388A (is")
IL (1) IL26554A (is")
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454575A (en) * 1967-03-06 1969-07-08 Ciba Geigy Corp Quaternary 5-ammonium-methyl-4-amino-2 cycloaliphatylpyrimidine salts
FR2181712A1 (is") * 1972-02-08 1973-12-07 Merck & Co Inc
US4006143A (en) * 1974-04-09 1977-02-01 Merck & Co., Inc. Heterocyclic substituted pyrimidine compounds
US4044133A (en) * 1974-04-18 1977-08-23 Merck & Co., Inc. Anticoccidial compositions
US6077981A (en) * 1998-08-28 2000-06-20 Eastman Chemical Company Process for the production of cyclopropylmethyl halides
US6118032A (en) * 1999-08-03 2000-09-12 Eastman Chemical Company Process for the production of cyclopropylmethyl halides
WO2002066029A3 (en) * 2001-02-21 2003-02-20 Univ Gent Antiprotozoal methods, compositions and feedstuffs
CN111760032A (zh) * 2020-07-22 2020-10-13 广州白云山宝神动物保健品有限公司 防治鸡耐药性球虫病的组合物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3042676A (en) * 1960-02-02 1962-07-03 Merck & Co Inc Pyridinium quaternary salts and methods of preparing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3042676A (en) * 1960-02-02 1962-07-03 Merck & Co Inc Pyridinium quaternary salts and methods of preparing the same

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454575A (en) * 1967-03-06 1969-07-08 Ciba Geigy Corp Quaternary 5-ammonium-methyl-4-amino-2 cycloaliphatylpyrimidine salts
FR2181712A1 (is") * 1972-02-08 1973-12-07 Merck & Co Inc
US4006143A (en) * 1974-04-09 1977-02-01 Merck & Co., Inc. Heterocyclic substituted pyrimidine compounds
US4044133A (en) * 1974-04-18 1977-08-23 Merck & Co., Inc. Anticoccidial compositions
US6077981A (en) * 1998-08-28 2000-06-20 Eastman Chemical Company Process for the production of cyclopropylmethyl halides
US6118032A (en) * 1999-08-03 2000-09-12 Eastman Chemical Company Process for the production of cyclopropylmethyl halides
WO2002066029A3 (en) * 2001-02-21 2003-02-20 Univ Gent Antiprotozoal methods, compositions and feedstuffs
CN111760032A (zh) * 2020-07-22 2020-10-13 广州白云山宝神动物保健品有限公司 防治鸡耐药性球虫病的组合物及其制备方法和应用
CN111760032B (zh) * 2020-07-22 2022-02-25 广州白云山宝神动物保健品有限公司 防治鸡耐药性球虫病的组合物及其制备方法和应用

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GB1116388A (en) 1968-06-06
FR1503663A (fr) 1967-12-01
DK122326B (da) 1972-02-21
BE687779A (is") 1967-04-04
BR6683425D0 (pt) 1973-12-04
SE331786B (is") 1971-01-11
FI45115C (fi) 1972-03-10
NL6613987A (is") 1967-04-06
FI45115B (is") 1971-11-30
IL26554A (en) 1971-04-28
BE687778A (is") 1967-04-04
GB1116389A (en) 1968-06-06
NO122650B (is") 1971-07-26
BR6683424D0 (pt) 1973-12-04
NL6613986A (is") 1967-04-06
CH484168A (de) 1970-01-15
AT277653B (de) 1970-01-12
DE1670389A1 (de) 1970-11-05
AT281040B (de) 1970-05-11

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