BE641253A - - Google Patents

Description

       

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 EMI1.1
 

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 EMI2.1
 



  Alcox, y "'(ll çoy 1- (.. (p-'lJ'i, l no .. b" f1: lbno -tiul fOnI.l.M1dQ) "r ^, lrinc.a cf l" nur prr ) rjl1 (from} prdIJnrnt1on, ...
 EMI2.2
 preparation of G .. (r-amlro.-tra3ric..nulf cnmicai-yrlmiw 1'.1
 EMI2.3
 
 EMI2.4
 in which the one dos n'st-ss n and TU represented a lower alûoxy (tnféri ur) -t3ilcoyiiqu rent and the aûtr, 'r.pré: a' tm atone ri rx: og2ne, 1n remainder * lower alkyl, a lower alkoxy spleen, an alocxv (in, férieur) -lower alkyl or, a lcoxYirii "residue of. a7, caxy Inferln; jrppt of their N 1-acyldae derivatives with the exception of 6- (p -amlno-ben2ene-sulfonafflido) 2 *. mfahxyrneSttyl 4 met, ho.ywprrimidine.
 EMI2.5
 



  In the new compounds, the remains
 EMI2.6
 Lower alkyls are in particular alkyl residues comprising from one to 5 carbon atoms,
 EMI2.7
 for example Ion rente-9 methyl, ethyl * n-propyl or

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   iaopropyl, or a straight or branched butyl or pontyl residue linked at any point. Lower alooxy residues are, for example, those containing
 EMI3.1
 the alkyl annuities indicated above, in particular the mathoxy, ethoxy or propoxy annuities lower alkoxy contained in the lower alkoxy (lower) -alkylic radicals are, for example, mentioned above.

   The
 EMI3.2
 Alkyl moieties connecting the oxygen atom with the pyrimidine ring are preferably alkyl moieties comprising from 1 to 5, in particular from 1 to 3 atomic carbon, such as methylene residues, ethylene, propylene, butylene or pentylbrze linked in any position. The lower alooxy (lower) alkyl radicals Including, in particular, residues of formula
RO- (CH2) n in which R represents an alkyl residue having from one to 3 carbon atoms and n represents an integer with a value of one to 3.



   The alkoxy groups contained in the residues',. (lower) alkoxy-lower alkoxy are, for example, those indicated above. The alkylene residue linking these alcexy groups with the oxygen atom on the pyrimidine ring has, between the alkoxy group and the indicated oxygen atom, at least soft carbon atoms and preferably contains 2 to 5 carbon atoms. carbon atoms and especially represents a 1,2-ethylene residue, as well as a 1,2-, 2,3- or 1,3-propylene residue, a straight butylene or pentylene residue or

 <Desc / Clms Page number 4>

 branched which is 116 at any point,

   but separate neighboring oxygen atoms by at least two carbon atoms.



   As halogen atoms, in particular, chlorine or fluorine atoms are envisaged.
 EMI4.1
 As N, -acylated derivatives, mention will be made of. ,, t ',., particularly those in which the acyl residue is a lower aliphatic carboxylic residue or
 EMI4.2
 aromatic or graliphatic carboxylic residue, for example a carbalkoxy residue such as the cerbethox7 residue | or preferably the residue of a fatty acid, for example a lower fatty acid, as the 'residue': f.1 propionyl, butyryl, valeryl or caproyl, or that ..; of a higher fatty acid, for example the remainder
 EMI4.3
 lauroyie, palmityl or ol6yle # of a fatty acid phoûylique such as phenylacetic acid, or a bonzotquo acid such as bonzolque acid itself. In the first place, however, the acyl residue is the acetyl residue.



   The new compounds have good
 EMI4.4
 prnpribt L3 autib # tiriennoo, This is so for example that during an experimental infection practiced.
 EMI4.5
 on animal animals, for example on mice, they have a very good curative effect. Gram positive and Gram negative bacteria, eg vilJ-I! .. v1; utrcytococci, pncumacocuo3 and god collibacillest staphylococci They have before:!;, The vis-11-lives; comparable compounds Thus, according to the tests carried out, the
 EMI4.6
 fraction of Dultonullddc separated in human urine

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 is significantly less acetylated. They can by euite
 EMI5.1
 be used.

   GO: r :: 1 (: chemistry-therapeutics, for example dan.-5 the ca6 of bacterial infections, in particular dct? Vo.1.t :, uriwllrcu. Lia are however also suitable> -: r as adjuvants h.al4mentalreo aubotancea for animals and they can be used as intermediates for the preparation of other agents
 EMI5.2
 . ch1m1o ... t..herapO'lltiqu (: s p, t ° ciEUx ..



   The compounds of the formulas '.' Should be particularly emphasized.
 EMI5.3
 
 EMI5.4
 in the 3squ'Ulfc RI f t FI .... r) reprSsrr.tr.rt, remains',,. # aleoyl Lqvr> s lower t n represents. a number '.. Óg41, the unit, \ 2 or 3, as well as Ifs drifts'N, - # anyiés of these'compos68, k except for 6 (p-. ami.r.obe = nne t ; ul.i'nnamido -2-. (methoxymet} 1y'l) --metloxy-pyrimidin.
 EMI5.5
 



  Lps new capiposén can be obtained cnivant (set tricthodr ::, known in 01 l (: s ... mnmoli One proceeds in particular so that one makes react a compound of formula

 <Desc / Clms Page number 6>

 
 EMI6.1
 in which Y and Y1 are remnants that can be split during the reaction by abandoning the croup.

   ,
 EMI6.2
 181nog'nl -NH- contained in one of the aux, 1 Mpi '<"is $ the aminogenic group or a substituent 91 allowing the formation of the aminogenic group at II and, ga have the indicated meaning, then that in any order, in the compounds obtained containing the residue Z1, the aminogenic group in position pars
 EMI6.3
 of the benzene ring, and / or that the $ oomposia bie''p''ï! -benzene-'au! .fonyl06 obtained in the compounds, ieair "; Nono '<p'-Z-benzen" 8ulfonylea, and / or, and 0 11 <tt.1re, t that the compounds obtained are acylated on the asote atom Ni *
These reactions take place in a manner known per se, with the groups known in the chemistry of
 EMI6.4
 sulfonamides.

   Thus it is possible, for example, to condense a p benxiuaeu acid, taaiqus, preferably in the form of its functional reactive acid derivatives, for example a halide or an anhydride
 EMI6.5
 of an acid p.x.badsize..sulxani.que especially the chloride of such an acid, on a compound of formula

 <Desc / Clms Page number 7>

 
 EMI7.1
 in which Z, R1 and R2 have the meaning indicated
 EMI7.2
 below, in which case one can use ion uouolu condensing agents, for example alkali metal carbonates, but especially tertiary organic bases such as pyridine, picoline, lutidine,
 EMI7.3
 oollidinn, deu lower trlalcoylaminea such as trimÓthylumlno or trlethylamine, or dos N # Nl- t6tra-a1 coyl-d iamino-t \ lcuncu for example N, N'-tetramÓthyl-w,

  w '-di olr.iuohcxone, or 1'amine .. pyrimidine proper, and where appropriate the usual diluents such as water, benzene, toluene, methylene chloride, chloroform, methyl.
 EMI7.4
 ethyl <e <5tone, acetone, dioxane, nitrobenzene and the like, or mixtures of such diluents.

   In this case, depending on the conditions chosen for the reaction, for example depending on the condensing agents
 EMI7.5
 heat, normal temperature, diluting them or following the use of an excess of the sulphonyl halide, one obtains as a by-product or as
 EMI7.6
 mainly produced das, p -.- boz5xne-aultunybs compounds which can, in a manner known per se, be converted into the mono-pZ-benzene-oulfonylea compounds, optionally simultaneously with the conversion of Z into an aminogenic group .

   Thus the bis-compounds can, by hydrolysis or aminolysis, where appropriate at the same time as a possible hydrolysis of the

 <Desc / Clms Page number 8>

 remainder Z1, to be transformed into the mono-compounds. @
However, compounds of the formulations can also be made to react with each other.
 EMI8.1
 in which R1, R2 and Z have the meanings $ 'indicated above and Y represents an exchange residue
 EMI8.2
 geable against the p-2-benzene-sultonylaminogen group. 00 The Y radical is, in this case, for example a free or advantageously substituted mercapto group such as an alkylated or benzylated mercapto group, a substituted hydroxy group such as an alkylated hydroxy group, a group.

   
 EMI8.3
 alkylsulphonyl such as methylsulphonyl group, ammonium group or halogen atom. The reaction takes place in the usual way. We go advantageously
 EMI8.4
 from 6-halagna 2-Rl4Rpyrim.dinea, for example from f-chl, orra.2-, i.-4-R.pyrimidinQat or from that do.6- * ammonium'- 2-B1-4-R2-I ) yriniitlineu, for example of that of 6-triaicpyl-ammonium ..- Rl-4 ... Ra-pyrimidinel3, for example of halideo.



  If we start from 6-hellogeno-, -alkyl-aullonyl- or. snmoniumcnm3or; 3 the amide of p-2-ben ™, enēi3ulfonic acid is then used, advantageously in the form. of a metal salt, for example of an alkali metal or alkaline-torrous metal salt, or else one works in
 EMI8.5
 presence of 1 ufl> ntt1 of condensation forming such an oblate 'When using 6-alkyl-aultonyl- or 6. amnoti.fum - Rl.-R-3yrimidinazs, the use of an acid amido , for example a lower alkanoylamide

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 such as acetamide or dimethylformamide, as a diluent has proved to be particularly advantageous.



  The last mentioned processes, starting from 6-halo-, 6-alkyl-sulfonyl- or 6-ammonium-pyrimidines, have the advantage that they can be carried out very well with pZ- acid amides. benzene-sulfonates in which Z represents the free aminogenic group, while in the other processes, Z advantageously represents a Z1 residue allowing the formation of the aminogenic group,
The possible subsequent conversion of the residue Z1 into an aminogenic group takes place in a manner known per se.



   Another method of preparing the new compounds consists of compounds of the formula
 EMI9.1
 in which Z has the meaning indicated and one of the radicals R1 'and: R2' represents a (lower) alkoxy-lower alkyl and the other represents a radical X convertible into a halogen atom, into a. a lower alkoxy residue or a (lower) alkoxy - lower alkoxy residue, to be converted into a halogen atom, a lower alkoxy residue or a (lower) alkoxy - lower alkoxy residue, then, in the compounds obtained which contain the remainder Z1, possibly to be formed *. lomont the aminogenic group in the para position of;

   benzene ring, and / or, if desired, to acylate

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 the compounds obtained on the nitrogen atom N1.



   The remainder X is, for example, a group @ mmo-
 EMI10.1
 nium such as a trialkyl-omonium group which may in a known manner be converted into a lower alkoxy residue or into a lower (lower) alkoxy-lower alkoxy residue.



  This transformation takes place in a customary manner, for example by reaction with lower alkanolates or
 EMI10.2
 on alkoxy (interior) lower alkoxyalkanolates, for example on alkali metal compounds.



   The residue X can also, for example, be a hydroxyl group which can be converted into a halogen atom in a customary manner, for example by treatment with halides of sulfur or phosphorus.
 EMI10.3
 such as phosphorus oxychloride or phosphorus tribromide.



   The remainder R1 is advantageously a remainder
 EMI10.4
 usual in the chemistry of sulfonamides, transformable into an aminogenic group, especially a residue transformable .. into an aminogenic group by reduction or by hydrolysis, Residues transformable into an aminogenic group by
 EMI10.5
 hydrolysis are, for example, acylaminogenic groups, especially aliphatic acylaminogenic groups such as carbalkoxy-aminogenea groups, for example the cQrbethoxy * 8aninogen group, alca, gold ..., aminogen groups such as the propionylaminogen group, le. butyrylaminogenic group or the Capraylwainogzzé group "," but especially the acetylamizzagàné group, dlbalogeno-phosphorylaminogenic groups, for example the dichlarophoaphorylar3.na group;

  gene or methylidene aminogenic groups such as, for example, alkylidene groups

 <Desc / Clms Page number 11>

 
 EMI11.1
 or benzyXJUi ji ¯ttuiInogônuB, especially the isopropylidane-aminogen group or the benz) '11de-aminogen group.



  The ûcyloo suede roetes the BCY} {mnogen groups may aueei be 100 autan acyl dibao1lueo acids.



  It is: 8.1n01 that we can Ógnlomcnt use the starting eubotanoefl donation of formula
 EMI11.2
 
 EMI11.3
 in which R represents the acyl residue of a dibasic acid, especially carbonic acid, or by
 EMI11.4
 example also of a nleune-dicarboxylic acid, and YI # R1 'and R2' have the meanings indicated.
 EMI11.5
 A residue transformable by reduction to an amiuogenic group is, for example, an acylamino group.
 EMI11.6
 gene which can be cleaved by hydrogenolysis, for example the carbobonzoxy-aminogen group or the NO2 group, or an azo group such as an aryl-azo group, especially
 EMI11.7
 a ghny.aLCiuQ group, while in the latter case, in particular, as starting material,

   a compounds of formula

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 EMI12.1
 where Y1, R1 'and R2' have the indicated meanings.



   The hydrolysis, aminolysis or reduction of the groups indicated is carried out in a manner known per se.



   A particularly advantageous procedure consists in reacting p-acetylamino-benzene-sulfonyl chloride with a 6-amino-2-R1-pyrimidine and in hydrolyzing the condensation product.



   The N1-acylation is carried out in a customary manner using acylating agents on the nitrogen atom N1. Such agents are mainly anhydrides or acid halides, for example chlorides.



  The reaction is advantageously carried out in the presence 'of basic agents such as inorganic or organic bases, for example dos carbonates of alkali metals or tertiary amines such as pyridine, picoline, lutidine, collidine, trimethylamine, lu triethylamine, tributylamino or 1,6-bis-dimethylamino-hexane, and in the presence of inert diluents, in particular organic solvents such as dioxane, benzene, toluene, hydrocarbons. halogenated, for example methylene chloride or

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 chloroform, dimethylformamide, lower aliphatic ketones such as acetone or methyl ethyl ketone,

   or where appropriate in the presence of the basic agents proper, such as, for example, pyridine, or of mixtures thereof, for example a mixture of pyridine and acetone. Advantageously, work is carried out in a medium that is as anhydrous as possible. If an acid halide is used, then a metal salt of the aulfonamide can also be used, for example an alkali metal salt or better still the silver salt, so that it is superfluous, as recommended above. above, to add basic agents. However, there is nothing to prevent them from being used in addition, for example as thinners.



   When N1-acylating compounds in which Z is the amino group, care should be taken to ensure that the reaction is carried out under mild conditions using approximately equimolecular amounts of the reaction partners. , in order to prevent the formation of N1, N4-bis-acyl compounds or, by migration of the acyl residue, N4-acyl compounds. Consequently, the work is advantageously carried out at low temperature, for example below 40 ° C., for example between 10 ° C. and 30 ° C., and in an anhydrous medium. When using the acid halides, it is recommended to start from the metal salts of the sulfonamide, for example the silver salt.



   If the acyl residue is introduced into the nitrogen atom N1 of a compound in which Z does not represent an aminogenic group, then preferably one starts with compounds in which Z represents a transforming group.

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 mable to an aminogenic group by reduction. This group is then reduced in a manner known per se, advantageously by avoiding conditions of hydrolysis and high temperatures, in order to prevent a cleavage or a transposition of the Ni-acyl residue on the nitrogen atom N4, II. It is particularly suitable to carry out the reduction with hydrogen in the presence of catalysts, for example catalysts based on noble metals, for example based on palladium on carbon *
In the compounds obtained,

   it is possible, within the framework of the final substances defined at the beginning, to modify substituents in a customary manner or to replace them with hydrogen. Thus it is possible, for example) to replace halogen atoms, for example chlorine or bromine atoms, by interior alkoxy residues or by (lower) alkoxy-lower alkoxy residues, for example by reaction on lower alkanolates or on lower alkoxy) -alkanolates, for example on alkali metal compounds, or alternatively that halogen atoms can be replaced by hydrogen in a customary manner, by example by hydrogenation,

     in the presence of catalysts such as nickel catalysts. *
Depending on the operating conditions and the starting substances chosen, the final substances are obtained in free form or in the form of their salts which also form part of the present invention. As salts, special mention should be made of metal salts, in particular those with alkali metals, with aloalino-earth metals or with metals.

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 earthy, like sodium, potassium, calcium, magnesium or aluminum.

   The salts of the new compounds can, in a manner known per se, be converted into the free compounds, for example by reaction with acidic agents rather than acids themselves. Moreover, the free sulfonamides obtained which have a hydrogen atom on the nitrogen atom N1 can be transformed into their saws, by reaction on bases, in particular on bases which can be used therapeutically such!,; as alkali metal hydroxides,. alkaline earth metals or earth metals, for example on hydroxides of uodium, potassium or calcium.



   These or other salts of the new compounds can also be used for the purification of the sulfonamides obtained, while the free sulfonamides are converted into salts, the said salts are separated and from these they are again put into use. freedom the free aulfonamidee. By reason of the close relationship existing between the new compounds in free form and in the form of straining their salts, it is necessary in the same direction, by free compounds, in what precedes and in what follows, possible- also the corresponding salts.



   . The invention also relates to the embodiments of the process in which one starts from a compound obtained as an intermediate product at any stage of the process and carries out the phases still missing from said process, or interrupts the latter at any one of these. stages, or in which a starting substance is formed under the conditions

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 of the reaction or is used in the salt state.



   For the reactions according to the invention, above all, starting substances are used which provide the preferred compounds which have been mentioned above.



   The starting materials are partly known or may, when they are new, be
 EMI16.1
 obtained according to methods known per se.



  The 2-alkoxy (lower) -aie oyl (lower) * 4-R4-6-R? -Pyrimidines which are used as starting substances, and in which R4 represents an atom. hydrogen, a halogen atom, an alooxy residue
 EMI16.2
 lower or an interior (lower) alkoxy, and R? represents a free hydroxyl, morcapto or aminogen group, or a substituted mercapto group such as an alkyl- or bonzyl-mercapto group, or a halogen atom such that a chlorine or brew atom can be obtained, for example , by reacting alkoxy (interior) -alkene (interior) -orc amidines or their uels with diethyl malonate or diacetonitrile, then, if desired, by transforming, in the compounds obtained, the hydroxy groups. in position 4 and / or 6 in halogen atoms,

     and / or by converting hydroxy groups in position 6 to the mercapto group, and / or by converting halogen atoms in position 6 into free or substituted morcapto groups or into free aminogonal groups, and, where appropriate , by transforming free mercapto groups in position
 EMI16.3
 6 in 3aut..s substituted mercapto, and / or by transforming. into free amino groups free or substituted mercapto groups, and / or by transforming atoms

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 halogen in position 4 to lower alkoxy or inner (lower) alkoxy-inner alkoxy or replacing them with hydrogen.

   ?
The amidines mentioned above are obtained, for example, by converting the corresponding (lower) alkoxy (lower) alkane nitriles into their imido-ethers and by reacting the latter with ammonia.



   The reactions indicated are carried out in a manner known per se, advantageously in the presence of diluents and where appropriate at elevated temperature, and / or in the presence of condensing agents.



   The novel compounds can be used, for example, in the form of pharmaceutical preparations comprising the active ingredient in admixture with a pharmaceutical carrier material, organic or inorganic, solid or liquid, which is suitable for enterais, parenteral or other application. topical. For the formation of this support material, substances which do not react with the new compounds, such as, for example, water, gelatin, lactose, starch, colloidal silicic acid, magnesium stearate, are envisaged. talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petrolatum, cholesterin, or other known excipients.

   Pharmaceutical preparations can. present, for example, in the form of tablets, dragees, onfents, creams, or liquid form in the form of solutions, suspensions or emulsions.



  If necessary, they are sterilized and / or contain

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 auxiliary substances such as agents. conservation, stabilization, stirring or emulsifying agents, salts used to vary the osmotic pressure,

   or tampons. They may still contain other therapeutically valuable substances. The preparations are obtained according to the usual methods *
The new active compounds can, however, also be used as an adjuvant to animal feed substances.

   The invention therefore also relates to animal feed substances or animal feed adjuvants which contain the novel sulfonaaides of the type indicated, in admixture with the usual carrier materials.



   The invention also relates, as new industrial products, to the compounds obtained by carrying out the process defined above.
The invention is described in more detail in the non-limiting examples which follow, in which the temperatures are indicated in degrees centigrade.

   

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EXAMPLE 1 A mixture is heated for 2 hours at 150
 EMI19.1
 19.3 g of 2- (njethoxyraethyl) -4 (6-dichloro-pyrifflidine, 17.2 g of p-nminobcnz6nc-aulfonamide and 13.8 g of anhydrous potassium carbonate, which makes only carbon dioxide of carbon is evolved, producing foam The reaction mixture solidifies on cooling
 EMI19.2
 1 rp om3 of water is added thereto, 6pairs the non-disaffected p-amlho-bentene-sulfonamide and neutralizes the filtrate with concentrated hydrochloric acid, which causes it to precipitate 6- (p-amino-bcn1 .one-aultonamldo) -2- (m6thoX3-, methyl) 4 .chlûropyrimidine of formula
 EMI19.3
   It is purified by boiling with water and recrystallizing from alcohol, then melting 150-151.

   
 EMI19.4
 The .. (raéthaxy raéthy3) 4t6-dichloro pYximtdina used as starting material is prepared as follows t
To 300 car of ethanol, 355 g of
 EMI19.5
 methoxy-ac tonitrile and will pass 00, until saturation, hydrochloric acid dried over concentrated sulfuric acid. The reaction mixture is left to repoc overnight in a cooler at
 EMI19.6
 + 500.

   It is then quickly filtered off and, all eretrioi: t diamond, introduced the hydrochloride (still moistened with ether) of aethQxy-acetl # ino-ethyl ethor in

 <Desc / Clms Page number 20>

 500 cm3 of a 12% ammoniacal solution of ethanol. After shaking for 12 hours, the ammonium chloride which precipitated was filtered off and '' ;. concentrate the filtrate in vacuo to 50. The hydrochloride. methoxyacetamidine crystallizes and melts at 70 after recrystallization from a mixture of ethanol and. ether.



   148 g of this amidine hydrochloride are dissolved in 300 cm3 of methanol, together with 160 g of diethyl malonate; while stirring, a solution of sodium methoxide obtained from 69 g of sodium and 700 cm3 of methanol is added dropwise at 50 over the course of one hour, followed by stirring for 12 hours at this temperature. The reaction mixture is evaporated in vacuo to dryness. The residue is dissolved in hot water and neutralized with glacial acetic acid.

   On cooling it separates in the crystalline form 4,6-dihydroxy-2- (methoxy-methyD-pyrimidine. The substance decomposes at 210
In an oil bath, heated for an hour and a half at 140, 78 g of this compound with? 300 cm3 of phosphorus oxychloride and 101 g of triethylamine. By fractional dintillution, 2- (methoxy-methyl) -4,6-dichloropyrimidine, melting point 41, is obtained directly in pure form.

 <Desc / Clms Page number 21>

 



    'EXAMPLES
In 100 g of nitrobenzene, 35.3
 EMI21.1
 of p-acet, 71 amino-benzene-oulfoxl7l, All 'chloride, while stirring, is introduced to fi0 l 17 # 3 g of 2 (a & thax.



   ethyl) - chlorō6-amlno * pyriinidine | continues to stir for 20 minutes and then passes, at high temperature, 10 g of trimethylamine in the gaseous state.



  After 2 hours, the trimethylamine is removed by adding a pentanormal solution of sodium hydroxide
 EMI21.2
 and heating to a temperature of 100 to 105, .pui, e, saponifies. Nitrobenzene is separated and obtained from the aqueous layer by neutralization with
 EMI21.3
 concentrated hydrochloric acid, 6- (p-amino-benzen. suUfonamido) -2 - () Bethoxy-methyl) -4-chloropyrimidine which is identical to the product prepared in Example 1.



   EXAMPLE 3
 EMI21.4
 In 100 OM3 of pyridine, 10 g of (methaty-th!.) - mf, 6-hyl-acaina pyrimidine and 15 g of p-acetylamino-bonzene-sulfonyl chloride are dissolved. The mixture is maintained for one hour at 90, the filter hot and the cooled filtrate is brought to a pH of 2 to with concentrated hydrochloric acid. The precipitate separated by filtration is heated for two hours at 90-95 with 250 carbons of a binormal solution of sodium hydroxide, filter the filtered solution while hot, treat with activated carbon, then while cooling with ice, adjust ' the pH to a value of 6 with acetic acid
 EMI21.5
 to 50 96.

   6-Cp-amino-banxne-sultonamida) - (mthaxy., '' 'Ethy.j. 4.mthy.-uyrimidino of the formula

 <Desc / Clms Page number 22>

 
 EMI22.1
 
 EMI22.2
 which has form in the crystalline state mows, after recrystallization in a mixture of ethanol and water, at a
 EMI22.3
 temperature of rwc, 7 'ta 2- (n! ethoxy-ethyl) -4-! -cethyl-6-'aainp "pyriaidine used as starting material can be obtained ooame follows
 EMI22.4
 In a solution of 85 g of p "iaethoxy" 'propionitrile, and 60 em3 of ethanol, is passed to 0, until saturation,

   hydrochloric acid Spooned over concentrated sulfuric acid. We separate
 EMI22.5
 by draining the hydrochloride of 0-methoxy-propionimino-ethyl ether which precipitated and introduced it -
 EMI22.6
 still moistened with ether, in 200 cjn3 "of a 16% ammoniacal solution of ethanol, shake the mixture for
 EMI22.7
 12 hours and filtered off ammonium chloride which precipitated, the brine solution is concentrated to 50% vacuum.

   then suspends the crystalline mass with ether and separates by filtration the hydrochloride
 EMI22.8
 of 3methay-prapionamid. melts at 85-86% after rearification in a mixture of ethanol and ether.



   13.8 g of hydrochloride are sprayed together
 EMI22.9
 of p-methoxy-propionamidine and 8j2 g of diaoetonitril $, then heat for 8 hours at 120 with 50 carbons of glacial acetic acid. The precipitate obtained is separated by filtration and crystallized from water *
 EMI22.10
 There is thus obtained 2- (metho3ty-ethyl) -4-methyl- <6-amino-. , pyrimidine mp 254-255.

   

 <Desc / Clms Page number 23>

 
 EMI23.1
 In a similar way to that described here **
 EMI23.2
 above, from p-acetylamino-benzenc-aulfonyl chloride and a- (mthoxy-thyl) -6-amino-, 2. (mdthaxy-cthya) ¯c-chloro-6-araino- yrimidino can be 2. (rndtiaxy-ithyl) -4-mthoxy-6-aaxino pyricidin 'prlmldine of 4 (mcthoacy mthyl) fi-amino-pyritnidihe of 2-chloro..4 ... (ethoxy..mÓthyl) .. G-amino-PYr1midlr18, from 2-mthaxy + - (mthoxy-nsthyl) -6-amino-pyrimidind from, -di (muthoxy-mCthyl) -6-amino-pyrimidina from .methyl - + .- (methoo, y- ethyl) -6-amlna-pyrimidine '' from 2-chloro-4- (mÓthoxY-ôthyl) -6-am1no-pyrimidine or from mthoxy-4 .. (mthoxy-thyl) .6..amino-pyrim.dindx,
 EMI23.3
 get
 EMI23.4
 6- (p-aMino-benKene-sulfonac! ido) -2- (methoxy-ethyl) * pyripidine, 6- (p-anino-benxene-.sulfonamidoj..2 .. (cthoxr.ethyl) ..

   
 EMI23.5
 4-chloro-pyrimidine,
 EMI23.6
 the 6 (p-a.mina-benWne.u: .fonamido) .- 2- (mthoc, y-thyll..



  4-m, thoxy, pyrimidino 6- (p-aNino <-benKene-8Ulfonamido) -4 * - (methoxy-methyl) '"p1riidine, 3.a 6- (p-aminc-benwne.-sulfonamido) -2wchlord + -mbtha. methyD-pyrimidine, 6- (p-abino-benzen-gulfonamido) -2-melhe) xy-4- (meth'oxàr- methyl) -pyrim1dino, 6- (p-arina-.benz.ne . aul.fonaraido) -. 24di (mdthotyw methyl) -pyrimldine, la (ir-amt.no-.benz: ne..nulfonamido) 2-raethyl- - (mthaxr- thy: l) -pyrimidine,

 <Desc / Clms Page number 24>

 
 EMI24.1
 la6- (p-amino <-benzene "sulfonamido) -2-ohloro'-4 - '(Beth <Mcy' '-
 EMI24.2
 ethyD-pyrimidine or
 EMI24.3
 6 - '(p-amino-benzeneaulfonamido) -2-methoxy-4 * (metho9 <y eth3rl) -pyrimidine.
 EMI24.4
 



  EXAMPLE 4
 EMI24.5
 In 100 car of pyridine, 8 g of 2 (mthoer.méthy.) .. 6wami.na-pYr3, midine and 17 g of. ,. p-carbethaxy-amino-benzene-.sulari.y.a chloride
 EMI24.6
 let the mixture sit overnight, filter,
 EMI24.7
 and adjust the filtrate to pH 2-3 with hydrochloric acid (1: 1). After separating the precipitate '' '#. /' 'By filtration, it is heated for one hour. '900 with zocht CM3 of a binormal solution of hydrox'do' ,, * ,, # of sodium.

   Titillate carbon was added to the solution. # '#' ', # hot filter and, while cooling with ice #, precipitates filtrate at pH 5, with 50 acetic acid 6, 6- (pa! nino-b0nzeno-8ulfon <uoido) "\ '#', '' #" 2- (methoxy-raethyl) -pyrimidine of the formula '
 EMI24.8
 
 EMI24.9
 which melts 23V-2380 I1J, crystallization 4ana one, .. mixture of ethanol and water. '* "' 2- (meihoxy-methyl) -6-am1no..pyr1midine". used as a mutiôro de departure can be obtained
 EMI24.10
 as following : . '
 EMI24.11
 In an autoclave, 38 # 6 g of 2- (m6thoxy..methyl) ... J +, 6 are reacted at 800 # for 10 hours. , '.' dichloï'0-pyriaidinc aur 250 om3 of an ammonium solution1'411e "

 <Desc / Clms Page number 25>

 at 12% ethanol. After cooling, the mixture is evaporated to dryness.

   From the residue, we obtain, by
 EMI25.1
 recrystallization from water, 2 (methoxy aethyl) * 4.ch.aro-.amino-.pyxiraidine as a white needle, melting at 102.



   While adding 3 g of a 5% palladium on activated carbon catalyst and 4.4 g of magnesium oxide as a hydrochloric acid acceptor, we
 EMI25.2
 hydrogen bzz g of 2- (methoxy-methyl) -4-chloro-6'-amino-pyrimidine in 250 cm3 of absolute ethanol The catalyst is separated by filtration and the solution evaporated to dryness.



  The residue is taken up in water, neutralized with acetic acid and the solution extracted with chloroform. After having removed the solvent by distillation, the residue is recris * tallized in a mixture of ethyl acetate.
 EMI25.3
 and petroleum ether. In this way 2-CmÓthoxy-methyl) -6-amino-pyrimidine is obtained, melting at 111-112.



   EXAMPLE 5
 EMI25.4
 To 11.7 g of 2. (methoxy.mé thyl) - 4 Cp-methoxyw éthasy) w6.-amina-pyrituidine in solution in 100 om of absolute pyridine, 14.5 g of p- chloride are added in portions. oarbthoxy-um1no-b8nzàne-sultonYl., stir the solution for 72 hours at room temperature, then check it in a mixture of ice and hydrochloric acid while maintaining a pH of 2, which makes
 EMI25.5
 that it precipitates 6-Cp-carbethoxy-amino-benzene-aultanumido) - .. (methoxywmothyl) -4 .. (i-methoxy-thoxy pyrimidine which melts at 105-106. The saponification takes place by boiling for a period of time. hour with 250 cm3 of normal sodium hydroxide solution.

   Through

 <Desc / Clms Page number 26>

      
 EMI26.1
 acidification with acetic acid gac1al, it precipitates. 6- (p-aroino-ben? ene-oulfonanïido) -2 (methoxy-ttétbyl) -4 - (P-methoxy-thoxy) - 'pyri! nidiM of the formula
 EMI26.2
 which melts at 87.
 EMI26.3
 



  2- (methoxy-methyl) '- 4- (P' -! B6thoxy <-ethoxy) <- 6- 'amino-pyrimidine used as starting material is "formed by reacting 19) 3 g of 2-f mdthaxr ..bthy, 4 * chlorō6-omino-pyrimidinô on a solution of 5 g of sodium in 50 carm of glyool * monomethyl ether while heating for 24 hours at 100, then withdrawing the excess other, put the residue in suapenaioa in water, neutralized with acetic acid, separates
 EMI26.4
 by filtration and. rccristallioe in ethyl acetate f mdthaxy methyl) ..- (p.ndthaty..éthaxy) -6 amino pyrimidino well nech6ce It then melts at 1040.



    EXAMPLE 6
 EMI26.5
 In 160 cm3 of a 6.5 benzine solution? of trimethylamine, 17.2 g of 2- (aethox3r * mfth, 1) 4 rdthyl 6chiara-Pyri.ridine are dissolved and left to stand for 5 days. The benzene is then removed by vacuum distillation and 100% of absolute ether is added. ,
 EMI26.6
 The compound of 6 trioethylammonium is removed by filtration and added in 10 minutes at a temperature of 95 to 100% to a melt of 47 g of sodium N4 acetyl sulfanilanide and 48 g of acetamide, heated for another hour and a half at 105 and eliminates

 <Desc / Clms Page number 27>

 acetamide by vacuum distillation.

     We dissolve.
 EMI27.1
 then the residue dnna 100 cm of water, neutralized with glacial acetic acid and alkalinioe with sodium carbonate, left to stand in a cooler overnight, filter off excess N.-actylsulfan.lamide, adjust the filtrate to a pH 4 to 5, which means that it precipitated, after a few hours, the 6- (p-
 EMI27.2
 aaéCylar, ai, zxo-anx m - .; 3u tor: arida) -2-i mt t; haxytn thyl ..4- methyl-pyrimldino which, after recrystallization in water, melts A 194-1qo. With 100 cnr of a binormal solution of odium hydroxide, the acetylated compound is saponified in two hours to 6-iP-.amino-bena; new sultonamido) .. 2 ... (methyloxy-methyl) - 4-methyl-pyrimidine of the formula
 EMI27.3
 
 EMI27.4
 which precipitates after neutralization with acetic acid.



  -MZthoxy.thyl) .c-mcthyl-6ahlarQ :. pyrimidine used as a starting material is prepared as follows:
With 34.5 g of sodium in 200 car of methanol.
 EMI27.5
 62 g of the methoxy-ac6tnmidine hydrochloride which is described in Example 1 are condensed with 65% of ethyl acetate, with heating for 8 hours at 50.



  The methanol is removed by distillation, the residue dissolved in water, neutralized with acetic acid and the solution then evaporated to dryness. We extract the residue
 EMI27.6
 with ether after having it well 84çheo We recr1otallil8.

 <Desc / Clms Page number 28>

 
 EMI28.1
 in ether la. (mfth, oxymthyl., 4rmeth, Yl.-tdroxy, pyrimidine obtained. It then melts at 103.



     Was heated for two hours at 140, in an oil bath, 38.5 g of this composition with 150 cm3
 EMI28.2
 of phosphorus oxychloride and 25 g of triethylamin.



  We. removes phosphorus oxychloride by vacuum distillation, introduces the residue into ammoniacal water, ice-cold and then extracts by shaking with chloride
 EMI28.3
 of. methylono. 2- (methojcy "methyl) -4-methyl-6-chlora-pyriaidine, boiling at 730 soma, is obtained by distillation, a proof of 0.6 mm of mercury.



    EXAMPLE 7
To a mixture of 20.0 g of sulfanilamide, 20.0 g of acetamide and 16 g of anhydrous potassium carbonate is added dropwise at 130, with stirring,
 EMI28.4
 bzz0 g of 2-.methyl ... +. (uiëthcxy-mthylip6-ahloxo.pyxim.d3.te. The mixture is heated for 4 hours at 1400 and then cooled, then 100 cm3 of water are added. The mixture is separated by filtration.
 EMI28.5
 precipitate which forms 1.1 'Ht and adds binormal hydrochloric acid to the filtrate until it has a pH of 6 to 7. After a ropo s of some time, it forms a precipitate which is separated by filtration and stirred
 EMI28.6
 avoc 100 cm3 of water z? 0-800. The insoluble fraction is recrystallized from alcohol.

   We thus obtain 6 (ri-rminabsnre-: 7ul, Canamida) -2-m3thyl-4 .. (tathoxy methyl) -PY1.tmidin ±> do formula

 <Desc / Clms Page number 29>

 
 EMI29.1
 we form the crystals melting at 187-190.
 EMI29.2
 The 2mtby .- + (methoxy-methy..6ohlarapyrimidine used as starting material can be prepared as follows:
To a solution of 2.2 g of sodium in 50 car of absolute alcohol, 5.0 g of hydrochloride is added
 EMI29.3
 acetamidine and stir for 15 minutes at room temperature. A total of 8.0 g of ethyl ²-methoxy-acetylacetate is then added and the mixture is heated for 4 hours at the boil. The solution is then evaporated in vacuo. There remains a solid residue which is made, boiled with 100 cm3 of methylene chloride.

   After evaporation of the solvent, the crystalline 2-methyl-4- (methoxy-. Methyl) -6-hydroxy-pyrimidine remains which, after sublimation, melts at 173-174.



     10.0 g of hydroxy-pyrimidine 'coats are introduced into 100 cm3 of phosphorus oxychloride. After addition
 EMI29.4
 5.0 g of dimethylanilino, stirred for 4 hours at room temperature and then evaporated in vacuo, the residue is dissolved in 100 cm3 of methylene chloride and the solution is poured into a cold 3% solution of hydroxide. ammonium. After shaking well, the organic phase is separated, dried over sodium sulphate and the solvent is removed by distillation. By distilling the residue, 2-methyl-4- (methoxy-

 <Desc / Clms Page number 30>

 
 EMI30.1
 m <! thyJL) <. 6-chior <pyrI) î'iaine which boils at 9fJloo -oub:; /,, 'a pressure of 11 Mn of mercury in 10.

   CM3 deacdt-one and i3 from PYrlül, te.,. we put in euisperittlon 5 * 4 g ue 6- (p> ûmlno b # nzbn 8ul.fon * miclo) .2. (m # ttioxy-mdthyl) -4-mdthoxympyrimldlne * We added. enaulte got4tte-h-goiitte during z10 minute * 2.3 t! '. of anhy <it'id '! mcdtiquoj, pglt #, losing 5 hours do more and laiûao still rest for 2 days, which makes,>, that it precipitates a white product After addition of 2ô cm3 of a 'Holution of nrcxmntscue 2 * 3% in r4t 'ro, alAl; nant with ice, we oeaoro quickly and the pn obtains the I1 aatyl ... (p..aino..bnxneaulro $ mido'j - .. (rathoxx. ', rnfchyl) "- 4-methoxy î) yrimidine of rormula
 EMI30.2
 
 EMI30.3
 which, zpr2s, rr.itt, llisatlcn in de, ethonal, melts at $ i7B¯i7. -. '#' '# ";

   ta 6 * (p - &! nino-bcnz'np-8ulfonMtldo) "g- (m <tho '' '\ t. methyl) -4 * methoxy-pyrln4.dino used as starting material ..., starting, little Ûtru prepared as follows ,,. ## - '. ## In autoclave * dissolve in 150 otn3 of' # / mthxna., 11, '2 g of 2. (mthaxymhyl) .. 4.ohlarawG. Tnito, ,, '. pyrit41n ", pui, adds to the whole 3,0,8 of Methyte d; z, aacliu, 'au by shaking it, the mixture is maintained. '/ ,! . for 10 hours at 120 and then evaporated to eeo

 <Desc / Clms Page number 31>

 
 EMI31.1
 aproa cooling. Mthoxymcthylfnmirit31 tndthoxy-pyrlmidine t'oria h 95 940, a solution of 6, 'jg of É m; thoxy1 (t61.3y1w ,, rnthsxycj.avminc7hyrimicftr: c ditnsi 75 cm' 'of pyridlne # is added, seen shaking, to the course of timed bzz, 13 g of per.; tylr3mttTCS-tr <c; rtrtc, .aulfonyl chloride. After ofSHtion <1 <- In reaction, one for one hour '900.

   On 1, J @ itc ccui t, e 75 () om 3 of water and, while re r O 1 d 1 e L il nt the lact, adjust the fold to a value of about 'CI and% adding of concentrated hydrochloric acid, the precipitate formed is boiled for 2 hcu: 'cs {tv'c f, 0ü cm i 3a binormalo solution of hydro-
 EMI31.2
 sodium xide, separates the alkaline solution by
 EMI31.3
 filtration and neutralize the still hot filtrate with 1 ml concentrated hydrochloric acid. Ln (ptmin4 .. bpnzbnc'-nulfonamldo) -2 - () * ithoxy-n) thyl) 4-m 5thoxy- pyrimidino which would have formed * ne utr) are then in crystalline form Al) t, bLi recriijttillization in de alcohol, it melts h 1 d..l + 0.



  KXKMPLE 9.



  Datie 200 cm 'of pyrldliie, gold. diosout 18.3 g of 2wmêLtaoxyrr; thyl) -étt.nxy - amino..pYrimidl3e, add in portions 29 g of p-oarbethoxyx amino benxne-sult'onyl chloride, stir the mixture for 48
 EMI31.4
 hours at room temperature, then pour into
 EMI31.5
 ice water and adjust the fold to about 2 per adri-
 EMI31.6
 tion of concentrated hydrochloric acid. We separate. the

 <Desc / Clms Page number 32>

 precipitates by spinning, boils for one hour with 500 carbs of a normal hydroxide solution
 EMI32.1
 sodium,, treats the hot solution with activated carbon $ filter and, while cooling with ice,
 EMI32.2
 PH gate to a value of 5 # 5 to 6 with acetic acid.

   It precipitates under crystalline volume 6- (p- x, no-benxneweult'onamido2 (m6thaxy-metll) .4-etb, lsr, pyrimidine of formula
 EMI32.3
 who mows. 144-145.
 EMI32.4
 



  The 2- (etho3cy-ffleth3rl) -4 ethoxy-e ftaino- pyrialdiae used as a starting material is prepared as follows
Has sodium ethoxide solution obtained
 EMI32.5
 from 4.6 g of sodium in 100% 3 ethanol, 17.7 g of 2- (nethoxy-aethyl) - 4 chloro 6-tain-pyrimidine are added and the mixture is stirred for 10 hours at 600. Oven completely separate the eel of nodiumi pass carbon dioxide and add 50 cm3
 EMI32.6
 4ther absolute, separate the sol by filtration and evaporate the filtrate 'to dryness. The 2- (métboX1.m'th11) ,. 'tho-6.am1no pyrimidine of formula
 EMI32.7
 
 EMI32.8
 hit at 996 apr6. recr1stallisat1on 4ana the carbon t'tr.ob1o.

 <Desc / Clms Page number 33>

 



    EXAMPLE 10
 EMI33.1
 To a solution of 19 $ 7 S of 2 - (. 'Tbo²7..4tbJl) JI 4-i80prQPoX7-6-am! No-P1rimid1n8 in 250 * 5 of p, absolute r1diQI, we add in portions 29 th of ôhlorutfe of p-carb6thoxy-amino-bonsene-sultonyl and stirred for 12 hours. Room temperature. The solution is then poured into a mixture of ice and hydrochloric acid.
 EMI33.2
 funny # of dead that the pH remains around 2. The precipitate is filtered off and saponified for one hour at 90 ° C with 500 carbons of normal sodium hydroxide solution.

   By adding acetic acid, we obtain
 EMI33.3
 6 - '(p-amino-benzene-'8ul <onaaido) -2 *' (Nethoxy-aethyl) - 4-isopropoxy-pyrimidîne of the formula
 EMI33.4
 
 EMI33.5
 which melts at 166 ° after recrystallization from 1 .. 'thanol.



  The 2 - (! Nethoxy-mothyl) -4-iBopropoxy * '6-amino-pyrimidine used as the starting material is formed by reacting for 24 hours * 170) 1 of 2- (Zdthoxy- in a solution
 EMI33.6
 sodium inopropylate obtained from 4.6 g of sodium and 200 car doloopropacol at 606. The compound of formula

 <Desc / Clms Page number 34>

 
 EMI34.1
 
 EMI34.2
 melts at 64 * after reeristalllsatlon in benzene * EXAMPLE 11 DaM a solution of 1803e of 2 * (ethexy, w4thyl) '- 4- <tethoxy *' 6- <mino-pyri <idiM in & 90 on> of absolute pyridine on add per serving $ 29 <! p-c rbethoxy-amino-i9en ** nt-ittlfOBgrl chloride, continue to stir for 24 hours at room temperature # then vorae the solution in a mixture of ice and hydrochloric acid,

   in such a way that the pH drops to around 2 and the temperature below 10. The precipitate separated by filtration is heated for one hour at 90 ° C. with 500 carbons of normal sodium hydroxide solution, finally with the addition of activated carbon.

   After filtration,.
 EMI34.3
 it is acidified with crystallizable acetic acid r '. ; while cooling with ice, so that it
 EMI34.4
 precipitates 6- (p-amino-benzenesulfonamido) -2- (ethyl) * 4-methoxy-pyrimidine of the formula
 EMI34.5
 which melts at 154.

 <Desc / Clms Page number 35>

 
 EMI35.1
 2w (ëthaxywméthrl .réthox..faamin-lxipid, only used as a starting material can be prepared as follows:
 EMI35.2
 Hydrochloric acid, dried over concentrated sulfuric acid, is passed to saturation in a solution of lu g of ethar,., Cbtani trile and 69 g of ethanol.

   After having separated by
 EMI35.3
 dewatering the hydrochloride of ethoxy-acetiailnoethyl ether is introduced into 600 cm3 of a 12% ammoniacal solution of ethanol, shakes the mixture for 12 hours $ separates by filtration the ammonium chloride which has precipitated and concentrate the filtrate to 50. The crystalline mass is then suspended with ether and separated by suction.
 EMI35.4
 



  95 of this 6thoX1-aaetataidiae hydrochloride is introduced into a sodium methoxide solution obtained from 4.5 g of sodium and 800 car of methanol. 110 g of diethyl malonate are added dropwise at room temperature and heated for 16 hours at 60. The mixture is evaporated to dryness and taken up in water. By neutralizing with
 EMI35.5
 of glacial acetic acid it precipitates 2- (etho: ty-methyl) .4,6-dihydroxy-pyrimidine which melts at 2199 on decomposition.



   68 g of this compound are chlorinated with 300 cm3
 EMI35.6
 of phosphorus oxychloride and 110 because of triethylamin Zn fractionating, we obtain 2- (ethoxy-methyl) -4.6 dichloro-pyrimidine boiling at 49 soue a pressure of 0.03 mm of mercury.



   54.9 g of this compound are heated for 10

 <Desc / Clms Page number 36>

 
 EMI36.1
 collision $ in autoclave at 700 with 200,033 approximately 41 imouîa * liquid. After changing the unaoniac, the residue is reoriifcaiiite in water. The 2 <'(ethoxy-eetayl) -4 <' 6MeM'-6-amino-pyriaidiae shears at 117'-118% 44.8 g of this pyriaidin are heated for 24 hours at 50 'with a solution of aadi Nthyltte. , u. obtained at pMt of Il 8 de ecdiua dam 900 0 & 3 de mbtao., We follow neutrality! with MQtMt acid, evaporated to dryness # ce suspended in water and recriatalline the residue in carbon tetrachloride.

   We thus obtain 2- (fthoxyaetlax.) .., .. methoxy '* 6 "Mtino-'pyria! Idine melting z 10.',,,
 EMI36.2
 EXAMPLE 12
 EMI36.3
 To a solution of 13 # 9 g of 2¯ (methoxymett) lyl) -6-ttinino-pyrimidine in 100 enr of pyridine is added in portions, to 50 ', 24 g of / p-nitrobenzene-oulfonyl chloride . After stirring for 48 hours, the precipitate is separated by filtration, the filtrate on the back side on ice and the pE is adjusted to
 EMI36.4
 a value of 2 to 3 with concentrated hydrochloric acid. It is hydrogenated with nickel
 EMI36.5
 Ranoy in an alkaline mixture of ethanol and water * Or
 EMI36.6
 separates the catalyst by filtration and concentrates
 EMI36.7
 the filtrate so that it precipitates the 6 .. (p..a, aaânnd benzno-6Ulfonaioido) -2- (methoxy-aet: hyl) * pyriaidine.



  This mows at 237-2380 after crystallization from a mixture of ethanol and water.

 <Desc / Clms Page number 37>

 



    EXAMPLE 13
 EMI37.1
 To a molten test of 17.2 1 d..utaD1..1A., 14 g of anhydrous potassium carbonate and 7 # 5 9 dfacetamid, and 1001 c of 2.4- are added at $ 115 per portion. dl- (metfaoxy-methyl) -6-chloro-pyrimidine. When the gaiiux release is "} 8ift ', one eeatiam of ifitep for a further shock, 1") 1'1.114 dates 100 ef of water and treats the solution to 90 with activated carbon The pH of the filtered solution is adjusted to a value of 8
 EMI37.2
 to about 8.2, causing excess sultanilamide to precipitate on cooling. It is separated by filtration.

   By neutralizing the solution, it precipitates
 EMI37.3
 6- (p-araino-oenaene-aulf onaaido) -2, 4¯dī (ajethoxymethyl) -pyrimidine of the formula
 EMI37.4
 
 EMI37.5
 which melts at 125-126 after reoriotallation in a mixture of ethanol and water.



  2,4..d1 .. (mâthoy-métb, r,) .. bah3rap'xim.d.a used as starting material can be prepared as follows
 EMI37.6
 13 g of methoxyac'tam141n are added to a solution of 5.9% of potassium in 100% of absolute ethanol. in 100 om3 of absolute ethanol and 20 g of 0-cito-y-methox, ethyl y-butyrate, then refluxed for 4 hours. The solvent is removed by distillation, the residue is taken up in water, neutralized

 <Desc / Clms Page number 38>

 and extracting the solution with methylene chloride. The solution is dried, and it. remainder, after removal of the
 EMI38.1
 Methylene chloride by distillation, 2 # 4-di- (it4thoxy.



   etbyl) 6 hydroxy-pyri idine which melts at 98 * 990 after recrystallization in dan. ethyl acetate.
 EMI38.2
 



  15 B of this compound is chlorinated with Iloula phosphorus chloride by adding tr1'th71a1ne, the phosphorus oxychloride is removed by distillation, the residue on ice, neutralized with ammonia and extracted with methylene chloride. *   We
 EMI38.3
 splits the .olutlo86ch'o. 2,4-d1 - (. 'TboX7- .6th11) -6-chloro-P1rimid1 boils at 17-78, "all at 0.15 mm Hg."



  EXAMPLE 14
 EMI38.4
 mmmmmmmmmm 4 A metoulgo of 1800 e of suitatiluide 1 do 18.0 g of acetamide and 15 g of anhydrous potassium carbonate, one adds dropwise to 1000 while stirring, 9.0 g of 4- (m6tboX1-meth11) -6-chloro-PTria11n't After 4 hours, cool and add 100 car of water. The precipitate which has formed is separated by filtration and binormal hydrochloric acid is added to the filtrate until a pH value of 6 to 7 is obtained. After some time a mixture is formed. precipitate
 EMI38.5
 which is crystallized in alcohol.

   We obtain 6- (p-am1no-benz ne-cultoDam1do) -I + - (m'thoX1-c'th11) - pyrimidine of formula
 EMI38.6
 

 <Desc / Clms Page number 39>

 
 EMI39.1
 At a melting point the strength of crystals <207-209 * 'The 4- (methoxy-mothyl) -6-chl6ro-py!' ieidiM used as starting material can be prepared as follows
To a solution of 4.7 g of sodium in 200 cm3 of alcohol, 10.4 g of forat * midin acetate and 16.4 g of ethyl -methoxy-acetylaoetate are added.



    Stirred for 10 hours at 50, the precipitate formed is filtered off and the filtrate evaporated to dryness.



    The residue is dissolved in water and the solution neutralized by adding binormal hydrochloric acid. Evaporated to aec. A residue remains which is boiled with methylene chloride. The extract is dried and evaporated. Little is added to the residue
 EMI39.2
 acetone, whereupon the 4 <.hydroxy "() & ethoxy <'Bethyl) pyrimidine precipitates out to form crystals melting at 155.



   8 g of the above compound are stirred for 10 hours at room temperature with 50 µg of phosphorus oxychloride, after adding 3 g of triethylamine. Then evaporated in vacuo, the residue dissolved in methylene chloride and poured onto 3% ammonia. The methylene chloride solution is evaporated off. By distillation, 4-chloro-
 EMI39.3
 6. f mdtharmethl-pyrisnidine which boils 90-93 * under a pressure of 12 mm of mercury.


    

Claims (1)

EMI40.1 e v e n d 1 a, t 1 n fi -. '. '#,' '' I, - A process for preparing dQ 6 <. (P'-nlno ", '.benzn6-8Ulfonamido) -pyritnldine8 of formula #': \; EMI40.2 EMI40.3 in which one of the residues R. and Ra represents a .. # - '' * remain alca, xy (inside), lcoyllqu, a lower and the other 'represents an atony of hydrogbnel, an atom of ihnlonp , .., 4, a lower alkyl residue, a lower alkoxy residue * an iilroxy (itifilieiii,) - lower tilcoyli4ue route or uH. 'remainder {j.lcoxy (infërieur) -alkoxy lower and leUr ddfivda N -acyldu, except for 6- (p * aiîiino * <benxhne-au.i'prmido)? - (mthoxy-mt, hyl ) -4..m ° thoXypyri. midine, said, proceed? t, ar4 aract: driaé by the fact. EMI40.4 that we react a compound of formula EMI40.5 EMI40.6 on a compound of Ot ": IU LC ' EMI40.7 EMI40.8 where Y and Yi are (tue i-, zitc ,: 3 can be split, cir3,, of, the reaction by abandoning the immune group N1i, contained in one of them?> Represents the amind- g group,> ne or a; u2,:, t, tt, u ; mL N allowing the formation of the rmtco group; rrr, t Ri and R2 have aignifloation; ln (ilqu! e, or else qu (itiiil a compound of formula, <Desc / Clms Page number 41> EMI41.1 in which Z has the meaning indicated and one of the radicals R1 'and R2' represents a (lower) alkoxy-lower alooyl radical and the other represents an X radical convertible into a halogen atom, into an alkoxy radical lower or into a (lower) alkoxy - lower alkoxy residue, this residue X is converted into a halogen atom, into a lower alkoxy residue or into a (lower) alkoxy-lower alkoxy residue and that, in the compounds obtained containing the Z1 residue, the aminogenic group is formed in the para position of the benzene ring, and / or the bis-p-benzene-sulfonyl compounds obtained are split into the mono-pZ-benzene-sulfonyl compounds, or if it is necessary and / or, if desired /, that the compounds obtained be acylated to the nitrogen atom N1 and / or that in compounds obtained as part of the final substances, substituents or them are modified replaces with hydrogen, and / or that the free compounds obtained are converted into their salts or that the salts are converted into the free compounds. The present process can be further characterized by the following points: 1) Starting substances of the formulas (II) and (III) indicated under I.-, in which Y is an aminogenic group and -80-Y-, is used. a functionally modified reactive sulfonic group, in particular a sulfonyl halide group. <Desc / Clms Page number 42> 2) Starting substances from EMI42.1 formulas 01) and M) indicated August I. **, in which Y is an aminogenic group and Y is a chlorine atom. 3) The reaction is carried out in the presence of a condensing agent. 4) We use starting substances of formulated (II) and (EU) indicated to us I.-, in which. Y represents a residue exchangeable against the group p-Z- EMI42.2 benz6ne '<' 8ulfonylMinogen and Y1 represents the aminogenic group. 5) Starting substances from EMI42.3 formulated (II) and (III) indicated all 1, *, in which Y represents a free or substituted tnazrcapto group or an alkylated hydroxyl group. 6) Starting substances of $ EMI42.4 formulas (II) and (III) given to us I.-, in which Y represents a halogen atom and Y represents the aminogenic group, 7) Starting substances from EMI42.5 .o; rudat ati indicated under 16-j 4 & nf les that Y represents an atuaoniua group OR a 9140yl * Bulfonyl group, and Y, represents the aminogenic group 8) We use starting substances of formulas (II) and (III) indicated under I.-, in which Y represents a chlorine atom and Y1 represents the EMI42.6 tUBinogenic group. 9) Starting substances of the formulas (II) and (III) indicated under 1 .., where h represents a trialkyl-amaonlua group and Y represents the aminogenic group, are used. <Desc / Clms Page number 43> 10) The reaction is carried out using a metal salt of p-2-benzene-sulfonamide or in the presence of condensing agents giving rise to the formation of such. 11) The reaction is carried out in the presence of an acid amide. 12) We use the starting substances of the formula (IV) indicated under I.-, in which X is an ammonium group, and convert this, by reaction with a lower alkanolate or with a lower alkoxy - lower alkanolate into a lower alkoxy group or into a (lower) alkoxy-lower alkoxy group, or part of compounds in which X represents a hydroxyl group, and converts this into a halogen atom. 13) Starting substances of the formulas indicated noua I.-, in which Z is a residue convertible into an amino group by reduction or by hydrolysis, are used. 14) The starting point is a compound in which Z is an acylaminogenic residue or a methylidene-aminogenic group. 15) We start with compounds in which Z is a carbobenzoxy-aminogen group or an NO2 group or an azo group. 16) We start with compounds in which represents the acetylaminogen group or the NO2 group. 17) Is acetylated on the nitrogen atom N1, in a manner known per se 6- (p-Z2-benzene-sulfonamido) - 2-R1-4-R2-pyrimidines, in which Z2 represents the aminogenic group or a residue that can be transformed into such <Desc / Clms Page number 44> group by reduction, and R1 and R2 have the meanings indicated under I.- 'and, in the compound obtained comprising a residue Z2 convertible into the aminogenic group, said annuity is converted by reduction into the free aminogenic group. 18) Acid halide or acid anhydride is used. 19) As an acylating agent, an acetylating agent is used. 20) In the compounds obtained, in which R1 or R2 represents a halogen atom, this halogen atom is exchanged, by subsequent reaction on a lower aloanolate or on a lower alkoxy - lower alkanolate, against a group lower alooxy 'or against a (lower) alkoxy-lower alkoxy group, or it is replaced by hydrogen by hydrogenation 21) Starting from a compound obtained as an intermediate product at any stage of the process and carrying out. : the still missing phases of said preceding, or interrupts the latter at any of its stages, or forms a starting substance under the conditions of the reaction or uses it in the form of salts 22) Compounds of formula EMI44.1 or formula <Desc / Clms Page number 45> EMI45.1 EMI45.2 in which R 5 and R6 represent lower resteei 'alooyiiquee and n is a number equal to the unit / to> 2 or to 2 # in free form or in the form of their d. $ 9t $ au of their derivatives N I- acylt,: 8 * with the exception of the 6 "(p '' aminobaxxre sultonamidcy -2w (mthaxy-methyl methoxy EMI45.3 pyrimidine ... EMI45.4 23) We prepare to derive Nl-aoylea from 6 * (p- arnina.banzina uult'anam.do j 2- (methoxy mthyl) -4rtihoxy EMI45.5 pyrimidine, EMI45.6 1 .. As new industrial products EMI45.7 24) The compounds obtained by the implementation EMI45.8 of the process defined in 1, - and 1) & 23), 25) The 6 (p ^ aminowbanxéna suli'onamido.pyrim, w ",, EMI45.9 EMI45.10 in which one of the radicals R, and RZ represents a lower aleaxyiiri'ricur) a2cny, ic residue and the other represents a hydron atom, a halogen atom * a lower ulcyl residue, a lower alooxy residue, a residue lower alkoxy (lnfërifjur) -alooyl or a refute alkoxy (infér'1 ±.: ur) ,,!, lower lcoxy, except for (paminobanxën: uuli'onamido) 2rt {mthoxywmtbyl j '4-methoxy-pyrimidine . EMI45.11 26) Formula compounds <Desc / Clms Page number 46> EMI46.1 EMI46.2 in which R5 ot, R6 ropr6autnt don remains. aloo, l1q, 8. lower ** and n are equal to unity, to 2 or k3 .. and their derivatives Nl ", acyléa, z except for the 6. (p..am1nÓ.benz'n" '"8ulfonamldiô) 8- (mdthoxy-methyl) -4-fflethoxy pyrimidint 27) b- (p-am1no.bcnzbno..ultonam1do) .2. (MethoXy-methyl) -4-chlQro-pyrlmldlneo .. , 28) 6- (p''aino '') nne''8ulfonMnido) '' 2- (methoxy¯ethyl) -4-m <Hethyl pyrimidine * 29), La 6 .. (p-amlno-hcnd: nè-uulronam1do) .. e .. (methg, xy-methyl) -pyrlmidine. 30) La 6 .. (p-amlno-bcn% l: ne-e'ulfonamldo) -2- ', (rr, ethoxy..môthyl) ..4 ... (B-methQx.r..ethoxy) -pyrimidine. -31) The 6 .. (p-amino..bcnzne..sultQnamldo). (methoxy-methyl) .. 4-methyl-pyrimidine. 32) 6 * (p-aMno benz ± ne-aulfonainldo) * 2 methyl..4- (methoxy..methyl) .pyrimltt1ne. 33) 6- (p amtno-b nzene * attifonamidô) * 2f4 di (methoxy..methyl) ... pyr1midine. ',. "34) The new suitonamides indicate aouw. EMI46.3 25) 33) in free form. <Desc / Clms Page number 47> 35) New sulfonamides shown here EMI47.1 25) a 33) 4oua Id shape of their 6010 .. 56 Private Lan Ni..neyirs of the compensations indicated under and 27) to 3.). zaza La ML-'nctyJ * '6- (p-amino *' benzno-sulfonMtldo) '- 2 * (ffldthoxy-w 5thyl) - mt5thoxy-jiyrimidlne, z58) La <> 1 (p nmlno beni5ene' Uulfon {unido ) 2 '(methoxy ... meibyl) ..4..tt} lOxy ",,' y ri mi d 1ne, bzz) i4li <- (p-cmina.bonxétmi-culfonamidg) 2, (methoxy ... methyl ) lj ..1stJpropoxy ... pyrlm1dine ... '40) La E'> - (1-aminoben.nc .. ±; ül.Ponamido) -2 '(ethoxy-methyi) "4-m Khoxy pyrimidine. 41) The c;> - (patnino-bettx2sneulfonamido) 4. (methoxf "mthYl)" pY1 "1m.1 dl11 <:. 48) The:, ulfonam1: hJ8 indicated under 38) to, l), in free form. EMI47.2 '4; 3) The uulfonMl1dea Indicate noua} 8) h 41),,! '.' in the form of their 80ls, 44) of the N-acylated derivatives of the compounds indicated. 'under .38) to. 41) < 45) Pharmaceutical preparations comprising, together with a pharmaceutical carrier material, compounds of the kind indicated under 25) to 36). 46) Food substances for EMI47.3 Animals and Animal Feed Adjuvants containing compounds of the kind indicated under 25) to 36). <Desc / Clms Page number 48> EMI48.1 47) Such pharmaceutical preparations contain, together with a carrier material ph rnj # ceutiquoe compounds of the genus of those indicated 6oUs (J7). 44). '. 48) Foodstuffs for animals and additives to animal feed. which contain compounds of the type indicated under 37) 4 44), EMI48.2 49) Los compounds of formula EMI48.3 EMI48.4 wherein one of the radicals R, and Ru represents an alkoxy (1nt'h, 1t \ ul ') .. lower alooyliquu route and the other represents a iktydroEtne atom, a halogen atom, a lower aloyllic reete, a lower alkoxy residue,, an ulcoxy residue (inl '' ': f'icur) ..alkyliquf.' lower or lower alkoxy (tni'él'lùr) .. lower o.lt.1oxy; and Z, .repr- areo a recto tr! \ lwfo} 'mnbl0 one aminogenic group by EMI48.5 hydrolysis or reduction * EMI48.6 go) Le :, blu- (p-Z-bcnzèno-oulfonyl) -6 ùinino ..I; 1 .- .. I; .. pyz.irrl <iinc.u in which one of the reatus Rl and H? roprt4i; cnto alooxy (lower) - alooy, lower l1QUC and the other represents a hydrogen atom, a halogen atom, a lower alooxy t-egte, a lower alkoxy route, a rem <! 111coXY (1nfdri l: lr) ... 'alcoy1tqul' i n1'o t'l NIl 'Oll un l'catt3 alooxy (1 nfer1eul') .. lower alkoxy, and Z represents an amino residue on <Desc / Clms Page number 49> EMI49.1 a residue which can be transformed into an aminogenic group by hydrolje EMI49.2 or reduction. 51) The *? pyrimidines of the formula EMI49.3 EMI49.4 in which one of the radicals R. and B2 represents a lower alkoxy (lower) alkyl radical and the other represents a hydrogen atom, an atom, of lhglogen., EMI49.5 a lower alkyl residue, a lower alooxy residue, EMI49.6 an aloaxy (1ni'éri, e, r) .e, T.coyT, ique residue or a alkoxy (.nferier) -lower alkoxy, 91 '. represents a free hydroxyl group, a free meroapto group or an aminoskne group, an alkoxy group, an ammonium group, a halogen atom or an alkyl r3uli'onyl group. 52) The 6. (Pacftyl.cmin4benzéneeuli'onamido) - EMI49.7 pyrimidines EMI49.8 a3) Ia 6 (p acetylftmino ben? <fene-8Ulfanamido) "2 (mthaxy-thyl â -4 mt, hyi-yrimidinQ, 54) La 6 (p¯carbethoxy-aminobenzene Bulfonamido) 2 (methcxywtnthyli.nayritnict. 55) La 6 * (pc rb <5thoxy¯amino-ben2èrie '8ulfonaniido) - 2- (methoxy methyl) -4- (f.> ¯mdthoxy ethoxy) -pyrirtidine La 6- (p-ae! 6tylamJno "bonzbne' ' sulfonamido) - 2 (methoxy "n] <f'thyl) -4-methyl-pyrlmidine, 5) La 6- (p.cfrbethoxy-amino.benxnQ-suli'ona midcr) ..2. (r hoxy-me: hy 1) -t-ethoxy-pyx, imidine; EMI49.9 <Desc / Clms Page number 50> EMI50.1 58) La 6 (p. Aurbdthaxy-amirio benxneaui, fan mido) '- S "(n) ethoxy''methyl)' '4-j.sopfOpoxy-'pyrin) id.inet 59) e 6- (p-oarbethoxy -amino-bena5ne aulfona mi da - (é thaxy wmdhyl) 4m6thaxy pyrimi di nv. 60) ta G .. (p ni trobanxna-aulfanamido} 2 (methoxy-mdthyl) -pyrlmldlne, 6l) La 5 {p acdylamirtowbenxônc sult anonavmidow 2 (methoxy mttyl} #. Mthaxypyrimidine. 6,! P) 6- (p-nitrobenzene-sultonamido) * - 2-o {methoxy mthyv} .... methoxypyrimldine. gas) Chloride of 6 (p-aminapbenxèra buaiaw namida} w (mthaxy-méhyt} - {trim6thyl emman3um) pyrîmldlne4 64) Los new pyrimidines described in the exampleiso with the exception of 6- (p <' amino-benzen <'<* sulfonm.dn) .2 {mthaxy-mdthyl ù-mdthaxt-pyrimidi.a.