CA1242198A - Process for the preparation of 2-substituted-5- nitroso-4,6-diaminopyrimidines - Google Patents
Process for the preparation of 2-substituted-5- nitroso-4,6-diaminopyrimidinesInfo
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- CA1242198A CA1242198A CA000524438A CA524438A CA1242198A CA 1242198 A CA1242198 A CA 1242198A CA 000524438 A CA000524438 A CA 000524438A CA 524438 A CA524438 A CA 524438A CA 1242198 A CA1242198 A CA 1242198A
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- salt
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- amidine
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- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
-
- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A process is disclosed for the preparation of 2-substituted-5-nitroso-4,6-diaminopyrimidines of the general formula:
in which R represents aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl, which comprises reacting malonic acid dinitrile with an amidine of the general formula:
A process is disclosed for the preparation of 2-substituted-5-nitroso-4,6-diaminopyrimidines of the general formula:
in which R represents aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl, which comprises reacting malonic acid dinitrile with an amidine of the general formula:
Description
This invention relates to a process or the preparation oE 2-substituted-5-nitroso-4~6-diaminopyrimidines.
It is known that 5-ni-troso-2,4,6-triaminopyrimidines can be prepared from malonic acid dini-trile and a guanidine salt. Thus, condensa-tion oE malonic acid dini-trile and guanidine hydrochloride or nitrate in -the presence of sodium alcoholate in alcoholic solution gives 2,4,6-triaminopyrimidine in high yield [W. Traube, Ber. 37, 4544 (1904); Il. Sato et al. J. Chem. Soc. Japan Pure Chem. Sect. 72, 866 (1951), Chem. ~bstr. 47 5946 (1953)].
This pyrimidine can then be nitrosated wi-th nitrous acid to form 5-nltroso-2,4,6--triaminopyrimidine [M.F.
Malle-t-te e-t al, JO Am. Chem. Soc. 69, 1814 (197~)].
This process suffers from the disadvantage that it is too complica-ted for manufacture on a large scale and that the yield of 5-nitroso-2,4,6-triaminopyrimidine amounts to a maximum of 75 to 78%, based on the malonic acid dinitrile.
An attempt to simplify this process has been made by not isolating -the 2,4,6-triaminopyrimidine in-ter-mediate product (see Swiss Patent No. 630,616). However this process still retains various di.sadvantages, namely tha-t it employs expensive sodium alcoholate, tha-t at least two mols of salts (sodium chloride and sodium acetate) are accumulated per mol of malonic acid dinitrile employed, -that it mus-t be carried ou-t wi-th relatively dilu-te reaction solu-tions (abou-t 2 litres oE solvent per mol oE product), and finally tha-t the recovery of the solven-t af-ter the reaction is very difficult, since a 4-componen-t solvent mixture (methanol, ethanol, glacial ace-tic acid, water and by-products) is involved.
Another method of preparing 5-nitroso-2,4,6-triaminopyrimidine is described by E.C. Taylor, O. Vogl and C.C. Cheng~ J. em. Chem. Soc. 81, 2442 (1959). By heating -the potassium sal-t of isoni-troso-malononitrile with guanidine carbonate in dime-thyl formamide, 5-nitroso-f . Ye .
It is known that 5-ni-troso-2,4,6-triaminopyrimidines can be prepared from malonic acid dini-trile and a guanidine salt. Thus, condensa-tion oE malonic acid dini-trile and guanidine hydrochloride or nitrate in -the presence of sodium alcoholate in alcoholic solution gives 2,4,6-triaminopyrimidine in high yield [W. Traube, Ber. 37, 4544 (1904); Il. Sato et al. J. Chem. Soc. Japan Pure Chem. Sect. 72, 866 (1951), Chem. ~bstr. 47 5946 (1953)].
This pyrimidine can then be nitrosated wi-th nitrous acid to form 5-nltroso-2,4,6--triaminopyrimidine [M.F.
Malle-t-te e-t al, JO Am. Chem. Soc. 69, 1814 (197~)].
This process suffers from the disadvantage that it is too complica-ted for manufacture on a large scale and that the yield of 5-nitroso-2,4,6-triaminopyrimidine amounts to a maximum of 75 to 78%, based on the malonic acid dinitrile.
An attempt to simplify this process has been made by not isolating -the 2,4,6-triaminopyrimidine in-ter-mediate product (see Swiss Patent No. 630,616). However this process still retains various di.sadvantages, namely tha-t it employs expensive sodium alcoholate, tha-t at least two mols of salts (sodium chloride and sodium acetate) are accumulated per mol of malonic acid dinitrile employed, -that it mus-t be carried ou-t wi-th relatively dilu-te reaction solu-tions (abou-t 2 litres oE solvent per mol oE product), and finally tha-t the recovery of the solven-t af-ter the reaction is very difficult, since a 4-componen-t solvent mixture (methanol, ethanol, glacial ace-tic acid, water and by-products) is involved.
Another method of preparing 5-nitroso-2,4,6-triaminopyrimidine is described by E.C. Taylor, O. Vogl and C.C. Cheng~ J. em. Chem. Soc. 81, 2442 (1959). By heating -the potassium sal-t of isoni-troso-malononitrile with guanidine carbonate in dime-thyl formamide, 5-nitroso-f . Ye .
2,4,6-triaminopyrimidine is ohtained in 88% yield. However, since the po-tassium sal-t is ob-tained from the silver salt of isonitroso-maloni-trile, this process can not be considered for large scale produc-tion.
In French Patent No. l,364,734, a process is described in which malonic acid dinitrile in aqueous acetlc ac:id solution is firs-t ni-trosated with sodium nitrite, -then -the ob-tained isonitroso-malononi-trile solution is -treated with guanidine carbona-te resul-ting 10 in the evolution of carbon dioxide and precipita-tion of the guanidine sal-t of isoni-trosomalononi-trile. This sal-t suspension is then cooled to about 0C, Eiltered and the guanidine salt isonitrosomalononitrile is dried.
The salt is then hea-ted under reflux in dime-thyl Eormamide 15 after addition of potassium carbona-te, in order to complete isomerization of 5-nitroso-2,4,6-triaminopyrimidine.
This process constitutes a certain improvement over the process of Taylor et al, but still exhibits further disadvan-tages. Thus, the acetic acid mus-t be 20 used in excess (1096 according to the Example). This excess must be neu-tralized with guanidine carbonate in order to obtain complete conversion to the guanidine salt of isoni-trosomalono-nitrile. Cooling of the aqueous solu-tion -to abou-t 0C
gives rise -to technical difficulties, since a crus-t 25 of ice builds up on the inner surface of -the reac-tion vessel. Cooling to a lesser degree resul-ts in incomple-te precipi-ta-tion oE -the sal-t.
The drying oE -the guanidine sa]-t oE isoni:trosomalono-nitrile is risky on technical safe-ty grounds. In -the 30 -treatment oE a crude ison:i:trosolr~lononitrile solution with guanidine carbona-te one equitlalent o:E carbon dioxide is given oEE. The reac-tion mix-ture -thereEore has a tendency -to Eoam during -this procedure so -tha-t the reac-tion vessel can not be op-timally utilized.
From European paten-t applica-tion No. 115~325~
it is further known -to prepare 2-subs-ti-tu-ted-5-nitroso-4,6-diaminopyrimidines by treatment of malonic acid dinitrile with an amidine ln -the presence of a nitrite salt under acld conditions and in water or alcohol as solvent -to :Eorm the amidine salt oE the isoni-trosomalono-nitrile and further converting this salt by hea-ting 5 in dimethyl :Eormamide under basic conditions to form the desired produc-t. A signi:ficant disadvan-tage of this process is that the use of dimethyl formamicle libera-tes dime-thyl ni-trosamine.
I-t i.s an object o:E the presen-t invention to avoid -the above disadvantages and to provide a process that enables 2-substituted-5-nitroso-4,6-diaminopyrimidines to be prepared in a simple, economic and especially risk free manner and in high yield.
Accordingly, the invention provides a process Eor preparing a 2-substitu-ted-5-nitroso-~,6-diaminopyrimidine of the general formula:
/~ ~NH
wherein R represents arylr alkyl, alkyl-thio, amino, substitu-ted amino or arylalkyl, which comprises reac-ting malonic acid dinitrile with an amidine o:E the general formula:
NH i 30\ NH2 wherei.n A represents Of So, HSO~, N03, ace-tate or phosphate and R is as de:Eined above, in water or alcohol and in acid medium in the presence oE a nitrite salt, so as to :Eorm the corresponding amidine salt o:E isoni-troso-malononitrile, and :Eurther converting the amidine salt with heating in a polar aprotic solven-t selected prom dimethyl sulFoxide, N-methyl-2-pyrrolidone, N,N-dimethyl-acetamide, hexame-thylphosphoric acid triamide, 1,3-dimethyl-2-oxo-hexahydropyri.midine, tetrahydro--thiophene-l,l-dioxide, 2-methylglutarodinitrile and cyclohexanone, to form the corresponding 2-substi.tu-ted-5-ni-troso-4,6-diaminopyrimidine.
Thus, -the malonic acid dini-trile, advantageously in water or alcohol as solven-t, is nitrosa-ted with an amidine under acid conditions in the presence of a nitrite salt, whereby to obtain directly the amidine salt of isoni-trosomalononi-trile wi-thou-t -the need Eor isola-tion thereof. The addition of a polar aprotic solvent after removal of -the water or the alcohol, and heating under basic conditions resul.ts in formation of the corresponding 2-substituted-5-nitroso-4,6-diaminopyrimidine. According to the invention, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethyl ace-tamide, hexamethyl phosphoric acid triamide, l,3-dimethyl-2-oxo-hexhydropyrimidine or tetrahydrothiophene-l,l-dioxide is preEerably employed as the polar aprotic solvent, with dimethyl sulfoxide being most preferred. Apart from -these solvents, a pyridine base can a.lso be added, such as ~-picoline, ~-picoline, ~-pi.coline, 2-me-thyl-5-e-thylpyridine or lutidine.
The reac-tion proceeds according to the general :Eormula:
NH ilA NC NC NO H No NaN02 Jo NaA
N
R N~l2
In French Patent No. l,364,734, a process is described in which malonic acid dinitrile in aqueous acetlc ac:id solution is firs-t ni-trosated with sodium nitrite, -then -the ob-tained isonitroso-malononi-trile solution is -treated with guanidine carbona-te resul-ting 10 in the evolution of carbon dioxide and precipita-tion of the guanidine sal-t of isoni-trosomalononi-trile. This sal-t suspension is then cooled to about 0C, Eiltered and the guanidine salt isonitrosomalononitrile is dried.
The salt is then hea-ted under reflux in dime-thyl Eormamide 15 after addition of potassium carbona-te, in order to complete isomerization of 5-nitroso-2,4,6-triaminopyrimidine.
This process constitutes a certain improvement over the process of Taylor et al, but still exhibits further disadvan-tages. Thus, the acetic acid mus-t be 20 used in excess (1096 according to the Example). This excess must be neu-tralized with guanidine carbonate in order to obtain complete conversion to the guanidine salt of isoni-trosomalono-nitrile. Cooling of the aqueous solu-tion -to abou-t 0C
gives rise -to technical difficulties, since a crus-t 25 of ice builds up on the inner surface of -the reac-tion vessel. Cooling to a lesser degree resul-ts in incomple-te precipi-ta-tion oE -the sal-t.
The drying oE -the guanidine sa]-t oE isoni:trosomalono-nitrile is risky on technical safe-ty grounds. In -the 30 -treatment oE a crude ison:i:trosolr~lononitrile solution with guanidine carbona-te one equitlalent o:E carbon dioxide is given oEE. The reac-tion mix-ture -thereEore has a tendency -to Eoam during -this procedure so -tha-t the reac-tion vessel can not be op-timally utilized.
From European paten-t applica-tion No. 115~325~
it is further known -to prepare 2-subs-ti-tu-ted-5-nitroso-4,6-diaminopyrimidines by treatment of malonic acid dinitrile with an amidine ln -the presence of a nitrite salt under acld conditions and in water or alcohol as solvent -to :Eorm the amidine salt oE the isoni-trosomalono-nitrile and further converting this salt by hea-ting 5 in dimethyl :Eormamide under basic conditions to form the desired produc-t. A signi:ficant disadvan-tage of this process is that the use of dimethyl formamicle libera-tes dime-thyl ni-trosamine.
I-t i.s an object o:E the presen-t invention to avoid -the above disadvantages and to provide a process that enables 2-substituted-5-nitroso-4,6-diaminopyrimidines to be prepared in a simple, economic and especially risk free manner and in high yield.
Accordingly, the invention provides a process Eor preparing a 2-substitu-ted-5-nitroso-~,6-diaminopyrimidine of the general formula:
/~ ~NH
wherein R represents arylr alkyl, alkyl-thio, amino, substitu-ted amino or arylalkyl, which comprises reac-ting malonic acid dinitrile with an amidine o:E the general formula:
NH i 30\ NH2 wherei.n A represents Of So, HSO~, N03, ace-tate or phosphate and R is as de:Eined above, in water or alcohol and in acid medium in the presence oE a nitrite salt, so as to :Eorm the corresponding amidine salt o:E isoni-troso-malononitrile, and :Eurther converting the amidine salt with heating in a polar aprotic solven-t selected prom dimethyl sulFoxide, N-methyl-2-pyrrolidone, N,N-dimethyl-acetamide, hexame-thylphosphoric acid triamide, 1,3-dimethyl-2-oxo-hexahydropyri.midine, tetrahydro--thiophene-l,l-dioxide, 2-methylglutarodinitrile and cyclohexanone, to form the corresponding 2-substi.tu-ted-5-ni-troso-4,6-diaminopyrimidine.
Thus, -the malonic acid dini-trile, advantageously in water or alcohol as solven-t, is nitrosa-ted with an amidine under acid conditions in the presence of a nitrite salt, whereby to obtain directly the amidine salt of isoni-trosomalononi-trile wi-thou-t -the need Eor isola-tion thereof. The addition of a polar aprotic solvent after removal of -the water or the alcohol, and heating under basic conditions resul.ts in formation of the corresponding 2-substituted-5-nitroso-4,6-diaminopyrimidine. According to the invention, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethyl ace-tamide, hexamethyl phosphoric acid triamide, l,3-dimethyl-2-oxo-hexhydropyrimidine or tetrahydrothiophene-l,l-dioxide is preEerably employed as the polar aprotic solvent, with dimethyl sulfoxide being most preferred. Apart from -these solvents, a pyridine base can a.lso be added, such as ~-picoline, ~-picoline, ~-pi.coline, 2-me-thyl-5-e-thylpyridine or lutidine.
The reac-tion proceeds according to the general :Eormula:
NH ilA NC NC NO H No NaN02 Jo NaA
N
R N~l2
3~
in which A represents Cl, SO4, HSO~, NO3, acetate or phospha-te and R represents aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl.
Examples of suitable arni.dines include acetamidine hydrochloride, benz.amidine hydrochloride, S-methylisothio-urea sulfate and guanidine hydrochloride. The preferred amidine is guanidine hydrochloride.
Suitable nitrite salts include alkali me-tal and alkal.ine earth me-tal nitrites, preferably sodium ni-trite.
By -the -term acidic medium is to be unders-tood a medium having a pEI value o:E less than 6.9.
Regarding the propor-tions of the reactants, advantageously from 0.1 to 1.1 mol of ni-trite, preferably from 1.0 to 1.02 mol, is used per mol of malonic acid dinitrile.
The amount of the solvent for the firs-t reaction step is not critical and is advantageously from 200 to 2,000 ml per mol of malonic acid dini-trile. Preferably from 300 to 400 ml of solvent is employed per mol of malonic acid dinitrile. The reac-tion temperature for the first s-tep is conveniently be-tween 10 and 50C.
after a reaction time of approximately 0.5 to 15 hours and after cus-tomary working up, for example by means of filtra-tion and subsequently drying, the amidine salt of i.sonitrosomaloni-trile can be ob-tained.
The ami.dine salt o:E isoni-trosomalonitrile can also be reac-ted withou-t isolation from the reaction mediwn directly in the second reac-tion s-tep by -the addition of clime-thyl sulfoxide as solvent. In -the second reaction step, wi-th dimethyl sul:Eoxide as solvent, :Erom 100 to 2,000 ml, pre:Eerably from 300 -to 800 ml, o:E solvent is employed per mol of malonic acid dini-trile.
The necessary basic medium can be ob-tained advantageously by the addition o:E sodium hydroxide, sodium carbonate, potassium hydroxide, po-tassium carbonate or a subs-tituted pyridine. Preferred bases are sodium carbonate and potassium carbonate.
For the final hea-t treatmen-t the reaction mixture is advan-tageously heated to a tempera-ture oE Erom 100 to 1~0C, preEerably from 130 to 160C, advantageously for a period of 0.25 to 6 hours, preferably from 1 to
in which A represents Cl, SO4, HSO~, NO3, acetate or phospha-te and R represents aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl.
Examples of suitable arni.dines include acetamidine hydrochloride, benz.amidine hydrochloride, S-methylisothio-urea sulfate and guanidine hydrochloride. The preferred amidine is guanidine hydrochloride.
Suitable nitrite salts include alkali me-tal and alkal.ine earth me-tal nitrites, preferably sodium ni-trite.
By -the -term acidic medium is to be unders-tood a medium having a pEI value o:E less than 6.9.
Regarding the propor-tions of the reactants, advantageously from 0.1 to 1.1 mol of ni-trite, preferably from 1.0 to 1.02 mol, is used per mol of malonic acid dinitrile.
The amount of the solvent for the firs-t reaction step is not critical and is advantageously from 200 to 2,000 ml per mol of malonic acid dini-trile. Preferably from 300 to 400 ml of solvent is employed per mol of malonic acid dinitrile. The reac-tion temperature for the first s-tep is conveniently be-tween 10 and 50C.
after a reaction time of approximately 0.5 to 15 hours and after cus-tomary working up, for example by means of filtra-tion and subsequently drying, the amidine salt of i.sonitrosomaloni-trile can be ob-tained.
The ami.dine salt o:E isoni-trosomalonitrile can also be reac-ted withou-t isolation from the reaction mediwn directly in the second reac-tion s-tep by -the addition of clime-thyl sulfoxide as solvent. In -the second reaction step, wi-th dimethyl sul:Eoxide as solvent, :Erom 100 to 2,000 ml, pre:Eerably from 300 -to 800 ml, o:E solvent is employed per mol of malonic acid dini-trile.
The necessary basic medium can be ob-tained advantageously by the addition o:E sodium hydroxide, sodium carbonate, potassium hydroxide, po-tassium carbonate or a subs-tituted pyridine. Preferred bases are sodium carbonate and potassium carbonate.
For the final hea-t treatmen-t the reaction mixture is advan-tageously heated to a tempera-ture oE Erom 100 to 1~0C, preEerably from 130 to 160C, advantageously for a period of 0.25 to 6 hours, preferably from 1 to
4 hours.
In a preEerred embodimen-t of the invention,
In a preEerred embodimen-t of the invention,
5-ni-troso-2,4,6--triaminopyrimidine is prepared, namely by reactiny malonic acid dinitrile and guanidine-hydro-chloride at a pH below 6.9 in the presence of sodiumnitrite -to produce the guanidine salt oE isoni-troso-malononitrile, which is then converted -to 5-nitroso-2,4,6--triaminopyrimidine by heating at 150C in dimethyl sulfoxide in the presence of sodium carbonate.
The 2-subs-tituted-5-nitroso-4,6-diaminopyrimidines obtained by the process of the invention can be separa-ted in conventional manner by filtration or centrifuging, washed with water and dried. The 2-substituted-5-nitroso-2,4,6-diaminopyrimidines obtained by the process of the invention, in particular 5-nitroso-2,4,6--triamino-pyrimidine~ are versatile intermediate products useful, for example, for the preparation oE medicamen-ts, such as triamterene and me-thothrexate, and for the manuEacture of dyes-tuf:E componen-ts, such as 2,4,5,6-te-traaminopyrimidine.
The following Examples illustrate the inven-tion.
Example 1 To a suspension of 66 g of malonic acid dinitrile and 100 g oE guanidine hydrochloride in 200 g oE wa-ter, a solution of 70 g oE sodium nitrile in 120 ml of water was added dropwise a-t a pH of 4 and at room temperature.
After stirring :Eor 4 hours at room temperature, 21 g of sodium carbonate and 770 g of a polar apro-tic solvent were added thereto and the wa-ter was dis-tilled oE:E under reduced pressure. Subsequently, the reaction mix-ture was heated for 3 hours at a temperature of 140-150C, whereby isomerization of 5-nitroso-2,4,6-triaminopyrimidine took place. Af-ter t:he end oE the reaction, 750 g of water were added and the product was Eiltered ofE and washed wi-th wa-ter. The resul-ts of experiments with various polar aprotic solvents are set out in the following Table 1.
. .~
Amoun-t o:E Produc-t Yield Example Solvent g %
. . _ 1-1 Dime-thylsulfoxi.de 138 89.6 1-2 Dimethyl acetamide 118 76.6 1-3 N-Methyl-2-pyrrol.idone 142 92.2 1-4 Tetrahydro-thiophene-l,l147 95.5 dioxide 1-5 3-Picoline 130 84.4 1-6 4-Picoline 144 93.5 1-7 2-Methyl-5-e-thylpyridine 151 98.0 ~1-8* Dimethyl Eormamide 128 83.1) 1-9 2-Me-thylglutarodini-trile 111 72.1 1-10 Cyclohexanone 86 55.8 1-11 Hexamethyl phosphoric acid 141 91.6 triamide 1-12 1,3-Dimethyl-2-oxo-hexa- 145 94.2 hydropyrimidine L
* Comparison tes-t Example 2 To a suspension o 33 g of malonitrile and 52 g of acetamidine hydrochl.oride in 100 g of wa-ter -there was added dxopwise at a pH of 4 and at room temperature a solu-tion of 37.5 y o:E sodium nitrite in 60 g of water.
After -the reaction had proceeded :Eor 4 hours, the reaction mix-ture was cooled to 0C and the product :Eiltered of-E.
The acetamidine salt o:E isonitrosomalononitrile was obtained with a mel-ting point o:E 142 -to 143C (decomposi-tion) in almost quan-ti-tative yield (84% isolated).
Example 3 To a suspension oE 13.2 g of malonitrile and 32 g of benzami.dine hydrochloride in 25 g of water, there was added dropwise at a pH of 3 -to 5 and at 20C
a solu-tion of 14 g of sodium nitrite in 25 g of water.
After a reacti.on time of 5 hours and cooling to 0C, the reaction product was :Eil-tered and dried. The benzamidine salt o:E isonitrosomalonitrile having a melting poin-t of 150C (decomposi-tion) was obtained in prac-tically quantita-tive yield (94% isola-ted).
Example 4 To a suspension o:E 33 g of maloni-tril.e and 70 g o:E S-methyl-iso-thiourea sulfate in 100 ml of wa-ter, there was added dropwise a-t a pH of 4 and a-t room temperature a solut:ion of 35 g of sodium nitrite in 60 ml of water.
After a reac-tion period of 5 hours, the reaction mixture was cooled to 4C and :Eiltered. After drying, the S-methylisothiouronium salt o:E isoni-trosomalononitrile was ob-tained in very high yield (76~ i.sola-ted), melting point l.23 to 124C (decomposi-tion).
Example 5 To a suspension of 66 g of malonitrile and 97 g of guanidine hydrochloride in 120 ml of water there was added at a pH of 4 and at room -temperature a soluti.on of 70 g o:E sodi.um ni-tri.te in 120 ml. of water. A:E-ter stirring for 4 hou:rs, the reaction mixture was cooled to 0C and filtered. A:E-ter drying in a vacuum, the ~;~L~2~L98 guanidine salt of isonitrosomalonitrile was ob-tained in practically quantitative yield (84% isolated), meltiny point 160-161C (decomposition).
The Eurther conversion o:E -these amidine salts oE isoni.trosomalononitrile obtained in Examples 2-to 5 into-the correspondiny 2-substitu-ted-5-ni-troso-4,6-diaminopyrimidines can be carried ou-t as described in the literature (E.C.
Taylor et al, J. em. Chem. So. 81, 2442 (1959).
The 2-subs-tituted-5-nitroso-4,6-diaminopyrimidines obtained by the process of the invention can be separa-ted in conventional manner by filtration or centrifuging, washed with water and dried. The 2-substituted-5-nitroso-2,4,6-diaminopyrimidines obtained by the process of the invention, in particular 5-nitroso-2,4,6--triamino-pyrimidine~ are versatile intermediate products useful, for example, for the preparation oE medicamen-ts, such as triamterene and me-thothrexate, and for the manuEacture of dyes-tuf:E componen-ts, such as 2,4,5,6-te-traaminopyrimidine.
The following Examples illustrate the inven-tion.
Example 1 To a suspension of 66 g of malonic acid dinitrile and 100 g oE guanidine hydrochloride in 200 g oE wa-ter, a solution of 70 g oE sodium nitrile in 120 ml of water was added dropwise a-t a pH of 4 and at room temperature.
After stirring :Eor 4 hours at room temperature, 21 g of sodium carbonate and 770 g of a polar apro-tic solvent were added thereto and the wa-ter was dis-tilled oE:E under reduced pressure. Subsequently, the reaction mix-ture was heated for 3 hours at a temperature of 140-150C, whereby isomerization of 5-nitroso-2,4,6-triaminopyrimidine took place. Af-ter t:he end oE the reaction, 750 g of water were added and the product was Eiltered ofE and washed wi-th wa-ter. The resul-ts of experiments with various polar aprotic solvents are set out in the following Table 1.
. .~
Amoun-t o:E Produc-t Yield Example Solvent g %
. . _ 1-1 Dime-thylsulfoxi.de 138 89.6 1-2 Dimethyl acetamide 118 76.6 1-3 N-Methyl-2-pyrrol.idone 142 92.2 1-4 Tetrahydro-thiophene-l,l147 95.5 dioxide 1-5 3-Picoline 130 84.4 1-6 4-Picoline 144 93.5 1-7 2-Methyl-5-e-thylpyridine 151 98.0 ~1-8* Dimethyl Eormamide 128 83.1) 1-9 2-Me-thylglutarodini-trile 111 72.1 1-10 Cyclohexanone 86 55.8 1-11 Hexamethyl phosphoric acid 141 91.6 triamide 1-12 1,3-Dimethyl-2-oxo-hexa- 145 94.2 hydropyrimidine L
* Comparison tes-t Example 2 To a suspension o 33 g of malonitrile and 52 g of acetamidine hydrochl.oride in 100 g of wa-ter -there was added dxopwise at a pH of 4 and at room temperature a solu-tion of 37.5 y o:E sodium nitrite in 60 g of water.
After -the reaction had proceeded :Eor 4 hours, the reaction mix-ture was cooled to 0C and the product :Eiltered of-E.
The acetamidine salt o:E isonitrosomalononitrile was obtained with a mel-ting point o:E 142 -to 143C (decomposi-tion) in almost quan-ti-tative yield (84% isolated).
Example 3 To a suspension oE 13.2 g of malonitrile and 32 g of benzami.dine hydrochloride in 25 g of water, there was added dropwise at a pH of 3 -to 5 and at 20C
a solu-tion of 14 g of sodium nitrite in 25 g of water.
After a reacti.on time of 5 hours and cooling to 0C, the reaction product was :Eil-tered and dried. The benzamidine salt o:E isonitrosomalonitrile having a melting poin-t of 150C (decomposi-tion) was obtained in prac-tically quantita-tive yield (94% isola-ted).
Example 4 To a suspension o:E 33 g of maloni-tril.e and 70 g o:E S-methyl-iso-thiourea sulfate in 100 ml of wa-ter, there was added dropwise a-t a pH of 4 and a-t room temperature a solut:ion of 35 g of sodium nitrite in 60 ml of water.
After a reac-tion period of 5 hours, the reaction mixture was cooled to 4C and :Eiltered. After drying, the S-methylisothiouronium salt o:E isoni-trosomalononitrile was ob-tained in very high yield (76~ i.sola-ted), melting point l.23 to 124C (decomposi-tion).
Example 5 To a suspension of 66 g of malonitrile and 97 g of guanidine hydrochloride in 120 ml of water there was added at a pH of 4 and at room -temperature a soluti.on of 70 g o:E sodi.um ni-tri.te in 120 ml. of water. A:E-ter stirring for 4 hou:rs, the reaction mixture was cooled to 0C and filtered. A:E-ter drying in a vacuum, the ~;~L~2~L98 guanidine salt of isonitrosomalonitrile was ob-tained in practically quantitative yield (84% isolated), meltiny point 160-161C (decomposition).
The Eurther conversion o:E -these amidine salts oE isoni.trosomalononitrile obtained in Examples 2-to 5 into-the correspondiny 2-substitu-ted-5-ni-troso-4,6-diaminopyrimidines can be carried ou-t as described in the literature (E.C.
Taylor et al, J. em. Chem. So. 81, 2442 (1959).
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a 2-substituted-5-nitroso-4,6-diaminopyrimidine of the general formula:
wherein R represents aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl, which comprises reacting malonic acid dinitrile with an amidine of the general formula=
wherein A represents C1, ? S04, HS04, N03, acetate or phosphate and R is as defined above, in water or alcohol and in acid medium in the presence of a nitrite salt, so as to form the corresponding amidine salt of isonitrosomalono-nitrile, and further converting the amidine salt with heating in a polar aprotic solvent selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethyl-acetamide, hexamethylphosphoric acid triamide, 1,3-dimethyl-2-oxo-hexahydropyrimidine, tetrahydro-thiophene-1,1-dioxide, 2-methylglutarodinitrile and cyclohexanone, to form the corresponding 2-substituted-5-nitroso-4,6-diaminopyrimidine.
wherein R represents aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl, which comprises reacting malonic acid dinitrile with an amidine of the general formula=
wherein A represents C1, ? S04, HS04, N03, acetate or phosphate and R is as defined above, in water or alcohol and in acid medium in the presence of a nitrite salt, so as to form the corresponding amidine salt of isonitrosomalono-nitrile, and further converting the amidine salt with heating in a polar aprotic solvent selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethyl-acetamide, hexamethylphosphoric acid triamide, 1,3-dimethyl-2-oxo-hexahydropyrimidine, tetrahydro-thiophene-1,1-dioxide, 2-methylglutarodinitrile and cyclohexanone, to form the corresponding 2-substituted-5-nitroso-4,6-diaminopyrimidine.
2. A process according to claim 1 for the preparation of 5-nitroso-2,4,6-triaminopyrimidine, which comprises reacting malonic acid dinitrile with guanidine hydrochloride in water at a pH below 6.9 in the presence of sodium nitrite to form the guanidine salt of isonitroso-malononitrile, and converting the product to the desired end product by heating in dimethyl sulfoxide.
3. A process according to claim 1 or 2, wherein the heating step is carried out under basic conditions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH5215/85A CH667089A5 (en) | 1985-12-06 | 1985-12-06 | METHOD FOR PRODUCING 2-SUBSTITUTED 5-NITROSO-4,6-DIAMINO-PYRIMIDINES. |
| CH5215/85 | 1985-12-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1242198A true CA1242198A (en) | 1988-09-20 |
Family
ID=4289875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000524438A Expired CA1242198A (en) | 1985-12-06 | 1986-12-03 | Process for the preparation of 2-substituted-5- nitroso-4,6-diaminopyrimidines |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0225614A3 (en) |
| JP (1) | JPS62138480A (en) |
| CA (1) | CA1242198A (en) |
| CH (1) | CH667089A5 (en) |
| DK (1) | DK570886A (en) |
| FI (1) | FI864736A (en) |
| HU (1) | HU197885B (en) |
| IL (1) | IL80857A0 (en) |
| YU (1) | YU206686A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113173887A (en) * | 2021-04-01 | 2021-07-27 | 河北利德检测技术有限公司 | Synthetic method of triamterene intermediate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3122540A (en) * | 1962-08-09 | 1964-02-25 | American Home Prod | 2-aryl-4, 7-diamino-n-(aminoalkyl)-6-pteridine-carboxamides |
| CH660589A5 (en) * | 1983-01-28 | 1987-05-15 | Lonza Ag | METHOD FOR PRODUCING 2-SUBSTITUTED 5-NITROSO-4,6-DIAMINO-PYRIMIDINES. |
-
1985
- 1985-12-06 CH CH5215/85A patent/CH667089A5/en not_active IP Right Cessation
-
1986
- 1986-11-20 FI FI864736A patent/FI864736A/en not_active IP Right Cessation
- 1986-11-27 DK DK570886A patent/DK570886A/en not_active Application Discontinuation
- 1986-12-03 IL IL80857A patent/IL80857A0/en unknown
- 1986-12-03 JP JP61288644A patent/JPS62138480A/en active Pending
- 1986-12-03 CA CA000524438A patent/CA1242198A/en not_active Expired
- 1986-12-03 YU YU02066/86A patent/YU206686A/en unknown
- 1986-12-04 EP EP86116911A patent/EP0225614A3/en not_active Withdrawn
- 1986-12-05 HU HU865043A patent/HU197885B/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113173887A (en) * | 2021-04-01 | 2021-07-27 | 河北利德检测技术有限公司 | Synthetic method of triamterene intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0225614A2 (en) | 1987-06-16 |
| CH667089A5 (en) | 1988-09-15 |
| YU206686A (en) | 1988-02-29 |
| HU197885B (en) | 1989-06-28 |
| DK570886A (en) | 1987-06-07 |
| IL80857A0 (en) | 1987-03-31 |
| JPS62138480A (en) | 1987-06-22 |
| HUT43576A (en) | 1987-11-30 |
| FI864736A0 (en) | 1986-11-20 |
| FI864736A (en) | 1987-06-07 |
| DK570886D0 (en) | 1986-11-27 |
| EP0225614A3 (en) | 1988-04-06 |
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