CA1241958A - 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
- Publication number
- CA1241958A CA1241958A CA000445565A CA445565A CA1241958A CA 1241958 A CA1241958 A CA 1241958A CA 000445565 A CA000445565 A CA 000445565A CA 445565 A CA445565 A CA 445565A CA 1241958 A CA1241958 A CA 1241958A
- Authority
- CA
- Canada
- Prior art keywords
- salt
- nitrite
- water
- nitroso
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D239/48—Two 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (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. Malonic dini-trile and an amidine are nitrosated in water or alcohol, in an acidic medium, and in the presence of a nitrite salt, to form the corresponding amidine salt of isonitrosomalononi-trile. The latter is converted to the desired end product by heat treatment in a basic medium, in the presence of dimethylformamide or of a pyridine base, and after removal of the water or alcohol.
A process is disclosed for the preparation of 2-substituted 5-nitroso-4,6-diaminopyrimidines. Malonic dini-trile and an amidine are nitrosated in water or alcohol, in an acidic medium, and in the presence of a nitrite salt, to form the corresponding amidine salt of isonitrosomalononi-trile. The latter is converted to the desired end product by heat treatment in a basic medium, in the presence of dimethylformamide or of a pyridine base, and after removal of the water or alcohol.
Description
-I1 ~2~58 I The lnventlon relates to a process for the preparatlon ! f 2-3ubstltuted 5-nltroso-2,6-dlamlnopyrimldlnes.
.1 .
It 19 known that 5-nltroso-2,4,6-trlamlnopyrlmldlne can be prepared from malonlc nltrlle and a guanldlne salt.
.1 .
It 19 known that 5-nltroso-2,4,6-trlamlnopyrlmldlne can be prepared from malonlc nltrlle and a guanldlne salt.
2,4,6-Trlaminopyrlmidlne ls obtalned ln moderate yleld by the condensatlon of malonlc dlnltrlle and guanldlne hydrochlorlde or nltrate ln the presence of a sodlum alcoholate ln alcohollc solutlon [W. Traube, Ber. 37, 4544 (1904); H Sato et al., J. Chem. Soc. Japan Pure Chem. Sect. 72, 866 (1951); and Chem. Abstr. 47, 5946 (1953)]. Thls pyrlmldlne 13 then nltrosated to 5-nltroso-2,4,6-trlamlnopyrlmldlne, uslng nltrous acld ~M.F. Mallette et al., J. Am. Chem. Soc. 69, 1814 (1947)].
such processes have the dlsadvantages that they are too troublesome when relatlvely large amounts have to be prepared and that the maxlmum yleld of 5-nltro~o-2,4,6-triamlnopyrlmldlne 18 75 to 78 percent, relatlve to malonlc dlnltrlle.
Attempts have been made to slmpllry the process by not ,! 1301atlng the lntermedlate product 2,4,6-trlamlnopyrlmldlne (see Swlss Patent Speclflcatlon No 630,616). However, the proce3s stlll has varlous dlsadvantages: expenslve sodlum alchololate has to be used; at least two mols of salt (NaCl and Na acetate) are produced per mol Or malonlc dlnltrlle employed; the reactlon has to be carrled out uslng relatlvely dllute solutlons (approxlmately 2 llters of solvent per mol of product); and flnally, the recovery of the solvent ls a very dlfflcult ~LZ4~958 procedure, slnce a 4-component solvent mlxture (methanol, ethanol, glaclal acetlc acld, water and by-products) ls present.
Another route for the preparatlon of 5-nltroso-2,4,6-trlamlnopyrlmldlne ls descrlbed by C. Taylor, 0. Vogl and C.C.
ln J. Am. Chem. Soc. 81, 2442 (1959). 5-Nltroso-2,4,6-trlamlnopyrlmldlne ls obtalned ln 88 percent yleld by heatlng the potasslum salt Or lsonltroso-malononltrlle wlth guanldlne carbonate ln dlmethylformamlde. Slnce the potasslum salt ls prepared from the sllver salt of lsonltrosomalononltrlle, the process ls unsultable for large-scale lndustrlal productlon.
French Patent Speclflcatlon No. 1,364,734 descrlbes a proceas ln whlch malonic dinitrile in aqueous acetic acid solution is ~lrst nitrosated with sodium nitrite, and then the resultant isonitrosomalononitrile solution is treated with guanldlne carbonate, C02 belng evolved and the guanldlne salt of lsonltrosomalononltrlle belng obtalned. The salt suspenslon 18 then cooled to approxlmately 0C. and flltered, and the guanldlne salt Or lsonltrosomalononltrlle ls drled. After the addltlon of R2C03 to the salt ln dlmethylformamlde, the mlxture ls heated under reflux ln order to effect lsomerlzatlon to 5-nltroso-2,4,6-trlamlnopyrlmldlne.
Such process represents a certaln degree of progress compared wlth the process accordlng to Taylor et al., but lt stlll has several dlsadvantages. Thus, the acetlc acld has to be used ln exoe~s (10 percent, accordlng to the example). Thls excess has to be neutrallzed wlth guanldlne carbonate ln order for the formatlon of the guandlne salt of lsonltrosomalono-nlerlle eO 6 to cc~pleelon~
:' 41~58 Cooling the aqueous suspension to approxlmately 0C.
lnvolves technical dlfficulties, slnce a crust of ice ls formed on the inside of the reaction vessel. When the mixture i9 cooled to temperatures whlch are not quite so low, the salt is not completely preclpltated.
From the polnt of view of safety, drying the guanidine salt of lsonitrosomalononitrile involve rlsks.
In the treatment of crude lsonltrosomalononltrlle solution wlth guanidine carbonate, one equlvalent of C02 ls liberated. The reaction mixture therefore has a tendency to foam during the operation and accordingly the reactlon vessel cannot be optimally utilized.
An obJect of the lnventlon ls to avold the above-mentloned disadvantages. Another object Or the lnventlon 18 to provlde a process whlch makes lt posslble to prepare 2-substituted 5-nltroso-4,6-dlamlnopyrlmldlnes ln a slmple and economlcal manner and ln hlgh yleld.
The invention involves a process for the pre-paration of 2-substituted 5-nitroso-4,6-diaminopyrimi-dines of the formula:
5~3 ¦ NH2 NO
R~ NH2 wherein R is aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl. Malonlc dinitrile is reacted with an amidine of the formula:
/~IH HA
R
wherein A is Cl, l/2 S04, HS04, N03, acetate or phosphate and R
has the above meaning, ln water or alcohol, in an acidlc medium, and in the presence of a nitrite salt, to provide the correspondlng amidlne salt of isonitrosomalononitrile. The amidlne salt of the lsonltrosomalononitrile, in dimethyl~ormamide or a pyrldine base, and in a basic medium, is converted by heat treatment to the corresponding 2-substituted 5-nitroso-4,6-dlamlnopyrlmldlne.
In the process of the lnventlon, the malonlc dinitrlle, in water or alcohol as the solvent, is nltrosated wlth an amldine in an acidic medium and in the presence of a nitrite salt. The amidine salt ox isonitrosomalononitrile is dlreotly ~orme~ In tle quequ: o :lcqùollo :u:p:n:lon. Such ~4~5~3 .1, salt is not isolated; lnstead, the mixture ls rendered basic.
Then, after dimethylformamide or a pyridine base has been added, the water or the alcohol is distilled off under reduced pressure. After the water or the alcohol has been virtually completely removed, the reactlon mixture ls subjected to heat treatment, advantageously heated under reflux. The correspondlng 2-substituted 5-nltroso-4,6-diaminopyrlmldlne ls formed. As used herein acldic medium or acldic pH means a pH
value of below 6.9. Also as used herein, baslc medium or basic pH means a pH value of above 7.1.
The inventlon reactlon take place accordlng to general equatlon: _ NH . HA No NC NO H2N+
R _ + ¦ + NaN02 --I \ baa N
whereln A ls Cl, 1/2 S04, HS04, N03, acetate or phosphate and R
denotes aryl, alkyl, alkylthlo, amlno, substltuted amlno or j arylalkyl.
I Examples of amldlnes are acetamldlne hydrochlorlde, ;'l benzamldlne hydrochlorlde, S-methylisothlourea sulfate and guanldlne hydrochlorlde. The alkall metal or alkallne earth metal nitrltes, preferably sodlum nltrlte, can be used as the nltrlte salt. Regardlng the proportions, advantageously 0.1 to 4i958 1.1 mol of nltrlte, preferably 1.01 mol of nltrlte, ls used per mol of malonlc dlnltrlle.
The amount of solvent (water or ethanol) for the flrst stage of the reactlon ls not crltlcal, and is advantageou31y 200 to 2,000 ml per mol of malonlc dlnitrlle. Preferably 300 to 400 I ml of solvent are employed per mol of malonlc dlnltrlle.
¦ In the second stage of the reactlon, wlth dlmethylformamlde or a pyrldlne base as the solvent, 100 to 2,000 ml, preferably 300 to 500 ml, of solvent can be employed ; per mol of malonodlnltrlle.
In a preferred embodlment, 5-nltroso-2,4,6-trlamlnopyrlmldlne 18 prepared as follows: malonlc dlnltrlle and guanldlne hydrochlorlde are reacted at a pH of below 6.9 ln the presence of sodlum nltrlte to glve the guanldlne salt of lsonltrosomalononltrlle, and the guanldlne salt of isonitrosomalononitrile 18 converted to 5-nltroso-2,4,6-trlamlnopyrlmldlne by bolllng under reflux ln dlmethyformamlde.
After the lsomerlzatlon reactlon, the red suspenslon of 5-nltroso-2,4,6-trlaminopyrlmldlne ln dlmethylformamlde can be dlluted wlth water, and the product can be separated off by flltratlon or centrlfuglng, and washed wlth water. For many , reaction the molst product can be used. If necessary, lt can be drled by heatlng by any convenlent method. 5-nltroso-2,4,6-trlamlnopyrlmldlne 18 a versatlle lntermedlate product for example for the preparatlon of medlcaments, such as, trlamterene and methotrexate, and for the preparatlon of dyestuff components, such as, 2,4,5,6-tetramlnopyrlmldlne.
Thls lnventlon also lncludes a composltlon of malonlc 1, -dlnltrile, water or alcohol, a nltrlte salt and an amldine havlng the formula:
NH HA
R _ i whereln A ls Cl, l/2 S04, HS04, N03, acetate or phosphate and R
18 aryl, alkyl, alkylthlo, amlno, substltuted amlno or arylalkyl. The pH 18 acldlc.
The following Examples illustrate the invention.As used hereln, all percentages, ratlos, proportlons and parts are on a welght basls unless otherwlse stated hereln or otherwlse obvlous herefrom to one ordlnarlly skllled ln the art.
A solutlon Or 70 g Or sodlum nltrlte ln 120 g of water j was added dropwlse at room temperature to a suspenslon of 66 g malononltrlle and 96 g of guanldlne hydrochlorlde ln 200 g Or water, and the PH was kept at 4 by the addltlon of hydrochlorlc acld. After the reactlon had contlnued ror 4 hours at room temperature, 21 g of sodlum carbonate and 400 g of dlmethylformamlde were added. The water was dlstllled Orr under reduced pressure. Thereafter, the reactlon mlxture was heated at 140C. for l hour, lsomerlzatlon to 5-nltroso-2,4,6-trlamlno-, 95~3 ."
I pyrlmldlne taklng place. After the reactlon was complete, 400ml of water were added, and the product was filtered off and washed wlth water. After the product had been drled, 140 g of a pure raspberry-red 5-nltroso-2,4,6-trlamlnopyrlmldlne were obtained. The melting polnt of the product was above 340C. and the yleld was 91 percent.
A solutlon of 37.5 g of sodium nitrite in 60 g of water was added dropwlse to a suspenslon of 33 g of malono-nltrile and 52 g of acetamldlne hydrochloride ln lO0 g of water at pH 4 and at room temperature. After the reactlon had contlnued for 4 hours, the reactlon mlxture was cooled to 0C.
and the product was flltered off. The acetamldlne salt of lsonltrosomalononltrlle, havlng a meltlng polnt 142 to 143C.
(decomposltlon), was obtalned ln vlrtually quantltatlve yleld (84 per¢ent lsolated).
A solutlon of 14 g of sodlum nltrlte ln 25 g of water was added dropwlse to a suspenslon of 13.2 g of malononltrlle and 32 g of benzamldine hydrochlorlde ln 25 g of water at pH 3 I to 5 and at 20C. After the reactlon had contlnued for 5 hours l and the mlxture had been cooled to 0C., the reactlon product was flltered off under suctlon and drled. The benzamldlne salt of lsonltrosomalononltrlle, havlng a meltlng polnt of 150C.
(decomposltlon), was obtalned ln vlrtually quantltatlve yleld (94 percent lsolated).
i A solutlon of 35 g of sodlum nltrlte ln 60 ml of water 1, lZ41958 was added dropwise to a suspenslon of 33 g of malononltrile and 70 g of S-methyllsothlourea sulfate ln 100 ml of water at pH 4 and at room temperature. After the reactlon had contlnued for 5 hours, the reactlon mixture was cooled to 4C., and the product was flltered off. After the product had been drled, the S-methyllsothlouronlum salt of lsonltrosomalononltrlle was obtalned ln very hlgh yleld (76 percent lsolated). The salt had a meltlng polnt of 123 to 124C. (decomposltlon).
A solutlon of 70 g of sodlum nltrlte ln 120 ml of water was added dropwlse to a suspenslon of 66 g of malononltrlle and 97 g of guanldlne hydrochlorlde ln 120 ml of water at pH 4 and at room temperature. The mlxture was stlrred for 4 hourR and then was cooled to 0C., and the product was flltered off. After the product had been drled under vacuum, the guanldlne salt of lsonltrosomalononltrlle was obtalned ln vlrtually quantltatlve yleld (84 percent lsolated). The salt hmd a meltlng point of 160~ to 161C. (decompo9ltlon1.
such processes have the dlsadvantages that they are too troublesome when relatlvely large amounts have to be prepared and that the maxlmum yleld of 5-nltro~o-2,4,6-triamlnopyrlmldlne 18 75 to 78 percent, relatlve to malonlc dlnltrlle.
Attempts have been made to slmpllry the process by not ,! 1301atlng the lntermedlate product 2,4,6-trlamlnopyrlmldlne (see Swlss Patent Speclflcatlon No 630,616). However, the proce3s stlll has varlous dlsadvantages: expenslve sodlum alchololate has to be used; at least two mols of salt (NaCl and Na acetate) are produced per mol Or malonlc dlnltrlle employed; the reactlon has to be carrled out uslng relatlvely dllute solutlons (approxlmately 2 llters of solvent per mol of product); and flnally, the recovery of the solvent ls a very dlfflcult ~LZ4~958 procedure, slnce a 4-component solvent mlxture (methanol, ethanol, glaclal acetlc acld, water and by-products) ls present.
Another route for the preparatlon of 5-nltroso-2,4,6-trlamlnopyrlmldlne ls descrlbed by C. Taylor, 0. Vogl and C.C.
ln J. Am. Chem. Soc. 81, 2442 (1959). 5-Nltroso-2,4,6-trlamlnopyrlmldlne ls obtalned ln 88 percent yleld by heatlng the potasslum salt Or lsonltroso-malononltrlle wlth guanldlne carbonate ln dlmethylformamlde. Slnce the potasslum salt ls prepared from the sllver salt of lsonltrosomalononltrlle, the process ls unsultable for large-scale lndustrlal productlon.
French Patent Speclflcatlon No. 1,364,734 descrlbes a proceas ln whlch malonic dinitrile in aqueous acetic acid solution is ~lrst nitrosated with sodium nitrite, and then the resultant isonitrosomalononitrile solution is treated with guanldlne carbonate, C02 belng evolved and the guanldlne salt of lsonltrosomalononltrlle belng obtalned. The salt suspenslon 18 then cooled to approxlmately 0C. and flltered, and the guanldlne salt Or lsonltrosomalononltrlle ls drled. After the addltlon of R2C03 to the salt ln dlmethylformamlde, the mlxture ls heated under reflux ln order to effect lsomerlzatlon to 5-nltroso-2,4,6-trlamlnopyrlmldlne.
Such process represents a certaln degree of progress compared wlth the process accordlng to Taylor et al., but lt stlll has several dlsadvantages. Thus, the acetlc acld has to be used ln exoe~s (10 percent, accordlng to the example). Thls excess has to be neutrallzed wlth guanldlne carbonate ln order for the formatlon of the guandlne salt of lsonltrosomalono-nlerlle eO 6 to cc~pleelon~
:' 41~58 Cooling the aqueous suspension to approxlmately 0C.
lnvolves technical dlfficulties, slnce a crust of ice ls formed on the inside of the reaction vessel. When the mixture i9 cooled to temperatures whlch are not quite so low, the salt is not completely preclpltated.
From the polnt of view of safety, drying the guanidine salt of lsonitrosomalononitrile involve rlsks.
In the treatment of crude lsonltrosomalononltrlle solution wlth guanidine carbonate, one equlvalent of C02 ls liberated. The reaction mixture therefore has a tendency to foam during the operation and accordingly the reactlon vessel cannot be optimally utilized.
An obJect of the lnventlon ls to avold the above-mentloned disadvantages. Another object Or the lnventlon 18 to provlde a process whlch makes lt posslble to prepare 2-substituted 5-nltroso-4,6-dlamlnopyrlmldlnes ln a slmple and economlcal manner and ln hlgh yleld.
The invention involves a process for the pre-paration of 2-substituted 5-nitroso-4,6-diaminopyrimi-dines of the formula:
5~3 ¦ NH2 NO
R~ NH2 wherein R is aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl. Malonlc dinitrile is reacted with an amidine of the formula:
/~IH HA
R
wherein A is Cl, l/2 S04, HS04, N03, acetate or phosphate and R
has the above meaning, ln water or alcohol, in an acidlc medium, and in the presence of a nitrite salt, to provide the correspondlng amidlne salt of isonitrosomalononitrile. The amidlne salt of the lsonltrosomalononitrile, in dimethyl~ormamide or a pyrldine base, and in a basic medium, is converted by heat treatment to the corresponding 2-substituted 5-nitroso-4,6-dlamlnopyrlmldlne.
In the process of the lnventlon, the malonlc dinitrlle, in water or alcohol as the solvent, is nltrosated wlth an amldine in an acidic medium and in the presence of a nitrite salt. The amidine salt ox isonitrosomalononitrile is dlreotly ~orme~ In tle quequ: o :lcqùollo :u:p:n:lon. Such ~4~5~3 .1, salt is not isolated; lnstead, the mixture ls rendered basic.
Then, after dimethylformamide or a pyridine base has been added, the water or the alcohol is distilled off under reduced pressure. After the water or the alcohol has been virtually completely removed, the reactlon mixture ls subjected to heat treatment, advantageously heated under reflux. The correspondlng 2-substituted 5-nltroso-4,6-diaminopyrlmldlne ls formed. As used herein acldic medium or acldic pH means a pH
value of below 6.9. Also as used herein, baslc medium or basic pH means a pH value of above 7.1.
The inventlon reactlon take place accordlng to general equatlon: _ NH . HA No NC NO H2N+
R _ + ¦ + NaN02 --I \ baa N
whereln A ls Cl, 1/2 S04, HS04, N03, acetate or phosphate and R
denotes aryl, alkyl, alkylthlo, amlno, substltuted amlno or j arylalkyl.
I Examples of amldlnes are acetamldlne hydrochlorlde, ;'l benzamldlne hydrochlorlde, S-methylisothlourea sulfate and guanldlne hydrochlorlde. The alkall metal or alkallne earth metal nitrltes, preferably sodlum nltrlte, can be used as the nltrlte salt. Regardlng the proportions, advantageously 0.1 to 4i958 1.1 mol of nltrlte, preferably 1.01 mol of nltrlte, ls used per mol of malonlc dlnltrlle.
The amount of solvent (water or ethanol) for the flrst stage of the reactlon ls not crltlcal, and is advantageou31y 200 to 2,000 ml per mol of malonlc dlnitrlle. Preferably 300 to 400 I ml of solvent are employed per mol of malonlc dlnltrlle.
¦ In the second stage of the reactlon, wlth dlmethylformamlde or a pyrldlne base as the solvent, 100 to 2,000 ml, preferably 300 to 500 ml, of solvent can be employed ; per mol of malonodlnltrlle.
In a preferred embodlment, 5-nltroso-2,4,6-trlamlnopyrlmldlne 18 prepared as follows: malonlc dlnltrlle and guanldlne hydrochlorlde are reacted at a pH of below 6.9 ln the presence of sodlum nltrlte to glve the guanldlne salt of lsonltrosomalononltrlle, and the guanldlne salt of isonitrosomalononitrile 18 converted to 5-nltroso-2,4,6-trlamlnopyrlmldlne by bolllng under reflux ln dlmethyformamlde.
After the lsomerlzatlon reactlon, the red suspenslon of 5-nltroso-2,4,6-trlaminopyrlmldlne ln dlmethylformamlde can be dlluted wlth water, and the product can be separated off by flltratlon or centrlfuglng, and washed wlth water. For many , reaction the molst product can be used. If necessary, lt can be drled by heatlng by any convenlent method. 5-nltroso-2,4,6-trlamlnopyrlmldlne 18 a versatlle lntermedlate product for example for the preparatlon of medlcaments, such as, trlamterene and methotrexate, and for the preparatlon of dyestuff components, such as, 2,4,5,6-tetramlnopyrlmldlne.
Thls lnventlon also lncludes a composltlon of malonlc 1, -dlnltrile, water or alcohol, a nltrlte salt and an amldine havlng the formula:
NH HA
R _ i whereln A ls Cl, l/2 S04, HS04, N03, acetate or phosphate and R
18 aryl, alkyl, alkylthlo, amlno, substltuted amlno or arylalkyl. The pH 18 acldlc.
The following Examples illustrate the invention.As used hereln, all percentages, ratlos, proportlons and parts are on a welght basls unless otherwlse stated hereln or otherwlse obvlous herefrom to one ordlnarlly skllled ln the art.
A solutlon Or 70 g Or sodlum nltrlte ln 120 g of water j was added dropwlse at room temperature to a suspenslon of 66 g malononltrlle and 96 g of guanldlne hydrochlorlde ln 200 g Or water, and the PH was kept at 4 by the addltlon of hydrochlorlc acld. After the reactlon had contlnued ror 4 hours at room temperature, 21 g of sodlum carbonate and 400 g of dlmethylformamlde were added. The water was dlstllled Orr under reduced pressure. Thereafter, the reactlon mlxture was heated at 140C. for l hour, lsomerlzatlon to 5-nltroso-2,4,6-trlamlno-, 95~3 ."
I pyrlmldlne taklng place. After the reactlon was complete, 400ml of water were added, and the product was filtered off and washed wlth water. After the product had been drled, 140 g of a pure raspberry-red 5-nltroso-2,4,6-trlamlnopyrlmldlne were obtained. The melting polnt of the product was above 340C. and the yleld was 91 percent.
A solutlon of 37.5 g of sodium nitrite in 60 g of water was added dropwlse to a suspenslon of 33 g of malono-nltrile and 52 g of acetamldlne hydrochloride ln lO0 g of water at pH 4 and at room temperature. After the reactlon had contlnued for 4 hours, the reactlon mlxture was cooled to 0C.
and the product was flltered off. The acetamldlne salt of lsonltrosomalononltrlle, havlng a meltlng polnt 142 to 143C.
(decomposltlon), was obtalned ln vlrtually quantltatlve yleld (84 per¢ent lsolated).
A solutlon of 14 g of sodlum nltrlte ln 25 g of water was added dropwlse to a suspenslon of 13.2 g of malononltrlle and 32 g of benzamldine hydrochlorlde ln 25 g of water at pH 3 I to 5 and at 20C. After the reactlon had contlnued for 5 hours l and the mlxture had been cooled to 0C., the reactlon product was flltered off under suctlon and drled. The benzamldlne salt of lsonltrosomalononltrlle, havlng a meltlng polnt of 150C.
(decomposltlon), was obtalned ln vlrtually quantltatlve yleld (94 percent lsolated).
i A solutlon of 35 g of sodlum nltrlte ln 60 ml of water 1, lZ41958 was added dropwise to a suspenslon of 33 g of malononltrile and 70 g of S-methyllsothlourea sulfate ln 100 ml of water at pH 4 and at room temperature. After the reactlon had contlnued for 5 hours, the reactlon mixture was cooled to 4C., and the product was flltered off. After the product had been drled, the S-methyllsothlouronlum salt of lsonltrosomalononltrlle was obtalned ln very hlgh yleld (76 percent lsolated). The salt had a meltlng polnt of 123 to 124C. (decomposltlon).
A solutlon of 70 g of sodlum nltrlte ln 120 ml of water was added dropwlse to a suspenslon of 66 g of malononltrlle and 97 g of guanldlne hydrochlorlde ln 120 ml of water at pH 4 and at room temperature. The mlxture was stlrred for 4 hourR and then was cooled to 0C., and the product was flltered off. After the product had been drled under vacuum, the guanldlne salt of lsonltrosomalononltrlle was obtalned ln vlrtually quantltatlve yleld (84 percent lsolated). The salt hmd a meltlng point of 160~ to 161C. (decompo9ltlon1.
Claims (9)
1. Process for the preparation of a 2-substituted 5-nitroso-4,6-diaminopyrimidine having the formula:
wherein R is aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl, comprising: (a) reacting malonic dinitrile with an amidine having the formula:
wherein A is C1, 1/2 SO4, HSO4, NO3, acetate or phosphate and R
has the meaning given above, in water or alcohol, in an acidic medium and in the presence of a nitrite salt, to give the corresponding amidine salt of isonitrosomalononitrile; and (b) converting the amidine salt of isonitrosomalononitrile, in dimethylformamide or a pyridine base, and in a basic medium, by heat treatment to the corresponding 2-substituted 5-nitroso-4,6-diaminopyrimidine.
wherein R is aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl, comprising: (a) reacting malonic dinitrile with an amidine having the formula:
wherein A is C1, 1/2 SO4, HSO4, NO3, acetate or phosphate and R
has the meaning given above, in water or alcohol, in an acidic medium and in the presence of a nitrite salt, to give the corresponding amidine salt of isonitrosomalononitrile; and (b) converting the amidine salt of isonitrosomalononitrile, in dimethylformamide or a pyridine base, and in a basic medium, by heat treatment to the corresponding 2-substituted 5-nitroso-4,6-diaminopyrimidine.
2. Process as claimed in Claim 1 wherein step (a) is carried out in an acidic medium at a pH of below 6.9.
3. Process as claimed in Claim 2 wherein an alkali metal nitrite or an alkaline earth metal nitrite, is used as the nitrite salt.
4. Process as claimed in claim 3, wherein the alkali metal nitrite is sodium nitrite.
5. Process as claimed in claim 3, wherein for the preparation of 5-nitroso-2,4,6-triaminopyrimidine, malonic dinitrile is reacted with guanidine hydrochloride in water at a pH of below 6.9, in the presence of sodium nitrite, to give the guanidine salt of isonitrosomalononitrile and the guanidine salt of isonitrosomalononitrile is converted in a basic medium to 5-nitroso-2,4,6-triamino-pyrimidine by boiling water under reflux in a solvent.
6. Process as claimed in claim 3, wherein the water or alcohol is removed between step (a) and step (b).
7. Process as claimed in claim 6, wherein dimethylformamide is present in step (b).
8. Process as claimed in claim 6, wherein a pyridine base is present in step (b).
9. Process as claimed in claim 1, wherein the nitrite salt is an alkali metal nitrite or an alkaline earth metal nitrite.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH48283A CH660589A5 (en) | 1983-01-28 | 1983-01-28 | METHOD FOR PRODUCING 2-SUBSTITUTED 5-NITROSO-4,6-DIAMINO-PYRIMIDINES. |
| CH482/83 | 1983-01-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1241958A true CA1241958A (en) | 1988-09-13 |
Family
ID=4188010
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000445565A Expired CA1241958A (en) | 1983-01-28 | 1984-01-18 | Process for the preparation of 2-substituted 5- nitroso-4,6-diaminopyrimidines |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0115325B1 (en) |
| JP (1) | JPS59141566A (en) |
| CA (1) | CA1241958A (en) |
| CH (1) | CH660589A5 (en) |
| DE (1) | DE3465083D1 (en) |
| DK (1) | DK159681C (en) |
| IE (1) | IE56419B1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH667089A5 (en) * | 1985-12-06 | 1988-09-15 | Lonza Ag | METHOD FOR PRODUCING 2-SUBSTITUTED 5-NITROSO-4,6-DIAMINO-PYRIMIDINES. |
| US4959475A (en) * | 1989-01-04 | 1990-09-25 | Lonza Ltd. | Process for the production of 2,4-diamino-6-piperidinyl-pyrimidine-3-N-oxide |
| PL351088A1 (en) * | 1999-04-15 | 2003-03-24 | Basf Ag | Process for the preparation of substituted pyrimidines |
| US6281358B1 (en) | 1999-04-15 | 2001-08-28 | American Cyanamid Company | Process for the preparation of substituted pyrimidines |
| DE10024886A1 (en) * | 2000-05-19 | 2001-11-22 | Henkel Kgaa | Colorant for keratin fibers, especially human hair, contains optionally substituted nitrosopyridine and -pyrimidine compound(s) as coloring component |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1364734A (en) * | 1963-05-15 | 1964-06-26 | Lumiere Lab | Process for the preparation of acyclic and cyclic derivatives of guanidine |
| DE2651794C2 (en) * | 1976-11-12 | 1982-09-23 | Henkel KGaA, 4000 Düsseldorf | Process for the preparation of 5-nitroso-2,4,6-triaminopyrimidine |
| JPS5818367A (en) * | 1981-07-27 | 1983-02-02 | Kohjin Co Ltd | Preparation of nitrosopyrimidine derivative |
-
1983
- 1983-01-28 CH CH48283A patent/CH660589A5/en not_active IP Right Cessation
- 1983-12-12 IE IE292683A patent/IE56419B1/en not_active IP Right Cessation
-
1984
- 1984-01-17 DK DK19784A patent/DK159681C/en active
- 1984-01-18 CA CA000445565A patent/CA1241958A/en not_active Expired
- 1984-01-24 EP EP84100718A patent/EP0115325B1/en not_active Expired
- 1984-01-24 DE DE8484100718T patent/DE3465083D1/en not_active Expired
- 1984-01-27 JP JP1216784A patent/JPS59141566A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| IE832926L (en) | 1984-07-28 |
| DK159681B (en) | 1990-11-19 |
| EP0115325A2 (en) | 1984-08-08 |
| JPH0549666B2 (en) | 1993-07-26 |
| DE3465083D1 (en) | 1987-09-03 |
| DK19784A (en) | 1984-07-29 |
| JPS59141566A (en) | 1984-08-14 |
| DK159681C (en) | 1991-04-29 |
| EP0115325A3 (en) | 1984-09-12 |
| DK19784D0 (en) | 1984-01-17 |
| CH660589A5 (en) | 1987-05-15 |
| IE56419B1 (en) | 1991-07-31 |
| EP0115325B1 (en) | 1987-07-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2495296C (en) | Process for preparing the calcium salt of rosuvastatin | |
| US4940793A (en) | Pharmacologically active piperazino derivatives | |
| CN114805314B (en) | Synthesis method of Entecavir | |
| CA1241958A (en) | Process for the preparation of 2-substituted 5- nitroso-4,6-diaminopyrimidines | |
| WO1995007265A1 (en) | Improved process for preparing 2-amino-4,6-dichloropyrimidine | |
| CA2002671C (en) | Process for the production of 4,5-dichloro-6-ethyl-pyrimidine | |
| CA2063827A1 (en) | Process for preparing 2,5-diamino-4,6-dichloropyrimidine | |
| KR100260977B1 (en) | Process for the production of guanidine derivatives | |
| US2464247A (en) | Preparation of guanidine sulfates | |
| WO2004007497A1 (en) | Process for preparing 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine | |
| CN113200907B (en) | Novel method for treating amination reaction wastewater of monosultap synthesis process | |
| US5037982A (en) | Method of purifying 2-methyl-4-amino-5-aminomethylpyrimidine | |
| US4831139A (en) | Process for the preparation of 2-substituted 5-nitroso-4,6-diaminopyrimidines | |
| CA1171081A (en) | Production of purine derivatives and intermediates therefor | |
| JPS63316773A (en) | Manufacture of 4-nitro-5-imidazolyl ether and -thioether | |
| CN1035874C (en) | Preparation of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt abstract of the disclosure | |
| CA1242198A (en) | Process for the preparation of 2-substituted-5- nitroso-4,6-diaminopyrimidines | |
| CA1251796A (en) | 2-pyrimidyl alkanesulfonates and methods for their preparation and use | |
| JP2724881B2 (en) | Improved method for precipitating cytosine from alkaline solution with sulfuric acid | |
| EP1229029B1 (en) | Process for producing benzylamine compound | |
| CA2014533A1 (en) | Process for the production of 4 - hydroxy -6- polyfluoroalkylpyrimidines | |
| US2362070A (en) | Preparation of isocytosine | |
| CA1042915A (en) | 2-iminomethyl-3',4',5'-trimethoxycinnamic acids and esters thereof, and their production | |
| US4226994A (en) | Process for making 4-methyl-4,5-dihydrotetrazolo [1,5-a] quinazolin-5-one | |
| CA1080244A (en) | Process for the preparation of tris (hydroxymethyl)-amino-methan-lactate-dihydroxyaluminate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |