CA1174679A - Process for the preparation of 2,4-diamino-5-(3',4', 5'-trimethoxy-benzyl)-pyrimidine - Google Patents
Process for the preparation of 2,4-diamino-5-(3',4', 5'-trimethoxy-benzyl)-pyrimidineInfo
- Publication number
- CA1174679A CA1174679A CA000406060A CA406060A CA1174679A CA 1174679 A CA1174679 A CA 1174679A CA 000406060 A CA000406060 A CA 000406060A CA 406060 A CA406060 A CA 406060A CA 1174679 A CA1174679 A CA 1174679A
- Authority
- CA
- Canada
- Prior art keywords
- general formula
- trimethoxy
- compound
- benzyl
- formula
- 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
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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
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A B S T R A C T
The invention relates to an improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine of the general formula I
(I) by reacting a compound of the general formula II
(II) (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing the said compound of the general formula II by reacting .alpha.-(3,4,5-trimethoxy-benzal)-.beta.-methoxy-propionitrile of the formula III
(III) with ethylene glycol monoalkylether of the general formula IV
HO-CH2-CH2-OR (IV) (wherein R is as stated above) in the presence of an alkali alkoxide at a temperature between 60 °C and 90 °C
and reacting the compound of the general formula II thus obtained - if desired without isolation - with guanidine in the presence of an alkanol having 4-8 carbon atoms.
The advantage of the process is that it is economical and can be carried out with high yields even on industrial scale and provides a product of high purity.
The compound of the formula I obtained ie a known chemotherapeutical drug.
The invention relates to an improved process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine of the general formula I
(I) by reacting a compound of the general formula II
(II) (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing the said compound of the general formula II by reacting .alpha.-(3,4,5-trimethoxy-benzal)-.beta.-methoxy-propionitrile of the formula III
(III) with ethylene glycol monoalkylether of the general formula IV
HO-CH2-CH2-OR (IV) (wherein R is as stated above) in the presence of an alkali alkoxide at a temperature between 60 °C and 90 °C
and reacting the compound of the general formula II thus obtained - if desired without isolation - with guanidine in the presence of an alkanol having 4-8 carbon atoms.
The advantage of the process is that it is economical and can be carried out with high yields even on industrial scale and provides a product of high purity.
The compound of the formula I obtained ie a known chemotherapeutical drug.
Description
1174~;79 IMPROVED PROCESS FOR THE PR:EPARATION OF 2, 4-DIAMI~O-~-- ( 3 ', 4 ', 5 ' -TRIMETHOXY-BENZ YL ) -PYRIMIDINE
This invention relates to an impro~ed process fo.r the preparation of 2,4-diamino-5-(3',4',~'-trimethoxy-ben~yL)-pyrimidine by reacting a oompound of the generaL
fo.rmuLa (II) ~ CN
L0 CH30 ~ / \ ~ CH2-C
>=/ CH-O -CH2 -CH2 -OR ( II ) (wherein R is an aLkyL group having L-4 carbon atoms) L~ with guanidine The 2,4-diamino-~-(3',4',~'-trimethoxy-benzyL)--pyrimidine of the formula (I) 20 C~30 ~ CH2 ~ \ ~ ~2 (I) is a weLL known chemotherapeuticaL drug (referred to
This invention relates to an impro~ed process fo.r the preparation of 2,4-diamino-5-(3',4',~'-trimethoxy-ben~yL)-pyrimidine by reacting a oompound of the generaL
fo.rmuLa (II) ~ CN
L0 CH30 ~ / \ ~ CH2-C
>=/ CH-O -CH2 -CH2 -OR ( II ) (wherein R is an aLkyL group having L-4 carbon atoms) L~ with guanidine The 2,4-diamino-~-(3',4',~'-trimethoxy-benzyL)--pyrimidine of the formula (I) 20 C~30 ~ CH2 ~ \ ~ ~2 (I) is a weLL known chemotherapeuticaL drug (referred to
2~ further on as Trimethop.rim).
SeveraL procedures are known for the pre-paration of the compound of the formula (I); some of the said processes take pLace via ~-(3,4,~-trimethoxy--benzyl)-~-(substituted)-acrylic-nitriles.
,~
X
,. . .
- l~'Y4f~
According to Hungarian Patent No. L49,799
SeveraL procedures are known for the pre-paration of the compound of the formula (I); some of the said processes take pLace via ~-(3,4,~-trimethoxy--benzyl)-~-(substituted)-acrylic-nitriles.
,~
X
,. . .
- l~'Y4f~
According to Hungarian Patent No. L49,799
3,4,~-trimethoxy-benzaLdehyde is condensed with B-aLkoxy--propionitriLe. The yieLd of the condensation reaction is higher than 80 % and the condensation product thus obtained consist~ of about 80 % of ~-(3,4,~-trimethoxy-benzaL)-B-alkoxy-propionitriLe and 20 % of ~-(3,4,~-tri-methoxy-benzyL)-B-aLkoxy-acryLic-nitriLe The condensa-tion product is subsequentLy reacted with guanidine.
However, onLy the benzyL deri~ati~e participates in the reaction with guanidine, whiLe the benzaL compound iso-merises to the benzyL derivati~e practicaLLy but to a very smalL extent. Thus the yieLd of Trimethoprim does not exceed 28 % and the total yield reLated to 3,4,~--trimethoxybenzaldehyde is not higher than 20-24 %.
1~ Acoording to Hungarian Patent No. 162,316 the abo~e known process is rendered more economical by con-densing 3,4~-trimethoxy-benzaldehyde with a B-alkoxy--propionitriLe, reacting the condensation product thus obtained with an amine, isomerising the ~-(3,4,~-tri-methoxy-benzal)-B-aminopropionitrile deri~ative thus obtained into the corresponding benzyL derivative and reacting the Latter compound with guanidine. The total yield of Trimethoprim related to the 3,4,~-trimethoxy--benzaldehyde starting material is, howe~er, moderate.
2~ According to Hungarian patent No. 174,318 3,4,~-trimethoxy-benzaldehyde i9 reacted with a B--(2-aLkoxyethoxy)-propionitrile. Thus a ~-(3,4,~-tri-methoxy-b~nzal)-B-(2-alkoxy-ethoxy)-propionitrile of 117'~679 the generaL formuLa (IIa) S ~ ~ C~=ClN (II~) is obtained (wherein R is as stated abo~e) with a yieLd of abo~e 80 %, which is then isola-ted, thoroughLy purified, subjected to isomerisation at 90-9~ C in the presence of a base into the corresponding ben~yL isomer of the generaL formuLa (II) which is then reacted with guanidine to gi~e Trimethoprim with a yield of about L~ 80 %, Thus the totaL yield of the Laboratory scaLe Trimethoprim production is about 64-72 %, ALthough the above process is significantL~
more economical than the previousL~ described methods, the industriaL scaLe use thereof is met with serious probLems, In the reaction of 3,4,5-trimethoxy-benzaL-dehyde and B-(2-aLkox~-ethoxy)-propionitriLe water is formed which is distiLLed off at a high temperature of about L20 C. At this high temperature hydrolysis of the ~-(3,4,~-trimethoxy-benzaL)-B-(2-aLkox~-ethox~)-2~ -propionitriLe with the water being present takes place, According to our experiments the nitriLe group h~droL~ses and the corresponding carbox~Lic acid X
~74f~i79 is foxmed in an amount of some per cents, This side reaction ~ives rise to the formation of tarry side products which comes particuLarLy into prominence as the batch size is increased, Thus the Laboratory scaLe totaL yieLd of 64-72 % decreases to about ~0-~ % aLready when the batch size is of about a LO moLar amount, It can be stated that the above known process is unsatis-factory from economic point of view, The aim of the present invention is the eLab-LO oration of an economicaL industriaL scaLe process forthe preparation of 2~4-diamino-~-(3'~4',5'-trimethoxy--benzyL)-pyrimidine, It has been found that the ~-(3,4,~-trimethoxy-benzaL)-~-methoxy-propionitriLe of the formula (III) 1~ CH30 \ _ CN
C~30 ~ CH=C (III) r CH2-O~H3 can be trans-etherified into the correspondin~ benzaL
isomer of the generaL formuLa (IIa) aLmost with quan-titative yieLds by reactin~ with an ethyLene gLycoL
2~ monoaLkyLether of the ~eneraL formuLa (IV) HO-CH2-CH2-OR ~IV) 11746~79 (wherein R is as stated abo~e) and the compound of the general formula (II~) can be converted easily into the oorresponding benzyL isomer of the generaL formula (II) almost by theoretical yields. The benzyL isomer of the generaL formuLa (II) is so pure that it can be reacted without isoLation and purification with guanidine to give Trimethoprim.
According to the present invention there is provided a process for the preparation of 2,4-diamino-~--(3~4',~'-trimethoxy-benzyl)-pyrimidine of the general formula (I) by reacting a compound of th0 general formula (II) (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing the said com-pound of the general formula (II) b~ reacting ~-(3,4,~-1~ -trimethoxy-benzal)-~-methoxy-propionitrile of the for-mula (III) with an ethylene glycole monoalkylether of the general formula (IV) (wherein R is as stated abo~e) in the presence of an aLkali aLkoxide at a temperature bet-ween 60 C and 90 C and reacting the compound of the 20 general formula (II~ thus obtained - if desired without isolation - with guanidine in the presenoe of an aLkanol ha~ing 4-8 carbon atoms.
As compound of the general formula (IV) prefer-ably eth~Lene gLycol monomethylether can be used, The 2~ compound of the general formula (IV) is preferabLy used in an excess and plays the role of the solvent, too.
AB alkali alkoxide preferably sodium methylate can be used.
X
11746';~9 I* is not necessary to isolate the benzal isomer of the general formuLa (IIa) obtained in the reaction of the ~-(3,4,~-trimethoxy-benzal)-~-methoxy--propionitriLe of the formuLa (III) and the ethyLene ~LycoL monoaLkyLether of the ~eneraL formula (IV). Under the reaction conditions used at 60-go C - preferabLy at 80-90 C - the benzyL isomer is quantitati~ely formed within a few hours. The benzyl isomer of the general formula (II) can be isoLated or, if desired, reacted with guanidine without isolation.
The benzyL isomer of the generaL formuLa (II) is X
li746~7~
reacted with guanidine in the presence of an alcohol having 4-8 carbon atoms, For this purpose pre~erabLy tertiar~ butanoL or isobutanol can be used. The reac-tion between the benzyl isomer and guanidine can be carried out in the presence of a further organic solvent (e,g, an other alcohol, such as methanol) in addition to the alcohol having 4-8 carbon atoms.
If according to a preferred embodiment of the process of the present invention the compound of the general formula (II) is reacted with guanidine without isolation, the eth~LenegLycol monomethyl ether of the general formula (IV) is always present in the ring clo-sure stage of the reactiDn, pro~ided it was used in an excesq in the preparation of the benz~l deri~ative, It is preferred to add guanidine in the form of an aoid addition salt - e.g, the hydroohLoride - to the benzyl derivative and to set free the guanidine from its aoid addition salt in the reaotion mixture with the aid Df a base, preferably an alkali alkoxide.
The reaotion of the benz~l isomer and guanidine is carried out preferably at 70-100 C, ad~antageously at~
the boiling point Df the reaotion mixture, The ~-(3,4,~-trimethoxy-benzaL)-B-methoxy--propionitriLe of the formuLa (III) is prepared in a 2~ known manner by reaoting 3,4,~-trimethoxy-benzaLdehyde with B-methoxy-propionitriLe. The Latter ~-methoxy--propionitrile is prepared by reaoting aoryLio nitriLe with methanol in alkaline medium, 746~79 The process o~ the present in~ention enables the economicaL industrial scaLe manufacture of Tri-methoprim, The drawbacks of the process accordin~ to Hun~arian patent No, L74,318 are eliminated, The totaL yield related to 3~4~5-trimethoxy--benzaldehyde is about 80 %, According to the process of the present invention Trimethoprim can be manu~actured from the compound of the formula (III) by a one-step technoLo~y, The purity of the product obtained meets L0 the therapeuticaL requirements, Further detaiLs of the present in~ention are to be found in the ExampLes without Limitin~ our inven-tion to the said ExampLes, 1~ Example 1 Preparation of the startin~ materiaL
1.75 ~, of potassium hydroxide are dissol~ed in lL5 ml of methanol, To the solution 5~ g of acr~Lic nitrile are added within 20 minutes at a temperature below 40 C, The mixture is stirred at 40 C for an hour, whereupon L00 g, of 3~4~5-trimethoxy~benzaLdehyde are added, The reaction mixture is stirred at 60 C for 8 hours where-upon it is cooLed to 30 C, 55 mL of methanoL and in por-tions 30 ~, of potassium hydroxide are added, The sus-pension form~ed is stirred for 5 hours, cooLed to 20 Cand 500 ml of water are added within 15 minutes, The prod-uct is cr~stallized at 5-10 C~ filtered, washed three times ~ith 1~ ml, of methanoL and three times with 100 ml, X
~.. .
: ' ' -`- ` 1179~79 g of water each and dried, Thus 116 g, of ~-(3,4,5-tri-methoxy-benzal)-~-methoxy-propionitriLe are ~btained, Mp,: 81-83 C, YieLd: 86 ~0, Example 2 Preparation of 2,4-diamino-~-(3' ~ 4',~'-tri-methoxy-benzyl)-pyrimidine A mixture ~f 100 g, of ~-(3,4,5-trimeth~xy--benzaL)-~-methoxy-propi~nitrile~ 100 mL, of anhydrous ethylene ~lycol m~nomethylether and ~ ~, of sodium methoxide is stirred at 82-84 C for 3 hours, The re-action mixture is cooled to 30 C, then 160 mL. of iso-bùtanol, 40 ml, of methanol, 8~ ~, of guanidine-hydro-ohloride and ~0 ~, of powdered qodium methoxide are added, 1~ The reaotion mixture is stirred at 3~-40 C for an hour and at 90-92 C for 7 hours, The orystaL suspension is oooled to 20 C, filtered and washed on the filter three times with 20 ml. of methanol each, The mvist substance thus obtained is washed with 500 mL, of lukewarm water (30-3~ C) and dried, Thus 102,~ g, of the title com-pound are obtained~ yield: 93,6 %, mp,: L98-201 C,
However, onLy the benzyL deri~ati~e participates in the reaction with guanidine, whiLe the benzaL compound iso-merises to the benzyL derivati~e practicaLLy but to a very smalL extent. Thus the yieLd of Trimethoprim does not exceed 28 % and the total yield reLated to 3,4,~--trimethoxybenzaldehyde is not higher than 20-24 %.
1~ Acoording to Hungarian Patent No. 162,316 the abo~e known process is rendered more economical by con-densing 3,4~-trimethoxy-benzaldehyde with a B-alkoxy--propionitriLe, reacting the condensation product thus obtained with an amine, isomerising the ~-(3,4,~-tri-methoxy-benzal)-B-aminopropionitrile deri~ative thus obtained into the corresponding benzyL derivative and reacting the Latter compound with guanidine. The total yield of Trimethoprim related to the 3,4,~-trimethoxy--benzaldehyde starting material is, howe~er, moderate.
2~ According to Hungarian patent No. 174,318 3,4,~-trimethoxy-benzaldehyde i9 reacted with a B--(2-aLkoxyethoxy)-propionitrile. Thus a ~-(3,4,~-tri-methoxy-b~nzal)-B-(2-alkoxy-ethoxy)-propionitrile of 117'~679 the generaL formuLa (IIa) S ~ ~ C~=ClN (II~) is obtained (wherein R is as stated abo~e) with a yieLd of abo~e 80 %, which is then isola-ted, thoroughLy purified, subjected to isomerisation at 90-9~ C in the presence of a base into the corresponding ben~yL isomer of the generaL formuLa (II) which is then reacted with guanidine to gi~e Trimethoprim with a yield of about L~ 80 %, Thus the totaL yield of the Laboratory scaLe Trimethoprim production is about 64-72 %, ALthough the above process is significantL~
more economical than the previousL~ described methods, the industriaL scaLe use thereof is met with serious probLems, In the reaction of 3,4,5-trimethoxy-benzaL-dehyde and B-(2-aLkox~-ethoxy)-propionitriLe water is formed which is distiLLed off at a high temperature of about L20 C. At this high temperature hydrolysis of the ~-(3,4,~-trimethoxy-benzaL)-B-(2-aLkox~-ethox~)-2~ -propionitriLe with the water being present takes place, According to our experiments the nitriLe group h~droL~ses and the corresponding carbox~Lic acid X
~74f~i79 is foxmed in an amount of some per cents, This side reaction ~ives rise to the formation of tarry side products which comes particuLarLy into prominence as the batch size is increased, Thus the Laboratory scaLe totaL yieLd of 64-72 % decreases to about ~0-~ % aLready when the batch size is of about a LO moLar amount, It can be stated that the above known process is unsatis-factory from economic point of view, The aim of the present invention is the eLab-LO oration of an economicaL industriaL scaLe process forthe preparation of 2~4-diamino-~-(3'~4',5'-trimethoxy--benzyL)-pyrimidine, It has been found that the ~-(3,4,~-trimethoxy-benzaL)-~-methoxy-propionitriLe of the formula (III) 1~ CH30 \ _ CN
C~30 ~ CH=C (III) r CH2-O~H3 can be trans-etherified into the correspondin~ benzaL
isomer of the generaL formuLa (IIa) aLmost with quan-titative yieLds by reactin~ with an ethyLene gLycoL
2~ monoaLkyLether of the ~eneraL formuLa (IV) HO-CH2-CH2-OR ~IV) 11746~79 (wherein R is as stated abo~e) and the compound of the general formula (II~) can be converted easily into the oorresponding benzyL isomer of the generaL formula (II) almost by theoretical yields. The benzyL isomer of the generaL formuLa (II) is so pure that it can be reacted without isoLation and purification with guanidine to give Trimethoprim.
According to the present invention there is provided a process for the preparation of 2,4-diamino-~--(3~4',~'-trimethoxy-benzyl)-pyrimidine of the general formula (I) by reacting a compound of th0 general formula (II) (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine, which comprises preparing the said com-pound of the general formula (II) b~ reacting ~-(3,4,~-1~ -trimethoxy-benzal)-~-methoxy-propionitrile of the for-mula (III) with an ethylene glycole monoalkylether of the general formula (IV) (wherein R is as stated abo~e) in the presence of an aLkali aLkoxide at a temperature bet-ween 60 C and 90 C and reacting the compound of the 20 general formula (II~ thus obtained - if desired without isolation - with guanidine in the presenoe of an aLkanol ha~ing 4-8 carbon atoms.
As compound of the general formula (IV) prefer-ably eth~Lene gLycol monomethylether can be used, The 2~ compound of the general formula (IV) is preferabLy used in an excess and plays the role of the solvent, too.
AB alkali alkoxide preferably sodium methylate can be used.
X
11746';~9 I* is not necessary to isolate the benzal isomer of the general formuLa (IIa) obtained in the reaction of the ~-(3,4,~-trimethoxy-benzal)-~-methoxy--propionitriLe of the formuLa (III) and the ethyLene ~LycoL monoaLkyLether of the ~eneraL formula (IV). Under the reaction conditions used at 60-go C - preferabLy at 80-90 C - the benzyL isomer is quantitati~ely formed within a few hours. The benzyl isomer of the general formula (II) can be isoLated or, if desired, reacted with guanidine without isolation.
The benzyL isomer of the generaL formuLa (II) is X
li746~7~
reacted with guanidine in the presence of an alcohol having 4-8 carbon atoms, For this purpose pre~erabLy tertiar~ butanoL or isobutanol can be used. The reac-tion between the benzyl isomer and guanidine can be carried out in the presence of a further organic solvent (e,g, an other alcohol, such as methanol) in addition to the alcohol having 4-8 carbon atoms.
If according to a preferred embodiment of the process of the present invention the compound of the general formula (II) is reacted with guanidine without isolation, the eth~LenegLycol monomethyl ether of the general formula (IV) is always present in the ring clo-sure stage of the reactiDn, pro~ided it was used in an excesq in the preparation of the benz~l deri~ative, It is preferred to add guanidine in the form of an aoid addition salt - e.g, the hydroohLoride - to the benzyl derivative and to set free the guanidine from its aoid addition salt in the reaotion mixture with the aid Df a base, preferably an alkali alkoxide.
The reaotion of the benz~l isomer and guanidine is carried out preferably at 70-100 C, ad~antageously at~
the boiling point Df the reaotion mixture, The ~-(3,4,~-trimethoxy-benzaL)-B-methoxy--propionitriLe of the formuLa (III) is prepared in a 2~ known manner by reaoting 3,4,~-trimethoxy-benzaLdehyde with B-methoxy-propionitriLe. The Latter ~-methoxy--propionitrile is prepared by reaoting aoryLio nitriLe with methanol in alkaline medium, 746~79 The process o~ the present in~ention enables the economicaL industrial scaLe manufacture of Tri-methoprim, The drawbacks of the process accordin~ to Hun~arian patent No, L74,318 are eliminated, The totaL yield related to 3~4~5-trimethoxy--benzaldehyde is about 80 %, According to the process of the present invention Trimethoprim can be manu~actured from the compound of the formula (III) by a one-step technoLo~y, The purity of the product obtained meets L0 the therapeuticaL requirements, Further detaiLs of the present in~ention are to be found in the ExampLes without Limitin~ our inven-tion to the said ExampLes, 1~ Example 1 Preparation of the startin~ materiaL
1.75 ~, of potassium hydroxide are dissol~ed in lL5 ml of methanol, To the solution 5~ g of acr~Lic nitrile are added within 20 minutes at a temperature below 40 C, The mixture is stirred at 40 C for an hour, whereupon L00 g, of 3~4~5-trimethoxy~benzaLdehyde are added, The reaction mixture is stirred at 60 C for 8 hours where-upon it is cooLed to 30 C, 55 mL of methanoL and in por-tions 30 ~, of potassium hydroxide are added, The sus-pension form~ed is stirred for 5 hours, cooLed to 20 Cand 500 ml of water are added within 15 minutes, The prod-uct is cr~stallized at 5-10 C~ filtered, washed three times ~ith 1~ ml, of methanoL and three times with 100 ml, X
~.. .
: ' ' -`- ` 1179~79 g of water each and dried, Thus 116 g, of ~-(3,4,5-tri-methoxy-benzal)-~-methoxy-propionitriLe are ~btained, Mp,: 81-83 C, YieLd: 86 ~0, Example 2 Preparation of 2,4-diamino-~-(3' ~ 4',~'-tri-methoxy-benzyl)-pyrimidine A mixture ~f 100 g, of ~-(3,4,5-trimeth~xy--benzaL)-~-methoxy-propi~nitrile~ 100 mL, of anhydrous ethylene ~lycol m~nomethylether and ~ ~, of sodium methoxide is stirred at 82-84 C for 3 hours, The re-action mixture is cooled to 30 C, then 160 mL. of iso-bùtanol, 40 ml, of methanol, 8~ ~, of guanidine-hydro-ohloride and ~0 ~, of powdered qodium methoxide are added, 1~ The reaotion mixture is stirred at 3~-40 C for an hour and at 90-92 C for 7 hours, The orystaL suspension is oooled to 20 C, filtered and washed on the filter three times with 20 ml. of methanol each, The mvist substance thus obtained is washed with 500 mL, of lukewarm water (30-3~ C) and dried, Thus 102,~ g, of the title com-pound are obtained~ yield: 93,6 %, mp,: L98-201 C,
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of 2,4-diamino-5-(3',4',5'-trimethoxy-benzyl)-pyrimidine of the general formula I
(I) which comprises reacting a compound of the general formula II
(II) (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine in the pres-ence of an alkanol having 4-8 carbon atoms.
(I) which comprises reacting a compound of the general formula II
(II) (wherein R is an alkyl group having 1-4 carbon atoms) with guanidine in the pres-ence of an alkanol having 4-8 carbon atoms.
2. A process according to claim 1 wherein the compound of formula II as defined in claim 1 is prepared by reacting .alpha.-(3,4,5-trimethoxy-benzal)-.beta.-methoxy-propionitrile of the formula III
(III) with an ethylene glycol monoalkylether of the general formula IV
HO-CH2-CH2-OR (IV) (wherein R is as defined in claim 1) in the presence of an alkali alkoxide at a temperature between 60°C and 90°C.
(III) with an ethylene glycol monoalkylether of the general formula IV
HO-CH2-CH2-OR (IV) (wherein R is as defined in claim 1) in the presence of an alkali alkoxide at a temperature between 60°C and 90°C.
3. A process according to claim 1, which comprises carrying out the reac-tion of the compounds of the formulae III
(III) and IV
HO-CH2-CH2-OR (IV) at a temperature between 80°C and 90°C.
(III) and IV
HO-CH2-CH2-OR (IV) at a temperature between 80°C and 90°C.
4. A process according to claim 2, which comprises using sodium methoxideas alkali alkoxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU811869A HU187370B (en) | 1981-06-26 | 1981-06-26 | Improved process for producing 2,4-diamino-5-bracket-3-comma above, 4-comma above,5-comma above-trimethoxy-benzyl-bracket closed-pyrimidine |
| HU1869/81 | 1981-06-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1174679A true CA1174679A (en) | 1984-09-18 |
Family
ID=10956594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000406060A Expired CA1174679A (en) | 1981-06-26 | 1982-06-25 | Process for the preparation of 2,4-diamino-5-(3',4', 5'-trimethoxy-benzyl)-pyrimidine |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5838266A (en) |
| AT (1) | AT387961B (en) |
| AU (1) | AU547823B2 (en) |
| BE (1) | BE893611A (en) |
| CA (1) | CA1174679A (en) |
| CH (1) | CH648834A5 (en) |
| CS (1) | CS244908B2 (en) |
| DD (1) | DD202703A5 (en) |
| DK (1) | DK155434C (en) |
| ES (1) | ES8304949A1 (en) |
| FI (1) | FI76790C (en) |
| FR (1) | FR2508450B1 (en) |
| GB (1) | GB2104508B (en) |
| GR (1) | GR76159B (en) |
| HU (1) | HU187370B (en) |
| IE (1) | IE53466B1 (en) |
| IL (1) | IL66132A (en) |
| IT (1) | IT1190889B (en) |
| SE (1) | SE451133B (en) |
| SU (1) | SU1145929A3 (en) |
| YU (1) | YU42774B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2602507B1 (en) * | 1986-08-08 | 1989-06-09 | Sanofi Pharma | PROCESS FOR THE PREPARATION OF 2,4-DIAMINO-BENZYL-5 PYRIMIDINES |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB743221A (en) * | 1953-05-26 | 1956-01-11 | Wellcome Found | Improvements in or relating to the manufacture of acrylonitriles |
| DE1303727B (en) * | 1959-09-03 | 1976-02-05 | Ausscheidung aus: 14 45 176 The Wellcome Foundation Ltd., London | Alpha-arylidene-substituted propioni-iriles |
| NL122146C (en) * | 1960-09-02 | |||
| US4033962A (en) * | 1975-06-26 | 1977-07-05 | Hoffman-La Roche Inc. | 2,4-Diamino-pyrimidine derivatives and processes |
| DE2635765C3 (en) * | 1976-08-09 | 1979-02-08 | Ludwig Heumann & Co Gmbh, 8500 Nuernberg | Process for the preparation of 2,4-EMamino-5- (3 ', 4'r5'-trimethoxybenzyl) -pyrimidine |
| US4115650A (en) * | 1976-11-17 | 1978-09-19 | Hoffmann-La Roche Inc. | Process for preparing 2,4-diamino-5-(substituted benzyl)-pyrimidines |
| DE2730467A1 (en) * | 1977-07-06 | 1979-01-18 | Basf Ag | BENZYLPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THE SAME |
-
1981
- 1981-06-26 HU HU811869A patent/HU187370B/en not_active IP Right Cessation
-
1982
- 1982-06-23 SE SE8203914A patent/SE451133B/en not_active IP Right Cessation
- 1982-06-23 BE BE1/10544A patent/BE893611A/en not_active IP Right Cessation
- 1982-06-24 FI FI822268A patent/FI76790C/en not_active IP Right Cessation
- 1982-06-24 AT AT0244982A patent/AT387961B/en not_active IP Right Cessation
- 1982-06-24 IT IT22035/82A patent/IT1190889B/en active
- 1982-06-24 CS CS824717A patent/CS244908B2/en unknown
- 1982-06-24 GR GR68560A patent/GR76159B/el unknown
- 1982-06-24 GB GB08218310A patent/GB2104508B/en not_active Expired
- 1982-06-24 SU SU823456294A patent/SU1145929A3/en active
- 1982-06-24 IL IL66132A patent/IL66132A/en unknown
- 1982-06-25 JP JP57109647A patent/JPS5838266A/en active Pending
- 1982-06-25 YU YU1385/82A patent/YU42774B/en unknown
- 1982-06-25 FR FR8211151A patent/FR2508450B1/en not_active Expired
- 1982-06-25 DD DD82241097A patent/DD202703A5/en not_active IP Right Cessation
- 1982-06-25 ES ES513482A patent/ES8304949A1/en not_active Expired
- 1982-06-25 CH CH3908/82A patent/CH648834A5/en not_active IP Right Cessation
- 1982-06-25 IE IE1520/82A patent/IE53466B1/en not_active IP Right Cessation
- 1982-06-25 DK DK288082A patent/DK155434C/en not_active IP Right Cessation
- 1982-06-25 AU AU85346/82A patent/AU547823B2/en not_active Ceased
- 1982-06-25 CA CA000406060A patent/CA1174679A/en not_active Expired
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