CA1166636A - Process for the preparation of 4-amino-2- mercaptopyrimidine - Google Patents
Process for the preparation of 4-amino-2- mercaptopyrimidineInfo
- Publication number
- CA1166636A CA1166636A CA000384806A CA384806A CA1166636A CA 1166636 A CA1166636 A CA 1166636A CA 000384806 A CA000384806 A CA 000384806A CA 384806 A CA384806 A CA 384806A CA 1166636 A CA1166636 A CA 1166636A
- Authority
- CA
- Canada
- Prior art keywords
- process according
- formula
- thiourea
- carried out
- reaction
- 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
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
The present invention relates to a process for the preparation of 4-amino-2-mercaptopyrimidines characterized in that thiourea is reacted with a suitable acrylonitrile derivative.
The present invention relates to a process for the preparation of 4-amino-2-mercaptopyrimidines characterized in that thiourea is reacted with a suitable acrylonitrile derivative.
Description
L`166636 The invention relates to a process for the preparation of 4-amino-2-mercaptopyrimidines.
For the preparation of 4-amino-2-mercaptopyrimidines of formula, there have been described the reaction of uracil, which can optionally be substituted in the 5-position, with phosphorus pentasulphide and then substitution of -the 4-mercapto group in the thus obtained 2,4-dimercaptopyrimidine with the aid of ammonia (U.S. Patent Specification 2,682,542); the condensation of cyanoacetic acid with thiourea to 4-amino-5-carbethoxy-2-mercaptopyrimidine and then saponification and decarboxylation (J. Org. Chem. 27 (1962) 4211); hydrolysis of 4-amino-2-methylmercaptopyrimidine which is only obtainable in a multistep process, with sodium/ammonia (Bull. Soc. Chim.
Belges 79 (1970) 329) and the reaction of 2-thiouracil with phosphoric acid triamide (Isv. Akad. SSSR 1969, 655).
The known processes according to the state of the art all exhibit great disadvantages in their use of expensive reagents and/or expensive process steps.
The task of the present invention was the creation of a process for the preparation of 4-amino-2-mercapto-pyrimidines with simpler reaction procedure and use of inexpensive starting and auxiliary materials.
Generally, the present invention relates to a process for the preparation of 4-amino-2-mercaptopyrimidines charac-teriæed in that thiourea is reacted with an acrylonitrile derivative which includes a suitable leaving group or groups and from which an acrylonitrile residue is containcd in the product.
Thus, the present invention relates to a process for the preparation of 4-amino-2-mercaptopyrimidines of formula (I') ~' C, - 1 - :' 116~36 MH
B \ ~ 1 N~
N ~ SH
wherein B is H or a carbon containing organic group characterized in that thiourea is reacted with a member of the group consisting of A-CH=C-CN
B
and (A)2-CH~CH-CN
wherein B is as defined above and A is a suitable leaving group ; A and B being inert groups which permit the formation of a pyramidine ring i.e. substances of formula (I') abo~e A process in accordance with the present invention can for example bé characterized by a reaction according to the following equation R" O-CH=C-CN
or SH
R" O~
~ CH-,CH-CN
R" O R (3) or Rl\
/ N-CH=C-CN (4) R R
wherein R, R" R' and R2 can be defined for example as below.
In particular, the present invention provides a process for the preparation of 4-amino-2-mercaptopyrimidines of the formula 116~636 ,R, ~\N
~.l `~ SH (1~) wherein R is a hydrogen, straight-chain, branched or cyclic alkyl group with 1 to 20 carbon atoms, straight-chain or branched group (CH2)n-CN (CH2)ncR ~ (CH2)nNH2' (CH2)n OR'~
(CH2)nCyc, wherein Cyc is an alicyclic or heterocyclic mono- or polycyclic ring structure or an aromatic or heterocyclic ring with mono or polycyclic structure which can optionally carry substituents on the ring, R' is an alkyl group with 1 to 12 carbon atoms or residue of a monovalent phenol and n = 1 to 5, characterised in that thiourea is reacted with a 3-alkoxyacrylonitrile of the formula R" -O-CH=C-CN (2) R
wherein R has the above indicated meaning and R'l the meaning of a hydrogen,straight-chain or branched chain alkyl or alkenyl group with 1 to 12 carbon atoms, alicyclic or heterocyclic mononuclear or polynuclear aromatic or cycloaliphatic ring system which optionally bears substituents, or (CH2)mCyc with Cyc having the previously given meaning, the residue (CH2)mOR'" or (CH2-CH2-O)pR'" with m = 1 to 5 and p = 1 to 4 and R"' is a hydrogen, straight-chain or branched chain alkyl group with 1 to 12 carbon atoms, or an acetal of the formula R" O
/CH-CH-CN (3) R" O R
wherein R and R" have the above indicated meaning or a 3-aminoacrylonitriles of the formula R
N-CH=C-CN (4) R R
-~, - 3 -1 166~36 wherein Rl and R2 have the meaning H, the same or different straight-chain or branched chain alkyl-, alkenyl-, or alkynyl residues with 1 to 12 carbon atoms, -Cyc, -(CH2)n-Cyc, wherein Cyc is an alicyclic or heterocyclic mononuclear or polynuclear aromatic or cycloaliphatic ring systems which can optionally carry substituents on the rings and n = o to 5, the grouping X-R4, wherein X is straight-chain, branched-chain or cyclic alkylene or alkenyl residue with
For the preparation of 4-amino-2-mercaptopyrimidines of formula, there have been described the reaction of uracil, which can optionally be substituted in the 5-position, with phosphorus pentasulphide and then substitution of -the 4-mercapto group in the thus obtained 2,4-dimercaptopyrimidine with the aid of ammonia (U.S. Patent Specification 2,682,542); the condensation of cyanoacetic acid with thiourea to 4-amino-5-carbethoxy-2-mercaptopyrimidine and then saponification and decarboxylation (J. Org. Chem. 27 (1962) 4211); hydrolysis of 4-amino-2-methylmercaptopyrimidine which is only obtainable in a multistep process, with sodium/ammonia (Bull. Soc. Chim.
Belges 79 (1970) 329) and the reaction of 2-thiouracil with phosphoric acid triamide (Isv. Akad. SSSR 1969, 655).
The known processes according to the state of the art all exhibit great disadvantages in their use of expensive reagents and/or expensive process steps.
The task of the present invention was the creation of a process for the preparation of 4-amino-2-mercapto-pyrimidines with simpler reaction procedure and use of inexpensive starting and auxiliary materials.
Generally, the present invention relates to a process for the preparation of 4-amino-2-mercaptopyrimidines charac-teriæed in that thiourea is reacted with an acrylonitrile derivative which includes a suitable leaving group or groups and from which an acrylonitrile residue is containcd in the product.
Thus, the present invention relates to a process for the preparation of 4-amino-2-mercaptopyrimidines of formula (I') ~' C, - 1 - :' 116~36 MH
B \ ~ 1 N~
N ~ SH
wherein B is H or a carbon containing organic group characterized in that thiourea is reacted with a member of the group consisting of A-CH=C-CN
B
and (A)2-CH~CH-CN
wherein B is as defined above and A is a suitable leaving group ; A and B being inert groups which permit the formation of a pyramidine ring i.e. substances of formula (I') abo~e A process in accordance with the present invention can for example bé characterized by a reaction according to the following equation R" O-CH=C-CN
or SH
R" O~
~ CH-,CH-CN
R" O R (3) or Rl\
/ N-CH=C-CN (4) R R
wherein R, R" R' and R2 can be defined for example as below.
In particular, the present invention provides a process for the preparation of 4-amino-2-mercaptopyrimidines of the formula 116~636 ,R, ~\N
~.l `~ SH (1~) wherein R is a hydrogen, straight-chain, branched or cyclic alkyl group with 1 to 20 carbon atoms, straight-chain or branched group (CH2)n-CN (CH2)ncR ~ (CH2)nNH2' (CH2)n OR'~
(CH2)nCyc, wherein Cyc is an alicyclic or heterocyclic mono- or polycyclic ring structure or an aromatic or heterocyclic ring with mono or polycyclic structure which can optionally carry substituents on the ring, R' is an alkyl group with 1 to 12 carbon atoms or residue of a monovalent phenol and n = 1 to 5, characterised in that thiourea is reacted with a 3-alkoxyacrylonitrile of the formula R" -O-CH=C-CN (2) R
wherein R has the above indicated meaning and R'l the meaning of a hydrogen,straight-chain or branched chain alkyl or alkenyl group with 1 to 12 carbon atoms, alicyclic or heterocyclic mononuclear or polynuclear aromatic or cycloaliphatic ring system which optionally bears substituents, or (CH2)mCyc with Cyc having the previously given meaning, the residue (CH2)mOR'" or (CH2-CH2-O)pR'" with m = 1 to 5 and p = 1 to 4 and R"' is a hydrogen, straight-chain or branched chain alkyl group with 1 to 12 carbon atoms, or an acetal of the formula R" O
/CH-CH-CN (3) R" O R
wherein R and R" have the above indicated meaning or a 3-aminoacrylonitriles of the formula R
N-CH=C-CN (4) R R
-~, - 3 -1 166~36 wherein Rl and R2 have the meaning H, the same or different straight-chain or branched chain alkyl-, alkenyl-, or alkynyl residues with 1 to 12 carbon atoms, -Cyc, -(CH2)n-Cyc, wherein Cyc is an alicyclic or heterocyclic mononuclear or polynuclear aromatic or cycloaliphatic ring systems which can optionally carry substituents on the rings and n = o to 5, the grouping X-R4, wherein X is straight-chain, branched-chain or cyclic alkylene or alkenyl residue with
2 to 12 carbon atoms, -Cyc-, -(CH2)n-Cyc- or -(CH2)n-Cyc-(CH2)n~
with Cyc and n having the previously given meanings and R4 =
-N-CH=C-CN , R R
Rl and R having the above indicated meanings or R and R form together alkylene or alkenylene residues of a rin~ with
with Cyc and n having the previously given meanings and R4 =
-N-CH=C-CN , R R
Rl and R having the above indicated meanings or R and R form together alkylene or alkenylene residues of a rin~ with
3 to 6 members which is optionally interrup-ted by one or more hetero atoms .
In accordance with the present invention R" , Rl and R2 can,for example, be hydrogen or alkyl of 1 to 4 carbon atoms.
In accordance with the present invention,R can be hydrogen, a branched or straight-chain alkyl of 1 to 6 carbon atoms (preferably a straight-chain), a halo derivative of such alkyl groups, eg., monochloro derivative thereof, phenyl benzyl or -~CH)nOalc, n being an integer from 1 to 6 and alc being an alkyl group of 1 to 6 carbon atoms, phenyl or benzyl.
Cyc can be any ring system of aromatic and cycloali-phatic structure of only carbon atoms and of carbon atoms and one or more heteroatoms.
In accordance with the present invention Heteroatoms can, for example be N, O or S.
The alkoxyacrylonitriles of formula (2) are known and can advantageously be prepared according to German Offenlegungsschrift 2912345.3.
The process of the invention can be so carried out ci 1 16~636 that the alkoxyacrylonitrile (2) or the acetal (3) are brought together with thiourea and a base ln a solvent and reacted at elevated temperature. In this way the addition of the reactants can take place in desired sequence.
The reaction with 3-aminoacrylonitrile is corres-pondlngly preferably carried out, but in the absence of any external solvent used as such.
Examples of solvents which can be used are polar solvents such as water, alcohols, especially those with 1 to
In accordance with the present invention R" , Rl and R2 can,for example, be hydrogen or alkyl of 1 to 4 carbon atoms.
In accordance with the present invention,R can be hydrogen, a branched or straight-chain alkyl of 1 to 6 carbon atoms (preferably a straight-chain), a halo derivative of such alkyl groups, eg., monochloro derivative thereof, phenyl benzyl or -~CH)nOalc, n being an integer from 1 to 6 and alc being an alkyl group of 1 to 6 carbon atoms, phenyl or benzyl.
Cyc can be any ring system of aromatic and cycloali-phatic structure of only carbon atoms and of carbon atoms and one or more heteroatoms.
In accordance with the present invention Heteroatoms can, for example be N, O or S.
The alkoxyacrylonitriles of formula (2) are known and can advantageously be prepared according to German Offenlegungsschrift 2912345.3.
The process of the invention can be so carried out ci 1 16~636 that the alkoxyacrylonitrile (2) or the acetal (3) are brought together with thiourea and a base ln a solvent and reacted at elevated temperature. In this way the addition of the reactants can take place in desired sequence.
The reaction with 3-aminoacrylonitrile is corres-pondlngly preferably carried out, but in the absence of any external solvent used as such.
Examples of solvents which can be used are polar solvents such as water, alcohols, especially those with 1 to
4 carbon atoms, ether alcohols such as for example methylglycol, polaraprotic solvents such as for example dimethylformamide, pyridine, high boiling amines or dimethylsulphoxide or mixtures of non-polar solvents with polar solvents (for example toluene/alcohol mixtures). A further suitable solvent is for example acetonitrile.
The reaction can preferably be carried out in the pre~ence of a suitable base or optionally in the absence of such a base.
For example thiourea and a base, preferably in the absence of a separate solvent, may be suspended in a 3-amino-acrylonitrile, which serves as substrate and solvent, and reacted at elevated temperature. Generally the molar ratio of thiourea to 3-aminoacrylonitrile may amount to 1:1 to 1:4 and optionally there can be used a greater excess of 3-amino-acrylonitrile, for example in order to achieve good stirrability e.g. molar ratio of thiourea to 3-aminoacrylo-nitrile can be l:n, n being a number greater than 4. In the presence of solvents, the excess of 3-aminoacrylonitrile can be small or a smaller excess of thiourea is used. The molar ratio of thiourea to base may amount to 0,5: to 1.5:1.
Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides or alkali metal or alkaline ..... .~
earth metal alcoholatesi likewise suitable are strong organic bases such as for example tertiary amines. Th~ molar ratio of alkoxyacrylonitrile (2) or acetal (3) to base advantageously can amount to 1:1.0 to 1:3.0, preferably , 1:1.0 to 1:1.5.
Optionally there can be employed so-called phase-transfer catalysts, such as ~uaternary ammonium salts or quaternary phosphonium salts or cyclic ethers in amounts of in general 0.5 to 20 mol ~ to the thiourea used, for increasing the yield. Phase-transfer catalysts are des-cribed inter alia in Zeitschrift fur Angewandte Chemie 89 (1977) 521, while catalysts which are quaternary ammonium salts and cyclic ethers are described in German Offenlegungsschrift 2912345.
The molar ratio of alkoxyacrylonitrile (2) or acetal ( 3 ) to thiourea advantageously can amount to 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.5.
The concentration of the reaction partners is determined chiefly according to their solubility, and in general the starting concentration of the alkoxyacrylonitrile (2) or the acetyl (3) may be 0.5 to 10 mol per litre, preferably 1 to 4 mol per litre.
The reaction can take place at increased temperatures in the range of 40 to 250C, preferably at the reflux temperature of the solvent. For reaction of substances of formulae (21 and (3?, preferred temperatures are 40 to 160C, and with substances of formula (4?, loo to 200C.
The reaction takes place in general under normal pressure although it is optionally also possible to work 30 under an excess pressure, for example up to 30 bar.
The reaction time can be from about 0.2 to 10 hours, in general 0.5 to 5 hours.
i - 6 -,, i 1 1~663~
The 4-amino-2-mercaptopyrimidine of formula tl) is generally obtained chiefly as water soluble alkali metal or alkaline earth metal salt which can be converted by acidi-fication at a pH value of 7 + 3 into the free compound which possess poor water solubility.
The working up of the mixture takes place in general so that the solvent is stripped off, the remaining alkali metal or alkaline earth metal salt of the 4-amino-2-mercaptopyrimidine is taken up in water to which generally an inorganic base is added and the free compound is isolated by addition of an organic acid such as for example acetic acid or a mineral acid such as hydrochloric acid or sulphuric acid for adjustment to a pH value of 7 + 3. The mixture can also be acidified for example without previous stripping off of solvent. The product is isolated after filtration, drying and optionally recrystallisation.
4-Amino-2-mercaptopyrimidines can find use for example as additives in photographic material (Japanese Patents 52 058532, 50 019428, 48 59827), as fungicides (Netherlands Patent 68 14057) of as possible chemotherapeutic agents: J. Cell. Physiol. 78 (1971) 25, (C.A. 76, 87 c);
Chromosones Today 1972, 118 (C.A. 81, 100180 Z); Phytopathology 52 (1962) 432 (C.A. 57, 17192 e).
Accordingly the substituent,R has to be determined according to the function in the actual product so that R
can have very different types of structure, with an inert behaviour in the preparation being the sole limitation placed thereon.
The type of substituted amino group RlR2N is determined essentially by the availability of the actual 3~aminoacrylonitrile, as well as by the separability of the starting material and contamination of the product, inter alia.
,, .
Especially noteworthy are the dimethylamino-, diethylamino- and the morpholino groups.
4-Amino-2-mercaptopyrimidine Example 1 97 g (1 mol) of 3-ethoxyacrylonitrile and 91 g (1.2 mol) of thiourea are heated in 460 g of a 16.3 % by weight ethanolic sodium ethylate solution (1~1 mol sodium ethylate) for 3 hours under reflux. The solvent is stripped off in vacuum and the residue ~aken up in 900 ml water. Through addition of hydrochloric acid, a pH value of 7 is achieved and the product precipitated. After filtration, washing with water and dried in vacuo, 112.3 g (88.4% of theoretical) of 4-amino-2-mercaptopyrimidine are obtained. Melting point:
275-80C (decomposition), Molecular weight (mass spectroscopy) 127.
Example 2 9.7 g (0.1 mol) of 2-ethoxyacrylonitrile and 9.1 g (0.12 mol) thiourea are heated in 100 ml of a solution of 0.1 mol natrium-n-butylat in 100 ml n-butanol for 3 hours under reflux. After working up as in Example 1, 11.2 g (88.2%
of theoretical) of the end product are obtained.
Example 3 9.7 g (0.1 mol) of 3-ethoxyacrylonitrile and 9.1 g (0.12 mol) of thiourea are heated in 20 g of a 30% methanolic sodium solution ~0.11 mol of sodium ethylate) for 3 hours under reflux. After working up as in Example 1, 9.3 g (73.9% of theoretical) of end product are obtained.
Example 4 9.7 g (0.1 mol) of 3-ethoxyacrylonitrile and 9.1 g (0.12 mol) of thiourea are heated in 82.5 g of an 8~ ethanolic sodium ethylate solution (0.11 mol sodium ethylate) for 3 hours 1 ~66B36 under reflux. After working up as in Example 1, 9.1 g (71.7% of theoret~cal) of end product are obtained.
Example 5 14.6 g (0.1 mol) of cyanoacetaldehydediethylacetal and 9.1 g (0.12 mol) of thiourea are heated under reflux for 3 hours in 46 g of a 16.3% ethanolic sodium ethylate solution ~0.11 mol sodium ethylate). After working up as ~n Example 1, 11.2 g (88.2~ of theoretical) of end product are obtained.
4-Amino-2-mercapto-5-methylE~rimidine Example 6 8.3 g (0.075 mol) of 3-ethoxy-2-methylacrylonitrile and 6.8 g (0.09 mol) thiourea are heated under reflux for 3 hours in 34.5 g of a 16.3% ethanolic sodium ethylate solution (0.085 mol sodium ethylate). After working up as in Example 1, 6.5 g (61.5% of theoretical) of 4-amino-2-mercapto-5-methyl-pyrimidine are obtained. Melting point: 265-270C
(decomposition) molecular weight (mass spectroscopy) 141.
4-Amino-2-mercapto-5-benzylpyrimidine Example 7 14 g (0.075 mol) of 3-ethoxy-2-benzylacrylonitrile and 6.8 g (0.09 mol) of thiourea are heated under reflux for 3 hours in 34.5 g of a 16.3% ethanolic sodium ethylate solution (0.0825 mol sodium ethylate). After working up as in Example 1, 15.3 g (94.0% of theoretical) of 4-amino-5-benzyl-2-mercaptopyrimidine are obtained. Melting point:
295-305C (decomposition), molecular weight (mass spectroscopy) 217.
4-Amino-2-mercapto-5-methoxymethylpyrimidine Example 8 7.1 g (0.05 mol) of 3-ethoxy-2-methoxymethylacrylo-nitrile and 4.6 g (0.06 mol) of thiourea are heated for 3 hours _ g _ ~ 166636 under reflux in 20.5 g of a 1.83% ethanolic sodium ethylate solution (0.055 mol sodium ethylate). After working up as in Example 1, 6.8 g (79.5% of theoretical) of 4-amino-2-mercapto-
The reaction can preferably be carried out in the pre~ence of a suitable base or optionally in the absence of such a base.
For example thiourea and a base, preferably in the absence of a separate solvent, may be suspended in a 3-amino-acrylonitrile, which serves as substrate and solvent, and reacted at elevated temperature. Generally the molar ratio of thiourea to 3-aminoacrylonitrile may amount to 1:1 to 1:4 and optionally there can be used a greater excess of 3-amino-acrylonitrile, for example in order to achieve good stirrability e.g. molar ratio of thiourea to 3-aminoacrylo-nitrile can be l:n, n being a number greater than 4. In the presence of solvents, the excess of 3-aminoacrylonitrile can be small or a smaller excess of thiourea is used. The molar ratio of thiourea to base may amount to 0,5: to 1.5:1.
Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides or alkali metal or alkaline ..... .~
earth metal alcoholatesi likewise suitable are strong organic bases such as for example tertiary amines. Th~ molar ratio of alkoxyacrylonitrile (2) or acetal (3) to base advantageously can amount to 1:1.0 to 1:3.0, preferably , 1:1.0 to 1:1.5.
Optionally there can be employed so-called phase-transfer catalysts, such as ~uaternary ammonium salts or quaternary phosphonium salts or cyclic ethers in amounts of in general 0.5 to 20 mol ~ to the thiourea used, for increasing the yield. Phase-transfer catalysts are des-cribed inter alia in Zeitschrift fur Angewandte Chemie 89 (1977) 521, while catalysts which are quaternary ammonium salts and cyclic ethers are described in German Offenlegungsschrift 2912345.
The molar ratio of alkoxyacrylonitrile (2) or acetal ( 3 ) to thiourea advantageously can amount to 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.5.
The concentration of the reaction partners is determined chiefly according to their solubility, and in general the starting concentration of the alkoxyacrylonitrile (2) or the acetyl (3) may be 0.5 to 10 mol per litre, preferably 1 to 4 mol per litre.
The reaction can take place at increased temperatures in the range of 40 to 250C, preferably at the reflux temperature of the solvent. For reaction of substances of formulae (21 and (3?, preferred temperatures are 40 to 160C, and with substances of formula (4?, loo to 200C.
The reaction takes place in general under normal pressure although it is optionally also possible to work 30 under an excess pressure, for example up to 30 bar.
The reaction time can be from about 0.2 to 10 hours, in general 0.5 to 5 hours.
i - 6 -,, i 1 1~663~
The 4-amino-2-mercaptopyrimidine of formula tl) is generally obtained chiefly as water soluble alkali metal or alkaline earth metal salt which can be converted by acidi-fication at a pH value of 7 + 3 into the free compound which possess poor water solubility.
The working up of the mixture takes place in general so that the solvent is stripped off, the remaining alkali metal or alkaline earth metal salt of the 4-amino-2-mercaptopyrimidine is taken up in water to which generally an inorganic base is added and the free compound is isolated by addition of an organic acid such as for example acetic acid or a mineral acid such as hydrochloric acid or sulphuric acid for adjustment to a pH value of 7 + 3. The mixture can also be acidified for example without previous stripping off of solvent. The product is isolated after filtration, drying and optionally recrystallisation.
4-Amino-2-mercaptopyrimidines can find use for example as additives in photographic material (Japanese Patents 52 058532, 50 019428, 48 59827), as fungicides (Netherlands Patent 68 14057) of as possible chemotherapeutic agents: J. Cell. Physiol. 78 (1971) 25, (C.A. 76, 87 c);
Chromosones Today 1972, 118 (C.A. 81, 100180 Z); Phytopathology 52 (1962) 432 (C.A. 57, 17192 e).
Accordingly the substituent,R has to be determined according to the function in the actual product so that R
can have very different types of structure, with an inert behaviour in the preparation being the sole limitation placed thereon.
The type of substituted amino group RlR2N is determined essentially by the availability of the actual 3~aminoacrylonitrile, as well as by the separability of the starting material and contamination of the product, inter alia.
,, .
Especially noteworthy are the dimethylamino-, diethylamino- and the morpholino groups.
4-Amino-2-mercaptopyrimidine Example 1 97 g (1 mol) of 3-ethoxyacrylonitrile and 91 g (1.2 mol) of thiourea are heated in 460 g of a 16.3 % by weight ethanolic sodium ethylate solution (1~1 mol sodium ethylate) for 3 hours under reflux. The solvent is stripped off in vacuum and the residue ~aken up in 900 ml water. Through addition of hydrochloric acid, a pH value of 7 is achieved and the product precipitated. After filtration, washing with water and dried in vacuo, 112.3 g (88.4% of theoretical) of 4-amino-2-mercaptopyrimidine are obtained. Melting point:
275-80C (decomposition), Molecular weight (mass spectroscopy) 127.
Example 2 9.7 g (0.1 mol) of 2-ethoxyacrylonitrile and 9.1 g (0.12 mol) thiourea are heated in 100 ml of a solution of 0.1 mol natrium-n-butylat in 100 ml n-butanol for 3 hours under reflux. After working up as in Example 1, 11.2 g (88.2%
of theoretical) of the end product are obtained.
Example 3 9.7 g (0.1 mol) of 3-ethoxyacrylonitrile and 9.1 g (0.12 mol) of thiourea are heated in 20 g of a 30% methanolic sodium solution ~0.11 mol of sodium ethylate) for 3 hours under reflux. After working up as in Example 1, 9.3 g (73.9% of theoretical) of end product are obtained.
Example 4 9.7 g (0.1 mol) of 3-ethoxyacrylonitrile and 9.1 g (0.12 mol) of thiourea are heated in 82.5 g of an 8~ ethanolic sodium ethylate solution (0.11 mol sodium ethylate) for 3 hours 1 ~66B36 under reflux. After working up as in Example 1, 9.1 g (71.7% of theoret~cal) of end product are obtained.
Example 5 14.6 g (0.1 mol) of cyanoacetaldehydediethylacetal and 9.1 g (0.12 mol) of thiourea are heated under reflux for 3 hours in 46 g of a 16.3% ethanolic sodium ethylate solution ~0.11 mol sodium ethylate). After working up as ~n Example 1, 11.2 g (88.2~ of theoretical) of end product are obtained.
4-Amino-2-mercapto-5-methylE~rimidine Example 6 8.3 g (0.075 mol) of 3-ethoxy-2-methylacrylonitrile and 6.8 g (0.09 mol) thiourea are heated under reflux for 3 hours in 34.5 g of a 16.3% ethanolic sodium ethylate solution (0.085 mol sodium ethylate). After working up as in Example 1, 6.5 g (61.5% of theoretical) of 4-amino-2-mercapto-5-methyl-pyrimidine are obtained. Melting point: 265-270C
(decomposition) molecular weight (mass spectroscopy) 141.
4-Amino-2-mercapto-5-benzylpyrimidine Example 7 14 g (0.075 mol) of 3-ethoxy-2-benzylacrylonitrile and 6.8 g (0.09 mol) of thiourea are heated under reflux for 3 hours in 34.5 g of a 16.3% ethanolic sodium ethylate solution (0.0825 mol sodium ethylate). After working up as in Example 1, 15.3 g (94.0% of theoretical) of 4-amino-5-benzyl-2-mercaptopyrimidine are obtained. Melting point:
295-305C (decomposition), molecular weight (mass spectroscopy) 217.
4-Amino-2-mercapto-5-methoxymethylpyrimidine Example 8 7.1 g (0.05 mol) of 3-ethoxy-2-methoxymethylacrylo-nitrile and 4.6 g (0.06 mol) of thiourea are heated for 3 hours _ g _ ~ 166636 under reflux in 20.5 g of a 1.83% ethanolic sodium ethylate solution (0.055 mol sodium ethylate). After working up as in Example 1, 6.8 g (79.5% of theoretical) of 4-amino-2-mercapto-
5-methoxymethylpyrimidine are obtained. Melting point 260-270C (decomposition), molecular weight (mass spectroscopy) 171.
4-Amino-2-mercaptopyrimidine Example 9 5.7 g (0.075 mol) of thiourea, 19.2 g (0.2 mol) of 10 3-dimethylaminoacrylonitrile and 4.05 g (0.075 mol) of sodium methylate (solid) were heated under nitrogen for 2 hours at 140C. After addition of 50 ml of 10% sodium hydroxide containing two phases, the organic phase was separated off after addition of methylene chloride, dried and freed from solvent. Residue:11.2 g of 3-dimethylaminoacrylonitrile.
The aqueous phase was brought with concentrated hydrochloric acid,to a pH value of 7. A solid material separated out which was filtered and dried: 6.86 g (72.0%) of 4-amino-2-mercaptopyrimidine. Melting point: 272-4C.
Example 10 3.8 g (0.05 mol) thiourea, 14.4 g (0.15 mol) 3-dimethylaminoacrylonitrile and 3.74 g (0.055 mol) sodium ethylate (solid) were reacted as in Example 9 and worked up.
Residue: 9.4 g 3-dimethylaminoacrylonitrile.
4-amino-2-mercaptopyrimidine: 1.8 g (28.3 % of theoretical).
Example ll Example 10 is repeated, but with addition of 1.61 g (0.005 mol) tetra-n-butylammoniumbromide.
Residue:11.6 g3-dimethylaminoacrylonitrile. 4-Amino-2-30 mercaptopyrimidine: 2.67 g (42.0% of theoretical).
Example 12 3.04 g (0.04 mol) thiourea, 2.7 g (0.05 mol) 116663~
sodium methylate and 13.8 g 3-morpholinoacrylonitrile are heated for 3 hours under nitrogen at 140C. After working up as in Example 9, 6.3 g (45.7% of theoretical) of 3-morpholinoacrylonitrile were recovered and 1.95 g (38.4%) of 4-amino-2-mercaptopyrimidine were obtained.
4-Amino-2-mercapto-5-meth~lpyrimidine Example 13 1.9 g (0.025 mol) of thiourea, 1.49 g (0.027 mol) of sodium ethylate and 5.5 g (0.05 mol) of 3~dimethylamino-2-methylacrylonitrile are warmed for 5 hours under nitrogen at 140C. After working up as in Example 9, 0.84 g (23.9%
of theoretical) of 4-amino-2-mercapto-5-methylpyrimidine were obtained. Melting point: 263-7C.
4-Amino-2-mercapto-5-benzylpyrimidine Example 14 3.8 g (0.05 mol) of thiourea, 2.96 g (0.055 mol) sodium ethylate and 18.6 g (0.1 mol) of 3-dimethylamino-2-benzylacrylonitrile are heated for 5 hours under nitrogen at 140C. After working up as in Example 9, 5.6 g (51.6%
of theoretical) of 4-amino-2-mercapto-5-benzylpyrimldine were obtained. Melting point: 300-302C (decomposition).
4-Amino-2-mercaptopyrimidine Example 9 5.7 g (0.075 mol) of thiourea, 19.2 g (0.2 mol) of 10 3-dimethylaminoacrylonitrile and 4.05 g (0.075 mol) of sodium methylate (solid) were heated under nitrogen for 2 hours at 140C. After addition of 50 ml of 10% sodium hydroxide containing two phases, the organic phase was separated off after addition of methylene chloride, dried and freed from solvent. Residue:11.2 g of 3-dimethylaminoacrylonitrile.
The aqueous phase was brought with concentrated hydrochloric acid,to a pH value of 7. A solid material separated out which was filtered and dried: 6.86 g (72.0%) of 4-amino-2-mercaptopyrimidine. Melting point: 272-4C.
Example 10 3.8 g (0.05 mol) thiourea, 14.4 g (0.15 mol) 3-dimethylaminoacrylonitrile and 3.74 g (0.055 mol) sodium ethylate (solid) were reacted as in Example 9 and worked up.
Residue: 9.4 g 3-dimethylaminoacrylonitrile.
4-amino-2-mercaptopyrimidine: 1.8 g (28.3 % of theoretical).
Example ll Example 10 is repeated, but with addition of 1.61 g (0.005 mol) tetra-n-butylammoniumbromide.
Residue:11.6 g3-dimethylaminoacrylonitrile. 4-Amino-2-30 mercaptopyrimidine: 2.67 g (42.0% of theoretical).
Example 12 3.04 g (0.04 mol) thiourea, 2.7 g (0.05 mol) 116663~
sodium methylate and 13.8 g 3-morpholinoacrylonitrile are heated for 3 hours under nitrogen at 140C. After working up as in Example 9, 6.3 g (45.7% of theoretical) of 3-morpholinoacrylonitrile were recovered and 1.95 g (38.4%) of 4-amino-2-mercaptopyrimidine were obtained.
4-Amino-2-mercapto-5-meth~lpyrimidine Example 13 1.9 g (0.025 mol) of thiourea, 1.49 g (0.027 mol) of sodium ethylate and 5.5 g (0.05 mol) of 3~dimethylamino-2-methylacrylonitrile are warmed for 5 hours under nitrogen at 140C. After working up as in Example 9, 0.84 g (23.9%
of theoretical) of 4-amino-2-mercapto-5-methylpyrimidine were obtained. Melting point: 263-7C.
4-Amino-2-mercapto-5-benzylpyrimidine Example 14 3.8 g (0.05 mol) of thiourea, 2.96 g (0.055 mol) sodium ethylate and 18.6 g (0.1 mol) of 3-dimethylamino-2-benzylacrylonitrile are heated for 5 hours under nitrogen at 140C. After working up as in Example 9, 5.6 g (51.6%
of theoretical) of 4-amino-2-mercapto-5-benzylpyrimldine were obtained. Melting point: 300-302C (decomposition).
Claims (25)
1. A process for the preparation of 4-amino-2-mercaptopyrimidines of the formula (1) wherein R is a hydrogen. atom, R a straight-chain, branched or cyclic alkyl group with 1 to 20 carbon atoms, a straight-chain or branched group (CH2)n-CN, (CH2)nCOOR', (CH2)nNH2, (CH2)nOR', (CH2)nCyc, wherein Cyc is an alicyclic or heterocyclic mono- or poly- cyclic structure or an aromatic or heterocyclic ring with mono or polycyclic structure which can optionally carry substituents on the ring, R' is an alkyl group with 1 to 12 carbon atoms or residue of monovalent phenol and n = 1 to 5, characterised in that thiourea is reacted with a member of the group consisting of (a) 3-alkoxyacrylonitriles of the formula R'' -O-CH=?-CN (2) wherein R has the above indicated meaning and R'' the meaning of a straight-chain. or branched ckain alkyl or alkenyl group with 1 to 12 carbon atoms, alicyclic or heterocyclic, mononuclear or polynuclear aromatic or cycloaliphatic ring system which optionally bear substituents, or (CH2)mCyc with Cyc havlng the prevlously given meanlng, the residue (CH2)mOR''' or (CH2-CH2-O)pR''' with m = 1 to 5 and p = 1 to 4 and R''' is a straight-chain or branched chain alkyl group with 1 to 12 carbon atoms, (b) acetals of the formula (3) wherein R and R" have the above i.ndicated meaning and (c) 3-aminoacrylonitriles of the formula (4) wherein R1 and R2 have the meaning H, the same or different straight-chain or branched chain alkyl-, alkenyl-, or alkynyl residues with 1 to 12 carbon atoms, -Cyc, -(CH2)n-Cyc, wherein Cyc is an alicyclic or heterocyclic mononuclear or polynuclear aromatic or cycloaliphatic ring systems which can optionally carry substituents on the rings and n = 0 to 5, the grouping X-R4, wherein X is straight-chain, branched-chain or cyclic alkylene or alkenyl residue with 2 to 12 carbon atoms, -Cyc, -(CH2)n-Cyc- or -(CH2)n-Cyc-(CH2)n- with Cyc and n having the previously given meanings and R4 =
R1 and R having the above indicated meanings or R1 and R2 form together alkylene or alkenylene residues of a ring with 3 to 6 members which is optionally interrupted by one or more hetero atoms .
R1 and R having the above indicated meanings or R1 and R2 form together alkylene or alkenylene residues of a ring with 3 to 6 members which is optionally interrupted by one or more hetero atoms .
2. Process according to claim 1, characterized in that thiourea is reacted either with a 3-alkoxyacrylonitrile of formula (2) or an acetal of formula (3).
3. Process according to claim 1,characterized in that thiourea is reacted with a 3-aminoacrylonitrile of formula (4).
4. Process according to claim 1, characterized in that the reaction is carried out in the presence of a suitable polar solvent or a suitable polar aprotic solvent.
5. Process according to claim 2, characterized in that the reaction is carried out in the presence of a suitable polar solvent or a suitable polar aprotic solvent.
6. Process according to claim 1, characterized in that it is carried out in the presence of a suitable solvent selected from the group consisting of water, alcohols and ether alcohols.
7. Process according to claim 1, characterized in that it is carried out in the presence of a suitable solvent selected from the group consisting of water, alcohols of 1 to 4 carbon atoms, methylglycol, dimethylformamide and dimethyl-sulphoxide.
8. Process according to claim 3, characterized in that the reaction is carried out in the absence of an external solvent.
9. Process according to any one of claims 1, 5 and 8 characterized in that the reaction is carried out in the presence of a suitable base.
10. Process according to claim 5, characterized in that the reaction is carried out in the presence of a suitable base selected from the group consisting of alkali-metal or alkaline-earth metal hydroxides or alkali-metal or alkaline earth-metal alcoholites.
11. Process according to claim 10, characterized in that the molar ratio of 3-alkoxyacrylonitrile of formula (2) or acetal of formula (3) to said suitable base amounts to 1:1.0 to 1:3Ø
12. Process according to claim 10, characterized in that the moral ratio of 3-alkoxyacrylonitrile of formula (2) or acetal of formula (3) to said suitable base amounts to 1:1.0 to 1:1.5.
13. Process according to claim 2, characterized in that the molar ratio of 3-alkoxyacrylonitrile of formula (2) or acetal of formula (3) to thiourea amounts to 1:1.0 to 1:2Ø
14. Process according to claim 2, characterized in that the molar ratio of 3-alkoxyacrylonitrile of formula (2) or acetal of formula (3) to thiourea amounts to 1:1.0 to 1:1.5.
15. Process according to claim 11, characterized in that the molar ratio of 3-alkoxyacrylonitrile of formula (2) or acetal of formula (3) to thiourea amounts to 1:1.0 to 1:2Ø
16. Process according to claim 1, characterized in that the reaction is carried out in a temperature range of between 40°C to 250°C.
17. Process according to claim 1, characterized in that the reaction is carried out at a pressure in the range of normal pressure to 30 bar.
18. Process according to claim 15, characterized in that the reaction is carried out in a temperature range of between 40°C to 250°C and at a pressure in the range of normal pressure to 30 bar.
19. Process according to claim 8, characterized in that the reaction is carried out in the presence of a suitable base selected from the group consisting of alkali-metal or alkaline-earth metal hydroxides or alkali-metal or alkaline earth-metal alcoholites.
20. Process according to claim 19, characterized in that the molar ratio of thiourea to said suitable base amounts to 0:5.1 to 1:5.1.
21. Process according to claim 3, characterized in that the molar ratio of 3-aminoacrylonitrile of formula (4) to thiourea is equal to or greater then 1:1.
22. Process according to claim 3, characterized in that the molar ratio of 3-aminoacrylonitrile of formula (4) amounts to 1:1 to 4:1.
23. Process according to claim 20, characterized in that the molar ratio of 3-aminoacrylonitrile of formula (4) to thiourea is equal to or greater than 1:1.
24. Process according to claim 20, characterized in that the molar ratio of 3-aminoacrylonitrile of formula (4) amounts to 1:1 to 4:1.
25. Process according to claim 23, characterized in that the reaction is carried out in a temperature range of between 40°C to 250°C and at a pressure in the range of normal pressure to 30 bar.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3032548.5 | 1980-08-29 | ||
| DE19803032548 DE3032548A1 (en) | 1980-08-29 | 1980-08-29 | 4-Amino-2-mercapto-pyrimidine derivs. prodn. - by reaction of 3-alkoxy-acrylonitrile, 2-formyl-propionitrile acetal or 3-amino-acrylonitrile with thiourea |
| DEP3045076.1 | 1980-11-29 | ||
| DE19803045076 DE3045076A1 (en) | 1980-11-29 | 1980-11-29 | 4-Amino-2-mercapto-pyrimidine derivs. prodn. - by reaction of 3-alkoxy-acrylonitrile, 2-formyl-propionitrile acetal or 3-amino-acrylonitrile with thiourea |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1166636A true CA1166636A (en) | 1984-05-01 |
Family
ID=25787491
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000384806A Expired CA1166636A (en) | 1980-08-29 | 1981-08-28 | Process for the preparation of 4-amino-2- mercaptopyrimidine |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0046856A3 (en) |
| CA (1) | CA1166636A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6083468A (en) * | 1996-04-10 | 2000-07-04 | Basf Aktiengesellschaft | Method of manufacturing a hydrogenation catalyst |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1303727B (en) * | 1959-09-03 | 1976-02-05 | Ausscheidung aus: 14 45 176 The Wellcome Foundation Ltd., London | Alpha-arylidene-substituted propioni-iriles |
| DE1620729A1 (en) * | 1965-07-08 | 1970-08-20 | Wellcome Found | Process for the preparation of substituted benzylpyrimidines |
-
1981
- 1981-07-11 EP EP81105426A patent/EP0046856A3/en not_active Ceased
- 1981-08-28 CA CA000384806A patent/CA1166636A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6083468A (en) * | 1996-04-10 | 2000-07-04 | Basf Aktiengesellschaft | Method of manufacturing a hydrogenation catalyst |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0046856A2 (en) | 1982-03-10 |
| EP0046856A3 (en) | 1982-07-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0224339B1 (en) | Pyrimidine derivative, process for preparing same and agricultural or horticultural fungicidal composition containing same | |
| EP0585014B1 (en) | Process for the preparation of 2-(un)substituted 4-alkylimidazoles | |
| US5216161A (en) | Process for preparing 2,5-diamino-4,6-dichloropyrimidine | |
| HU195785B (en) | Process for production of 2-methil-4-amin-5-/formilamin-methil/-piramidine | |
| CA1166636A (en) | Process for the preparation of 4-amino-2- mercaptopyrimidine | |
| US4831138A (en) | Process for the preparation of aminopyrimidines | |
| US4650892A (en) | Process for the preparation of herbicidal sulfonamides | |
| PL119712B1 (en) | Process for preparing 6-piperidin-2,4-diaminopyrimidine 3-oxideina | |
| US4886881A (en) | Preparation of 2-amino triazines | |
| US5070201A (en) | Process for the preparation of aminopyrimidines | |
| KR100273823B1 (en) | Process for the preparation of 5-substituted cytosines and other 4,5-disubstituted pyrimidine-2(1h)-ones | |
| CA2083790C (en) | Process for the production of 2-substituted 4,6-dialkoxypyrimidines | |
| US4658035A (en) | Preparation of 2-alkyl-4,5-dihydroxymethylimidazoles | |
| US5536841A (en) | Process for the preparation of 2-substituted 5-chloroimidazole-4-carbaldehydes | |
| US5717096A (en) | Process for the preparation of a 2-alkoxy-6-(trifluoromethyl)pyrimidin-4-ol | |
| US3549630A (en) | Method of preparing isocyanuric acids and their salts | |
| CA2101821C (en) | Process for the production of 2-halo-4,6-dialkoxypyrimidines | |
| US6340757B1 (en) | 6-(1-fluoroalkyl)-4-pyrimidones and processes for producing the same | |
| KR870002019B1 (en) | Process for preparation of amine derivatives | |
| CA2234132A1 (en) | Process to chloroketoamines using carbamates | |
| US5208337A (en) | Process for the preparation of aminopyrimidines | |
| US4748245A (en) | Process for making phenylthiopyrimidines | |
| US4536574A (en) | Preparation of 2-alkylthiomethyl-4-hydroxypyrimidines | |
| US5286861A (en) | Process for preparing uracil derivatives | |
| US6410730B2 (en) | Process for preparation of sulfonylurea salts |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |