CA2227949A1 - Method of producing dihydroxypyrimidine derivatives - Google Patents
Method of producing dihydroxypyrimidine derivatives Download PDFInfo
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- CA2227949A1 CA2227949A1 CA002227949A CA2227949A CA2227949A1 CA 2227949 A1 CA2227949 A1 CA 2227949A1 CA 002227949 A CA002227949 A CA 002227949A CA 2227949 A CA2227949 A CA 2227949A CA 2227949 A1 CA2227949 A1 CA 2227949A1
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- general formula
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- malonic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
Abstract
The invention concerns a novel method of producing dihydroxypyrimidine derivatives of general formula (I), in which R1 and R2 are identical or different and designate a hydrogen atom, a C1 - C4 alkyl group or an aryl group. In the first step, as a substrate, a compound of general formula (II), in which R2 has the above meaning and R3 designates -CN or COOR4, R4 being a C1 - C4 alkyl group, is converted by microorganisms of the Rhodococcus species into a malonic acid derivative of general formula (III), in which R2 has the above meaning and R5 designates a C1 - C4 alkoxy group or -NH2, and this derivative is then cyclized in the second step with a carboxylic acid amide of general formula (IV), in which R1 has the above meaning, in the presence of a base to form an end product according to formula (I).
Description
WO 9,~/08152 PCT/EP96/03826 Process for the preparation of dihydroxypyrimidine derivatives The invention relates to a novel process for the preparation of dihydroxypyrimidine derivatives of the general formula R~
HO ~ OH
NON
in which R1 and R2 are identical or different and are a hydrogen atom, aryl group or a C1-C4-alkyl group, start:ing from a compound of the general formula ~ - CH- ~
in which R2 has the meAn; ng mentioned and R3 is -CN or CooR4, in which R4 is a C1-C4-alkyl group.
Dihydroxypyrimidine is an important intermediate for the preparation of insecticides such as, for examE)le, for the preparation of 4,6-pyrimidinediyl-bis(t:hiono)(thiol)phosphoric(phosphonic) acid esters (DE
25 2~, 324).
To date, several processes for the preparation of di.hydroxypyrimidine or its derivatives are known.
For example, the preparation of dihyclropyrimidine starting from malonamide (German Patent Specification 12 00 308) i~ known. In this preparation, malonamide is cyclized with formamide in WO 9,l/08152 - 2 - PCT/EP96/03826 the presence of sodium methanolate to give the dihyclroxypyrimidine.
This process has the disadvantage that the start:ing material malonamide is relatively costly.
D.J. Brown (J. Chem. Soc., 1956, pp. 2312 2314) also describes a process for the preparation of dihyclroxypyrimidine starting from malonamide. In this process, malonamide is cyclized in the presence of sodi~L ethoxide and ethyl formate to give the dihyclroxypyrimidine. This process on the one hand has the disadvantage that dihydroxypyrimidine is only obtained in moderate yield. On the other hand, as alreaLdy described above, the starting material malonamide is relatively costly.
JP 4260 comprises a process for the preparation of dLihydroxypyrimidine by reaction of malonate with formamide in the presence of an alkali metal Al ko~;de. A
disacLvantage of this process iq that the formamide has to be! used in a large excess.
US Patent Specification 17 66 748 describes a proce!ss for the preparation of 2-aryl-4,6-dihydroxy-pyrimidines starting from diethyl malonate. In this proce!ss, diethyl malonate is cyclized in the presence of an amidine of an arylcarboxylic acid to give the corres-po~; ng product. This process has the disadvantage that the correspo~; ng amidines are very costly.
The object of the present invention was to make available a more economical and ecologically more favourable process for the preparation of dihydLroxypyrimidine derivatives, in which the dihydLroxypyrimidine can be isolated in good yield and purity.
WO 9,'/08152 - 3 - PCT/EP96/03826 This object was achieved by the novel process according to Claim 1.
In the first process stage, as substrate, a compound of the general formula CN -- CH R3 ll in which R2 and R3 have the m~An;ng mentioned, is conver-ted by means of microorganisms of the genus Rhodococcus into a malonic acid derivative of the general formula O O
~ ' ~ Rs III
in which R2 has the me~n;ng mentioned and R5 is a C1-C4-alko~cy group or NH2-The compounds of the general formula II such asmethyl or ethyl cyanoacetate are commercially available compounds.
Expediently, the first stage is carried out using microorganisms of the species Rhodococcus rhodochrous, Rhodococcus sp. 5 - 6 or Rhodococcus equi, preferably using microorganisms of the species Rhodococcus sp. 5 - 6 (FERM BP-687), Rhodococcus rhodochrous J1 (FERM BP-1478) or using microorganisms of the species Rhodococcus egui TG328 (FERM BP-3791 or DSM
6710). In particular, the reaction is carried out by means of microorgani~ms of the species Rhodococcus rhodochrous (FERM BP-1478). The microorganisms of the species Rhodococcus sp. 5 - 6, Rhodococcus rhodochrous WO 9,'/08152 - 4 - PCT/EP96/03826 Jl aLnd Rhodococcus ecrui TG328 are microorganisms described in the literature. Rhodococcus rhodochrous J1 (FERM BP-1478) is described in detail in EP-B 307 928, Rhodococcus sp. 5 - 6 (FERM BP-687) in EP-A 0 188 316 and ~odococcus eclui TG328 (FERM BP-3791) in US Patent Specification 5 258 305.
Also suitable for the process are the function-ally equivalent variantq and mutants of these micro-orgarLisms. "Functionally equivalent variants and mutants" are understood as m~ning microorganisms which esserLtially have the same properties and functions as the original microorganisms. Variants and mutants of this type can be r~n~nmly formed, for example, by means of U~' irradiation.
Customarily, the microorganiqms are cultured (grown) according to EP-B 307 928 before the actual biotransformation and the active enzymes are induced.
Prefe~rably, the biotransformation is carried out, in a m~nner customary to those skilled in the art, using immok,ilized microorganism cells.
Expediently, the biotransformation is carried out in a pH range from 3 to 7, preferably in a pH range from 4 to 6.
The biotransformation can be carried out at a temperature from 0 to 30~C, preferably from 3 to 20~C.
As substrates, compounds of the general formula II are used in which R2 is a hydrogen atom, aryl group or a C1-C4-alkyl group and R3 is -CN or CooR4, in which R4 is a Cl-C4-alkyl group. As a C1-C4-alkyl group, methyl-, ethyl-, propyl-, i-propyl-, butyl-, i-butyl- or t-butyl-can be used. As aryl-, for example, phenyl-, substituted or unsubstituted, or naphthyl- can be used. Preferably, W0 9,'/08152 - 5 - PCT/EP96/03826 R2 i~3 a hydrogen atom and R3 is methyl-, ethyl-, i-propyl- or -CN.
After a customary reaction time of 1 to 100 h, the amides formed can be i~301ated in a simple m~nne~
5 e.g. by L~l,o~,al of water.
In the second process stage, the malonic acid derivative of the general formula O O
H2N/~\R5 is cy clized with a carboxamide of the general formula Rl I NH IV
in tlhe presence of a base to give the final product according to formula I.
The radical R5 is a Cl-C4-alkoxy group such as methc,xy-, ethoxy-, propoxy-, butoxy-, i-butoxy-, 15 t-butoxy- or -NH2. Preferably, R5 is methoxy- or ethoxy-.
The radical R2 has the definition already described.
The radical Rl is either C1-C4-alkyl- such as methyl-, ethyl-, propyl-, i-propyl-, butyl-, t-butyl-, i-butyl- or a hydrogen atom. Preferably, Rl is a 20 hydrogen atom.
Expediently, the carboxamide is used in a ratio from 2 to 8 mol per mole of malonic acid derivative, preferably in a ratio of 2 to 3 mol.
As a ba~3e, expediently an alkali metal 25 alcoholate such as ~30dium or potassium methanolate, ethanolate, propanolate, butanolate, i-butanolate, t-butanolate, amylate or i-amylate is used. Preferably, sodium methanolate is used.
The concentration of the base can vary in a range from 2 to 6 mol per mole of malonic acid derivative, preferably in a range from 3 to 4 mol.
As solvents for the second stage, polar solvents such as methanol, ethanol, propanol or butanol can be used, preferably methanol is used.
Expediently, the second stage is carried out at a temperature from 30~C up to the reflux temperature of the c:orrespon~;ng solvent, preferably at reflux tempera-ture of the correspon~; ng solvent.
After a further reaction time of 1 to 6 h, the dihyclroxypyrimidine derivative of the formula I can be isolaLted by customary working-up methods.
ExamE~les ExamE~le 1 Prepa~ration of malonic acid monoamide monoesters (carbamoylacetic acid esters) from methyl cyanoacetate, ethyl cyanoacetate and isopropyl cyanoacetate In a glass vessel ecIuipped with a maLgnetic stirrer, 200 ml of water, 0.62 g of Jl biomass (FERM BP-1478) (calculated as dry weight) and 50 g of the corres-pon~; ng cyanoacetic acid ester were incubated at room tempe!rature for 16 hours. The pH was approximately 5. By mean~' of GC ar~Lalysis, starting maLterial could no longer be detected at this time. The biomass was filtered off and t:he water was removed from the product under reduced prescure. Traces of water were then L~..o~ed azeotropic-ally by addition of toluene to the residue. The isolated WO 9,'/08152 - 7 - PCT/EP96/03826 yielcl was ~90% and the purity of the carbamoylacetic acid ester formed was ~95% according to GC. Isopropyl carbaLmoylacetate precipitated from aqueous solution under these conditions during the biotransformation. In this case, the suspension was first warmed to 50~C in order to bring the isopropyl ester into solution before filte!ring off the biomass.
ExamE~le 2 Influence of the pH on the conversion of methyl cyano-acetaLte to methyl carbamoylacetate A 1 l Applikon fermenter was used for the experiments. The biotransformation batch contained 200 g of methyl cyanoacetate, 800 ml of water and 1.2 g of Jl biomass (FERM BP-687) (calculated as dry weight). The vesse!l was stirred at 200 rpm and the te~Lperature was 12~C - 17~C. The reaction was terminated after 16 h. It was not possible to detect any starting material at this time by means of GC analysis. The pH in batch A was not kept constant and fell from an initial value of 5.7 to 4.7 at the end of the reaction.
In batch B the pH during the entire reaction time was kept constant at a value of 8Ø To do this, 30% N~aOH solution was used.
Working up was carried out as described above.
By means of titration, it was possible to detect a sicrnificant amount of methyl carba~Loylacetate both in batch A and in batch B. In contrast to batch B, however, the p~roduct in batch A was significantly purer.
CA 02227949 l998-0l-26 ExamE~le 3 Conversion of malononitrile to malonamide using J1 biomaLss (FERM BP-1478) In a glass vessel equipped with a magnetic stirrer, 90 ml of water, O. 3 g of J1 biomass (calculated as dry weight) and 10 g of malononitrile were incubated at room temperature for 6 h. It was no longer possible to detect any starting material at this time by means of GC ,~nalysis. Malonamide precipitated from aqueous solut;ion under these conditions during the biotransformation. The suspension was warmed to 50~C in order to bring the product into solution before the bioma.ss was filtered off.
The water was removed from the product under reduced pressure. The isolated yield was ~90% and the purity of the malonamide formed was ~95% (GC).
ExamF,le 4 Prepa.ration of dihydroxypyrimidine (Rl = R2 = H) Formamide (26.43 g; 575 mmol) was added to sodium methylate solution (157.56 g; 875 mmol) at room temperature in the course of 5 minutes, the solution warming to 28~C. The solution was heated to reflux (64~C) and ~kept at this temperature for 15 minutes. Malonic acid monoamide monoester, dissolved in 30 ml of metha.nol, was added dropwise to this warm solution at 64~C. In the course of this a colourless suspension gradu.ally resulted. The readily stirrable suspension was refluxed for 3 h and then cooled to room temperature.
125 ml of water were added such that the temperature was about 25~C. At the end of the addition, a slightly yellcw solution was obtained. The pH was adjuRted to 4.0 by the addition of 82.0 g of conc. HCl solution (the WO 9J~/O8152 - 9 - PCT/EP96/03826 tempe!rature was between 25 and 30~C). The suspension was stirred at room temperature for 15 min, and the precipitated solid was filtered off and thoroughly waqhe!d twice with 45 ml of water. The pale yellow solid 5 wa~ ,~ried in a vacuum drying oven at 60~C for 24 h.
22.67 g (content 97.0% according to HPLC), correspo~Aing to a yield of 78.5%, were obtained.
lH NMR (DMSOd6) ~: 5.22 (a, lH);
8.05 (~, lH);
11.5 - 12.2 (~, br, 2H) .
3C NMR (DMSOd6) ~: 89.99;
149.90;
166.17.
HO ~ OH
NON
in which R1 and R2 are identical or different and are a hydrogen atom, aryl group or a C1-C4-alkyl group, start:ing from a compound of the general formula ~ - CH- ~
in which R2 has the meAn; ng mentioned and R3 is -CN or CooR4, in which R4 is a C1-C4-alkyl group.
Dihydroxypyrimidine is an important intermediate for the preparation of insecticides such as, for examE)le, for the preparation of 4,6-pyrimidinediyl-bis(t:hiono)(thiol)phosphoric(phosphonic) acid esters (DE
25 2~, 324).
To date, several processes for the preparation of di.hydroxypyrimidine or its derivatives are known.
For example, the preparation of dihyclropyrimidine starting from malonamide (German Patent Specification 12 00 308) i~ known. In this preparation, malonamide is cyclized with formamide in WO 9,l/08152 - 2 - PCT/EP96/03826 the presence of sodium methanolate to give the dihyclroxypyrimidine.
This process has the disadvantage that the start:ing material malonamide is relatively costly.
D.J. Brown (J. Chem. Soc., 1956, pp. 2312 2314) also describes a process for the preparation of dihyclroxypyrimidine starting from malonamide. In this process, malonamide is cyclized in the presence of sodi~L ethoxide and ethyl formate to give the dihyclroxypyrimidine. This process on the one hand has the disadvantage that dihydroxypyrimidine is only obtained in moderate yield. On the other hand, as alreaLdy described above, the starting material malonamide is relatively costly.
JP 4260 comprises a process for the preparation of dLihydroxypyrimidine by reaction of malonate with formamide in the presence of an alkali metal Al ko~;de. A
disacLvantage of this process iq that the formamide has to be! used in a large excess.
US Patent Specification 17 66 748 describes a proce!ss for the preparation of 2-aryl-4,6-dihydroxy-pyrimidines starting from diethyl malonate. In this proce!ss, diethyl malonate is cyclized in the presence of an amidine of an arylcarboxylic acid to give the corres-po~; ng product. This process has the disadvantage that the correspo~; ng amidines are very costly.
The object of the present invention was to make available a more economical and ecologically more favourable process for the preparation of dihydLroxypyrimidine derivatives, in which the dihydLroxypyrimidine can be isolated in good yield and purity.
WO 9,'/08152 - 3 - PCT/EP96/03826 This object was achieved by the novel process according to Claim 1.
In the first process stage, as substrate, a compound of the general formula CN -- CH R3 ll in which R2 and R3 have the m~An;ng mentioned, is conver-ted by means of microorganisms of the genus Rhodococcus into a malonic acid derivative of the general formula O O
~ ' ~ Rs III
in which R2 has the me~n;ng mentioned and R5 is a C1-C4-alko~cy group or NH2-The compounds of the general formula II such asmethyl or ethyl cyanoacetate are commercially available compounds.
Expediently, the first stage is carried out using microorganisms of the species Rhodococcus rhodochrous, Rhodococcus sp. 5 - 6 or Rhodococcus equi, preferably using microorganisms of the species Rhodococcus sp. 5 - 6 (FERM BP-687), Rhodococcus rhodochrous J1 (FERM BP-1478) or using microorganisms of the species Rhodococcus egui TG328 (FERM BP-3791 or DSM
6710). In particular, the reaction is carried out by means of microorgani~ms of the species Rhodococcus rhodochrous (FERM BP-1478). The microorganisms of the species Rhodococcus sp. 5 - 6, Rhodococcus rhodochrous WO 9,'/08152 - 4 - PCT/EP96/03826 Jl aLnd Rhodococcus ecrui TG328 are microorganisms described in the literature. Rhodococcus rhodochrous J1 (FERM BP-1478) is described in detail in EP-B 307 928, Rhodococcus sp. 5 - 6 (FERM BP-687) in EP-A 0 188 316 and ~odococcus eclui TG328 (FERM BP-3791) in US Patent Specification 5 258 305.
Also suitable for the process are the function-ally equivalent variantq and mutants of these micro-orgarLisms. "Functionally equivalent variants and mutants" are understood as m~ning microorganisms which esserLtially have the same properties and functions as the original microorganisms. Variants and mutants of this type can be r~n~nmly formed, for example, by means of U~' irradiation.
Customarily, the microorganiqms are cultured (grown) according to EP-B 307 928 before the actual biotransformation and the active enzymes are induced.
Prefe~rably, the biotransformation is carried out, in a m~nner customary to those skilled in the art, using immok,ilized microorganism cells.
Expediently, the biotransformation is carried out in a pH range from 3 to 7, preferably in a pH range from 4 to 6.
The biotransformation can be carried out at a temperature from 0 to 30~C, preferably from 3 to 20~C.
As substrates, compounds of the general formula II are used in which R2 is a hydrogen atom, aryl group or a C1-C4-alkyl group and R3 is -CN or CooR4, in which R4 is a Cl-C4-alkyl group. As a C1-C4-alkyl group, methyl-, ethyl-, propyl-, i-propyl-, butyl-, i-butyl- or t-butyl-can be used. As aryl-, for example, phenyl-, substituted or unsubstituted, or naphthyl- can be used. Preferably, W0 9,'/08152 - 5 - PCT/EP96/03826 R2 i~3 a hydrogen atom and R3 is methyl-, ethyl-, i-propyl- or -CN.
After a customary reaction time of 1 to 100 h, the amides formed can be i~301ated in a simple m~nne~
5 e.g. by L~l,o~,al of water.
In the second process stage, the malonic acid derivative of the general formula O O
H2N/~\R5 is cy clized with a carboxamide of the general formula Rl I NH IV
in tlhe presence of a base to give the final product according to formula I.
The radical R5 is a Cl-C4-alkoxy group such as methc,xy-, ethoxy-, propoxy-, butoxy-, i-butoxy-, 15 t-butoxy- or -NH2. Preferably, R5 is methoxy- or ethoxy-.
The radical R2 has the definition already described.
The radical Rl is either C1-C4-alkyl- such as methyl-, ethyl-, propyl-, i-propyl-, butyl-, t-butyl-, i-butyl- or a hydrogen atom. Preferably, Rl is a 20 hydrogen atom.
Expediently, the carboxamide is used in a ratio from 2 to 8 mol per mole of malonic acid derivative, preferably in a ratio of 2 to 3 mol.
As a ba~3e, expediently an alkali metal 25 alcoholate such as ~30dium or potassium methanolate, ethanolate, propanolate, butanolate, i-butanolate, t-butanolate, amylate or i-amylate is used. Preferably, sodium methanolate is used.
The concentration of the base can vary in a range from 2 to 6 mol per mole of malonic acid derivative, preferably in a range from 3 to 4 mol.
As solvents for the second stage, polar solvents such as methanol, ethanol, propanol or butanol can be used, preferably methanol is used.
Expediently, the second stage is carried out at a temperature from 30~C up to the reflux temperature of the c:orrespon~;ng solvent, preferably at reflux tempera-ture of the correspon~; ng solvent.
After a further reaction time of 1 to 6 h, the dihyclroxypyrimidine derivative of the formula I can be isolaLted by customary working-up methods.
ExamE~les ExamE~le 1 Prepa~ration of malonic acid monoamide monoesters (carbamoylacetic acid esters) from methyl cyanoacetate, ethyl cyanoacetate and isopropyl cyanoacetate In a glass vessel ecIuipped with a maLgnetic stirrer, 200 ml of water, 0.62 g of Jl biomass (FERM BP-1478) (calculated as dry weight) and 50 g of the corres-pon~; ng cyanoacetic acid ester were incubated at room tempe!rature for 16 hours. The pH was approximately 5. By mean~' of GC ar~Lalysis, starting maLterial could no longer be detected at this time. The biomass was filtered off and t:he water was removed from the product under reduced prescure. Traces of water were then L~..o~ed azeotropic-ally by addition of toluene to the residue. The isolated WO 9,'/08152 - 7 - PCT/EP96/03826 yielcl was ~90% and the purity of the carbamoylacetic acid ester formed was ~95% according to GC. Isopropyl carbaLmoylacetate precipitated from aqueous solution under these conditions during the biotransformation. In this case, the suspension was first warmed to 50~C in order to bring the isopropyl ester into solution before filte!ring off the biomass.
ExamE~le 2 Influence of the pH on the conversion of methyl cyano-acetaLte to methyl carbamoylacetate A 1 l Applikon fermenter was used for the experiments. The biotransformation batch contained 200 g of methyl cyanoacetate, 800 ml of water and 1.2 g of Jl biomass (FERM BP-687) (calculated as dry weight). The vesse!l was stirred at 200 rpm and the te~Lperature was 12~C - 17~C. The reaction was terminated after 16 h. It was not possible to detect any starting material at this time by means of GC analysis. The pH in batch A was not kept constant and fell from an initial value of 5.7 to 4.7 at the end of the reaction.
In batch B the pH during the entire reaction time was kept constant at a value of 8Ø To do this, 30% N~aOH solution was used.
Working up was carried out as described above.
By means of titration, it was possible to detect a sicrnificant amount of methyl carba~Loylacetate both in batch A and in batch B. In contrast to batch B, however, the p~roduct in batch A was significantly purer.
CA 02227949 l998-0l-26 ExamE~le 3 Conversion of malononitrile to malonamide using J1 biomaLss (FERM BP-1478) In a glass vessel equipped with a magnetic stirrer, 90 ml of water, O. 3 g of J1 biomass (calculated as dry weight) and 10 g of malononitrile were incubated at room temperature for 6 h. It was no longer possible to detect any starting material at this time by means of GC ,~nalysis. Malonamide precipitated from aqueous solut;ion under these conditions during the biotransformation. The suspension was warmed to 50~C in order to bring the product into solution before the bioma.ss was filtered off.
The water was removed from the product under reduced pressure. The isolated yield was ~90% and the purity of the malonamide formed was ~95% (GC).
ExamF,le 4 Prepa.ration of dihydroxypyrimidine (Rl = R2 = H) Formamide (26.43 g; 575 mmol) was added to sodium methylate solution (157.56 g; 875 mmol) at room temperature in the course of 5 minutes, the solution warming to 28~C. The solution was heated to reflux (64~C) and ~kept at this temperature for 15 minutes. Malonic acid monoamide monoester, dissolved in 30 ml of metha.nol, was added dropwise to this warm solution at 64~C. In the course of this a colourless suspension gradu.ally resulted. The readily stirrable suspension was refluxed for 3 h and then cooled to room temperature.
125 ml of water were added such that the temperature was about 25~C. At the end of the addition, a slightly yellcw solution was obtained. The pH was adjuRted to 4.0 by the addition of 82.0 g of conc. HCl solution (the WO 9J~/O8152 - 9 - PCT/EP96/03826 tempe!rature was between 25 and 30~C). The suspension was stirred at room temperature for 15 min, and the precipitated solid was filtered off and thoroughly waqhe!d twice with 45 ml of water. The pale yellow solid 5 wa~ ,~ried in a vacuum drying oven at 60~C for 24 h.
22.67 g (content 97.0% according to HPLC), correspo~Aing to a yield of 78.5%, were obtained.
lH NMR (DMSOd6) ~: 5.22 (a, lH);
8.05 (~, lH);
11.5 - 12.2 (~, br, 2H) .
3C NMR (DMSOd6) ~: 89.99;
149.90;
166.17.
Claims (11)
1. Process for the preparation of dihydroxy-pyrimidine derivatives of the general formula in which R1 and R2 are identical or different and are a hydrogen atom, a C1-C4-alkyl group or an aryl group, characterized in that in the first stage, as substrate, a compound of the general formula in which R2 has the meaning mentioned and R3 is -CN or COOR4, in which R4 is a C1-C4-alkyl group, is converted by means of microorganisms of the genus Rhodococcus into a malonic acid derivative of the general formula in which R2 has the meaning mentioned and R5 is a C1-C4-alkoxy group or -NH2, and this is cyclized in the second stage with a carboxamide of the general formula in which R1 has the meaning mentioned, in the presence of a base to give the final product according to formula I.
2. Process according to Patent Claim 1, characterized in that the conversion in the first stage is carried out by means of microorganisms of the species Rhodococcus rhodochrous or with their functionally equivalent variants and mutants.
3. Process according to Patent Claim 2, characterized in that the conversion is carried out in the first stage by means of immobilized microorganisms of the species Rhodococcus rhodochrous or with their functionally equivalent variants and mutants.
4. Process according to at least one of Patent Claims 1 to 3, characterized in that the conversion in the first stage is carried out at a pH from 3 to 7 and a temperature from 0 to 30°C.
5. Process according to at least one of Patent Claims 1 to 4, characterized in that in the first stage, as compound of the general formula II, methyl cyanoacetate, ethyl cyanoacetate, isopropyl cyanoacetate or malononitrile is used.
6. Process according to at least one of Patent Claims 1 to 5, characterized in that in the second stage, as malonic acid derivative, malonic acid monoamide monomethyl ester or malonic acid monoamide monoethyl ester is used.
7. Process according to at least one of Patent Claims 1 to 6, characterized in that in the second stage, as carboxamide, formamide is used.
8. Process according to at least one of Patent Claims 1 to 7, characterized in that in the second stage, as base, an alkali metal alcoholate is used.
9. Process according to at least one of Patent Claims 1 to 8, characterized in that the second stage is carried out at a temperature from 30°C up to the reflux temperature of the corresponding solvent.
10. Process for the preparation of malonic acid derivatives of the general formula in which R2 and R5 have the meaning mentioned, characterized in that a compound of the general formula in which R2 and R3 have the meaning mentioned, is converted into the malonic acid derivative of the general formula III by means of microorganisms of the genus Rhodococcus.
11. Process according to Patent Claim 10, characterized in that the conversion is carried out at a temperature from 0 to 30°C and at a pH from 3 to 7.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH2474/95 | 1995-08-31 | ||
| CH247495 | 1995-08-31 | ||
| PCT/EP1996/003826 WO1997008152A1 (en) | 1995-08-31 | 1996-08-30 | Method of producing dihydroxypyrimidine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2227949A1 true CA2227949A1 (en) | 1997-03-06 |
Family
ID=4234620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002227949A Abandoned CA2227949A1 (en) | 1995-08-31 | 1996-08-30 | Method of producing dihydroxypyrimidine derivatives |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US6248571B1 (en) |
| EP (1) | EP0852580B1 (en) |
| JP (1) | JP2000507911A (en) |
| AT (1) | ATE197150T1 (en) |
| AU (1) | AU6985796A (en) |
| CA (1) | CA2227949A1 (en) |
| DE (1) | DE59606057D1 (en) |
| DK (1) | DK0852580T3 (en) |
| ES (1) | ES2152563T3 (en) |
| PT (1) | PT852580E (en) |
| WO (1) | WO1997008152A1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10140269A1 (en) | 2001-08-16 | 2003-02-27 | Degussa | Process for the preparation of 4,6-dihydroxypyrimidine |
| KR20100013352A (en) * | 2001-10-31 | 2010-02-09 | 알콘, 인코퍼레이티드 | Bone morphogenic proteins (bmp), bmp receptors and bmp binding proteins and their use in the diagnosis and treatment of glaucoma |
| US20030143601A1 (en) * | 2001-11-16 | 2003-07-31 | Hansen Thomas R. | Methods and compositions for the detection of bovine pregnancy which utilize members of the 1-8 family of interferon inducible genes |
| EP1599468B1 (en) | 2003-01-14 | 2007-10-03 | Arena Pharmaceuticals, Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
| AR045047A1 (en) | 2003-07-11 | 2005-10-12 | Arena Pharm Inc | ARILO AND HETEROARILO DERIVATIVES TRISUSTITUIDOS AS MODULATORS OF METABOLISM AND PROFILAXIS AND TREATMENT OF DISORDERS RELATED TO THEMSELVES |
| US7854756B2 (en) * | 2004-01-22 | 2010-12-21 | Boston Scientific Scimed, Inc. | Medical devices |
| AU2011305525B2 (en) | 2010-09-22 | 2016-08-18 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
| CZ305457B6 (en) | 2011-02-28 | 2015-09-30 | Ústav organické chemie a biochemie, Akademie věd ČR v. v. i. | Pyrimidine compounds inhibiting formation of nitrogen monoxide and prostaglandin E2, process for their preparation and use |
| CN102442954B (en) * | 2011-09-06 | 2014-01-08 | 淄博万昌科技股份有限公司 | Method for preparing 4,6-dihydroxy-pyrimidine from byproduct hydrocyanic acid of acrylonitrile |
| CN116850181A (en) | 2015-01-06 | 2023-10-10 | 艾尼纳制药公司 | Treatment and S1P 1 Methods of receptor-related disorders |
| ES2929526T3 (en) | 2015-06-22 | 2022-11-29 | Arena Pharm Inc | (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl) acid L-arginine crystal salt acetic acid for use in disorders associated with the S1P1 receptor |
| CN113227058A (en) * | 2018-12-28 | 2021-08-06 | 赛拓有限责任公司 | Improved process for preparing 4, 6-dihydroxypyrimidine |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3306900A (en) * | 1964-02-21 | 1967-02-28 | Kyowa Hakko Kogyo Kk | Method for producing 4,6-dihydroxy-pyrimidine |
| FR1424940A (en) * | 1964-02-21 | 1966-01-14 | Kyowa Hakko Kogyo Kk | Process for the production of 4, 6-dihydroxypyrimidine |
| JPH06256278A (en) * | 1993-03-03 | 1994-09-13 | Nissan Chem Ind Ltd | Optically active alpha-carbamoylalkanoic acid derivative and its production |
| JPH0799983A (en) * | 1993-10-05 | 1995-04-18 | Nippon Kayaku Co Ltd | Production of p-nitrobenzyl alcohol malonic acid monoester by bacterium |
-
1996
- 1996-08-30 AU AU69857/96A patent/AU6985796A/en not_active Abandoned
- 1996-08-30 WO PCT/EP1996/003826 patent/WO1997008152A1/en active IP Right Grant
- 1996-08-30 JP JP9509864A patent/JP2000507911A/en active Pending
- 1996-08-30 PT PT96930988T patent/PT852580E/en unknown
- 1996-08-30 ES ES96930988T patent/ES2152563T3/en not_active Expired - Lifetime
- 1996-08-30 DK DK96930988T patent/DK0852580T3/en active
- 1996-08-30 AT AT96930988T patent/ATE197150T1/en not_active IP Right Cessation
- 1996-08-30 CA CA002227949A patent/CA2227949A1/en not_active Abandoned
- 1996-08-30 DE DE59606057T patent/DE59606057D1/en not_active Expired - Fee Related
- 1996-08-30 EP EP96930988A patent/EP0852580B1/en not_active Expired - Lifetime
- 1996-08-30 US US09/029,230 patent/US6248571B1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| ATE197150T1 (en) | 2000-11-15 |
| EP0852580A1 (en) | 1998-07-15 |
| JP2000507911A (en) | 2000-06-27 |
| ES2152563T3 (en) | 2001-02-01 |
| WO1997008152A1 (en) | 1997-03-06 |
| PT852580E (en) | 2001-02-28 |
| US6248571B1 (en) | 2001-06-19 |
| EP0852580B1 (en) | 2000-10-25 |
| DK0852580T3 (en) | 2000-11-20 |
| AU6985796A (en) | 1997-03-19 |
| DE59606057D1 (en) | 2000-11-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |