HK1111685A - Process for the production of pyrimidine-5-carboxylates - Google Patents

Description

Process for preparing pyrimidine-5-carboxylates

Technical Field

The present invention relates to a process for the preparation of pyrimidine-5-carboxylates represented by the following structural formula (I),

wherein R is C_1-4Alkyl radical, R¹Is C_1-4Alkyl, trifluoromethyl or optionally substituted phenyl, R²Is hydrogen or C_1-4Alkyl, X is hydroxy, chloro or bromo; or a hydrate of said pyrimidine-5-carboxylic acid ester wherein X is hydroxy. The invention also relates to said hydrates which are novel compounds.

In this and the following description, it is understood that C_1-4Alkyl means any straight or branched alkyl group having 1 to 4 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. The phenyl group may be substituted with any substituent that does not interfere with the reaction. In particular, the phenyl group may be substituted by 1 to 5 substituents, which may be the same or different, selected from C_1-4Alkyl, halogen, C_1-4Alkoxy, and the like.

Compounds of the formula I, in particularR in formula I¹Is trifluoromethyl and R²Compounds which are hydrogen are useful intermediates, for example, in the preparation of fungicides (EP-A-0569912) and anti-inflammatory compounds (US-A-5852028).

Background

Synthesis of ethyl 2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylate (I, R ═ Et, R¹＝CF₃，R²H, X ═ OH) includes reacting ethyl 4, 4, 4-trifluoroacetoacetate with triethyl orthoformate to produce ethyl 2-ethoxymethylene-4, 4, 4-trifluoroacetoacetate, and reacting the ethoxymethylene compound with urea, followed by hydrolysis of the intermediate ureidomethylene compound (m.s.s.palaki et al, j.med.chem.2000, 43, 3995-; US-A-5852028; see EP-A-0569912). This three-step process has the disadvantage that in the first step, drastic reaction conditions are required (acetic anhydride, 120 ℃ C.) and the overall process takes a relatively long time.

The reaction of ethyl trifluoroacetoacetate with ethyl orthoformate and urea can also be combined in one step (E.D. Bergmann et al, J.chem.Soc.Abstr.1959, 3278-. However, the yield is moderate and the ureidomethylene compound must be isolated before the cyclization reaction can be carried out.

It is also known that phosphorus oxychloride can be used to convert 2-hydroxypyrimidine-5-carboxylate to 2-chloro compounds (U.S. Pat. No. 3, 5852028). The disadvantage of this reaction is the large amount of phosphate waste.

Disclosure of Invention

It is an object of the present invention to provide a further simple process for preparing pyrimidine-5-carboxylic acid esters of the formula I, which is suitable for industrial scale production.

It has been found that under relatively mild conditions, it is possible to synthesize 2-hydroxypyrimidine-5-carboxylates in a one-pot reaction (one-pot reaction) without isolating any intermediate.

According to the present invention, a pyrimidine-5-carboxylic acid ester of formula (I) is prepared by the following process:

wherein R is C_1-4Alkyl radical, R¹Is C_1-4Alkyl or trifluoromethyl, R²Is hydrogen or C_1-4Alkyl, X is hydroxy, chloro or bromo;

(i) reacting a 3-oxoalkanoate of the following structural formula (II) with urea and an orthoester of the following structural formula (III) to produce a 2-acyl-3-ureido acrylate of the following structural formula (IV);

in the formula, R and R¹In accordance with the above definition,

R²C(OR)₃ (III)，

in the formula, R and R²In accordance with the above definition,

in the formula, R, R¹And R²In accordance with the above definition,

(ii) reacting said 2-acyl-3-ureido acrylate (IV) to produce a 2-hydroxypyrimidine-5-carboxylate of the following structural formula (I),

wherein R is as defined above, and optionally,

(iii) (iii) converting said 2-hydroxypyrimidine-5-carboxylic acid ester to the corresponding chlorine or bromine compound (I, X ═ Cl, Br), so that steps (I) and (ii) can be carried out in a one-pot reaction without isolation of any intermediate.

It has been found that depending on the operating conditions and the substituent R¹And R²The 2-hydroxypyrimidine-5-carboxylate may form a hydrate of the following structural formula (Ia), or a tautomer thereof,

in the formula, R, R¹And R²As defined above.

The cyclisation step (ii) can be carried out in the presence of a strong base, preferably an alkali metal alkoxide of formula (V) below,

M-OR (V)

wherein M is an alkali metal and R is as defined above.

However, it has been found that the base is not mandatory in the cyclisation step (II) and that both reaction steps (i) and (II) can be carried out not only in a one-pot reaction but also in the same process step, without the addition of a base, by simply heating a mixture of the starting materials (II), (III) and urea for a sufficient time.

In a preferred embodiment, R in the 3-oxoalkanoate (II), orthoester (III) and alkoxide (V) when present, as well as in the Intermediate (IV) and product (I), are all ethyl groups.

In another preferred embodiment, R in the 3-oxoalkanoate (II)¹Is trifluoromethyl, i.e. the 3-oxoalkanoate is trifluoroacetoacetate, thus yielding4-trifluoromethylpyrimidine-5-carboxylate (I).

Preferably, the orthoester (III), and the resulting R in the 2-acyl-3-ureidoacrylate (IV) and pyrimidine-5-carboxylate (I)²Is hydrogen, i.e. the orthoester is an orthoformate.

As the alkali metal M of the alkali metal alkoxide (V) when present, any alkali metal, i.e., lithium, sodium, potassium, , or cesium may be used. The alkali metal is preferably sodium.

The reaction of 2-hydroxypyrimidine-5-carboxylate to 2-chloro-or 2-bromo-pyrimidine-5-carboxylate may be carried out using methods known in the art for converting 2-hydroxy-pyrimidine to 2-halopyrimidine.

As the pyrimidine-5-carboxylate, a compound in which X is chlorine is preferable. The conversion of the 2-hydroxypyrimidine-5-carboxylic acid ester into the 2-chloropyrimidine-5-carboxylic acid ester is preferably carried out using phosphorus oxychloride or thionyl chloride, particularly preferably thionyl chloride in the presence of N, N-dimethylformamide.

The reaction steps (i) and (ii) of the process of the present invention may be carried out in any inert solvent having a boiling point at or above the desired reaction temperature, for example aromatic hydrocarbons like toluene, or ethers like tetrahydrofuran. It is even possible to use no solvent, in particular because three moles of alcohol (ROH) are formed as a by-product in reaction step (i).

In a preferred embodiment, the reaction steps (i) and (II) may be carried out using as solvent an alcohol of formula R-OH, wherein R is the same C as in 3-oxoalkanoate (II), orthoester (III) and alkali metal alkoxide (V)_1-4An alkyl group.

As solvent in the halogenation step (iii) any solvent which is inert under the reaction conditions can be used. Preferably an aromatic hydrocarbon solvent such as toluene, or a halogenated hydrocarbon such as methylene chloride or chloroform.

The reaction temperature is not critical, step (i) is preferably in the range from 60 to 100 ℃, step (ii) is preferably in the range from 0 to 50 ℃ and step (iii) is preferably in the range from 60 to 110 ℃ if a base is used.

The reaction time depends on the reaction temperature and the reactivity of the starting materials.

As described above, 2-hydroxypyrimidine-5-carboxylate may form hydrates such as those shown in formula Ia above. Whether hydrates are formed depends primarily on the substituent R¹And R²The characteristics of (a) and the operating conditions. These hydrates can be in several tautomeric forms, and formula Ia represents the tautomer that most closely matches the NMR data observed.

R of formula Ia is C_1-4Alkyl radical, R¹Is trifluoromethyl, R²Is hydrogen or C_1-4The 4-hydroxy-2-oxo-4-trifluoromethyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate in the case of alkyl is a novel compound and is also an object compound of the present invention. Particularly preferred is where R is methyl or ethyl and R is²Those 4-hydroxy-2-oxo-4-trifluoromethyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid esters which are hydrogen.

The invention is illustrated by the following non-limiting examples.

Example 1

2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester

(I，R＝Et，R¹＝CF₃，R²＝H，X＝OH)

Urea (2.9g, 0.05 mol), ethyl 4, 4, 4-trifluoro-3-oxobutyrate (8.9g, 0.05 mol) and triethyl orthoformate (7.9g, 0.05 mol) were dissolved in ethanol (10mL) under a nitrogen atmosphere, and the solution was heated to 80 ℃ for 4 hours. The reaction mixture was then cooled to 20 ℃ and sodium ethoxide solution (21 wt% ethanol solution, 16.9g, 0.05 mol) was added with stirring at the same temperature over 15 minutes. The reaction mixture was stirred for 2 hours, then water (75mL) and acetic acid (2mL) were added at 20-30 ℃. The resulting slurry was filtered, and the filter cake was washed with water (20mL) and dried at 45 ℃.

Yield: 8.2g (72%) of a white solid

¹H NMR(400MHz，(CD₃)₂SO)：δ＝8.69(s，1H)，4.24(q，J＝7.1Hz，2H)，1.28(t，J＝7.1Hz，3H)。

¹³C NMR(100MHz，(CD₃)₂SO)：δ＝161.4，158.7(q，J＝35Hz)，155.5，154.7，119.2(q，J＝278Hz)，105.7，61.3，13.7。

Example 2

2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester hydrate

(4-hydroxy-2-oxo-4-trifluoromethyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester-Ia, R ═ Et, R¹＝CF₃，R²＝H)

Urea (1.63kg, 27.1 moles), ethyl 4, 4, 4-trifluoro-3-oxobutyrate (5.00kg, 27.1 moles) and triethyl orthoformate (4.43kg, 29.9 moles) were dissolved in ethanol (5.0L) under a nitrogen atmosphere, and the solution was heated to 80 ℃ for 5 hours. The reaction mixture was then cooled to 20 ℃ and sodium ethoxide solution (21 wt% ethanol solution, 9.68kg, 29.9 mol) was added with stirring at the same temperature over 1-2 hours. The reaction mixture was stirred for an additional 1 hour, then a mixture of hydrochloric acid (33 wt%, 4.50kg, 40.7 moles) and water (15.0L) was added at 20-30 ℃. The resulting slurry was filtered and the filter cake was washed with water (24L) and dried at 50 ℃ for 15 hours.

Yield: 4.98kg (72%) of a white solid

¹H NMR(400MHz，(CD₃)₂SO)：δ＝9.90(d，J＝5.1Hz，1H，NH)，8.42(s，1H，NH)，7.49(d，J＝6.1Hz，1H)，7.39(s，1H，OH)，4.16-4.06(m，2H)，1.20(t，J＝7.0Hz，3H)。

¹³C NMR(100MHz，(CD₃)₂SO)：δ＝163.6，149.4，140.7，123.5(q，J＝290Hz)，97.6，81.6(q，J＝34Hz)，59.5，14.0。

Example 3

2-chloro-4- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester

(I，R＝Et，R¹＝CF₃，R²＝H，X＝Cl)

Ethyl 2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylate hydrate (3.00kg, 11.8 moles; prepared as in example 2) was dissolved in toluene (15L) and N, N-dimethylformamide (0.46kg, 6.4 moles) and thionyl chloride (3.78kg, 31.8 moles) were added. The mixture was heated to 70 ℃ for 1 hour with stirring and then cooled to room temperature. Water (9L) was added and the mixture was warmed to 40 ℃. The organic phase was separated and separated after treatment again with water (9L) at 40 ℃. The solvent and N, N-dimethylformamide were distilled off under reduced pressure (120 → 20 mbar, 40 → 60 ℃ C.) and a residue (3.4kg) was obtained by distillation at 100 ℃/5 mbar.

Yield: 2.66kg (88%) of a colorless oil.

¹H NMR(400MHz，CDCl₃)：δ＝9.16(s，IH)，4.48(q，J＝7.2Hz，2H)，1.44(t，J＝7.2Hz，3H)。

¹³C NMR(100MHz，CDCl₃)：δ＝163.1，162.7，162.3，155.6(q，J＝38Hz)，123.2，119.5(q，J＝277Hz)，63.5，13.9。

Example 4

2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylic acid methyl ester

(I，R＝Me，R¹＝CF₃，R²＝H，X＝OH)

Urea (14.1g, 0.24 mol), methyl 4, 4, 4-trifluoro-3-oxobutyrate (40.0g, 0.24 mol), and trimethyl orthoformate (27.5g, 0.26 mol) were dissolved in methanol (35mL) under a nitrogen atmosphere, and the solution was heated to 65 ℃ for 20 hours. The reaction mixture was then cooled to 20 ℃ and sodium methoxide (22.0g, 0.41 mole) and methanol (25mL) were added with stirring at the same temperature. The reaction mixture was stirred for 12 hours, then water (100mL) and acetic acid (50mL) were added at 20-30 ℃. The resulting slurry was filtered, and the filter cake was washed with water (80mL) and dried at 50 ℃.

Yield: 24.9g (48%) of a white solid

¹H NMR(400MHz，(CD₃)₂SO)：δ＝13.30(br s，IH，OH)，8.71(s，IH)，3.81(s，3H)。¹³CNMR(100MHz，(CD₃)₂SO)：δ＝161.8，159.0(q，J＝36Hz)，155.6，154.6，119.2(q，J＝278Hz)，105.4，52.4。

Example 5

2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylic acid methyl ester hydrate

(4-hydroxy-2-oxo-4-trifluoromethyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester-Ia, R ═ Me, R¹＝CF₃，R²＝H)

Urea (12.0g, 0.20 mol), methyl 4, 4, 4-trifluoro-3-oxobutyrate (33.5g, 0.20 mol), and trimethyl orthoformate (23.3g, 0.22 mol) were dissolved in methanol (35mL) under a nitrogen atmosphere, and the solution was heated to 65 ℃ for 15 hours. Then, the reaction mixture was cooled to 20 ℃, and sodium methoxide (21 wt% methanol solution, 59.3g, 0.23 mol) was added under stirring at the same temperature. The reaction mixture was stirred for 20 hours, then a mixture of hydrochloric acid (37 wt%, 21.7g, 0.22 mol) and water (136mL) was added slowly at 20-30 ℃. The resulting slurry was filtered and the filter cake was washed with water (136mL) and dried at 50 ℃.

Yield: 17.5g (37%) of a white solid

¹H NMR(400MHz，(CD₃)₂SO)：δ＝9.89(d，J＝5.1Hz，1H，NH)，8.44(s，1H，NH)，7.50(d，J＝6.0Hz，1H)，7.42(s，1H，OH)，3.64(s，3H)。

¹³C NMR(100MHz，(CD₃)₂SO)：δ＝164.0，149.5，141.0，123.5(q，J＝290Hz)，97.4，81.6(q，J＝34Hz)，51.1。

Example 6

2-hydroxy-4-methylpyrimidine-5-carboxylic acid ethyl ester

(I，R＝Et，R¹＝Me，R²＝H，X＝OH)

Urea (15.7g, 0.26 mol), ethyl 3-oxobutyrate (34.0g, 0.26 mol) and triethyl orthoformate (23.3g, 0.22 mol) were heated to 80 ℃ for 28 hours under a nitrogen atmosphere while distilling off ethanol. The reaction mixture was then cooled to 20 ℃ and ethanol (100mL) and sodium ethoxide solution (21 wt% ethanol solution, 127.0g, 0.39 mol) were added with stirring at the same temperature over 1 hour. The reaction mixture was heated to 80 ℃ and stirred for 2 hours. The reaction mixture was then cooled to 20 ℃ and then water (136mL) and acetic acid (19mL) were added at 20-30 ℃. The resulting slurry was filtered and the filter cake was washed with water (172mL) and dried at 50 ℃.

Yield: 23.1g (48%) of an off-white solid

¹H NMR(400MHz，(CD₃)₂SO)：δ＝8.72(s，1IH)，4.22(q，J＝7.1Hz，2H)，2.50(s，3H)，1.28(t，J＝7.1Hz，3H)。

¹³C NMR(100MHZ，(CD₃)₂SO)：δ＝167.3，163.6，162.1，156.6，105.9，60.1，21.0，14.0。

Example 7

2-hydroxy-4-phenylpyrimidine-5-carboxylic acid ethyl ester

(I，R＝Et，R¹＝Me，R²＝H，X＝OH)

Urea (7.8g, 0.13 mol), ethyl benzoylacetate (25.0g, 0.13 mol) and triethyl orthoformate (23.3 g) were heated under a nitrogen atmosphere0.16 mol) to 80 ℃ for 20 hours while distilling off ethanol. The reaction mixture was then cooled to 20 ℃ and ethanol (150mL) and sodium ethoxide solution (21 wt% ethanol solution, 63.2g, 0.20 mol) were added with stirring at the same temperature over 1 hour. The reaction mixture was heated to 80 ℃ and stirred for 2 hours. The reaction mixture was then cooled to 20 ℃ and then water (80mL) and acetic acid (20mL) were added at 20-30 ℃. The resulting solution was extracted with ethyl acetate (2X 150 mL). The combined organic phases are evaporated and passed through SiO₂The above chromatography was used for purification.

Yield: 6.3g (27%) of an off-white solid

¹H NMR(400MHz，(CD₃)₂SO)：δ＝12.50(br s，1H，OH)，8.61(s，1H)，7.52-7.42(m，5H)，4.03(q，J＝7.1Hz，2H)，1.01(t，J＝7.1Hz，3H)。

¹³C NMR(100MHz，(CD₃)₂SO)：δ＝163.7，155.2，130.0，128.1，127.7，107.3，60.4，13.5。

Example 8

2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylic acid methyl ester hydrate

(4-hydroxy-2-oxo-4-trifluoromethyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid methyl ester-Ia, R ═ Me, R¹＝CF₃，R²＝H)

Urea (8.8g, 0.15 mol), methyl 4, 4, 4-trifluoro-3-oxobutyrate (25.0g, 0.15 mol) and trimethyl orthoformate (17.2g, 0.16 mol) were heated to 65 ℃ under a nitrogen atmosphere for 5 hours. The reaction mixture was then cooled to 0 ℃. The resulting slurry was filtered, and the filter cake was washed with methanol (100mL) and dried at 50 ℃.

Yield: 12.8g (36%) of a white solid

NMR: see example 5.

Example 9

2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester hydrate

(4-hydroxy-2-oxo-4-trifluoromethyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester-Ia, R ═ Et, R¹＝CF₃，R²＝H)

Urea (13.1kg, 217.0 moles), ethyl 4, 4, 4-trifluoro-3-oxobutyrate (39.9kg, 216.3 moles) and triethyl orthoformate (35.4kg, 239.1 moles) were heated to 80 ℃ under a nitrogen atmosphere for 5 hours. The reaction mixture was then cooled to 0 ℃. The resulting slurry was filtered, and the filter cake was washed with ethanol (40L) and dried at 50 ℃ for 15 hours.

Yield: 40.1kg (73%) of a white solid

NMR: see example 2.

Example 10

2-chloro-4- (trifluoromethyl) pyrimidine-5-carboxylic acid ethyl ester

(I，R＝Et，R¹＝CF₃，R²＝H，X＝Cl)

Ethyl 2-hydroxy-4- (trifluoromethyl) pyrimidine-5-carboxylate (2.0g, 0.01 mole) was dissolved in toluene (20mL), and N, N-dimethylformamide (0.31g, ca. 0.004 mole) and thionyl chloride (5.05g, 0.04 mole) were added. The mixture was heated to 70 ℃ for 2 hours with stirring and then cooled to room temperature. The solution was washed with water (3X 20 mL). The solvent and N, N-dimethylformamide were distilled off under reduced pressure (120 → 30 mbar, 45 ℃) to give the crude product as a yellow oil (2.3 g).

Claims (12)

1. A process for the preparation of pyrimidine-5-carboxylates of formula (I),

in the formula (I), the compound is shown in the specification,

r is C_1-4An alkyl group, a carboxyl group,

R¹is C_1-4Alkyl, trifluoromethyl or optionally substituted phenyl,

R²is hydrogen or C_1-4An alkyl group, a carboxyl group,

x is hydroxy, chloro or bromo;

or, if X is hydroxy, is a hydrate of the pyrimidine-5-carboxylate,

the method comprises the following steps:

(i) reacting the 3-oxoalkanoate of formula (II) with urea and an orthoester of formula (III) to produce a 2-acyl-3-ureido acrylate of formula (IV),

in the formula, R and R¹In accordance with the above definition,

R²C(OR)₃ (III)，

in the formula, R and R²In accordance with the above definition,

in the formula, R, R¹And R²As defined above;

(ii) reacting the 2-acyl-3-ureido acrylate (IV) to produce a 2-hydroxypyrimidine-5-carboxylate of formula (I) or a hydrate thereof,

in the formula, R, R¹And R²As defined above, and optionally

(iii) (iii) converting the 2-hydroxypyrimidine-5-carboxylic acid ester or its hydrate into the corresponding chloro-or bromo-compound (I, X ═ Cl, Br), characterized in that step (I) and step (ii) are carried out in a one-pot reaction without isolation of any intermediate.

2. The process of claim 1, wherein step (ii) is carried out in the presence of an alkali metal alkoxide of the formula,

M-OR(V)，

wherein M is an alkali metal and R is as defined above.

3. The process of claim 1, wherein step (ii) is carried out in the absence of added base.

4. The method of any one of claims 1-3, wherein R is ethyl.

5. The method of any one of claims 1-4, wherein R is¹Is trifluoromethyl.

6. The method of any one of claims 1-5, wherein R is²Is hydrogen.

7. The method of any one of claims 1-6, wherein X is chlorine.

8. The process of claim 7, wherein the conversion reaction of step (iii) is carried out with phosphorus oxychloride or thionyl chloride.

9. The process of claim 8, wherein the conversion reaction of step (iii) is carried out with thionyl chloride in the presence of N, N-dimethylformamide.

10. The process according to any one of claims 1 to 9, wherein steps (i) and (ii) are carried out in an alcohol of formula R-OH as solvent, R of R-OH being as defined in claim 1.

11. 4-hydroxy-2-oxo-4-trifluoromethyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate of the following structural formula or a tautomer thereof,

wherein R is C_1-4Alkyl radical, R²Is hydrogen or C_1-4An alkyl group.

12. The 4-hydroxy-2-oxo-4-trifluoromethyl-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate of claim 11 wherein R is methyl or ethyl and R is²Is hydrogen.