HK1119667A - Process for preparation of 2-alkoxy-6-(trifluoromethyl)pyrimidin-4-ol - Google Patents

Description

Process for preparing 2-alkoxy-6- (trifluoromethyl) pyrimidin-4-ols

The present application is a divisional application entitled "method for preparing 2-alkoxy-6- (trifluoromethyl) pyrimidin-4-ol" filed on 2.2.2004 under the name of application No. 200480003335.3 (international application No. PCT/EP 2004/000932).

The subject of the present application is a novel process for the preparation of 2-alkoxy-6- (trifluoromethyl) pyrimidin-4-ol.

US 5717096, by the same applicant as the present applicant, teaches a process for the preparation of the title compound. 2-alkoxy-6- (trifluoromethyl) pyrimidin-4-ol is an important compound for the production of acaricides. Due to the wide application of acaricides in public health, a method for efficiently producing raw materials is important for its wide application. The process disclosed in US 5717096 relates to the reaction of cyanamide with an alcohol under acidic conditions to give the corresponding alkoxyisourea hydrochloride which is then further converted under base-catalysed conditions to 2-alkoxy-6- (trifluoromethyl) pyrimidin-4-ol. The last reaction step is carried out in aqueous solution in the presence of acetoacetate in the presence of sodium hydroxide. The total yield is 52% to 69%.

As a disadvantage, this method requires careful neutralization of the reaction solution between the first and second reaction steps. The reaction mixture first needs to be cooled at least to ambient temperature before neutralization. On a larger scale, the neutralization reaction additionally creates heat transfer problems. Therefore, the process of step 1 and step 2 is very time consuming and may adversely affect the yield. The yields of this process are not entirely satisfactory and are difficult to control.

The object of the present invention is to devise another method which does not have said disadvantages. This object is solved by the method of independent claim 1.

The process of the present invention for preparing 2-alkoxy-6- (trifluoromethyl) pyrimidin-4-ol of the formula:

wherein R is C1-C6 alkyl,

in a first step, a cyanogen halide selected from the group consisting of cyanogen chloride Cl-CN and cyanogen bromide Br-CN is reacted with a C1-C8 alcohol R-OH and/or the respective C1-C8 alcoholate in the presence of a base to give the corresponding symmetrical imidocarbonic acid dialkyl ester of formula II:

in a second step, the dialkyl imidocarbonate is further reacted with ethyl trifluoroacetoacetate or any other C1-C6 alkyl ester thereof in the presence of ammonia to give compound I.

Suitable C1-C6 alkyl trifluoroacetoacetates are, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, heptyl, hexyl esters. Preferably, the ester is a methyl, ethyl, n-propyl, isopropyl, isobutyl or butyl ester.

Preferably, the cyanogen halide is added to the reaction mixture at a temperature below 20 ℃.

The product of formula II is preferably obtained by removing the salt precipitate from the reaction solution of the first step only, preferably at a temperature of < 10 ℃. The resulting crude product was sufficiently purified to obtain the best yield in the second reaction step. Removal can be achieved quickly and efficiently, for example by filtration, making the overall process more simplified and efficient. More preferably, this embodiment is carried out as a one-pot reaction (one-pot reaction), i.e. the alcoholic solution comprising the product of formula II with the solid salts removed from the solution is directly used in the second reaction step to give the product of formula I. The alcohol may serve as both a reagent and a solvent for the first reaction step.

Another possible method of operation may be to add water to the reaction cell to enable separation of the aqueous and non-aqueous phases for conventional operations. It is also possible to use the reaction solution directly without any further separation/operation for the next reaction step. This simple one-pot reaction sequence is another preferred embodiment of the present invention.

Preferably, the second reaction step is carried out in the presence of 1.5 to 3 molar equivalents of ammonia.

Preferably, the second reaction step is carried out in an aprotic polar solvent. Such a solvent, e.g. the alcohol used in the first reaction step, or a suitable mixture of the alcohol of the first reaction step and such a solvent, may ensure solubility of the reagents while preventing base-catalyzed hydrolysis side reactions. If ammonia is conveniently provided as an aqueous solution, a quantity of water may be introduced by the ammonia. More preferably, the second reaction is carried out in one pot as described above, and further using the alcohol reagent of the first step as a solvent. Most preferably, the second reaction is carried out in isopropanol.

Preferably, the second reaction step is carried out at a temperature of 50 to 100 ℃, preferably 60 to 90 ℃. Obviously, the alcohol reagent which conveniently provides the solvent for the reaction is selected to have a boiling point within those preferred temperature ranges and may thus limit the maximum applicable temperature, requiring the solvent to be refluxed during the reaction. More preferably, the second reaction step is carried out in two time-ordered temperature intervals, the preferred range for the first time interval being below 65 ℃ and the preferred range for the second time interval being above 70 ℃.

Preferably, the product compound of formula I is purified from the reaction cell by first removing the solvent and second crystallizing the compound of formula I from the aqueous solution. More preferably, the pH is controlled to pH 5-7 during the crystallization step. Crystallization from water after removal of the alcohol as solvent and reagent may enable instantaneous recovery of pure product (> 98% purity by HPLC). In addition, water is the best solvent in view of environmental issues. Conveniently, water is added in a volume of about 10 times the volume of the reaction cell after removal of the alcohol.

In another preferred embodiment, the product compound of formula I is purified from the reaction cell by extraction with methylcyclohexene, crystallizing the product compound from the organic phase.

If an alcoholate is used, this alcoholate salt can be used in a quantitative amount in the presence of a suitable inert solvent, such as an alcohol, preferably a secondary or tertiary alcohol, or else in a substoichiometric or catalytic amount in the presence of an alcohol which is reacted with a cyanogen halide and acts as solvent.

Preferably, the alcohol or alcoholate of the invention is a C1-C8 alkyl alcohol, preferably a C3-C5 alkyl alcohol. This is understood to mean that the reaction is carried out without addition of an alcoholate reagent, including without addition of a substoichiometric amount of such alcoholate salt. The alcohol is a monovalent alcohol. The alkyl moiety R of such monovalent alcohols ROH may be branched or straight-chain. Examples of such C1-C8 alcohols are methanol, ethanol, propanol, butanol, isobutanol, isopropanol, tert-butanol, hexanol, heptanol, octanol and the like, their structural isomers and mixtures thereof. More preferably, the alcohol is propanol, isopropanol, isobutanol or n-butanol. Most preferably, isopropanol.

The term "solid" in the context of the present invention is to be understood as meaning powders, granules, pellets and the like. Suitable hydroxide may be any metal hydroxide, preferably it is an alkaline earth metal hydroxide or an alkali metal hydroxide, most preferably it is sodium hydroxide, lithium hydroxide or potassium hydroxide.

Another object of the present invention is a process for the preparation of dialkyl imidocarbonates of formula III,

wherein R1, R2 are alkyl, preferably a symmetrical esteriminocarbonate of the formula III in which R1 and R2 are identical,

which comprises the step of reacting cyanogen chloride Cl-CN with at least one C3-C5 secondary or tertiary alcohol ROH wherein R is R1 or R2, and wherein the alcohol comprises a solid hydroxide in suspended form.

Similar base-catalyzed reactions for the preparation of iminates have been described (with nitroalkyl-substituted cyanides: Schaefer et al, 1961, J.org.chem.26: 412; with cyanogen bromide: Lopyrev et al, 1989, Izvestia Akademiii Nauk SSSR, Seriya Khimiciceskaya, 10: 2363, ISSN: 0002-; in the absence of an alkoxide, the described synthesis does not work for secondary or tertiary alkyl alcohols, whereas primary alcohols were found to be sufficiently reactive in the absence of an alkoxide or alkoxide. Surprisingly, the present invention can perform this reaction using a combination of cyanogen chloride and suspended hydroxide solids. Alcoholate salts are relatively expensive reagents and, due to their water-absorbing nature, are not easy to handle, especially for industrial scale operations.

The preferred embodiments of the present application described above apply equally to the other objects of the invention in connection with the reaction of such cyanogen halides. Specifically, the preferred alcohol is a C3-C5 alcohol, more preferably isopropanol. In addition, it is preferred that the reaction is carried out without the addition of any of the alcoholate reagents already specifically described above.

Examples

Possible embodiments for the synthesis of 2-isopropoxy-6- (trifluoromethyl) pyrimidin-4-ol (4) according to the following reaction scheme are given in the examples.

Example 1

Synthesis of diisopropyl imidocarbonate (2)

2 moles (123g) of cyanogen chloride gas were injected into a suspension of isopropanol (720g/12mol) and solid NaOH pellets (88.3g/2.21mol) under stirring at 12-17 ℃ over 2-5 hours. Then, the reaction was further maintained at 20 ℃ for 3 hours. The mixture was then filtered under cooling at 5 ℃ to remove the salt precipitate. The filtrate gave compound 2 in 86% yield, containing impurities (23.3 wt% by GC). Further distillation at 63 ℃ and 33 mbar gave pure compound 2 (98% by weight, determined by GC; cf. Matacz et al, 1988, Bulletin Polish Acad.Sci.chemistry, 36: 139 ff; further identification of the product peak by GC/MS gave a mass peak m/z 62 in 74% yield of [ CH/z 62 ]₄NO₂]⁺). However, a crude filtrate is sufficient for use as educt in the next reaction step (example 3).

Pure product 2:¹H-NMR(CCl₄)：5.97ppm(s，1H)，4.84ppm(sept，1H)，4.55ppm(sept，1H)，1.20ppm(d，6H)，1.17ppm(d，6H)

example 2

Synthesis of 2-isopropoxy-6- (trifluoromethyl) pyrimidin-4-ol (4)

14.87(1 eq/0.1 mol) of 98.5% pure Compound 2 was reacted with 2.35mol NH at room temperature₃(25% aqueous solution) and 71.2g (1.2 eq) of isopropanol. Thereto was gradually added 20.92g (1.2 equivalents/0.11 mole) of ethyl trifluoroacetoacetate, and the resulting mixture was stirred at 60 ℃ for 6.5 hours and at 78 ℃ for another 2.5 hours in a hermetically sealed reaction flask. Most of the isopropanol was then removed by distillation to give a yellowish clear oil (about 80% of compound 4) which was then transferred to ten times its amount of deionized water (200ml) at about 45 ℃. Product 4 precipitated quantitatively immediately. The precipitate was filtered under cooling at 5 ℃ and dried under vacuum. The product was 98% pure as determined by HPLC. The analytical yield was 65%. Product 4 can be obtained again in 88% purity in 20% yield by slow crystallization from the residual filtrate with cooling, which can be obtained by further recrystallization in 14% final yield (> 98% purity by HPLC).

And (3) a product 4:

¹H-NMR(CCl₄)：12.83ppm(s，1H)，6.43ppm(s，1H)，5.25ppm(sept，1H)，1.34ppm(d，6H)。

example 3

Synthesis of 2-isopropoxy-6- (trifluoromethyl) pyrimidin-4-ol (4) in a one-pot process

The synthesis was carried out essentially as described in example 1+2, except that 124g (0.21mol/l equivalent) of the crude, filtered product solution from example 1 (24 wt%) were used as product 2 starting material for the reaction. In addition, the reaction was first carried out at 60 ℃ for 2 hours and then at 80 ℃ for 6 hours. Product 4 was obtained in 65% yield > 98% pure. The overall yield including the reaction step of example 1 was 59%.

Example 4

Synthesis of 2-isopropoxy-6- (trifluoromethyl) pyrimidin-4-ol (4)

The synthesis was carried out essentially as described in example 3, except that 1.2 equivalents of methyl trifluoroacetoacetate were used. Product 4 was obtained in 67% yield with > 97.7% purity.

Example 5

Synthesis of 2-isopropoxy-6- (trifluoromethyl) pyrimidin-4-ol (4)

The synthesis was essentially performed as described in example 3, except that 1.2 equivalents of isopropyl trifluoroacetoacetate were used. But only after additional slow crystallization from isopropanol gave product 4 in 39% yield > 97.7% purity.

Claims (4)

1. A process for preparing dialkyl imidocarbonates of the formula III, in which R1, R2 are C1-C8 alkyl,

preferred is a process for the preparation of a symmetrical esterified dialkyl imidocarbonate of formula III wherein R1 ═ R2, comprising the step of reacting cyanogen chloride Cl-CN with at least one C1-C8 alcohol ROH wherein R is R1 or R2, and wherein the alcohol comprises a solid hydroxide in suspended form.

2. The process according to claim 1, characterized in that the alcohol is a C3-C5 alcohol, more preferably isopropanol.

3. The process of claim 1, characterized in that the reaction is carried out without addition of an alcoholate reagent.

4. A process for preparing dialkyl imidocarbonates of formula II wherein R is a C1-C8 alkyl group

Comprising the step of reacting cyanogen chloride Cl-CN with a C1-C8 alcohol ROH, and wherein the alcohol comprises a solid hydroxide in suspended form.