RU2036908C1 - Method of synthesis of lower alkyl oxy- or thio-derivatives 4-(lower alkyl)-2,6-bis-(trifluoromethyl)-(dihydro- or tetrahydro)-pyridine-3,5-dicarboxylic acids - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: alkyl esters of oxy- or thio-derivatives 4-(lower alkyl)-2,6-bis-(trifluoromethyl)-(dihydro- or tetrahydro)-pyridine-3,5-dicarboxylic acids. Reagent 1: piperidine of the formula given in description . Reagent 2: hydrogen chloride or hydrochloric acid. Reaction conditions: concentration of hydrochloric acid is 30%, not less, at 60-80 C, molar ratio of hydrogen chloride or hydrochloric acid to piperidine is 5-15. Synthesized compounds were used in agriculture. EFFECT: improved method of synthesis. 2 cl, 3 tbl

Description

 The invention relates to acid esters, in particular to an improved method for the production of lower alkyl hydroxy or thio derivatives of 4- (lower alkyl) -2,6-bis- (trifluoromethyl) - (dihydro or tetrahydro) pyridine-3,5-dicarboxylic acids that are used as herbicides.

The terms used in the description have the following meanings:
Dithiopyr 2-difluoromethyl-4- (2-methylpropyl) -6-trifluoromethyl-3,5-dicarboxylic acid, S, S-dimethyl ether;
DAVCO 1,4-diiazobicyclo [2.2.2] octane;
DBU 1,8-diazobicyclo- [5.4.0] -unden-7-ene;
ETFAA ethyl 4,4,4-trifluoro-3-oxo-butanoate;
IVA isovaleriandehyde or 3-methyl-butanal;
TMTFAA methyl 4,4,4-trifluoro-3-oxobutanethioate (thiomethyl trifluoroacetate acetate);
NMR nuclear magnetic resonance;
GLC gas-liquid chromatography;
Mass analysis in the required product;
Yield 100 x mol of the desired product (mol of the initial IVA starting material.

 Note: where, when discussing the effect of changing process parameters, the output is shown, all process variables that are not explicitly shown as variable are considered constant.

 A known method of producing dimethyl-2-difluoromethyl-4- (2-methylpropyl) -6-trifluoro-methyl-3,5-pyridinedicarbioates using a base catalyzed Hanzsh-type intermolecular cyclization of ethyl-4,4,4-trifluoro-3-oxo - butanoate (ethyl trifluoroacetoacetate or ETFAA) and isovaleriandehyde with the formation of substituted dihydroxypyran followed by ammonolysis. Dehydration of the resulting dehydroxypiperidines gives a mixture of 1,4- and 3,4-dihydropyridine isomers. Dehydrofluorination of dihydropyridines using an organic base such as DBU or 2,6-lutidine leads to good yields (in total 80%) of pyridine diethyl ethers. The saponification of diesters, the conversion of the resulting diacid to diacid, and subsequent thioesterification give the preferred dithiopyr pyridine dicarbioate herbicide. The seven-stage process carried out according to the specified reaction conditions using the solvents and reagents described in the prior art gives a yield of dithiopyr in the range of 60% based on the initial IVA.

 By analogy, it would be possible to conclude that a process using TMTFAA rather than ETFAA could be developed, which would provide the necessary pyridine dicarbothioate directly in four reaction steps, rather than seven using the same process conditions, or similar to those which are set forth in the prior art. However, in practice, using the general reaction sequence and carrying out the reaction through pyran as an intermediate product using solvents and reagents used in the first four stages gives a low yield of pyridine dicarbothioate based on the starting TMТFAA. This is shown below in a comparative example.

 The aim of the invention is to simplify the process, increasing the yield of the target product.

где А кислород или сера;
R низший алкил; подвергают взаимодействию с дегидратирующим агентом хлористым водородом или соляной кислотой с концентрацией не менее 30% или PCl₃ в присутствии уксусной кислоты в качестве растворителя при температуре, по крайней мере, 50^оС. Желательно, чтобы молярное отношение дегидратирующего агента к пиперидину составляло 5-15.This goal is achieved by the proposed method for the production of lower alkyl hydroxy or thio derivatives 4- (lower alkyl) -2,6-bis- (trifluoromethyl) - (dihydro- or tetrahydro) -pyridine-3,5-dicarboxylic acids using the dehydration of the corresponding derivatives 2 , 6-bis- (hydroxy) -piperidine, the distinguishing feature of which is that piperidine of the general formula:

where A is oxygen or sulfur;
R lower alkyl; subjected to interaction with a dehydrating agent with hydrogen chloride or hydrochloric acid with a concentration of not less than 30% or PCl ₃ in the presence of acetic acid as a solvent at a temperature of at least 50 ^about C. It is desirable that the molar ratio of dehydrating agent to piperidine is 5-15 .

 The general process for the preparation of the pyridinedicarbothioate product from TMTFAA consists of three procedures that can be carried out in a single reaction vessel, without isolation of intermediates. These three procedures are: piperidine formation, dehydration, dehydrofluorination.

 The formation of piperidine.

The initial step in this process consists of a Hanzsh-type cyclization reaction, which is carried out mainly in a solvent, which is lower alkyl nitrile, butyronitrile and acetonitrile are particularly preferred. In this reaction, two TMTFAA molecules and an IVA (isovaleriandehyde) molecule and an ammonia molecule interact to give intermediate dihydroxy piperidines. The source of ammonia (NH ₃ ) at this stage of the reaction may be anhydrous ammonia or an ammonium salt (including ammonium hydroxide), which readily produces ammonia, ammonium hydroxide is less desirable since its use entails the addition of water in the process, and thus added water must be removed prior to the dehydration step that follows.

CH

SCH₃

H₄
IVA обычно является лимитирующим реагентом в этой реакции, тогда как в известном уровне техники в основном лимитирующим реагентом является трифторацетатоацетатный эфир. Наиболее предпочтительным методом ведения процесса с точки зрения стоимости выхода продукта является процесс, в котором используются по существу стехиометрические количества каждого из реагентов. Наиболее предпочтительное воплощение этого процесса: ацетонитрил, или бутиронитрил помещаются в реакционный сосуд, в количестве по весу равном общему весу реагентов наряду с необходимым количеством TMTFAA. Газообразный аммиак (NH₃) добавляется ниже поверхности при температуре ниже 20^оС. Затем по каплям добавляется необходимое количество изовалерианового альдегида, при этом температура реакционной смеси поддерживается ниже 20^оС. Реакционной смеси дают возможность подогреться до 25^оС, а затем она нагревается в течение 4 ч при 65^оС. После завершения вышеизложенной реакционной последовательности, удаляются в вакууме летучие вещества при 50-60^оС и 10 мм рт.ст. (1,33 кПа), при подготовке к реакции дегидратации. Следует отметить, что на первой, только что описанной стадии, порядок добавления реагентов, температуры и катализатор отличаются от описанных, в частности, TMTFAA обрабатывается аммиаком, или перед добавлением альдегида или в присутствии альдегида, до реакции TMTFAA и IVA с образованием пирана, при температуре примерно ниже 30^оС, предпочтительнее ниже 20^оС, и без добавления пиридина как катализатора согласно известным способом.When using NH _3, it can optionally be added to a small portion of the total TMTFAA to form the ammonium salt of TMTFAA, and this salt can be added to the remainder of TMTFAA and IVA. It is believed that this ammonium salt of TMBFAA is formed in the process described here in any case, and this technique may provide some advantages in handling the process reagents. Salt has the formula and can be isolated:
F ₃ c

CH

SCH ₃

H ₄
IVA is usually the limiting reagent in this reaction, whereas in the prior art, the trifluoroacetate acetate ester is mainly the limiting reagent. The most preferred method of conducting the process from the point of view of the cost of product yield is a process in which essentially stoichiometric amounts of each of the reagents are used. The most preferred embodiment of this process: acetonitrile, or butyronitrile are placed in the reaction vessel, in an amount by weight equal to the total weight of the reactants along with the required amount of TMTFAA. Gaseous ammonia (NH ₃₎ is added below the surface at a temperature below 20 ° ^C. Then was added dropwise a necessary amount of isovaleraldehyde, wherein the reaction temperature is maintained below 20 ^C. The reaction mixture was allowed to warm ^to 25 ° C and then it is heated for 4 hours at 65 ^C. After completion of the above reaction sequence, volatiles are removed in vacuo substance at 50-60 ^{° C} and 10 mm Hg (1.33 kPa), in preparation for the dehydration reaction. It should be noted that at the first stage just described, the order of addition of the reagents, the temperature and the catalyst are different from those described, in particular, TMTFAA is treated with ammonia, either before the addition of the aldehyde or in the presence of the aldehyde, before the reaction of TMTFAA and IVA with the formation of pyran, at a temperature below about 30 ^° C, more preferably below 20 ^° C, and without the addition of pyridine as a catalyst according to a known method.

The influence of some process parameters at this stage on the overall product yield is shown in Table 1. In all experiments, the solvent used was acetonitrile and ammonia addition was carried out at a temperature below 20 ° ^C.

Dehydration
The second stage of this process involves the dehydration of dihydroxypiperidines obtained in the first stage of the process. At this stage, two water molecules are removed from piperidines to give a mixture of the dehydropyridine isomers. In practice, this is achieved by treating the crude dihydroxy piperidine residue from step I with either a pure dehydrating reagent or in solution. It is preferable to dehydrate the pure piperidine product (i.e., without solvent) using anhydrous or concentrated aqueous HCl. The crude dihydroxypiperidine residue from the first stage is mixed with 32% aqueous HCl in a ratio of about 5 to 15 mol of HCl per mol of IVA used in the first stage, and is heated to 80 ^° C for 1-2 hours. The mixture is cooled to 40 ^° C and toluene is added in an amount equal to the weight of the initially added portion of acetonitrile. A mixture of toluene and HCl is stirred for 30 minutes, after which the mixing is stopped and the two phases are allowed to separate. The lower aqueous acid layer is removed. A sufficient amount of an aqueous solution of the base is added to the toluene solution to establish a stable pH in the range of 8-10. Additional experiments showing the effect of the temperature of the dehydration reaction, the concentration of HCl, the reaction time of the dehydration and the molar ratio of HCl and IVA used in the first stage on the product yield are given in Table 2. All experiments were carried out without the use of an organic solvent at this stage.

In an alternative embodiment of this dehydration step using a solvent, the most suitable combination of solvent and dehydrating reagent is acetic acid and PCl ₃ .

It was unexpectedly discovered that when using a new dehydration process using either HCl to treat pure starting material, or PCl ₃ with acetic acid as a solvent, a significant amount of the new compound is obtained. This new compound is 2-chloro-1,2,3,4-tetrahydro-4- (2-methyl-propyl) -2,6-bis (trifluoromethyl) - S, S-S-dimethyl ester of 3,5-pyridinecarbio acid , melting point 154-155 ^about C.

 Such dehydration of dihydroxypiperidine thioesters, carried out using HCl as a dehydrating agent, is also applicable for the dehydration of the corresponding hydroxyesters. The use of HCl as a dehydrating reagent for oxyesters gives significant advantages in the process compared to the dehydration method using sulfuric acid for dehydration of oxyesters, according to a known method.

Dehydrofluorination
The final step of the process is the dehydrofluorination of the dihydropyridines obtained in the previous step to obtain the final pyridine of the dicarbothioate product using the DABCO, in contrast to the prior art dehydrofluorination step in which DBU or 2,6-lutidine is used as the organic base.

At this stage of the process, DABCO can be used in either astoichiometric or catalytic amounts. Since DABCO is a difunctional base, in the stoichiometric method of using DABCO, at least 0.5 mol of DABCO per mole of starting IVA is taken. It is preferable to use 1 mol of ABCO. The catalytic method of using DABCO, on the other hand, uses significantly less DABCO, namely 0.01-0.50, and preferably 0.05-0.20 mol, of DABCO per theoretical mole of dehydropyridines (i.e., per mole of initial IVA) in combination with the amount of additional base, which is sufficient for complete dehydrofluorination. An additional base used in a process where DABCO is used as a catalyst is a base selected from the group consisting of K ₂ CO ₃ , Na ₂ CO ₃ , triethylamine and tributylamine. The use of catalytic amounts of DABCO in this way can result in substantial economic benefits to the process.

 Whatever dehydrofluorination method is used, the presence of a certain amount of water in the process is necessary to dissolve salts (such as, for example, hydrofluoric salt of DABCO and / or an additional base, if used) that may be formed in the process.

 When using DABCO in either catalytic or stoichiometric amounts, the new compound 2-chloro-1,2,3,4-tetrahydro-4- (2-methylpropyl) -2,6-bis- (trifluoromethyl) -S, S-dimethyl ether, 3,5-pyridinecarboxylic acid, is dehydrohalogenated to dithiopyr by loss of HCl and HF from the molecule.

Whatever specific dehydrofluorination method is used, it is necessary to carry out this stage of the process in the presence of an inert aprotic solvent. Such solvents include, but are not limited to: benzene, toluene, xylenes, cyclohexane, monochlorobenzene, butyronitrile, and the like. Furthermore, although the temperature used in this step of the process is not particularly critical, it is preferable to use a temperature in the range 50-120 ^{° C,} 60-80 ° ^C. better

In a most preferred embodiment of the process using the catalytic DABCO dehydrofluorination method, the toluene solution from step II is vigorously purged with nitrogen to reduce oxidation by-products to the limit. An aqueous solution of 40% K ₂ CO ₃ containing 0.6-1.0 mol K ₂ CO ₃ per theoretical mole of dihydropyridine (or per mole / mole of the initial IVA) is also degassed with nitrogen. The two solutions are combined and a catalytic amount of DABCO (5-20 mol. Based on the molar amount of the initial IVA) is added as a solid. The resulting blood red solution is heated at a temperature of 60-100 ^{° C} for 4 hours, cooled and the aqueous layer was removed. The toluene layer is distilled off in vacuo, giving crude pyridine dicarbothioate with a total yield of 65-70% based on the initially taken amount of IVA in the range of 80-85%
When using the dehydrofluorination method using stoichiometric amounts of DABCO, the toluene solution from stage II is vigorously purged with nitrogen to minimize by-products of the oxidation of DABCO in aqueous solution, preferably in a state of saturation or near saturation, in a ratio of more than 0.50 mol, and preferably about 1 mol per theoretical mole of dihydropyridines (or 1 mol / mol of the initial IVA) is also purged with nitrogen, and the two solutions are combined. The resulting blood red solution is heated at ⁷⁰ ° C for 2 hours, cooled and the aqueous layer was removed. The toluene layer is washed with two portions of 1N. HCl to remove residual DABCO, then distilled off in vacuo to give crude pyridine dicarbothioate with a total yield of 65-70% based on the initial amount of TMTFAA loaded according to mass analysis within 80-85%
Examples 1 and 2 illustrate the process of using the proposed method to obtain a specific pyridinicarbothioate compound of dithiopyr shown in the comparative example.

 Example 1 illustrates the use of a catalytic amount of DABCO in the dehydrofluorination step and concentrated HCl in the dehydration step.

The reaction vessel was charged with TMTFAA (0,025 mol, 5 g) and 15 g of acetonitrile, the content is cooled to 10 ^C. Ammonia (0.43 g, 0.025 mole) is blown below the surface of acetonitrile and TMTFAA, wherein the temperature is maintained below 20 ° ^C. after adding ammonia mixture was dropwise added to TMTFAA (0,025 mol, 5 g) and IVA (0,025 mol 2.19 g), the temperature continues to be maintained below 20 ^C. after addition, the reaction mixture was stirred for 30 min at ²⁰ ° C or less, It is then heated for 4 hours at 65 ^C. After the reaction was completed, increasing the pressure in the reactor tsya to atmospheric with nitrogen. To distilled off in step I product is added 32% -ing HCl (29 g, 0.25 mol) and the mixture was heated for 2 hours at 80 ^C. The reactor was added toluene (15 g), the reaction mixture was cooled to 30 ° ^C and is left for phase separation for 1 h. After removal of the lower aqueous layer, the pH of the toluene solution is adjusted to 8-9 with 30% K ₂ CO ₃ . A portion of 30% K ₂ CO ₃ (11.36 g, 0.025 mol) and DABCO (0.14 g, 0.0013 mol) are added to the reactor. The mixture was then heated to reflux temperature (85 ^{° C)} for 4 hours. When the reaction is complete the contents cooled to 30 ° ^C and an opportunity for phase separation. After removal of the lower aqueous layer, the toluene solvent is removed in vacuo to give 7.73 g of a crude product with 79% according to analysis of the desired compound. The total yield of pyridine carbodithioate in the process of 61%
The effect of the solvent used in this step is shown in Table 3, in which each experiment was conducted at a temperature of 85 ^{° C,} the time was 4 hours, the catalytic amount of DABCO was 6% of the initial molar amount of IVA, and the molar ratio of K ₂ CO ₃ to initial IVA was 1.0.

EXAMPLE 2 shows the use of a stoichiometric amount of DABCO for dehydrofluorination, and PCl ₃ for dehydration.

TMTFAA (0,025 mol, 5 g) and 15 g of acetonitrile was loaded into a vessel and cooled to 10 ^C. Ammonia (0.43 g, 0.025 mole) is blown below the surface into the solution while the temperature is maintained below 20 ^C. Following the ammonia addition dropwise to the mixture was added acetonitrile solution TMTFAA (0,025 mole) and IVA (0,025 moles, 2.19 g), the temperature again kept below 20 ^C. The mixture was stirred for 30 min at ²⁵ ° C or below, then heated to ^about 65 C for 4 hours until completion of the reaction. The acetonitrile solvent is removed by slowly lowering the pressure in the reactor to 10 mmHg. (1.33 kPa) and maintain the temperature 65 ^C. The reactor is returned to atmospheric pressure by introducing nitrogen, and 15 g of toluene was added, and then PCl ₃ (0.03 mol). The reaction vessel was heated to 70 ^{° C} and held for one hour, then cooled to a temperature below 30 ° ^C. Slowly add water in an amount by weight of toluene equal loading (15 g) while maintaining the temperature 30 ^C. The aqueous layer was separated and removed, then the pH of the toluene solution is adjusted with 8% NaOH to 8-9, after which the aqueous layer is removed with DABCO (0.025 mol, 2.8 g) and 2.8 g of water are combined, purged with nitrogen and added to the toluene solution, which is purged nitrogen. The mixture was heated to 70 ^{° C for} 2 hours, then cooled to 25-30 ^C and the aqueous layer was removed. The organic layer is washed with two portions of 1 N. HCl (20 g), separated and dried over MgSO ₄ . Toluene is removed in vacuo to give the crude product dithiopyr. The total yield of dithiopyr in this example is 66%
Although the proposed process has been specifically illustrated with respect to the pyridine dicarbothioate product, it is also applicable to the preparation of other pyridine compounds. The choice of aldehyde starting material will be determined by the substituent at the 4 position of the final pyridine product. Similarly, lower alkyl trifluoroacetate-acetate esters other than methylthioether can equally be used.

A rp e r example The reaction of TMTFAA (2 equiv.) And isovaleriandehyde (1 equiv.) In the presence of catalytic pyridine in toluene, an exothermic reaction was observed. After stirring for 12 hours at 25 ° ^C. 19 _F-NMR showed the presence pyrans.

When the pyranation reaction was essentially complete (after about 12 hours), NH _{3 was} bubbled into the toluene solution until it reached saturation. The resulting solution was stirred overnight at room temperature, after which the 19 _F NMR spectrum confirmed the presence of the cis and trans isomers of dihydroxy piperidine.

The toluene solution of dihydroxypiperidines was treated with concentrated H ₂ SO ₄ as a dehydrating agent at low temperature to form a mixture of dihydropyridine isomers. The reaction mixture was stirred for another 2 hours and then poured onto ice. After drying, the toluene solution was treated with tributylamine under reflux conditions for dehydrofluorination of dihydropyridines, giving the desired product dithiopyr. The presence of this product was confirmed by analysis, but the yield was very low (less than 20% by weight).

 The proposed method allows to increase the yield of the target product 64% against 20% in the known method.

Claims (2)

1. METHOD FOR PRODUCING LOWER ALKYL OXY-OR THIODIVERS 4- (LOW ALKYL) -2,6-BIS- (TRIFFORMETHYL) - (DYHYDRO- OR TETHYRIDRO) -PYRIDIN-3,5-DIKARBTONE with 2 corresponding deisides -bis- (hydroxy) -piperidine, characterized in that piperidine of the General formula

where A is oxygen or sulfur;
R lower alkyl,
subjected to interaction with a dehydrating agent with hydrogen chloride or hydrochloric acid with a concentration of not less than 30% or PCl ₃ in the presence of acetic acid as a solvent at a temperature of at least 50 ^o C.  2. The method according to claim 1, characterized in that the molar ratio of dehydrating agent to piperidine is 5 to 15.

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