KR101730393B1 - New process for preparing pyrazole carboxylic acid derivatives - Google Patents
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- KR101730393B1 KR101730393B1 KR1020150111185A KR20150111185A KR101730393B1 KR 101730393 B1 KR101730393 B1 KR 101730393B1 KR 1020150111185 A KR1020150111185 A KR 1020150111185A KR 20150111185 A KR20150111185 A KR 20150111185A KR 101730393 B1 KR101730393 B1 KR 101730393B1
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- dimethylamino
- carboxylic acid
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- difluoromethyl
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- C—CHEMISTRY; METALLURGY
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The present invention relates to a process for preparing pyrazolecarboxylic acid derivatives and more particularly to a process for the preparation of pyrazolecarboxylic acid derivatives of formula (I), which is useful as intermediates for the preparation of pyrazolecarboxanilide- 4-carboxylic acid (1-alkyl-3-haloalkyl pyrazole-4-carboxylic acid).
[Formula (I)]
In the formula (I), R 1 is a lower alkyl group having 1 to 3 carbon atoms, and R 2 is any one of CHF 2 , CF 3, CHCl 2 and CCl 3.
Description
The present invention relates to a process for preparing pyrazolecarboxylic acid derivatives and more particularly to a process for the preparation of pyrazolecarboxylic acid derivatives of formula (I), which is useful as intermediates for the preparation of pyrazolecarboxanilide- 4-carboxylic acid (1-alkyl-3-haloalkyl pyrazole-4-carboxylic acid).
[Formula (I)]
In the formula (I), R 1 is a lower alkyl group having 1 to 3 carbon atoms, and R 2 is any one of CHF 2 , CF 3, CHCl 2 and CCl 3.
The pyrazolecarboxylic acid derivative of the above formula (I) is a known compound and is used for producing a pyrazolecarboxanilide-based fungicide such as isopyrazam, Sedaxane, Bixafen, It is an important intermediate.
As a method for preparing the above-mentioned pyrazolecarboxylic acid derivatives known in the art, PCT / EP 2011/053786 (March 14, 2011) discloses a process for producing a pyrazolecarboxylic acid derivative by reacting ethyl 4,4-difluoroacetoacetate with triethylorthoformate Methyl-3-difluoromethyl-1 H-pyrazole-4-carboxylic acid was obtained via ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutylate . However, this method requires a large amount of the triethylorthoformate, which results in a high specific gravity and an isomer of 10 to 15% when pyrazole ring is formed, which causes the yield to drop.
In addition, in PCT / EP2007 / 007377 (Aug. 22, 2007), a salt was prepared by reacting N, N-dimethyl-1,1,2,2-tetrafluoroethylamine with a Lewis acid, and ethyldimethylaminoacrylate (Ethoxycarbonyl) prop-2-en-1-ylidene] -N-methyl ester was prepared by reacting N - [(2E) -1- (difluoromethyl) -3- Methane is used to produce minimetetrafluoroborate and then reacted with methylhydrazine to produce the desired compound. However, this method uses N, N-dimethyl-1,1,2,2-tetrafluoroethylamine and Lewis acid (BF3), which are very difficult to transport and handle and are sensitive to moisture, I do not.
In PCT / EP2004 / 011376 (October 12, 2004), dichloroacetyl chloride or difluoroacetyl chloride and ethyldimethylaminoacrylate were reacted with various bases in a toluene solvent to obtain ethyl 2- (dichloroacetyl) -3 - (dimethylamino) acrylate or ethyl-2- (difluoroacetyl) -3- (dimethylamino) acrylate. This method is disadvantageous in that the production cost is high due to the two steps of producing the desired compound via ester using the expensive aminoacrylic ester and the purification step.
In addition, PCT / EP 2008/004829 (December 31, 2008) discloses that a hydrazone is prepared by reacting ketone with methylhydrazine, pyrazolecarbaldehyde is prepared by subsequent reaction with a Billsmeier reagent without separation, Pyrazolecarboxylic acid is obtained through the reaction. However, this method has a problem in that a low yield can not be avoided because it requires passing through unstable carbaldehyde.
Thus, the conventional preparation methods for the pyrazole carboxylic acid derivatives have a problem that the starting materials and the reaction materials are too expensive and side reactions occur. Therefore, it is required to develop a new manufacturing method that can solve such problems .
Accordingly, the inventors of the present invention have found that, in the course of studying an improved preparation method of the pyrazolecarboxylic acid derivative, Diketone, which is an important intermediate before cyclization in a pyrazole form, is reacted with a catalytic gas phase reaction product, (E) -4- (dimethylamino) but-3-en-2-one in the form of an acrylate and an acrylamine in a very easy and high yield, The present invention has been completed.
It is an object of the present invention to provide a pyrazolecarboxylic acid derivative of the formula (I), which is useful as a production intermediate of a pyrazolecarboxanilide-series fungicide, with less side reaction than the conventional production method, And to provide a novel method for preparing the compound.
A process for preparing a pyrazolecarboxylic acid derivative according to the present invention comprises reacting (E) -4- (dialkylamino) but-3-en-2-one of the following formula (II) with a haloacetyl (E) -3 - ((dialkylamino) methylene) -1,1-halopentane-2,4-dione of formula (IV) (III) is reacted with a compound of the formula (V) to produce a 1- (3- (halomethyl) -1-alkyl-1H-pyrazol-4-yl) ethanone of the formula ; Alkyl-3-haloalkylpyrazole-4-carboxylic acid of formula (I) by oxidation reaction of the compound of formula (V); .
[Formula (I)]
[Formula (II)] < EMI ID =
[Formula (III)]
[Chemical formula (IV)]
[Formula V]
In the above formulas (I) to (V), R1 is a lower alkyl group of C1-C3 and R2 is any one of CHF₂, CF₃, CHCl₂ and CCl₃.
According to the present invention, there is provided a process for producing (E) -4- (dialkylamino) but-3-en-2-one of the formula (II) used as a starting material and a raw material for producing the haloacetyl fluoride of the formula (I), which is useful as an intermediate of various bactericides, can be easily obtained at low cost and can be easily obtained at a low cost and can produce diketone derivatives with high yield and minimize side reaction products. It is possible to easily produce a carboxylic acid derivative at a low cost.
Hereinafter, the present invention will be described in detail. However, in order to facilitate the description of the present invention, it is assumed that the pyrazolecarboxylic acid derivative of the formula (1) is 1-methyl-3-difluoromethyl-1H-4-pyrazolecarboxylic acid, Will be described step by step. In this case, the starting compound represented by the above formula (II) is (E) -4- (dimethylamino) but-3-en-2-one and the compound represented by the above formula (III) is difluoroacetyl fluoride.
(1) Synthesis of (E) -4- (dimethylamino) Boot -3-en-2-one
1 equivalent of acetone and 2.5 equivalents of methyl formate were simultaneously added dropwise thereto at a temperature of 40 ° C in the presence of an alkali to prepare a formalin acetone sodium salt (Na-salt), and the pH was adjusted to 0 to 1 with sulfuric acid to prepare 4,4- dimethoxybutane- 2-on. (E) -4- (dimethylamino) but-3-en-2-one can be obtained in a high yield of 80% by distillation purification after reacting it with 50% dimethylamine at room temperature for 4 hours. At this time, the excessive use of methyl formate and methanol can be recovered and used in the next reaction, thereby reducing the cost.
(2) Difluoroacetyl Fluoride Produce
When 1,1,2,2-tetrafluoro-1-methoxyethane is contacted with a spherical or cylindrical gamma-alumina catalyst at a temperature of 200 to 300 ° C and then cooled, difluoroacetyl fluoride is easily obtained have. The catalyst preferably has a specific surface area of 100 to 250 m 2 / g, a specific gravity of 0.5 to 1.0 g / ml and a pore volume of 0.3 to 0.5 ml / g.
(3) Synthesis of (E) -3 - ((dimethylamino) methylene) -1,1- Difluoropentane -2,4- Dion Manufacturing
The reaction of (E) -4- (dimethylamino) but-3-en-2-one with difluoroacetyl fluoride in toluene at 20-30 ° C with triethylamine as base gives 3 - ((dimethylamino) methylene) -1,1-difluoropentane-2,4-dione can be obtained.
This process was performed by adding a toluene solvent and (E) -4- (dimethylamino) but-3-en-2-one to a receiver flask while producing difluoroacetyl fluoride in a gas- It is possible. At this time, at least one solvent selected from the group consisting of xylene, dichloromethane and ethylene dichloride can be used in addition to the toluene. As the base, at least one base selected from sodium carbonate and caustic soda besides triethylamine can be used have.
(4) Cyclization and oxidation reaction
When the (E) -3 - ((dimethylamino) methylene) -1,1-difluoropentane-2,4-dione is cyclized with methyl hydrazine at a temperature of -25 to 15 ° C, 1- (3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) ethanone is prepared. If the reaction temperature is lower than -25 ° C, the reaction is slow. On the other hand, if the reaction temperature is higher than 15 ° C, a side reaction is excessively generated.
Subsequently, the ketone functional group of the 1- (3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) ethanone is oxidized using sodium hypochlorite (NaClO) Methyl-3-difluoromethyl-1H-4-pyrazolecarboxylic acid.
Hereinafter, the present invention will be described in detail with reference to examples.
[Example 1] Preparation of (E) -4- (dimethylamino) but-3en-2-one [
(1-1) Formyl acetone Sodium salt Produce
257 g of methanol and 100 g (1.852 mol) of sodium methoxide are dissolved in a 2-L three-necked flask and maintained at 40 占 폚. A mixture of 118.1 g (2.036 mol) of acetone and 333.6 g (5.555 mol) of methyl formate was added dropwise at 40 ° C. for 4 hours and further stirred for 1 hour and then cooled to 20 ° C. to obtain 184 g (1.704 mol) of formalin acetone sodium salt (Sodium methoxide standard, HPLC quantitative yield 92%).
(1-2) 4,4- Dimethoxy -2- Butanone Produce
370 ml of methanol and 6.2 g (0.063 mol) of sulfuric acid are added to the 4L 3L reactor and maintained at 30 ° C. The formyl acetone reaction solution and 93.8 g (0.957 mol) of sulfuric acid are added dropwise at 30 ° C or lower for 1 hour or more while maintaining the pH at 0-1. After addition, the mixture is further stirred at the same temperature for 4 hours and cooled to 20 ° C. Adjust the pH to 7-8 with 20% caustic soda solution and filter the resulting salt. The filtrate was distilled to obtain 195.6 g (1.479 mol) of 4,4-dimethoxy-2-butanone (80.0% based on sodium methoxide, 87.0% based on sodium formate acetone).
(1-3) Synthesis of (E) -4- (dimethylamino) Boot -3-en-2-one
195.6 g (1.479 mol) of 4,4-dimethoxy-2-butanone and 146.8 g (1.631 mol) of 50% dimethylamine aqueous solution were placed in a three-necked 1 L reactor and reacted at 25 ° C for 4 hours. After completion of the reaction, distillation was conducted to obtain 159 g of (E) -4- (dimethylamino) but-3-en-2-one (G, C purity 95%, separation yield 95%, sodium methoxide 76%).
1 H-NMR (CDCl 3, delta (ppm)); D, J = 12.7 Hz), 2.10 (3H, S), 2.94 (6H, brs), 5.05
[Example 2] Preparation of difluoroacetyl fluoride
Gamma alumina is added to the catalytic gas phase reactor, and nitrogen is flowed at a temperature of 250 ° C or more for 12 hours, followed by activation with HF for 12 hours. 200 g (1.515 mol) of 1,1,2,2-tetrafluoro-1-methoxyethane is added for 2 to 3 hours while maintaining the temperature of the catalytic gas phase reactor at 220 to 230 ° C. The resulting difluoroacetyl fluoride is collected in a receiver cooled to -10 캜 (yield 140.6 g, G, C purity 95%, yield 90%).
[Example 3] Preparation of (E) -3 - ((dimethylamino) methylene) -1,1-difluoropentane-2,4-dione
100 g (0.758 mol) of (E) -4- (dimethylamino) but-3-en-2-one, 76.5 g (0.758 mol) of triethylamine and 500 g of dichloromethane are placed in a 2 L three- . 118.7 g of difluoroacetyl fluoride (G, C 95%, 1.150 mol) was added dropwise at the same temperature and further stirred for 30 minutes. When the reaction is completed, the reaction mixture is cooled to 0 ° C, 500 g of H 2 O is maintained at 10 ° C or lower for 1 hour, and the water layer is removed by layer separation. The thus obtained mixture of (E) -3 - ((dimethylamino) methylene) -1,1-difluoropentane-2,4-dione dichloromethane was used in the next reaction without separation and purification (GC quantitation yield 80% 135.4 g (0.708 mol)).
[Example 4] Preparation of 1- (3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) ethanone
Add 89.36 g (0.779 mol) of 40% methylhydrazine aqueous solution and 89.4 g of dichloromethane to a 1 L three-necked flask, and maintain the temperature at -25 to -15 ° C. (G, C in a quantitative yield of 80%, 135.4 g (0.708 mol)) of (E) -3 - ((dimethylamino) methylene) -1,1-difluoropentane-2,4-dione dichloromethane And the mixture is stirred at 0 ° C for 1 hour. The reaction solution was washed with 150 g of water and the dichloromethane layer was concentrated to remove the solvent to obtain 98.6 g (0.566 mol) of 1- (3- (difluoromethyl) -1-methyl-1H-pyrazol- , G, C purity 85%, yield 80%).
[Example 5] Preparation of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid
1391 g (1.868 mol) of 10% sodium hypochlorite aqueous solution was added to a 3 L 2L reactor, and thereto was added dropwise a solution of 1- (3- (difluoromethyl) -1-methyl-1H-pyrazol- g (0.566 mol) is added at a temperature of 35 DEG C or less while paying attention to heat generation. After completion of the addition, the mixture is stirred at room temperature for 3 hours, and an excessive amount of sodium hypochlorite is removed with an aqueous solution of sodium sulfite.
The chloroform layer formed during the reaction is separated and removed, and the aqueous layer is adjusted to pH 1 or lower with sulfuric acid to give 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid as crystals. The mixture was stirred at 0 ° C for 1 hour, filtered and dried to obtain 94.7g (0.538 mol, yield 95%) of difluoromethyl-1H-pyrazole-4-carboxylic acid.
≪ 1 > H-NMR (d6-acetone); 1H), 8.25 (s, 1H, ArH), 11.2 (broad s, 1H, CO2H)
As described above, the process for producing a pyrazolecarboxylic acid derivative according to the present invention is characterized in that the starting material is cheap and readily available, and the ketone functional group of the pyrazole is oxidized to an acid at a high yield, The desired compound can be prepared.
Claims (6)
(E) -3- ((dimethylamino) methylene) -1,1-difluoro-3-enyl- (B), < / RTI >
The above (E) -3 - ((dimethylamino) methylene) -1,1-difluoropentane-2,4-dione was cyclized with methylhydrazine to give 1- (3- (difluoromethyl) Methyl-1H-pyrazol-4-yl) ethanone;
(Trifluoromethyl) -1-methyl-1H-pyrazol-4-yl) ethanone was oxidized to give 3- (difluoromethyl) (D) obtaining 4-carboxylic acid;
≪ / RTI > wherein R < 1 >
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| CN105541716B (en) | 2015-03-26 | 2024-02-23 | Ａｇｃ株式会社 | Process for producing pyrazole derivative |
| WO2018201272A1 (en) * | 2017-05-02 | 2018-11-08 | Solvay Fluor Gmbh | Process for the manufacture of carboxylic acids or carboxylic acid derivatives |
| EP3495351A1 (en) | 2017-12-08 | 2019-06-12 | Solvay Sa | Oxidation of a pyrazolyl ketone compound to the corresponding carboxylic acid |
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