JP4568404B2 - Method for producing pyrazole carboxylic acid ester derivative - Google Patents
Method for producing pyrazole carboxylic acid ester derivative Download PDFInfo
- Publication number
- JP4568404B2 JP4568404B2 JP2000144516A JP2000144516A JP4568404B2 JP 4568404 B2 JP4568404 B2 JP 4568404B2 JP 2000144516 A JP2000144516 A JP 2000144516A JP 2000144516 A JP2000144516 A JP 2000144516A JP 4568404 B2 JP4568404 B2 JP 4568404B2
- Authority
- JP
- Japan
- Prior art keywords
- carboxylic acid
- general formula
- acid ester
- pyrazole carboxylic
- ester derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Description
【０００１】
【発明の属する技術分野】
本発明は、医薬、農薬の合成中間体として有用なピラゾールカルボン酸エステル誘導体の製造法に関する。
【０００２】
【従来の技術】
Jornal of the Chemical Society Chemicl Communication,p.2484-2488,(1970).によると、アセト酢酸エステル類にビルスマイヤー反応を行うと、β−クロロ−α−ホルミルビニルエステル類が得られることが知られている。しかし、このβ−クロロ−α−ホルミルビニルエステル類を用いたピラゾールカルボン酸誘導体の合成法については、全く知られていない。
【０００３】
【発明が解決しようとする課題】
本発明はβ−クロロ−α−ホルミルビニルエステル類を用いて、医薬、農薬の合成中間体として有用なピラゾールカルボン酸エステル誘導体の製造法を提供することを目的とする。
【０００４】
【課題を解決するための手段】
本発明者らは、上記課題について鋭意検討を行ったところ、β−クロロ−α−ホルミルビニルエステル類とヒドラジン類を反応させることでピラゾールカルボン酸エステル誘導体を製造することができることを見いだし、本発明を完成した。すなわち、本発明は、一般式（１）（化４）
【０００５】
【化４】
【０００６】
（式中、Ｒはトリフルオロメチル基を示し、Ｒ1は水素原子を示し、Ｒ2は炭素数１〜６のアルキル基を示す。）で示されるピラゾールカルボン酸エステル誘導体の製造法であって、一般式（２）（化５）
【０００７】
【化５】
【０００８】
（式中Ｒ、Ｒ2は前記と同様）で示される化合物と、一般式（３）（化６）
【０００９】
【化６】
【００１０】
（式中Ｒ1は前記と同様）で示される化合物を反応させて得ることを特徴とする、一般式（１）で示されるピラゾールカルボン酸エステル誘導体の製造法。
【００１１】
【発明の実施の形態】
本発明において、Ｒは、トリフルオロメチル基である。Ｒ1は水素原子である。Ｒ2で示される炭素数１〜６のアルキル基としては、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、ペンチル基、ヘキシル基、シクロヘキシル基等のアルキル基が挙げられる。一般式（２）に示される波線は一般式（２）の化合物がＥ体、Ｚ体もしくはＥ体とＺ体の混合物のいずれでも良いことを意味する。以下に本発明の製造法について詳細に説明する。本発明に係わる製造方法は以下の反応式１に示される反応により行われる（化７）。
【００１２】
【化７】
【００１３】
（Ｒ、Ｒ1、Ｒ2は前記と同様）
【００１４】
出発物質であるβ−クロロ−α−ホルミルビニルエステル類は、Jornal of the Chemical Society Chemicl Communication,p.2484-2488,(1970).に記載された方法、すなわち以下の反応式２に従い合成することができる（化８）。
【００１５】
【化８】
【００１６】
（Ｒ、Ｒ2は前記と同様）
【００１７】
本発明は、一般式（２）で示されるβ−クロロ−α−ホルミルビニルエステル類と一般式（３）で示されるヒドラジン類とを反応させて、一般式（１）で示されるピラゾールカルボン酸エステルを得る反応である。本反応における一般式（３）で示される化合物の使用量は、通常一般式（２）で示される化合物１．０モルに対して、０．２〜２０．０モル、好ましくは０．５〜５．０モル、特に好ましくは１．０〜２．５モルの割合である。本反応で必要により使用される溶媒としては、通常、ヘキサン、石油エーテル等の脂肪族炭化水素、ベンゼン、トルエン、クロロベンゼン、アニソール等の芳香族類、メタノール、エタノール等のアルコール類、ジオキサン、テトラヒドロフラン、ジエチルエーテル等のエーテル類、アセトニトリル、プロピオニトリル等のニトリル類、酢酸エチル等のエステル類、ジクロロメタン、クロロホルム、１，２−ジクロロエタン等のハロゲン化炭化水素、ジメチルホルムアミド、ジメチルスルホキシド等の非プロトン性極性溶媒、またこれらの溶媒の混合溶媒が挙げられ、好ましくは、メタノール、エタノール等のアルコール類である。本反応における溶媒の使用量は、一般式（２）で示される化合物１ｇに対して通常０．１〜２００ｍｌ、好ましくは１〜２０ｍｌである。本反応は塩基がなくても進行するが、塩基の存在下で反応を行っても良く、用いられる塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム等のアルカリ金属およびアルカリ土類金属の水酸化物、水素化ナトリウム、水素化カルシウム等のアルカリ金属およびアルカリ土類金属の水素化物、炭酸ナトリウム、炭酸カルシウム、炭酸マグネシウム等のアルカリ金属およびアルカリ土類金属の炭酸塩、炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属およびアルカリ土類金属の炭酸水素塩、ナトリウムメトキシド、ナトリウムエトキシド、カリウム−ｔ−ブトキシド、ジメトキシマグネシウム等のアルカリ金属およびアルカリ土類金属のアルコキシド、トリエチルアミン、ピリジン等の種々の有機塩基類が挙げられる。これらの塩基の使用量は、一般式（２）で示される化合物１モルに対して、通常０．０１〜２０．０モル、好ましくは０．１〜２．０モルである。反応温度は通常−７０℃〜２５０℃、好ましくは−２０℃〜１００℃、特に好ましくは０℃〜４０℃である。反応時間は通常１分間〜７２時間、好ましくは１０分間〜１０時間である。本反応における種々の条件、即ち、一般式（２）、一般式（３）で示される化合物の使用量、溶媒の種類および使用量、塩基の種類および使用量、反応温度ならびに反応時間各々の設定に際しては、各々の条件毎に示された通常の範囲の数値と好ましい範囲の数値と特に好ましい範囲の数値から適宜相互に選択し、組み合わせることができる。
【００１８】
【実施例】
本発明を更に具体的に説明するため、以下に実施例を示すが、本発明はこの実施例に限定されるものではない。
【００１９】
実施例１ ３−トリフルオロメチルピラゾール−４−カルボン酸エチルエステルの合成
３−クロロ−４，４，４−トリフルオロ−２−ホルミル−２−ブテン酸エチルエステル３．０ｇ（１３．０ｍｍｏｌ）をエタノール９ｍｌに装入し、８℃まで冷却した。反応温度を８〜１０℃に保ちながら、エタノール６ｍｌに混合させたヒドラジン一水和物１．３ｇ（２６．０ｍｍｏｌ）を滴下した。室温で４時間攪拌した後、水を１５ｍｌ加え、減圧下エタノールを留去したところ、結晶が析出した。これを濾取した後、水で洗浄し、減圧下乾燥することで、目的物 ２．１２ｇを結晶として得た。（収率：７９％)。
1H-NMR(CDCl3,ppm):1.39(3H,t,J=7.3Hz),4.37(2H,q,J=7.3Hz),8.24(1H,s).
【００２０】
【発明の効果】
本発明によれば、一般式（２）の化合物と一般式（３）の化合物とを反応させると、一般式（１）で表されるピラゾールカルボン酸誘導体を簡便且つ高収率で製造できる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a pyrazole carboxylic acid ester derivative useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
According to Jornal of the Chemical Society Chemicl Communication, p.2484-2488, (1970), it is known that β-chloro-α-formyl vinyl esters can be obtained by conducting Vilsmeier reaction on acetoacetic esters. ing. However, there is no known method for synthesizing pyrazole carboxylic acid derivatives using these β-chloro-α-formyl vinyl esters.
[0003]
[Problems to be solved by the invention]
An object of this invention is to provide the manufacturing method of the pyrazole carboxylic acid ester derivative useful as a synthetic intermediate of a pharmaceutical and an agricultural chemical using (beta) -chloro- (alpha) -formyl vinyl ester.
[0004]
[Means for Solving the Problems]
As a result of intensive studies on the above problems, the present inventors have found that pyrazole carboxylic acid ester derivatives can be produced by reacting β-chloro-α-formyl vinyl esters with hydrazines. Was completed. That is, the present invention relates to the general formula (1)
[0005]
[Formula 4]
[0006]
(Wherein, R represents a trifluoromethyl group, R 1 represents a hydrogen atom, R 2 represents. Alkyl group having 1 to 6 carbon atoms) was in the preparation of pyrazole carboxylic acid ester derivative represented by the General formula (2)
[0007]
[Chemical formula 5]
[0008]
(Wherein R and R 2 are as defined above), and a compound represented by the general formula (3)
[0009]
[Chemical 6]
[0010]
A method for producing a pyrazole carboxylic acid ester derivative represented by the general formula (1), which is obtained by reacting a compound represented by the formula (wherein R 1 is the same as described above).
[0011]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, R is a preparative trifluoromethyl group. R 1 is a hydrogen atom. Examples of the alkyl group having 1 to 6 carbon atoms represented by R 2 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. And alkyl groups such as a cyclohexyl group. The wavy line shown in the general formula (2) means that the compound of the general formula (2) may be any of E-form, Z-form, or a mixture of E-form and Z-form. The production method of the present invention will be described in detail below. The production method according to the present invention is carried out by the reaction shown in the following reaction formula 1 (Chemical Formula 7).
[0012]
[Chemical 7]
[0013]
(R, R 1 and R 2 are the same as above)
[0014]
The starting β-chloro-α-formyl vinyl esters are synthesized according to the method described in Journal of the Chemical Society Chemicl Communication, p.2484-2488, (1970). (Chemical Formula 8)
[0015]
[Chemical 8]
[0016]
(R and R 2 are the same as above)
[0017]
In the present invention, a β-chloro-α-formyl vinyl ester represented by the general formula (2) is reacted with a hydrazine represented by the general formula (3) to give a pyrazole carboxylic acid represented by the general formula (1). This is a reaction to obtain an ester. The amount of the compound represented by the general formula (3) used in this reaction is usually 0.2 to 20.0 mol, preferably 0.5 to the mol of 1.0 mol of the compound represented by the general formula (2). The ratio is 5.0 mol, particularly preferably 1.0 to 2.5 mol. Solvents used as necessary in this reaction are usually aliphatic hydrocarbons such as hexane and petroleum ether, aromatics such as benzene, toluene, chlorobenzene and anisole, alcohols such as methanol and ethanol, dioxane, tetrahydrofuran, Ethers such as diethyl ether, nitriles such as acetonitrile and propionitrile, esters such as ethyl acetate, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, aprotic such as dimethylformamide and dimethyl sulfoxide Examples include polar solvents and mixed solvents of these solvents, and alcohols such as methanol and ethanol are preferred. The usage-amount of the solvent in this reaction is 0.1-200 ml normally with respect to 1 g of compounds shown by General formula (2), Preferably it is 1-20 ml. This reaction proceeds even without a base, but the reaction may be carried out in the presence of a base. Examples of the base used include alkali metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and alkaline earth. Alkali metal hydroxides, alkali metal and alkaline earth metal hydrides such as sodium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates such as sodium carbonate, calcium carbonate and magnesium carbonate, hydrogen carbonate Alkali metal and alkaline earth metal hydrogen carbonates such as sodium and potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, dimethoxymagnesium and other alkali metal and alkaline earth metal alkoxides, triethylamine, pyridine And various organic bases such as It is. The usage-amount of these bases is 0.01-20.0 mol normally with respect to 1 mol of compounds shown by General formula (2), Preferably it is 0.1-2.0 mol. The reaction temperature is usually -70 ° C to 250 ° C, preferably -20 ° C to 100 ° C, particularly preferably 0 ° C to 40 ° C. The reaction time is usually 1 minute to 72 hours, preferably 10 minutes to 10 hours. Various conditions in this reaction, that is, setting of the amount of the compound represented by the general formula (2) and the general formula (3), the type and amount of the solvent, the type and amount of the base, the reaction temperature, and the reaction time In this case, the numerical values in the normal range, the preferable range, and the particularly preferable range indicated for each condition can be appropriately selected and combined with each other.
[0018]
【Example】
In order to describe the present invention more specifically, examples are shown below, but the present invention is not limited to these examples.
[0019]
Example 1 Synthesis of 3-trifluoromethylpyrazole-4-carboxylic acid ethyl ester 3.0 g (13.0 mmol) of 3-chloro-4,4,4-trifluoro-2-formyl-2-butenoic acid ethyl ester The solution was charged in 9 ml of ethanol and cooled to 8 ° C. While maintaining the reaction temperature at 8 to 10 ° C., 1.3 g (26.0 mmol) of hydrazine monohydrate mixed with 6 ml of ethanol was added dropwise. After stirring at room temperature for 4 hours, 15 ml of water was added, and ethanol was distilled off under reduced pressure to precipitate crystals. This was collected by filtration, washed with water, and dried under reduced pressure to obtain 2.12 g of the desired product as crystals. (Yield: 79%).
1 H-NMR (CDCl 3 , ppm): 1.39 (3H, t, J = 7.3 Hz), 4.37 (2H, q, J = 7.3 Hz), 8.24 (1H, s).
[0020]
【The invention's effect】
According to the present invention, when the compound of the general formula (2) is reacted with the compound of the general formula (3), the pyrazole carboxylic acid derivative represented by the general formula (1) can be easily produced at a high yield.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000144516A JP4568404B2 (en) | 2000-05-17 | 2000-05-17 | Method for producing pyrazole carboxylic acid ester derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000144516A JP4568404B2 (en) | 2000-05-17 | 2000-05-17 | Method for producing pyrazole carboxylic acid ester derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2001322983A JP2001322983A (en) | 2001-11-20 |
| JP4568404B2 true JP4568404B2 (en) | 2010-10-27 |
Family
ID=18651161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000144516A Expired - Fee Related JP4568404B2 (en) | 2000-05-17 | 2000-05-17 | Method for producing pyrazole carboxylic acid ester derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4568404B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201105636A (en) | 2009-07-28 | 2011-02-16 | Syngenta Participations Ag | Processes relating to the alkylation of pyrazoles |
| AR077332A1 (en) | 2009-07-31 | 2011-08-17 | Syngenta Participations Ag | PROCESSES FOR THE RENTAL OF PIRAZOLES |
| MX342390B (en) | 2010-08-10 | 2016-09-28 | Syngenta Participations Ag | Process for the preparation of 3-haloalkylpyrazoles. |
| CN110872255A (en) * | 2019-12-10 | 2020-03-10 | 武威金仓生物科技有限公司 | Preparation method of 3, 4-dimethylpyrazole and phosphate thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000044541A (en) * | 1998-08-03 | 2000-02-15 | Mitsui Chemicals Inc | Production of 1,3-dialkylpyrazole-4-carboxylic acid ester |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000212166A (en) * | 1999-01-26 | 2000-08-02 | Mitsui Chemicals Inc | Production of 1,3-dialkylpyrazole-4-carboxlic acid ester |
-
2000
- 2000-05-17 JP JP2000144516A patent/JP4568404B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000044541A (en) * | 1998-08-03 | 2000-02-15 | Mitsui Chemicals Inc | Production of 1,3-dialkylpyrazole-4-carboxylic acid ester |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001322983A (en) | 2001-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4725977B2 (en) | Process for producing 2-dihaloacyl-3-amino-acrylic acid ester and 3-dihalomethyl-pyrazole-4-carboxylic acid ester | |
| NO314456B1 (en) | Methods and intermediates useful for preparing antifolates | |
| JP2005247690A (en) | Method for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and its tautomer | |
| JP4568404B2 (en) | Method for producing pyrazole carboxylic acid ester derivative | |
| EP0990647B1 (en) | Process for producing quinolone derivatives | |
| JP2008545623A (en) | Method for preparing carboxamide derivatives | |
| KR20080031910A (en) | Process for the preparation of 1-[cyano(4-hydroxyphenyl)methyl]cyclohexanol compounds | |
| JP4026233B2 (en) | Method for producing 4,5-dichloro-6- (α-fluoroalkyl) pyrimidine | |
| WO1999044997A1 (en) | 6-(α-FLUOROALKYL)-4-PYRIMIDONES AND PROCESS FOR PRODUCING THE SAME | |
| JP2608714B2 (en) | Method for producing 1,2,3-triazole and its derivative | |
| JP2984848B2 (en) | Process for producing N-alkylpyrazole derivatives | |
| JP3283959B2 (en) | D-biotin intermediate and method for producing the same | |
| JP2649122B2 (en) | 4,5-Dihalogeno-6- (α-substituted ethyl) pyrimidine and process for producing the same | |
| JP3855686B2 (en) | 3,3-dialkoxy-2-hydroxyimino derivative and process for producing the same | |
| JP4055246B2 (en) | 5-chloro-6- (α-fluoroalkyl) -4-pyrimidone and process for producing the same | |
| JP4123606B2 (en) | Process for producing 4,5-dichloro-6- (α-fluoroalkyl) pyrimidine | |
| JP2784920B2 (en) | 1,3-cyclohexanedione derivative | |
| JP2743441B2 (en) | Cyclopenta [1,2-C] -3-pyrazolecarboxylic acid derivative | |
| JP3864763B2 (en) | 3-halo-2-hydrazono-1-hydroxyiminopropane derivative and process for producing the same | |
| JPH11335329A (en) | Alpha-(alkoxyoxalyl)fatty acid ester and alpha-alkyl or alkenylacrylic esters and synthesis of phenidones using the same | |
| JP4013772B2 (en) | 2-Hydroxyimino-3-oxopropionitrile and process for producing the same | |
| JPH09143178A (en) | Production of 4-butanolide derivative | |
| JPH01319496A (en) | Uracil derivative | |
| US20060217554A1 (en) | Processes for producing pyrazoloacridone derivative and synthetic intermediate thereof | |
| JP2004026652A (en) | beta-ALKOXYACRYLONITRILE DERIVATIVE |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20060614 |
|
| RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20071018 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100216 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A712 Effective date: 20100318 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100323 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100413 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100415 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20100727 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100809 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130813 Year of fee payment: 3 |
|
| LAPS | Cancellation because of no payment of annual fees |