JP2000239223A - Production of 2-bromo-5-fluorobenzoic acid derivative - Google Patents
Production of 2-bromo-5-fluorobenzoic acid derivativeInfo
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- JP2000239223A JP2000239223A JP11040371A JP4037199A JP2000239223A JP 2000239223 A JP2000239223 A JP 2000239223A JP 11040371 A JP11040371 A JP 11040371A JP 4037199 A JP4037199 A JP 4037199A JP 2000239223 A JP2000239223 A JP 2000239223A
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- JP
- Japan
- Prior art keywords
- bromo
- fluorobenzoic acid
- acid derivative
- formula
- acid
- 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.)
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- 0 *c(c(C(O)=O)c1)cc(*)c1F Chemical compound *c(c(C(O)=O)c1)cc(*)c1F 0.000 description 2
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、３−ブロモ−５−
フルオロ安息香酸誘導体の新規な製造方法に関する。３
−ブロモ−５−フルオロ安息香酸誘導体は医農薬中間体
として有用であり、特にキノロンカルボン酸系抗菌剤の
重要な合成中間体である。TECHNICAL FIELD The present invention relates to 3-bromo-5-
The present invention relates to a novel method for producing a fluorobenzoic acid derivative. 3
-Bromo-5-fluorobenzoic acid derivatives are useful as intermediates for medical and agricultural chemicals, and are especially important synthetic intermediates for quinolone carboxylic acid antibacterial agents.
【０００２】[0002]
【従来の技術】従来より、３−ブロモ−５−フルオロ安
息香酸誘導体の製造方法としては、以下のような方法が
提案されている。 （１）テトラフルオロフタロニトリルを臭化リチウムで
臭素化した後、加水分解および脱炭酸して３−ブロモ−
２，４，５−トリフルオロ安息香酸とする方法（特開平
３−２８４６４９）。2. Description of the Related Art Conventionally, the following method has been proposed as a method for producing a 3-bromo-5-fluorobenzoic acid derivative. (1) Bromination of tetrafluorophthalonitrile with lithium bromide followed by hydrolysis and decarboxylation to give 3-bromo-
Method for preparing 2,4,5-trifluorobenzoic acid (Japanese Patent Laid-Open No. 3-284649).
【０００３】（２）３−クロロ−４−フルオロアニリン
をニトロ化した後、酢酸中で臭素により臭素化し、つぎ
にサンドマイヤー型反応により塩素原子を導入し、さら
に、環上の塩素原子をフッ素原子に、ニトロ基をカルボ
キシル基に変換して３−ブロモ−２，４，５−トリフル
オロ安息香酸とする方法（特開昭６２−５０２６３）。 （３）オキサゾリン環で保護された２，４，５−トリフ
ルオロ安息香酸から得られるアニオンと、臭素化剤を反
応させた後、加水分解しオキサゾリン環を外して３−ブ
ロモ−２，４，５−トリフルオロ安息香酸とする方法
（Ｊ．Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ．，３３，
１４０７（１９９６））。(2) After nitrating 3-chloro-4-fluoroaniline, bromination is performed with bromine in acetic acid, and then a chlorine atom is introduced by a Sandmeier-type reaction. A method of converting a nitro group into a carboxyl group into an atom to give 3-bromo-2,4,5-trifluorobenzoic acid (JP-A-62-50263). (3) After reacting an anion obtained from 2,4,5-trifluorobenzoic acid protected with an oxazoline ring with a brominating agent, hydrolysis is performed to remove the oxazoline ring, and 3-bromo-2,4,4 is removed. 5-trifluorobenzoic acid (J. Heterocyclic Chem., 33,
1407 (1996)).
【０００４】[0004]
【発明が解決しようとする課題】しかし、（１）〜
（３）の製造方法はいずれも工程数が長く、収率が低い
問題があり、大規模の合成方法としては実用的でない問
題があった。However, (1)-
Each of the production methods (3) has a problem that the number of steps is long and the yield is low, and there is a problem that it is not practical as a large-scale synthesis method.
【０００５】[0005]
【課題を解決するための手段】本発明は、従来の技術の
欠点を解決する目的でなされたものであり、短工程かつ
簡便な操作で、医農薬中間体として有用な３−ブロモ−
５−フルオロ安息香酸誘導体を製造する方法を提供す
る。DISCLOSURE OF THE INVENTION The present invention has been made for the purpose of solving the drawbacks of the prior art, and has a short process and simple operation, and is useful as an intermediate for medicinal and agricultural chemicals.
Provided is a method for producing a 5-fluorobenzoic acid derivative.
【０００６】すなわち本発明は、下式１で表されるフル
オロ安息香酸誘導体とＮ−ブロモイミド型臭素化剤と
を、硫酸存在下で反応させることを特徴とする下式２で
表される３−ブロモ−５−フルオロ安息香酸誘導体の製
造方法である。ただし、式中のＸおよびＹは、それぞれ
ハロゲン原子を示す。That is, the present invention provides a method for reacting a fluorobenzoic acid derivative represented by the following formula 1 with an N-bromoimide type brominating agent in the presence of sulfuric acid, wherein This is a method for producing a bromo-5-fluorobenzoic acid derivative. However, X and Y in the formula each represent a halogen atom.
【０００７】[0007]
【化２】 Embedded image
【０００８】[0008]
【発明の実施の形態】式１中のＸおよびＹは、それぞ
れ、ハロゲン原子を示す。ハロゲン原子としては、フッ
素原子、塩素原子、臭素原子、またはヨウ素原子であ
り、フッ素原子または塩素原子が中間体の有用性の点か
ら好ましい。BEST MODE FOR CARRYING OUT THE INVENTION X and Y in Formula 1 each represent a halogen atom. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a fluorine atom or a chlorine atom is preferable from the viewpoint of usefulness of the intermediate.
【０００９】フルオロ安息香酸誘導体（式１）として
は、ＸおよびＹがいずれもフッ素原子、Ｘがフッ素原子
でありＹが塩素原子である、またはＸおよびＹがいずれ
も塩素原子である化合物、すなわち、２，４，５−トリ
フルオロ安息香酸、２−クロロ−４，５−ジフルオロ安
息香酸、または２，４−ジクロロ−５−フルオロ安息香
酸が、中間体の有用性の点から好ましい。フルオロ安息
香酸誘導体（式１）は、市販されており、容易に入手で
きる。As the fluorobenzoic acid derivative (formula 1), compounds wherein X and Y are both fluorine atoms, X is a fluorine atom and Y is a chlorine atom, or X and Y are both chlorine atoms, , 2,4,5-trifluorobenzoic acid, 2-chloro-4,5-difluorobenzoic acid or 2,4-dichloro-5-fluorobenzoic acid are preferred from the viewpoint of usefulness of the intermediate. Fluorobenzoic acid derivatives (Formula 1) are commercially available and readily available.
【００１０】本発明においては、式１で表されるフルオ
ロ安息香酸誘導体を、Ｎ−ブロモイミド型臭素化剤で臭
素化する。Ｎ−ブロモイミド型臭素化剤とは、イミド構
造を有する化合物のイミド結合を形成する窒素原子がモ
ノブロモ化された化合物からなり、イミド構造を有する
環状化合物のイミド結合を形成する窒素原子がモノブロ
モ化された化合物からなるのが好ましい。In the present invention, the fluorobenzoic acid derivative represented by the formula 1 is brominated with an N-bromoimide type brominating agent. The N-bromoimide type brominating agent is a compound in which a nitrogen atom forming an imide bond of a compound having an imide structure is monobrominated, and a nitrogen atom forming an imide bond of a cyclic compound having an imide structure is monobrominated. Preferably, the compound comprises
【００１１】Ｎ−ブロモイミド型臭素化剤としては、公
知の化合物が挙げられ、Ｎ−ブロモコハク酸イミド、Ｎ
−ブロモグルタル酸イミド、１，３−ジブロモ−５，５
−ジメチルヒダントイン、Ｎ，Ｎ’，Ｎ”−トリブロモ
イソシアヌル酸、Ｎ，Ｎ’−ジブロモイソシアヌル酸カ
リウム、またはＮ，Ｎ’−ジブロモイソシアヌル酸ナト
リウムが好ましく、特に入手の容易さ、反応性等の点か
ら１，３−ジブロモ−５，５−ジメチルヒダントインが
好ましい。Examples of the N-bromoimide type brominating agent include known compounds, such as N-bromosuccinimide and N-bromosuccinimide.
-Bromoglutarimide, 1,3-dibromo-5,5
-Dimethylhydantoin, N, N ', N "-tribromoisocyanuric acid, potassium N, N'-dibromoisocyanurate or sodium N, N'-dibromoisocyanurate are preferred, and particularly, such as ease of availability and reactivity. From the viewpoint, 1,3-dibromo-5,5-dimethylhydantoin is preferred.
【００１２】Ｎ−ブロモイミド型臭素化剤の使用量は、
フルオロ安息香酸誘導体（式１）に対して０．３〜２倍
モルが好ましく、特に０．５〜１．０倍モルが好まし
い。The amount of the N-bromoimide type brominating agent used is
The molar amount is preferably 0.3 to 2 times, more preferably 0.5 to 1.0 times the mol of the fluorobenzoic acid derivative (formula 1).
【００１３】フルオロ安息香酸誘導体（式１）の臭素化
反応は、硫酸の存在下で実施する。本発明の反応は、反
応系中に水が大量に存在すると収率が低くなるおそれが
あるために、硫酸としては、９７％以上の硫酸を使用す
るのが好ましく、特に濃硫酸を使用するのが好ましい。
硫酸量はフルオロ安息香酸誘導体（式１）の１モルに対
して０．２〜２０Ｌを使用するのが好ましく、特に０．
５〜５Ｌを使用するのが好ましい。フルオロ安息香酸誘
導体（式１）、硫酸、Ｎ−ブロモイミド型臭素化剤は、
市販されているものを精製することなく使用できる。The bromination of the fluorobenzoic acid derivative (formula 1) is carried out in the presence of sulfuric acid. In the reaction of the present invention, since the yield may be reduced if a large amount of water is present in the reaction system, it is preferable to use 97% or more sulfuric acid as the sulfuric acid, and particularly to use concentrated sulfuric acid. Is preferred.
The amount of sulfuric acid is preferably 0.2 to 20 L per 1 mol of the fluorobenzoic acid derivative (formula 1), particularly preferably 0.1 to 0.2 L.
It is preferred to use 5-5L. Fluorobenzoic acid derivatives (formula 1), sulfuric acid, N-bromoimide type brominating agents
A commercially available product can be used without purification.
【００１４】臭素化反応は、−４０〜＋１００℃で実施
するのが好ましく、特に−２０℃〜室温で実施するのが
好ましい。また、臭素化反応の反応時間は、５〜４８時
間が好ましい。また、反応時の圧力は、加圧であって
も、減圧であっても、常圧であってもよく、常圧である
のが好ましい。また、反応の手法としては、通常の有機
反応の手法が採用できる。The bromination reaction is preferably carried out at -40 to + 100 ° C, more preferably at -20 ° C to room temperature. The reaction time of the bromination reaction is preferably 5 to 48 hours. The pressure during the reaction may be pressurized, depressurized, or normal pressure, and is preferably normal pressure. Further, as a reaction technique, a usual organic reaction technique can be adopted.
【００１５】本発明の反応で生成する反応生成物は、通
常の後処理方法や、目的に応じた精製を行うのが好まし
い。たとえば、（方法１）：反応生成物を水で希釈し、
つぎにジクロロメタン、ジエチルエーテル、酢酸エチル
等の非水溶性有機溶媒を加えて分液し、有機層を乾燥し
た後に、該有機層を濃縮し単離する方法、（方法２）反
応生成物に、炭酸水素ナトリウム、炭酸水素カリウム、
水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、
炭酸カリウム等の無機塩基、または無機塩基の水溶液、
トリエチルアミン、ジエチルアミン、トリメチルアミ
ン、ジメチルアミン等の有機塩基、または有機塩基の水
溶液を加えて、ｐＨ６〜１１に調整し、つぎに不溶物を
ろ過し、ろ液に、硫酸、塩酸、リン酸、または酢酸等の
鉱酸を加えてｐＨ１〜５にして、つぎに結晶化させて単
離する方法、が挙げられる。The reaction product produced in the reaction of the present invention is preferably subjected to a usual post-treatment method or purification according to the purpose. For example, (method 1): diluting the reaction product with water,
Next, a water-insoluble organic solvent such as dichloromethane, diethyl ether, ethyl acetate or the like is added and liquid separation is performed. After drying the organic layer, the organic layer is concentrated and isolated. (Method 2) Sodium bicarbonate, potassium bicarbonate,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
An inorganic base such as potassium carbonate, or an aqueous solution of an inorganic base,
An organic base such as triethylamine, diethylamine, trimethylamine, and dimethylamine, or an aqueous solution of an organic base is added to adjust the pH to 6 to 11, and then the insolubles are filtered. A pH of 1 to 5 by adding a mineral acid such as the above, followed by crystallization and isolation.
【００１６】本発明の反応では、フルオロ安息香酸誘導
体（式１）の３位に臭素原子が導入された３−ブロモ−
５−フルオロ安息香酸誘導体（式２）が得られる。ただ
し、式２中のＸおよびＹは、原料として用いたフルオロ
安息香酸誘導体（式１）と同一のハロゲン原子をそれぞ
れ示し、ＸおよびＹがいずれもフッ素原子、Ｘがフッ素
原子でありＹが塩素原子である、またはＸおよびＹがい
ずれも塩素原子である化合物が好ましい。In the reaction of the present invention, a 3-bromo-bromo-benzoic acid derivative (formula 1) in which a bromine atom is introduced at the 3-position is used.
A 5-fluorobenzoic acid derivative (formula 2) is obtained. However, X and Y in Formula 2 each represent the same halogen atom as the fluorobenzoic acid derivative (Formula 1) used as the raw material, X and Y are both fluorine atoms, X is a fluorine atom, and Y is chlorine. Compounds which are atoms or where X and Y are both chlorine atoms are preferred.
【００１７】３−ブロモ−フルオロ安息香酸誘導体（式
２）の具体例としては、つぎの化合物が挙げられる。３
−ブロモ−２，４，５−トリフルオロ安息香酸、３−ブ
ロモ−２−クロロ−４，５−ジフルオロ安息香酸、３−
ブロモ−２，４−ジクロロ−５−フルオロ安息香酸。Specific examples of the 3-bromo-fluorobenzoic acid derivative (formula 2) include the following compounds. 3
-Bromo-2,4,5-trifluorobenzoic acid, 3-bromo-2-chloro-4,5-difluorobenzoic acid, 3-
Bromo-2,4-dichloro-5-fluorobenzoic acid.
【００１８】３−ブロモ−フルオロ安息香酸誘導体（式
２）は、医農薬中間体として有用な化合物であり、たと
えば、公知の方法にしたがってキノロンカルボン酸系抗
菌剤に導くことができる。The 3-bromo-fluorobenzoic acid derivative (formula 2) is a compound useful as an intermediate for medical and agricultural chemicals, and can be led to, for example, a quinolone carboxylic acid antibacterial agent according to a known method.
【００１９】[0019]
【実施例】以下に実施例を示して、本発明をさらに詳し
く説明するが、本発明はこれらに限定されない。The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.
【００２０】［例１］撹拌器、内温計を備えた１Ｌのフ
ラスコに、２，４，５−トリフルオロ安息香酸１００．
０ｇをはかりとり、９６％硫酸５７０ｍＬを加えて溶解
させ、氷冷した。これに１，３−ジブロモ−５，５−ジ
メチルヒダントイン１２１．４ｇを少量ずつ加えて撹拌
した。２０時間後、反応混合物を氷水中へ投入した。析
出した結晶をろ別し、得られた粗結晶をジクロロメタン
に溶解し、飽和炭酸水素ナトリウム水溶液で洗浄した。
つぎに水層を分離し、塩酸で水層を酸性化し、再び結晶
を析出させた。析出した結晶をろ別し、メタノールと水
の混合溶媒による再結晶に付し、３−ブロモ−２，４，
５−トリフルオロ安息香酸６１．８ｇを得た。２，４，
５−トリフルオロ安息香酸からの収率は４７％であっ
た。Example 1 In a 1 L flask equipped with a stirrer and an internal thermometer, 2,4,5-trifluorobenzoic acid 100.
0 g was weighed, 570 mL of 96% sulfuric acid was added to dissolve the mixture, and the mixture was ice-cooled. To this, 121.4 g of 1,3-dibromo-5,5-dimethylhydantoin was added little by little and stirred. After 20 hours, the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration, and the obtained crude crystals were dissolved in dichloromethane and washed with a saturated aqueous solution of sodium hydrogen carbonate.
Next, the aqueous layer was separated, the aqueous layer was acidified with hydrochloric acid, and crystals were precipitated again. The precipitated crystals were separated by filtration and recrystallized with a mixed solvent of methanol and water to give 3-bromo-2,4,4.
61.8 g of 5-trifluorobenzoic acid were obtained. 2,4
The yield from 5-trifluorobenzoic acid was 47%.
【００２１】［例２］２−クロロ−４，５−ジフルオロ
安息香酸９６．６ｇ、９６％硫酸５００ｍＬおよび１，
３−ジブロモ−５，５−ジメチルヒダントイン１０７．
６ｇを用い、例１と同様の操作により、３−ブロモ−２
−クロロ−４，５−ジフルオロ安息香酸７０．９ｇを得
た。２−クロロ−４，５−ジフルオロ安息香酸からの収
率は５２％であった。Example 2 96.6 g of 2-chloro-4,5-difluorobenzoic acid, 500 mL of 96% sulfuric acid and 1,
3-dibromo-5,5-dimethylhydantoin 107.
Using 6 g, 3-bromo-2 was obtained in the same manner as in Example 1.
70.9 g of -chloro-4,5-difluorobenzoic acid were obtained. The yield from 2-chloro-4,5-difluorobenzoic acid was 52%.
【００２２】［例３］２、４−ジクロロ−５−フルオロ
安息香酸９３．６ｇ、９６％硫酸４５０ｍＬおよび１，
３−ジブロモ−５，５−ジメチルヒダントイン９６．１
ｇを用い、例１と同様の操作により、３−ブロモ−２，
４−ジクロロ−５−フルオロ安息香酸８３．９ｇを得
た。２，４−ジクロロ−５−フルオロ安息香酸からの収
率は６５％であった。Example 3 93.6 g of 2,4-dichloro-5-fluorobenzoic acid, 450 mL of 96% sulfuric acid and 1,
3-dibromo-5,5-dimethylhydantoin 96.1
g, 3-bromo-2,
83.9 g of 4-dichloro-5-fluorobenzoic acid were obtained. The yield from 2,4-dichloro-5-fluorobenzoic acid was 65%.
【００２３】[0023]
【発明の効果】本発明の方法によれば、入手容易なフル
オロ安息香酸誘導体（式１）から短工程で、かつ簡便に
３−ブロモ−フルオロ安息香酸誘導体（式２）を得るこ
とができる。本発明の製造方法は、特別な反応条件や反
応装置を用いることなしに実施でき、反応の収率も高い
ことから、工業的な大規模の製造方法として有用な方法
である。According to the method of the present invention, a 3-bromo-fluorobenzoic acid derivative (formula 2) can be obtained easily and easily from a fluorobenzoic acid derivative (formula 1) which is easily available. The production method of the present invention can be carried out without using special reaction conditions or a reaction apparatus, and the reaction yield is high. Therefore, the production method is useful as an industrial large-scale production method.
Claims (4)
とＮ−ブロモイミド型臭素化剤とを、硫酸存在下で反応
させることを特徴とする下式２で表される３−ブロモ−
５−フルオロ安息香酸誘導体の製造方法。ただし、式中
のＸおよびＹは、それぞれハロゲン原子を示す。 【化１】 1. A method of reacting a fluorobenzoic acid derivative represented by the following formula 1 with an N-bromoimide type brominating agent in the presence of sulfuric acid:
A method for producing a 5-fluorobenzoic acid derivative. However, X and Y in the formula each represent a halogen atom. Embedded image
ッ素原子でありＹが塩素原子である、またはＸおよびＹ
がいずれも塩素原子である請求項１に記載の製造方法。2. X and Y are both fluorine atoms, X is a fluorine atom and Y is a chlorine atom, or X and Y
The production method according to claim 1, wherein each is a chlorine atom.
ジブロモ−５，５−ジメチルヒダントインである請求項
１または２に記載の製造方法。3. The method according to claim 1, wherein the N-bromoimide type brominating agent is 1,3-
The production method according to claim 1, wherein the production method is dibromo-5,5-dimethylhydantoin.
２、または３に記載の製造方法。4. The method according to claim 1, wherein concentrated sulfuric acid is used as the sulfuric acid.
4. The production method according to 2 or 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11040371A JP2000239223A (en) | 1999-02-18 | 1999-02-18 | Production of 2-bromo-5-fluorobenzoic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11040371A JP2000239223A (en) | 1999-02-18 | 1999-02-18 | Production of 2-bromo-5-fluorobenzoic acid derivative |
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| JP2000239223A true JP2000239223A (en) | 2000-09-05 |
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| JP11040371A Pending JP2000239223A (en) | 1999-02-18 | 1999-02-18 | Production of 2-bromo-5-fluorobenzoic acid derivative |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002193851A (en) * | 2000-12-27 | 2002-07-10 | Sumitomo Chem Co Ltd | Method for producing bromoaromatic condensed cyclic compound |
| WO2006109661A1 (en) * | 2005-04-06 | 2006-10-19 | Chugai Seiyaku Kabushiki Kaisha | Process for production of 2,3,4-trifluoro-5-(iodo or bromo)benzoic acid |
| CN106892803A (en) * | 2017-02-27 | 2017-06-27 | 浙江朗华制药有限公司 | The preparation method of the fluorobenzaldehyde of 2,6 dichloro 3 and the preparation method of fluorine quinolone compounds |
| CN115073282A (en) * | 2022-06-08 | 2022-09-20 | 都创(重庆)医药科技有限公司 | Method for rapidly preparing 3-bromo-2, 4-difluorobenzoic acid based on microchannel continuous flow technology |
| CN118047736A (en) * | 2024-04-16 | 2024-05-17 | 广州佳途科技股份有限公司 | Synthesis method of 2,2', 6' -tetrafluoro- [1,1' -biphenyl ] compounds |
-
1999
- 1999-02-18 JP JP11040371A patent/JP2000239223A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002193851A (en) * | 2000-12-27 | 2002-07-10 | Sumitomo Chem Co Ltd | Method for producing bromoaromatic condensed cyclic compound |
| JP4569002B2 (en) * | 2000-12-27 | 2010-10-27 | 住友化学株式会社 | Process for producing bromoaromatic condensed ring compound |
| WO2006109661A1 (en) * | 2005-04-06 | 2006-10-19 | Chugai Seiyaku Kabushiki Kaisha | Process for production of 2,3,4-trifluoro-5-(iodo or bromo)benzoic acid |
| US8022247B2 (en) | 2005-04-06 | 2011-09-20 | Chugai Seiyaku Kabushiki Kaisha | Process for production of 2,3,4-trifluoro-5-(iodo or bromo)-benzoic acid |
| JP5025466B2 (en) * | 2005-04-06 | 2012-09-12 | 中外製薬株式会社 | Process for producing 2,3,4-trifluoro-5- (iodo or bromo) benzoic acid |
| CN106892803A (en) * | 2017-02-27 | 2017-06-27 | 浙江朗华制药有限公司 | The preparation method of the fluorobenzaldehyde of 2,6 dichloro 3 and the preparation method of fluorine quinolone compounds |
| CN106892803B (en) * | 2017-02-27 | 2020-08-14 | 浙江朗华制药有限公司 | Preparation method of 2, 6-dichloro-3-fluorobenzaldehyde and preparation method of fluoroquinolone compound |
| CN115073282A (en) * | 2022-06-08 | 2022-09-20 | 都创(重庆)医药科技有限公司 | Method for rapidly preparing 3-bromo-2, 4-difluorobenzoic acid based on microchannel continuous flow technology |
| CN118047736A (en) * | 2024-04-16 | 2024-05-17 | 广州佳途科技股份有限公司 | Synthesis method of 2,2', 6' -tetrafluoro- [1,1' -biphenyl ] compounds |
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