CN1431189A - 2,4-dihalide-3-difluoro methoxybenzoic acid alkyl ester, its synthesizing method and usage - Google Patents

Abstract

The invention discloses an alkyl 2,4-halo-3-difluoromethoxy benzoate and a synthetic method for strengthening purposes. The compound has the following structural formula: wherein R=H or C _1-18 alkyl, X=halogen, and can be used to synthesize fluoroquinolone antibacterial drugs. The method of the invention not only has the advantages of simple method and product separation, but also is suitable for industrial production.

Description

Alkyl 2,4-dihalo-3-difluoromethoxybenzoate, synthesis method and use

technical field

The invention relates to an alkyl 2,4-dihalogen-3-difluoromethoxybenzoate and derivatives, a synthesis method and application.

technical background

Many drug molecules contain fluorine, which is of interest to drug designers because of its special properties. In addition to hydrogen, fluorine has the smallest covalent bond radius, which is similar to hydrogen. The C-H bond of organic compounds is changed to C-F bond, which will not affect the size of the molecule, which means that it will not interfere with the three-dimensional effect of the molecule in the enzyme reaction. The binding energy of the C-F bond is higher than that of the C-H bond, so the fluorine-containing drug has greater stability to oxidation. The hydrogen on the benzene ring may be oxidized to a hydroxyl group during metabolic transformation in the body, and further condensed with glucuronic acid, which is easily excreted from the body and reduces the half-life of the drug. However, after replacing hydrogen with fluorine, it is not easy to be metabolized and oxidized, thereby improving the fat solubility of the molecule and making it easier to penetrate the cell membrane, thus facilitating the absorption and transport of drugs. Fluorine has high electronegativity, which polarizes the molecule, and the charge distribution in the molecule is more conducive to the combination with enzyme molecules or drug receptors, thus enhancing its biological activity. Quinolones have antibacterial and other pharmacological activities. After introducing fluorine into the molecule to become fluoroquinolones, the pharmacological effects are greatly increased and become an important class of antibacterial drugs. Dhagan, D; Rzepa, H.S. Some influence of fluorine in Bioorganic Chemistry, Chem . Commun. 1997, 645. After 20 years of vigorous development, fluoroquinolones have become one of the main varieties of anti-infective drugs. Its rapid development and many varieties on the market are rare in the history of drug development. At present, fluoroquinolones are still the main field of developing new antibacterial drugs (Walker RC: Thefluoroguinolona Mayo.Clin.Proc.1999,74,1030).

The fluorine-containing compound 2,4-dihalogen-3-difluoromethoxyalkyl benzoate and its derivatives are important synthetic raw materials for the synthesis of fluoroquinolone antibacterial drugs. The general synthesis of aromatic compounds substituted with difluoromethoxy is obtained through the insertion of phenolic compounds and difluorocarbene, while difluorocarbene is generated by the action of difluorochloromethane (Freon-22) and inorganic bases . People are still constantly searching for a method for preparing 2,4-dihalogen-3-difluoromethoxyalkyl benzoate and its derivatives and its preparation method which has practical value, can be prepared in large quantities and is easy to separate.

Contents of the invention

The object of the present invention is to provide a kind of 2,4-dihalogen-3-difluoromethoxy benzoic acid alkyl ester and its derivatives.

Another object of the present invention is to provide a method for synthesizing the above-mentioned alkyl 2,4-dihalogen-3-difluoromethoxybenzoate and its derivatives.

The object of the present invention is also to provide the use of the above-mentioned alkyl 2,4-dihalogen-3-difluoromethoxybenzoate and its derivatives.

2,4-dihalogen-3-difluoromethoxyalkyl benzoate and derivatives of the present invention have the following structural formula:

Wherein R=H or C _1-18 alkyl, X=halogen, such as F, Cl, Br, I.

The synthesis method of 2,4-dihalogen-3-difluoromethoxyalkyl benzoate and derivatives of the present invention is as follows: in an organic solvent and in the presence of an inorganic base, 2,4-dihalogen-3-hydroxybenzene Alkyl formate and Freon-22 are reacted at 30-100°C for 0.5-10 hours, and the molar ratio of 2,4-dihalogen-3-hydroxybenzoic acid alkyl ester, Freon-22 and inorganic base is 1 in sequence : 1-10: 1-20, using more Freon-22 and inorganic base has no effect on the reaction. The recommended molar ratio is 1:1-3:2-7 in sequence. The organic solvent can be one or more mixed solvents of methanol, ethanol, propanol, isopropanol, acetic acid, acetonitrile, water and polar solvents miscible with water.

The inorganic base may be hydroxide, carbonate, bicarbonate, sulfate, bisulfate, etc. of a monovalent or divalent metal. Such as KOH, NaOH, K ₂ SO ₄ , KHSO ₄ , Na ₂ SO ₄ , K ₂ CO ₃ , Na ₂ CO ₃ , NaHCO ₃ , CaCO ₃ and other inorganic bases.

The fluorine-containing compound 2,4-dihalogen-3-difluoromethoxybenzoic acid and its derivatives of the present invention are important synthetic raw materials for synthesizing fluoroquinolone antibacterial drugs. The method of the invention has the advantages of simplicity, easy separation and preparation method suitable for industrial production.

Detailed ways

The following examples will help to understand the present invention, but do not limit the content of the present invention.

Example

Preparation of methyl 2,4-dibromo-3-difluoromethoxybenzoate

Add 15.5 g of methyl 2,4-dibromo-3-hydroxybenzoate and 90 ml of isopropanol into a 150 ml three-necked bottle equipped with a reflux condenser, a thermometer, a mechanical stirrer, a dropping funnel and a gas inlet, and wait for the mixture to After the temperature was raised to 70°C, 47ml of 30% KOH was slowly added dropwise, and at the same time, 6.5g of Freon-22 was passed through, and the dropwise addition and ventilation were completed within 2 hours. After the reaction was completed and cooled to room temperature, the pH was adjusted to 4 with 10% NaHSO _aqueous solution, the solid was filtered off, water and isopropanol were evaporated, and the remaining solid was the crude product, which was recrystallized with dichloromethane to obtain 10 white crystals, the content is 99% after chromatographic analysis.

Melting point: 68～70℃

Mass spectrometry MS:

362(40) 360(82) 358(45) 331(46) 329(93) 327(50)312(43) 310(89) 308(47) 281(49) 279(100) 277(52) 51( 71)

Nuclear Magnetic Resonance ¹ HNMR (300MHz, CDCl ₃ )

7.65(d, J＝7.0Hz 1H) 7.52(d, J＝7.0Hz 1H) 6.65(t J＝75.0Hz 1H)3.94(s 3H)ppm

¹⁹ F NMR (282Hz CDCl ₃ )

-80.5(d, J=75.0Hz)ppm

Infrared IR:

1737, 1575, 1279 ^{, 1123, 1082, 768cm -1}

When using alkyl 2,4-dihalo-3-hydroxybenzoate with different substituents, the spectral data of several other compounds are as follows:

R X MS ¹ H NMR ¹⁹ F NMR

H Br 346(40) 7.62(d, 2H) -80.5(d)

296(100) 7.50(d, 2H)

279(31) 6.60(t, 1H)

51(24)

458(56) 0.78(t, 3H) -80.5(d)-C ₈ H ₁₇ Br 1.12～1.42(m, 10H)

1.68(m, 2H)

398(73) 4.20(d, t, 2H)

7.62 (d, 2H)

329(100) 7.50(d, 2H)

6.60(t, 1H)

279(86)

129(30)

51(49) _CH3Cl 270(62) 7.46(d, 1H) -80.3(d) 239(74) 7.34(d, 1H) 220(68) 6.48(t, 1H) 189(100) 3.92(s, 3H)51(52)

Claims (6)

1. A 2,4-dihalo-3-difluoromethoxyalkyl benzoate, which has the following structural formula:

Wherein R=H or C _1-18 alkyl, X=halogen, such as F, Cl, Br, I. 2. a kind of 2 as claimed in claim 1, the synthetic method of 4-dihalo-3-difluoromethoxy benzoic acid alkyl ester is characterized in that in organic solvent and in the presence of inorganic base, 2, 4-Dihalo-3-hydroxybenzoic acid alkyl ester and Freon-22 react at 30-100°C for 0.5-10 hours, 2,4-dihalogen-3-hydroxybenzoic acid alkyl ester, Freon-22 The molar ratio of 2 and inorganic base is 1:1-10:1-20 in turn. 3. a kind of 2 as claimed in claim 2, the synthetic method of 4-dihalo-3-difluoromethoxyalkyl benzoate is characterized in that in organic solvent and in the presence of inorganic base, 2, The molar ratio of 4-dihalo-3-hydroxybenzoic acid alkyl ester to Freon-22 is 1:1-3:2-7 in sequence. 4. a kind of 2 as claimed in claim 2, the synthetic method of 4-dihalo-3-hydroxybenzoic acid alkyl ester is characterized in that described inorganic base can be the hydroxide of monovalent or divalent metal compounds, carbonates, bicarbonates, sulfates or bisulfates. 5. a kind of 2 as claimed in claim 2, the synthetic method of 4-dihalo-3-hydroxybenzoic acid alkyl ester is characterized in that described organic solvent can be methyl alcohol, ethanol, propanol, isopropyl alcohol One or more mixed solvents of alcohol, acetic acid, acetonitrile, water and polar solvents that are miscible with water. 6. A kind of 2 as claimed in claim 2, the purposes of 4-dihalo-3-hydroxybenzoic acid alkyl ester is characterized in that it is used for synthesizing fluoroquinolone antibacterial drugs.