A method for synthesizing deuterium-labeled diclosan

Abstract

The invention discloses a synthesis method of deuterium-labeled diclosan, wherein 4-chlorophenol-D4 is used as a deuterium-labeled raw material, and the synthesis of deuterium-labeled diclosan is achieved through a two-step reaction. The invention screens out the optimal synthesis route and reaction conditions through a large number of experiments, and the purity of the prepared target product can reach more than 99%, and the isotope abundance can reach 99.0%. The invention provides a reference standard for the research and promotion of diclosan, and has practical application value.

Description

Technical Field

[0001] The invention belongs to a method for synthesizing a compound, and particularly relates to a method for synthesizing deuterium-labeled diclosan. Background Art

[0002] Diclosan, with the trade name of Elixin and the chemical name of 4,4-dichloro-2-hydroxydiphenyl ether, referred to as HP-100, is a safe and effective broad-spectrum antibacterial agent suitable for household and fabric care products, kitchen utensils or hard surface cleaning.

[0003] Diclosan is a highly effective broad-spectrum antimicrobial agent that has a wide range of killing and inhibiting effects on Gram-positive and Gram-negative bacteria, fungi, yeasts and viruses that cause infection or pathogens, to combat pathogenic and odor-producing microorganisms. Due to its long-lasting antimicrobial effect on treated surfaces, it has a long-lasting freshness and antimicrobial protection effect on fabrics, hard surfaces and cleaning utensils.

[0004]

[0005] Currently, triclosan or triclosan ingredients are added to many antibacterial products. Some studies cited by the U.S. Food and Drug Administration show that long-term exposure to triclosan or triclosan in antibacterial products will affect the body's drug resistance or hormone levels, causing health risks. This has caused consumers to have psychological shadows on the safety of triclosan and triclosan, and their recognition of such products has declined. Since diclosan has one less chlorine atom than triclosan, it is less irritating to the human body, so there is a trend of replacing triclosan.

[0006] Diclosan can be used in home care and industrial and institutional cleaning to effectively remove bacteria, prevent cross-contamination and re-contamination, and meet people's hygiene needs. For example, it can be added to detergents, fabric softeners, hard surface cleaners, food and feed area disinfection, and industrial equipment and facility disinfection.

[0007] Therefore, as a chemical substance that may remain in fabrics, food, feed, containers and other items, diclosan may affect the human body and the environment through contact with human skin, direct consumption of food with residues, and agricultural products enriched by livestock. Therefore, conducting relevant metabolic studies on deuterium-labeled diclosan can make it easier for practitioners to assess the safety of diclosan and eliminate possible risks as early as possible.

[0008]

[0009] The above reaction formula is a commonly used diclosan synthesis method at this stage (CN113045390A).

[0010]

[0011] The above reaction formula is another dichlorosan synthesis method disclosed at this stage (CN107353185A). On the basis of the above two methods, when 4-chlorophenol-D4 is used to replace 4-chlorophenol as a deuterium labeling reagent to introduce deuterium atoms, a technical problem of reduced deuterium abundance will be encountered. After a large number of attempts, the applicant still cannot avoid the phenomenon of deuterium loss. Therefore, through the existing public synthesis method, it is impossible to obtain a deuterium-labeled dichloro product that meets the standards. Summary of the invention

[0012] Purpose of the invention: The present invention aims to provide a method for synthesizing deuterium-labeled dichlorosan, which has reasonable process design, strong operability, high product chemical purity, high isotope abundance, and can achieve repeated production.

[0013] Technical solution: The method for synthesizing deuterium-labeled diclosan of the present invention comprises the following steps:

[0014]

[0015] (1) dissolving compound I or II and 4-chlorophenol-D4 (III) in a solvent, and carrying out a Chan-Lam coupling reaction with a base and a molecular sieve in the presence of a copper catalyst to obtain an intermediate IV;

[0016]

[0017] (2) The intermediate IV obtained in step (1) is dissolved in a solvent and reacted with a demethyl ether reagent to obtain compound V, i.e., deuterium-labeled diclosan.

[0018] In step (1), the solvent is dichloromethane, dichloroethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile, tert-butyl alcohol, etc. Preferably, the solvent is dichloromethane, acetonitrile, tetrahydrofuran. Particularly preferably, the solvent is tetrahydrofuran.

[0019] In step (1), in the Chan-Lam coupling reaction reagent, the raw material is selected from compound I or II, and the molar ratio with compound III is 1 to 10:1. Preferably, compound II is selected, and particularly preferably, the molar ratio is 1:5; the copper catalyst is selected from anhydrous copper acetate and hydrated copper acetate, and the molar ratio of the copper catalyst to compound III is 0.1 to 1.5:1. Preferably, the copper catalyst is anhydrous copper acetate, and the molar ratio is 0.1 to 0.5:1. Particularly preferably, the molar ratio is 0.3:1; the base is triethylamine, DIPEA, pyridine, DMAP, potassium carbonate, cesium carbonate, etc., and the molar ratio of the base to compound III is 0.1 to 3:1. Preferably, the base is triethylamine, pyridine, and cesium carbonate. Particularly preferably, the base is pyridine and triethylamine, and the molar ratio is 1:1; the molecular sieve uses 3A molecular sieve, 4A molecular sieve, 5A molecular sieve, etc., and the mass ratio of the molecular sieve to compound III is 0.5-10:1. Preferably, the molecular sieve is 4A molecular sieve, and the mass ratio is 0.5-3:1. Particularly preferably, the mass ratio is 1:1; the gas is high-purity nitrogen, dry air, air, high-purity oxygen, and high-purity helium. Preferably, the gas is selected from dry air and high-purity oxygen. Particularly preferably, the gas is selected from dry air.

[0020] In step (1), the reaction temperature is -10°C to 120°C, and the reaction time is 1 to 96 hours. Preferably, the reaction temperature is 30°C, and the reaction time is 48 hours.

[0021] In step (2), the solvent is dichloromethane, dichloroethane, toluene, tetrahydrofuran, dioxane, DMF, water, etc. Preferably, the solvent is dichloromethane, toluene, dioxane, and particularly preferably, dichloromethane.

[0022] In step (2), the demethylated ether reagent is aluminum chloride, pyridine hydrochloride, hydrobromic acid, hydroiodic acid, boron tribromide, boron trichloride, sodium ethanethiolate, lithium bromide, etc., and the molar ratio of the reagent to the intermediate IV is 1 to 10: 1. Preferably, the reagent is pyridine hydrochloride, hydrobromic acid, boron tribromide, and particularly preferably, the reagent is boron tribromide, and the molar ratio is 3: 1.

[0023] In step (2), the reaction temperature is -78°C to 135°C, and the reaction time is 0.1 to 18 hours. Preferably, the reaction temperature is -20°C, and the reaction time is 2 hours.

[0024] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the present invention realizes the synthesis of deuterium-labeled diclosan for the first time, uses 4-chlorophenol-D4 as a raw material, designs and implements a new method for synthesizing deuterium-labeled diclosan, and screens out the optimal synthesis route and reaction conditions through a large number of experiments. The purity of the prepared target product can reach more than 99%, the isotope abundance can reach up to 99.1%, and the yield is ≥26%. It provides a reference standard for the research and promotion of diclosan, and has practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Schematic diagram of the synthesis reaction process of deuterium-labeled diclosan;

[0026] Figure 2 The IR spectrum of deuterium-labeled diclosan prepared in Example 1 is shown;

[0027] Figure 3 The NMR spectrum of deuterium-labeled diclosan prepared in Example 1 is shown;

[0028] Figure 4 HPLC spectrum of deuterium-labeled diclosan obtained in Example Preparation. DETAILED DESCRIPTION

[0029] The technical solution of the present invention is further described below in conjunction with specific examples.

[0030] Example

[0031] The synthesis method of deuterium-labeled diclosan comprises the following steps (reaction formula as shown in Figure 1 shown):

[0032] (1) Synthesis of Intermediate IV

[0033] The reaction process is:

[0034]

[0035] Take 1 gram of compound III and dissolve it in 20 times the volume of solvent. After adding intermediate I or II, add copper catalyst, base, molecular sieve in sequence, then evacuate the system and restore the pressure to normal pressure with corresponding gas. After repeating the operation three times, connect a balloon of corresponding gas to react to obtain intermediate IV, [M+H] + =273.0, yield and deuterium abundance are shown in the table below.

[0036]

[0037]

[0038] (2) Deuterium-labeled diclosan (V)

[0039] The reaction process is:

[0040]

[0041] Take 200 mg of intermediate IV with a deuterium abundance of 99.2% and dissolve it in 20 times the volume of solvent, add demethyl ether reagent, and after the reaction is completed, treat and purify to obtain deuterium-labeled dichlorosan (V), [MH] - =257.1, 259.0, deuterium abundance and yield are shown in the table below, IR Figure 2 As shown, 1 H-NMR Figure 3 As shown, HPLC Figure 4 shown.

[0042]

[0043] Comparative Example 1

[0044] 200 mg of deuterated 4-chlorophenol with a deuterium abundance of 99.0% was dissolved in xylene, and 2,5-dichloroacetophenone (1.2 equivalents), potassium carbonate (1.5 equivalents) and copper oxide (0.05 equivalents) were added in sequence for reaction. After treatment and purification, the isotopic abundance of the intermediate was detected. The results are shown in the table below.

[0045] temperature time Yield Deuterium abundance 1 80℃ 96h <5％ N / A 2 100℃ 96h <10％ 95.8％ 3 120℃ 60h 35％ 92.2％ 4 120℃ 48h 27％ 93.6％ 5 140℃ 16h 66％ 85.3％ 6 140℃ 12h 58％ 87.5％ 7 140℃ 8h 43％ 89.0％ 8 160℃ 8h 39％ 82.5％ 9 160℃ 4h 24％ 86.1％

[0046] Comparative Example 2

[0047] 200 mg of deuterated 4-chlorophenol with a deuterium abundance of 99.0% was dissolved, and 2,5-dichloronitrobenzene (1.2 equivalents) and a base were added in sequence for reaction. After treatment and purification, the isotopic abundance of the intermediate was detected. The results are shown in the table below.

[0048]

Claims

1. A method for synthesizing deuterium-labeled diclosan, characterized in that: The following steps are involved: ； (1) dissolving compound I or II and compound III in a solvent, and carrying out a Chan-Lam coupling reaction with a base and a molecular sieve in the presence of a copper catalyst to obtain an intermediate IV; (2) dissolving intermediate IV in a solvent and reacting with a demethyl ether reagent to obtain compound V, i.e., deuterium-labeled diclosan; The copper catalyst is selected from anhydrous copper acetate or hydrated copper acetate; The demethylated ether reagent is aluminum chloride, pyridine hydrochloride, hydrobromic acid, hydroiodic acid, boron tribromide, boron trichloride, sodium ethanethiolate or lithium bromide.

2. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: In step (1), the solvent is dichloromethane, dichloroethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, acetonitrile or tert-butanol.

3. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: In step (1), the molar ratio of the raw material I or II to the compound III is 1 to 10:

1.

4. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: In step (1), the molar ratio of the copper catalyst to compound III is 0.1 to 1.5:

1.

5. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: In step (1), the base is triethylamine, DIPEA, pyridine, DMAP, potassium carbonate or cesium carbonate, and the molar ratio of the base to compound III is 0.1 to 3:

1.

6. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: In step (1), the molecular sieve uses 3A molecular sieve, 4A molecular sieve or 5A molecular sieve, and the mass ratio of the molecular sieve to compound III is 0.5~10:

1.

7. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: In step (1), the reaction is carried out in dry air or air atmosphere.

8. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: The reaction temperature of step (1) is -10°C to 120°C, and the reaction time is 1 to 96 hours.

9. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: In step (2), the solvent is dichloromethane, dichloroethane, toluene, tetrahydrofuran, dioxane, DMF or water.

10. The method for synthesizing deuterium-labeled diclosan according to claim 1, characterized in that: In step (2), the molar ratio of the demethylation etherification reaction reagent to the intermediate IV is 1 to 10:1; the demethylation etherification reaction temperature is -78°C to 135°C, and the reaction time is 0.1 to 18 hours.

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