Hydrogenation one-pot preparation method of icaridin

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a hydrogenation one-pot preparation method of icaridin, which comprises the following steps: in a hydrogen environment, under heating and pressurizing conditions, performing catalytic hydrogenation on 2-hydroxyethyl pyridine and sec-butyl formate or tri-sec-butyl orthoformate in a solvent. The one-pot method for preparing the icaridin has the advantages of low temperature and pressure requirements, mild catalytic hydrogenation conditions, high yield, few impurities and easiness in purification, and is suitable for industrial popularization and application.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and particularly relates to a one-pot hydrogenation method for preparing Icaridin. Background Art

[0002] Icaridin, also known as hydroxy-piperonate, isobutyl 2-(2-hydroxyethyl)piperidine-1-carboxylate, with the chemical name of 1-(sec-butyl carboxylate)-2-(2-hydroxyethyl)piperidine and CAS NO 119515-38-7, is a safe, effective and environmentally friendly insect repellent. Icaridin does not directly kill insects, but effectively repels insects through the volatilization of its odor, protecting users from mosquito bites without harming their health, and can replace the unpleasant-smelling and viscous DEET. Icaridin has been proven to be an effective mosquito repellent ingredient and plays an important role in the prevention and control of highly lethal vector-borne diseases such as malaria, dengue fever, hemorrhagic fever, yellow fever, West Nile virus, Lyme disease, and tick-borne encephalitis. It should be particularly noted that Icaridin has been recommended by the World Health Organization (WHO) as an effective preventive for diseases such as malaria transmitted by mosquito bites. Icaridin has some advantages that other insect repellents do not have: it has a wide range of applications and is effective against mosquitoes, lice, sandflies, horseflies, etc.; it is extremely gentle on the skin, without a sticky feeling, irritation, allergic reaction, is not easily absorbed by the skin, and is safe without side effects; it does not damage plastics, synthetic materials, plastic coatings, sealants, fibers, and adhesives; it can be used by children aged 2 and above, as well as pregnant and lactating women.

[0003] Icaridin was initially developed as an active ingredient by the German chemical company Bayer in 1998 and named Bayrepel. The advantage of this new insect repellent is that, compared to DEET which can cause various skin problems, Icaridin has very good skin compatibility. It entered the US market in 2005 and has currently been recognized and approved by the US Environmental Protection Agency and countries such as Sweden, Norway, and Denmark, with broad development prospects. Regarding the preparation method of Icaridin, there have been some literature and patent reports at home and abroad. The US patent US4900834 (1988) application document first disclosed the activity and synthesis method of Icaridin and a series of compounds. Subsequently, subsequent patents such as DE4133516A1 (1993), CN101323588A (2008), CN101698658A (2010), CN102167681A1 (2011) reported similar preparation methods and improvements in their details. The above patents all use 2-(2-hydroxyethyl)piperidine as the starting material, condense it with sec-butyl chloroformate to obtain the crude product, and then obtain the finished product Icaridin through high-vacuum rectification. The reaction equation is as follows:

[0004]

[0005] We repeated the above-mentioned method for preparingicaridin and found the following problems: 1) In the process of preparing 2-hydroxyethylpiperidine from 2-hydroxypyridine as the raw material, the hydrogenation conditions are harsh, with high temperature (160 - 200 °C) and high pressure (1000 - 2000 psi). 2) In the process of preparing sec-butyl chloroformate through triphosgene, dichlorosgene and phosgene, it is found that the raw materials are highly toxic, the reaction is not easy to control, the operation is inconvenient, and the solvent recovery rate is low; in addition, sec-butyl chloroformate is not stable enough and there are certain problems in storage for a long time; in short, the cost is high, the environment is unfriendly, and the risk is high. 3) In the process of preparing icaridin, due to the high reaction activity of sec-butyl chloroformate, the reaction control is poor, and impurities such as intramolecular cyclization (4) and two sec-butoxycarbonyl groups (5) are easily generated, resulting in an increase in the subsequent purification cost. As shown below:

[0006] Summary of the Invention

[0007] In view of the deficiencies of the prior art, the present invention synthesizes icaridin starting from 2-hydroxypyridine and sec-butyl formate or tri-sec-butyl orthoformate. The raw materials and operations involved in the synthesis process are safe, the reaction conditions are relatively mild, the generation of impurities is less, it is easy to purify, the cost is lower, and it has the advantages of more industrial production.

[0008] The technical solution of the present invention is a one-pot hydrogenation preparation method of icaridin, and the steps include:

[0009] In a hydrogen environment, under heating and pressurization conditions, 2-hydroxypyridine and sec-butyl formate or tri-sec-butyl orthoformate are catalytically hydrogenated in a solvent to obtain icaridin.

[0010] Further, in a hydrogen environment, under heating and pressurization conditions, sec-butyl formate or tri-sec-butyl orthoformate is slowly added to the solvent containing 2-hydroxypyridine for catalytic hydrogenation. Even further, in a hydrogen environment, under heating and pressurization conditions, sec-butyl formate or tri-sec-butyl orthoformate is added dropwise to the solvent containing 2-hydroxypyridine for catalytic hydrogenation.

[0011] The method for generating the hydrogen environment is that the reaction vessel is first purged with nitrogen and then purged with hydrogen. Even further, it is purged with nitrogen three times first and then purged with hydrogen twice.

[0012] The heating temperature is maintained at 60 °C - 150 °C, preferably 70 °C - 110 °C, further preferably 70 °C - 90 °C, further preferably 75 °C - 85 °C, and even further preferably 80 °C.

[0013] The pressure of the pressurization is maintained at 4 - 10 Mpa, preferably 4 - 9 Mpa, further preferably 4 - 9 Mpa, further preferably 4 - 7 Mpa, and even more preferably 4 - 5 Mpa.

[0014] The solvent includes an organic solvent, water, or a mixture of an organic solvent and water. The organic solvent includes any one or any combination of methanol, toluene, tetrahydrofuran, pyridine, triethylamine, methylcyclohexane, sec-butanol, or N-methylmorpholine, preferably any one or any combination of sec-butanol, methanol, or toluene, and more preferably sec-butanol or methanol.

[0015] The catalyst for the catalytic hydrogenation includes any one or any combination of ruthenium on carbon, palladium on carbon, or Raney nickel, preferably Raney nickel.

[0016] The molar ratio of 2-hydroxyethylpyridine to sec-butyl formate or tri-sec-butyl orthoformate is 1:1 - 2, preferably 1:1 - 1.5, and further preferably 1:1 - 1.2; the dosage ratio of 2-hydroxyethylpyridine to the solvent is 1 mol:150 - 350 g, preferably 1 mol:200 - 300 g, further preferably 1 mol:220 - 260 g, and even more preferably 1 mol:230 - 250 g.

[0017] The molar ratio of 2-hydroxyethylpyridine to the catalytically active substance in the catalyst for catalytic hydrogenation is 1:0.02 - 0.2, preferably 1:0.04 - 0.15, further preferably 1:0.08 - 0.12, and even more preferably 1:0.1. The catalytically active substance in the catalyst is a catalytically active metal and / or metal oxide, such as the catalytically active metal when any one or any combination of ruthenium on carbon, palladium on carbon, or Raney nickel is used as the catalyst.

[0018] After the reaction solution obtained by catalytic hydrogenation is filtered to remove the catalyst, purification is carried out, and the purification includes: distilling and recovering the solvent (such as n-butanol), distilling the residue, adding an organic phase solvent (such as toluene), washing the organic phase with sulfuric acid (such as 2N sulfuric acid), washing the organic phase with saturated brine until neutral, drying the organic phase, recovering the organic phase solvent (such as toluene), and distilling the residue at 120 °C / 1 mbar.

[0019] The present invention provides an Icaridin compound prepared by the above-mentioned one-pot hydrogenation preparation method. This Icaridin compound has a high yield and few impurities.

[0020] Compared with the prior art, the advantages of the present invention are as follows:

[0021] The present invention uses 2-hydroxyethylpyridine and sec-butyl formate or tri-sec-butyl orthoformate as raw materials to prepare Icaridin by a one-pot method. The temperature and pressure requirements are low, the catalytic hydrogenation conditions are mild, the yield is high, the impurities are few, and it is easy to purify. Detailed implementation manners

[0022] The following takes specific examples to illustrate the technical solutions of the present invention, but is not intended to limit the scope to be protected by the present invention.

[0023] The present invention uses sec-butyl formate compound (3) or tri-sec-butyl orthoformate (4) as raw materials, and reacts with 2-hydroxyethylpyridine (2) under catalytic hydrogenation conditions to prepareicaridin (1).

[0024] Currently, for the preparation of icaridin compound (1), we use 2-hydroxyethylpyridine (2) and sec-butyl formate (3) as raw materials. 0.5 mol of 2-hydroxyethylpyridine, and the molar ratio of 2-hydroxyethylpyridine to sec-butyl formate is 1:1.1. Different catalysts, reaction pressures, solvents and temperatures are screened, and the experimental results are as follows in the table and figure:

[0025]

[0026]

[0027]

[0028]

[0029] When we tried to hydrogenate pyridine to form piperidine, further form a quaternary imine with the aldehyde group of sec-butyl formate, and then hydrogenate to form the target compound. The preparation method of sec-butyl formate refers to Organic Preparations and Procedures International (1982), 14(3), 177. The results are shown in the above table. After investigating factors such as the catalyst, solvent, pressure, and temperature of this one-pot reaction, it was found that in the 16th example, both the mildness of the reaction conditions and the yield met our expectations. In view of the above experimental results, we used tri-sec-butyl orthoformate (4) to replace sec-butyl formate (3) for the above reaction. The specific reaction conditions are that the catalyst is 10% Raney nickel 3124 (the molar ratio of the catalytically active metal to 2-hydroxyethylpyridine is 0.1:1), the temperature is 80 °C, the pressure is 4 MPa, and tri-sec-butyl orthoformate (4) is gradually added dropwise during the hydrogenation reaction. The reaction ends after 12 hours. After the post-treatment and purification steps in the example, the product is obtained with a yield of 84%. The reaction equation is as follows:

[0030]

[0031] Examples of preparing icaridin by one-pot hydrogenation of sec-butyl formate are as follows:

[0032] 61.5 g of 2 - hydroxyethylpyridine (0.5 mol), 120 g of sec - butanol and 10% Raney nickel 3124 (the molar ratio of catalytically active metallic nickel to 2 - hydroxyethylpyridine is 0.1:1) were added to an autoclave. The autoclave was purged with nitrogen three times and then with hydrogen twice. The temperature was slowly raised to 80 °C with stirring and the hydrogen pressure was maintained at 4 Mpa. Subsequently, 56 g of sec - butyl formate (0.55 mol) was added dropwise. The reaction was carried out for 12 hours. Gas chromatographic analysis showed that the content of 2 - hydroxyethylpyridine was 0.36%, and the reaction was terminated. The reaction mixture was filtered to remove the catalyst, sec - butanol was recovered by distillation, and the residue was distilled. 340 ml of toluene was added. Then the organic phase was washed twice with 120 ml of 2N sulfuric acid solution and then twice with saturated brine until neutral. The organic phase was dried, toluene was recovered, and the residue was distilled at 120 °C / 1 mbar. 89.4 g was obtained with a purity of 99.1% and a yield of 78%. 1 HNMR(CDCl 3 , 400 MHz) δ: 4.79(m, 1H), 4.49(d, J = 12 Hz, 1H), 4.04(d, J = 12 Hz, 1H), 3.63(m, 1H), 3.41(s, 1H), 2.74(m, 1H), 1.98(m, 1H), 1.77(s, 1H), 1.58(m, 7H), 1.53(m, 1H), 1.24(d, J = 8 Hz, 3H), 0.93(t, J = 8 Hz, 3H). HRMS(ESI+) m / z: Calcd for(C 12 H 24 NO 3 )+: 230.1751; Found: 230.1749, Calcd for(C 12 H 23 NO 3 Na)+: 252.1570; Found: 252.1566.

[0033] Note: The above examples are only used to illustrate the present invention and do not limit the technical solutions described in the present invention; therefore, although the present specification has described the present invention in detail with reference to the above - mentioned various embodiments, those of ordinary skill in the art should understand that the present invention can still be modified or equivalently replaced; and all technical solutions and their improvements that do not depart from the spirit and scope of the present invention should be covered by the scope of the claims of the present invention.

Claims

1. A one-pot hydrogenation method for preparing icaridin, characterized in that the steps include: In a hydrogen environment, under heating and pressurized conditions, 2-hydroxyethylpyridine and sec-butyl formate or tri-sec-butyl orthoformate are catalytically hydrogenated in a solvent to obtain icaridin.

2. The one-pot hydrogenation preparation method according to claim 1, characterized in that: Slowly add sec-butyl formate or tri-sec-butyl orthoformate to a solvent containing 2-hydroxyethylpyridine.

3. The one-pot hydrogenation preparation method according to claim 1 or 2, characterized in that: The molar ratio of the 2-hydroxyethylpyridine to sec-butyl formate or tri-sec-butyl orthoformate is 1:1-2, the usage ratio of the 2-hydroxyethylpyridine to the solvent is 1 mol:150-350 g, and the molar ratio of the 2-hydroxyethylpyridine to the catalytically active substance in the catalyst for catalytic hydrogenation is 1:0.02-0.

2.

4. The one-pot hydrogenation preparation method according to claim 3, characterized in that: The catalyst for catalytic hydrogenation includes any one or any combination of ruthenium carbon, palladium carbon, or Raney nickel.

5. The one-pot hydrogenation preparation method according to claim 1, characterized in that: The heating temperature is maintained at 60°C-150°C.

6. The one-pot hydrogenation preparation method according to claim 1, characterized in that: The pressurized pressure is maintained at 4-10 MPa.

7. The one-pot hydrogenation preparation method according to claim 1 or 2, characterized in that: The solvent includes an organic solvent, water, or a mixture of an organic solvent and water.

8. The one-pot hydrogenation preparation method according to claim 7, characterized in that: The organic solvent includes any one or any combination of methanol, toluene, tetrahydrofuran, pyridine, triethylamine, methylcyclohexane, sec-butanol, or N-methylmorpholine.

9. The one-pot hydrogenation preparation method according to claim 1, characterized in that: The method for generating the hydrogen environment is to first replace the reaction container with nitrogen and then replace it with hydrogen.

10. An icaridin compound, characterized in that The product is prepared by the one-pot hydrogenation preparation method according to any one of claims 1 to 9.

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