A process for preparation of pyridyl carbamates

Abstract

The present invention relates to a process for preparation of pyridyl carbamates of formula (I).

Description

[0001] A process for preparation of pyridyl carbamates

[0002] The present invention relates to a process for preparation of pyridyl carbamates of formula (I), which are valuable intermediates for the synthesis of pesticidal active compounds. Therefore, there is a need for processes that easily make them available.

[0003] WO 2017 / 202768 (p. 180, Example 1.3) describes a process for the preparation of structurally related compounds by treating of the respective amino-compounds with substituted haloformates in the presence of a base. Said process, however, entails some disadvantages, especially for an industrial scale process. The conditions described in WO 2017 / 202768 lead to desired compounds in a yield of about 60%, which is not sufficient. The inventors of the present invention observed the formation of significant amounts of undesired by-products, the main of which is the urea (II).

[0004] Therefore, it was an object of the present invention to develop a process for the preparation of compounds of formula (I), which process is efficient, cheap and leads to the desired product in high yield, hence being suitable for an upscale to industrially relevant amounts. The formation of the urea II shall be minimized. In addition, the process should be environmentally friendly.

[0005] The inventors of the present invention surprisingly have found that the reaction conducted using from 2 to 10 mol of compound III per 1 mol of compound II produces high yields of target compounds (I) and low amounts of undesirable side products, in particular the urea II.

[0006] Accordingly, the present invention relates to a process for preparation of a compound of formula

[0007] (I) by reacting a compound of formula II with a compound III

[0008] O 111R5O Hal wherein R1is halogen,

[0009] R2is halogen,

[0010] R3is selected from halogen, -CH3, or -OCH3, n is 0, 1, or 2, R4is selected from Ci-C4-alkyl or benzyl,

[0011] R5is selected from Ci-C4-alkyl or phenyl,

[0012] Hal is halogen, using from 2 to 10 mol of compound III per 1 mol of compound II.

[0013] The process according to the present invention entails a series of advantages and overcomes drawbacks of the prior art processes. The compounds of formula (I) are obtained in high yields and undesired side reactions leading to unwanted by-products, especially urea II, are minimized. Sometimes, the product can be employed further without purification. These advantages make the process efficient, industrially simple and environmentally friendly.

[0014] Starting compound (II) can be synthesized as known to the skilled person, e.g. as described in WO 2017 / 202768. The compounds (III) are either commercially available or can be prepared using synthetic procedures that are well known to the skilled person.

[0015] The term “Ci-Cn-alkyl” refers to a straight-chained or branched saturated hydrocarbon group having 1 to n carbon atoms. In particular, the term "Ci-C4-alkyl" refers to a straight-chained or branched saturated hydrocarbon group having 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, 1- methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 , 1-dimethylethyl.

[0016] The term “halogen” refers to F, Cl, Br or I.

[0017] In compounds described herein

[0018] R1is halogen, preferably F, Cl or Br. According to one embodiment, R1is F. According to another embodiment, R1is Cl. According to still another embodiment, R1is Br. R2is halogen, preferably F, Cl or Br. According to one embodiment, R2is F. According to another embodiment, R2is Cl. According to still another embodiment, R2is Br.

[0019] R3is selected from halogen, -CH3, or -OCH3. n is 0, 1 , or 2; preferably 0 or 1 . According to one embodiment, n is 0. According to another embodiment, n is 1. According to still another embodiment, n is 2. If n is 2, both R4can be the same or different.

[0020] R4is selected from Ci-C4-alkyl or benzyl. According to one embodiment, R4is a Ci-C4-alkyl, preferably methyl, ethyl, propyl or i-propyl, most preferably methyl. According to another embodiment, R4is benzyl.

[0021] R5is selected from Ci-C4-alkyl or phenyl. According to one embodiment, R5is a Ci-C4-alkyl, preferably methyl, ethyl, propyl or i-propyl, most preferably ethyl. According to another embodiment, R5is phenyl.

[0022] Hal is halogen, preferably F, Cl or Br, more preferably Cl or Br, most preferably Cl. According to one embodiment, Hal is F. According to another embodiment, Hal is Cl. According to still another embodiment, Hal is F. Preferably Hal is Cl.

[0023] According to a specific embodiment,

[0024] R1is halogen, preferably F

[0025] R2is halogen, preferably Cl, n = 0,

[0026] R4is Ci-C4-alkyl, and

[0027] R5is Ci-C4-alkyl.

[0028] Compound (III) is preferably ethyl chloroform ate.

[0029] According to the present invention, the compound (III) is used in an amount of at least 2 mol per one mol of compound (II). Preferably, the compound (III) is used in an amount of 2 to 10 mol, more preferably 2.5 to 9 mol, most preferably 2.5 to 7 mol mol per one mol of compound (II). Compound (III) can be also used in an amount of at least 3 mol per one mol of compound (II). Preferably, the compound (III) is used in an amount of 3 to 10 mol, more preferably 3 to 9 mol, most preferably 3 to 7 mol mol per one mol of compound (II).

[0030] The reaction can be carried out in the presence of an additive. Suitable additives are selected from aliphatic or cyclic ethers, aliphatic alcohols or phenol.

[0031] According to one embodiment, the additive is selected from aliphatic or cyclic ethers. Aliphatic or cyclic ethers are usually selected from mono, oligo or polyethers, preferably having C1-C4- alkyl chains. According to one embodiment, the additive is selected from aliphatic ethers. Ac- cording to another embodiment, the additive is selected from cyclic ethers. Examples of the suitable ether additives are 1,4-dioxane; diglyme; diethyl glycol di-Ci-C4-alkylethers, such es diethylene glycol dimethylether, diethylene glycol diethylether, diethylene glycol dipropylether, diethylene glycol dibutylether, dipropylene glycol dimethyl ether; Ci-C4-alkylene glycol C1-C4- alkyl ether acetates, such as propylene glycol methyl ether acetate polyalkylene glycols, such as polyethylene glycol, polypropylene glycol, mixed polyethylene polypropylene glycols; or crown ethers, such as 12-crown-4, 15-crown-5, 18-crown-6.

[0032] According to another embodiment, the additive is selected from aliphatic alcohols or phenol. According to one embodiment, the additive is selected from aliphatic alcohols. According to another embodiment, the additive is phenol. Aliphatic alcohols are usually selected from alcohols having Ci-C4-alkyl chains. Examples of the suitable alcohol additives are methanol, ethanol, propanol, iso-propanol, butanol, i-butanol, tert-butanol. According to one specific embodiment the additive is ethanol.

[0033] The amount of the additive can vary. Usually, it is used in an amount of 0.01 to 5 mol, preferably in an amount of 0.05 to 3 mole, more preferably in an amount of 0.1 to 1 mol per 1 mol of compound II.

[0034] The reaction can be carried out with or without a base.

[0035] According to the present invention, the reaction can be carried out with or without a solvent. According to one embodiment, the reaction is carried out with a solvent. According to another embodiment the reaction is carried out without a solvent.

[0036] Suitable solvents for the process of the present invention are aliphatic, alicyclic or aromatic hydrocarbons. In case of aromatic hydrocarbons the aromatic core is preferably benzene or naphthalene, whereas the aromatic core is unsubstituted or substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of Ci-C4-alkyl, Ci-C4-alkoxy and halogen. Examples of the suitable solvents are hexane, heptane, cyclohexane, benzene, ethylbenzene, cymene, toluene, o-, m- and p-xylenes, mesitylene, chlorobenzenes, such as chlorobenzene, 1,2- dichlorobenzene, 1 ,3-dichlorobenzene, 1,4-dichlorobenzene, trichlorobenzenes. Preferred are aromatic hydrocarbons. They are preferably selected from toluene, ethylbenzene, cymene, mesitylene, o-xylene, m-xylene, p-xylene, chlorobenzenes or any mixture thereof; more preferably from toluene, o-xylene, m-xylene, p-xylene, mesitylene, ethylbenzene, chlorobenzene or any mixture thereof. In a specific embodiment, the solvent is selected from o-xylene, m-xylene, p- xylene, ethylbenzene, or any mixtures thereof.

[0037] The temperature in the process of the present invention can be varied in a wide range. Usually, the temperature is kept in the range between room temperature and the reflux temperature of the used solvent. Preferably, the reaction temperature is kept between 50 and 140°C, more preferably between 60 and 130°C, most preferably between 70 and 120°C. The reaction time is not critical and can be appropriately selected depending on the batch size and on the temperature. The short reaction times are preferred. The reaction is generally carried out within 4 to 96 hours; preferably within 5 to 48 hours, more preferably within 6 to 24 hours.

[0038] The order of adding reagents to the reaction mixture is variable. Compounds (II) and (III) can be added simultaneously (in parallel) or in succession. According to one embodiment, the compounds (II) and (III) are added simultaneously. According to another embodiment, they are added in succession. In this case, the order of adding is also variable. Either compound (II) or compound (III) can be added at first.

[0039] The process is generally carried out under atmospheric pressure. However, it is also possible as an alternative to work under reduced pressure or under superatmospheric pressure.

[0040] The process can be carried out batchwise or continuously.

[0041] Generally, the raw product obtained after evaporation of the solvent(s) can directly be used in a further step, if desired. However, the raw product can also be further worked up and / or purified as generally known to the skilled person.

[0042] The present invention is further illustrated by means of the following working examples.

[0043] 187 g (694 mmol, 1 equivalent) of amine (11-1) are suspended in 187 g Xylene and optionally 9.6 g Ethanol (208 mmol, 0.3 equivalents). To this, 226 g (2082 mmol, 3 equivalents) ethyl chloroformate (111-1) is added at r.t. The mixture is heated up to 90 °C and stirred for 19 hours at 90 °C. The in situ generated HCI is stripped with a slight nitrogen flow and quenched in a scrubber with aq. NaOH. HPLC analysis shows complete conversion to the desired product. Excess of ethyl chloroformate and xylene are evaporated completely in vacuo to receive the target compound.

[0044] The Examples 2-6 and 7 were carried out analogously.

[0045] Example 1-c (comparative) reproduces the conditions of Example 1.2 of WO 2017 / 202768 except that xylene is used as a solvent. Example 2-c (comparative) additionally skips the base. As can be seen from these two examples, the yield of compound (I) is low and the urea U-1 is formed in significant amounts.

[0046] Examples 1-6 demonstrate that using of higher amounts of compound (III) leads to higher yields of the compound (I) and less formation of the urea U-1. Example 7 shows that the use of 2 equivalents of compound (III) leads not only to better conversion (i.e. complete versus 17% educt left in comparison example 2-c), but also to higher yield (88% versus 58% in comparison example 2-c) and less formation of the urea U-1 (only 6% versus 24% in comparison example 2-c).

Claims

Claims:

1. A process for preparation of a compound of formula Iby reacting a compound of formula IIwith a compound IIIwhereinR1is halogen,R2is halogen,R3is selected from halogen, -CH3, or -OCH3, n is 0, 1, or 2,R4is selected from Ci-C4-alkyl or benzyl,R5is selected from Ci-C4-alkyl or phenyl,Hal is halogen, using from 2 to 10 mol of compound III per 1 mol of compound II.

2. The process according to claim 1, wherein the reaction is carried out in a hydrocarbon solvent.

3. The process according to claim 1 or 2, wherein the reaction is carried out in an aromatic hydrocarbon solvent.

4. The process according to claim 3, wherein the aromatic hydrocarbon solvent is selected from benzene, toluene, ethylbenzene, cymene, mesitylene, o-xylene, m-xylene, p-xylene, chlorobenzene or any mixture thereof.

5. The process according to claim 3 or 4, wherein the aromatic hydrocarbon solvent is selected from solvent toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, or any mixture thereof.

6. The process according claim 1, wherein reaction is carried out without a solvent.

7. The process according to any one of claims 1 to 6, wherein the reaction is carried out in the presence of an additive selected from aliphatic or cyclic ethers, aliphatic alcohols or phenol.

8. The process according to any one of claims 1 to 7, wherein the reaction is carried out in the presence of an aliphatic alcohol.

9. The process according to any one of claims 1 to 8, wherein the reaction is carried out in the presence of ethanol.

10. The process according to any one of claims 1 to 9, wherein the compound III is used in an amount of from 2 to 8 mol per 1 mol of compound II.

11. The process according to any one of claims 1 to 10, wherein the reaction temperature is kept between 50 and 140 °C.

12. The process according to any one of claims 1 to 11, wherein the reaction time is kept between 4 and 96 hours.

13. The process according to any one of claims 1 to 12, wherein Hal is Cl.

14. The process according to any one of claims 1 to 13, wherein R1is F, Br or Cl and R2is F, Br or Cl.

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