Improved process for preparation of cyclopropyl compounds from olefins

Abstract

The present invention relates to an improved process for the preparation of cyclopropyl compounds from olefins, in particular to an improved process for the preparation of cyclopropyl compounds from olefins by reaction (cyclopropanation reaction) of olefins in the presence of bromochloromethane, elemental zinc and elemental copper or copper compounds.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202080064272.1, filed on September 9, 2020, entitled "An Improved Method for Preparing Cyclopropyl Compounds from Olefins". Technical Field

[0002] This invention relates to an improved method for preparing cyclopropyl compounds from olefins by a reaction (cyclopropanation) in the presence of bromochloromethane, element zinc, and element copper or copper compounds. Background Technology

[0003] The conversion of alkenes to homologous cyclopropyl compounds is known by the Simmons-Smith reaction, in which a dihaloalkane (often diiodomethane) is reacted in the presence of zinc and copper. In this reaction, zinc carbene (carbene body) is generated as an intermediate via copper-activated zinc (zinc-copper couple), whose methylene group undergoes double bond addition with the alkene.

[0004] While cyclopropanation in the presence of diiodomethane often yields high yields due to the high reactivity of diiodomethane, which is indeed necessary for the formation of zinc carbene intermediates, reactions with chlorinated or bromine-containing alkanes as carbene precursors are generally less favorable. Variations of this reaction are therefore described in the prior art, for example, using dibromomethane as a dihaloalkane; in these variations, zinc or zinc-copper coupling is further activated by sonication (J. Org. Chem. [Organic Chemistry Journal] 50, 1985, 4640; Friedrich et al.), by titanium tetrachloride catalysis (J. Org. Chem. [Organic Chemistry Journal] 1989, 54, 2388; Friedrich et al.), or by sodium dihydrobis(2-methoxyethoxy)aluminate (SDBA) (EP 0321409 A2).

[0005] There are also variations of the reaction that use bromochloromethane as a dihaloalkane, which only yield the desired cyclopropyl compound in acceptable yields with additional activation by zinc or a zinc-copper couple.

[0006] In J. Org. Chem., 56 (10), 3255, 1991 (Sibille et al.), for example, the electrochemical cyclopropanation of allyl alcohol with dibromomethane or bromochloromethane using a zinc anode and a carbon fiber cathode is described. However, the disadvantages of this reaction are that it is expensive, laborious, and difficult to control when carried out on a relatively large industrial scale.

[0007] As prior art, WO 2017 / 024126 describes another method in which dibromomethane or bromochloromethane is used instead of diiodomethane as a dihaloalkane and in which zinc or zinc-copper coupling is additionally activated. A haloalkylsilane, such as trimethylchlorosilane, is absolutely necessary as an activator to obtain acceptable yields. The required silicon-containing activator means that this method is also more laborious and expensive than the classic Simonds-Smith reaction when carried out on a larger scale, as the classic Simonds-Smith reaction itself is uneconomical on a relatively large scale due to the high price of the required diiodomethane.

[0008] Cyclopropyl compounds prepared by the method according to the invention are, for example, intermediates or final products for various commercial uses, such as flavorings or agrochemicals. Compounds having formula (II) are, for example, intermediates of the azole fungicide cyclozazole (DE 3406993, CN 105820128, CN 101857576).

[0009] Therefore, it is still necessary to provide a variant of the Simmons-Smith reaction that does not have the disadvantages of the prior art, and therefore it is necessary to address the technical issues of this variant. Summary of the Invention

[0010] Surprisingly, a method for preparing cyclopropyl compounds has now been discovered, comprising reacting a corresponding olefin containing at least one carbon-carbon double bond with bromochloromethane in the presence of (i) elemental zinc, (ii) a catalytically active amount of elemental copper and / or copper (I) compounds and / or copper (II) compounds, and (iii) at least one solvent, characterized in that the reaction of the olefin is carried out in the absence of organosilicon compounds, preferably in the absence of haloalkylsilanes, and / or without the addition of organosilicon compounds, preferably without the addition of haloalkylsilanes, and the elemental zinc has a lead content of not more than 0.005% (50 ppm) by weight, preferably not more than 0.002% (20 ppm) by weight.

[0011] The olefins used for the purposes of this invention are organic compounds having at least one carbon-carbon double bond. For the purposes of this invention, the carbon-carbon double bond is an aliphatic double bond rather than an aromatic double bond. The olefin can be straight-chain, branched, or cyclic. The aliphatic carbon-carbon double bond can be terminal or non-terminal. If the olefin contains more than one carbon-carbon double bond, they can be conjugated or non-conjugated. The olefins used in the methods according to the invention can have additional substituents (such as additional aliphatic or aromatic groups), which can also be substituted or unsubstituted.

[0012] The olefin used is preferably a compound having formula (I).

[0013] (I).

[0014] In cyclopropanation, the olefin leads to the formation of corresponding homologue cyclopropyl compounds, which should be understood in form as products of carbene "CH2" addition to the olefin double bond. When compounds having formula (I) are preferably used as the olefin, compounds having formula (II) form cyclopropyl compounds.

[0015] (II).

[0016] The bromochloromethane (CH2BrCl) used as the haloalkane is commercially available or can be prepared internally using suitable methods, and preferably has a purity of at least 98% by weight and a water content of less than 0.02% by weight, preferably less than 0.007% by weight.

[0017] Bromochloromethane, used as a haloalkane, can also be used, for example, as a mixture with dibromomethane. However, the reaction becomes less economical as the proportion of dibromomethane increases. Furthermore, the yield decreases with increasing dibromomethane proportion.

[0018] The method according to the invention is carried out in the presence of elemental zinc. Elemental zinc is typically present in a finely dispersed form. For the purposes of this invention, a finely dispersed form should be understood to mean, preferably, a powdery, fine-grained, or granular solid that is easy to pour and therefore easy to measure. The method according to the invention presupposes that the elemental zinc has a lead content of no more than 0.005% by weight, preferably no more than 0.002% by weight. The lead content within this concentration range is typically measured using atomic absorption spectrometry.

[0019] The method according to the invention preferably uses elemental zinc in a finely dispersed form, i.e., as having a particle size distribution D90 of no more than 0.5 mm. 质量 The element zinc. For the purposes of this invention, a particle size distribution D90 of no more than 0.5 mm is specified. 质量 This means that 90% of the measured samples, by weight, have a particle size of 0.5 mm or smaller. Particle size distribution D90 质量 This is typically determined by sieving and subsequent weighing of the sieved particles, and has high accuracy. In another embodiment, the zinc metal preferably has a sieve distribution of no more than 15% by weight of particles with a size greater than 250 μm, 25% to 50% by weight of particles with a size from 150 to 250 μm, 30% to 60% by weight of particles with a size from 45 to 150 μm, and no more than 15% by weight of particles with a size less than 45 μm, but wherein the overall distribution conforms to a particle size distribution D90 of no more than 0.5 mm. 质量 .

[0020] In addition to a lead content of no more than 0.005% by weight, preferably no more than 0.002% by weight, element zinc further preferably has a total content of no more than 1% by weight, preferably 0.1% by weight, and more preferably 0.05% by weight of other metals. These other metals are, for example, cadmium, iron, mercury, bismuth, or indium. The content of other metals is usually determined by atomic absorption spectrometry.

[0021] The elemental zinc is further preferably at a zinc content of at least 99.0% by weight, preferably at least 99.9% by weight. The zinc content is usually determined by atomic absorption spectrometry.

[0022] In the method according to the invention, it is preferred to use 1.0 mol of olefin, more preferably 1.0 mol of compound having formula (I), and from 1.5 to 4 mol, more preferably from 2 to 3 mol of metallic zinc.

[0023] The method according to the invention uses elemental copper, copper(I) compounds or copper(II) compounds, or mixtures thereof.

[0024] In addition to a lead content of no more than 0.005% by weight, preferably no more than 0.002% by weight, elemental copper preferably has a total content of no more than 1% by weight, preferably 0.1% by weight, and more preferably 0.05% by weight of other metals. These other metals are, for example, cadmium, iron, mercury, bismuth, or indium. The content of other metals is usually determined by atomic absorption spectrometry.

[0025] When a copper (I) compound is used in the method according to the invention, it is preferably cuprous chloride (I). When a copper (II) compound is used in the method according to the invention, these are preferably copper chloride (II), copper phosphate (II), copper carbonate (II), or mixtures thereof.

[0026] The amount of copper or copper compound used depends on the number of carbon-carbon double bonds undergoing cyclopropanation in the olefin. If the olefin has only one cyclopropanated double bond, then elemental copper and / or copper (I) compound and / or copper (II) compound are used in catalytically active amounts based on 1.0 mol of the olefin, preferably based on 1.0 mol of the compound having formula (I), in total amounts from 0.001 to 0.1 mol, preferably from 0.001 to 0.01 mol. For each additional mole of aliphatic carbon-carbon double bond in the olefin undergoing cyclopropanation, the corresponding integer multiples of the above amounts are used.

[0027] The amount of bromochloromethane used in the method according to the invention also depends on the number of double bonds in the olefin undergoing cyclopropanation. When a single double bond is present in the olefin, for example, for compounds having formula (I), 1 to 3 mol, preferably 1.7 to 2.2 mol of bromochloromethane is used based on 1.0 mol of the olefin, preferably based on 1.0 mol of the compound having formula (I). For each additional mole of carbon-carbon double bond in the olefin undergoing cyclopropanation, the corresponding integer multiple of the above amounts is used.

[0028] The method according to the invention is carried out in the absence of organosilicon compounds. "In the absence of organosilicon compounds, preferably in the absence of haloalkylsilanes" means that throughout the entire duration of the olefin reaction, an organosilicon compound, preferably no more than 0.1% by weight and a haloalkylsilane, preferably no more than 0.02% by weight, based on the mass of elemental zinc, is present in the reaction mixture. In alternative embodiments, the method according to the invention is carried out without the addition of organosilicon compounds, preferably without the addition of haloalkylsilanes. For the purposes of this invention, "without adding an organosilicon compound" means that no organosilicon compound, preferably no haloalkylsilane, is added to the olefin, preferably to a compound having formula (I), to bromochloromethane, to a cyclopropyl compound, preferably to a compound having formula (II), to elemental zinc, to elemental copper and / or copper (I) compounds and / or copper (II) compounds, to a solvent, to other starting materials added to the reaction mixture, or to the reaction mixture itself, at any point during or before the reaction. Only when a suitable amount of organosilicon compound, preferably haloalkylsilane, is added to one of the reaction mixtures or starting materials before or during the reaction can it be envisioned that the organosilicon compound in the reaction mixture exceeds 0.1% by weight, preferably 0.02% by weight, based on the mass of elemental zinc. The organosilicon compound will not appear as a natural impurity in the starting materials—olefin, bromochloromethane, elemental zinc, elemental copper and / or copper (I) compounds and / or copper (II) compounds, and (iii) the solvent. The organosilicon compound is preferably a haloalkylsilane. Haloalkylsilanes are, for example, trialkylchlorosilanes. Preferred representatives of trialkylchlorosilanes are trimethylchlorosilane, triethylchlorosilane, tributylchlorosilane, triisobutylchlorosilane, or trihexylchlorosilane.

[0029] Solvents that can be used in the method according to the invention are, for example, ethers and / or aromatic hydrocarbons. Preferred ethers are diethyl ether, 1,2-dimethoxyethane, methyl tert-butyl ether, tetrahydrofuran, cyclopentylmethyl ether, and mixtures thereof. Preferred aromatic hydrocarbons are toluene. It is preferred to use 0.7 to 1.5 mol, preferably 1.0 to 1.2 mol, of ether and / or 2.0 to 6.0 mol, preferably 2.0 to 3.0 mol, of aromatic hydrocarbon per mol of olefin.

[0030] The method according to the invention is described in more detail below:

[0031] All steps in the reaction are typically carried out under an inert gas atmosphere before the reaction mixture is hydrolyzed. Examples of suitable inert gases are nitrogen or argon.

[0032] In one embodiment of the method according to the invention, starting materials—olefins, preferably compounds having formula (I), element zinc, element copper and / or copper (I) compounds and / or copper (II) compounds, and solvent—are first added to the reaction vessel at a temperature from 15°C to 80°C, preferably from 50°C to 70°C. This produces a non-homogeneous two-phase mixture, which is first mechanically or hydraulically mixed to obtain a two-phase mixture that is as homogeneous as possible. Since the mixing of the above-mentioned starting materials is not exothermic at ambient temperature, the various starting materials can be added discontinuously or continuously and in any order. Preferably, the solvent is added first, followed by the addition and mixing of other starting materials. This prevents the solid starting materials from clumping together. The temperature can be raised to 85°C after or during the addition of the starting materials. Bromochloromethane is then added to the reaction mixture. This is carried out discontinuously or continuously, preferably continuously. Preferably, 0.05 to 0.1 mol of bromochloromethane per mol of olefin, preferably a compound having formula (I), is first added to the reaction mixture. The reaction then begins exothermically within 1 to 240 minutes, resulting in an increase in the temperature of the reaction mixture by 1.5°C to 10°C. Once exothermic action begins, the temperature of the reaction mixture is maintained in the range of 55°C to 85°C, preferably in the range of 60°C to 80°C, and more preferably in the range of 67°C to 73°C, by cooling, preferably by external cooling of the reaction vessel. The addition of bromochloromethane continues until the complete amount of bromochloromethane has been added. If the addition of bromochloromethane is exothermic and the reaction progress decreases as a result, elemental copper and / or copper(I) compounds and / or copper(II) compounds can be metered into the reaction mixture. This usually causes exothermic action, and thus the reaction progress resumes. After the complete amount of bromochloromethane has been added, the reaction mixture is further mixed at a temperature in the range of 55°C to 85°C, preferably in the range of 60°C to 80°C, and more preferably in the range of 65°C to 75°C for 2 to 5 hours. Preferably, the reaction temperature is from 55°C to 85°C, more preferably from 60°C to 80°C, and even more preferably from 65°C to 75°C during and after the addition of bromochloromethane. During this period, samples of the reaction mixture can be taken and analyzed after treatment to determine the content of olefins, preferably olefins having formula (I), and / or cyclopropyl compounds, preferably compounds having formula (II). Once the reaction is complete, the reaction mixture (i.e., the mixture of all starting materials added up to that point in time) is referred to as the crude mixture.

[0033] In a preferred embodiment of the method according to the invention, based on the amount of the olefin used, preferably having formula (I), 0.01% to 5% by weight, preferably 0.1% to 1% by weight, of the crude mixture from the previous reaction is added to the reaction mixture, based on the total weight of the crude mixture. It is generally sufficient to leave the residue of the crude mixture from the previous reaction in the reactor. The crude mixture from the previous reaction corresponds to the reaction mixture after the reaction has ended but before the mixture has hydrolyzed. The crude mixture from the previous reaction can be added to the reaction vessel at the beginning of the addition of the starting materials—olefin, preferably having formula (I), element zinc, element copper and / or copper (I) compounds and / or copper (II) compounds, and solvent—or still present in the same reaction vessel, from the previous reaction. However, the crude mixture from the previous reaction can also be added at a later point in time after the mixing of the starting materials—olefin, preferably having formula (I), element zinc, element copper and / or copper (I) compounds and / or copper (II) compounds, and solvent. This facilitates the initiation of an exothermic reaction. In another embodiment, the initiation of the exothermic reaction can also be facilitated by carrying out the reaction according to the invention in the presence of 0.1% to 5% by weight of zinc halide, preferably zinc chloride or zinc bromide, based on the amount of the compound of formula (II) used. The zinc halide is preferably added at the start of the reaction.

[0034] The reaction progress can be determined by analyzing a sample treated in the same manner as the reaction mixture. The amounts of reactants and products can usually be determined by HPLC or gas chromatography, as an area percentage in the absence of an external standard or as a weight percentage in the presence of an external standard.

[0035] Once the reaction is complete, the crude mixture is typically hydrolyzed. This is done, for example, by adding 1 to 5 kg of water and / or ice per kg of the olefin used, preferably the compound of formula (I) used, to a separate reaction vessel, and adding the crude mixture thereto, preferably by mechanical and / or hydraulic mixing. Then, 0.5 to 1.5 mol of hydrogen chloride and / or hydrogen bromide per mole of the olefin used, preferably the compound of formula (I) used, preferably in the form of a 20% to 35% aqueous acid solution, is added to the mixture. The hydrolysis that occurs is exothermic. During the hydrolysis, it is preferable to ensure that the temperature of the mixture does not rise above 35°C. Once hydrogen chloride is added, the pH of the reaction mixture is, for example, from 6.5 to 7.5. If the water is completely or partially replaced by ice, the amount of ice is ideally chosen such that no ice remains in the reaction mixture at the end of the hydrolysis.

[0036] Once hydrolysis is complete, the hydrolyzed reaction mixture is washed, for example, by adding a water-immiscible solvent, preferably an aromatic hydrocarbon, and more preferably toluene, preferably by mechanical and / or hydraulic mixing. After phase separation into an organic phase containing the cyclopropane product and an aqueous phase, the extraction of the aqueous phase can be repeated. The separated organic phases are then preferably combined.

[0037] An organic phase containing a cyclopropyl compound, preferably a compound having formula (II), can be used as is in a new reaction or further processed to isolate the cyclopropyl compound, preferably a compound having formula (II).

[0038] This separation is carried out, for example, by distilling off the solvent so that the cyclopropyl compound, preferably the compound having formula (II), remains as the substrate.

[0039] The method according to the invention unexpectedly provides—even in the absence of organosilicon compounds, preferably in the absence of haloalkylsilanes, and / or in the absence of organosilicon compounds, preferably in the absence of haloalkylsilanes—cyclopropyl compounds, preferably compounds having formula (II), in yields of 85% to 95% of the theoretical value. Detailed Implementation

[0040] Example:

[0041] Example 1 (according to the present invention) [1-(4-chlorophenyl)-2-cyclopropylprop-1-ol; compounds having formula (II)]

[0042] All steps of the reaction were carried out under a nitrogen atmosphere prior to the hydrolysis of the reaction mixture. At ambient temperature, 79.4 g (0.85 mol) of dimethoxyethane, 152.0 g of 4-(4-chlorophenyl)-3-methylbut-1-en-4-ol [a compound having formula (I)] (97.0% by weight, 0.75 mol), 193.3 g (2.07 mol) of toluene, 120 g of zinc powder (1.84 mol), and 0.188 g (1.9 mmol) of cuprous chloride (I), along with 1–2 g of unhydrolyzed reaction mixture from the previous reaction, were first added to the reactor. The mixture was heated to 85°C with stirring. After reaching this temperature, 7.25 g of bromochloromethane was metered in over 10 minutes. After 6 minutes, the exothermic reaction began, and the reaction mixture heated 2°C. The reaction mixture was then cooled to a temperature range of 67°C to 73°C. Then, 179.1 g (1.38 mol) of bromochloromethane was metered into the reaction mixture, maintaining the temperature of the reaction mixture in the range of 67°C to 73°C. This was accompanied by the escape of gaseous chloromethane from the reaction mixture, which was discharged from the reactor to a scrubber via a nitrogen stream. At the end of the metered addition, the reaction mixture was stirred for 3 hours. The temperature of the reaction mixture was then lowered to 45°C with stirring. To hydrolyze the reaction mixture, the thus cooled reaction mixture was added with stirring to a mixture of 110 g of hydrochloric acid (30% by weight) and 500 g of water, such that the pH of the aqueous phase of the two-phase mixture was between 6.5 and 7.5. After phase separation, the first upper organic phase was separated. The first lower aqueous phase was mixed with 50 g of toluene, stirred, and allowed to stand to allow phase separation. The second upper organic phase was separated and combined with the first upper organic phase. The solvent was removed from the combined organic phases by distillation at 90°C and 20 hPa to give the crude product (1-(4-chlorophenyl)-2-cyclopropylprop-1-ol) (168.4 g, purity: 85.4% by weight), with a yield of 91% of the theoretical value.

[0043] Table 1: The experiments based on Examples 2 and 3 were performed in a similar manner to the procedure in Example 1, but using the parameters listed in the table.

[0044]

[0045] *) Based on olefins.

Claims

1. A process for the preparation of a cyclopropyl compound, which process comprises the reaction of a corresponding alkene containing at least one carbon-carbon double bond with bromochloromethane in the presence of (i) elemental zinc, (ii) a catalytically active amount of elemental copper and / or a copper (I) compound and / or a copper (II) compound, and (iii) at least one solvent, characterized in that, The reaction of the olefin is carried out without addition of organosilicon compounds, preferably without addition of halogenated alkylsilanes, and the elemental zinc has a lead content of not more than 0.005% by weight, preferably not more than 0.002% by weight.

2. The process for the preparation of a cyclopropyl compound according to claim 1, wherein the olefin is a compound of formula (I), (I)， and the obtained cyclopropyl compound is a compound of formula (II), (I) and (II).

3. The method of claim 1 or 2, wherein the elemental zinc has a particle size distribution D90 of not more than 0.5 mm 质量 .

4. The process according to any one of claims 1 to 3, wherein the elemental zinc has a total content of other metals of not more than 1 % by weight.

5. The process according to any one of claims 1 to 4, wherein the elemental copper has a total content of other metals of not more than 1 % by weight.

6. The process according to any one of claims 1 to 5, wherein the copper compound is selected from cuprous chloride (I), cupric chloride (II), copper (II) phosphate, copper (II) carbonate or mixtures thereof.

7. The process according to any one of claims 1 to 6, wherein the halogenated alkylsilane is a trialkylchlorosilane.

8. The process according to any one of claims 1 to 7, wherein the trialkylchlorosilane is selected from trimethylchlorosilane, triethylchlorosilane, tributylchlorosilane, triisobutylchlorosilane, trihexylchlorosilane and mixtures thereof.

9. The process according to any one of claims 1 to 8, wherein the at least one solvent is an ether, preferably selected from diethyl ether, 1,2-dimethoxyethane, methyl tert-butyl ether, tetrahydrofuran, cyclopentyl methyl ether and mixtures thereof, and / or an aromatic hydrocarbon, preferably toluene.

10. The process according to any one of claims 1 to 9, wherein the bromochloromethane has a purity of at least 98% by weight and / or a water content of less than 0.02% by weight.

11. The process according to any one of claims 1 to 10, wherein from 1.5 to 4 mol, preferably from 2 to 3 mol of metallic zinc are used based on 1.0 mol of the olefin, preferably based on 1.0 mol of the compound of formula (I).

12. The process according to any one of claims 1 to 11, wherein from 0.001 to 0.1 mol, preferably from 0.001 to 0.01 mol of the catalytically active amount of elemental copper and / or copper (I) compound and / or copper (II) compound is used based on 1.0 mol of the olefin, preferably based on 1.0 mol of the compound of formula (I).

13. The process according to any one of claims 1 to 12, wherein from 1 to 3 mol, preferably from 1.7 to 2.2 mol of bromochloromethane is used based on 1.0 mol of the olefin, preferably based on 1.0 mol of the compound of formula (I).

14. The process according to any one of claims 1 to 13, wherein the reaction temperature is from 55 °C to 85 °C, preferably from 60 °C to 80 °C, and more preferably from 65 °C to 75 °C during and after addition of bromochloromethane.

15. The process of any one of claims 1 to 14, wherein the olefin, preferably the compound of formula (I), bromochloromethane, elemental zinc, a catalytically active amount of elemental copper and / or a copper (I) compound and / or a copper (II) compound, and at least one solvent are mixed together to produce the cyclopropyl compound, preferably the compound of formula (II), resulting in a crude mixture, and the crude mixture is hydrolyzed at the end of the preparation.

16. The process of any one of claims 1 to 15, wherein the preparation of the cyclopropyl compound, preferably the compound of formula (II), is carried out in the presence of 0.1% to 5% by weight, based on the total weight of the crude mixture, of a crude mixture from a previous preparation of the cyclopropyl compound, preferably the compound of formula (II), based on the amount of olefin used, preferably based on the amount of compound of formula (I) used.

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