Process for preparation of 4-chloro-2-(trifluoromethyl) phenyl Grignard compounds and derivatives thereof

Abstract

The present invention relates to a process for providing a 4-chloro-2-(trifluoromethyl) phenyl Grignard compound. Furthermore, the present invention relates to a process for the preparation of 4-chloro-2-(trifluoromethyl) phenyl compounds from 4-chloro-2-(trifluoromethyl) phenyl Grignard compounds, in particular for the preparation of substituted phenoxy-phenyl ketones.

Description

[0001] The present invention relates to a method for providing a 4-chloro-2-(trifluoromethyl)phenyl Grignard compound. Furthermore, the present invention relates to a method for preparing a 4-chloro-2-(trifluoromethyl)phenyl compound from a 4-chloro-2-(trifluoromethyl)phenyl Grignard compound, in particular a method for preparing a substituted phenoxyphenyl ketone.

[0002] 4-Halo-2-(trifluoromethyl)phenyl Grignard compounds are valuable intermediates for the synthesis of various pharmaceutical and agrochemical compounds as well as polymers. They are typically prepared starting from 2,5-dihalotrifluoromethylbenzenes.

[0003] WO 2020 / 157199 describes the preparation of Grignard compounds in which the starting compound has the same halogen in the 2- and 5-positions. 2,5-Dibromotrifluoromethylbenzene undergoes Grignardization at the 5-position:

[0004]

[0005] In order to invert the reported reactivity and selectively allow Grignard reaction of the halogen at the 2-position of 2,5-dihalotrifluoromethylbenzene, a more reactive halogen is typically introduced at the 2-position of the starting material compared to its 5-position, in the order I > Br > Cl > F.

[0006] The synthesis of 2,5-dihalotrifluoromethylbenzenes having different halogens at the 2- and 5-positions requires at least two different halogenation steps in its production, increasing the complexity of the synthesis and typically generating more chemical waste and wastewater. An example of such a synthesis is described in CN 104447183. It includes the following steps:

[0007]

[0008] Accordingly, there is a continuing need for a method for readily obtaining 4-halo-2-(trifluoromethyl)phenyl Grignard compounds in good yield using readily available and resource-saving starting materials.

[0009] Accordingly, it is an object of the present invention to develop an efficient and environmentally friendly method for preparing 4-halo-2-(trifluoromethyl)phenyl Grignard compounds, thereby producing the desired product in high yield and being suitable for scale-up to industrially relevant amounts.

[0010] It has now surprisingly been found that 2,5-dichlorotrifluoromethylbenzene forms a Grignard compound almost exclusively at the 2-position with solid Mg, which is completely contrary to the reported regioselectivity of 2,5-dibromotrifluoromethylbenzene. Furthermore, the Grignard preparation by the usual practice of trans-Grignardization also shows slow conversion and poor selectivity, as demonstrated in Comparative Example 12.

[0011] The present invention

[0012]

[0013] WO2020 / 157199

[0014]

[0015] Comparative Example 12

[0016]

[0017] The production process of the starting material 2,5-dichlorobenzotrifluoride is short and allows for the efficient synthesis of 4-chloro-2-(trifluoromethyl)phenylmagnesium compounds. This also makes possible the efficient synthesis of phenoxyphenyl ketones.

[0018] Grignard compound (I)

[0019] In one aspect, the present invention thus relates to a method for preparing a Grignard compound having formula (I)

[0020]

[0021] The method comprises the following steps:

[0022] (i) reacting a compound having formula (A)

[0023]

[0024] with Mg in the presence of a solvent.

[0025] In step (i), 2,5-dichloro-benzotrifluoride having formula (A) is reacted with magnesium (Mg).

[0026] The method according to the present invention has a series of advantages. It is simple, inexpensive and produces the product in high yield. Compared with the methods known in the prior art, the number of steps required for compound (I) and thus the amount of waste are reduced, since the synthesis of the starting 2,5-dichlorobenzotrifluoride requires fewer steps than the synthesis of 2,5-dihalobenzotrifluoride with different halogens. Any of these advantages saves resources and energy and makes the method simple and environmentally friendly in industry.

[0027] Further embodiments of the present invention are apparent from the claims, the description and the examples. It should be understood that the individual features of the subject matter of the present invention described herein can be applied not only in the combinations given in each specific case, but also in other combinations without departing from the scope of the present invention.

[0028] The starting compound (A) is commercially available or can be synthesized as known to the person skilled in the art.

[0029] Generally, in step (i), compound (A) or Mg can be used in excess. Alternatively, compound (A) and Mg can be used in equimolar amounts.

[0030] According to one embodiment, Mg is used in excess. Preferably, 1 to 2 mol, more preferably 1 to 1.5 mol, most preferably 1 to 1.1 mol of Mg is used relative to 1 mol of compound (I).

[0031] According to another embodiment, compound (A) is used in excess. Preferably, 1 to 5 mol, more preferably 1 to 2 mol, most preferably 1 to 1.2 mol of compound (I) is used relative to 1 mol of Mg.

[0032] According to another embodiment, compound (A) and Mg are used in equimolar amounts.

[0033] After completion of the reaction, the concentration of the Grignard compound in the solution can vary. Generally, it is up to 3 mol / L, preferably 0.4 to 3 mol / L, more preferably 0.5 to 2 mol / L, most preferably 0.6 to 1.5 mol / L of compound (I), most preferably 1.0 - 1.25 mol / L.

[0034] According to one embodiment of the process of the present invention, the Mg surface is activated by using methods or reagents known in the art, for example, 2 , alkyl bromides such as 2 - bromopropane, 1,2 - dibromoethane; diisobutylaluminum hydride (DIBAH), Red - Al, LiAlH 4 , BH 3 ·SMe 2 , NaBH 4 . According to a preferred embodiment, 2 - bromopropane is used. For further details, see, for example, Asian J. Org. Chem [Asian Journal of Organic Chemistry], 2016, 5, 636 - 45, Org. Proc. Res & Dev. [Organic Process Research and Development] 2002, 906 - 910.

[0035] According to a specific embodiment of the method of the present invention, LiCl is added as a catalyst to the reaction mixture of step (i). The addition of LiCl results in a higher yield of the Grignard compound (I) and in less formation of by-products. The use of LiCl together with Grignard reagents is generally known in the art, see for example Angew. Chem. Int. Ed. [Angewandte Chemie International Edition] 2004, 43, 3333 and Angew. Chem. Int. Ed. [Angewandte Chemie International Edition] 2006, 45, 159. Preferably, 0.01 to 0.5 mol, more preferably 0.01 to 0.3 mol, and most preferably 0.01 to 0.1 mol of LiCl are used relative to one mol of compound (I).

[0036] Suitable solvents for step (i) are, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons such as hexane, heptane, cyclohexane, toluene, o-, m- and p-xylene, mesitylene, ethers such as ethyl propyl ether, tert-amyl methyl ether, methyl tert-butyl ether, n-butyl methyl ether, anisole, phenetole, cyclohexyl methyl ether, cyclopentyl methyl ether, dimethyl ether, diethyl ether, dimethylglycol diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, bis(2-methoxyethyl) ether, isopropyl ethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane and polyethers of ethylene oxide and / or propylene oxide. In one embodiment, the preferred solvents can be selected from tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl-tert-butyl ether (MTBE), toluene, m-xylene, o-xylene, p-xylene, or any mixture thereof. In another embodiment, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether and mixtures of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether with toluene and / or xylene are preferably used. Specifically, THF is preferred.

[0037] Step (i) is generally carried out at atmospheric pressure. However, as an alternative, it is also possible to work under reduced pressure or under superatmospheric pressure. According to one embodiment, the reaction can be carried out in an inert gas atmosphere such as nitrogen or argon. The reaction time is not critical and can be appropriately selected according to the batch size and the temperature.

[0038] During reaction step (i), the temperature is preferably kept at a maximum of 120 °C, more preferably a maximum of 80 °C, most preferably a maximum of 45 °C, and particularly preferably a maximum of 30 °C. Generally, a reaction temperature of -80 °C to 120 °C, especially -40 °C to 80 °C, in particular -5 °C to 45 °C is preferred. In another embodiment, the temperature is 10 °C to 30 °C.

[0039] As is generally known to those skilled in the art, the structure of Grignard reagents can be described by the so-called Schlenck equilibrium. Grignard reagents undergo a solvent-dependent equilibrium between different magnesium compounds. The Schlenck equilibrium of the Grignard reagents used according to the present invention can be schematically illustrated as follows:

[0040]

[0041] where Ar represents

[0042]

[0043] Furthermore, it is known that solvent molecules commonly used to react with Grignard reagents, especially ethers such as diethyl ether or THF, can be added to the magnesium of the Grignard reagent to form an etherate. It is clear to those skilled in the art that depending on the solvent used in the reaction, other solvent molecules may also be present. For general information on the structure of Grignard reagents, see also Milton Orchin, Journal of Chemical Education, Vol. 66, No. 7, 1999, pp. 586-588.

[0044] In the case of THF, examples of the species (including etherates) that can be found in the equilibrium are described below:

[0045]

[0046]

[0047] Note 1: Ar or Cl with two bonds represents a three-center two-electron bond.

[0048] Note 2: If Mg carries four substituents, it is tetrahedrally coordinated. Therefore, depending on the specific structure, stereoisomers (diastereoisomers and / or enantiomers) (marked with *) may exist. This is demonstrated in the following specific examples:

[0049]

[0050] The different magnesium compounds present in the process according to the invention, especially those of the types shown above, and the possible adducts with solvent molecules are also an aspect of the present invention.

[0051] 4-chloro-2-(trifluoromethyl)phenyl Compound

[0052] In another embodiment of the present invention, a Grignard compound having the formula (I) is used for the synthesis of a 4-chloro-2-(trifluoromethyl)phenyl compound.

[0053] Accordingly, in another aspect, the present invention relates to a method for preparing a compound of formula (II)

[0054]

[0055] wherein:

[0056] R 1 is selected from -CR a R b OH, -C(O)R c , -B(OH) 2 , B(OC 1 -C 4 -alkyl) 2 ;

[0057] R a and R b are independently selected from H or C 1 -C 4 -alkyl or phenyl, wherein the phenyl may be unsubstituted or carry 1, 2 or 3 substituents selected from halogen or C 1 -C 6 -alkyl; or

[0058] R a and R b together with the C-atom to which they are attached form a C 3 -C 6 -cycloalkyl ring;

[0059] R c is selected from H, OH or C 1 -C 4 -alkyl or phenyl, wherein the phenyl may be unsubstituted or carry 1, 2 or 3 substituents selected from halogen or C 1 -C 6 -alkyl;

[0060] The method comprises the following steps:

[0061] (i) preparing a compound of formula (I)

[0062]

[0063] by reacting a compound of formula (A)

[0064]

[0065] with Mg in the presence of a solvent;

[0066] (ii) reacting the compound of formula (I) with an electrophile (E).

[0067] As the electrophilic reagent, any suitable electrophilic reagent can be used. Examples of suitable electrophilic reagents are

[0068] (E1)R a C(O)R b ,

[0069] (E2)R c C(O)X,

[0070] (E3)B(OC 1 -C 4 -alkyl) 3 ,

[0071] (E4)CO 2 ,

[0072] (E5) or

[0073] (E6)R c CN

[0074] wherein

[0075] R a and R b are independently selected from H or C 1 -C 4 -alkyl or phenyl, wherein the phenyl may be unsubstituted or carry 1, 2 or 3 substituents selected from halogen or C 1 -C 6 -alkyl; or

[0076] R a and R b together with the C-atom to which they are attached form a C 3 -C 6 -cycloalkyl ring;

[0077] R c is selected from H, C 1 -C 4 -alkyl or phenyl, wherein the phenyl may be unsubstituted or carry 1, 2 or 3 substituents selected from halogen or C 1 -C 6 -alkyl;

[0078] X is selected from halogen or -NR a R b 、-N(C 1 -C 4 -alkyl)-O-(C 1 -C 4 -alkyl), N-morpholino.

[0079] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0080] The term "C 1 -C 6 -alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms, such as CH 3 、C 2 H 5 、n-C 3 H 7 、CH(CH 3 ) 2 、n-butyl, isobutyl and tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. C 1 -C 6 -alkyl preferred embodiments are C 2 -C 4 -alkyl. Similarly, the term "C 1 -C 4 -alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, such as CH 3 、C 2 H 5 、n-C 3 H 7 、CH(CH 3 ) 2 、n-butyl, isobutyl and tert-butyl.

[0081] The term "C 3 -C 6 -cycloalkyl" refers to a monocyclic saturated hydrocarbon group having 3 to 6 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0082] In one embodiment of the present invention, the electrophile is (E1) R a C(O)R b , such as aldehydes, such as formaldehyde or acetic aldehyde, or ketones, such as acetone, methyl ethyl ketone.

[0083] In another embodiment of the present invention, the electrophile is (E2) R c C(O)X, such as acyl halides, such as acetyl chloride (AcCl).

[0084] In another embodiment of the present invention, the electrophile is (E3) B (OC 1 -C 4 -alkyl) 3 .

[0085] In another embodiment of the present invention, the electrophile is (E4) CO 2 .

[0086] In another embodiment of the present invention, the electrophile is (E5) such as acetic anhydride (Ac 2 O).

[0087] In another embodiment of the present invention, the electrophile is (E6) R c CN, such as alkyl cyanide, such as (C 1 -C 4 -alkyl) CN.

[0088] The electrophile (E) is preferably used in an equimolar amount or in excess compared to the Grignard compound (I). The excess depends on the electrophile used. For example, the electrophile selected from (E1), (E2), (E3), (E5) or (E6) is used in an amount of 1 to 3 mol, preferably 1 to 2.5 mol, more preferably 1 to 2 mol, relative to one mole of compound (I). In particular, according to the present invention, an amount of 1 to 1.5 moles, more particularly 1.05 to 1.1 moles, per mole of compound (I) may be advantageous. The electrophile (E4) is usually passed through the reaction mixture until all of the Grignard compound (I) has been converted.

[0089] Suitable solvents for step (ii) are, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons such as toluene, o-, m- and p-xylene, mesitylene, ethers such as ethyl propyl ether, tert-amyl methyl ether, methyl tert-butyl ether, n-butyl methyl ether, anisole, phenetole, cyclohexyl methyl ether, cyclopentyl methyl ether, dimethyl ether, diethyl ether, dimethylglycol diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane and polyethers of ethylene oxide and / or propylene oxide. In one embodiment, the preferred solvents may be selected from tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl-tert-butyl ether (MTBE), toluene, m-xylene, o-xylene, p-xylene, or any mixture thereof. In another embodiment, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, and mixtures of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether with toluene and / or xylene are preferably used. Specifically, THF is preferred.

[0090] Step (ii) is usually carried out at atmospheric pressure. However, as an alternative, it is also possible to work under reduced pressure or under superatmospheric pressure.

[0091] The reaction time is not critical and can be appropriately selected according to the batch size and temperature.

[0092] The order of adding the reagents to the reaction mixture is variable. The compound (I) and the electrophile (E) can be added simultaneously (in parallel) or sequentially. According to one embodiment, they are added in parallel. According to another embodiment, they are added sequentially. In this case, the addition order is not critical. The compound (I) or the electrophile (E) can be added first. Alternatively, a part of the compound (I) and the electrophile (E) is added in parallel to the remaining part of the electrophile (E).

[0093] The reaction temperature in step (ii) is preferably maintained at a maximum of 70 °C, particularly a maximum of 50 °C, more preferably a maximum of 35 °C. Generally, a reaction temperature of -78 °C to 70 °C, particularly -78 °C to 50 °C, especially -50 °C to 25 °C is preferred. In another embodiment, the temperature is 0 °C to 15 °C, particularly 0 °C to 5 °C.

[0094] During the further course of reaction step (ii), the temperature is preferably maintained at a maximum of 70 °C, particularly a maximum of 50 °C, more preferably a maximum of 45 °C. Generally, a reaction temperature of 30 °C to 50 °C, particularly 35 °C to 45 °C is preferred. In another embodiment, the temperature is 20 °C to 35 °C, particularly 25 °C to 30 °C.

[0095] According to one embodiment, step (ii) can be carried out in the presence of a Cu(I) catalyst, such as a Cu(I) salt or Cu(I) oxide, particularly a Cu(I) salt such as Cu(I)Cl or Cu(I)Br or any mixture thereof. According to a specific embodiment, Cu(I)Cl is used. Preferably, 0.01 to 0.5 mol, more preferably 0.01 to 0.2 mol, most preferably 0.01 to 0.05 mol, particularly preferably 0.1 to 0.02 mol of the Cu(I) catalyst is used relative to one mol of the compound (I).

[0096] The Grignard compound (I) is added in a manner common to those skilled in the art. In particular, the solution obtained in step (i) can be directly used in step (ii). If Mg is used in excess, the undissolved Mg particles can be removed before use. These removed Mg particles can be used in the next batch.

[0097] 4-Chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-2-(trifluoromethyl)benzene

[0098] On the other hand, the present invention relates to a process for preparing 4-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-2-(trifluoromethyl)benzene (III).

[0099]

[0100] The process comprises the following steps

[0101] (i) preparing a compound having the formula (I)

[0102]

[0103] by reacting a compound having the formula (A)

[0104]

[0105] with Mg in the presence of a solvent;

[0106] (iii) dimerizing the compound having the formula (I), optionally in the presence of a catalyst.

[0107] In step (iii), a catalyst can be used. It is preferably selected from iron, copper, cobalt, manganese, nickel, zinc, titanium, vanadium and ruthenium catalysts.

[0108] According to one embodiment, step (iii) is carried out in the presence of a terminal oxidant preferably selected from molecular oxygen, diaziridinone or 1,2-dihaloethane.

[0109] Suitable solvents for step (iii) are those suitable for step (i).

[0110] Step (iii) is generally carried out at atmospheric pressure. However, as an alternative, it is also possible to work under reduced pressure or under superatmospheric pressure.

[0111] The reaction time is not critical and can be appropriately selected according to the batch size and temperature.

[0112] Phenoxyphenyl ketone

[0113] On the other hand, the present invention relates to a process for preparing a phenoxyphenyl ketone having the formula (IV)

[0114]

[0115] wherein

[0116] R c is C 1 -C 4 -alkyl;

[0117] R2 is F or Cl;

[0118] The method comprises the following steps:

[0119] (i) Preparing a compound having the formula (I)

[0120]

[0121] by reacting a compound having the formula (A)

[0122]

[0123] with Mg in the presence of a solvent;

[0124] (ii) Preparing a compound having the formula (II-A),

[0125]

[0126] by reacting a compound having the formula (I) with an electrophile selected from

[0127] (E2-1) R c C(O)Hal, (E2-2) R c C(O)N(C 1 -C 4 -alkyl)-O-(C 1 -C 4 -alkyl) or

[0128] (E5) or

[0129] (E6) R c CN

[0130] wherein

[0131] R c is C 1 -C 4 -alkyl, and

[0132] Hal is a halogen

[0133] (iv) Reacting the compound (II-A) with a phenol derivative having the formula (V)

[0134]

[0135] If R” is hydrogen, the reaction is carried out in the presence of a base;

[0136] wherein the variables are defined as follows:

[0137] R 2 is F or Cl;

[0138] "R” is hydrogen, N(C 1 -C 8 -alkyl) 4 cation or an alkali metal cation.

[0139] Compound (II-A) can be used directly from step (ii) without further purification, or can be used in purified form.

[0140] Examples of suitable solvents for step (iv) are aprotic organic solvents such as dimethylformamide (DMF), dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), dimethylimidazolinone (DMI), tetramethylurea (TMU), N,N-dimethylpropyleneurea (DMPU), dimethyl sulfoxide (DMSO), toluene, o-xylene and any mixture thereof. In particular, DMF, DMAC, NMP and toluene or any mixture, and more specifically, DMF, DMAC and NMP are particularly suitable.

[0141] According to one embodiment, the base used in step (iv) is preferably an inorganic base selected from NaOH, KOH, Na 2 CO 3 、K 2 CO 3 、Na 3 PO 4 and K 3 PO 4 。 According to one embodiment, NaOH is used. According to another embodiment, KOH is used. According to still another embodiment, Na 2 CO 3 is used. According to still another embodiment, K 2 CO 3 is used. According to still another embodiment, Na 3 PO 4 is used. According to still another embodiment, K 3 PO 4 is used.

[0142] The base can be used in solid form or as a solution (such as an aqueous solution).

[0143] The reagents for step (iv) are preferably added at ambient temperature and then the reaction temperature is raised, where the reaction temperature after the reagents have been added is preferably maintained at a maximum of 160 °C, particularly a maximum of 145 °C, more preferably a maximum of 140 °C. Generally, a reaction temperature of 20 °C to 160 °C, particularly 50 °C to 150 °C, more particularly 100 °C to 140 °C is preferred.

[0144] After step (iv), the reaction mixture can be worked up by procedures known in a general manner to those skilled in the art. Generally, water is added and the aqueous phase is extracted with a suitable solvent such as toluene or o-xylene. If desired, the crude product obtained after evaporation of the solvent can be used directly in further steps. However, the crude product can also be further worked up and / or purified as is generally known to the person skilled in the art.

[0145] Each of steps (i), (ii), (iii) or (iv) can be carried out batchwise or continuously.

[0146] Example

[0147] The following examples further illustrate the invention and do not limit the invention in any way.

[0148] Example 1 : Synthesis of the Grignard compound (I)

[0149] 0.240 g (10.0 mmol) of magnesium turnings were placed in a flask and 2 g of THF were added, followed by 120 mg (2.8 mmol) of LiCl. 60 mg (0.5 mmol) of 2-bromopropane were added to activate the magnesium. After 5 min, 2.0 g (9.3 mmol) of 2,5-dichloro-trifluoromethylbenzene in 4 ml of THF were added and the temperature was allowed to reach 50 °C. The mixture was stirred post-reaction at 40 °C for 1 h. The mixture was cooled to 5 °C and 0.4 g of methanol was added. Water and tert-butyl methyl ether (MTBE) were added, followed by 32% HCl. The organic phase was concentrated and analyzed by GC to show a ratio of 3-chloro-trifluoromethylbenzene / 2-chloro-trifluoromethylbenzene of 30:1.

[0150] GC-method: Agilent Technologies 7890A, column DB-XLB 30 x 250 µm x 1 µm, inlet 280 °C, detector 320 °C, constant flow rate 1.145 mL / min He, split ratio 50, 0 min: 55 °C, 2 min: 55 °C, 27.5 min: 310 °C, 40 min: 310 °C.

[0151] Retention times: 3-chloro-trifluoromethylbenzene 9.0 min and 2-chloro-trifluoromethylbenzene 10.3 min.

[0152] Example 2 : Synthesis of the Grignard compound (I)

[0153] Place 13.5 g (0.56 mol, 1.1 eq) of Mg chips in the reaction vessel, followed by 6.3 g of LiCl (0.15 mol, 30 mol%). Add 80 g of THF. Add 3.1 g (25 mmol, 5 mol%) of 2-bromopropane to initiate Grignard formation. Ten minutes after the exothermic reaction starts, at a constant reaction temperature of 25 °C, add a solution of 109 g (99%, 0.50 mol, 1.0 eq) of 2,5-dichloro-trifluoromethylbenzene in 600 g of THF over 3 h. Stir the mixture at 25 °C for an additional 1 h to complete Grignard formation. Transfer most of the formed Grignard solution (765 g) to a storage bottle through a conduit. Excess Mg remains in the reaction vessel with approximately 50 g of the Grignard solution. Add 50 g of fresh THF to dilute the residue in the reaction vessel.

[0154] Example 3 : Synthesis of Grignard compound (I)

[0155] Add 12.2 g of Mg chips (0.50 mol, 1.0 eq) and 2.2 g of LiCl (52 mmol, 0.1 eq) to the Mg residue of Example 2. At a constant reaction temperature of 25 °C, add a solution of 109 g (99%, 0.50 mol, 1.0 eq) of 2,5-dichloro-trifluoromethylbenzene in 600 g of THF over 3 h. Stir the mixture at 25 °C for an additional 1 h to complete Grignard formation. Transfer most of the formed Grignard solution to a storage bottle through a conduit. Excess Mg remains in the reaction vessel with approximately 50 g of the Grignard solution. Add 50 g of fresh THF to dilute the residue in the reaction vessel.

[0156] Example 4 : Reaction of Grignard compound (I) with acetyl chloride

[0157] Dilute 4.0 g (0.05 mol) of acetyl chloride with 120 g of toluene. Add 2.5 g (25 mmol) of copper(I) chloride, and adjust the temperature to 0 °C. In parallel, add a solution of 41.7 g (0.53 mol) of acetyl chloride in 120 g of toluene and 765 g of the Grignard solution (from Example 2). Maintain the reaction temperature at 0 °C - 2 °C during the addition. Stir the mixture at 0 °C for an additional 60 min to complete acylation. Add 245 g of water within 15 min and separate the phases. Wash the organic phase with 150 g of 2.5% HCl, followed by 115 g of 3% NH3-solution. Concentrate the organic phase to 102 g of an oily residue, which contains 83.3% of 1-[4-chloro-2-(trifluoromethyl)phenyl]ethanone (by quantitative GC). The yield is 0.38 mol.

[0158] 1 H-NMR (400 MHz, CDCl3 ): 2.56 (s, 3H), 7.43 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 8.3, 1.9 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H).

[0159] Example 5 : Reaction of the Grignard compound (I) with cyclohexanone

[0160] At 0 °C, 2.8 g (28 mmol) of cyclohexanone in 8 ml of THF was added to 50 g of the prepared Grignard solution (from Example 2). The mixture was stirred at 0 °C for 1 h and then at 23 °C for 2 h. Saturated NH 4 Cl and water (to dissolve the precipitated salts) were added and the product was extracted with MTBE. The solvent was removed under reduced pressure to give 4.0 g of an oily residue. The product 1-[4-chloro-2-(trifluoromethyl)phenyl]cyclohexanol was determined by NMR.

[0161] 1 H-NMR (400 MHz, DMSO-d 6 ): 1.16 - 1.29 (m, 1H), 1.42 - 1.67 (m, 4H), 1.70 - 1.82 (m, 5H), 4.81 (s, 1H), 7.64 (dd, J = 8.8, 2.2 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H).

[0162] Example 6 : Reaction of the Grignard compound (I) with trimethyl borate

[0163] 3.0 g of trimethyl borate (29 mmol) was dissolved in 8 g of THF. 50 g of the Grignard solution (from Example 2) was added at 0 °C. The mixture was warmed to 25 °C and stirred for 2 h. 14 g of 10% HCl was added and the mixture was stirred at 50 °C for 2 h. The aqueous phase was removed. The organic phase was washed with water and the combined aqueous phases were extracted with MTBE. The combined organic phases were concentrated to 5.0 g of an organic residue. The product [4-chloro-2-(trifluoromethyl)phenyl]boronic acid was determined by NMR.

[0164] 1 H-NMR (400 MHz, DMSO-d 6 ): 4.25 (br, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.73 (s, 1H), 8.34 (br, 1H).

[0165] Example 7 : Reaction of the Grignard compound (I) with carbon dioxide

[0166] Cool 50 g of the Grignard solution (from Example 2) to 0 °C and bubble CO 2 through the solution until the exothermic reaction subsides. Bubble additional CO 2 through the solution for 1 h, add 5 g of water, and then add 20 g of 5% HCl. Warm the mixture to 70 °C, remove the aqueous phase, and wash the organic phase with water. Extract the combined aqueous phases with MTBE and concentrate the combined organic phases under reduced pressure to obtain 7.0 g of residue. Determine the product 4-chloro-2-(trifluoromethyl)benzoic acid by NMR.

[0167] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.85 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 13.2 (br, 1H).

[0168] Example 8 : Reaction of the Grignard compound (I) with DMF

[0169] Cool 50 g of the Grignard solution (from Example 2) to -72 °C and add 4.0 g of DMF (0.54 mol) at -72 °C. Warm the solution slowly to 0 °C and stir post-reaction at 0 °C for 1 h. Add saturated KH 2 PO 4 solution, and then add 5% HCl to dissolve the precipitated salts. Extract the mixture with MTBE and concentrate the organic phase under reduced pressure to obtain 3.0 g of a brown oil. Determine the product 4-chloro-2-(trifluoromethyl)benzaldehyde by NMR.

[0170] 1 H-NMR (400 MHz, DMSO-d 6 ): 7.94 - 8.02 (m, 2H), 8.13 (d, J = 8.3 Hz, 1H), 10.26 (s, 1H).

[0171] Example 9 : Synthesis of the Grignard compound (I) and reaction with acetic anhydride

[0172] 14.5 g (0.60 mol, 1.2 eq) of Mg turnings were placed in the reaction vessel, followed by 6.2 g of LiCl (0.15 mol, 30 mol%). 80 g of THF were added. 3.1 g (25 mmol, 5 mol%) of 2-bromopropane were added to initiate Grignard formation. The start of the reaction was accompanied by an increase in temperature. 10 min after the start of the exothermic reaction, at a constant reaction temperature of 25 °C, a solution of 109 g (99%, 0.50 mol, 1.0 eq) of 2,5-dichloro-trifluoromethylbenzene in 600 g of THF was added over 3 h. The mixture was stirred post-reaction at 25 °C for 1 h to complete Grignard formation. Most of the formed Grignard solution (785 g) was transferred via a tube and discarded. Excess Mg remained in the reaction vessel together with approximately 50 g of the Grignard solution. 50 g of fresh THF were added to dilute the residue in the reaction vessel.

[0173] 12.2 g of Mg turnings (0.50 mol, 1.0 eq) and 2.2 g of LiCl (52 mmol, 0.1 eq) were added to the residue of the first batch. At a constant reaction temperature of 25 °C, a solution of 109 g (99%, 0.50 mol, 1.0 eq) of 2,5-dichloro-trifluoromethylbenzene in 600 g of THF was added over 3 h. The mixture was stirred post-reaction at 25 °C for 1 h to complete Grignard formation. The formed Grignard solution was transferred via a tube to a storage bottle (755 g). Excess Mg remained in the reaction vessel together with approximately 50 g of the Grignard solution. 50 g of fresh THF were added to dilute the residue in the reaction vessel.

[0174] 2.5 g of acetic anhydride (25 mmol, 0.05 eq) were mixed with 120 g of THF and cooled to -5 °C. Over 3 h, the above Grignard solution and, in parallel, 51.5 g of acetic anhydride (0.50 mol, 1.0 eq) were added via an injection pump, maintaining the temperature at a maximum of 2 °C. After addition was complete, the reaction mixture was stirred post-reaction at 0 °C for 1 h. 260 g of water were added, followed by 3.8 g of concentrated HCl to adjust the pH to 7. The biphasic mixture was stirred for 30 min and the aqueous phase was removed. The organic phase was concentrated to 107 g of a brown oil. By GC, the purity of the desired product 1-[4-chloro-2-(trifluoromethyl)phenyl]ethanone was 89%. The chemical yield was 85%.

[0175] Less than 1% of the impurity 1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone, resulting from substitution of the unwanted chlorine substituent in step (i) and reaction with acetic anhydride, was detected, demonstrating the exceptional selectivity in step (i).

[0176] Example 10 : dimerization

[0177] 50 g of the Grignard solution (from Example 2) was mixed with 20 g of toluene and 0.24 g of CuCl (2.4 mmol). The mixture was stirred in a flask open to the atmosphere for 4 h. After 30 min, the internal temperature peaked at 35 °C and then dropped again to 23 °C. 5% aqueous HCl was added until all the solids dissolved. The phases were separated and the organic phase was concentrated under reduced pressure to give 5.0 g of a brown oil. The product 4-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-2-(trifluoromethyl)benzene was determined by NMR to be consistent with the literature values (Liebigs Ann. [Liebig's Annalen] 1995, 5, 781 - 6).

[0178] 1 1H-NMR (400 MHz, MeOD): 7.34 (d, J = 8.6 Hz, 2H), 7.68 (dd, J = 8.6, 2.2 Hz, 2H), 7.82 (d, J = 2.2 Hz, 2H).

[0179] Example 11 : Synthesis of 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone

[0180] 117 g of p-chlorophenol (0.91 mol, 2.0 equiv) was dissolved in 668 g of NMP. 36.4 g of solid KOH (90%, 0.58 mol, 1.3 equiv) was added and the temperature was raised to 100 °C until all the KOH dissolved. 104.2 g (96%, 0.45 mol, 1.0 equiv) of molten 1-[4-chloro-2-(trifluoromethyl)phenyl]ethenone was added via a dropping funnel. 223 g of NMP was used to wash all the acetophenone into the reaction flask. The temperature was gradually raised to 145 °C and the mixture was stirred for 14 h to complete the reaction. NMP was removed by distillation. 500 g of toluene and 1400 g of water were added. 207 g of 10% aqueous NaOH (0.52 mol, 1.15 equiv) was added and the phases were separated. The aqueous phase was extracted twice with 500 g of toluene. The combined organic phases were washed with 450 g of water and 45 g of 10% NaOH (0.11 mol, 0.25 equiv). The phases were separated. The organic phase was concentrated under reduced pressure to give 141 g of an oily product (88% (by HPLC), 0.39 mol, 88% chemical yield).

[0181] 1 1H-NMR (400 MHz, CDCl 3 ): 2.57 (s, 3H), 6.98 - 7.03 (m, 2H), 7.12 (dd, J = 8.8, 2.5 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.35 - 7.40 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H).

[0182] Example 12: Comparative Example Trans-Grignard:

[0183]

[0184] Dissolve 2.1 g (10 mmol) of 2,5-dichloro-trifluoromethylbenzene in 15 g of THF. Add 0.2 g (5 mmol) of LiCl, and warm the mixture to 30 °C. Add 5.6 mL of isopropylmagnesium chloride solution (2 M in THF, 11 mmol) over 30 min. Stir the mixture at 30 °C for 3 h and let stand overnight. Reheat it to 50 °C for 2 h to improve the conversion. Add toluene and 10% aqueous HCl, separate the phases, and analyze the organic phase by GC. GC shows 77% starting material, 3% 3-chloro-trifluoromethylbenzene, and 6% 2-chloro-trifluoromethylbenzene (by area).

[0185] Example 13 : Synthesis of the Grignard compound (I) in the absence of LiCl, for analytical purposes, reacted with acetic anhydride:

[0186] Suspend 14.6 g of Mg turnings (0.60 mol, 1.2 equiv) in 135 mL of THF. Add 10 g of isopropylmagnesium chloride (2.0 M in THF, 0.975 g / ml) to consume all the residual water. Add 2.2 g (18 mmol) of 2-bromopropane to activate the magnesium, showing an exotherm to 31 °C. When a small amount of 2,5-dichloro-trifluoromethylbenzene is added, no exotherm is observed. Add another 1.5 g (12 mmol) of 2-bromopropane to ensure smooth Grignard formation. At a constant reaction temperature of 25 °C - 27 °C, add a solution of 109 g (99%, 0.50 mol, 1.0 equiv) of 2,5-dichloro-trifluoromethylbenzene in 203 g of THF over 4 h. Stir the mixture at 25 °C for 1 h post-reaction. Transfer most of the formed Grignard solution to a storage bottle through a conduit. Excess Mg remains in the reaction vessel with approximately 50 g of the Grignard solution.

[0187] React a small sample with excess acetic anhydride to control the quality of the Grignard solution by GC. GC reveals the presence of several impurities formed by the reaction of (I) with the starting material (A) in abnormally high amounts when there is an accumulation of (A) during Grignard formation:

[0188] 3-chlorobenzotrifluoride: 17.5 area% (if 10 mol% LiCl is present during Grignard formation, typical value < 10%)

[0189] 1-[4-chloro-2-(trifluoromethyl)phenyl]ethanone: 62.1 area% (15.6 min, typical value > 75%)

[0190] 1-[2,5-Dichloro-3-(trifluoromethyl)phenyl]ethanone: 5.7 area % (17.5 min, typical value < 2%)

[0191] 1-[2,5-Dichloro-4-(trifluoromethyl)phenyl]ethanone: 6.5 area % (17.7 min, typical value < 2%)

[0192] (THF was ignored in the area % calculation).

Claims

1. A method for preparing a Grignard compound having formula (I) The method comprises the following steps: (ii) reacting a compound having formula (A) with Mg in the presence of a solvent.

2. The method according to claim 1, wherein the Mg is activated.

3. The method according to claim 2, wherein the magnesium activator is 2-bromopropane.

4. The method according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of LiCl.

5. The method according to any one of claims 1 to 4, wherein the solvent is selected from aliphatic, cycloaliphatic or aromatic hydrocarbons, ethers and polyethers of ethylene oxide and / or propylene oxide.

6. The method according to any one of claims 1 to 5, wherein the solvent is selected from hexane, heptane, cyclohexane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl tert-butyl ether (MTBE), toluene, m-xylene, o-xylene, p-xylene, or any mixture thereof.

7. The method according to any one of claims 1 to 6, wherein the solvent is THF.

8. A method for preparing a compound having formula (II) wherein: R 1 Selected from -CR a R b OH, -C(O)R c , -B(OH) 2 , B(OC 1 -C 4 -alkyl) 2 R a and R b are independently selected from H or C 1 -C 4 -alkyl or phenyl, where the phenyl may be unsubstituted or carry 1, 2 or 3 substituents selected from halogen or C 1 -C 6 -alkyl; or R a and R b together with the C-atoms to which they are attached form a C 3 -C 6 -cycloalkyl ring; R c selected from H, OH or C 1 -C 4 -alkyl or phenyl, wherein the phenyl may be unsubstituted or carry 1, 2 or 3 substituents selected from halogen or C 1 -C 6 -alkyl; The method comprises the following steps: (iii) preparing a compound having formula (I) as claimed in claim 1, (iv) reacting the compound having formula (I) with an electrophilic reagent, wherein the electrophilic reagent is selected from (E1)R a C(O)R b , (E2)R c C(O)X, (E3)B(OC 1 -C 4 -alkyl) 3 , (E4)CO 2 , (E5) or (E6)R c CN wherein R a and R b are independently selected from H or C 1 -C 4 -alkyl or phenyl, wherein the phenyl may be unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen or C 1 -C 6 -alkyl; or R a and R b together with the C-atoms to which they are attached form a C 3 -C 6 -cycloalkyl ring; R c selected from H, C 1 -C 4 -alkyl or phenyl, where the phenyl may be unsubstituted or carry 1, 2 or 3 substituents selected from halogen or C 1 -C 6 -alkyl; X is selected from halogen or -N(C 1 -C 4 -alkyl) 2 、-N(C 1 -C 4 -alkyl)-O-(C 1 -C 4 -alkyl), N-morpholine.

9. The method according to claim 8, wherein the electrophilic reagent is selected from (E2-1)R c C(O)X, wherein X represents a halogen, (E2-2)R c C(O)N(C 1 -C 4 -alkyl)-O-(C 1 -C 4 -alkyl), (E5) or (E6)R c CN。 10. The method according to claim 9, wherein The electrophilic reagent is selected from acetyl chloride (AcCl) or acetic anhydride (Ac 2 O).

11. The method according to any one of claims 8 to 10, wherein the reaction is carried out in the presence of a Cu catalyst.

12. A method for preparing a compound having formula (III) The method comprises the following steps: (i) preparing a compound having formula (I) as claimed in claim 1, (iii) dimerizing the compound having formula (I).

13. The method according to claim 12, wherein the dimerization is carried out in the presence of a catalyst.

14. The method according to claim 12 or 13, wherein the reaction is carried out in the presence of a terminal oxidant selected from molecular oxygen, diaziridinone or 1,2-dihaloethane.

15. A method for preparing a compound having formula (IV) wherein R c is C 1 -C 4 -alkyl; R 2 is F or Cl; The method comprises the following steps: (i) preparing a compound having formula (I) as claimed in claim 1, (ii) preparing a compound having formula (II-A) as claimed in claim 9, wherein R c is C 1 -C 4 -alkyl, (iv) reacting compound (II-A) with a phenol derivative having formula (V) If R” is hydrogen, the reaction is carried out in the presence of a base; wherein the variables are defined as follows: R 2 is F or Cl; "R” is hydrogen, N(C 1 -C 8 -alkyl) 4 cation or an alkali metal cation.

Images