Preparation method of α-methyl-[4-(nitro)-2-(trifluoromethyl)]-benzyl nitrate

Abstract

The present invention relates to a method for preparing α-methyl-[4-(nitro)-2-(trifluoromethyl)]-benzyl nitrate and to α-methyl-[4-(nitro)-2-(trifluoromethyl)]-benzyl nitrate.

Description

[0001] The invention relates to a method for preparing α-methyl-[4-(nitro)-2-(trifluoromethyl)]-benzyl nitrate.

[0002] α-Methyl-[4-(nitro)-2-(trifluoromethyl)]-benzyl nitrate (I) is a valuable substrate for the synthesis of insecticidally active compounds. Therefore, there is a need for methods to make it readily accessible.

[0003] One way to prepare nitro compounds is the nitration of the corresponding precursors.

[0004] GB 735545, Meditsinskaya Promyshlennost SSSR, 1956, 10 (4), pp. 9-10 and Zhurnal Obshchei Khimii, 1958, 28, 1608-10 describe the nitration of α-(alkyl or haloalkyl)-benzyl alcohols in which the phenyl ring is unsubstituted or substituted in the ortho or meta position. The substrate is reacted with nitric acid in the presence of sulfuric acid or sulfanilic acid. Typically, a mixture of regioisomeric nitrobenzyl nitrates is formed. The yield of p-nitrobenzyl nitrate is 40 to 70% in total.

[0005] CN106699729 and WO 2005 / 063720 describe the nitration of 2-trifluoromethyl-benzyl alcohol using nitric acid in the presence of sulfuric acid to give 2-trifluoromethyl-4-nitro-benzyl alcohol (yield 42%) and 2-trifluoromethyl-4-nitrobenzyl nitrate (yield 38%), respectively.

[0006] The yields are often unsatisfactory, especially considering scale-up to industrially relevant quantities. Additionally, some of these reactions require large excesses of nitric acid.

[0007] In addition, it is well known that nitration reactions are often highly exothermic and have a high risk of runaway explosion. Nitration of aromatic products must be handled with care due to their explosive potential. For this reason, safety issues must always be considered when developing nitration processes.

[0008] It was therefore an object of the present invention to develop a process for preparing α-methyl-[4-(nitro)-2-(trifluoromethyl)]-benzyl nitrate which is safe, inexpensive and produces the desired product in high yields and is therefore suitable for scale-up to industrially relevant quantities.

[0009] Surprisingly, an efficient process has now been found for the nitration of α-methyl-2-(trifluoromethyl)-benzyl alcohol, affording α-methyl-[4-(nitro)-2-(trifluoromethyl)]-benzyl nitrate in high yields.

[0010] Accordingly, the present invention relates to a method for preparing a compound of formula (I)

[0011]

[0012] It includes the following steps:

[0013] (i) making a compound of formula (II)

[0014]

[0015] The reaction is carried out with nitric acid in the presence of sulfuric acid or fuming sulfuric acid, wherein the nitric acid is used in an amount of 2 to 20 molar equivalents per 1 mole of the compound (II).

[0016] Compounds of formula (I) are also part of the present invention.

[0017] In step (i), compound (A) is formed as an intermediate compound. Compound (A) is also part of the present invention.

[0018]

[0019] The method according to the invention brings a series of advantages. It is safe, cheap and produces products in high yield. Undesirable side reactions (such as oxidation or elimination of hydroxyl groups or nitration at, for example, the meta or ortho position) that lead to unwanted by-products are minimized. Nitration occurs regioselectively and almost quantitatively. The method can be carried out at room temperature and does not require complex cooling equipment. If necessary, the product can be used in the next reaction step without purification. According to some embodiments, the amount of nitric acid and / or sulfuric acid can be significantly reduced. Any of these advantages saves resources and energy and makes the method industrially simple and environmentally friendly.

[0020] Further embodiments of the invention are apparent from the claims, the description and the examples.It is to be understood that the individual features of the subject matter of the invention described herein are applicable not only in the combination given in each specific case but also in other combinations without departing from the scope of the invention.

[0021] The starting compound (II) is commercially available or can be synthesized as known to the skilled person, for example from Polymer 52, (2011), 949-953.

[0022] Step (i) according to the invention can be carried out batchwise or continuously. According to one embodiment, it is carried out batchwise. According to another embodiment, it is carried out continuously.

[0023] The nitric acid suitable for use in the present invention preferably has a concentration of at least 20 mol %. It usually has a concentration of 20 to 100 mol %, preferably 60 to 100 mol %, more preferably 80 to 100 mol %, most preferably 90 to 100 mol %, particularly preferably 95 to 100 mol %. It may contain dissolved nitrogen dioxide or be substantially free of dissolved nitrogen dioxide. "Substantially free" means that it contains 0.5 mol % or less of dissolved nitrogen dioxide.

[0024] According to a particular embodiment, the nitric acid is red fuming nitric acid.

[0025] According to another particular embodiment, the nitric acid is white fuming nitric acid (also known as 100% nitric acid).

[0026] According to another specific embodiment, nitric acid is prepared in situ by contacting a nitrate salt, such as NaNO 3 or KNO 3 , with sulfuric acid.

[0027] Nitric acid is usually used in an amount of 2 to 20 molar equivalents per 1 mole of compound (II), preferably 2 to 10 molar equivalents per 1 mole of compound (II), more preferably 2 to 8 molar equivalents per 1 mole of compound (II), most preferably 2 to 4 molar equivalents per 1 mole of compound (II), particularly preferably 2.1 to 2.5 molar equivalents per 1 mole of compound (II).

[0028] If step (i) is carried out batchwise, nitric acid is preferably used in an amount of 2 to 8 molar equivalents per 1 mole of compound (II), preferably 2 to 6 molar equivalents per 1 mole of compound (II), more preferably 2 to 3.5 molar equivalents per 1 mole of compound (II), most preferably 2 to 3 molar equivalents per 1 mole of compound (II), particularly preferably 2.1 to 2.5 molar equivalents per 1 mole of compound (II).

[0029] If step (i) is carried out continuously, nitric acid is preferably used in an amount of 2 to 20 molar equivalents per 1 mole of compound (II), preferably 2 to 16 molar equivalents per 1 mole of compound (II), more preferably 2 to 12 molar equivalents per 1 mole of compound (II), most preferably 2 to 10 molar equivalents per 1 mole of compound (II), particularly preferably 2 to 8 molar equivalents per 1 mole of compound (II).

[0030] The reaction is carried out in the presence of sulfuric acid or oleum.

[0031] According to one embodiment, the reaction is carried out in the presence of oleum.

[0032] According to another embodiment, the reaction is carried out in the presence of sulfuric acid.

[0033] The sulfuric acid suitable for the present invention preferably has a concentration of at least 50 mol %. Usually it has a concentration of 50 to 100 mol %, preferably 70 to 100 mol %, more preferably 80 to 100 mol %, most preferably 90 to 100 mol %, particularly preferably 95 to 100 mol %.

[0034] Sulfuric acid is usually used in an amount of 2 to 40 molar equivalents per 1 mole of compound (II), preferably 3 to 30 molar equivalents per 1 mole of compound (II), more preferably 5 to 20 molar equivalents per 1 mole of compound (II), most preferably 5 to 10 molar equivalents per 1 mole of compound (II), particularly preferably 5 to 7 molar equivalents per 1 mole of compound (II).

[0035] The molar ratio of nitric acid to sulfuric acid is generally 1:1 to 1:20, preferably 1:1 to 1:15, more preferably 1:1 to 1:10, most preferably 1:1 to 1:8, particularly preferably 1:1 to 1:4. According to one specific embodiment, the ratio is 1:1 to 1:2. According to another specific embodiment, the ratio is 1:1.

[0036] The nitration according to the invention can be carried out at room temperature, for example at 20 to 25° C. However, it can be carried out at elevated or reduced temperature, generally at -30 to 80° C., preferably at -15 to 60° C., more preferably at 0 to 50° C., most preferably at 5 to 45° C., particularly preferably at 10 to 40° C.

[0037] The reaction can be carried out with or without a solvent.

[0038] According to one embodiment, the reaction is carried out without solvent.

[0039] According to another embodiment, the reaction is carried out in a solvent. Suitable solvents are selected from halogenated aliphatic solvents, such as dichloromethane (CH2Cl2), chloroform (CHCl3), tetrachloroethane (CCl4), 1,2-dichloroethane or any mixture of the above solvents. The solvent is preferably selected from dichloromethane, chloroform, tetrachloroethane, 1,2-dichloroethane or any mixture thereof. Alternatively, excess H2SO4 can be used as solvent.

[0040] According to a particular embodiment, the solvent is dichloromethane.

[0041] According to another specific embodiment, the solvent is chloroform.

[0042] According to another particular embodiment, the solvent is tetrachloroethane.

[0043] According to another particular embodiment, the solvent is 1,2-dichloroethane.

[0044] According to another specific embodiment, an excess of H2SO4 is used as solvent.

[0045] According to a specific embodiment, in step (i)

[0046] a) first reacting compound (II) with at least 1 molar equivalent of nitric acid per 1 mole of compound (II) to obtain intermediate compound (A)

[0047]

[0048] b) removing water and

[0049] c) Compound (A) is further reacted with 1 to 2.5 molar equivalents of nitric acid per 1 mole of compound (A) to obtain compound (I).

[0050] The amount of nitric acid used in step (i) a) is preferably 1 to 15 molar equivalents per 1 mole of compound (II), more preferably 1 to 10 molar equivalents per 1 mole of compound (II), most preferably 1 to 5 molar equivalents per 1 mole of compound (II), particularly preferably 1 to 2.5 molar equivalents per 1 mole of compound (II), especially 1 to 1.5 molar equivalents per 1 mole of compound (II).

[0051] In step (i) b), water can be removed as known to the skilled person. For example, it can be carried out by extracting the intermediate compound (A) with an organic solvent that is immiscible with water, for example a halogenated aliphatic solvent as described above. If the reaction is carried out in such a halogenated aliphatic solvent, the organic phase can be separated from the aqueous phase as known to the skilled person. Alternatively, a stoichiometric amount of oleum can be added to the reaction mixture.

[0052] The water to be removed in step (i)b) includes water formed during the reaction in step (i)a) and, in case an aqueous solution of nitric acid and / or sulfuric acid is used in step (i)a), also water from this aqueous solution.

[0053] According to one particular embodiment, after step (i)a) has ended, excess nitric acid and sulfuric acid or oleum can be removed from the reaction mixture together with water in step (i)b).

[0054] The order in which the reagents are added to the reaction mixture may vary.

[0055] According to one embodiment, nitric acid is premixed with sulfuric acid or oleum and this mixture is added to compound (II). The premixed acids can be added to the reaction mixture all at once or gradually. According to one embodiment, they are added to the reaction mixture all at once. According to another embodiment, they are added to the reaction mixture gradually. Gradual addition is preferred.

[0056] According to another embodiment, compound (II) is added to a premixed acid comprising nitric acid and sulfuric acid or oleum. Compound (II) can be added to the reaction mixture once or gradually. According to one embodiment, it is added to the reaction mixture once. According to another embodiment, it is added to the reaction mixture gradually. Gradually adding is preferred.

[0057] After step (i), the post-treatment of the reaction mixture can be carried out by a procedure generally known to those skilled in the art. For example, the reaction mixture is diluted with water or ice, and the aqueous phase is extracted with a suitable solvent, such as toluene or o-xylene. If the reaction is carried out in the presence of a halogenated organic solvent, the organic phase containing the product can be directly separated from the nitrating acid. If necessary, the organic phase can be washed with water to remove residual acid. If necessary, the crude product obtained after solvent evaporation can be directly used in further steps. However, the crude product can also be further post-treated and / or purified as generally known to the technician.

[0058] The method may further comprise a further step (ii), whereby excess nitric acid and sulfuric acid or oleum is separated from the reaction mass after step (i) and returned to the nitration step (i). If necessary, the concentration of the separated acid may be adjusted to the initial concentration before returning the separated acid to step (i).

[0059] According to one particular embodiment, excess nitric acid and sulphuric acid or oleum is returned to step (i) a).

[0060] This separation can be carried out by procedures generally known to those skilled in the art. The separated material is subsequently treated with oleum or sulfur trioxide to remove the water formed during the reaction and to achieve the initial concentration of sulfuric acid. The recycled concentrated sulfuric acid is reused in the production process.

[0061] The present invention is illustrated by the following examples but is not limited or restricted thereto.

[0062] Experimental Section

[0063] HPLC method: Agilent 1200; column: Hailo C-18 150×4,6 mm; mobile phase A: acetonitrile, mobile phase B: H2O+0.5% 0.5 mol / L H2SO4; flow rate 1.0 mL / min; gradient: 0 min 80% B–15 min 22% B–18 min 0% B–20 min 80% B; temperature 30°C, wavelength 230 nm.

[0064] The product was located at 13.6 min.

[0065] Example 1

[0066] 12.5 ml of 100% nitric acid (0.30 mol) was treated with 25 ml of 96% sulfuric acid (0.47 mol) under cooling. 2.9 g of molten α-methyl-2-(trifluoromethyl)-benzyl alcohol (15 mmol) was added to the mixture in 10 minutes while the temperature was maintained at 0-5°C. After 15 minutes, a solid precipitated from the mixture. The entire mixture was poured into 250 ml of cold water and the product was extracted with 50 ml of CH2Cl2. The organic phase was washed with sodium bicarbonate aqueous solution and water. CH2Cl2 was removed by rotary evaporation, keeping the temperature below 25°C. The product was obtained as an oil, which solidified within a few minutes when standing. By qualitative HPLC, the yield was 4.1 g (14.6 mmol), 97%, which was determined to be substantially pure by NMR.

[0067] 1 H-NMR: (500MHz, CDCl3): 8.58 (d, 1H, J = 2.0Hz), 8.48 (dd, 1H, J = 8.6, 2.0Hz), 7.89 (d, 1H, J = 8.6Hz), 6.32 (q, 1H, J = 6.6Hz), 1.65 (d, 3H, J = 6.6Hz) ppm.

[0068] 13 C-NMR: (125MHz, CDCl3): 20.8, 76.3 (q, J = 2.5Hz), 121.9 (q, J = 6.0Hz), 122.7 (q, J = 275Hz), 127.6, 127.7, 128.7 (q, J = 33.1Hz), 145.9, 147.5.

[0069] Example 2

[0070] 10 g of 65% nitric acid (0.10 mol) were treated with 31 g of 98% sulfuric acid (0.31 mol) under cooling. While allowing the temperature to reach 50-55° C., 5.0 g of molten α-methyl-2-(trifluoromethyl)-benzyl alcohol (26 mmol) were added to the mixture. The mixture was cooled to 23° C. and stirred for 1 hour before pouring it into 65 g of cold water. The temperature reached 55° C. The precipitated product was filtered and washed with 15 g of water, followed by 2×15 g of 5% aqueous sodium bicarbonate solution and 2×15 g of water. The product was dried at 60° C. / 80 mbar. By qualitative HPLC, the yield was 6.5 g (24.3 mmol), 97%, which was determined to be substantially pure by NMR.

[0071] Example 3

[0072] 28.5 g of 99% nitric acid (0.45 mmol) was slowly added to 105 g of 98% sulfuric acid (1.05 mol) under cooling. 61.5 g of 1,2-dichloroethane was added. 28.5 g of α-methyl-2-(trifluoromethyl)-benzyl alcohol (0.15 mol) dissolved in 28.5 g of 1,2-dichloroethane was added over 48 minutes while keeping the temperature at 19-23°C. The two-phase mixture was stirred for 5 hours. The phases were separated. The organic phase contained the desired product in 98% yield as determined by qualitative HPLC.

[0073] Example 4

[0074] 18.4 g of 98% sulfuric acid (184 mmol) was added to 11.7 g of 99% nitric acid (184 mmol) at 0°C to form the nitrating acid. α-Methyl-2-(trifluoromethyl)-benzyl alcohol (5 g, 26.3 mmol) was dissolved in 1,2-dichloromethane (15 ml). The solution and nitrating acid were metered into a continuous reactor maintained at 40°C at a rate of approximately 2 ml / min per solution. The reactor was rinsed with 1,2-dichloromethane (12 ml) after metering was completed. The combined phases were collected, the organic phase was separated and characterized by HPLC. The content of the desired product was 20.9% w / w (yield 91%).

[0075] Example 5

[0076] α-Methyl-2-(trifluoromethyl)-benzyl alcohol (28.5 g, 150 mmol) was dissolved in 1,2-dichloroethane (90 g) and the solution was cooled to 0° C. A mixture of 11.2 g nitric acid (99%, 0.18 mol, 1.2 eq.) and 17.7 g sulfuric acid (98%, 0.18 mol, 1.2 eq.) was added over 27 minutes with vigorous stirring, keeping the temperature at 0-5° C. Stirring was continued at 5° C. for 90 minutes and the phases were separated. The upper organic phase containing α-methyl-2-(trifluoromethyl)-benzyl nitrate remained in the reactor. A mixture of 14.0 g nitric acid (99%, 0.22 mol, 1.5 eq.) and 29.4 g sulfuric acid (98%, 0.30 mol, 2.0 eq.) was added over 30 minutes with vigorous stirring, keeping the temperature at 2-9° C. The mixture was stirred overnight at 15-20° C. The phases were separated and the organic phase (109.9 g) was analyzed. The content of the desired product was 34.2% w / w (134 mmol, yield 89%).

[0077] Example 6

[0078] A mixture of 160 grams of 96% sulfuric acid (1.57 moles) and 101 grams of 98% nitric acid (1.57 moles) was prepared. 0.55 g / min (0.30 mL / min, 3.2 mmol / mol, 5.8 eq) of this mixture was continuously pumped into a 5 ml container with overflow. In parallel, a 25 wt % solution of α-methyl-2-(trifluoromethyl)-benzyl alcohol in 1,2-dichloroethane (0.32 mL / min, 0.42 g / min, 0.55 mmol / min) was pumped into the container under strong stirring. The temperature was maintained at 20° C. by external cooling. After reaching steady state, the product stream was collected. The phases were separated and the organic phase was washed with water. Quantitative HPLC analysis of the dichloroethane solution showed a product concentration of 31.0 wt %, equivalent to 94% chemical yield.

[0079] Example 7

[0080] 4.0 g of nitric acid (99% by weight, 64 mmol, 0.15 eq.) and 141.4 g of sulfuric acid (98% by weight, 1.41 mol, 3.0 eq.) were mixed under cooling. 152 g of 1,2-dichloroethane were added. The mixture was cooled to 5°C. A solution of 90.0 g of α-methyl-2-(trifluoromethyl)-benzyl alcohol (0.47 mol) in 129 g of 1,2-dichloroethane was added over 118 minutes. In parallel, 86 g of nitric acid (99% by weight, 1.35 mol, 2.85 eq.) was added over 97 minutes. In the first half of the addition, the temperature was maintained at a maximum of 5°C and at a maximum of 15°C during the remainder of the metered addition. The two-phase mixture was post-stirred for 5 hours at 20°C. The phases were separated. Quantitative HPLC analysis of the dichloroethane solution (422 g) showed a product concentration of 28.8% by weight, equivalent to a 92% chemical yield.

[0081] The isolated dry product (Compound (I)) was shock sensitive.

Claims

1. A method for preparing a compound of formula (I) It includes the following steps: (i) making a compound of formula (II) Reacting with nitric acid in the presence of sulfuric acid or fuming sulfuric acid, wherein the nitric acid is used in an amount of 2 to 20 molar equivalents per 1 mole of compound (II), wherein the nitric acid has a concentration of 60 to 100 mole % or is fuming nitric acid, the sulfuric acid has a concentration of 95 to 100 mole %, and the molar ratio of nitric acid to sulfuric acid or fuming sulfuric acid is 1:1 to 1:

6.

2. The process of claim 1, wherein nitric acid is used in an amount of 2 to 10 molar equivalents per 1 mole of compound (II).

3. The process of claim 1, wherein the nitric acid has a concentration of 95 to 100 mol % or is fuming nitric acid.

4. The method of claim 2, wherein the nitric acid has a concentration of 95 to 100 mol % or is fuming nitric acid.

5. The process according to any one of claims 1 to 4, wherein the reaction is carried out in the presence of sulfuric acid.

6. The process of any one of claims 1 to 4, wherein the reaction is carried out in the presence of oleum.

7. The method of any one of claims 1 to 4, wherein the molar ratio of nitric acid to sulfuric acid or oleum is from 1:1 to 1:

4.

8. The process of any one of claims 1 to 4, wherein the reaction is carried out in a chlorinated aliphatic solvent.

9. The process of claim 5, wherein the reaction is carried out in a chlorinated aliphatic solvent.

10. The process of claim 6, wherein the reaction is carried out in a chlorinated aliphatic solvent.

11. The method of any one of claims 1 to 4, wherein in step (i) a) first reacting compound (II) with at least 1 molar equivalent of nitric acid per 1 mole of compound (II) to obtain intermediate compound (A) b) removing water from the reaction mixture, optionally together with excess nitric acid and sulfuric acid or oleum, and c) Compound (A) is further reacted with 1 to 2.5 molar equivalents of nitric acid per 1 mole of compound (A) to obtain compound (I).

12. The process of claim 11, wherein 1 to 1.5 molar equivalents of nitric acid per 1 mole of compound (II) are used in step (i) a).

13. The process of any one of claims 1 to 4, wherein it is carried out in a continuous operation mode.

14. The method of any one of claims 1 to 4, further comprising the steps of (ii) separating excess nitric acid and sulphuric acid or oleum from the reaction mass, optionally adjusting the concentration to reach the initial concentration, and thereafter returning it to the nitration step i).

15. The process according to any one of claims 1 to 4, wherein excess nitric acid and sulphuric acid or oleum is returned to step (i) a).

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